CLINICAL PHARMACOLOGY IN ADULTS
GI Effects
Famotidine is a competitive inhibitor of histamine H2-receptors. 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.
In normal volunteers and hypersecretors, famotidine inhibited basal and nocturnal gastric secretion, as well as secretion stimulated by food and pentagastrin. After oral administration, 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 and 40 mg was 10 to 12 hours.
Single evening oral doses of 20 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 6-8 hours. There was no cumulative effect with repeated doses. The nocturnal intragastric pH was raised by evening doses of 20 and 40 mg of famotidine to mean values of 5.0 and 6.4, respectively. When famotidine was given after breakfast, the basal daytime interdigestive pH at 3 and 8 hours after 20 or 40 mg of famotidine was raised to about 5.
Famotidine had little or no effect on fasting or postprandial serum gastrin levels. Gastric emptying and exocrine pancreatic function were not affected by famotidine.
Other Effects
Systemic effects of famotidine in the CNS, cardiovascular, respiratory or endocrine systems were not noted in clinical pharmacology studies. Also, no antiandrogenic effects were noted. (See ADVERSE REACTIONS.) Serum hormone levels, including prolactin, cortisol, thyroxine (T4), and testosterone, were not altered after treatment with famotidine.
Pharmacokinetics
Famotidine is incompletely absorbed. The bioavailability of oral doses is 40-45%. Bioavailability may be slightly increased by food, or slightly decreased by antacids; however, these effects are of no clinical consequence. Famotidine undergoes minimal first-pass metabolism. The peak plasma concentration is reached about 2½ hours after administration of FLUXID™. Plasma levels after multiple doses are similar to those after single doses. Fifteen to 20% of famotidine in plasma is protein bound. The elimination half-life of famotidine is approximately 5 hours after administration of FLUXID™. Famotidine is eliminated by renal (65-70%) and metabolic (30-35%) routes. 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.
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 (see PRECAUTIONS, DOSAGE AND ADMINISTRATION).
In elderly patients, there are no clinically significant age-related changes in the pharmacokinetics of famotidine. However, in elderly patients with decreased renal function, the clearance of the drug may be decreased (see PRECAUTIONS, Geriatric Use).
Clinical Studies
Duodenal Ulcer
In a U.S. multicenter, double-blind study in outpatients with endoscopically confirmed duodenal ulcer, orally administered famotidine was compared to placebo. As shown in Table 1, 70% of patients treated with famotidine 40 mg h.s. were healed by week 4.
Table 1 Outpatients with Endoscopically Confirmed Healed Duodenal Ulcers | Famotidine
40 mg h.s.
(N=89) | Famotidine
20 mg b.i.d. (N=84) | Placebo
h.s.
(N=97) |
| Week 2 |
32% | 38% | 17% |
| Week 4 | 70% | 67% | 31% |
Patients not healed by week 4 were continued in the study. By week 8, 83% of patients treated with famotidine had healed versus 45% of patients treated with placebo. The incidence of ulcer healing with famotidine was significantly higher than with placebo at each time point based on proportion of endoscopically confirmed healed ulcers.
In this study, time to relief of daytime and nocturnal pain was significantly shorter for patients receiving famotidine than for patients receiving placebo; patients receiving famotidine also took less antacid than the patients receiving placebo.
Long-Term Maintenance
Treatment of Duodenal Ulcers
Famotidine, 20 mg p.o. h.s. was compared to placebo h.s. as maintenance therapy in two double-blind, multicenter studies of patients with endoscopically confirmed healed duodenal ulcers. In the U.S. study, the observed ulcer incidence within 12 months in patients treated with placebo was 2.4 times greater than in the patients treated with famotidine. The 89 patients treated with famotidine had a cumulative observed ulcer incidence of 23.4% compared to an observed ulcer incidence of 56.6% in the 89 patients receiving placebo (p<0.01). These results were confirmed in an international study where the cumulative observed ulcer incidence within 12 months in the 307 patients treated with famotidine was 35.7%, compared to an incidence of 75.5% in the 325 patients treated with placebo (p<0.01).
Gastric Ulcer
In both a U.S. and an international multicenter, double-blind study in patients with endoscopically confirmed active benign gastric ulcer, orally administered famotidine, 40 mg h.s., was compared to placebo h.s. Antacids were permitted during the studies, but consumption was not significantly different between the famotidine and placebo groups. As shown in Table 2, the incidence of ulcer healing (dropouts counted as unhealed) with famotidine was statistically significantly better than placebo at weeks 6 and 8 in the U.S. study, and at weeks 4, 6 and 8 in the international study, based on the number of ulcers that healed, confirmed by endoscopy.
