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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.

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 clinical trials [see Clinical Studies (14.4) ]. 20 mg once daily; or 40 mg every other day 20 mg every other day 40 mg once daily 20 mg once daily 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) ] . Avoid use Doses 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 PEPCID for pathological hypersecretory conditions is unknown. Reduction of the risk of DU recurrence 20 mg every other day (see footnote) Recommended dosage regimen is 10 mg every other day. Since 20 mg or 40 mg tablet strength cannot be used for this dosage regimen, use an alternate famotidine formulation 2.3 Administration Instructions • PEPCID once daily before bedtime or twice daily in the morning and before bedtime, as recommended. • PEPCID may be taken with or without food [see Clinical Pharmacology (12.3) ]. • PEPCID may be given with antacids.

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)

5 WARNINGS AND PRECAUTIONS • Central Nervous System (CNS) Adverse Reactions: Elderly patients and patients with renal impairment at increased risk; reduce the dosage. ( 2.2 , 5.1 , 8.5 , 8.6 ) • GI Malignancy: Absence of GI symptoms does not preclude the presence of gastric malignancy; evaluate prior to initiating therapy. ( 5.2 ) 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 PEPCID. Since famotidine blood levels are higher in patients with renal impairment than in patients with normal renal function, dosage adjustments are recommended in patients with renal impairment [see Dosage and Administration (2.2), Clinical Pharmacology (12.3)]. 5.2 Concurrent Gastric Malignancy In adults, symptomatic response to therapy with PEPCID 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 PEPCID.

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)].

he 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 overall differences in safety or effectiveness were observed between elderly and younger patients. In postmarketing experience, CNS adverse reactions have been reported in elderly patients with and without renal impairment receiving PEPCID [see Warnings and Precautions (5.1)]. Famotidine is known to be substantially excreted by the kidney, and the risk of adverse reactions to PEPCID may be greater in elderly patients, particularly those with impaired renal function [see Use in Specific Populations (8.6)]. In general, use the lowest effective dose of PEPCID for an elderly patient and monitor renal function [see Dosage and Administration (2.2)]. 8.6 Renal Impairment CNS adverse reactions and prolonged QT intervals have been reported in patients with moderate and severe renal impairment [see Warnings and Precautions (5.1)] . The clearance of famotidine is reduced in adults with moderate and severe renal impairment compared to adults with normal renal function [see Clinical Pharmacology (12.3)]. No dosage adjustment is needed in patients with mild renal impairment (creatinine clearance greater than or equal to 60 mL/minute). Dosage reduction is recommended in adult and pediatric patients greater than or equal to 40 kg with moderate or severe renal impairment (creatinine clearance less than 60 mL/minute) [see Dosage and Administration (2.2)].

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.

8.4 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 overall differences in safety or effectiveness were observed between elderly and younger patients. In postmarketing experience, CNS adverse reactions have been reported in elderly patients with and without renal impairment receiving PEPCID [see Warnings and Precautions (5.1)]. Famotidine is known to be substantially excreted by the kidney, and the risk of adverse reactions to PEPCID may be greater in elderly patients, particularly those with impaired renal function [see Use in Specific Populations (8.6)]. In general, use the lowest effective dose of PEPCID for an elderly patient and monitor renal function [see Dosage and Administration (2.2)].

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.

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

12 CLINICAL PHARMACOLOGY 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. 12.2 Pharmacodynamics Adults PEPCID inhibited both basal and nocturnal gastric secretion, as well as secretion stimulated by food and pentagastrin. After oral administration of PEPCID, the onset of the antisecretory effect occurred within one hour; the maximum effect was dose-dependent, occurring within one to three hours. Duration of inhibition of secretion by doses of 20 mg and 40 mg was 10 to 12 hours. Single evening oral doses of 20 mg and 40 mg inhibited basal and nocturnal acid secretion in all subjects; mean nocturnal gastric acid secretion was inhibited by 86% and 94%, respectively, for a period of at least 10 hours. The same doses given in the morning suppressed food-stimulated acid secretion in all subjects. The mean suppression was 76% and 84%, respectively, 3 to 5 hours after administration, and 25% and 30%, respectively, 8 to 10 hours after administration. In some subjects who received the 20 mg dose, however, the antisecretory effect was dissipated within 6 to 8 hours. There was no cumulative effect with repeated doses. The nocturnal intragastric pH was raised by evening doses of 20 mg and 40 mg of PEPCID to mean values of 5.0 and 6.4, respectively. When PEPCID was given after breakfast, the basal daytime interdigestive pH at 3 and 8 hours after 20 mg or 40 mg of PEPCID was raised to about 5. PEPCID had little or no effect on fasting or postprandial serum gastrin levels. Gastric emptying and exocrine pancreatic function were not affected by PEPCID. In clinical pharmacology studies, systemic effects of PEPCID in the CNS, cardiovascular, respiratory or endocrine systems were not noted. Also, no anti-androgenic effects were noted. Serum hormone levels, including prolactin, cortisol, thyroxine (T4), and testosterone, were not altered after treatment with PEPCID. Pediatric Patients Pharmacodynamics of famotidine, assessed by gastric pH, were evaluated in 5 pediatric patients 2 to 13 years of age using the sigmoid Emax model. These data suggest that the relationship between serum concentration of famotidine and gastric acid suppression is similar to that observed in adults (see Table 3). Table 3: Serum Concentrations of Famotidine Associated with Gastric Acid Reduction in PEPCID-Treated Pediatric and Adult Patients Using the Sigmoid E max model, serum concentrations of famotidine associated with 50% maximum gastric acid reduction are presented as means ± SD. EC 50 (ng/mL)a Pediatric Patients 26 ± 13 Adults Healthy adult subjects 26.5 ± 10.3 Adult patients with upper GI bleeding 18.7 ± 10.8 In a study examining the effect of famotidine on gastric pH and duration of acid suppression in pediatric patients, four pediatric patients ages 11 to 15 years of age using the oral formulation at a dose of 0.5 mg/kg, maintained a gastric pH above 5 for 13.5 ± 1.8 hours. 12.3 Pharmacokinetics Absorption Famotidine is incompletely absorbed. The bioavailability of oral doses is 40 to 45%. Bioavailability may be slightly increased by food, or slightly decreased by antacids; however, these effects are of no clinical consequence.

mg/kg, maintained a gastric pH above 5 for 13.5 ± 1.8 hours. 12.3 Pharmacokinetics Absorption Famotidine is incompletely absorbed. The bioavailability of oral doses is 40 to 45%. Bioavailability may be slightly increased by food, or slightly decreased by antacids; however, these effects are of no clinical consequence. Peak famotidine plasma levels occur in 1 to 3 hours. Plasma levels after multiple dosages are similar to those after single doses. Distribution Fifteen to 20% of famotidine in plasma is protein bound. Elimination Metabolism Famotidine undergoes minimal first-pass metabolism. Twenty-five to 30% of an oral dose was recovered in the urine as unchanged compound. The only metabolite identified in humans is the S-oxide. Excretion Famotidine has an elimination half-life of 2.5-3.5 hours. Famotidine is eliminated by renal (65 to 70%) and metabolic (30 to 35%) routes. Renal clearance is 250 to 450 mL/minute, indicating some tubular excretion. Specific Populations Pediatric Patients Bioavailability studies of 8 pediatric patients (11 to 15 years of age) showed a mean oral bioavailability of 0.5 compared to adult values of 0.42 to 0.49. Oral doses of 0.5 mg per kg achieved AUCs of 580 ± 60 ng•hr/mL in pediatric patients 11 to 15 years of age, compared to 482 ± 181 ng•hr/mL in adults treated with 40 mg orally. Patients with Renal Impairment In adult patients with severe renal impairment (creatinine clearance less than 30 mL/minute), the systemic exposure (AUC) of famotidine increased at least 5-fold. In patients with moderate renal impairment (creatinine clearance between 30 to 60 mL/minute), the AUC of famotidine increased at least 2-fold [see Dosage and Administration (2.2), Use in Specific Populations (8.6)]. Drug Interaction Studies Human Organic Anion Transporter (OAT) 1 and 3: In vitro studies indicate that famotidine is a substrate for OAT1 and OAT3. Following coadministration of probenecid (1500 mg), an inhibitor of OAT1 and OAT3, with a single oral 20 mg dose of famotidine in 8 healthy subjects, the serum AUC0-10h of famotidine increased from 424 to 768 ng•hr/mL and the maximum serum concentration (Cmax) increased from 73 to 113 ng/mL. Renal clearance, urinary excretion rate and amount of famotidine excreted unchanged in urine were decreased. The clinical relevance of this interaction is unknown. Multidrug and Toxin Extrusion Protein 1 (MATE-1): An in vitro study showed that famotidine is an inhibitor of MATE-1. However, no clinically significant interaction with metformin, a substrate for MATE-1, was observed. CYP1A2: Famotidine is a weak CYP1A2 inhibitor.

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.

12.2 Pharmacodynamics Adults PEPCID inhibited both basal and nocturnal gastric secretion, as well as secretion stimulated by food and pentagastrin. After oral administration of PEPCID, the onset of the antisecretory effect occurred within one hour; the maximum effect was dose-dependent, occurring within one to three hours. Duration of inhibition of secretion by doses of 20 mg and 40 mg was 10 to 12 hours. Single evening oral doses of 20 mg and 40 mg inhibited basal and nocturnal acid secretion in all subjects; mean nocturnal gastric acid secretion was inhibited by 86% and 94%, respectively, for a period of at least 10 hours. The same doses given in the morning suppressed food-stimulated acid secretion in all subjects. The mean suppression was 76% and 84%, respectively, 3 to 5 hours after administration, and 25% and 30%, respectively, 8 to 10 hours after administration. In some subjects who received the 20 mg dose, however, the antisecretory effect was dissipated within 6 to 8 hours. There was no cumulative effect with repeated doses. The nocturnal intragastric pH was raised by evening doses of 20 mg and 40 mg of PEPCID to mean values of 5.0 and 6.4, respectively. When PEPCID was given after breakfast, the basal daytime interdigestive pH at 3 and 8 hours after 20 mg or 40 mg of PEPCID was raised to about 5. PEPCID had little or no effect on fasting or postprandial serum gastrin levels. Gastric emptying and exocrine pancreatic function were not affected by PEPCID. In clinical pharmacology studies, systemic effects of PEPCID in the CNS, cardiovascular, respiratory or endocrine systems were not noted. Also, no anti-androgenic effects were noted. Serum hormone levels, including prolactin, cortisol, thyroxine (T4), and testosterone, were not altered after treatment with PEPCID. Pediatric Patients Pharmacodynamics of famotidine, assessed by gastric pH, were evaluated in 5 pediatric patients 2 to 13 years of age using the sigmoid Emax model. These data suggest that the relationship between serum concentration of famotidine and gastric acid suppression is similar to that observed in adults (see Table 3). Table 3: Serum Concentrations of Famotidine Associated with Gastric Acid Reduction in PEPCID-Treated Pediatric and Adult Patients Using the Sigmoid E max model, serum concentrations of famotidine associated with 50% maximum gastric acid reduction are presented as means ± SD. EC 50 (ng/mL)a Pediatric Patients 26 ± 13 Adults Healthy adult subjects 26.5 ± 10.3 Adult patients with upper GI bleeding 18.7 ± 10.8 In a study examining the effect of famotidine on gastric pH and duration of acid suppression in pediatric patients, four pediatric patients ages 11 to 15 years of age using the oral formulation at a dose of 0.5 mg/kg, maintained a gastric pH above 5 for 13.5 ± 1.8 hours.

