FAMOTIDINE

The active ingredient in famotidine for oral suspension, USP is a histamine-2 (H 2 ) receptor antagonist. Famotidine, USP is N' -(aminosulfonyl)-3-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]propanimidamide. The empirical formula of famotidine, USP 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: carboxymethyl cellulose sodium, flavors (banana, cherry and peppermint), fumaric acid, microcrystalline cellulose, sucrose, xanthan gum. Added as preservatives are sodium benzoate 0.42%, sodium methyl paraben 0.08%, and sodium propyl paraben 0.02%. Famotidine, USP is a white to pale yellow-white crystalline compound that is freely soluble in dimethylformamide and in glacial acetic acid, slightly soluble in methanol, very slightly soluble in water, and practically insoluble in ethanol, chloroform, ether and in ethyl acetate. Chemical Structure

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 (H 2 ) 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

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, USP in adults with normal renal function is shown in Table 1. Table 1: Recommended Dosage and Duration of Famotidine for Oral Suspension After preparation, the concentration of famotidine oral suspension, USP is 8 mg/mL [See Dosage and Administration (2.3)] . , USP in Adults with Normal Renal Function Indication Recommended Dosage Recommended Duration Active 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 GU 40 mg once daily. Up to 8 weeks Symptomatic nonerosive GERD 20 mg twice daily. Up to 6 weeks Erosive esophagitis due to GERD, diagnosed by endoscopy 20 mg twice daily; or 40 mg twice daily . 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 , or as clinically indicated 2.2 Recommended Dosage in Pediatric Patients The recommended dosage and duration of famotidine for oral suspension, USP in pediatric patients with normal renal function is shown in Table 2. Table 2: Recommended Dosage and Duration of Famotidine for Oral Suspension, USP in Pediatric Patients with Normal Renal Function Indication Pediatric Age Range Recommended Dosage After preparation, the concentration of famotidine oral suspension, USP is 8 mg/mL [See Dosage and Administration (2.3)] . 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 Treatment duration based on adult recommendations (see Table 1) . Individualize the dose and duration based upon clinical response and/or pH determinations (gastric or esophageal) and endoscopy. GERD Birth to less than 3 months Starting dosage 0.5 mg/kg once daily. May increase to 1 mg/kg once daily . Up to 8 weeks , Use conservative measures (e.g., thickened feedings) concurrently [see Use in Specific Populations (8.4)] . , After 4 weeks of treatment re-evaluate the patient. Consider an additional 4 weeks of treatment if treatment benefit outweighs potential risks. 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. 6 to 12 weeks 2.3 Recommended Dosage in Adults with Renal Impairment Recommended dosage adjustments for adults with moderate to severe renal impairment (creatinine clearance less than 60 mL/min) by indication are shown in Table 3. Use the lowest effective dosage [see Use in Specific Populations (8.6) ] . A safe and effective dosage has not been established in pediatric patients with renal impairment. Table 3: Recommended Maximum Dosage of Famotidine for Oral Suspension, USP in Adults 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 DU 20 mg once daily; or 40 mg every other day 10 mg once daily; or 20 mg every other day Active GU 20 mg once daily; or 40 mg every other day 10 mg once daily; or 20 mg every other day Symptomatic nonerosive GERD 20 mg once daily 10 mg once daily; or 20 mg every other day Erosive esophagitis due to GERD, 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 clinical trials [see Clinical Studies (14.4)] . 20 mg once daily; or 40 mg every other day The dosage required to treat pathological hypersecretory conditions may exceed the maximum dosage evaluated in patients with impaired renal function. The risk for increased adverse reactions in renally impaired patients treated with famotidine for oral suspension, USP for pathological hypersecretory conditions is unknown. 10 mg once daily; or 20 mg every other day 40 mg once daily 20 mg once daily Pathological hypersecretory conditions Avoid use Reduction of the risk of DU recurrence 10 mg once daily; or 20 mg every other day 10 mg every other day 2.4 Administration Instructions Preparation of Constituted Suspension by a Healthcare Provider Prior to Dispensing Prior to dispensing, constitute famotidine for oral suspension, USP by slowly adding below volume of purified water to the bottle. Shake vigorously for 5 to 10 seconds immediately after adding the water. The constituted suspension contains 40 mg of famotidine, USP per 5 mL, and should be a smooth, mobile, white to off-white, and homogeneous suspension. Bottle Size Volume of Purified Water for Reconstitution 50 mL 46 mL 100 mL 92 mL 150 mL 138 mL Administration and Storage of Constituted Suspension Shake the bottle of constituted famotidine, USP suspension vigorously for 5 to 10 seconds prior to each use. Take famotidine for oral suspension, USP once daily before bedtime or twice daily in the morning and before bedtime, as recommended. Famotidine for oral suspension, USP may be taken with or without food [see Clinical Pharmacology (12.3) ] . Famotidine for oral suspension, USP may be given with antacids. Store the constituted suspension at 25°C (77°F). Protect from freezing. Discard unused constituted suspension after 30 days.

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 )

The most common adverse reactions are: headache, dizziness, constipation, and diarrhea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Upsher-Smith Laboratories, LLC at 1-855-899-9180 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 U.S. and international placebo- and active-controlled trials in approximately 2,500 patients [see Clinical Studies (14) ] . A total of 1,442 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 Post marketing 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

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.

Storage Store famotidine for oral suspension dry powder and constituted suspension at 25°C (77°F); excursions permitted to 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.