Famotidine

1 INDICATIONS AND USAGE Famotidine for oral suspension is indicated in adults 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. • treatment of pathological hypersecretory conditions (e.g., Zollinger-Ellison syndrome, multiple endocrine neoplasias). • reduction of the risk of duodenal ulcer recurrence. Famotidine for oral suspension is indicated in pediatric patients 1 year of age and older for the treatment of: • peptic ulcer disease. • GERD with or without esophagitis and ulcerations. Famotidine for oral suspension is indicated in pediatric patients from birth to less than 1 year of age for the treatment of: • GERD. Famotidine for oral suspension is a histamine-2 (H2) receptor antagonist indicated ( 1 ): In adults 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. • treatment of pathological hypersecretory conditions (e.g., Zollinger-Ellison syndrome, multiple endocrine neoplasias). • reduction of the risk of DU recurrence. In pediatric patients 1 year of age and older for the treatment of: • peptic ulcer • GERD with or without esophagitis and ulcerations In pediatric patients from birth to less than 1 year of age for the treatment of: • GERD.

2 DOSAGE AND ADMINISTRATION Recommended adult dosage by indication (2.1) : Active DU 40 mg once daily; or 20 mg twice daily Active GU 40 mg once daily Symptomatic Nonerosive GERD 20 mg twice daily Erosive Esophagitis due to GERD 20 mg twice daily; or 40 mg twice daily 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 Recommended pediatric dosage by indication (2.2) : Peptic Ulcer Disease 1 year to less than 17 years Starting dosage 0.5 mg/kg once daily; or 0.25 mg/kg twice daily; may increase to 1 mg/kg once daily at bedtime or 0.5 mg/kg twice daily; Maximum of 40 mg per day GERD Birth to less than 3 months Starting dosage 0.5 mg/kg once daily; may increase to 1 mg/kg once daily 3 months to less than 1 year Starting dosage 0.5 mg/kg twice daily; may increase to 1 mg/kg twice daily; Maximum of 40 mg per day GERD with or without esophagitis and ulcerations 1 year to less than 17 years 0.5 mg/kg twice daily Maximum of 40 mg twice daily See full prescribing information for complete dosing information in adults and pediatrics, recommended treatment duration by indication, and dosage adjustment for adult patients with renal impairment. (2.1 , 2.2 , 2.3) 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 in Adults The recommended dosage and duration of Famotidine for oral suspension in adults with normal renal function is shown in Table 1. Table 1: Recommended Dosage and Duration of Famotidine for Oral Suspension a in Adults with Normal Renal Function Indication Recommended Dosage Recommended Duration Active DU 40 mg once daily; or 20 mg twice daily b Up to 8 weeks c,d Active GU 40 mg once daily Up to 8 weeks d Symptomatic nonerosive GERD 20 mg twice daily Up to 6 weeks d Erosive esophagitis due to GERD, diagnosed by endoscopy 20 mg twice daily; or 40 mg twice daily b Up to 12 weeks Pathological hypersecretory conditions 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 c,d or as clinically indicated a After preparation, the concentration of famotidine oral suspension is 8 mg/mL [see DOSAGE AND ADMINISTRATION (2.3) ] b Both dosages demonstrated effectiveness in clinical trials [see CLINICAL STUDIES (14) ]. c 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) ]. d Longer treatment durations have not been studied in clinical trials [see CLINICAL STUDIES (14.1 , 14.2 , 14.3) ]. 2.2 Recommended Dosage in Pediatric Patients The recommended dosage and duration of famotidine for oral suspension in pediatric patients with normal renal function is shown in Table 2. Table 2: Recommended Dosage and Duration of Famotidine for Oral Suspension a in Pediatric Patients with Normal Renal Function Indication Pediatric Age Range Recommended Dosage a Duration Peptic Ulcer Disease 1 year to less than 17 years Starting dosage 0.5 mg/kg once daily; or 0.25 mg/kg twice daily. May increase to 1 mg/kg once daily at bedtime or 0.5 mg/ kg twice daily Maximum of 40 mg per day 8 weeks b GERD Birth to less than 3 months Starting dosage 0.5 mg/kg once daily. May increase to 1 mg/kg once daily b Up to 8 weeks b,c,d 3 months to less than 1 year Starting dosage 0.5 mg/kg twice daily. May increase to 1 mg/kg twice daily c Maximum of 40 mg per day GERD with or without esophagitis and ulcerations 1 year to less than 17 years 0.5 mg/kg twice daily Maximum of 40 mg twice daily 6 to 12 weeks b a After preparation, the concentration of famotidine oral suspension is 8 mg/mL [see DOSAGE AND ADMINISTRATION (2.3) ] b Treatment duration based on adult recommendations (see Table 1). Indiv …

3 DOSAGE FORMS AND STRENGTHS For Oral Suspension: 14.3 g as a white to off-white granular powder. When constituted as directed, famotidine for oral suspension, USP is an white to off-white, homogeneous suspension with flavors (cherry, banana, and peppermint) containing 55 mL after reconstitution (40 mg of famotidine, USP per 5 mL). For oral suspension: 55 mL after reconstitution (40 mg/5mL) ( 3 )

