FAMOTIDINE — famotidine for suspension
Novel Laboratories, Inc.
The active ingredient in Famotidine for Oral Suspension is a histamine H2 -receptor antagonist. Famotidine is N-(aminosulfonyl)-3-[[[2-[(diaminomethylene)amino]-4- thiazolyl]methyl]thio]propanimidamide. The empirical formula of famotidine is C8 H15 N7 O2 S3 and its molecular weight is 337.43. Its structural formula is:
Each 5 mL of the oral suspension when prepared as directed contains 40 mg of famotidine and the following inactive ingredients: anhydrous citric acid, flavors (cherry, banana, and mint), microcrystalline cellulose and carboxymethylcellulose sodium, confectioner’s sugar, corn starch, colloidal silicon-dioxide and xanthan gum. Added as preservatives are sodium benzoate and sodium methylparaben.
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 to 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.
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.
Famotidine is incompletely absorbed. The bioavailability of oral doses is 40 to 45%. Famotidine Tablets and Famotidine for Oral Suspension are bioequivalent. 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. After oral doses, peak plasma levels occur in 1 to 3 hours. Plasma levels after multiple doses are similar to those after single doses. Fifteen to 20% of Famotidine in plasma is protein bound. Famotidine has an elimination half-life of 2.5 to 3.5 hours. Famotidine is eliminated by renal (65 to 70%) and metabolic (30 to 35%) routes. Renal clearance is 250 to 450 mL/min, indicating some tubular excretion. Twenty-five to 30% of an oral dose and 65 to 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).
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.
|Famotidine 40 mg h.s. (N = 89)||Famotidine 20 mg b.i.d. (N = 84)||Placebo h.s (N = 97)|
|** Statistically significantly different than placebo (p<0.001)|
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.
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).
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.
|U.S. Study||International Study|
|***,† Statistically significantly better than placebo (p≤0.05, p≤0.01 respectively)|
|Famotidine 40 mg h.s. (N=74)||Placebo h.s. (N=75)||Famotidine 40 mg h.s. (N=149)||Placebo h.s. (N=145)|
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).
|Famotidine 20 mg b.i.d. (N=154)||Famotidine 40 mg h.s. (N=149)||Placebo (N=73)|
|†† p≤0.01 vs Placebo|
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).
|Famotidine 40 mg b.i.d. (N=127)||Famotidine 20 mg b.i.d. (N=125)||Placebo (N=66)|
|††† p≤0.01 vs Placebo‡ p≤0.05 vs Famotidine 20 mg b.i.d.‡‡ p≤0.01 vs Famotidine 20 mg b.i.d.|
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.
|Famotidine 40 mg b.i.d.(N=175)||Famotidine 20 mg b.i.d.(N=93)||Ranitidine 150 mg b.i.d.(N=172)|
|‡‡‡ p≤0.05 vs Ranitidine 150 mg b.i.d.|
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.
Table 6 presents pharmacokinetic data from clinical trials and a published study in pediatric patients (<1 year of age; N=27) given famotidine I.V. 0.5 mg/kg and from published studies of small numbers of pediatric patients (1 to 15 years of age) given famotidine intravenously. Areas under the curve (AUCs) are normalized to a dose of 0.5 mg/kg I.V. for pediatric patients 1 to 15 years of age and compared with an extrapolated 40 mg intravenous dose in adults (extrapolation based on results obtained with a 20 mg I.V. adult dose).
|Age (N=number of patients)||Area Under the Curve (AUC) (ng hr/mL)||Total Clearance (Cl) (L/hr/kg)||Volume of Distribution (V d ) (L/kg)||Elimination Half-life (T 1/2 ) (hours)|
|a Values are presented as means ±SD unless indicated otherwise.b Mean value only.c Single center study.d Multicenter study.|
|0-1 monthc (N=10)||NA||0.13 ± 0.06||1.4 ± 0.4||10.5 ± 5.4|
|0-3 monthsd (N=6)||2688 ± 847||0.21 ± 0.06||1.8 ± 0.3||8.1 ± 3.5|
|>3–12 monthsd (N=11)||1160 ± 474||0.49 ± 0.17||2.3 ± 0.7||4.5 ± 1.1|
|1-11 yrs (N=20)||1089 ± 834||0.54 ± 0.34||2.07 ± 1.49||3.38 ± 2.60|
|11-15 yrs (N=6)||1140 ± 320||0.48 ± 0.14||1.5 ± 0.4||2.3 ± 0.4|
|Adult (N=16)||1726b||0.39 ± 0.14||1.3 ± 0.2||2.83 ± 0.99|
Plasma clearance is reduced and elimination half-life is prolonged in pediatric patients 0 to 3 months of age compared to older pediatric patients. The pharmacokinetic parameters for pediatric patients, ages >3 months to 15 years, are comparable to those obtained for adults.
Bioavailability studies of 8 pediatric patients (11 to 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 AUCs of 645 ± 249 ng-hr/mL and 580 ± 60 ng-hr/mL in pediatric patients <1 year of age (N=5) and in pediatric patients 11 to 15 years of age, respectively, compared to 482 ± 181 ng-hr/mL in adults treated with 40 mg orally.
Pharmacodynamics of famotidine were evaluated in 5 pediatric patients 2 to 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).
|EC 50 (ng/mL)*|
|*Serum concentration of famotidine associated with 50% maximum gastric acid reduction. Values are presented as means ± SD.|
|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:
|Dosage||Route||Effect a||Number of Patients (age range)|
|a Values reported in published literature.b Means ± SD.c Mean (95% confidence interval).|
|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 for8.7 ± 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 abovebaseline 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).
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