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Famotidine
The active ingredient in Pepcid 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 C8H15N7O2S3 and its molecular weight is 337.43. Famotidine is a white to pale yellow crystalline compound that is freely soluble in glacial acetic acid, slightly soluble in methanol, very slightly soluble in water, and practically insoluble in ethanol. Each tablet for oral administration contains either 20 mg or 40 mg of famotidine. Inactive Ingredients: Hydroxypropyl cellulose, hydroxypropyl methylcellulose, iron oxides, magnesium stearate, microcrystalline cellulose, starch, talc, titanium dioxide. Each Pepcid RPD orally disintegrating tablet for oral administration contains either 20 mg or 40 mg of famotidine and the following inactive ingredients: aspartame, mint flavor, gelatin, mannitol, red ferric oxide, and xanthan gum. Each 5 ml of the oral suspension when prepared as directed contains 40 mg of famotidine and the following inactive ingredients: citric acid, flavors, microcrystalline cellulose and carboxymethylcellulose sodium, sucrose and xanthan gum. Added as preservatives are sodium benzoate 0.1%, sodium methylparaben 0.1%, and sodium propylparaben 0.02%. Each ml of the solution
for intravenous injection
contains 10 mg of famotidine. Inactive Ingredients: L-aspartic
acid 4 mg, mannitol 20 mg, and
Water for Injection q.s. 1 ml. The multidose injection also contains benzyl
alcohol 0.9% added as preservative.
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. After intravenous administration, the maximum effect was achieved within 30 minutes. Single intravenous doses of 10 and 20 mg inhibited nocturnal secretion for a period of 10 to 12 hours. The 20 mg dose was associated 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 6-8 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%. Famotidine tablets, famotidine oral suspension and famotidine orally disintegrating tablets 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 1-3 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 2.5-3.5 hours. 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 may be necessary. (See PRECAUTIONS, DOSAGE AND ADMINISTRATION.) In elderly patients, there are no clinically significant age-related changes in the pharmacokinetics of famotidine. CLINICAL STUDIESDuodenal 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.
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.
Gastroesophageal Reflux Disease (GERD) 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. (See TABLE 3.)
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. (See TABLE 4.)
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. (See TABLE 5.) There was, however, no significant difference among treatments in symptom relief.
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. 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.
Famotidine is indicated in: 1. Short Term Treatment of Active Duodenal Ulcer: Most 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. 2. Maintenance Therapy for Duodenal Ulcer Patients at Reduced Dosage After Healing of an Active Ulcer: Controlled studies have not extended beyond one year. 3. Short Term Treatment of Active Benign Gastric Ulcer: Most 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. 4. Short Term Treatment of Gastroesophageal Reflux Disease (GERD): Famotidine is indicated for short term treatment of patients with symptoms of GERD (see 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 STUDIES.) 5. Treatment of Pathological Hypersecretory Conditions: (e.g., Zollinger-Ellison Syndrome, multiple endocrine adenomas). Famotidine injection premixed or famotidine injection is indicated in some hospitalized patients with pathological hypersecretory conditions or intractable ulcers, or as an alternative to the oral dosage forms for short-term use in patients who are unable to take oral medication for the above conditions.