<table ID="_RefID0EK1AE" width="100%"><caption>Table 3: Serum Concentrations of Famotidine Associated with Gastric Acid Reduction in PEPCID-Treated Pediatric and Adult Patients<footnote ID="_Ref22287567">Using the Sigmoid E_maxmodel, serum concentrations of famotidine associated with 50% maximum gastric acid reduction are presented as means &#xB1; SD.</footnote></caption><col width="50%"/><col width="50%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"/><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>EC₅₀(ng/mL)a</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Pediatric Patients</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>26 &#xB1; 13</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Adults</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Healthy adult subjects</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>26.5 &#xB1; 10.3 </paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph> Adult patients with upper GI bleeding</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>18.7 &#xB1; 10.8</paragraph></td></tr></tbody></table>

12.3 Pharmacokinetics Absorption Famotidine is incompletely absorbed. The bioavailability of oral doses is 40 to 45%. Bioavailability may be slightly increased by food, or slightly decreased by antacids; however, these effects are of no clinical consequence. Peak famotidine plasma levels occur in 1 to 3 hours. Plasma levels after multiple dosages are similar to those after single doses. Distribution Fifteen to 20% of famotidine in plasma is protein bound. Elimination Metabolism Famotidine undergoes minimal first-pass metabolism. Twenty-five to 30% of an oral dose was recovered in the urine as unchanged compound. The only metabolite identified in humans is the S-oxide. Excretion Famotidine has an elimination half-life of 2.5-3.5 hours. Famotidine is eliminated by renal (65 to 70%) and metabolic (30 to 35%) routes. Renal clearance is 250 to 450 mL/minute, indicating some tubular excretion. Specific Populations Pediatric Patients Bioavailability studies of 8 pediatric patients (11 to 15 years of age) showed a mean oral bioavailability of 0.5 compared to adult values of 0.42 to 0.49. Oral doses of 0.5 mg per kg achieved AUCs of 580 ± 60 ng•hr/mL in pediatric patients 11 to 15 years of age, compared to 482 ± 181 ng•hr/mL in adults treated with 40 mg orally. Patients with Renal Impairment In adult patients with severe renal impairment (creatinine clearance less than 30 mL/minute), the systemic exposure (AUC) of famotidine increased at least 5-fold. In patients with moderate renal impairment (creatinine clearance between 30 to 60 mL/minute), the AUC of famotidine increased at least 2-fold [see Dosage and Administration (2.2), Use in Specific Populations (8.6)]. Drug Interaction Studies Human Organic Anion Transporter (OAT) 1 and 3: In vitro studies indicate that famotidine is a substrate for OAT1 and OAT3. Following coadministration of probenecid (1500 mg), an inhibitor of OAT1 and OAT3, with a single oral 20 mg dose of famotidine in 8 healthy subjects, the serum AUC0-10h of famotidine increased from 424 to 768 ng•hr/mL and the maximum serum concentration (Cmax) increased from 73 to 113 ng/mL. Renal clearance, urinary excretion rate and amount of famotidine excreted unchanged in urine were decreased. The clinical relevance of this interaction is unknown. Multidrug and Toxin Extrusion Protein 1 (MATE-1): An in vitro study showed that famotidine is an inhibitor of MATE-1. However, no clinically significant interaction with metformin, a substrate for MATE-1, was observed. CYP1A2: Famotidine is a weak CYP1A2 inhibitor.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenic potential of famotidine was assessed in a 106-week oral carcinogenicity study in rats and a 92-week oral carcinogenicity study in mice. In the 106-week study in rats and the 92-week study in mice at oral doses of up to 2000 mg/kg/ day (approximately 243 and 122 times, respectively, based on body surface area, the recommended human dose of 80 mg per day for the treatment of erosive esophagitis), there was no evidence of carcinogenic potential for famotidine. Famotidine was negative in the microbial mutagen test (Ames test) using Salmonella typhimurium and Escherichia coli with or without rat liver enzyme activation at concentrations up to 10,000 mcg/plate. In in vivo studies in mice, with a micronucleus test and a chromosomal aberration test, no evidence of a mutagenic effect was observed. In studies with rats given oral doses of up to 2000 mg/kg/day (approximately 243 times, based on body surface area, the recommended human dose of 80 mg per day) fertility and reproductive performance were not affected.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenic potential of famotidine was assessed in a 106-week oral carcinogenicity study in rats and a 92-week oral carcinogenicity study in mice. In the 106-week study in rats and the 92-week study in mice at oral doses of up to 2000 mg/kg/ day (approximately 243 and 122 times, respectively, based on body surface area, the recommended human dose of 80 mg per day for the treatment of erosive esophagitis), there was no evidence of carcinogenic potential for famotidine. Famotidine was negative in the microbial mutagen test (Ames test) using Salmonella typhimurium and Escherichia coli with or without rat liver enzyme activation at concentrations up to 10,000 mcg/plate. In in vivo studies in mice, with a micronucleus test and a chromosomal aberration test, no evidence of a mutagenic effect was observed. In studies with rats given oral doses of up to 2000 mg/kg/day (approximately 243 times, based on body surface area, the recommended human dose of 80 mg per day) fertility and reproductive performance were not affected.

14 CLINICAL STUDIES 14.1 Active Duodenal Ulcer In a U.S. multicenter, double-blind trial in adult outpatients with endoscopically confirmed duodenal ulcer (DU), orally administered PEPCID was compared to placebo. As shown in Table 4, 70% of patients treated with PEPCID 40 mg at bedtime were healed by Week 4. Most patients’ DU healed within 4 weeks. Patients not healed by Week 4 were continued in the trial. By Week 8, 83% of patients treated with PEPCID had healed DU, compared to 45% of patients treated with placebo. The incidence of DU healing with PEPCID was greater than with placebo at each time point based on proportion of endoscopically confirmed healed DUs. Trials have not assessed the safety of PEPCID in uncomplicated active DU for periods of more than 8 weeks. Table 4: Patients with Endoscopically Confirmed Healed Duodenal Ulcers PEPCID 40 mg at bedtime (N=89) PEPCID 20 mg twice daily (N=84) Placebo at bedtime (N=97) Week 2 32% p<0.001 vs. placebo 38% 17% Week 4 70% 67% 31% In this study, time to relief of daytime and nocturnal pain was shorter for patients receiving PEPCID than for patients receiving placebo; patients receiving PEPCID also took less antacid than patients receiving placebo. 14.2 Active Gastric Ulcer In both a U.S. and an international multicenter, double-blind trials in patients with endoscopically confirmed active gastric ulcer (GU), orally administered PEPCID 40 mg at bedtime was compared to placebo. Antacids were permitted during the trials, but consumption was not significantly different between the PEPCID and placebo groups. As shown in Table 5, the incidence of GU healing confirmed by endoscopy (dropouts counted as unhealed) with PEPCID was greater than placebo at Weeks 6 and 8 in the U.S. trial, and at Weeks 4, 6 and 8 in the international trial. In these trials, most PEPCID-treated patients healed within 6 weeks. Trials have not assessed the safety of PEPCID in uncomplicated active GU for periods of more than 8 weeks. Table 5: Patients with Endoscopically Confirmed Healed Gastric Ulcers U.S. Study (N=149) International Study (N=294) PEPCID 40 mg at bedtime (N=74) Placebo at bedtime (N=75) PEPCID 40 mg at bedtime (N=149) Placebo at bedtime (N=145) Week 4 45% 39% 47% p≤0.01 vs. placebo 31% Week 6 66% 44% 65% 46% Week 8 78% p≤0.05 vs. placebo 64% 80% 54% Time to complete relief of daytime and nighttime pain was statistically significantly shorter for patients receiving PEPCID than for patients receiving placebo; however, neither trial demonstrated a statistically significant difference in the proportion of patients whose pain was relieved by the end of the trial (Week 8). 14.3 Symptomatic Gastroesophageal Reflux Disease (GERD) Orally administered PEPCID was compared to placebo in a U.S. trial that enrolled patients with symptoms of GERD and without endoscopic evidence of esophageal erosion or ulceration. As shown in Table 6, patients treated with PEPCID 20 mg twice daily had greater improvement in symptomatic GERD than patients treated with 40 mg at bedtime or placebo. Table 6: Patients with Improvement of Symptomatic GERD (N=376) PEPCID 20 mg twice daily (N=154) PEPCID 40 mg at bedtime (N=149) Placebo at bedtime (N=73) Week 6 82% p≤0.01 vs. placebo 69% 62% 14.4 Erosive Esophagitis due to GERD Healing of endoscopically verified erosion and symptomatic improvement were studied in a U.S. and an international double-blind trials. Healing was defined as complete resolution of all erosions visible with endoscopy.

Placebo at bedtime (N=73) Week 6 82% p≤0.01 vs. placebo 69% 62% 14.4 Erosive Esophagitis due to GERD Healing of endoscopically verified erosion and symptomatic improvement were studied in a U.S. and an international double-blind trials. Healing was defined as complete resolution of all erosions visible with endoscopy. The U.S. trial comparing orally-administered PEPCID 40 mg twice daily to placebo and orally administered PEPCID 20 mg twice daily showed a significantly greater percentage of healing of erosive esophagitis for PEPCID 40 mg twice daily at Weeks 6 and 12 (Table 7). Table 7: Patients with Endoscopic Healing of Erosive Esophagitis - U.S. Study (N=318) PEPCID 40 mg twice daily (N=127) PEPCID 20 mg twice daily (N=125) Placebo twice daily (N=66) Week 6 48% p≤0.01 vs. placebo ≤0.01 vs. PEPCID 20 mg twice daily 32% 18% Week 12 69% ≤0.05 vs. PEPCID 20 mg twice daily 54% 29% As compared to placebo, patients in the U.S. trial who received PEPCID had faster relief of daytime and nighttime heartburn, and a greater percentage of PEPCID-treated patients experienced complete relief of nighttime heartburn. These differences were statistically significant. In the international trial, when orally administered PEPCID 40 mg twice daily was compared to orally administered ranitidine 150 mg twice daily, a statistically significantly greater percentage of healing of erosive esophagitis was observed with PEPCID 40 mg twice daily at Week 12 (Table 8). There was, however, no significant difference in symptom relief among treatment groups. Table 8: Patients with Endoscopic Healing of Erosive Esophagitis International Study (N=440) PEPCID 40 mg twice daily (N=175) PEPCID 20 mg twice daily (N=93) Ranitidine 150 mg twice daily (N=172) Week 6 48% 52% 42% Week 12 71% p≤0.05 vs ranitidine 150 mg twice daily 68% 60% 14.5 Pathological Hypersecretory Conditions In trials of patients with pathological hypersecretory conditions such as Zollinger-Ellison syndrome with or without multiple endocrine neoplasias, PEPCID significantly inhibited gastric acid secretion and controlled associated symptoms. Orally administered PEPCID dosages from 20 mg to 160 mg every 6 hours maintained basal acid secretion below 10 mEq/hour; initial dosages were titrated to the individual patient need and subsequent adjustments were necessary with time in some patients. 14.6 Risk Reduction of Duodenal Ulcer Recurrence Two randomized, double-blind, multicenter trials in patients with endoscopically confirmed healed DUs demonstrated that patients receiving treatment with orally administered PEPCID 20 mg at bedtime had lower rates of DU recurrence, as compared with placebo. • In the U.S. trial, DU recurrence within 12 months was 2.4 times greater in patients treated with placebo than in the patients treated with PEPCID. The 89 PEPCID-treated patients had a cumulative observed DU recurrence rate of 23%, compared to a 57% in the 89 patients receiving placebo (p<0.01). • In the international trial, the cumulative observed DU recurrence within 12 months in the 307 PEPCID-treated patients was 36%, compared to 76% in the 325 patients who received placebo (p<0.01). Controlled trials have not extended beyond one year.

<table ID="_RefID0ERAAG" width="100%"><caption>Table 4: Patients with Endoscopically Confirmed Healed Duodenal Ulcers</caption><col width="25%"/><col width="25%"/><col width="25%"/><col width="25%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"/><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>PEPCID</paragraph><paragraph>40 mg at bedtime (N=89)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>PEPCID</paragraph><paragraph>20 mg twice daily (N=84)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>Placebo </paragraph><paragraph>at bedtime (N=97)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Week 2</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>32%<footnote ID="_Ref22288437">p&lt;0.001 vs. placebo</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>38%<footnoteRef IDREF="_Ref22288437"/></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>17%</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Week 4</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>70%<footnoteRef IDREF="_Ref22288437"/></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>67%<footnoteRef IDREF="_Ref22288437"/></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>31%</paragraph></td></tr></tbody></table>

"top"><paragraph>70%<footnoteRef IDREF="_Ref22288437"/></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>67%<footnoteRef IDREF="_Ref22288437"/></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>31%</paragraph></td></tr></tbody></table> <table ID="_RefID0EBEAG" width="100%"><caption>Table 5: Patients with Endoscopically Confirmed Healed Gastric Ulcers</caption><col width="20%"/><col width="20%"/><col width="20%"/><col width="20%"/><col width="20%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"/><td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>U.S. Study (N=149)</paragraph></td><td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>International Study (N=294)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"/><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>PEPCID</paragraph><paragraph>40 mg at bedtime (N=74)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Placebo </paragraph><paragraph>at bedtime (N=75)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>PEPCID</paragraph><paragraph>40 mg at bedtime (N=149)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Placebo </paragraph><paragraph>at bedtime (N=145)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Week 4</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>45%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>39%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>47%<footnote ID="_Ref22288921">p&#x2264;0.01 vs. placebo</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>31%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Week 6</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>66%<footnoteRef IDREF="_Ref22288921"/></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>44%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>65%<footnoteRef IDREF="_Ref22288921"/></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>46%</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Week 8</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>78%<footnote ID="_Ref172719327">p&#x2264;0.05 vs. placebo</footnote></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>64%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>80%<footnoteRef IDREF="_Ref22288921"/></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>54%</paragraph></td></tr></tbody></table>

Code="Rrule Botrule Lrule " valign="top"><paragraph>64%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>80%<footnoteRef IDREF="_Ref22288921"/></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>54%</paragraph></td></tr></tbody></table> <table ID="_RefID0EFJAG" width="100%"><caption>Table 6: Patients with Improvement of Symptomatic GERD (N=376)</caption><col width="25%"/><col width="25%"/><col width="25%"/><col width="25%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"/><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>PEPCID </paragraph><paragraph>20 mg twice daily (N=154)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>PEPCID </paragraph><paragraph>40 mg at bedtime (N=149)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>Placebo </paragraph><paragraph>at bedtime (N=73)</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Week 6 </paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>82%<footnote ID="_Ref172726739">p&#x2264;0.01 vs. placebo</footnote></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>69%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>62%</paragraph></td></tr></tbody></table>

lign="top"><paragraph>82%<footnote ID="_Ref172726739">p&#x2264;0.01 vs. placebo</footnote></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>69%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>62%</paragraph></td></tr></tbody></table> <table ID="_RefID0EKLAG" width="100%"><caption>Table 7: Patients with Endoscopic Healing of Erosive Esophagitis - U.S. Study (N=318)</caption><col width="25%"/><col width="25%"/><col width="25%"/><col width="25%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"/><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>PEPCID</paragraph><paragraph>40 mg twice daily (N=127)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>PEPCID</paragraph><paragraph>20 mg twice daily (N=125)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>Placebo</paragraph><paragraph>twice daily (N=66)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Week 6</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>48%<footnote ID="_Ref173321766">p&#x2264;0.01 vs. placebo</footnote><footnote ID="_Ref173321773">&#x2264;0.01 vs. PEPCID 20 mg twice daily</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>32%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>18%</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Week 12</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>69%<footnoteRef IDREF="_Ref173321766"/><footnote ID="_Ref173321788">&#x2264;0.05 vs. PEPCID 20 mg twice daily</footnote></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>54%<footnoteRef IDREF="_Ref173321766"/></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>29%</paragraph></td></tr></tbody></table>

">&#x2264;0.05 vs. PEPCID 20 mg twice daily</footnote></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>54%<footnoteRef IDREF="_Ref173321766"/></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>29%</paragraph></td></tr></tbody></table> <table ID="_RefID0EDOAG" width="100%"><caption>Table 8: Patients with Endoscopic Healing of Erosive Esophagitis International Study (N=440)</caption><col width="25%"/><col width="25%"/><col width="25%"/><col width="25%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"/><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>PEPCID</paragraph><paragraph>40 mg twice daily (N=175)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>PEPCID</paragraph><paragraph>20 mg twice daily (N=93)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>Ranitidine</paragraph><paragraph>150 mg twice daily (N=172)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Week 6</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>48%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>52%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>42%</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Week 12</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>71%<footnote ID="_Ref22289632">p&#x2264;0.05 vs ranitidine 150 mg twice daily</footnote></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>68%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>60%</paragraph></td></tr></tbody></table>

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.

