AHFS Class:

• Histamine H2-Antagonists 56:28.12

Generic Name(s):

• Famotidine

Famotidine is a histamine H₂-receptor antagonist.1,3,4,6,23,46,48,114

Famotidine is used orally for the treatment of active duodenal or gastric ulcer, gastroesophageal reflux disease, endoscopically diagnosed erosive esophagitis, and as maintenance therapy for duodenal ulcer.1,4,5,6,7,10,12,16,18,19,22,51,91,92,93,94,114,122,123,124,128,129,130,132,135 Oral famotidine also is used for the management of pathological GI hypersecretory conditions.1,4,5,10,51,93,114,122,132 IV famotidine is used in hospitalized individuals with pathological GI hypersecretory conditions or intractable ulcers, or when oral therapy is not feasible.240

Duodenal Ulcer

Acute Therapy

Famotidine is used for the short-term treatment of endoscopically or radiographically confirmed active duodenal ulcer.1,4,5,6,7,12,16,18,19,22,91,92,93,94,114,123,124,128,129,130,135 Antacids may be used concomitantly as needed for relief of pain.1,4,6,7,16,18,19,49,94 In controlled studies in patients with endoscopically confirmed duodenal ulcers, reported rates of ulcer healing for famotidine were substantially higher than those for placebo.1,16,93,123,129 In a multicenter, double-blind study in patients with endoscopically confirmed duodenal ulcer, reported rates of ulcer healing for oral famotidine dosages of 40 mg at bedtime daily, 20 mg twice daily, or 40 mg twice daily vs placebo were 32, 38, or 34%, respectively, vs 17%, at 2 weeks; 70, 67, or 75%, respectively, vs 31%, at 4 weeks; and 82-83% for these famotidine dosage regimens vs 45% for placebo, at 8 weeks.1,4,16,93,129 Famotidine also produced greater reductions in daytime and nocturnal pain and antacid consumption than did placebo,1,16,93,114,129 with complete relief of pain in most patients usually occurring within 2 weeks after initiation of famotidine therapy.7,18,19,93,114

Famotidine appears to be at least as effective as cimetidine4,22,56,69 or ranitidine4,6,7,18,19,22,56,69,91,92,93,94,130,133,135,140 for the short-term treatment of active duodenal ulcer. An oral famotidine dosage of 40 mg at bedtime daily generally appears to be more effective than an oral cimetidine dosage of 800 mg daily4,56,69 and as effective as an oral ranitidine dosage of 300 mg daily (as a single or divided dose)4,6,7,19,22,56,69,93,94,130,135 in this condition. In a multicenter, double-blind study in patients with endoscopically confirmed duodenal ulcers, 68-81 or 76% of ulcers were healed following administration of famotidine (20 mg twice daily, 40 mg at bedtime daily, or 40 mg twice daily) or ranitidine (150 mg twice daily), respectively, for 4 weeks and 87-92 or 90%, respectively, were healed following therapy for 8 weeks.7,93,114,130 In geriatric patients, famotidine and ranitidine, in dosages of 40 mg at bedtime daily and 150 mg twice daily, respectively, were equally effective in healing active duodenal ulcers and providing symptomatic relief; 57 and 51% of ulcers were healed following administration of famotidine and ranitidine, respectively, for 8 weeks.94 In several studies, there appeared to be little difference between famotidine and ranitidine in reductions of daytime and nocturnal pain and antacid consumption.6,7,94,114,130,135

Daily bedtime doses of famotidine generally appear to be as effective as a twice-daily regimen of the drug in healing active duodenal ulcer,4,7,16,18,91,92,93,114,129,130 although the bedtime regimen may be slightly less effective than twice-daily regimens at 4 but not 8 weeks.16,93,129 Ulcer healing rates averaged 32, 34, or 38% at 2 weeks; 68-70, 75-81, or 67-77% at 4 weeks; and 83-87, 82-92, or 82-92 at 8 weeks following oral famotidine dosages of 40 mg at bedtime daily, 40 mg twice daily, or 20 mg twice daily, respectively.16,93,129 Antacid consumption appeared to be similar with the various famotidine dosage regimens employed.16,18,129 Evidence from a multicenter, controlled study indicates that healing rates for duodenal ulcers in patients receiving famotidine may not be affected substantially by cigarette smoking16,114 or alcohol consumption,16 although healing rates were slightly higher in nonsmokers than in smokers.16

