Pepcid

1 INDICATIONS AND USAGE PEPCID tablets are indicated in adult and pediatric patients 40 kg and greater for the treatment of: • active duodenal ulcer (DU). • active gastric ulcer (GU). • symptomatic nonerosive gastroesophageal reflux disease (GERD). • erosive esophagitis due to GERD, diagnosed by biopsy. PEPCID tablets are indicated in adults for the: • treatment of pathological hypersecretory conditions (e.g., Zollinger-Ellison syndrome, multiple endocrine neoplasias). • reduction of the risk of duodenal ulcer recurrence. PEPCID is a histamine-2 (H2) receptor antagonist indicated (1): In adult and pediatric patients 40 kg and greater for the treatment of: • active duodenal ulcer (DU). • active gastric ulcer. • symptomatic nonerosive gastroesophageal reflux disease (GERD). • erosive esophagitis due to GERD, diagnosed by biopsy. In adults for the: • treatment of pathological hypersecretory conditions (e.g., Zollinger-Ellison syndrome, multiple endocrine neoplasias). • reduction of the risk of DU recurrence.

2 DOSAGE AND ADMINISTRATION Indication Recommended Dosage ( 2.1 ) Adult and Pediatric Patients 40 kg and greater Active DU 40 mg once daily; or 20 mg twice daily Active Gastric Ulcer 40 mg once daily GERD 20 mg twice daily Erosive Esophagitis 20 mg twice daily; or 40 mg twice daily Adults Pathological Hypersecretory Conditions 20 mg every 6 hours; adjust to patient needs; maximum 160 mg every 6 hours Risk Reduction of DU Recurrence 20 mg once daily • See full prescribing information for complete dosing information, including dosing in renal impairment, and recommended treatment duration. ( 2.1 , 2.2 ) Administration ( 2.3 ): • Take once daily before bedtime or twice daily in the morning and before bedtime with or without food 2.1 Recommended Dosage Table 1 shows the recommended dosage of PEPCID 20 mg and 40 mg tablets in adult and pediatric patients weighing 40 kg and greater with normal renal function. The use of PEPCID 20 mg and 40 mg tablets is not recommended in pediatric patients weighing less than 40 kg because the lowest available strength (20 mg) exceeds the recommended dose for these patients. Use another famotidine formulation for pediatric patients weighing less than 40 kg. Table 1: Recommended Dosage and Duration of PEPCID Tablets in Adult and Pediatric Patients 40 kg and Greater with Normal Renal Function Indication Recommended Dosage Recommended Duration Active duodenal ulcer (DU) 40 mg once daily; or 20 mg twice daily Both dosages demonstrated effectiveness in clinical trials [see Clinical Studies (14) ]. Up to 8 weeks In clinical trials, the majority of patients healed within 4 weeks. For patients who do not heal after 4 weeks, consider an additional 2 to 4 weeks of treatment [see Clinical Studies (14.1) ]. Longer treatment durations have not been studied in clinical trials [see Clinical Studies (14.1 , 14.2 , 14.3) ]. Active gastric ulcer 40 mg once daily Up to 8 weeks Symptomatic nonerosive GERD 20 mg twice daily Up to 6 weeks Erosive esophagitis diagnosed by endoscopy 20 mg twice daily; or 40 mg twice daily Up to 12 weeks Pathological hypersecretory conditions In pediatric patients, the safety and effectiveness of PEPCID have not been established for the reduction of the risk of duodenal ulcer recurrence or for treatment of pathological hypersecretory conditions [see Use in Specific Populations (8.4) ]. Starting dosage: 20 mg every 6 hours; adjust dosage to individual patient needs Maximum dosage 160 mg every 6 hours As clinically indicated Reduction of the risk of DU recurrence 20 mg once daily 1 year or as clinically indicated 2.2 Dosage in Renal Impairment Dosage adjustments of PEPCID are recommended for patients with moderate to severe renal impairment (creatinine clearance less than 60 mL/min) [see Use in Specific Populations (8.6)]. Table 2 shows the recommended maximum dosage of PEPCID 20 mg or 40 mg tablets for patients with renal impairment, by indication. Use the lowest effective dose. Some dosage adjustments may require switching to other formulations of famotidine (e.g., oral suspension, lower dose tablet). Table 2: Maximum Dosage of PEPCID Tablets in Adult and Pediatric Patients 40 kg and Greater with Moderate and Severe Renal Impairment Indication Recommended Maximum Dosages Creatinine clearance 30 to 60 mL/minute Creatinine clearance less than 30 mL/minute Active duodenal ulcer (DU) 20 mg once daily; or 40 mg every other day 20 mg every other day An alternate dosage regimen is 10 mg once daily. Since 20 mg or 40 mg tablet strength cannot be used for this dosage regimen, use an alternate famotidine formulation. Active gastric ulcer 20 mg once daily; or 40 mg every other day 20 mg every other day Symptomatic nonerosive GERD 20 mg once daily 20 mg every other day Erosive esophagitis diagnosed by endoscopy Dosage adjustments for renal impairment are provided for both dosing regimens (20 mg twice daily and 40 mg twice daily) which showed effectiveness for the treatment of erosive esophagitis in cli …

