ave 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 ).

so be receiving conservative measures (e.g., thickened feedings). the use of intravenous famotidine in pediatric patients <1 year of age with gerd has not been adequately studied. dosage for pediatric patients 1 to 16 years of age see precautions , pediatric patients 1 to 16 years of age . the studies described in precautions , pediatric patients 1 to 16 years of age suggest that the starting dose in pediatric patients 1 to 16 years of age is 0.25 mg/kg intravenously (injected over a period of not less than two minutes or as a 15-minute infusion) q 12 h up to 40 mg/day. while published uncontrolled clinical studies suggest effectiveness of famotidine in the treatment of peptic ulcer, data in pediatric patients are insufficient to establish percent response with dose and duration of therapy. therefore, treatment duration (initially based on adult duration recommendations) and dose should be individualized based on clinical response and/or gastric ph determination and endoscopy. published uncontrolled studies in pediatric patients 1 to 16 years of age have demonstrated gastric acid suppression with doses up to 0.5 mg/kg intravenously q 12 h. dosage adjustments for patients with moderate or severe renal insufficiency in adult patients with moderate (creatinine clearance <50 ml/min) or severe (creatinine clearance <10 ml/min) renal insufficiency, the elimination half-life of famotidine is increased. for patients with severe renal insufficiency, it may exceed 20 hours, reaching approximately 24 hours in anuric patients. since cns adverse effects have been reported in patients with moderate and severe renal insufficiency, to avoid excess accumulation of the drug in patients with moderate or severe renal insufficiency, the dose of famotidine injection may be reduced to half the dose, or the dosing interval may be prolonged to 36 to 48 hours as indicated by the patient’s clinical response. based on the comparison of pharmacokinetic parameters for famotidine in adults and pediatric patients, dosage adjustment in pediatric patients with moderate or severe renal insufficiency should be considered. pathological hypersecretory conditions (e.g., zollinger-ellison syndrome, multiple endocrine adenomas) the dosage of famotidine in patients with pathological hypersecretory conditions varies with the individual patient. the recommended adult intravenous dose is 20 mg q 12 h. doses should be adjusted to individual patient needs and should continue as long as clinically indicated. in some patients, a higher starting dose may be required. oral doses up to 160 mg q 6 h have been administered to some adult patients with severe zollinger-ellison syndrome. to prepare intravenous solutions, aseptically dilute 2 ml of famotidine injection (solution containing 10 mg/ml) with 0.9% sodium chloride injection or other compatible intravenous solution (see stability ) to a total volume of either 5 ml or 10 ml and inject over a period of not less than 2 minutes. to prepare intravenous infusion solutions, aseptically dilute 2 ml of famotidine injection with 100 ml of 5% dextrose or other compatible solution (see stability ), and infuse over a 15 to 30 minute period. concomitant use of antacids antacids may be given concomitantly if needed. stability parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. when added to or diluted with most commonly used intravenous solutions, e.g., water for injection, 0.9% sodium chloride injection, 5% and 10% dextrose injection, or lactated ringer’s injection, diluted famotidine injection is physically and chemically stable (i.e., maintains at least 90% of initial potency) for 7 days at room temperature - see how supplied, storage. when added to or diluted with sodium bicarbonate injection, 5%, famotidine injection at a concentration of 0.2 mg/ml (the recommended concentration of famotidine intravenous infusion solutions) is physically and chemically stable (i.e., maintains at least 90% of initial potency) for 7 days at room temperature - see how supplied, storage . however, a precipitate may form at higher concentrations of famotidine injection (>0.2 mg/ml) in sodium bicarbonate injection, 5%.

hmia, av block, palpitation, prolonged qt interval gastrointestinal: cholestatic jaundice, hepatitis, elevated liver enzyme, vomiting, nausea, abdominal discomfort, anorexia, dry mouth hematologic: agranulocytosis, pancytopenia, leukopenia, thrombocytopenia hypersensitivity: anaphylaxis, angioedema, orbital or facial edema, urticaria, rash, conjunctival injection, bronchospasm musculoskeletal: rhabdomyolysis, musculoskeletal pain, muscle cramps, arthralgia nervous system/psychiatric: seizure, hallucinations, confusion, agitation, depression, anxiety, decreased libido; paresthesia; insomnia; somnolence. respiratory: interstitial pneumonia skin: toxic epidermal necrolysis/stevens johnson syndrome, pruritus, dry skin, flushing special senses: tinnitus, taste disorder other: impotence the adverse reactions reported for famotidine tablets may also occur with famotidine for oral suspension or famotidine injection. in addition, transient irritation at the injection site has been observed with famotidine injection. pediatric patients in a clinical study in 35 pediatric patients <1 year of age with gerd symptoms [e.g., vomiting (spitting up), irritability (fussing)], agitation was observed in 5 patients on famotidine that resolved when the medication was discontinued.