<table width="100%"><col width="25%"/><col width="25%"/><col width="25%"/><col width="25%"/><tbody><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">NDC</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Strength</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Quantity</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Description</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0187-4420-30</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>20 mg</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>unit of use bottles of 30</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>round, white to off-white film-coated tablets coded with MP 973 on one side and the other side plain</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0187-4420-10</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>20 mg</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>unit of use bottles of 100</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>round, white to off-white film-coated tablets coded with MP 973 on one side and the other side plain</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0187-4440-30</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>40 mg</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>unit of use bottles of 30</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>round, white to off-white film-coated tablets coded with MP 974 on one side and the other side plain</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>0187-4440-10</paragraph></td><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>40 mg</paragraph></td><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>unit of use bottles of 100</paragraph></td><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>round, white to off-white film-coated tablets coded with MP 974 on one side and the other side plain</paragraph></td></tr></tbody></table>

17 PATIENT COUNSELING INFORMATION Central Nervous System (CNS) Adverse Reactions Advise elderly patients and those with moderate and severe renal impairment of the risk of CNS adverse reactions, including confusion, delirium, hallucinations, disorientation, agitation, seizures, and lethargy [see Warnings and Precautions (5.1)] . Report symptoms immediately to a healthcare provider. QT Prolongation Advise patients with moderate and severe renal impairment of the risk of QT interval prolongation [see Use in Specific Populations (8.6)] . Report new cardiac symptoms, such as palpitations, fainting and dizziness or lightheadedness immediately to a healthcare provider. Administration Advise patients: • Take PEPCID once daily before bedtime or twice daily in the morning and before bedtime, as recommended. • PEPCID may be taken with or without food. • PEPCID may be given with antacids. Distributed by: Bausch Health US, LLC Bridgewater, NJ 08807 USA Manufactured by: Carlsbad Technology, Inc. Carlsbad, CA 92008 The trademark PEPCID is used under license. © 2024 Bausch Health Companies Inc. or its affiliates M97201

DESCRIPTION The active ingredient in Famotidine Injection, USP is a histamine H 2 -receptor antagonist. Famotidine is [1-Amino-3-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio] propylidene] sulfamide. Its structural formula is: C 8 H 15 N 7 O 2 S 3 MW 337.45 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. Famotidine Injection is supplied as a sterile concentrated solution for intravenous injection. Each mL of the single-dose solution contains 10 mg of famotidine and the following inactive ingredients: L-aspartic acid 4 mg, mannitol 20 mg, and Water for Injection q.s. 1 mL. The multi-dose solution also contains benzyl alcohol 0.9% added as preservative. Structural Formula

<table width="100%" styleCode="Noautorules"><col width="50.000%" align="left"/><col width="50.000%" align="left"/><tbody><tr><td colspan="2" align="center" valign="top"><renderMultiMedia ID="f01" referencedObject="mm01"/></td></tr><tr><td align="right" valign="top">C ₈H ₁₅N ₇O ₂S ₃ </td><td align="left" valign="top"> MW 337.45</td></tr></tbody></table>

CLINICAL PHARMACOLOGY IN ADULTS GI Effects Famotidine is a competitive inhibitor of histamine 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. In normal volunteers and hypersecretors, famotidine inhibited basal and nocturnal gastric secretion, as well as secretion stimulated by food and pentagastrin. After oral administration, the onset of the antisecretory effect occurred within one hour; the maximum effect was dose-dependent, occurring within one to three hours. Duration of inhibition of secretion by doses of 20 and 40 mg was 10 to 12 hours. After intravenous administration, the maximum effect was achieved within 30 minutes. Single intravenous doses of 10 and 20 mg inhibited nocturnal secretion for a period of 10 to 12 hours. The 20 mg dose was associated with the longest duration of action in most subjects. Single evening oral doses of 20 and 40 mg inhibited basal and nocturnal acid secretion in all subjects; mean nocturnal gastric acid secretion was inhibited by 86% and 94%, respectively, for a period of at least 10 hours. The same doses given in the morning suppressed food-stimulated acid secretion in all subjects. The mean suppression was 76% and 84%, respectively, 3 to 5 hours after administration, and 25% and 30%, respectively, 8 to 10 hours after administration. In some subjects who received the 20 mg dose, however, the antisecretory effect was dissipated within 6 to 8 hours. There was no cumulative effect with repeated doses. The nocturnal intragastric pH was raised by evening doses of 20 and 40 mg of famotidine to mean values of 5.0 and 6.4, respectively. When famotidine was given after breakfast, the basal daytime interdigestive pH at 3 and 8 hours after 20 or 40 mg of famotidine was raised to about 5. Famotidine had little or no effect on fasting or postprandial serum gastrin levels. Gastric emptying and exocrine pancreatic function were not affected by famotidine. Other Effects Systemic effects of famotidine in the CNS, cardiovascular, respiratory or endocrine systems were not noted in clinical pharmacology studies. Also, no antiandrogenic effects were noted (see ADVERSE REACTIONS ). Serum hormone levels, including prolactin, cortisol, thyroxine (T 4 ), and testosterone, were not altered after treatment with famotidine. Pharmacokinetics Orally administered famotidine is incompletely absorbed, and its bioavailability is 40 to 45%. Famotidine undergoes minimal first-pass metabolism. After oral doses, peak plasma levels occur in 1 to 3 hours. Plasma levels after multiple doses are similar to those after single doses. Fifteen to 20% of famotidine in plasma is protein bound. Famotidine has an elimination half-life of 2.5 to 3.5 hours. Famotidine is eliminated by renal (65 to 70%) and metabolic (30 to 35%) routes. Renal clearance is 250 to 450 mL/min, indicating some tubular excretion. Twenty-five to 30% of an oral dose and 65 to 70% of an intravenous dose are recovered in the urine as unchanged compound. The only metabolite identified in man is the S-oxide. There is a close relationship between creatinine clearance values and the elimination half-life of famotidine.

ndicating some tubular excretion. Twenty-five to 30% of an oral dose and 65 to 70% of an intravenous dose are recovered in the urine as unchanged compound. The only metabolite identified in man is the S-oxide. There is a close relationship between creatinine clearance values and the elimination half-life of famotidine. In patients with severe renal insufficiency, i.e., creatinine clearance less than 10 mL/min, the elimination half-life of famotidine may exceed 20 hours and adjustment of dose or dosing intervals in moderate and severe renal insufficiency may be necessary (see PRECAUTIONS , DOSAGE AND ADMINISTRATION ). In elderly patients, there are no clinically significant age-related changes in the pharmacokinetics of famotidine. However, in elderly patients with decreased renal function, the clearance of the drug may be decreased (see PRECAUTIONS, Geriatric Use ). Clinical Studies The majority of clinical study experience involved oral administration of famotidine tablets, and is provided herein for reference. Duodenal Ulcer In a U.S. multicenter, double-blind study in outpatients with endoscopically confirmed duodenal ulcer, orally administered famotidine was compared to placebo. As shown in Table 1 , 70% of patients treated with famotidine 40 mg h.s. were healed by week 4. Table 1: Outpatients with Endoscopically Confirmed Healed Duodenal Ulcers * Statistically significantly different than placebo (p<0.001) Famotidine 40 mg h.s. (N=89) Famotidine 20 mg b.i.d. (N=84) Placebo h.s. (N=97) Week 2 *32% *38% 17% Week 4 *70% *67% 31% Patients not healed by week 4 were continued in the study. By week 8, 83% of patients treated with famotidine had healed versus 45% of patients treated with placebo. The incidence of ulcer healing with famotidine was significantly higher than with placebo at each time point based on proportion of endoscopically confirmed healed ulcers. In this study, time to relief of daytime and nocturnal pain was significantly shorter for patients receiving famotidine than for patients receiving placebo; patients receiving famotidine also took less antacid than the patients receiving placebo. Long-Term Maintenance Treatment of Duodenal Ulcers Famotidine, 20 mg p.o. h.s. was compared to placebo h.s. as maintenance therapy in two double-blind, multicenter studies of patients with endoscopically confirmed healed duodenal ulcers. In the U.S. study the observed ulcer incidence within 12 months in patients treated with placebo was 2.4 times greater than in the patients treated with famotidine. The 89 patients treated with famotidine had a cumulative observed ulcer incidence of 23.4% compared to an observed ulcer incidence of 56.6% in the 89 patients receiving placebo (p<0.01). These results were confirmed in an international study where the cumulative observed ulcer incidence within 12 months in the 307 patients treated with famotidine was 35.7%, compared to an incidence of 75.5% in the 325 patients treated with placebo (p<0.01). Gastric Ulcer In both a U.S. and an international multicenter, double-blind study in patients with endoscopically confirmed active benign gastric ulcer, orally administered famotidine, 40 mg h.s., was compared to placebo h.s. Antacids were permitted during the studies, but consumption was not significantly different between the famotidine and placebo groups. As shown in Table 2 , the incidence of ulcer healing (dropouts counted as unhealed) with famotidine was statistically significantly better than placebo at weeks 6 and 8 in the U.S. study, and at weeks 4, 6 and 8 in the international study, based on the number of ulcers that healed, confirmed by endoscopy. Table 2: Patients with Endoscopically Confirmed Healed Gastric Ulcers **,*** Statistically significantly better than placebo (p≤0.05, p≤0.01, respectively) U.S.

cebo at weeks 6 and 8 in the U.S. study, and at weeks 4, 6 and 8 in the international study, based on the number of ulcers that healed, confirmed by endoscopy. Table 2: Patients with Endoscopically Confirmed Healed Gastric Ulcers **,*** Statistically significantly better than placebo (p≤0.05, p≤0.01, respectively) U.S. Study International Study Famotidine 40 mg h.s. (N=74) Placebo h.s. (N=75) Famotidine 40 mg h.s. (N=149) Placebo h.s. (N=145) Week 4 45% 39% ***47% 31% Week 6 ***66% 44% ***65% 46% Week 8 **78% 64% ***80% 54% Time to complete relief of daytime and nighttime pain was statistically significantly shorter for patients receiving famotidine than for patients receiving placebo; however, in neither study was there a statistically significant difference in the proportion of patients whose pain was relieved by the end of the study (week 8). Gastroesophageal Reflux Disease (GERD) Orally administered famotidine was compared to placebo in a U.S. study that enrolled patients with symptoms of GERD and without endoscopic evidence of erosion or ulceration of the esophagus. Famotidine 20 mg b.i.d. was statistically significantly superior to 40 mg h.s. and to placebo in providing a successful symptomatic outcome, defined as moderate or excellent improvement of symptoms ( Table 3 ). Table 3: % Successful Symptomatic Outcome † p≤0.01 vs placebo Famotidine 20 mg b.i.d. (N=154) Famotidine 40 mg h.s. (N=149) Placebo (N=73) Week 6 82 † 69 62 By two weeks of treatment, symptomatic success was observed in a greater percentage of patients taking famotidine 20 mg b.i.d. compared to placebo (p≤0.01). Symptomatic improvement and healing of endoscopically verified erosion and ulceration were studied in two additional trials. Healing was defined as complete resolution of all erosions or ulcerations visible with endoscopy. The U.S. study comparing famotidine 40 mg p.o. b.i.d. to placebo and famotidine 20 mg p.o. b.i.d., showed a significantly greater percentage of healing for famotidine 40 mg b.i.d. at weeks 6 and 12 ( Table 4 ). Table 4: % Endoscopic Healing - U.S. Study †† p≤0.01 vs placebo ††† p≤0.05 vs famotidine 20 mg b.i.d. ‡ p≤0.01 vs famotidine 20 mg b.i.d. Famotidine 40 mg b.i.d. (N=127) Famotidine 20 mg b.i.d. (N=125) Placebo (N=66) Week 6 48 ††,‡ 32 18 Week 12 69 ††,††† 54 †† 29 As compared to placebo, patients who received famotidine had faster relief of daytime and nighttime heartburn and a greater percentage of patients experienced complete relief of nighttime heartburn. These differences were statistically significant. In the international study, when famotidine 40 mg p.o. b.i.d. was compared to ranitidine 150 mg p.o. b.i.d., a statistically significantly greater percentage of healing was observed with famotidine 40 mg b.i.d. at week 12 ( Table 5 ). There was, however, no significant difference among treatments in symptom relief. Table 5: % Endoscopic Healing - International Study ‡‡ p≤0.05 vs Ranitidine 150 mg b.i.d. Famotidine 40 mg b.i.d. (N=175) Famotidine 20 mg b.i.d. (N=93) Ranitidine 150 mg b.i.d. (N=172) Week 6 48 52 42 Week 12 71 ‡‡ 68 60 Pathological Hypersecretory Conditions (e.g., Zollinger-Ellison Syndrome, Multiple Endocrine Adenomas) In studies of patients with pathological hypersecretory conditions such as Zollinger-Ellison Syndrome with or without multiple endocrine adenomas, famotidine significantly inhibited gastric acid secretion and controlled associated symptoms. Orally administered doses from 20 to 160 mg q 6 h maintained basal acid secretion below 10 mEq/hr; initial doses were titrated to the individual patient need and subsequent adjustments were necessary with time in some patients.

