Famotidine

Famotidine is a potent competitive H₂-receptor antagonist. 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. Famotidine has a rapid onset of action and, at the recommended doses, has a long duration of action and is highly effective at relatively low blood concentrations.

Duration of action, plasma concentration and urinary recovery are dose related.

Famotidine reduces the acid and pepsin content, as well as the volume of basal, nocturnal and stimulated gastric secretion.

In clinical trials, famotidine provided effective and rapid symptom relief. When administered 15 minutes before a test meal, famotidine reduced symptoms that would otherwise have been expected. Administration of famotidine before an evening meal prevented nocturnal acid-related symptoms and therefore prevented symptom-related interference with sleep.

After oral administration, a dose-response relationship was clearly demonstrated for doses from 0.5 to 10 mg famotidine in terms of raising gastric pH between and after meals. Famotidine doses of 2.5 to 10 mg were demonstrated to produce a statistically significant effect on gastric pH as compared to placebo. The onset of effect for the 5 and 10 mg doses was seen at approximately 1.5 hours post-dose, while that of the 2.5 mg dose was not seen until 2.5 hours post-dose.

The maximum effect, as measured by peak mean pH value, occurred at 3.5 hours. The activity of the 5 and 10 mg doses continued until approximately 9 hours post-dose in daytime studies. Additionally, two night-time studies demonstrated that famotidine 10mg statistically significantly increased gastric pH for 12 hours post-dose as compared to placebo. Famotidine is well tolerated at these dose levels.

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.

Systemic effects of famotidine in the CNS, cardiovascular, respiratory or endocrine systems were not noted in clinical pharmacology studies. Serum hormone levels, including prolactin, cortisol, thyroxine (T4) and testosterone were not altered after treatment with famotidine.

Famotidine obeys linear kinetics.

In pharmacokinetic studies in the elderly, no clinically significant age-related changes were detected. However, in elderly patients with decreased renal function, the clearance of the drug may be decreased.

Compared to historical data from younger subjects, age does not appear to affect the bioavailability of single doses of famotidine: however, the elimination appears to be reduced in elderly subjects compared with younger subjects.

Famotidine is rapidly absorbed with dose-related peak plasma concentrations occurring at 1-3 hours. The mean bioavailability of an oral dose is 40-45%. Bioavailability is not clinically affected by the presence of food in the stomach. Famotidine undergoes minimal first-pass metabolism. Repeated doses do not lead to accumulation of the drug.

Protein binding in the plasma is relatively low (15-20%). The plasma half-life after a single oral dose or multiple repeated doses (for five days) was approximately three hours.

Metabolism of the drug occurs in the liver, with formation of the inactive sulphoxide metabolite.

Following oral administration, the mean urinary excretion of the absorbed dose of famotidine is 65-70%. Of the total oral dose administered, 25-30% is recovered as unchanged compound in the urine. Renal clearance is 250-450 ml/min, indicating some tubular excretion. Twenty-five to 30% of an oral dose and 65-70% of an intravenous dose are recovered in the urine as unchanged compound. The only metabolite identified in man is the S-oxide.

A 10mg chewable tablet of famotidine was found to be bioequivalent to a 10mg film-coated tablet of famotidine.

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.

The LD₅₀ of famotidine in CD-1 mice and Sprague-Dawley rats was in excess of 5g/kg (orally) and in excess of 400mg/kg intravenously.

Extensive preclinical safety studies have been performed in dogs, rats, mice and rabbits using oral and intravenous routes of administration of famotidine.

Minimal toxicological effects (after acute, subacute or chronic administration) have been observed, even at extremely high dosage levels (4000mg/kg/day) and for extended periods of administration. (2000 mg/kg/day for 105 weeks).

No evidence of teratogenic, mutagenic or carcinogenic effects or alteration of reproductive function have been seen. In a 106-week study in rats and a 92-week study in mice given oral doses of up to 2000mg/kg/day (approximately 5000 times the maximum recommended human dose), there was no evidence of carcinogenic potential for famotidine.

Famotidine was negative in the microbial mutagen test (Ames test) using Salmonella typhimurium and Escherichia coil with or without rat liver enzyme activation at concentrations of up to 10000mcg/plate. In in vivo studies in mice, a micronucleus test and a chromosomal aberration test, no evidence of mutagenic effect was observed.