PEPCID Film-coated tablet Ref.[10595] Active ingredients: Famotidine

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 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.

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 (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.

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.

14.1 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:

^* p<0.001 vs. placebo

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:

^* p≤0.01 vs. placebo
^† p≤0.05 vs. placebo

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):

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):

^* p≤0.01 vs. placebo
^† p≤0.01 vs. PEPCID 20 mg twice daily
^‡ p≤0.05 vs. PEPCID 20 mg twice daily

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):

^* p≤0.05 vs ranitidine 150 mg twice daily

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.