Duodenal Ulcer Acute Therapy: The recommended adult oral dosage for active duodenal ulcer is 40 mg once a day at bedtime. Most patients heal within 4 weeks; there is rarely reason to use famotidine at full dosage for longer than 6 to 8 weeks. A regimen of 20 mg b.i.d. is also effective. Maintenance Therapy: The recommended oral dose is 20 mg once a day at bedtime. Benign Gastric Ulcer Acute Therapy: The recommended adult oral dosage for active benign gastric ulcer is 40 mg once a day at bedtime. Gastroesophageal Reflux Disease (GERD) The recommended oral dosage for treatment of patients with symptoms of GERD is 20 mg b.i.d. for up to 6 weeks. The recommended oral dosage for the treatment of patients with esophagitis including erosions and ulcerations and accompanying symptoms due to GERD is 20 or 40 mg b.i.d. for up to 12 weeks (see CLINICAL STUDIES). 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 oral starting dose for pathological hypersecretory conditions is 20 mg q 6 h. In some patients, a higher starting dose may be required. Doses should be adjusted to individual patient needs and should continue as long as clinically indicated. Doses up to 160 mg q 6 h have been administered to some patients with severe Zollinger-Ellison Syndrome. Oral Suspension Famotidine oral suspension may be substituted for famotidine tablets in any of the above indications. Each five ml contains 40 mg of famotidine after constitution of the powder with 46 ml of Purified Water as directed. Directions for Preparing Famotidine Oral Suspension Prepare suspension at time of dispensing. Slowly add 46 ml of Purified Water. Shake vigorously for 5-10 seconds immediately after adding the water and immediately before use. Stability of Famotidine Oral Suspension Unused constituted oral suspension should be discarded after 30 days. Orally Disintegrating Tablets Famotidine orally disintegrating tablets may be substituted for famotidine tablets in any of the above indications at the same recommended dosages. Famotidine orally disintegrating tablets rapidly disintegrate on the tongue. No water is needed for taking the tablet. Patients should be instructed to open the tablet blister pack with dry hands, place the tablet on the tongue to disintegrate and be swallowed with saliva. Intravenous Administration In some hospitalized patients with pathological hypersecretory conditions or intractable ulcers, or in patients who are unable to take oral medication, famotidine I.V. may be administered. The recommended dosage for famotidine injection premixed is 20 mg every 12 hours, administered as an infusion over a 15-30 minute period. The recommended dosage for famotidine injection is 20 mg every 12 hours. The doses and regimen for parenteral administration in patients with GERD have not been established. Dosage Adjustments for Patients with Severe Renal Insufficiency In patients with severe renal insufficiency, i.e., with a creatinine clearance less than 10 ml/min, the elimination half-life of famotidine may exceed 20 hours, reaching approximately 24 hours in anuric patients. Although no relationship of adverse effects to high plasma levels has been established, to avoid excess accumulation of the drug, the dose of famotidine injection premixed or famotidine injection may be reduced to 20 mg h.s. or the dosing interval may be prolonged to 36-48 hours as indicated by the patient's clinical response. Preparation of Famotidine Injection Premixed Pepcid Injection Premixed, supplied in Galaxy containers (PL 2501 Plastic) is a 50 ml iso-osmotic solution premixed with 0.9% sodium chloride for administration as an infusion over a 15-30 minute period. This premixed solution is for intravenous use only using sterile equipment. Directions for Use of Galaxy Containers Check the container for minute leaks prior to use by squeezing the bag firmly. If leaks are found, discard solution as sterility may be impaired. Do not add supplementary medication. Do not use unless solution is clear and seal is intact. CAUTION: Do not use plastic containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is complete. Preparation for administration: 1. Suspend container from eyelet support. 2. Remove plastic protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. Preparation of Famotidine Injection Intravenous Solutions Dilute 2 ml of Pepcid I.V. (solution containing 10 mg/ml) with 0.9% Sodium Chloride Injection or other compatible intravenous solution to a total volume of either 5 ml or 10 ml and inject over a period of not less than 2 minutes. Preparation of Famotidine Injection for Intravenous Infusion Solutions Famotidine injection may also be administered as an infusion, 2 ml diluted with 100 ml of 5% dextrose or other compatible solution, and infused over a 15-30 minute period. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Concomitant Use of Antacids Antacids maybe given concomitantly if needed. Stability of Famotidine Injection Premixed Pepcid Injection Premixed, as supplied premixed in 0.9% sodium chloride in Galaxy containers (PL 2501 Plastic), is stable through the labeled expiration date when stored under the recommended conditions. (See HOW SUPPLIED, Storage.) Stability of Famotidine Injection Famotidine injection is stable for 48 hours at room temperature 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, Lactated Ringer's Injection, or Sodium Bicarbonate Injection, 5%. HOW SUPPLIED Oral Administration Pepcid Tablets, 20 mg: Are beige colored, U-shaped, film-coated tablets coded MSD 963 on one side and Pepcid on the other. Pepcid Tablets, 40 mg: Are light brownish-orange, U-shaped, film-coated tablets coded MSD 964 on one side and Pepcid on the other. Pepcid RPD Orally Disintegrating Tablets, 20 mg: Are pale rose colored, hexagonal-shaped, lyophilized tablets measuring 13.1 mm (side to side) and 15.2 mm (point to point), with a mint flavor. Pepcid RPD Orally Disintegrating Tablets, 40 mg: Are pale rose colored, hexagonal-shaped, lyophilized tablets measuring 15.9 mm (side to side) and 18.4 mm (point to point), with a mint flavor. Pepcid for Oral Suspension: Is a white to off-white powder containing 400 mg of famotidine for constitution. When constituted as directed, Pepcid for oral suspension is a smooth, mobile, off-white, homogeneous suspension with a cherry-banana-mint flavor, containing 40 mg of famotidine per 5 ml. Storage: Avoid storage of Pepcid tablets at temperatures above 40°C (104°F). Avoid storage of the powder for oral suspension at temperatures above 40°C (104°F). After constitution store the suspension below 30°C (86°F). Do not freeze. Discard unused suspension after 30 days. Intravenous Administration FOR INTRAVENOUS USE ONLY. Pepcid Injection Premixed 20 mg per 50 ml: Is a clear, non-preserved, sterile solution premixed in a vehicle made iso-osmotic with Sodium Chloride. Pepcid Injection 10 mg per 1 ml: Is a non-preserved, clear, colorless solution. Pepcid Injection 10 mg per 1 ml: Is a clear, colorless solution. Storage: Store Pepcid Injection Premixed in Galaxy containers at room temperature (25°C, 77°F). Exposure of the premixed product to excessive heat should be avoided. Brief exposure to temperatures up to 35°C (95°F) does not adversely affect the product. Storage: Store Pepcid Injection at 2-8°C (36-46°F).
If solution freezes, bring
to room temperature; allow sufficient
time to solubilize all the components.
The adverse reactions listed below have been reported during domestic and international clinical trials in approximately 2500 patients. In those controlled clinical trials in which famotidine tablets were compared to placebo, the incidence of adverse experiences in the group which received famotidine tablets, 40 mg at bedtime, was similar to that in placebo group. The following adverse reactions have been reported to occur in more than 1% of patients on therapy with famotidine in controlled clinical trials, and may be causally related to the drug: headache (4.7%), dizziness (1.3%), constipation (1.2%) and diarrhea (1.7%). The following other adverse reactions have been reported infrequently in clinical trials or since the drug was marketed. The relationship to therapy with famotidine has been unclear in many cases. Within each category the adverse reactions are listed in order of decreasing severity: Body as a Whole: Fever, asthenia, fatigue. Cardiovascular: Arrhythmia, AV block, palpitation. Gastrointestinal: Cholestatic jaundice, liver enzyme abnormalities, vomiting, nausea, abdominal discomfort, anorexia, dry mouth. Hematologic: Rare cases of agranulocytosis, pancytopenia, leukopenia, thrombocytopenia. Hypersensitivity: Anaphylaxis, angioedema, orbital or facial edema, urticaria, rash, conjunctival injection. Musculoskeletal: Musculoskeletal pain including muscle cramps, arthralgia. Nervous System/Psychiatric: Grand mal seizure; psychic disturbances, which were reversible in cases for which follow-up was obtained, including hallucinations, confusion, agitation, depression, anxiety, decreased libido; paresthesia; insomnia; somnolence. Respiratory: Bronchospasm. Skin: Toxic epidermal necrolysis (very rare), alopecia, acne, pruritus, dry skin, flushing. Special Senses: Tinnitus, taste disorder. Other: Rare cases of impotence and rare cases of gynecomastia have been reported; however, in controlled clinical trials, the incidence was not greater than that seen with placebo. The adverse reactions reported for famotidine tablets may also occur with famotidine oral suspension, famotidine orally disintegrating tablets, famotidine injection premixed or famotidine injection. In addition, transient irritation at the injection site has been observed with famotidine injection.
