Famotidine (Page 4 of 5)

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 2,000 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 2,000 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. multicentre, 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 had healed DU, compared to 45% of patients treated with placebo. The incidence of DU healing with famotidine 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 in uncomplicated active DU for periods of more than 8 weeks.

Table 4: Patients with Endoscopically Confirmed Healed Duodenal Ulcers

a p<0.001 vs. placebo

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%

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.

14.2 Active Gastric Ulcer

In both a U.S. and an international multicentre, double-blind trials in patients with endoscopically confirmed active gastric ulcer (GU), orally administered famotidine 40 mg at bedtime was compared to placebo. Antacids were permitted during the trials, but consumption was not significantly different between the famotidine and placebo groups.

As shown in Table 5, the incidence of GU healing confirmed by endoscopy (dropouts counted as unhealed) with famotidine 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 famotidine-treated patients healed within 6 weeks. Trials have not assessed the safety of famotidine in uncomplicated active GU for periods of more than 8 weeks.

Table 5: Patients with Endoscopically Confirmed Healed Gastric Ulcers

a p≤0.01 vs. placebo

b p≤0.05 vs. placebo

U.S Study (N=149) International Study (N=294)
Famotidine 40 mg at bedtime (N=74) Placebo At bedtime (N=75) Famotidine 40 mg at bedtime (N=149) Placebo At bedtime (N=145)
Week 4 45% 39% 47%a 31%
Week 6 66%a 44% 65%a 46%
Week 8 78%b 64% 80%a 54%

Time to complete relief of daytime and night time pain was statistically significantly shorter for patients receiving famotidine 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 famotidine 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 famotidine 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)

a p≤0.01 vs. placebo

Famotidine 20 mg twice daily (N=154) Famotidine 40 mg at bedtime (N=149) Placebo at bedtime (N=73)
Week 6 82%a 69% 62%

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