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 (1-15 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 1-15 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).
a Values are presented as means ± SD unless indicated otherwise.
b Mean value only.
c Single center study.
d Multicenter study.
|Age(N=numberof patients)||Area Underthe Curve(AUC)(ng-hr/mL)||TotalClearance(Cl)(L/hr/kg)||Volume ofDistribution(Vd )(L/kg)||EliminationHalf-life(T 1/2 )(hours)|
|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)||1726 b||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 0-3 months of age compared to older pediatric patients. The pharmacokinetic parameters for pediatric patients, ages >3 months-15 years, are comparable to those obtained for adults.
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 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 11-15 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 2-13 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.
|EC 50 (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).
|Dosage||Route||Effect a||Number ofPatients(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 ± 4.7 b 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 ± 1.8 b hours||4 (6-15 years)|
|0.5 mg/kg b.i.d.||oral||gastric pH >5 for 5.0 ± 1.1 b 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).
Famotidine is indicated in:
- 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.
- 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.
- 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.
- 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).
- Treatment of pathological hypersecretory conditions (e.g., Zollinger-Ellison Syndrome, multiple endocrine adenomas) (see CLINICAL PHARMACOLOGY IN ADULTS, Clinical Studies).
Hypersensitivity to any component of these products. 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.
Symptomatic response to therapy with famotidine does not preclude the presence of gastric malignancy.
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.
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