No drug interactions have been identified. Studies with famotidine in man, in animal models, and in vitro have shown no significant interference with the disposition of compounds metabolized by the hepatic microsomal enzymes, e.g., cytochrome P450 system. Compounds tested in man include warfarin, theophylline, phenytoin, diazepam, aminopyrine and antipyrine. Indocyanine green as an index of hepatic drug extraction has been tested and no significant effects have been found.
No information provided.
General Symptomatic response to therapy with famotidine does not preclude the presence of gastric malignancy. Patients with Severe Renal Insufficiency: Longer intervals between doses or lower doses may need to be used in patients with severe renal insufficiency (creatinine clearance <10 ml/min) to adjust for the longer elimination half-life of famotidine. (See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION.) However, currently, no drug-related toxicity has been found with high plasma concentrations of famotidine. Information for the Patient The patient should be instructed to shake the oral suspension vigorously for 5-10 seconds prior to each use. Unused constituted oral suspension should be discarded after 30 days. Patients should be instructed to leave the famotidine orally disintegrating tablet in the unopened package until the time of use. Patients should then open the tablet blister pack with dry hands, place the tablet on the tongue to dissolve and be swallowed with saliva. No water is needed for taking the tablet. Phenylketonurics: Phenylketonuric patients should be informed that famotidine contains phenylalanine 1.05 mg per 20 mg orally disintegrating tablet and 2.10 mg per 40 mg orally disintegrating tablet. Carcinogenesis, Mutagenesis,Impairment of Fertility In a 106 week study in rats and a 92 week study in mice given oral doses of up to 2000 mg/kg/day (approximately 2500 times the recommended human dose for active duodenal ulcer), there was no evidence of carcinogenic potential for famotidine. Famotidine was negative in the microbial mutagen test (Ames test) using Salmonella typhimurium and Escherichia coli with or without rat liver enzyme activation at concentrations up to 10,000 mcg/plate. In in vivo studies in mice, with a micronucleus test and a chromosomal aberration test, no evidence of a mutagenic effect was observed. In studies with rats given oral doses of up to 2000 mg/kg/day or intravenous doses of up to 200 mg/kg/day, fertility and reproductive performance were not affected. Pregnancy Category B Reproductive studies have been performed in rats and rabbits at oral doses of up to 2000 and 500 mg/kg/day, respectively, and in both species at I.V. doses of up to 200 mg/kg/day, and have revealed no significant evidence of impaired fertility or harm to the fetus due to famotidine. While no direct fetotoxic effects have been observed, sporadic abortions occurring only in mothers displaying marked decreased food intake were seen in some rabbits at oral doses of 200 mg/kg/day (250 times the usual human dose) or higher. There are, however, no adequate or well-controlled studies in pregnant women. Because animal reproductive studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Nursing Mothers Studies performed in lactating rats have shown that famotidine is secreted into breast milk. Transient growth depression was observed in young rats suckling from mothers treated with maternotoxic doses of at least 600 times the usual human dose. Famotidine is detectable in human milk. Because of the potential for serious adverse reactions in nursing infants from famotidine, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness in children have not been established. Geriatric Use No dosage adjustment is required based on age. (See CLINICAL PHARMACOLOGY, Pharmacokinetics.) Dosage adjustment in the case of severe renal impairment may be necessary.
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