NDA 19-510/S-029
`NDA 20-249/S-012
`
`Merck Research Laboratories 14 MAR 2001
`Attention: Michelle W. Kloss, Ph.D.
`BLA-20
`West Point, PA 19486-0004
`
`Dear Dr. Kloss:
`
`Please refer to your supplemental new drug applications dated December 20, 2001, received
`December 22, 2001, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act for
`the following Pepcid injection products.
`
`NDA 19-510/S-029: Pepcid™ (famotidine) Injection
`NDA 20-249/S-012: Pepcid™ (famotidine) Injection Premixed
`
`We acknowledge receipt of your submission dated March 13, 2001.
`
`These supplemental new drug applications provide for revisions to the package insert under the
`“Clinical Pharmacology in Adults” section; the “Dosage Adjustment for Patients with Severe Renal
`Insufficiency” subsection of the DOSAGE AND ADMINISTRATION section; and the “Geriatric Use”
`subsection of the PRECAUTIONS section to include a statement concerning the need for dosage
`adjustment in patients with both moderate and severe renal impairment.
`
`We have completed the review of these supplemental applications, as amended, and have concluded
`that adequate information has been presented to demonstrate that the drug products are safe and
`effective for use as recommended in the agreed upon enclosed labeling text. Accordingly, the
`supplemental applications are approved effective on the date of this letter.
`
`The final printed labeling (FPL) must be identical to the enclosed labeling (text for the package insert).
`
`Please submit the copies of final printed labeling (FPL) electronically according to the guidance for
`industry titled Providing Regulatory Submissions in Electronic Format - NDA (January 1999).
`Alternatively, you may submit 20 paper copies of the FPL as soon as it is available but no more than
`
`Sandoz Exhibit 1011 Page 1
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`NDAs 19-510/S-029, 20-249/S-012
`Page 2
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`30 days after it is printed. Please individually mount ten of the copies on heavy-weight paper or similar
`material. For administrative purposes, this submission should be designated "FPL for approved
`supplements NDA 19-510/S-029, and NDA 20-249/S-012." Approval of this submission by FDA is
`not required before the labeling is used.
`
`If a letter communicating important information about this drug product (i.e., a "Dear Health Care
`Professional" letter) is issued to physicians and others responsible for patient care, we request that you
`submit a copy of the letter to this NDA and a copy to the following address:
`
`MEDWATCH, HF-2
`FDA
`5600 Fishers Lane
`Rockville, MD 20857
`
`We remind you that you must comply with the requirements for an approved NDA set forth under
`21 CFR 314.80 and 314.81.
`
`If you have any questions, call Paul E. Levine, Jr., R.Ph., Regulatory Health Project Manager, at
`(301) 827-7310.
`
`Sincerely,
`
`Lilia Talarico, M.D.
`Director
`Division of Gastrointestinal and
` Coagulation Drug Products
`Office of Drug Evaluation III
`Center for Drug Evaluation and Research
`
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`NDAs 19-510/S-029, 20-249/S-012
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`PEPCID®
`(FAMOTIDINE) INJECTION PREMIXED
`PEPCID®
`(FAMOTIDINE) INJECTION
`
`DESCRIPTION
`The active ingredient in PEPCID* (famotidine) Injection Premixed and PEPCID (famotidine) Injection is a
`is N'-(aminosulfonyl)-3-[[[2-[(diaminomethylene)amino]-4-
`histamine H2-receptor antagonist. Famotidine
`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
`evening doses of 20 and 40 mg of PEPCID to mean values of 5.0 and 6.4, respectively. When PEPCID was given
`
`* Registered trademark of MERCK & CO., Inc.
`COPYRIGHT © MERCK & CO., Inc., 1993, 1995, 1996
`All rights reserved
`
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`NDAs 19-510/S-029, 20-249/S-012
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`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
`
`Placebo
`h.s.
`(N=97)
`17%
`31%
`
`PEPCID
`PEPCID
`20 mg b.i.d.
`40 mg h.s.
`(N=84)
`(N=89)
`**38%
`**32%
`Week 2
`Week 4
`**67%
`**70%
`** 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).
`
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`NDAs 19-510/S-029, 20-249/S-012
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`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
`International Study
`U.S. Study
`Placebo
`PEPCID
`Placebo
`PEPCID
`h.s.
`40 mg h.s.
`h.s.
`40 mg h.s.
`(N=145)
`(N=149)
`(N=75)
`(N=74)
`31%
`†47%
` 45%
`39%
`Week 4
`46%
`44%
`Week 6
` †66%
`†65%
`54%
`64%
`Week 8
`***78%
`†80%
`***,† 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
`PEPCID
`40 mg h.s.
`20 mg b.i.d.
`(N=154)
`(N=149)
`82††
`69
`Week 6
`†† 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
`PEPCID
`20 mg b.i.d.
`40 mg b.i.d.
`(N=127)
`(N=125)
` 48†††,‡‡
`32
`Week 6
`Week 12
` 54†††
`69†††,‡
`††† 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.
`
`Placebo
`(N=66)
`18
`29
`
`Placebo
`(N=73)
`62
`
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`NDAs 19-510/S-029, 20-249/S-012
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`Ranitidine
`150 mg b.i.d.
`(N=172)
`42
`60
`
`Table 5
`% Endoscopic Healing - International Study
`PEPCID
`PEPCID
`20 mg b.i.d.
`40 mg b.i.d.