3 DOSAGE FORMS AND STRENGTHS • 20 mg tablets: round, white to off-white film-coated tablets coded MP 973 on one side and the other side plain. • 40 mg tablets: round, white to off-white film-coated tablets coded MP 974 on one side and the other side plain. Tablets: 20 mg, 40 mg (3 )

4 CONTRAINDICATIONS PEPCID is contraindicated in patients with a history of serious hypersensitivity reactions (e.g., anaphylaxis) to famotidine or other histamine-2 (H2) receptor antagonists. History of serious hypersensitivity reactions (e.g., anaphylaxis) to famotidine or other H2 receptor antagonists. (4)

6 ADVERSE REACTIONS The most common adverse reactions are: headache, dizziness, constipation, and diarrhea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Bausch Health US, LLC at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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. PEPCID was studied in 7 US and international placebo- and active-controlled trials in approximately 2500 patients [see Clinical Studies (14)] . A total of 1442 patients were treated with PEPCID, including 302 treated with 40 mg twice daily, 456 treated with 20 mg twice daily, 461 treated with 40 mg once daily, and 396 treated with 20 mg once daily. The population was 17-91 years old, fairly well distributed between gender and race; however, the predominant race treated was Caucasian. The following adverse reactions occurred in greater than or equal to 1% of PEPCID-treated patients: headache, dizziness and constipation. The following other adverse reactions were reported in less than 1% of patients in clinical trials: Body as a Whole: fever, asthenia, fatigue Cardiovascular: palpitations Gastrointestinal: elevated liver enzymes, vomiting, nausea, abdominal discomfort, anorexia, dry mouth Hematologic: thrombocytopenia Hypersensitivity: orbital edema, rash, conjunctival injection, bronchospasm Musculoskeletal: musculoskeletal pain, arthralgia Nervous System/Psychiatric: seizure, hallucinations, depression, anxiety, decreased libido, insomnia, somnolence Skin: pruritus, dry skin, flushing Special Senses: tinnitus, taste disorder Other: impotence 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of famotidine. 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. Cardiovascular: arrhythmia, AV block, prolonged QT interval Gastrointestinal: cholestatic jaundice, hepatitis Hematologic: agranulocytosis, pancytopenia, leukopenia Hypersensitivity: anaphylaxis, angioedema, facial edema, urticaria Musculoskeletal: rhabdomyolysis, muscle cramps Nervous System/Psychiatric: confusion, agitation, paresthesia Respiratory: interstitial pneumonia Skin: toxic epidermal necrolysis/Stevens-Johnson syndrome

7 DRUG INTERACTIONS • Drugs Dependent on Gastric pH for Absorption: Systemic exposure of the concomitant drug may be significantly reduced leading to loss of efficacy. See full prescribing information for a list of interacting drugs. ( 7.1) • Tizanidine (CYP1A2) Substrate: Potential for substantial increases in blood concentrations of tizanidine resulting in hypotension, bradycardia or excessive drowsiness; avoid concomitant use, if possible. ( 7.2 ) 7.1 Drugs Dependent on Gastric pH for Absorption Famotidine can reduce the absorption of other drugs, due to its effect on reducing intragastric acidity, leading to loss of efficacy of the concomitant drug. Concomitant administration of PEPCID with dasatinib, delavirdine mesylate, cefditoren, and fosamprenavir is not recommended. See the prescribing information for other drugs dependent on gastric pH for absorption for administration instructions, including atazanavir, erlotinib, ketoconazole, itraconazole, ledipasvir/sofosbuvir, nilotinib, and rilpivirine. 7.2 Tizanidine (CYP1A2 Substrate) Although not studied clinically, famotidine is considered a weak CYP1A2 inhibitor and may lead to substantial increases in blood concentrations of tizanidine, a CYP1A2 substrate. Avoid concomitant use with PEPCID. If concomitant use is necessary, monitor for hypotension, bradycardia or excessive drowsiness. Refer to the full prescribing information for tizanidine.