Safety and efficacy of long-term famotidine therapy for active duodenal ulcer have not been determined.1 Studies to date have been limited to short-term treatment of active duodenal ulcer,1,6,7,16,22,93 and the safety and efficacy of treatment for active disease beyond 8 weeks have not been determined.1 Most patients with duodenal ulcer respond to famotidine therapy during the initial 4-week course of therapy; an additional 4 weeks of therapy may contribute to healing in some patients.1,4,7,16,18,22 However, short-term famotidine therapy (i.e., up to 8 weeks) for the treatment of active duodenal disease will not prevent recurrence following acute healing and discontinuance of the drug.96,103,116 Current epidemiologic and clinical evidence supports a strong association between gastric infection with Helicobacter pylori and the pathogenesis of duodenal and gastric ulcers; long-term H. pylori infection also has been implicated as a risk factor for gastric cancer.181,212,213,214,215,216,217,218,219,220,221,224,225,243

Conventional antiulcer therapy with H₂-receptor antagonists, proton-pump inhibitors, sucralfate, and/or antacids heals ulcers but generally is ineffective in eradicating H. pylori , and such therapy is associated with a high rate of ulcer recurrence (e.g., 60-100% per year).180,183,189,224,243,246,247 Duodenal ulcers have recurred within 6 months in 52-73% of patients following discontinuance of famotidine therapy.8,93,114 The American College of Gastroenterology (ACG), the National Institutes of Health (NIH), and most clinicians currently recommend that all patients with initial or recurrent duodenal or gastric ulcer and documented H. pylori infection receive anti-infective therapy for treatment of the infection.232,243,246,247,248 Although 3-drug regimens consisting of a bismuth salt (e.g., bismuth subsalicylate) and 2 anti-infective agents (e.g., tetracycline or amoxicillin plus metronidazole) administered for 10-14 days have been effective in eradicating the infection, resolving associated gastritis, healing peptic ulcer, and preventing ulcer recurrence in many patients with H. pylori -associated peptic ulcer disease,180,181,182,188,190,191,192,193,194,196,198,199,222,224,225,227,243,244,245,246,247,248,251,252 current evidence principally from studies in Europe suggests that 1 week of such therapy provides comparable H. pylori eradication rates.243,247,248 Other regimens that combine one or more anti-infective agents (e.g., clarithromycin, amoxicillin) with a bismuth salt and/or an antisecretory agent (e.g., omeprazole, lansoprazole, H₂-receptor antagonist) also have been used successfully for H. pylori eradication,180,181,190,207,208,209,210,211,222,223,224,225,226,227,231,233,234,242,243,248,250,255,256,257,258,259 and the choice of a particular regimen should be based on the rapidly evolving data on optimal therapy, including consideration of the patient's prior exposure to anti-infective agents, the local prevalence of resistance, patient compliance, and costs of therapy.232,243,247,252,253,254

Current evidence suggests that inclusion of a proton-pump inhibitor (e.g., omeprazole, lansoprazole) in anti- H. pylori regimens containing 2 anti-infectives enhances effectiveness, and limited data suggest that such regimens retain good efficacy despite imidazole (e.g., metronidazole) resistance.243,247,255 Therefore, the ACG and many clinicians243,249,250 currently recommend 1 week of therapy with a proton-pump inhibitor and 2 anti-infective agents (usually clarithromycin and amoxicillin or metronidazole), or a 3-drug, bismuth-based regimen (e.g., bismuth-metronidazole-tetracycline) concomitantly with a proton-pump inhibitor, for treatment of H. pylori infection.233,242,249

Maintenance Therapy

Famotidine is used in reduced dosage as maintenance therapy following healing of active duodenal ulcer to reduce ulcer recurrence.1,4,8,88,91,93,114 In placebo-controlled studies, duodenal ulcer recurrence rates after 3, 6, and 12 months ranged from 9-14, 16-30, and 23-38%, respectively, for 20 or 40 mg of famotidine at bedtime daily vs 39, 52-73, and 57-77%, respectively, for placebo.1,4,8,93,114 Because the efficacy of H₂-receptor antagonists in preventing duodenal ulcer recurrence appears to be substantially reduced in patients who are cigarette smokers compared with nonsmokers, patients who are cigarette smokers should be advised of the importance of discontinuing smoking in the prevention of ulcer recurrence.16,104,105,106 Maintenance therapy with famotidine has not been studied for longer than 1 year in placebo-controlled studies,1,4,8 and the effect of maintenance therapy with the drug in patients with previously healed duodenal ulcers remains to be more fully evaluated.4,93