4 CONTRAINDICATIONS Famotidine for oral suspension is contraindicated in patients with a history of serious hypersensitivity reactions (e.g., anaphylaxis) to famotidine or other histamine-2 (H 2 ) receptor antagonists. History of serious hypersensitivity reactions (e.g., anaphylaxis) to famotidine or other H 2 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 Carnegie Pharmaceuticals LLC at 1-732-783-7010 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. The safety of famotidine for oral suspension has been established based on adequate and well-controlled studies of another oral famotidine product [see CLINICAL STUDIES (14) ]. The following is a summary of the adverse reactions reported in those studies. Oral famotidine 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 famotidine, 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 to 91 years old, fairly well distributed between sex and race; however, the predominant race was Caucasian. The following adverse reactions occurred in greater than or equal to 1% of famotidine-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 Pediatric Patients Less Than One Year of Age In a clinical study in 35 pediatric patients less than 1 year of age with GERD symptoms, two patients discontinued due to adverse reactions. Agitation observed in 5 patients resolved when famotidine was discontinued [see USE IN SPECIFIC POPULATIONS (8.4) ]. 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

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. The safety of famotidine for oral suspension has been established based on adequate and well-controlled studies of another oral famotidine product [see CLINICAL STUDIES (14) ]. The following is a summary of the adverse reactions reported in those studies. Oral famotidine 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 famotidine, including 302 treated with 40 mg twice daily, 456 treated with 20 mg twice daily, 461 treated with 4 …

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 famotidine for oral suspension 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 famotidine for oral suspension. If concomitant use is necessary, monitor for hypotension, bradycardia or excessive drowsiness. Refer to the full prescribing information for tizanidine.

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 famotidine for oral suspension 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 famotidine for oral suspension. 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 in adults. (2.2 , 8.6) 8.1 Pregnancy Risk Summary Available data with H 2 -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 famotidine. 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 famotidine for oral suspension 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 Peptic Ulcer Disease and GERD With or Without Esophagitis and Ulcerations Pediatric Patients One Year to Less than 17 Years of Age: The safety and effectiveness of famotidine for oral suspension have been established in pediatric patients 1 year to less than 17 years of age for the treatment of peptic ulcer disease and GERD with or without esophagitis and ulcerations. Use of famotidine in this age group is supported by evidence from adequate and well-controlled studies of famotidine in adults with additional pharmacokinetic and pharmacodynamic data in pediatric patients 1 year to less than 17 years of age [see DOSAGE AND ADMINISTRATION (2.1) , CLINICAL PHARMACOLOGY (12.2 , 12.3) ]. The safety and effectiveness of famotidine for oral suspension for the treatment of peptic ulcer disease in pediatric patients less than one year of age have not been established. GERD Pediatric Patients Less Than One Year of Age: The safety and effectiveness of famotidine for oral suspension have been established in pediatric patients from birth to less than 1 year of age for the treatment of GERD. The use of famotidine this is age group is supported by evidence from adequate and well-controlled studies of famotidine in adults an …

12.1 Mechanism of Action Famotidine is a competitive inhibitor of histamine-2 (H 2 ) 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 famotidine for oral suspension, USP is a H 2 -receptor antagonist. Famotidine is N' -(aminosulfonyl)-3-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]propanimidamide. The molecular formula of famotidine is C 8 H 15 N 7 O 2 S 3 and its molecular weight is 337.43. Its structural formula is: Each 5 mL of famotidine for oral suspension, USP when prepared as directed contains 40 mg of famotidine, USP and the following inactive ingredients: banana flavor (contains propylene glycol), cherry flavor (contains acetic acid, propylene glycol and triethyl citrate), citric acid monohydrate, peppermint flavor (contains ethyl alcohol and water), powdered cellulose, sucrose and xanthan gum. Added as preservatives are methylparaben sodium 0.1%, propylparaben sodium 0.02% and sodium benzoate 0.1%. Each 5 mL of famotidine for oral suspension USP contains 2 mg of sodium. Famotidine, USP is a white to pale yellowish white crystalline powder that is freely soluble in dimethyl formamide, glacial acetic acid, slightly soluble in methanol, very slightly soluble in water, practically insoluble in acetone, in alcohol, in chloroform, in ether and in ethyl acetate. str

10 OVERDOSAGE The types of adverse reactions in overdosage of famotidine are similar to the adverse reactions encountered with use of recommended dosages [s ee 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 famotidine overdosage.

16 HOW SUPPLIED/STORAGE AND HANDLING Famotidine for oral suspension, USP is supplied as follows: NDC Strength Quantity Description 60219-­2090-4 40 mg Bottle white to off-white granular powder. When constituted as directed, famotidine for oral suspension, USP is a smooth, mobile, white to off-white homogeneous suspension with a cherry-banana-peppermint flavor free from lumps, containing 40 mg of famotidine, USP per 5 mL. Prior to dispensing, constitute famotidine for oral suspension, USP [see Dosage and Administration (2.3) ] Storage Store famotidine for oral suspension, USP dry powder and constituted suspension at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Protect from freezing. Discard unused constituted suspension after 30 days. Dispense in a USP tight, light-resistant container.