Famotidine

1 INDICATIONS AND USAGE Famotidine Injection is indicated for use in hospitalized adults, or as an alternative to oral famotidine 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 endoscopy. treatment of pathological hypersecretory conditions (e.g., Zollinger-Ellison syndrome, multiple endocrine neoplasias). reduction of the risk of duodenal ulcer recurrence. FAMOTIDINE Injection is a histamine-2 (H 2 ) receptor antagonist indicated: In hospitalized adults, or as an alternative to oral famotidine 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 endoscopy. treatment of pathological hypersecretory conditions (e.g., Zollinger-Ellison syndrome, multiple endocrine neoplasias). reduction of the risk of DU recurrence. In hospitalized pediatric patients 1 year of age and older, or as an alternative to oral famotidine in pediatric patients 1 year of age and older, for the treatment of: peptic ulcer disease. Pediatric Patients 1 Year of Age and Older Famotidine Injection is indicated in hospitalized pediatric patients 1 year of age and older, or as an alternative to oral famotidine in pediatric patients 1 year of age and older, for the treatment of peptic ulcer disease.

2 DOSAGE AND ADMINISTRATION Administration Information ( 2.1 ) Famotidine Injection is intended for use in adult and pediatric hospitalized patients, or as an alternative to oral famotidine. Discontinue as soon as the patient is able to tolerate oral treatment and switch to an appropriate oral medication. Recommended Dosage ( 2.2 ) Adults: 20 mg every 12 hours. For pathological hypersecretory conditions titrate the dosage to individual patient needs. Pediatric Patients 1 year of age and older: 0.25 mg/kg every 12 hours; titrate to a maximum of 0.5 mg/kg every 12 hours (up to maximum of 20 mg every 12 hours) based on clinical response and/or gastric pH determination and endoscopy. Administer as an intravenous injection over at least 2 minutes or an intravenous infusion over 15 minutes to 30 minutes. Refer to the prescribing information for oral famotidine products for the recommended duration of famotidine treatment. Renal Impairment ( 2.3 ) See the full prescribing information for the recommended dosage for adult patients with moderate or severe renal impairment. 2.1 Important Administration Information Famotidine Injection is intended for use in adult and pediatric hospitalized patients, or as an alternative to oral famotidine. Discontinue Famotidine Injection as soon as the patient is able to tolerate oral treatment and switch to an appropriate oral medication. 2.2 Recommended Dosage in Adults and Pediatric Patients 1 Year of Age and Older The recommended dosage of Famotidine Injection in adults and pediatric patients 1 year of age and older is shown in Tables 1 and 2 , respectively. Administer Famotidine Injection as an intravenous injection over at least 2 minutes or as an intravenous infusion over 15 minutes to 30 minutes [see Dosage and Administration ( 2.4 )]. Refer to the prescribing information for oral famotidine products for the recommended duration of famotidine treatment. Table 1. Recommended Dosage 1 of Famotidine Injection in Adults 1 Refer to the prescribing information for oral famotidine products for the recommended duration of famotidine treatment. Indication Recommended Dosage Active Duodenal Ulcer 20 mg every 12 hours Active Gastric Ulcer Symptomatic Nonerosive GERD Erosive Esophagitis Diagnosed by Endoscopy Reduction of the Risk of Duodenal Ulcer Recurrence Pathological Hypersecretory Conditions Starting dosage is 20 mg every 12 hours; titrate the dosage to individual patient needs Table 2. Recommended Dosage 1 of Famotidine Injection in Pediatric Patients 1 Year of Age and Older 1 Refer to the prescribing information for oral famotidine products for the recommended duration of famotidine treatment. Indication Recommended Dosage Peptic Ulcer Disease 0.25 mg/kg every 12 hours (maximum 20 mg every 12 hours) Titrate to a maximum dosage of 0.5 mg/kg every 12 hours (maximum of 20 mg every 12 hours) based on clinical response and/or gastric pH determination and endoscopy. 2.3 Recommended Dosage in Patients with Renal Impairment Adults The recommended dosage for adult patients with moderate to severe renal impairment is shown in Table 3 . Administer Famotidine Injection as an intravenous injection over at least 2 minutes or as an intravenous infusion over 15 minutes to 30 minutes [see Dosage and Administration ( 2.4 )]. Table 3. Recommended Dosage 1 of Famotidine Injection in Adults with Renal Impairment 1 Refer to the prescribing information for oral famotidine products for the recommended duration of famotidine treatment. 2 The dosage required to treat pathological hypersecretory conditions may exceed the maximum doses evaluated in patients with impaired renal function. The risk for increased adverse reactions in renally impaired patients treated with Famotidine Injection for pathological hypersecretory conditions is unknown. Indication Recommended Dosage Creatinine Clearance 30 to 60 mL/minute Creatinine Clearance less than 30 mL/minute Active Duodenal Ulcer 20 mg once daily 10 mg once daily Active Gastric Ul…