Table 2 Patients with Endoscopically Confirmed Healed Gastric Ulcers | U.S. Study | International Study |
| Famotidine
40 mg h.s.
(N=74) | Placebo h.s.
(N=75) | Famotidine
40 mg h.s.
(N=149) | Placebo
h.s.
(N=145) |
| Week 4 | 45% | 39% |
47% | 31% |
| Week 6 | 66% | 44% | 65% | 46% |
| Week 8 |
78% | 64% | 80% | 54% |
Time to complete relief of daytime and nighttime pain was statistically significantly shorter for patients receiving famotidine than for patients receiving placebo; however, in neither study was there a statistically significant difference in the proportion of patients whose pain was relieved by the end of the study (week 8).
Gastroesophageal Reflux Disease (GERD)
Orally administered famotidine was compared to placebo in a U.S. study that enrolled patients with symptoms of GERD and without endoscopic evidence of erosion or ulceration of the esophagus. Famotidine 20 mg b.i.d. was statistically significantly superior to 40 mg h.s. and to placebo in providing a successful symptomatic outcome, defined as moderate or excellent improvement of symptoms (Table 3).
Table 3 % Successful Symptomatic Outcome | Famotidine
20 mg b.i.d.
(N=154) | Famotidine
40 mg h.s.
(N=149) |
Placebo
(N=73) |
| Week 6 | 82
| 69 | 62 |
By two weeks of treatment symptomatic success was observed in a greater percentage of patients taking famotidine 20 mg b.i.d. compared to placebo (p < 0.01).
Symptomatic improvement and healing of endoscopically verified erosion and ulceration were studied in two additional trials. Healing was defined as complete resolution of all erosions or ulcerations visible with endoscopy. The U.S. study comparing famotidine 40 mg p.o. b.i.d. to placebo and famotidine 20 mg p.o. b.i.d. showed a significantly greater percentage of healing for famotidine 40 mg b.i.d. at weeks 6 and 12 (Table 4).
Table 4 % Endoscopic Healing – U.S. Study | Famotidine
40 mg b.i.d.
(N=127) | Famotidine
20 mg b.i.d.
(N=125) |
Placebo
(N=66) |
| Week 6 | 48
| 32 | 18 |
| Week 12 | 69
| 54 | 29 |
As compared to placebo, patients who received famotidine had faster relief of daytime and nighttime heartburn and a greater percentage of patients experienced complete relief of nighttime heartburn. These differences were statistically significant.
In the international study, when famotidine 40 mg p.o. b.i.d., was compared to ranitidine 150 mg p.o. b.i.d., a statistically significantly greater percentage of healing was observed with famotidine 40 mg b.i.d. at week 12 (Table 5). There was, however, no significant difference among treatments in symptom relief.
Table 5 % Endoscopic Healing – International Study | Famotidine
40 mg b.i.d.
(N=175) | Famotidine
20 mg b.i.d.
(N=93) | Ranitidine
150 mg b.i.d.
(N=172) |
| Week 6 | 48 | 52 | 42 |
| Week 12 | 71
| 68 | 60 |
Pathological Hypersecretory Conditions (e.g., Zollinger-Ellison Syndrome, Multiple Endocrine Adenomas)
In studies of patients with pathological hypersecretory conditions such as Zollinger-Ellison Syndrome with or without multiple endocrine adenomas, famotidine significantly inhibited gastric acid secretion and controlled associated symptoms. Orally administered doses from 20 to 160 mg q 6 h maintained basal acid secretion below 10 mEq/hr; initial doses were titrated to the individual patient need and subsequent adjustments were necessary with time in some patients. Famotidine was well tolerated at these high dose levels for prolonged periods (greater than 12 months) in eight patients, and there were no cases reported of gynecomastia, increased prolactin levels, or impotence which were considered to be due to the drug.
CLINICAL PHARMACOLOGY IN PEDIATRIC PATIENTS
Pharmacokinetics
Bioavailability studies of 8 pediatric patients (11-15 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/kg achieved an AUC of 580 + 60 ng-hr/mL in pediatric patients 11-15 years of age compared to 482 ± 181 ng-hr/mL in adults treated with 40 mg orally.
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 6).
Table 6 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 |
In 4 pediatric patients 11 – 15 years of age given oral famotidine 0.5 mg/kg twice daily, gastric pH was greater than 5 for 5.0 + 1.1 hours.
|