8 USE IN SPECIFIC POPULATIONS • Geriatric Use: Use the lowest effective dose for an elderly patient and monitor renal function. ( 2.2 , 5.1 , 8.5 ) • Renal Impairment: Risk of CNS adverse reactions and QT prolongation in patients with moderate and severe renal impairment; reduce the dosage. ( 2.2 , 8.6 ) 8.1 Pregnancy Risk Summary Available data with H2-receptor antagonists, including famotidine, in pregnant women are insufficient to establish a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies, no adverse development effects were observed with oral administration of famotidine at doses up to approximately 243 and 122 times, respectively, the recommended human dose of 80 mg per day for the treatment of erosive esophagitis (see Data) . The estimated background risk for major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data 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 intravenous 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 (about 49 times the recommended human dose of 80 mg per day, based on body surface area) 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. 8.2 Lactation Risk Summary There are limited data available on the presence of famotidine in human breast milk. There were no effects on the breastfed infant. There are no data on famotidine effects on milk production. Famotidine is present in the milk of lactating rats (see Data) . The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for famotidine and any potential adverse effects on the breastfed child from PEPCID or from the underlying maternal condition. Data Animal Data Transient growth depression was observed in young rats suckling from mothers treated with maternotoxic doses of famotidine at least 600 times the usual human dose. 8.4 Pediatric Use The safety and effectiveness of PEPCID have been established in pediatric patients for the treatment of peptic ulcer disease (i.e., duodenal ulcer, gastric ulcer) and GERD (i.e., symptomatic nonerosive GERD, erosive esophagitis as diagnosed by endoscopy). The use of PEPCID and the recommended dosage of PEPCID in these pediatric patients is supported by evidence from adequate and well-controlled studies of PEPCID in adults and published pharmacokinetic and pharmacodynamic data in pediatric patients [see Dosage and Administration (2.1), Clinical Pharmacology (12.2, 12.3)]. In pediatric patients, the safety and effectiveness for the treatment of pathological hypersecretory conditions and reduction of risk of duodenal ulcer recurrence have not been established. PEPCID 20 and 40 mg tablets are not recommended for use in pediatric patients weighing less than 40 kg because these tablet strengths exceed the recommended dose for these patients [see Dosage and Administration (2.1)] . For pediatric patients weighing less than 40 kg, consider another famotidine formulation (e.g., oral suspension, lower dose tablet). 8.5 Geriatric Use Of the 1442 PEPCID-treated patients in clinical studies, approximately 10% were 65 and older. In these studies, no overal …

12.1 Mechanism of Action Famotidine is a competitive inhibitor of histamine-2 (H2) receptors. The primary clinically important pharmacologic activity of famotidine is inhibition of gastric secretion. Both the acid concentration and volume of gastric secretion are suppressed by famotidine, while changes in pepsin secretion are proportional to volume output.

11 DESCRIPTION The active ingredient in PEPCID (famotidine) tablets is a histamine-2 (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: Each PEPCID tablet for oral administration contains either 20 mg or 40 mg of famotidine and the following inactive ingredients: hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, pregelatinized starch (modified corn starch), sodium starch glycolate, talc, titanium dioxide and triacetin. 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. chemstructure.jpg

10 OVERDOSAGE The types of adverse reactions in overdosage of PEPCID are similar to the adverse reactions encountered with use of recommended dosages [see Adverse Reactions (6.1)]. 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. Due to low binding to plasma proteins, famotidine is eliminated by hemodialysis. There is limited experience on the usefulness of hemodialysis as a treatment for PEPCID overdosage.

16 HOW SUPPLIED/STORAGE AND HANDLING PEPCID (famotidine) tablets are supplied as follows: NDC Strength Quantity Description 0187-4420-30 20 mg unit of use bottles of 30 round, white to off-white film-coated tablets coded with MP 973 on one side and the other side plain 0187-4420-10 20 mg unit of use bottles of 100 round, white to off-white film-coated tablets coded with MP 973 on one side and the other side plain 0187-4440-30 40 mg unit of use bottles of 30 round, white to off-white film-coated tablets coded with MP 974 on one side and the other side plain 0187-4440-10 40 mg unit of use bottles of 100 round, white to off-white film-coated tablets coded with MP 974 on one side and the other side plain Storage Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Dispense in a USP tight, light-resistant container.