Pathologic GI Hypersecretory Conditions

Famotidine is used for the treatment of pathologic GI hypersecretory conditions (e.g., Zollinger-Ellison syndrome, multiple endocrine adenomas).1,4,5,10,51,93,114,122,132 Famotidine reduces gastric acid secretion1,4,11,56,60,61,62,63,65,66,69,71,72,73,77,81,93,114,122 and associated symptoms (including diarrhea, nausea, and epigastric burning and pain)115,116,122 in patients with these conditions.1,93,114 Antimuscarinics (e.g., isopropamide iodide) have been used concomitantly with famotidine to augment famotidine-induced inhibition of gastric acid secretion in some patients with GI hypersecretory conditions.4,10,51,122,132

In a limited number of patients with GI hypersecretory conditions, famotidine has effectively inhibited gastric acid hypersecretion and produced inhibition of longer duration10,48,51,65,77,114,116,122,132 than cimetidine4,10,48,51,65,114,122,132 and somewhat longer than that of ranitidine.4,10,51,77,114,122,132 However, these drugs appear to be comparably effective for the treatment of hypersecretion when adequate, equipotent dosages are used and patient compliance is optimal.10,116 In one study, patients with GI hypersecretory conditions who were successfully treated with 1.2-9 or 0.6-5.4 g of cimetidine or ranitidine, respectively, alone daily subsequently were treated successfully with 50-800 mg of famotidine alone daily.4,10,114,122,132 Although famotidine, cimetidine, and ranitidine were equally effective in controlling gastric hypersecretion, substantially lower doses of famotidine were required4,10,51,114,122,132 and with less frequency than with cimetidine or ranitidine.10,132 Famotidine therapy alone or in combination with an antimuscarinic agent has been continued in a few patients for up to 34 months.4,10,93

Gastric Ulcer

Famotidine is used for short-term treatment of active, benign gastric ulcer.1,4,5,9,12,14,20,22,75,89,93,94,124,131,136,140 The efficacy of famotidine in the treatment of gastric ulcer appears to be similar to that of cimetidine4,9,14,22 or ranitidine,9,94 with 40-47, 36-71, or 40-76% of ulcers healed at 4 weeks; 65-68, 66-95, or 68-90% healed at 6 weeks; and 64-80, 67-86, or 79-91% healed at 8 weeks following therapy with famotidine, cimetidine, or ranitidine, respectively.9 In several other studies in patients with gastric ulcer, famotidine promoted healing of ulcers in about 42-65, 60-95, and 78 to greater than 91% of patients after 4, 6, and 8 weeks of treatment, respectively.1,4,20,89,93,123,124,131,136 Response of gastric ulcers to famotidine therapy does not appear to be affected by patient age or gender, cigarette smoking, alcohol consumption, or duration of disease.9,22,94,131 Patients with a history of chronic gastric ulcers (history of disease of 10 years or longer) appear to respond as well to famotidine therapy as patients with a brief history of disease.9,22 Famotidine also generally produced greater reductions in pain (fasting, postprandial, nocturnal) and other symptoms (including belching, nausea, anorexia) and in antacid consumption than did placebo.9,20,22,131,136 Safety and efficacy of famotidine in the treatment of gastric ulcer have not been established for periods exceeding 8 weeks;1 therefore, use of the drug for more prolonged treatment of active disease or for maintenance therapy of previously healed gastric ulcer remains to be more fully evaluated.4,93 If famotidine is used in the treatment of gastric ulcer, it should be kept in mind that symptomatic response does not preclude the presence of gastric malignancy.1

Current epidemiologic and clinical evidence supports a strong association between gastric infection with H. pylori and the pathogenesis of gastric ulcers, and the ACG, NIH, and most clinicians currently recommend that all patients with initial or recurrent gastric ulcer and documented H. pylori infection receive anti-infective therapy for treatment of the infection. The choice of a particular regimen should be based on the rapidly evolving data on optimal therapy, including consideration of the patient's prior exposure to anti-infective agents, the local prevalence of resistance, patient compliance, and costs of therapy.

