Famotidine (Page 2 of 5)

Gastroesophageal Reflux Disease (GERD)

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

***, † Statistically significantly better than placebo (p≤0.05, p≤0.01 respectively)

U.S. Study

International Study

Famotidine

Placebo

Famotidine

Placebo

40 mg h.s.

h.s.

40 mg h.s.

h.s.

(N = 74)

(N = 75)

(N = 149)

(N = 145)

Week 4

45%

39%

†47%

31%

Week 6

†66%

44%

†65%

46%

Week 8

***78%

64%

†80%

54%

Table 3: % Successful Symptomatic Outcome

††p≤0.01 vs. placebo

Famotidine

Famotidine

20 mg b.i.d.

40 mg h.s.

Placebo

(N = 154)

(N = 149)

(N = 73)

Week 6

82††

69

62

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

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).

Table 6: Pharmacokinetic Parameters a of Intravenous Famotidine

a Values are presented as means ± SD unless indicated otherwise.

b Mean value only.

c Single center study.

d Multicenter study.

Age (N=Number of Patients)

Area Under the

Total Clearance (CI)

Volume of Distribution (Vd) (L/kg)

Elimination Half-life (T½)

Curve (AUC) (ng-hr/mL)

(L/hr/kg)

(hours)

0 to 1 monthc(N=10)

NA

0.13 ± 0.06

1.4 ± 0.4

10.5 ± 5.4

0 to 3 monthsd (N=6)

2688 ± 847

0.21 ± 0.06

1.8 ± 0.3

8.1 ± 3.5

>3 to 12 monthsd(N=11)

1160 ± 474

0.49 ± 0.17

2.3 ± 0.7

4.5 ± 1.1

1 to 11 years (N=20)

1089 ± 834

0.54 ± 0.34

2.07 ± 1.49

3.38 ± 2.60

11 to 15 years (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

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).

Table 7: Pharmacodynamics of Famotidine Using The Sigmoid Emax Model

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

EC50 (ng/mL)*

Pediatric Patients

26 ± 13

Data from one study

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:

Table 8

a Values reported in published literature.

bMeans ± SD.

cMean (95% confidence interval).

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 to 19 days)

0.3 mg/kg, single dose

I.V.

gastric pH >3.5 for 8.7 ± 4.7b hours

6 (2 to 7 years)

0.4 to 0.8 mg/kg

I.V.

gastric pH >4 for 6 to 9 hours

18 (2 to 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 to 13 years)

0.5 mg/kg b.i.d.

I.V.

gastric pH >5 for 13.5 ±1.8b hours

4 (6 to 15 years)

0.5 mg/kg b.i.d.

oral

gastric pH >5 for 5 ±1.1b hours

4 (11 to 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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