with the longest duration of action in most subjects. 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. 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 (t 4 ), and testosterone, were not altered after treatment with famotidine. pharmacokinetics orally administered famotidine is incompletely absorbed and its bioavailability is 40 to 45%. 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 ). clinical studies the majority of clinical study experience involved oral administration of famotidine tablets, and is provided herein for reference. 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% * 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. 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% ** , *** statistically significantly better than placebo (p≤0.05, p≤0.01, respectively) 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 † 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). 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 †† 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. 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 ‡‡ 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. 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 iv 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 iv 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 iv adult dose). table 6: pharmacokinetic parameters a of intravenous famotidine age (n=number of patients) area under the curve (auc) (ng-hr/ml) total clearance (cl) (l/hr/kg) volume of distribution (vd) (l/kg) elimination half-life (t 1/2 ) (hours) 0 to 1 month c (n=10) na 0.13 ± 0.06 1.4 ± 0.4 10.5 ± 5.4 0 to 3 months d (n=6) 2688 ± 847 0.21 ± 0.06 1.8 ± 0.3 8.1 ± 3.5 >3 to 12 months d (n=11) 1160 ± 474 0.49 ± 0.17 2.3 ± 0.7 4.5 ± 1.1 1 to 11 yrs (n=20) 1089 ± 834 0.54 ± 0.34 2.07 ± 1.49 3.38 ± 2.6 11 to 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 a values are presented as means + sd unless indicated otherwise. b mean value only. c single center study. d multicenter study. 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 e max 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 e max model 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 * serum concentration of famotidine associated with 50% maximum gastric acid reduction. values are presented as means ± sd. 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 dosage route effect a number of patients (age range) 0.5 mg/kg, single dose iv gastric ph >4 for 19.5 hours (17.3, 21.8) c 11 (5 to 19 days) 0.3 mg/kg, single dose iv gastric ph >3.5 for 8.7 ± 4.7 b hours 6 (2 to 7 years) 0.4 to 0.8 mg/kg iv gastric ph >4 for 6 to 9 hours 18 (2 to 69 months) 0.5 mg/kg single dose iv 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. iv gastric ph >5 for 13.5 ± 1.8 b hours 4 (6 to 15 years) 0.5 mg/kg b.i.d. oral gastric ph >5 for 5 ± 1.1 b hours 4 (11 to 15 years) a values reported in published literature b means ± sd c mean (95% confidence interval). the duration of effect of famotidine iv 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).

� 474 0.49 ± 0.17 2.3 ± 0.7 4.5 ± 1.1 1 to 11 yrs (n=20) 1089 ± 834 0.54 ± 0.34 2.07 ± 1.49 3.38 ± 2.6 11 to 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 a values are presented as means + sd unless indicated otherwise. b mean value only. c single center study. d multicenter study. 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 e max 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 e max model 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 * serum concentration of famotidine associated with 50% maximum gastric acid reduction. values are presented as means ± sd. 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 dosage route effect a number of patients (age range) 0.5 mg/kg, single dose iv gastric ph >4 for 19.5 hours (17.3, 21.8) c 11 (5 to 19 days) 0.3 mg/kg, single dose iv gastric ph >3.5 for 8.7 ± 4.7 b hours 6 (2 to 7 years) 0.4 to 0.8 mg/kg iv gastric ph >4 for 6 to 9 hours 18 (2 to 69 months) 0.5 mg/kg single dose iv 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. iv gastric ph >5 for 13.5 ± 1.8 b hours 4 (6 to 15 years) 0.5 mg/kg b.i.d. oral gastric ph >5 for 5 ± 1.1 b hours 4 (11 to 15 years) a values reported in published literature b means ± sd c mean (95% confidence interval). the duration of effect of famotidine iv 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).

ee dosage and administration ). manufactured for: mylan institutional llc rockford, il 61103 u.s.a. manufactured by: mylan laboratories limited bangalore, india august 2020