Gastroesophageal Reflux Disease

Famotidine is used to provide short-term symptomatic relief of gastroesophageal reflux disease (GERD).1,139,167,168,169,170,171,172,173,174,175 Famotidine also is used for short-term treatment of esophagitis associated with gastroesophageal reflux, including endoscopically proven erosive or ulcerative disease.1,167,168,171 By increasing gastric pH, H₂-receptor antagonists have relieved heartburn and other symptoms of reflux and have been associated with somewhat higher healing rates of endoscopically proven esophagitis when compared with placebo and have reduced antacid consumption.1,153,154,155,156,157,158,161,162,163,164,165,166,167 166

Suppression of gastric acid secretion is considered by the ACG to be the mainstay of treatment for GERD, and a proton-pump inhibitor or histamine H₂- receptor antagonist is used to achieve acid suppression, control symptoms, and prevent complications of the disease.261 The ACG states that a histamine H₂- receptor antagonist administered daily in divided doses is effective in many patients with less severe GERD, and over-the-counter (OTC) antacids and histamine H₂- receptor antagonists are appropriate for self -medication as initial therapy in such individuals.261 A histamine H₂-receptor antagonist is particularly useful when taken before certain activities (e.g., heavy meal, exercise) that may result in acid reflux symptoms in some patients.261 The ACG states that H₂-receptor antagonists generally may be used interchangeably, although the drugs may differ in potency and in their onset and duration of action.261 However, proton-pump inhibitors are more effective (i.e., provide more frequent and more rapid symptomatic relief and healing of esophagitis) than histamine H₂-receptor antagonists in the treatment of GERD.261 Although higher doses and more frequent administration of histamine H₂-receptor antagonists appear to increase their efficacy, such dosages are less effective and more expensive than proton-pump inhibitor therapy.156,166,261,265 Once-daily administration of a histamine H₂-receptor antagonist at full dosage is not considered to be appropriate therapy for GERD.261

Based on data from a limited number of patients, famotidine 20 mg administered twice daily appears to be at least as effective as famotidine 40 mg administered at bedtime1,167,173,174 and more effective than placebo in improving symptoms of gastroesophageal reflux in patients who had no evidence of endoscopically proven erosive or ulcerative disease.1,167,173,174 Within 2 weeks of therapy, symptomatic relief was reported in a higher percentage of patients receiving famotidine compared with those receiving placebo;1,167 symptoms improved in 82, 69, and 62% of these patients at 6 weeks for famotidine 20 mg twice daily, famotidine 40 mg at bedtime, or placebo, respectively.1,173 In controlled studies in patients with endoscopically evaluated gastroesophageal reflux disease, reported rates of ulcer healing for famotidine were higher than those for placebo.1,167,168 Healing rates from controlled studies employing various dosage regimens were approximately 48, 32-34, 29, and 7-18% at 6 weeks and 69, 50-54, 43, and 26-29% at 12 weeks for famotidine 40 mg twice daily, 20 mg twice daily, 40 mg at bedtime, and placebo, respectively.1,167 Patients receiving famotidine reported faster relief of daytime and nocturnal heartburn and greater reduction in antacid consumption than those receiving placebo.1,167 Nocturnal heartburn relief was reported in a higher percentage of patients receiving famotidine than those receiving placebo;1 nocturnal heartburn relief occurred in about 58, 50, and 49% of patients receiving famotidine 20 mg twice daily, 40 mg at bedtime, and placebo, respectively,167 while daytime heartburn relief occurred in approximately 56, 42, and 46% of such patients, respectively.167 In a study in patients with gastroesophageal reflux who had endoscopically evaluated erosive or ulcerative disease, reported rates of ulcer or erosion healing at 6 weeks were 48 and 42% in patients receiving famotidine 40 mg twice daily or ranitidine 150 mg twice daily, respectively,1 while at 12 weeks rates of healing were 71 or 60% in patients receiving famotidine 40 mg twice daily or ranitidine 150 mg twice daily, respectively.1 However, ranitidine was as effective as famotidine in improving symptoms of gastroesophageal reflux.1

H₂-receptor antagonists also have been used in combination with metoclopramide in a limited number of patients who failed to respond to an H₂-receptor antagonist alone, but the ACG states that frequent and potentially severe adverse CNS effects of metoclopramide have appropriately decreased regular use of the drug for GERD.153,154,159,261,262 Although some clinicians have suggested that a histamine H₂- receptor antagonist also may be used in combination with bethanechol† in patients who fail to respond to a histamine H₂-receptor antagonist alone,153,159,164 the ACG states that bethanechol has limited efficacy in the treatment of GERD.261

