Famotidine (Page 3 of 5)

Pharmacodynamics

Pharmacodynamics of famotidine were evaluated in 5 pediatric patients 2-13 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 one study of adults (Table 7).

* Serum concentration of famotidine associated with 50% maximum gastric acid reduction. Values are presented as means ± SD.

Table 7 Pharmacodynamics of famotidine using the sigmoid Emax model
EC50 (ng/mL)*
Pediatric Patients 26 ± 13
Data from one study
a) healthy adult subjects 26.5 ± 10.3
b) adult patients with upper GI bleeding 18.7 ± 10.8

Five published studies (Table 8) examined the effect of famotidine on gastric pH and duration of acid suppression in pediatric patients. While each study had a different design, acid suppression data over time are summarized as follows:

a Values reported in published literature.

b Means ± SD.

c Mean (95% confidence interval).

Table 8
Dosage Route Effecta Number of Patients (age range)
0.5 mg/kg, single dose I.V. gastric pH >4 for 19.5 hours (17.3, 21.8)c 11 (5-19 days)
0.3 mg/kg, single dose I.V. gastric pH >3.5 for 8.7 ± 4.7b hours 6 (2-7 years)
0.4-0.8 mg/kg I.V. gastric pH >4 for 6-9 hours 18 (2-69 months)
0.5 mg/kg, single dose I.V. a >2 pH unit increase above baseline in gastric pH for >8 hours 9 (2-13 years)
0.5 mg/kg b.i.d. I.V. gastric pH >5 for 13.5 ± 1.8b hours 4 (6-15 years)
0.5 mg/kg b.i.d. oral gastric pH >5 for 5.0 ± 1.1b hours 4 (11-15 years)

The duration of effect of famotidine I.V. 0.5 mg/kg on gastric pH and acid suppression was shown in one study to be longer in pediatric patients <1 month of age than in older pediatric patients. This longer duration of gastric acid suppression is consistent with the decreased clearance in pediatric patients <3 months of age (see Table 6).

INDICATIONS AND USAGE

Famotidine tablets are indicated in:

1. Short term treatment of active duodenal ulcer. Most adult patients heal within 4 weeks; there is rarely reason to use famotidine at full dosage for longer than 6 to 8 weeks. Studies have not assessed the safety of famotidine in uncomplicated active duodenal ulcer for periods of more than eight weeks.

2. Maintenance therapy for duodenal ulcer patients at reduced dosage after healing of an active ulcer. Controlled studies in adults have not extended beyond one year.

3. Short term treatment of active benign gastric ulcer. Most adult patients heal within 6 weeks. Studies have not assessed the safety or efficacy of famotidine in uncomplicated active benign gastric ulcer for periods of more than 8 weeks.

4. Short term treatment of gastroesophageal reflux disease (GERD). Famotidine is indicated for short term treatment of patients with symptoms of GERD (see CLINICAL PHARMACOLOGY IN ADULTS, Clinical Studies).

Famotidine is also indicated for the short term treatment of esophagitis due to GERD including erosive or ulcerative disease diagnosed by endoscopy (see CLINICAL PHARMACOLOGY IN ADULTS, Clinical Studies).

5. Treatment of pathological hypersecretory conditions (e.g., Zollinger-Ellison Syndrome, multiple endocrine adenomas) (see CLINICAL PHARMACOLOGY IN ADULTS, Clinical Studies).

CONTRAINDICATIONS

Hypersensitivity to any component of this product. Cross sensitivity in this class of compounds has been observed. Therefore, famotidine should not be administered to patients with a history of hypersensitivity to other H2 -receptor antagonists.

PRECAUTIONS

General

Symptomatic response to therapy with famotidine does not preclude the presence of gastric malignancy.

Patients with Moderate or Severe Renal Insufficiency

Since CNS adverse effects have been reported in patients with moderate and severe renal insufficiency, longer intervals between doses or lower doses may need to be used in patients with moderate (creatinine clearance <50 mL/min) or severe (creatinine clearance <10 mL/min) renal insufficiency to adjust for the longer elimination half-life of famotidine (See CLINICAL PHARMACOLOGY IN ADULTS and DOSAGE AND ADMINISTRATION). Prolonged QT interval has been reported very rarely in patients with impaired renal function whose dose/dosing interval of famotidine may not have been adjusted appropriately.

Drug Interactions

No drug interactions have been identified. Studies with famotidine in man, in animal models, and in vitro have shown no significant interference with the disposition of compounds metabolized by the hepatic microsomal enzymes, e.g., cytochrome P450 system. Compounds tested in man include warfarin, theophylline, phenytoin, diazepam, aminopyrine and antipyrine. Indocyanine green as an index of hepatic drug extraction has been tested and no significant effects have been found.

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 106-week study in rats and a 92-week study in mice given oral doses of up to 2000 mg/kg/day (approximately 2500 times the recommended human dose for active duodenal ulcer), 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 or intravenous doses of up to 200 mg/kg/day, fertility and reproductive performance were not affected.

Pregnancy

Pregnancy Category B

Reproductive studies have been performed in rats and rabbits at oral doses of up to 2000 and 500 mg/kg/day, respectively, and in both species at l.V. doses of up to 200 mg/kg/day, and have revealed no significant evidence of impaired fertility or harm to the fetus due to famotidine. While no direct fetotoxic effects have been observed, sporadic abortions occurring only in mothers displaying marked decreased food intake were seen in some rabbits at oral doses of 200 mg/kg/day (250 times the usual human dose) or higher. There are, however, no adequate or well-controlled studies in pregnant women. Because animal reproductive studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

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