Famotidine

1 INDICATIONS AND USAGE Famotidine 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. Famotidine 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. Famotidine is a histamine-2 (H 2 ) receptor antagonist indicated ( Error! Hyperlink reference not valid. ): 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.

Purpose Acid reducer

2 DOSAGE AND ADMINISTRATION Indication Recommended Dosage ( Error! Hyperlink reference not valid. ) Adult and Pediatric Patients 40 kg and greater Active DU 40 mg once daily; or 20 mg twice daily Active GastricUlcer 40 mg once daily GERD 20 mg twice daily Erosive Esophagitis 20 mg twice daily; or40 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. ( Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. ) Administration ( Error! Hyperlink reference not valid. ): 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 famotidine 20 mg and 40 mg tablets in adult and pediatric patients weighing 40 kg and greater with normal renal function. The use of famotidine 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 Famotidine 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 a Up to 8 weeks b,c Active gastric ulcer 40 mg once daily Up to 8 weeks c Symptomatic nonerosive GERD 20 mg twice daily Up to 6 weeks c Erosive esophagitis diagnosed by endoscopy 20 mg twice daily; or 40 mg twice daily a Up to 12 weeks Pathological hypersecretory conditions d 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 d 20 mg once daily 1 year c or as clinically indicated a Both dosages demonstrated effectiveness in clinical trials [see Clinical Studies ( Error! Hyperlink reference not valid. )]. b 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 ( Error! Hyperlink reference not valid. )] . c Longer treatment durations have not been studied in clinical trials [see Clinical Studies ( Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. )] . d In pediatric patients, the safety and effectiveness of famotidine 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 ( Error! Hyperlink reference not valid. )]. 2.2 Dosage in Renal Impairment Dosage adjustments of famotidine tablets are recommended for patients with moderate to severe renal impairment (creatinine clearance less than 60 mL/min) [see Use in Specific Populations ( Error! Hyperlink reference not valid. )]. Table 2 shows the recommended maximum dosage of famotidine 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: Recommended Maximum Dosage of Famotidine 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; or40 mg every other day 20 mg every other day a Active gastric ulcer 20 mg once daily; or 40 mg every other day 20 mg every other day a Symptomatic nonero …

3 DOSAGE FORMS AND STRENGTHS Famotidine Tablets USP, 20 mg are light yellow, rounded square shaped, biconvex, film coated tablets debossed with "35" on one side and plain on the other side. Famotidine Tablets USP, 40 mg are white to off white, rounded square shaped, biconvex, film coated tablets debossed with "36" on one side and plain on the other side. Tablets: 20 mg, 40 mg ( 3 )

4 CONTRAINDICATIONS Famotidine tablets are 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. ( Error! Hyperlink reference not valid. )

Do not use if you have trouble or pain swallowing food, vomiting with blood, or bloody or black stools. These may be signs of a serious condition. See your doctor. if you have kidney disease, except under the advice and supervision of a doctor with other acid reducers

Ask a doctor before use if you have • had heartburn over 3 months. This may be a sign of a more serious condition. • heartburn with lightheadedness, sweating, or dizziness • chest pain or shoulder pain with shortness of breath; sweating; pain spreading to arms, neck or shoulders; or lightheadedness • frequent chest pain • frequent wheezing, particularly with heartburn • unexplained weight loss • nausea or vomiting • stomach pain • kidney disease

Stop use and ask a doctor if side effects occur. You may report side effects to FDA at 1-800-FDA-1088. your heartburn continues or worsens you need to take this product for more than 14 days