Short-term therapy (i.e., up to 12 weeks) with H₂-receptor antagonists for the treatment of GERD will not prevent recurrence following ulcer healing and discontinuance of such therapy.175 Esophagitis has recurred within 6 months in up to 80% of patients following discontinuance of H₂-receptor antagonist therapy.175,264 Because GERD is considered a chronic disease, many patients with GERD require long-term, even lifelong, treatment.261 The ACG states that proton-pump inhibitors are effective and appropriate as maintenance therapy in many patients with the disease.261 Maintenance therapy† with an H₂-receptor antagonist also has been used to reduce recurrence of GERD.263,264 However, many patients initially responding to proton-pump inhibitors experience symptomatic relapse and failure of esophageal healing with subsequent use of a histamine H₂-receptor antagonist.261,266

For further information on the treatment of GERD, see Uses: Gastroesophageal Reflux, in Omeprazole 56:28.36.

Other Uses

Famotidine may be used for self-medication for relief of symptoms of occasional heartburn (pyrosis), acid indigestion (hyperchlorhydria), or sour stomach and for prevention of such symptoms caused by consumption of food or beverages.238,260 Famotidine also may be used in fixed combination with calcium carbonate and magnesium hydroxide (Pepcid^® Complete) for self-medication for relief of symptoms of occasional heartburn (pyrosis) associated with acid indigestion (hyperchlorhydria) or sour stomach.260

Famotidine also has been used in a limited number of patients to control intragastric pH and/or stress-induced GI bleeding in critically ill patients (e.g., traumatized or postoperative patients, patients in shock or with respiratory insufficiency)†.74,90,137 In patients with GI bleeding† secondary to duodenal or stress ulcers or gastritis, the drug may control GI bleeding123,137,138 and reduce the need for emergency surgery,137 but may not prevent bleeding recurrence.137 Additional study to further evaluate the effect of famotidine on morbidity and mortality in patients with these conditions is necessary.116,123,137,138

Reconstitution and Administration

Famotidine is usually administered orally.1 The drug may also be given by slow IV injection or by slow IV infusion in hospitalized patients with pathologic hypersecretory conditions or intractable duodenal ulcers, or when oral therapy is not feasible.240 Antacids may be administered concomitantly as necessary for relief of pain.1,4,6,7,16,18,19,49,94,114

Parenteral solutions of famotidine should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.240

Oral Suspension

For oral administration, famotidine oral suspension may be substituted for famotidine tablets in patients who are unable to swallow tablets.1,114 The powder for suspension should be reconstituted at the time of dispensing by adding 46 mL of water to a bottle containing 400 mg of famotidine to provide a suspension containing 40 mg/5 mL.1,3,114 The suspension should be agitated well for 5-10 seconds after adding the water for reconstitution and again immediately prior to administration of each dose.1

Orally Disintegrating Tablets

Patients receiving famotidine orally disintegrating tablets should be instructed not to remove a tablet from the blister until just prior to dosing.1 The tablet should not be pushed through the foil.1 With dry hands, the blister package should be peeled completely off the blister.1 The tablet should then be gently removed and immediately placed on the tongue to dissolve and be swallowed with the saliva; administration with liquid is not necessary.1

IV Injection

Famotidine concentrate for injection must be diluted prior to IV administration.240 For IV injection, 20 mg of famotidine is diluted to a total of 5 or 10 mL with 0.9% sodium chloride injection or another comparable IV solution to provide a solution containing approximately 4 or 2 mg/mL, respectively.240 The appropriate dose is injected IV at a rate no faster than 10 mg/minute.240

IV Infusion

For intermittent IV infusion, 20 mg of famotidine as the concentrate is added to 100 mL of 5% dextrose injection or another compatible IV solution to provide a solution containing approximately 0.2 mg/mL.240 This solution is infused IV over 15-30 minutes.240

Alternatively, famotidine that is commercially available as a diluted solution (0.4 mg of famotidine per mL) in 0.9% sodium chloride may be used for intermittent IV infusion.240 The commercially available diluted solution should only be administered by IV infusion over 15-30 minutes.240 The container should be checked for minute leaks by firmly squeezing the bag.240 The injection should be discarded if the seal is not intact or leaks are found or if the solution is cloudy or contains a precipitate.240 Additives should not be introduced into the injection container.240 The injection should not be used in series connections with other plastic containers, since such use could result in air embolism from residual air being drawn from the primary container before administration of fluid from the secondary container is complete.240