`(N=175)
`(N=93)
`48
`Week 6
`52
`Week 12
` 71‡‡‡
`68
`‡‡‡ 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 published studies of small numbers of pediatric patients given
`famotidine intravenously. Areas under the curve (AUCs) are normalized to a dose of 0.5 mg/kg I.V. for pediatric
`patients 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
`Volume of
`Total
`Area Under
`Distribution (Vd)
`Clearance (Cl)
` the Curve (AUC)
`(L/hr/kg)
`(ng-hr/mL)
`(L/kg)
`
`Age
`(N=number of
`patients)
`
`Elimination
`Half-life (T1/2)
`(hours)
`
`2.07 ± 1.49
`1.5 ± 0.4
`1.3 ± 0.2
`
`3.38 ± 2.60
`2.3 ± 0.4
`2.83 ± 0.99
`
`0.54 ± 0.34
`1089 ± 834
`1-11 yrs (N=20)
`0.48 ± 0.14
`1140 ± 320
`11-15 yrs (N=6)
`0.39 ± 0.14
`1726b
`Adult (N=16)
`aValues are presented as means ± SD unless indicated otherwise.
`bMean value only.
`Values of pharmacokinetic parameters for pediatric patients, ages 1-15 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 an AUC of 580 ± 60 ng-hr/mL in pediatric
`patients 11-15 years of age 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)*
`26 ± 13
`
`Pediatric Patients
`Data from one study
`26.5 ± 10.3
`a) healthy adult subjects
`18.7 ± 10.8
`b) adult patients with upper GI bleeding
`*Serum concentration of famotidine associated with 50% maximum gastric acid reduction. Values are presented as means ± SD.
`Four 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:
`
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`NDAs 19-510/S-029, 20-249/S-012
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`Dosage
`
`0.3 mg/kg, single dose
`0.4-0.8 mg/kg
`0.5 mg/kg, single dose
`
`Route
`
`I.V.
`I.V.
`I.V.
`
`I.V.
`0.5 mg/kg b.i.d.
`oral
`0.5 mg/kg b.i.d.
`avalues reported in published literature.
`bMeans ± SD.
`
`Table 8
`
`Effecta
`gastric pH >3.5 for 8.7 ± 4.7b hours
`gastric pH >4 for 6-9 hours
`a >2 pH unit increase above baseline
`in gastric pH for >8 hours
`gastric pH >5 for 13.5 ± 1.8b hours
`gastric pH >5 for 5.0 ± 1.1b hours
`
`Number of Patients
`
`6
`18
`9
`
`4
`4
`
`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.
`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.
`
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`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
`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.
`No pharmacokinetic or pharmacodynamic data are available on pediatric patients under 1 year of age.
`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.
`
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`
`The following adverse reactions have been reported to occur in more than 1% of patients on therapy with PEPCID
`in controlled clinical trials, and may be causally related to the drug: headache (4.7%), dizziness (1.3%), constipation
`(1.2%) and diarrhea (1.7%).
`The following other adverse reactions have been reported infrequently in clinical trials or since the drug was
`marketed. The relationship to therapy with PEPCID has been unclear in many cases. Within each category the
`adverse reactions are listed in order of decreasing severity:
`Body as a Whole: fever, asthenia, fatigue
`Cardiovascular: arrhythmia, AV block, palpitation
`Gastrointestinal: cholestatic jaundice, liver enzyme abnormalities, vomiting, nausea, abdominal discomfort,
`anorexia, dry mouth
`Hematologic: rare cases of agranulocytosis, pancytopenia, leukopenia, thrombocytopenia
`Hypersensitivity: anaphylaxis, angioedema, orbital or facial edema, urticaria, rash, conjunctival injection
`Musculoskeletal: musculoskeletal pain including muscle cramps, arthralgia
`Nervous System/Psychiatric: grand mal seizure; psychic disturbances, which were reversible in cases for which
`follow-up was obtained, including hallucinations, confusion, agitation, depression, anxiety, decreased libido;
`paresthesia; insomnia; somnolence
`Respiratory: bronchospasm
`Skin: toxic epidermal necrolysis (very rare), alopecia, acne, pruritus, dry skin, flushing
`Special Senses: tinnitus, taste disorder
`Other: rare cases of impotence and rare cases of gynecomastia have been reported; however, in controlled
`clinical trials, the incidences were not greater than those seen with placebo.
`The adverse reactions reported for PEPCID Tablets may also occur with PEPCID for Oral Suspension, 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.
`
`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
`See PRECAUTIONS, Pediatric Patients.
`The studies described in PRECAUTIONS, Pediatric Patients suggest that the starting dose in pediatric patients
`1-16 years of age is 0.25 mg/kg intravenously (injected over a period of not less than two minutes or as a 15 minute
`infusion) q 12 h up to 40 mg/day.
`While published uncontrolled clinical studies suggest effectiveness of famotidine in the treatment of peptic ulcer,
`data in pediatric patients are insufficient to establish percent response with dose and duration of therapy. Therefore,
`treatment duration (initially based on adult duration recommendations) and dose should be individualized based on
`clinical response and/or gastric pH determination and endoscopy. Published uncontrolled studies in pediatric patients
`have demonstrated gastric acid suppression with doses up to 0.5 mg/kg intravenously q 12 h.
`No pharmacokinetic or pharmacodynamic data are available on pediatric patients under 1 year of age.
`
`Sandoz Exhibit 1011 Page 9
`
`

`

`NDAs 19-510/S-029, 20-249/S-012
`Page 10
`
`Dosage Adjustments for Patients with Moderate or Severe Renal Insufficiency
`In adult patients with moderate or (creatinine clearance <50 mL/min) or severe (creatinine clearance <10mL\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