amotidine significantly inhibited gastric acid secretion and controlled associated symptoms. Orally administered doses from 20 to 160 mg q 6 h maintained basal acid secretion below 10 mEq/hr; initial doses were titrated to the individual patient need and subsequent adjustments were necessary with time in some patients. Famotidine was well tolerated at these high dose levels for prolonged periods (greater than 12 months) in eight patients, and there were no cases reported of gynecomastia, increased prolactin levels, or impotence which were considered to be due to the drug.

amotidine significantly inhibited gastric acid secretion and controlled associated symptoms. Orally administered doses from 20 to 160 mg q 6 h maintained basal acid secretion below 10 mEq/hr; initial doses were titrated to the individual patient need and subsequent adjustments were necessary with time in some patients. Famotidine was well tolerated at these high dose levels for prolonged periods (greater than 12 months) in eight patients, and there were no cases reported of gynecomastia, increased prolactin levels, or impotence which were considered to be due to the drug. CLINICAL PHARMACOLOGY IN PEDIATRIC PATIENTS Pharmacokinetics Table 6 presents pharmacokinetic data from clinical trials and a published study in pediatric patients (<1 year of age; N=27) given famotidine IV 0.5 mg/kg and from published studies of small numbers of pediatric patients (1 to 15 years of age) given famotidine intravenously. Areas under the curve (AUCs) are normalized to a dose of 0.5 mg/kg IV for pediatric patients 1 to 15 years of age and compared with an extrapolated 40 mg intravenous dose in adults (extrapolation based on results obtained with a 20 mg IV adult dose). Table 6: Pharmacokinetic Parameters a of Intravenous Famotidine a Values are presented as means ± SD unless indicated otherwise b Mean value only c Single center study d Multicenter study Age (N=number of patients) Area Under the Curve (AUC) (ng-hr/mL) Total Clearance (Cl) (L/hr/kg) Volume of Distribution (V d ) (L/kg) Elimination Half-Life (T 1/2 ) (hours) 0 to 1 month c (N=10) NA 0.13 ± 0.06 1.4 ± 0.4 10.5 ± 5.4 0 to 3 months d (N=6) 2688 ± 847 0.21 ± 0.06 1.8 ± 0.3 8.1 ± 3.5 >3 to 12 months d (N=11) 1160 ± 474 0.49 ± 0.17 2.3 ± 0.7 4.5 ± 1.1 1 to 11 yrs (N=20) 1089 ± 834 0.54 ± 0.34 2.07 ± 1.49 3.38 ± 2.6 11 to 15 yrs (N=6) 1140 ± 320 0.48 ± 0.14 1.5 ± 0.4 2.3 ± 0.4 Adult (N=16) 1726 b 0.39 ± 0.14 1.3 ± 0.2 2.83 ± 0.99 Plasma clearance is reduced and elimination half-life is prolonged in pediatric patients 0 to 3 months of age compared to older pediatric patients. The pharmacokinetic parameters for pediatric patients, ages >3 months to 15 years, are comparable to those obtained for adults. Bioavailability studies of 8 pediatric patients (11 to 15 years of age) showed a mean oral bioavailability of 0.5 compared to adult values of 0.42 to 0.49. Oral doses of 0.5 mg/kg achieved AUCs of 645 ± 249 ng-hr/mL and 580 ± 60 ng-hr/mL in pediatric patients <1 year of age (N=5) and in pediatric patients 11 to 15 years of age, respectively, compared to 482 ± 181 ng-hr/mL in adults treated with 40 mg orally. Pharmacodynamics Pharmacodynamics of famotidine were evaluated in 5 pediatric patients 2 to 13 years of age using the sigmoid E max model. These data suggest that the relationship between serum concentration of famotidine and gastric acid suppression is similar to that observed in one study of adults ( Table 7 ). Table 7: Pharmacodynamics of Famotidine Using the Sigmoid E max Model * Serum concentration of famotidine associated with 50% maximum gastric acid reduction. Values are presented as means ± SD EC 50 (ng/mL)* Pediatric Patients 26 ± 13 Data from one study a) Healthy adult subjects 26.5 ± 10.3 b) Adult patients with upper GI bleeding 18.7 ± 10.8 Five published studies ( Table 8 ) examined the effect of famotidine on gastric pH and duration of acid suppression in pediatric patients. While each study had a different design, acid suppression data over time are summarized as follows: Table 8 a Values reported in published literature b Means ± SD c Mean (95% confidence interval) Dosage Route Effect a Number of Patients (age range) 0.5 mg/kg, single-dose IV gastric pH >4 for 19.5 hours (17.3, 21.8) c 11 (5 to 19 days) 0.3 mg/kg, single-dose IV gastric pH >3.5 for 8.7 ± 4.7 b hours 6 (2 to 7 years) 0.4 to 0.8 mg/kg IV gastric pH >4 for 6 to 9 hours 18 (2 to 69 months) 0.5 mg/kg, single-dose IV a >2 pH unit increase above baseline in gastric pH for >8 hours 9 (2 to 13 years) 0.5 mg/kg b.i.d. IV gastric pH >5 for 13.5 ± 1.8 b hours 4 (6 to 15 years) 0.5 mg/kg b.i.d.

ic pH >3.5 for 8.7 ± 4.7 b hours 6 (2 to 7 years) 0.4 to 0.8 mg/kg IV gastric pH >4 for 6 to 9 hours 18 (2 to 69 months) 0.5 mg/kg, single-dose IV a >2 pH unit increase above baseline in gastric pH for >8 hours 9 (2 to 13 years) 0.5 mg/kg b.i.d. IV gastric pH >5 for 13.5 ± 1.8 b hours 4 (6 to 15 years) 0.5 mg/kg b.i.d. Oral gastric pH >5 for 5 ± 1.1 b hours 4 (11 to 15 years) The duration of effect of famotidine IV 0.5 mg/kg on gastric pH and acid suppression was shown in one study to be longer in pediatric patients <1 month of age than in older pediatric patients. This longer duration of gastric acid suppression is consistent with the decreased clearance in pediatric patients <3 months of age (see Table 6 ).

Pharmacokinetics Orally administered famotidine is incompletely absorbed, and its bioavailability is 40 to 45%. Famotidine undergoes minimal first-pass metabolism. After oral doses, peak plasma levels occur in 1 to 3 hours. Plasma levels after multiple doses are similar to those after single doses. Fifteen to 20% of famotidine in plasma is protein bound. Famotidine has an elimination half-life of 2.5 to 3.5 hours. Famotidine is eliminated by renal (65 to 70%) and metabolic (30 to 35%) routes. Renal clearance is 250 to 450 mL/min, indicating some tubular excretion. Twenty-five to 30% of an oral dose and 65 to 70% of an intravenous dose are recovered in the urine as unchanged compound. The only metabolite identified in man is the S-oxide. There is a close relationship between creatinine clearance values and the elimination half-life of famotidine. In patients with severe renal insufficiency, i.e., creatinine clearance less than 10 mL/min, the elimination half-life of famotidine may exceed 20 hours and adjustment of dose or dosing intervals in moderate and severe renal insufficiency may be necessary (see PRECAUTIONS , DOSAGE AND ADMINISTRATION ). In elderly patients, there are no clinically significant age-related changes in the pharmacokinetics of famotidine. However, in elderly patients with decreased renal function, the clearance of the drug may be decreased (see PRECAUTIONS, Geriatric Use ).

y may be necessary (see PRECAUTIONS , DOSAGE AND ADMINISTRATION ). In elderly patients, there are no clinically significant age-related changes in the pharmacokinetics of famotidine. However, in elderly patients with decreased renal function, the clearance of the drug may be decreased (see PRECAUTIONS, Geriatric Use ). Pharmacokinetics Table 6 presents pharmacokinetic data from clinical trials and a published study in pediatric patients (<1 year of age; N=27) given famotidine IV 0.5 mg/kg and from published studies of small numbers of pediatric patients (1 to 15 years of age) given famotidine intravenously. Areas under the curve (AUCs) are normalized to a dose of 0.5 mg/kg IV for pediatric patients 1 to 15 years of age and compared with an extrapolated 40 mg intravenous dose in adults (extrapolation based on results obtained with a 20 mg IV adult dose). Table 6: Pharmacokinetic Parameters a of Intravenous Famotidine a Values are presented as means ± SD unless indicated otherwise b Mean value only c Single center study d Multicenter study Age (N=number of patients) Area Under the Curve (AUC) (ng-hr/mL) Total Clearance (Cl) (L/hr/kg) Volume of Distribution (V d ) (L/kg) Elimination Half-Life (T 1/2 ) (hours) 0 to 1 month c (N=10) NA 0.13 ± 0.06 1.4 ± 0.4 10.5 ± 5.4 0 to 3 months d (N=6) 2688 ± 847 0.21 ± 0.06 1.8 ± 0.3 8.1 ± 3.5 >3 to 12 months d (N=11) 1160 ± 474 0.49 ± 0.17 2.3 ± 0.7 4.5 ± 1.1 1 to 11 yrs (N=20) 1089 ± 834 0.54 ± 0.34 2.07 ± 1.49 3.38 ± 2.6 11 to 15 yrs (N=6) 1140 ± 320 0.48 ± 0.14 1.5 ± 0.4 2.3 ± 0.4 Adult (N=16) 1726 b 0.39 ± 0.14 1.3 ± 0.2 2.83 ± 0.99 Plasma clearance is reduced and elimination half-life is prolonged in pediatric patients 0 to 3 months of age compared to older pediatric patients. The pharmacokinetic parameters for pediatric patients, ages >3 months to 15 years, are comparable to those obtained for adults. Bioavailability studies of 8 pediatric patients (11 to 15 years of age) showed a mean oral bioavailability of 0.5 compared to adult values of 0.42 to 0.49. Oral doses of 0.5 mg/kg achieved AUCs of 645 ± 249 ng-hr/mL and 580 ± 60 ng-hr/mL in pediatric patients <1 year of age (N=5) and in pediatric patients 11 to 15 years of age, respectively, compared to 482 ± 181 ng-hr/mL in adults treated with 40 mg orally.