Dosage

Duodenal Ulcer

For the treatment of active duodenal ulcer, the usual adult oral dosage of famotidine is 40 mg at bedtime daily.1,2,4,114 Alternatively, 20 mg twice daily may be administered orally in adults.1,4,7,16,18,19,22,92,129,130 The advantage of one oral regimen over another for particular patients with active duodenal ulcer has not been determined,4,7,16,18,93,130 although a once-daily bedtime dosage may be used for patients in whom dosing convenience is considered important for patient compliance.7,16,18,69,129,130 Healing may occur within 2 weeks in some patients1,4,6,16,18,19,22 and within 4 weeks in most patients.1,4,6,7,16,18,19,22,93,114,129 Some patients may benefit from an additional 4 weeks of therapy.1,4,7,16,18,19,22,129 It occasionally may be necessary to continue full-dose famotidine therapy for longer than 6-8 weeks;1,114,116 however, the safety and efficacy of continuing full-dose therapy beyond 8 weeks have not been determined.1,4 In hospitalized adults with intractable duodenal ulcers or when oral therapy is not feasible, the manufacturer states that famotidine may be administered IV in a dosage of 20 mg every 12 hours.2,114,240

For maintenance therapy following healing of acute duodenal ulcer to reduce ulcer recurrence, the usual adult oral dosage of famotidine is 20 mg at bedtime daily.1,4,8,114

For the treatment of duodenal ulcer in children 1-16 years of age, the manufacturer recommends an oral famotidine dosage of 0.5 mg/kg daily given at bedtime or in 2 divided doses, up to a total daily dosage of 40 mg.1 In hospitalized children 1-16 years of age with intractable ulcers or when oral therapy is not feasible, the manufacturer states that a famotidine dosage of 0.25 mg/kg may be administered IV (over not less than 2 minutes or as a 15-minute infusion) every 12 hours, up to a total daily dosage of 40 mg.240 Data from uncontrolled studies in pediatric patients suggest that famotidine is effective for gastric acid suppression when given in dosages of up to 1 mg/kg daily; however, data are insufficient to establish the percentage of these patients who respond to a given dose and duration of therapy.1,240 Therefore, treatment duration (initially based on recommendations in adults) and dosage in such patients should be individualized based on clinical response and/or gastric or esophageal pH determination and endoscopy.1,240

Pathologic GI Hypersecretory Conditions

For the treatment of pathologic GI hypersecretory conditions (e.g., Zollinger-Ellison syndrome, multiple endocrine adenomas), dosages of famotidine should be individualized according to patient response and tolerance.1,4,114,122,141 The usual initial adult dosage is 20 mg orally every 6 hours;1,4,114 however, higher initial dosages may be necessary in some patients.1,10,114 Subsequent famotidine dosage should be adjusted according to the patient's requirements and response,1,4,10,51,114 and therapy continued as long as clinically necessary.1,4,10,114 Periodic (e.g., once to several times yearly) increases in famotidine dosage may be necessary during long-term therapy.122 Oral dosages ranging from 20-160 mg every 6 hours generally have been necessary to maintain basal gastric acid secretion at less than 10 mEq/hour;1,10,51,114,123,141 determination of gastric acid secretion during the hour prior to a dose may be useful in establishing optimum dosage.122,132 Dosages up to 800 mg daily in divided doses have been administered to individuals with severe disease,2,3,4,10,122 although the manufacturer recommends dosages only up to 160 mg every 6 hours (640 mg daily).1 In hospitalized patients with pathologic GI hypersecretory conditions or when oral therapy is not feasible, the manufacturer states that famotidine may be administered IV in a dosage of 20 mg every 6 hours in adults;240 however, higher initial doses may be necessary in some patients.10,114,115,116,240 Subsequent IV dosage should be adjusted according to the patient's requirements and response.115,116,240

The famotidine dosage necessary in patients who have previously received therapy with cimetidine or ranitidine is directly related to the severity of the GI hypersecretory condition4 and the dosage regimen of cimetidine or ranitidine.4,10,51,132 Patients who require low or high dosages of cimetidine or ranitidine will also require low or high dosages, respectively, of famotidine.10,51,132

Gastric Ulcer

For the short-term treatment of active, benign gastric ulcer, the usual adult oral dosage of famotidine is 40 mg daily at bedtime.1,9,22,93,131,136 Most patients demonstrate complete healing of gastric ulcers within 8 weeks;9,22,131,136 the safety and efficacy of continuing famotidine therapy beyond 8 weeks have not been determined.1