5 WARNINGS AND PRECAUTIONS Central Nervous System (CNS) Adverse Reactions : Reported in elderly patients and patients with moderate and severe renal impairment; monitor elderly patients for CNS adverse reactions. ( 5.1 , 8.5 , 8.6 ) Concurrent GI Malignancy : Absence of GI symptoms does not preclude the presence of gastric malignancy; evaluate prior to initiating therapy. ( 5.2 ) Risk of Benzyl Alcohol Toxicity in Neonates : Famotidine Injection is not approved in neonates. Serious and fatal adverse reactions have been reported in low-birth weight and preterm neonates who received benzyl-alcohol-containing drugs intravenously. The minimum amount of benzyl alcohol at which these serious adverse reactions may occur is not known. ( 5.3 ) 5.1 Central Nervous System Adverse Reactions Central nervous system (CNS) adverse reactions, including confusion, delirium, hallucinations, disorientation, agitation, seizures, and lethargy, have been reported in elderly patients and patients with moderate and severe renal impairment treated with famotidine. Monitor elderly patients for CNS adverse reactions [see Use in Specific Populations ( 8.5 )] . Dosage adjustments are recommended in adult patients with moderate and severe renal impairment due to higher famotidine systemic exposure compared to patients with normal renal function [see Dosage and Administration ( 2.3 ), Use in Specific Populations ( 8.6 ), and Clinical Pharmacology ( 12.3 )]. 5.2 Concurrent Gastric Malignancy In adults, symptomatic response to therapy with Famotidine Injection does not preclude the presence of gastric malignancy. Consider evaluation for gastric malignancy in adult patients who have a suboptimal response or an early symptomatic relapse after completing treatment with Famotidine Injection. 5.3 Risk of Benzyl Alcohol Toxicity in Neonates Famotidine Injection is not approved in neonates. Serious adverse reactions, including fatal reactions, of new onset or worsening metabolic acidosis that progressed to neurotoxicity, and in some cases gasping syndrome, have been reported in low-birth weight neonates (less than 2,500 grams) and preterm neonates (gestational age less than 34 weeks) who received benzyl alcohol (BA)-containing drugs intravenously. Gasping syndrome is a life-threatening condition in neonates caused by BA toxicity and is primarily characterized by multiorgan dysfunction secondary to metabolic acidosis, which leads to gasping respirations and death. The minimum amount of BA at which these serious adverse reactions, including fatal reactions, may occur is not known (Famotidine Injection contains 3.6 mg of BA per mL) [see Use in Specific Populations ( 8.4 )] .

4 CONTRAINDICATIONS Famotidine Injection is contraindicated in patients with a history of serious hypersensitivity reactions (e.g., anaphylaxis) to famotidine or other H 2 -receptor antagonists. History of serious hypersensitivity reactions (e.g., anaphylaxis) to famotidine or other H 2 -receptor antagonists. ( 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 the prescribing information for other drugs dependent on gastric pH for absorption. ( 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. See the prescribing information for other drugs dependent on gastric pH for absorption. 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 Injection. If concomitant use is necessary, monitor for hypotension, bradycardia or excessive drowsiness. Refer to the full prescribing information for tizanidine.

8.1 Pregnancy Risk Summary Available data with H 2 -receptor antagonists, including famotidine, in pregnant women over decades of use have not identified a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Reproductive studies have been performed in rats and rabbits at intravenous doses of up to 200 mg/kg/day, with no obvious adverse developmental effects (see Data ) . Famotidine Injection contains benzyl alcohol as a preservative [see How Supplied/Storage and Handling ( 16 )] . Because benzyl alcohol is rapidly metabolized by a pregnant female, benzyl alcohol exposure in the fetus is unlikely. The 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 2,000 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.

6 ADVERSE REACTIONS Most common adverse reactions (>1%) are: headache, dizziness, constipation, and diarrhea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Sagent Pharmaceuticals at 1-866-625-1618 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials 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 Injection has been established based on adequate and well-controlled studies of an oral famotidine product. 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. A total of 1,442 patients were treated with oral 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 White. Adverse reactions reported in ≥1% of patients treated with oral famotidine in clinical trials were: headache, dizziness, constipation, and diarrhea. The following other adverse reactions were reported in less than 1% of patients treated with oral famotidine in clinical trials: Body as a Whole : fever, asthenia, fatigue Cardiovascular : palpitations Gastrointestinal : cholestatic jaundice, 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 Respiratory : interstitial pneumonia Skin : pruritus, dry skin, flushing Special Senses : tinnitus, taste disorder Other : impotence Adverse reactions reported with oral famotidine may also occur with Famotidine Injection. In addition, transient irritation at the injection site was reported with intravenous famotidine. 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