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 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 tablets 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

Famotidine

40mg at bedtime (N=89)

Famotidine

20mg twice daily (N=84)

Placebo

at bedtime (N=97)

Week 2 32%  a 38%  a 17%
Week 4 70% 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.

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 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
U.S. Study (N=149) International Study (N=294)

Famotidine

40mg at bedtime (N-74)

Placebo

at bedtime (N=75)

Famotidine

40mg 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%

a p≤0.01 vs. placebo b p≤0.05 vs. placebo

Time to complete relief of daytime and nighttime 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)

Famotidine

20mg twice daily (N=154)

Famotidine

40mg at bedtime (N=149)

Placebo

at bedtime (N=73)

Week 6 82%  a 69% 62%

a p≤0.01 vs. placebo

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 Famotidine 40 mg twice daily to placebo and orally administered Famotidine 20 mg twice daily showed a significantly greater percentage of healing of erosive esophagitis for Famotidine 40 mg tablets twice daily at Weeks 6 and 12 (Table 7).

Table 7: Patients with Endoscopic Healing of Erosive Esophagitis — U.S. Study (N=318)

Famotidine

40mg twice daily (N=127)

Famotidine

20mg twice daily (N=125)

Placebo

twice daily (N=66)

Week 6 48% a,b 32% 18%
Week 12 69% a,c 54% a 29%

a p0.01 vs. placebo b p0.01 vs. Famotidine tablets 20 mg twice daily
c p0.05 vs. Famotidine tablets 20 mg twice daily

As compared to placebo, patients in the U.S. trial who received Famotidine had faster relief of daytime and nighttime heartburn, and a greater percentage of Famotidine-treated patients experienced complete relief of nighttime heartburn. These differences were statistically significant. In the international trial, when orally administered Famotidine 40 mg tablets 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 Famotidine 40 mg tablets 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)

Famotidine

40mg twice daily

(N=175)

Famotidine

20mg twice daily

(N=93)

Ranitidine

150mg twice daily

(N=172)

Week 6 48% 52% 42%
Week 12 71%  a 68% 60%

a p≤0.05 vs ranitidine 150 mg twice daily

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