<table ID="t6" width="100%"><caption>Table 6: Pharmacokinetic Parameters ^aof Intravenous Famotidine </caption><col width="20.956%" align="left"/><col width="14.997%" align="left"/><col width="21.016%" align="left"/><col width="18.016%" align="left"/><col width="25.015%" align="left"/><tfoot><tr><td colspan="5" align="left" valign="top"><paragraph styleCode="footnote">^aValues are presented as means &#xB1; SD unless indicated otherwise </paragraph></td></tr><tr><td colspan="5" align="left" valign="top"><paragraph styleCode="footnote">^bMean value only </paragraph></td></tr><tr><td colspan="5" align="left" valign="top"><paragraph styleCode="footnote">^cSingle center study </paragraph></td></tr><tr><td colspan="5" align="left" valign="top"><paragraph styleCode="footnote">^dMulticenter study </paragraph></td></tr></tfoot><tbody><tr><td align="center" styleCode="Toprule Botrule Lrule Rrule" valign="top">Age (N=number of patients) </td><td align="center" styleCode="Toprule Botrule Rrule" valign="top">Area Under the Curve (AUC) (ng-hr/mL) </td><td align="center" styleCode="Toprule Botrule Rrule" valign="top">Total Clearance (Cl) (L/hr/kg) </td><td align="center" styleCode="Toprule Botrule Rrule" valign="top">Volume of Distribution (V _d) (L/kg) </td><td align="center" styleCode="Toprule Botrule Rrule" valign="top">Elimination Half-Life (T _1/2) (hours) </td></tr><tr><td align="center" styleCode="Botrule Lrule Rrule" valign="top">0 to 1 month ^c (N=10) </td><td align="center" styleCode="Botrule Rrule" valign="top">NA</td><td align="center" styleCode="Botrule Rrule" valign="top">0.13 &#xB1; 0.06</td><td align="center" styleCode="Botrule Rrule" valign="top">1.4 &#xB1; 0.4</td><td align="center" styleCode="Botrule Rrule" valign="top">10.5 &#xB1; 5.4</td></tr><tr><td align="center" styleCode="Botrule Lrule Rrule" valign="top">0 to 3 months ^d (N=6) </td><td align="center" styleCode="Botrule Rrule" valign="top">2688 &#xB1; 847</td><td align="center" styleCode="Botrule Rrule" valign="top">0.21 &#xB1; 0.06</td><td align="center" styleCode="Botrule Rrule" valign="top">1.8 &#xB1; 0.3</td><td align="center" styleCode="Botrule Rrule" valign="top">8.1 &#xB1; 3.5</td></tr><tr><td align="center" styleCode="Botrule Lrule Rrule" valign="top">&gt;3 to 12 months ^d (N=11) </td><td align="center" styleCode="Botrule Rrule" valign="top">1160 &#xB1; 474</td><td align="center" styleCode="Botrule Rrule" valign="top">0.49 &#xB1; 0.17</td><td align="center" styleCode="Botrule Rrule" valign="top">2.3 &#xB1; 0.7</td><td align="center" styleCode="Botrule Rrule" valign="top">4.5 &#xB1; 1.1</td></tr><tr><td align="center" styleCode="Botrule Lrule Rrule" valign="top">1 to 11 yrs (N=20)</td><td align="center" styleCode="Botrule Rrule" valign="top">1089 &#xB1; 834</td><td align="center" styleCode="Botrule Rrule" valign="top">0.54 &#xB1; 0.34</td><td align="center" styleCode="Botrule Rrule" valign="top">2.07 &#xB1; 1.49</td><td align="center" styleCode="Botrule Rrule" valign="top">3.38 &#xB1; 2.6</td></tr><tr><td align="center" styleCode="Botrule Lrule Rrule" valign="top">11 to 15 yrs (N=6)</td><td align="center" styleCode="Botrule Rrule" valign="top">1140 &#xB1; 320</td><td align="center" styleCode="Botrule Rrule" valign="top">0.48 &#xB1; 0.14</td><td align="center" styleCode="Botrule Rrule" valign="top">1.5 &#xB1; 0.4</td><td align="center" styleCode="Botrule Rrule" valign="top

="top">11 to 15 yrs (N=6)</td><td align="center" styleCode="Botrule Rrule" valign="top">1140 &#xB1; 320</td><td align="center" styleCode="Botrule Rrule" valign="top">0.48 &#xB1; 0.14</td><td align="center" styleCode="Botrule Rrule" valign="top">1.5 &#xB1; 0.4</td><td align="center" styleCode="Botrule Rrule" valign="top ">2.3 &#xB1; 0.4</td></tr><tr><td align="center" styleCode="Botrule Lrule Rrule" valign="top">Adult (N=16) </td><td align="center" styleCode="Botrule Rrule" valign="top">1726 ^b</td><td align="center" styleCode="Botrule Rrule" valign="top">0.39 &#xB1; 0.14</td><td align="center" styleCode="Botrule Rrule" valign="top">1.3 &#xB1; 0.2</td><td align="center" styleCode="Botrule Rrule" valign="top">2.83 &#xB1; 0.99</td></tr></tbody></table>

Pharmacodynamics Pharmacodynamics of famotidine were evaluated in 5 pediatric patients 2 to 13 years of age using the sigmoid E max model. These data suggest that the relationship between serum concentration of famotidine and gastric acid suppression is similar to that observed in one study of adults ( Table 7 ). Table 7: Pharmacodynamics of Famotidine Using the Sigmoid E max Model * Serum concentration of famotidine associated with 50% maximum gastric acid reduction. Values are presented as means ± SD EC 50 (ng/mL)* Pediatric Patients 26 ± 13 Data from one study a) Healthy adult subjects 26.5 ± 10.3 b) Adult patients with upper GI bleeding 18.7 ± 10.8 Five published studies ( Table 8 ) examined the effect of famotidine on gastric pH and duration of acid suppression in pediatric patients. While each study had a different design, acid suppression data over time are summarized as follows: Table 8 a Values reported in published literature b Means ± SD c Mean (95% confidence interval) Dosage Route Effect a Number of Patients (age range) 0.5 mg/kg, single-dose IV gastric pH >4 for 19.5 hours (17.3, 21.8) c 11 (5 to 19 days) 0.3 mg/kg, single-dose IV gastric pH >3.5 for 8.7 ± 4.7 b hours 6 (2 to 7 years) 0.4 to 0.8 mg/kg IV gastric pH >4 for 6 to 9 hours 18 (2 to 69 months) 0.5 mg/kg, single-dose IV a >2 pH unit increase above baseline in gastric pH for >8 hours 9 (2 to 13 years) 0.5 mg/kg b.i.d. IV gastric pH >5 for 13.5 ± 1.8 b hours 4 (6 to 15 years) 0.5 mg/kg b.i.d. Oral gastric pH >5 for 5 ± 1.1 b hours 4 (11 to 15 years) The duration of effect of famotidine IV 0.5 mg/kg on gastric pH and acid suppression was shown in one study to be longer in pediatric patients <1 month of age than in older pediatric patients. This longer duration of gastric acid suppression is consistent with the decreased clearance in pediatric patients <3 months of age (see Table 6 ).

<table ID="t7" width="100%"><caption>Table 7: Pharmacodynamics of Famotidine Using the Sigmoid E _maxModel </caption><col width="70.750%" align="left"/><col width="29.250%" align="left"/><tfoot><tr><td colspan="2" align="left" valign="top"><paragraph styleCode="footnote">* Serum concentration of famotidine associated with 50% maximum gastric acid reduction. Values are presented as means &#xB1; SD</paragraph></td></tr></tfoot><tbody><tr><td align="justify" styleCode="Toprule Botrule Lrule Rrule" valign="top"/><td align="center" styleCode="Toprule Botrule Rrule" valign="top">EC ₅₀(ng/mL)* </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Pediatric Patients</td><td align="center" styleCode="Botrule Rrule" valign="top">26 &#xB1; 13</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Data from one study</td><td align="justify" styleCode="Botrule Rrule" valign="top"/></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">a) Healthy adult subjects</td><td align="center" styleCode="Botrule Rrule" valign="top">26.5 &#xB1; 10.3</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">b) Adult patients with upper GI bleeding</td><td align="center" styleCode="Botrule Rrule" valign="top">18.7 &#xB1; 10.8</td></tr></tbody></table>

althy adult subjects</td><td align="center" styleCode="Botrule Rrule" valign="top">26.5 &#xB1; 10.3</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">b) Adult patients with upper GI bleeding</td><td align="center" styleCode="Botrule Rrule" valign="top">18.7 &#xB1; 10.8</td></tr></tbody></table> <table ID="t8" width="100%"><caption>Table 8</caption><col width="25.381%" align="left"/><col width="8.702%" align="left"/><col width="43.311%" align="left"/><col width="22.606%" align="left"/><tfoot><tr><td colspan="4" align="left" valign="top"><paragraph styleCode="footnote">^aValues reported in published literature </paragraph></td></tr><tr><td colspan="4" align="left" valign="top"><paragraph styleCode="footnote">^bMeans &#xB1; SD </paragraph></td></tr><tr><td colspan="4" align="left" valign="top"><paragraph styleCode="footnote">^cMean (95% confidence interval) </paragraph></td></tr></tfoot><tbody><tr><td align="justify" styleCode="Toprule Botrule Lrule Rrule" valign="middle"><content styleCode="bold">Dosage</content></td><td align="center" styleCode="Toprule Botrule Rrule" valign="middle"><content styleCode="bold">Route</content></td><td align="center" styleCode="Toprule Botrule Rrule" valign="middle"><content styleCode="bold">Effect</content><content styleCode="bold">^a</content></td><td align="center" styleCode="Toprule Botrule Rrule" valign="middle"><content styleCode="bold">Number of Patients</content> <content styleCode="bold">(age range)</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">0.5 mg/kg, single-dose</td><td align="center" styleCode="Botrule Rrule" valign="top">IV</td><td align="justify" styleCode="Botrule Rrule" valign="top">gastric pH &gt;4 for 19.5 hours (17.3, 21.8) ^c</td><td align="center" styleCode="Botrule Rrule" valign="top">11 (5 to 19 days)</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">0.3 mg/kg, single-dose</td><td align="center" styleCode="Botrule Rrule" valign="top">IV</td><td align="left" styleCode="Botrule Rrule" valign="top">gastric pH &gt;3.5 for 8.7 &#xB1; 4.7 ^bhours </td><td align="center" styleCode="Botrule Rrule" valign="top">6 (2 to 7 years)</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">0.4 to 0.8 mg/kg</td><td align="center" styleCode="Botrule Rrule" valign="top">IV</td><td align="left" styleCode="Botrule Rrule" valign="top">gastric pH &gt;4 for 6 to 9 hours</td><td align="center" styleCode="Botrule Rrule" valign="top">18 (2 to 69 months)</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">0.5 mg/kg, single-dose</td><td align="center" styleCode="Botrule Rrule" valign="top">IV</td><td align="justify" styleCode="Botrule Rrule" valign="top">a &gt;2 pH unit increase above baseline in gastric pH for &gt;8 hours </td><td align="center" styleCode="Botrule Rrule" valign="top">9 (2 to 13 years)</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">0.5 mg/kg b.i.d.</td><td align="center" styleCode="Botrule Rrule" valign="top">IV</td><td align="left" styleCode="Botrule Rrule" valign="top">gastric pH &gt;5 for 13.5 &#xB1; 1.8 ^bhours </td><td align="center" styleCode="Botrule Rrule" valign="top">4 (6 to 15 years)</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">0.5 mg/kg b.i.d.</td><td align="center" styleCode="Botrule Rrule" valign="top">Oral</td><td align="left" styleCode="Botrule Rrule" valign="top">gastric pH &gt;5 for 5 &#xB1; 1.1 ^bhours </td><td align="center" styleCode="Botrule Rrule" valign="top">4 (11 to 15 years)</td></tr></tbody></table>

INDICATIONS AND USAGE Famotidine Injection, supplied as a concentrated solution for intravenous injection, is intended for intravenous use only. Famotidine Injection is indicated in some hospitalized patients with pathological hypersecretory conditions or intractable ulcers, or as an alternative to the oral dosage forms for short term use in patients who are unable to take oral medication for the following conditions: Short term treatment of active duodenal ulcer. Most adult patients heal within 4 weeks; there is rarely reason to use famotidine at full dosage for longer than 6 to 8 weeks. Studies have not assessed the safety of famotidine in uncomplicated active duodenal ulcer for periods of more than eight weeks. Maintenance therapy for duodenal ulcer patients at reduced dosage after healing of an active ulcer. Controlled studies in adults have not extended beyond one year. Short term treatment of active benign gastric ulcer. Most adult patients heal within 6 weeks. Studies have not assessed the safety or efficacy of famotidine in uncomplicated active benign gastric ulcer for periods of more than 8 weeks. Short term treatment of gastroesophageal reflux disease (GERD). Famotidine is indicated for short term treatment of patients with symptoms of GERD (see CLINICAL PHARMACOLOGY IN ADULTS, Clinical Studies ). Famotidine is also indicated for the short term treatment of esophagitis due to GERD including erosive or ulcerative disease diagnosed by endoscopy (see CLINICAL PHARMACOLOGY IN ADULTS, Clinical Studies ). Treatment of pathological hypersecretory conditions (e.g., Zollinger-Ellison Syndrome, multiple endocrine adenomas) (see CLINICAL PHARMACOLOGY IN ADULTS, Clinical Studies ).

CONTRAINDICATIONS Hypersensitivity to any component of these products. Cross sensitivity in this class of compounds has been observed. Therefore, Famotidine Injection should not be administered to patients with a history of hypersensitivity to other H 2 -receptor antagonists.

WARNINGS Famotidine Injection 4 mL and 20 mL multiple dose vials contain the preservative benzyl alcohol. There have been reports of fatal ‘gasping syndrome’ in neonates (children less than one month of age) following the administration of intravenous solutions containing the preservative benzyl alcohol. Symptoms include a striking onset of gasping respiration, hypotension, bradycardia, and cardiovascular collapse. Benzyl alcohol, given its small size, presumably crosses the placental barrier into immature fetal tissues as readily as it crosses the blood-brain barrier. Therefore, Famotidine Injection from multiple dose vials containing benzyl alcohol should not be used in neonates and pregnant women.

