Prescription Drug Information: Famotidine (Page 3 of 5)

11 DESCRIPTION

The active ingredient in Famotidine Tablets USP is a histamine-2 (H 2 ) receptor antagonist. Famotidine, USP is [1-Amino-3-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio] propylidene] sulfamide and has the following structural formula:

Structural Formula
(click image for full-size original)

C 8 H 15 N 7 O 2 S 3 M.W. 337.45


Each Famotidine Tablet USP for oral administration contains either 20 mg or 40 mg of famotidine, USP and has the following inactive ingredients: colloidal silicon dioxide, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, pregelatinized corn starch, sodium starch glycolate, talc, titanium dioxide, yellow iron oxide. In addition the 20 mg contains lactose monohydrate, red iron oxide and triacetin and the 40 mg contains FD&C blue No. 2 aluminum lake and FD&C yellow No. 6 aluminum lake.

Famotidine, USP 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.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Famotidine is a competitive inhibitor of histamine-2 (H 2 ) receptors. The primary clinically important pharmacologic activity of famotidine is inhibition of gastric secretion. Both the acid concentration and volume of gastric secretion are suppressed by famotidine, while changes in pepsin secretion are proportional to volume output.

12.2 Pharmacodynamics

Adults

Famotidine inhibited both basal and nocturnal gastric secretion, as well as secretion stimulated by food and pentagastrin. After oral administration of famotidine tablets, 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 famotidine tablets to mean values of 5.0 and 6.4, respectively. When famotidine tablets was given after breakfast, the basal daytime interdigestive pH at 3 and 8 hours after 20 mg 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 tablets.

In clinical pharmacology studies, systemic effects of famotidine 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 famotidine.

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 Famotidine Tablets-Treated Pediatric and Adult Patients a

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

a Using the Sigmoid Emax model, serum concentrations of famotidine associated with 50% maximum gastric acid reduction are presented as means ± SD.

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.

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 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/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 Population ( 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 AUC 0-10h of famotidine increased from 424 to 768 ng•hr/mL and the maximum serum concentration (C max ) 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.

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 famotidine was compared to placebo. As shown in Table 4, 70% of patients treated with famotidine 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 famotidine tablets had healed DU, compared to 45% of patients treated with placebo. The incidence of DU healing with famotidine tablets was greater than with placebo at each time point based on proportion of endoscopically confirmed healed DUs. Trials have not assessed the safety of famotidine tablets in uncomplicated active DU for periods of more than 8 weeks.

Table 4: Patients with Endoscopically Confirmed Healed Duodenal Ulcers

Famotidine 40 mg at bedtime (N=89)

Famotidine 20 mg twice daily (N=84)

Placebo at bedtime (N=97)

Week 2

32% a

38% a

17%

Week 4

70% a

67% a

31%

a p<0.001 vs. placebo

In this study, time to relief of daytime and nocturnal pain was shorter for patients receiving famotidine than for patients receiving placebo; patients receiving famotidine also took less antacid than patients receiving placebo.

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