6 ADVERSE REACTIONS The most common adverse reactions are: headache, dizziness, constipation, and diarrhea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact AvKARE at 1-855-361-3993 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. 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 gender and race; however, the predominant race treated 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 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 syndro To report SUSPECTED ADVERSE REACTIONS contact AvKARE at 1-855-361-3993; email drugsafety@avkare.com; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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. ( Error! Hyperlink reference not valid. ) • Tizanidine (CYP1A2) Substrate: Potential for substantial increases in blood concentrations of tizanidine resulting in hypotension, bradycardia or excessive drowsiness; avoid concomitant use, if possible. ( Error! Hyperlink reference not valid. ) 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 tablets 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 tablets. 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. ( Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. ) • Renal Impairment: Risk of CNS adverse reactions and QT prolongation in patients with moderate and severe renal impairment; reduce the dosage. ( Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. ) See 17 for Patient Counseling Information 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 tablets. 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 tablets 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 famotidine tablets 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 famotidine tablets and the recommended dosage of famotidine tablets in these pediatric patients is supported by evidence from adequate and well-controlled studies of famotidine tablets in adults and published pharmacokinetic and pharmacodynamic data in pediatric patients [see Dosage and Administration ( Error! Hyperlink reference not valid. ), Clinical Pharmacology ( Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. )] . 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. Famotidine 20 and 40 mg tablets are not recommended for use in pediatric patients weighing less than …

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 tablets, USP is a histamine-2 (H 2 ) receptor antagonist. Famotidine is 3-[({2-[(diaminomethylidene) amino]-1, 3-thiazol-4-yl} methyl) sulfanyl]-N- sulfamoyl propanimidamide. The molecular formula of famotidine is C 8 H 15 N 7 O 2 S 3 and its molecular weight is 337.45 g/mol. Its structural formula is: Each famotidine tablet for oral administration contains either 20 mg or 40 mg of famotidine USP and the following inactive ingredients: corn starch, hypromellose, magnesium stearate, microcrystalline cellulose, sodium starch glycolate, opadry white and opadry yellow. The opadry white contains hypromellose, hydroxypropyl cellulose, titanium dioxide, talc and carnauba wax. In addition, the 20 mg tablets contain red iron oxide, and yellow iron oxide. Famotidine USP is a White to pale yellowish-white, crystalline powder that is Freely soluble in dimethyl formamide, freely soluble in glacial acetic acid, slightly soluble in methanol, very slightly soluble in water, practically insoluble in acetone, practically insoluble in alcohol, practically insoluble in chloroform, practically insoluble in ether & practically insoluble in ethyl acetate. FDA approved dissolution test specifications differ from USP. Image

Active ingredient (in each tablet) Famotidine, USP 10 mg and 20 mg

10 OVERDOSAGE The types of adverse reactions in overdosage of famotidine tablets are similar to the adverse reactions encountered with use of recommended dosages [see Adverse Reactions ( Error! Hyperlink reference not valid. )] . 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 tablets overdosage.

16 HOW SUPPLIED/STORAGE AND HANDLING Famotidine tablets are supplied as follows: NDC Strength Quantity Description 76420-712-30 (repackaged from NDC 67877-842-XX) 20 mg 30 tablets in 1 HDPE container round, white to off-white film-coated tablets, debossed with “V” on one side and “15” on the other side. 76420-712-60 (repackaged from NDC 67877-842-XX) 60 tablets in 1 HDPE container round, white to off-white film-coated tablets, debossed with “V” on one side and “15” on the other side. 76420-712-90 (repackaged from NDC 67877-842-XX) 90 tablets in 1 HDPE container round, white to off-white film-coated tablets, debossed with “V” on one side and “15” on the other side. 76420-712-01 (relabeled from NDC 67877-842-01) 100 tablets in 1 HDPE container round, white to off-white film-coated tablets, debossed with “V” on one side and “15” on the other side. 76420-713-30 (repackaged from NDC 67877-889-XX) 40 mg 30 tablets in 1 HDPE container round, white to off-white film-coated tablets, debossed with “V” on one side and “45” on the other side. 76420-713-60 (repackaged from NDC 67877-889-XX) 60 tablets in 1 HDPE container round, white to off-white film-coated tablets, debossed with “V” on one side and “45” on the other side. 76420-713-90 (repackaged from NDC 67877-889-XX) 90 tablets in 1 HDPE container round, white to off-white film-coated tablets, debossed with “V” on one side and “45” on the other side. 76420-713-01 (repackaged from NDC 67877-889-01) 100 tablets in 1 HDPE container round, white to off-white film-coated tablets, debossed with “V” on one side and “45” on the other side. Storage Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) (See USP Controlled Room Temperature). Dispense in a USP tight, light-resistant container.