PRECAUTIONS General Symptomatic response to therapy with famotidine does not preclude the presence of gastric malignancy. Patients with Moderate or Severe Renal Insufficiency Since CNS adverse effects have been reported in patients with moderate and severe renal insufficiency, longer intervals between doses or lower doses may need to be used in patients with moderate (creatinine clearance <50 mL/min) or severe (creatinine clearance <10 mL/min) renal insufficiency to adjust for the longer elimination half-life of famotidine (see CLINICAL PHARMACOLOGY IN ADULTS , DOSAGE AND ADMINISTRATION ). Drug Interactions No drug interactions have been identified. Studies with famotidine in man, in animal models, and in vitro have shown no significant interference with the disposition of compounds metabolized by the hepatic microsomal enzymes, e.g., cytochrome P450 system. Compounds tested in man include warfarin, theophylline, phenytoin, diazepam, aminopyrine and antipyrine. Indocyanine green as an index of hepatic drug extraction has been tested and no significant effects have been found. Carcinogenesis, Mutagenesis, Impairment of Fertility In a 106 week study in rats and a 92 week study in mice given oral doses of up to 2,000 mg/kg/day (approximately 2,500 times the recommended human dose for active duodenal ulcer), there was no evidence of carcinogenic potential for famotidine. Famotidine was negative in the microbial mutagen test (Ames test) using Salmonella typhimurium and Escherichia coli with or without rat liver enzyme activation at concentrations up to 10,000 mcg/plate. In in vivo studies in mice, with a micronucleus test and a chromosomal aberration test, no evidence of a mutagenic effect was observed. In studies with rats given oral doses of up to 2,000 mg/kg/day or intravenous doses of up to 200 mg/kg/day, fertility and reproductive performance were not affected. Pregnancy 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 IV 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 (250 times the usual human dose) 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. Nursing Mothers Studies performed in lactating rats have shown that famotidine is secreted into breast milk. Transient growth depression was observed in young rats suckling from mothers treated with maternotoxic doses of at least 600 times the usual human dose. Famotidine is detectable in human milk. Because of the potential for serious adverse reactions in nursing infants from famotidine, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Patients <1 Year of Age Use of famotidine in pediatric patients <1 year of age is supported by evidence from adequate and well-controlled studies of famotidine in adults, and by the following studies in pediatric patients <1 year of age.

the drug, taking into account the importance of the drug to the mother. Pediatric Patients <1 Year of Age Use of famotidine in pediatric patients <1 year of age is supported by evidence from adequate and well-controlled studies of famotidine in adults, and by the following studies in pediatric patients <1 year of age. Two pharmacokinetic studies in pediatric patients <1 year of age (N=48) demonstrated that clearance of famotidine in patients >3 months to 1 year of age is similar to that seen in older pediatric patients (1 to 15 years of age) and adults. In contrast, pediatric patients 0 to 3 months of age had famotidine clearance values that were 2- to 4-fold less than those in older pediatric patients and adults. These studies also show that the mean bioavailability in pediatric patients <1 year of age after oral dosing is similar to older pediatric patients and adults. Pharmacodynamic data in pediatric patients 0 to 3 months of age suggest that the duration of acid suppression is longer compared with older pediatric patients, consistent with the longer famotidine half-life in pediatric patients 0 to 3 months of age (see CLINICAL PHARMACOLOGY IN PEDIATRIC PATIENTS, Pharmacokinetics and Pharmacodynamics ). In a double-blinded, randomized, treatment-withdrawal study, 35 pediatric patients <1 year of age who were diagnosed as having gastroesophageal reflux disease were treated for up to 4 weeks with famotidine oral suspension (0.5 mg/kg/dose or 1 mg/kg/dose). Although an intravenous famotidine formulation was available, no patients were treated with intravenous famotidine in this study. Also, caregivers were instructed to provide conservative treatment including thickened feedings. Enrolled patients were diagnosed primarily by history of vomiting (spitting up) and irritability (fussiness). The famotidine dosing regimen was once daily for patients <3 months of age and twice daily for patients ≥3 months of age. After 4 weeks of treatment, patients were randomly withdrawn from the treatment and followed an additional 4 weeks for adverse events and symptomatology. Patients were evaluated for vomiting (spitting up), irritability (fussiness) and global assessments of improvement. The study patients ranged in age at entry from 1.3 to 10.5 months (mean 5.6 ± 2.9 months), 57% were female, 91% were white and 6% were black. Most patients (27/35) continued into the treatment withdrawal phase of the study. Two patients discontinued famotidine due to adverse events. Most patients improved during the initial treatment phase of the study. Results of the treatment withdrawal phase were difficult to interpret because of small numbers of patients. Of the 35 patients enrolled in the study, agitation was observed in 5 patients on famotidine that resolved when the medication was discontinued; agitation was not observed in patients on placebo (see ADVERSE REACTIONS, Pediatric Patients ). These studies suggest that a starting dose of 0.5 mg/kg/dose of famotidine oral suspension may be of benefit for the treatment of GERD for up to 4 weeks once daily in patients <3 months of age and twice daily in patients 3 months to <1 year of age; the safety and benefit of famotidine treatment beyond 4 weeks have not been established. Famotidine should be considered for the treatment of GERD only if conservative measures (e.g., thickened feedings) are used concurrently and if the potential benefit outweighs the risk.

daily in patients 3 months to <1 year of age; the safety and benefit of famotidine treatment beyond 4 weeks have not been established. Famotidine should be considered for the treatment of GERD only if conservative measures (e.g., thickened feedings) are used concurrently and if the potential benefit outweighs the risk. Pediatric Patients 1 to 16 Years of Age Use of famotidine in pediatric patients 1 to 16 years of age is supported by evidence from adequate and well-controlled studies of famotidine in adults and by the following studies in pediatric patients: In published studies in small numbers of pediatric patients 1 to 15 years of age, clearance of famotidine was similar to that seen in adults. In pediatric patients 11 to 15 years of age, oral doses of 0.5 mg/kg were associated with a mean area under the curve (AUC) similar to that seen in adults treated orally with 40 mg. Similarly, in pediatric patients 1 to 15 years of age, intravenous doses of 0.5 mg/kg were associated with a mean AUC similar to that seen in adults treated intravenously with 40 mg. Limited published studies also suggest that the relationship between serum concentration and acid suppression is similar in pediatric patients 1 to 15 years of age as compared with adults. These studies suggest that the starting dose for pediatric patients 1 to 16 years of age is 0.25 mg/kg intravenously (injected over a period of not less than two minutes or as a 15-minute infusion) q 12 h up to 40 mg/day. While published uncontrolled clinical studies suggest effectiveness of famotidine in the treatment of peptic ulcer, data in pediatric patients are insufficient to establish percent response with dose and duration of therapy. Therefore, treatment duration (initially based on adult duration recommendations) and dose should be individualized based on clinical response and/or gastric pH determination and endoscopy. Published uncontrolled studies in pediatric patients have demonstrated gastric acid suppression with doses up to 0.5 mg/kg intravenously q 12 h. Geriatric Use Of the 4,966 subjects in clinical studies who were treated with famotidine, 488 subjects (9.8%) were 65 and older, and 88 subjects (1.7%) were greater than 75 years of age. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. However, greater sensitivity of some older patients cannot be ruled out. No dosage adjustment is required based on age (see CLINICAL PHARMACOLOGY IN ADULTS, Pharmacokinetics ). This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Dosage adjustment in the case of moderate or severe renal impairment is necessary (see PRECAUTIONS, Patients with Moderate or Severe Renal Insufficiency and DOSAGE AND ADMINISTRATION, Dosage Adjustment for Patients with Moderate or Severe Renal Insufficiency ).

Drug Interactions No drug interactions have been identified. Studies with famotidine in man, in animal models, and in vitro have shown no significant interference with the disposition of compounds metabolized by the hepatic microsomal enzymes, e.g., cytochrome P450 system. Compounds tested in man include warfarin, theophylline, phenytoin, diazepam, aminopyrine and antipyrine. Indocyanine green as an index of hepatic drug extraction has been tested and no significant effects have been found.

Carcinogenesis, Mutagenesis, Impairment of Fertility In a 106 week study in rats and a 92 week study in mice given oral doses of up to 2,000 mg/kg/day (approximately 2,500 times the recommended human dose for active duodenal ulcer), there was no evidence of carcinogenic potential for famotidine. Famotidine was negative in the microbial mutagen test (Ames test) using Salmonella typhimurium and Escherichia coli with or without rat liver enzyme activation at concentrations up to 10,000 mcg/plate. In in vivo studies in mice, with a micronucleus test and a chromosomal aberration test, no evidence of a mutagenic effect was observed. In studies with rats given oral doses of up to 2,000 mg/kg/day or intravenous doses of up to 200 mg/kg/day, fertility and reproductive performance were not affected.

Pregnancy 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 IV 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 (250 times the usual human dose) 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.

Nursing Mothers Studies performed in lactating rats have shown that famotidine is secreted into breast milk. Transient growth depression was observed in young rats suckling from mothers treated with maternotoxic doses of at least 600 times the usual human dose. Famotidine is detectable in human milk. Because of the potential for serious adverse reactions in nursing infants from famotidine, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Geriatric Use Of the 4,966 subjects in clinical studies who were treated with famotidine, 488 subjects (9.8%) were 65 and older, and 88 subjects (1.7%) were greater than 75 years of age. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. However, greater sensitivity of some older patients cannot be ruled out. No dosage adjustment is required based on age (see CLINICAL PHARMACOLOGY IN ADULTS, Pharmacokinetics ). This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Dosage adjustment in the case of moderate or severe renal impairment is necessary (see PRECAUTIONS, Patients with Moderate or Severe Renal Insufficiency and DOSAGE AND ADMINISTRATION, Dosage Adjustment for Patients with Moderate or Severe Renal Insufficiency ).

ADVERSE REACTIONS The adverse reactions listed below have been reported during domestic and international clinical trials in approximately 2,500 patients. In those controlled clinical trials in which famotidine tablets were compared to placebo, the incidence of adverse experiences in the group which received famotidine tablets, 40 mg at bedtime, was similar to that in the placebo group. The following adverse reactions have been reported to occur in more than 1% of patients on therapy with famotidine in controlled clinical trials, and may be causally related to the drug: headache (4.7%), dizziness (1.3%), constipation (1.2%) and diarrhea (1.7%). The following other adverse reactions have been reported infrequently in clinical trials or since the drug was marketed. The relationship to therapy with famotidine has been unclear in many cases. Within each category the adverse reactions are listed in order of decreasing severity. Body as a Whole: fever, asthenia, fatigue Cardiovascular: arrhythmia, AV block, palpitation, prolonged QT interval Gastrointestinal: cholestatic jaundice, hepatitis, elevated liver enzyme, vomiting, nausea, abdominal discomfort, anorexia, dry mouth Hematologic: agranulocytosis, pancytopenia, leukopenia, thrombocytopenia Hypersensitivity: anaphylaxis, angioedema, orbital or facial edema, urticaria, rash, conjunctival injection, bronchospasm Musculoskeletal: rhabdomyolysis, musculoskeletal pain, muscle cramps, arthralgia Nervous System/Psychiatric: seizure, hallucinations, confusion, agitation, depression, anxiety, decreased libido, paresthesia, insomnia, somnolence Respiratory: interstitial pneumonia Skin: toxic epidermal necrolysis/Stevens Johnson syndrome, pruritus, dry skin, flushing Special Senses: tinnitus, taste disorder Other: impotence The adverse reactions reported for Famotidine Tablets may also occur with Famotidine for Oral Suspension or Famotidine Injection. In addition, transient irritation at the injection site has been observed with Famotidine Injection. Pediatric Patients In a clinical study in 35 pediatric patients <1 year of age with GERD symptoms [e.g. vomiting (spitting up), irritability (fussing)], agitation was observed in 5 patients on famotidine that resolved when the medication was discontinued. 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 .

OVERDOSAGE The adverse reactions in overdose cases are similar to the adverse reactions encountered in normal clinical experience (see ADVERSE REACTIONS ). Oral doses of up to 640 mg/day have been given to adult patients with pathological hypersecretory conditions with no serious adverse effects. 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. The intravenous LD 50 of famotidine for mice and rats ranged from 254 to 563 mg/kg and the minimum lethal single IV dose in dogs was approximately 300 mg/kg. Signs of acute intoxication in IV treated dogs were emesis, restlessness, pallor of mucous membranes or redness of mouth and ears, hypotension, tachycardia and collapse. The oral LD 50 of famotidine in male and female rats and mice was greater than 3,000 mg/kg and the minimum lethal acute oral dose in dogs exceeded 2,000 mg/kg. Famotidine did not produce overt effects at high oral doses in mice, rats, cats and dogs, but induced significant anorexia and growth depression in rabbits starting with 200 mg/kg/day orally.

DOSAGE AND ADMINISTRATION In some hospitalized patients with pathological hypersecretory conditions or intractable ulcers, or in patients who are unable to take oral medication, Famotidine Injection may be administered until oral therapy can be instituted. The recommended dosage for Famotidine Injection in adult patients is 20 mg intravenously q 12 h. The doses and regimen for parenteral administration in patients with GERD have not been established. Dosage for Pediatric Patients <1 Year of Age Gastroesophageal Reflux Disease (GERD) See PRECAUTIONS, Pediatric Patients <1 Year of Age . The studies described in PRECAUTIONS, Pediatric Patients <1 Year of Age suggest the following starting doses in pediatric patients <1 year of age: Gastroesophageal Reflux Disease (GERD) - 0.5 mg/kg/dose of famotidine oral suspension for the treatment of GERD for up to 8 weeks once daily in patients <3 months of age and 0.5 mg/kg/dose twice daily in patients 3 months to <1 year of age. Patients should also be receiving conservative measures (e.g., thickened feedings). The use of intravenous famotidine in pediatric patients <1 year of age with GERD has not been adequately studied. Dosage for Pediatric Patients 1 to 16 Years of Age See PRECAUTIONS, Pediatric Patients 1 to 16 Years of Age . The studies described in PRECAUTIONS, Pediatric Patients 1 to 16 Years of Age suggest that the starting dose in pediatric patients 1 to 16 years of age is 0.25 mg/kg intravenously (injected over a period of not less than two minutes or as a 15-minute infusion) q 12 h up to 40 mg/day. While published uncontrolled clinical studies suggest effectiveness of famotidine in the treatment of peptic ulcer, data in pediatric patients are insufficient to establish percent response with dose and duration of therapy. Therefore, treatment duration (initially based on adult duration recommendations) and dose should be individualized based on clinical response and/or gastric pH determination and endoscopy. Published uncontrolled studies in pediatric patients 1 to 16 years of age have demonstrated gastric acid suppression with doses up to 0.5 mg/kg intravenously q 12 h. Dosage Adjustments for Patients with Moderate or Severe Renal Insufficiency In adult patients with moderate (creatinine clearance <50 mL/min) or severe (creatinine clearance <10 mL/min) renal insufficiency, the elimination half-life of famotidine is increased. For patients with severe renal insufficiency, it may exceed 20 hours, reaching approximately 24 hours in anuric patients. Since CNS adverse effects have been reported in patients with moderate and severe renal insufficiency, to avoid excess accumulation of the drug in patients with moderate or severe renal insufficiency, the dose of Famotidine Injection may be reduced to half the dose, or the dosing interval may be prolonged to 36 to 48 hours as indicated by the patient's clinical response. Based on the comparison of pharmacokinetic parameters for famotidine in adults and pediatric patients, dosage adjustment in pediatric patients with moderate or severe renal insufficiency should be considered. Pathological Hypersecretory Conditions (e.g., Zollinger-Ellison Syndrome, Multiple Endocrine Adenomas) The dosage of famotidine in patients with pathological hypersecretory conditions varies with the individual patient. The recommended adult intravenous dose is 20 mg q 12 h.

re renal insufficiency should be considered. Pathological Hypersecretory Conditions (e.g., Zollinger-Ellison Syndrome, Multiple Endocrine Adenomas) The dosage of famotidine in patients with pathological hypersecretory conditions varies with the individual patient. The recommended adult intravenous dose is 20 mg q 12 h. Doses should be adjusted to individual patient needs and should continue as long as clinically indicated. In some patients, a higher starting dose may be required. Oral doses up to 160 mg q 6 h have been administered to some adult patients with severe Zollinger-Ellison Syndrome. To prepare intravenous solutions, aseptically dilute 2 mL of Famotidine Injection (solution containing 10 mg/mL) with Sodium Chloride Injection 0.9% or other compatible intravenous solution (see Stability ) to a total volume of either 5 mL or 10 mL and inject over a period of not less than 2 minutes. To prepare intravenous infusion solutions, aseptically dilute 2 mL of Famotidine Injection with 100 mL of Dextrose 5% or other compatible solution (see Stability ), and infuse over a 15 to 30 minute period. Concomitant Use of Antacids Antacids may be given orally concomitantly if needed. Stability Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. When added to or diluted with most commonly used intravenous solutions, e.g., Water for Injection, Sodium Chloride Injection 0.9%, Dextrose Injection 5% and 10% or Lactated Ringer's Injection, diluted Famotidine Injection is physically and chemically stable (i.e., maintains at least 90% of initial potency) for 7 days at room temperature — see HOW SUPPLIED, Storage Conditions . When added to or diluted with Sodium Bicarbonate Injection 5%, Famotidine Injection at a concentration of 0.2 mg/mL (the recommended concentration of famotidine intravenous infusion solutions) is physically and chemically stable (i.e., maintains at least 90% of initial potency) for 7 days at room temperature — see HOW SUPPLIED, Storage Conditions . However, a precipitate may form at higher concentrations of Famotidine Injection (>0.2 mg/mL) in Sodium Bicarbonate Injection 5%.

HOW SUPPLIED FOR INTRAVENOUS USE ONLY Famotidine Injection, USP, is supplied as follows: NDC Famotidine Injection, USP (Preservative-free) Package Factor (10 mg per mL) 25021-753-02 20 mg per 2 mL Single-Dose Vial 25 vials per carton NDC Famotidine Injection, USP (Preservative) Package Factor (10 mg per mL) 25021-754-04 40 mg per 4 mL Two-Dose Vial 10 vials per carton 25021-754-20 200 mg per 20 mL Multi-Dose Vial 10 vials per carton Storage Conditions Store refrigerated between 2° and 8°C (36° and 46°F). If solution freezes, bring to room temperature; allow sufficient time to solubilize all the components. Although diluted Famotidine Injection has been shown to be physically and chemically stable for 7 days at room temperature, there are no data on the maintenance of sterility after dilution. Therefore, it is recommended that if not used immediately after preparation, diluted solutions of Famotidine Injection should be refrigerated and used within 48 hours (see DOSAGE AND ADMINISTRATION ). Sterile, Nonpyrogenic. The container closure is not made with natural rubber latex. sagent ® Mfd. for SAGENT Pharmaceuticals Schaumburg, IL 60195 (USA) Made in India ©2024 Sagent Pharmaceuticals August 2024

<table width="100%" styleCode="Noautorules"><col width="20.600%" align="left"/><col width="46.067%" align="left"/><col width="33.333%" align="left"/><tbody><tr><td align="justify" valign="top"><content styleCode="bold">NDC</content></td><td align="justify" valign="top"><content styleCode="bold">Famotidine Injection, USP (Preservative-free)</content></td><td align="justify" valign="top"><content styleCode="bold">Package Factor</content></td></tr><tr><td align="justify" valign="top"/><td align="justify" valign="top"><content styleCode="bold">(10 mg per mL)</content></td><td align="justify" valign="top"/></tr><tr><td align="left" valign="top">25021-753-02</td><td align="left" valign="top">20 mg per 2 mL Single-Dose Vial</td><td align="left" valign="top">25 vials per carton</td></tr><tr><td align="left" valign="top"> </td><td align="left" valign="top"/><td align="left" valign="top"/></tr><tr><td align="justify" valign="top"><content styleCode="bold">NDC</content></td><td align="justify" valign="top"><content styleCode="bold">Famotidine Injection, USP (Preservative)</content></td><td align="justify" valign="top"><content styleCode="bold">Package Factor</content></td></tr><tr><td align="justify" valign="top"/><td align="justify" valign="top"><content styleCode="bold">(10 mg per mL)</content></td><td align="justify" valign="top"/></tr><tr><td align="left" valign="top">25021-754-04</td><td align="left" valign="top">40 mg per 4 mL Two-Dose Vial</td><td align="left" valign="top">10 vials per carton</td></tr><tr><td align="left" valign="top">25021-754-20</td><td align="left" valign="top">200 mg per 20 mL Multi-Dose Vial</td><td align="left" valign="top">10 vials per carton</td></tr></tbody></table>

Storage Conditions Store refrigerated between 2° and 8°C (36° and 46°F). If solution freezes, bring to room temperature; allow sufficient time to solubilize all the components. Although diluted Famotidine Injection has been shown to be physically and chemically stable for 7 days at room temperature, there are no data on the maintenance of sterility after dilution. Therefore, it is recommended that if not used immediately after preparation, diluted solutions of Famotidine Injection should be refrigerated and used within 48 hours (see DOSAGE AND ADMINISTRATION ). Sterile, Nonpyrogenic. The container closure is not made with natural rubber latex. sagent ® Mfd. for SAGENT Pharmaceuticals Schaumburg, IL 60195 (USA) Made in India ©2024 Sagent Pharmaceuticals August 2024

<table ID="t6" width="100%"><caption>Table 6: Pharmacokinetic Parameters ^aof Intravenous Famotidine </caption><col width="20.956%" align="left"/><col width="14.997%" align="left"/><col width="21.016%" align="left"/><col width="18.016%" align="left"/><col width="25.015%" align="left"/><tfoot><tr><td colspan="5" align="left" valign="top"><paragraph styleCode="footnote">^aValues are presented as means &#xB1; SD unless indicated otherwise </paragraph></td></tr><tr><td colspan="5" align="left" valign="top"><paragraph styleCode="footnote">^bMean value only </paragraph></td></tr><tr><td colspan="5" align="left" valign="top"><paragraph styleCode="footnote">^cSingle center study </paragraph></td></tr><tr><td colspan="5" align="left" valign="top"><paragraph styleCode="footnote">^dMulticenter study </paragraph></td></tr></tfoot><tbody><tr><td align="center" styleCode="Toprule Botrule Lrule Rrule" valign="top">Age (N=number of patients) </td><td align="center" styleCode="Toprule Botrule Rrule" valign="top">Area Under the Curve (AUC) (ng-hr/mL) </td><td align="center" styleCode="Toprule Botrule Rrule" valign="top">Total Clearance (Cl) (L/hr/kg) </td><td align="center" styleCode="Toprule Botrule Rrule" valign="top">Volume of Distribution (V _d) (L/kg) </td><td align="center" styleCode="Toprule Botrule Rrule" valign="top">Elimination Half-Life (T _1/2) (hours) </td></tr><tr><td align="center" styleCode="Botrule Lrule Rrule" valign="top">0 to 1 month ^c (N=10) </td><td align="center" styleCode="Botrule Rrule" valign="top">NA</td><td align="center" styleCode="Botrule Rrule" valign="top">0.13 &#xB1; 0.06</td><td align="center" styleCode="Botrule Rrule" valign="top">1.4 &#xB1; 0.4</td><td align="center" styleCode="Botrule Rrule" valign="top">10.5 &#xB1; 5.4</td></tr><tr><td align="center" styleCode="Botrule Lrule Rrule" valign="top">0 to 3 months ^d (N=6) </td><td align="center" styleCode="Botrule Rrule" valign="top">2688 &#xB1; 847</td><td align="center" styleCode="Botrule Rrule" valign="top">0.21 &#xB1; 0.06</td><td align="center" styleCode="Botrule Rrule" valign="top">1.8 &#xB1; 0.3</td><td align="center" styleCode="Botrule Rrule" valign="top">8.1 &#xB1; 3.5</td></tr><tr><td align="center" styleCode="Botrule Lrule Rrule" valign="top">&gt;3 to 12 months ^d (N=11) </td><td align="center" styleCode="Botrule Rrule" valign="top">1160 &#xB1; 474</td><td align="center" styleCode="Botrule Rrule" valign="top">0.49 &#xB1; 0.17</td><td align="center" styleCode="Botrule Rrule" valign="top">2.3 &#xB1; 0.7</td><td align="center" styleCode="Botrule Rrule" valign="top">4.5 &#xB1; 1.1</td></tr><tr><td align="center" styleCode="Botrule Lrule Rrule" valign="top">1 to 11 yrs (N=20) </td><td align="center" styleCode="Botrule Rrule" valign="top">1089 &#xB1; 834</td><td align="center" styleCode="Botrule Rrule" valign="top">0.54 &#xB1; 0.34</td><td align="center" styleCode="Botrule Rrule" valign="top">2.07 &#xB1; 1.49</td><td align="center" styleCode="Botrule Rrule" valign="top">3.38 &#xB1; 2.6</td></tr><tr><td align="center" styleCode="Botrule Lrule Rrule" valign="top">11 to 15 yrs (N=6) </td><td align="center" styleCode="Botrule Rrule" valign="top">1140 &#xB1; 320</td><td align="center" styleCode="Botrule Rrule" valign="top">0.48 &#xB1; 0.14</td><td align="center" styleCode="Botrule Rrule" valign="top">1.5 &#xB1; 0.4</td><td align="center" styleCode="Botrule Rrule" valign="t

n="top">11 to 15 yrs (N=6) </td><td align="center" styleCode="Botrule Rrule" valign="top">1140 &#xB1; 320</td><td align="center" styleCode="Botrule Rrule" valign="top">0.48 &#xB1; 0.14</td><td align="center" styleCode="Botrule Rrule" valign="top">1.5 &#xB1; 0.4</td><td align="center" styleCode="Botrule Rrule" valign="t op">2.3 &#xB1; 0.4</td></tr><tr><td align="center" styleCode="Botrule Lrule Rrule" valign="top">Adult (N=16) </td><td align="center" styleCode="Botrule Rrule" valign="top">1726 ^b</td><td align="center" styleCode="Botrule Rrule" valign="top">0.39 &#xB1; 0.14</td><td align="center" styleCode="Botrule Rrule" valign="top">1.3 &#xB1; 0.2</td><td align="center" styleCode="Botrule Rrule" valign="top">2.83 &#xB1; 0.99</td></tr></tbody></table>

althy adult subjects</td><td align="center" styleCode="Botrule Rrule" valign="top">26.5 &#xB1; 10.3</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">b) Adult patients with upper GI bleeding</td><td align="center" styleCode="Botrule Rrule" valign="top">18.7 &#xB1; 10.8</td></tr></tbody></table> <table ID="t8" width="100%"><caption>Table 8</caption><col width="25.381%" align="left"/><col width="8.702%" align="left"/><col width="43.311%" align="left"/><col width="22.606%" align="left"/><tfoot><tr><td colspan="4" align="left" valign="top"><paragraph styleCode="footnote">^aValues reported in published literature </paragraph></td></tr><tr><td colspan="4" align="left" valign="top"><paragraph styleCode="footnote">^bMeans &#xB1; SD </paragraph></td></tr><tr><td colspan="4" align="left" valign="top"><paragraph styleCode="footnote">^cMean (95% confidence interval) </paragraph></td></tr></tfoot><tbody><tr><td align="justify" styleCode="Toprule Botrule Lrule Rrule" valign="middle"><content styleCode="bold">Dosage</content></td><td align="center" styleCode="Toprule Botrule Rrule" valign="middle"><content styleCode="bold">Route</content></td><td align="center" styleCode="Toprule Botrule Rrule" valign="middle"><content styleCode="bold">Effect</content><content styleCode="bold">^a</content></td><td align="center" styleCode="Toprule Botrule Rrule" valign="middle"><content styleCode="bold">Number of Patients</content> <content styleCode="bold">(age range)</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">0.5 mg/kg, single-dose</td><td align="center" styleCode="Botrule Rrule" valign="top">IV</td><td align="justify" styleCode="Botrule Rrule" valign="top">gastric pH &gt;4 for 19.5 hours (17.3, 21.8) ^c</td><td align="center" styleCode="Botrule Rrule" valign="top">11 (5 to 19 days)</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">0.3 mg/kg, single-dose</td><td align="center" styleCode="Botrule Rrule" valign="top">IV</td><td align="left" styleCode="Botrule Rrule" valign="top">gastric pH &gt;3.5 for 8.7 &#xB1; 4.7 ^bhours </td><td align="center" styleCode="Botrule Rrule" valign="top">6 (2 to 7 years)</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">0.4 to 0.8 mg/kg</td><td align="center" styleCode="Botrule Rrule" valign="top">IV</td><td align="left" styleCode="Botrule Rrule" valign="top">gastric pH &gt;4 for 6 to 9 hours</td><td align="center" styleCode="Botrule Rrule" valign="top">18 (2 to 69 months)</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">0.5 mg/kg, single-dose</td><td align="center" styleCode="Botrule Rrule" valign="top">IV</td><td align="justify" styleCode="Botrule Rrule" valign="top">a &gt;2 pH unit increase above baseline in gastric pH for &gt;8 hours</td><td align="center" styleCode="Botrule Rrule" valign="top">9 (2 to 13 years)</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">0.5 mg/kg b.i.d.</td><td align="center" styleCode="Botrule Rrule" valign="top">IV</td><td align="left" styleCode="Botrule Rrule" valign="top">gastric pH &gt;5 for 13.5 &#xB1; 1.8 ^bhours </td><td align="center" styleCode="Botrule Rrule" valign="top">4 (6 to 15 years)</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">0.5 mg/kg b.i.d.</td><td align="center" styleCode="Botrule Rrule" valign="top">Oral</td><td align="left" styleCode="Botrule Rrule" valign="top">gastric pH &gt;5 for 5 &#xB1; 1.1 ^bhours </td><td align="center" styleCode="Botrule Rrule" valign="top">4 (11 to 15 years)</td></tr></tbody></table>

PRECAUTIONS General Symptomatic response to therapy with famotidine does not preclude the presence of gastric malignancy. Patients with Moderate or Severe Renal Insufficiency Since CNS adverse effects have been reported in patients with moderate and severe renal insufficiency, longer intervals between doses or lower doses may need to be used in patients with moderate (creatinine clearance <50 mL/min) or severe (creatinine clearance <10 mL/min) renal insufficiency to adjust for the longer elimination half-life of famotidine (see CLINICAL PHARMACOLOGY IN ADULTS , DOSAGE AND ADMINISTRATION ). Drug Interactions No drug interactions have been identified. Studies with famotidine in man, in animal models, and in vitro have shown no significant interference with the disposition of compounds metabolized by the hepatic microsomal enzymes, e.g., cytochrome P450 system. Compounds tested in man include warfarin, theophylline, phenytoin, diazepam, aminopyrine and antipyrine. Indocyanine green as an index of hepatic drug extraction has been tested and no significant effects have been found. Carcinogenesis, Mutagenesis, Impairment of Fertility In a 106 week study in rats and a 92 week study in mice given oral doses of up to 2000 mg/kg/day (approximately 2500 times the recommended human dose for active duodenal ulcer), there was no evidence of carcinogenic potential for famotidine. Famotidine was negative in the microbial mutagen test (Ames test) using Salmonella typhimurium and Escherichia coli with or without rat liver enzyme activation at concentrations up to 10,000 mcg/plate. In in vivo studies in mice, with a micronucleus test and a chromosomal aberration test, no evidence of a mutagenic effect was observed. In studies with rats given oral doses of up to 2000 mg/kg/day or intravenous doses of up to 200 mg/kg/day, fertility and reproductive performance were not affected. Pregnancy 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 IV 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 (250 times the usual human dose) 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. Nursing Mothers Studies performed in lactating rats have shown that famotidine is secreted into breast milk. Transient growth depression was observed in young rats suckling from mothers treated with maternotoxic doses of at least 600 times the usual human dose. Famotidine is detectable in human milk. Because of the potential for serious adverse reactions in nursing infants from famotidine, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Patients <1 Year of Age Use of famotidine in pediatric patients <1 year of age is supported by evidence from adequate and well-controlled studies of famotidine in adults, and by the following studies in pediatric patients <1 year of age.

Carcinogenesis, Mutagenesis, Impairment of Fertility In a 106 week study in rats and a 92 week study in mice given oral doses of up to 2000 mg/kg/day (approximately 2500 times the recommended human dose for active duodenal ulcer), there was no evidence of carcinogenic potential for famotidine. Famotidine was negative in the microbial mutagen test (Ames test) using Salmonella typhimurium and Escherichia coli with or without rat liver enzyme activation at concentrations up to 10,000 mcg/plate. In in vivo studies in mice, with a micronucleus test and a chromosomal aberration test, no evidence of a mutagenic effect was observed. In studies with rats given oral doses of up to 2000 mg/kg/day or intravenous doses of up to 200 mg/kg/day, fertility and reproductive performance were not affected.

Pregnancy 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 IV 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 (250 times the usual human dose) 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.

ADVERSE REACTIONS The adverse reactions listed below have been reported during domestic and international clinical trials in approximately 2500 patients. In those controlled clinical trials in which famotidine tablets were compared to placebo, the incidence of adverse experiences in the group which received famotidine tablets, 40 mg at bedtime, was similar to that in the placebo group. The following adverse reactions have been reported to occur in more than 1% of patients on therapy with famotidine in controlled clinical trials, and may be causally related to the drug: headache (4.7%), dizziness (1.3%), constipation (1.2%) and diarrhea (1.7%). The following other adverse reactions have been reported infrequently in clinical trials or since the drug was marketed. The relationship to therapy with famotidine has been unclear in many cases. Within each category the adverse reactions are listed in order of decreasing severity. Body as a Whole: fever, asthenia, fatigue Cardiovascular: arrhythmia, AV block, palpitation, prolonged QT interval Gastrointestinal: cholestatic jaundice, hepatitis, elevated liver enzyme, vomiting, nausea, abdominal discomfort, anorexia, dry mouth Hematologic: agranulocytosis, pancytopenia, leukopenia, thrombocytopenia Hypersensitivity: anaphylaxis, angioedema, orbital or facial edema, urticaria, rash, conjunctival injection, bronchospasm Musculoskeletal: rhabdomyolysis, musculoskeletal pain, muscle cramps, arthralgia Nervous System/Psychiatric: seizure, hallucinations, confusion, agitation, depression, anxiety, decreased libido, paresthesia, insomnia, somnolence Respiratory: interstitial pneumonia Skin: toxic epidermal necrolysis/Stevens Johnson syndrome, pruritus, dry skin, flushing Special Senses: tinnitus, taste disorder Other: impotence The adverse reactions reported for Famotidine Tablets may also occur with Famotidine for Oral Suspension or Famotidine Injection. In addition, transient irritation at the injection site has been observed with Famotidine Injection. Pediatric Patients In a clinical study in 35 pediatric patients <1 year of age with GERD symptoms [e.g. vomiting (spitting up), irritability (fussing)], agitation was observed in 5 patients on famotidine that resolved when the medication was discontinued. To report SUSPECTED ADVERSE REACTIONS, contact Athenex Pharmaceutical Division, LLC. at 1-855-273-0154 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

OVERDOSAGE The adverse reactions in overdose cases are similar to the adverse reactions encountered in normal clinical experience (see ADVERSE REACTIONS ). Oral doses of up to 640 mg/day have been given to adult patients with pathological hypersecretory conditions with no serious adverse effects. 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. The intravenous LD 50 of famotidine for mice and rats ranged from 254 to 563 mg/kg and the minimum lethal single IV dose in dogs was approximately 300 mg/kg. Signs of acute intoxication in IV treated dogs were emesis, restlessness, pallor of mucous membranes or redness of mouth and ears, hypotension, tachycardia and collapse. The oral LD 50 of famotidine in male and female rats and mice was greater than 3000 mg/kg and the minimum lethal acute oral dose in dogs exceeded 2000 mg/kg. Famotidine did not produce overt effects at high oral doses in mice, rats, cats and dogs, but induced significant anorexia and growth depression in rabbits starting with 200 mg/kg/day orally.

HOW SUPPLIED FOR INTRAVENOUS USE ONLY Famotidine Injection, USP, is supplied as follows: Famotidine Injection, USP (Preservative-free) NDC (10 mg per mL) Package Factor 70860-751-02 20 mg per 2 mL Single-Dose Vial 25 vials per carton Famotidine Injection, USP (Preservative) NDC (10 mg per mL) Package Factor 70860-752-04 40 mg per 4 mL Two-Dose Vial 10 vials per carton 70860-753-20 200 mg per 20 mL Multi-Dose Vial 10 vials per carton Storage Conditions Store Famotidine Injection refrigerated between 2° and 8°C (36° and 46°F). If solution freezes, bring to room temperature; allow sufficient time to solubilize all the components. Although diluted Famotidine Injection has been shown to be physically and chemically stable for 7 days at room temperature, there are no data on the maintenance of sterility after dilution. Therefore, it is recommended that if not used immediately after preparation, diluted solutions of Famotidine Injection should be refrigerated and used within 48 hours (see DOSAGE AND ADMINISTRATION ). Sterile, Nonpyrogenic. The container closure is not made with natural rubber latex. Athenex Mfd. for Athenex Schaumburg, IL 60173 (USA) Made in India ©2020 Athenex July 2020

<table width="100%" styleCode="Noautorules"><col width="21.800%" align="left"/><col width="52.633%" align="left"/><col width="25.567%" align="left"/><tbody><tr><td align="justify" valign="top"/><td align="justify" valign="top"><content styleCode="bold">Famotidine Injection, USP (Preservative-free)</content></td><td align="justify" valign="top"/></tr><tr><td align="justify" valign="top"><content styleCode="bold">NDC</content></td><td align="justify" valign="top"><content styleCode="bold">(10 mg per mL)</content></td><td align="justify" valign="top"><content styleCode="bold">Package Factor</content></td></tr><tr><td align="left" valign="top">70860-751-02</td><td align="left" valign="top">20 mg per 2 mL Single-Dose Vial</td><td align="left" valign="top">25 vials per carton</td></tr><tr><td align="left" valign="top"> </td><td align="left" valign="top"/><td align="left" valign="top"/></tr><tr><td align="justify" valign="top"/><td align="justify" valign="top"><content styleCode="bold">Famotidine Injection, USP (Preservative)</content></td><td align="justify" valign="top"/></tr><tr><td align="justify" valign="top"><content styleCode="bold">NDC</content></td><td align="justify" valign="top"><content styleCode="bold">(10 mg per mL)</content></td><td align="justify" valign="top"><content styleCode="bold">Package Factor</content></td></tr><tr><td align="left" valign="top">70860-752-04</td><td align="left" valign="top">40 mg per 4 mL Two-Dose Vial</td><td align="left" valign="top">10 vials per carton</td></tr><tr><td align="left" valign="top">70860-753-20</td><td align="left" valign="top">200 mg per 20 mL Multi-Dose Vial</td><td align="left" valign="top">10 vials per carton</td></tr></tbody></table>

Storage Conditions Store Famotidine Injection refrigerated between 2° and 8°C (36° and 46°F). If solution freezes, bring to room temperature; allow sufficient time to solubilize all the components. Although diluted Famotidine Injection has been shown to be physically and chemically stable for 7 days at room temperature, there are no data on the maintenance of sterility after dilution. Therefore, it is recommended that if not used immediately after preparation, diluted solutions of Famotidine Injection should be refrigerated and used within 48 hours (see DOSAGE AND ADMINISTRATION ). Sterile, Nonpyrogenic. The container closure is not made with natural rubber latex. Athenex Mfd. for Athenex Schaumburg, IL 60173 (USA) Made in India ©2020 Athenex July 2020