For the treatment of gastric ulcer in children 1-16 years of age, the manufacturer recommends an oral famotidine dosage of 0.5 mg/kg daily given at bedtime or in 2 divided doses, up to a total daily dosage of 40 mg.1 In hospitalized children 1-16 years of age with intractable ulcers or when oral therapy is not feasible, the manufacturer states that a famotidine dosage of 0.25 mg/kg may be administered IV (over not less than 2 minutes or as a 15-minute infusion) every 12 hours, up to a total daily dosage of 40 mg.240 Data from uncontrolled studies in pediatric patients suggest that famotidine is effective for gastric acid suppression when given in dosages of up to 1 mg/kg daily; however, data are insufficient to establish the percentage of these patients who respond to a given dose and duration of therapy.1,240 Therefore, treatment duration (initially based on recommendations in adults) and dosage in such patients should be individualized based on clinical response and/or gastric or esophageal pH determination and endoscopy.1

Gastroesophageal Reflux

For the symptomatic relief of gastroesophageal reflux, the usual adult oral dosage of famotidine is 20 mg twice daily for up to 6 weeks.1,167,173,174 Famotidine dosages of 40 mg at bedtime also have been used for the symptomatic relief of gastroesophageal reflux;1,139,167,168 however, famotidine administered twice daily appears to be more effective in improving symptoms of gastroesophageal reflux than famotidine administered just at bedtime.1,167,168 In addition, the American College of Gastroenterology (ACG) states that once-daily administration of a histamine H₂-receptor antagonist at full dosage is not considered to be appropriate therapy for gastroesophageal reflux disease (GERD).261 For the symptomatic relief of esophagitis associated with gastroesophageal reflux, including endoscopically proven erosive or ulcerative disease, the usual adult oral dosage of famotidine is 20 or 40 mg twice daily for up to 12 weeks.1,167,168,171

For the symptomatic relief of gastroesophageal reflux with or without esophagitis including erosions and ulcerations in children 1-16 years of age, the manufacturer recommends an initial oral famotidine dosage of 1 mg/kg daily in 2 divided doses, up to 40 mg twice daily.1 Data from uncontrolled studies in pediatric patients suggest that famotidine is effective in the management of gastroesophageal reflux with or without esophagitis including erosions and ulcerations when given in oral dosages of up to 2 mg/kg daily; however, data are insufficient to establish the percentage of these patients who respond to a given dose and duration of therapy.1 Therefore, treatment duration (initially based on recommendations in adults) and dosage in such patients should be individualized based on clinical response and/or gastric or esophageal pH determination and endoscopy.1

The manufacturer states that dosages and dosage regimens for parenteral famotidine in patients with gastroesophageal reflux disease have not been established.240

Self-medication

For self-medication in relieving symptoms of occasional heartburn, acid indigestion, or sour stomach or in preventing such symptoms caused by consumption of food or beverages in patients 12 years of age or older, a famotidine dosage of 10 or 20 mg once or twice daily is recommended; when used prophylactically, the dose should be taken 10 minutes to 1 hour before eating or drinking.238,239,267,268 269 When the fixed combination of famotidine, calcium carbonate, and magnesium hydroxide (Pepcid^® Complete) is used for self-medication for relief of occasional heartburn associated with acid indigestion or sour stomach, the usual dosage in adults and children 12 years of age or older is 1 tablet (10 mg of famotidine) once or twice daily.260 When famotidine chewable tablets are used for self-medication , the tablets should be chewed thoroughly before swallowing.238,260 When the 10-mg tablets are used for self-medication , the manufacturer recommends that the dosage of famotidine not exceed 20 mg in 24 hours.238,260,269 Alternatively, when the 20-mg tablets are used for self-medication , the manufacturer recommends that dosage of famotidine not exceed 40 mg in 24 hours.267,268 Famotidine for self-medication should not exceed 2 weeks of continuous therapy unless otherwise directed by a clinician. Persistent symptoms should be reported to a clinician.238,260,238,260,267,268,269

Dosage in Renal Impairment

In patients with renal impairment, doses and/or frequency of administration of famotidine can be modified in response to the degree of renal impairment.1,4,86,114 Adverse CNS effects have been reported in patients with moderate or severe renal insufficiency receiving famotidine, and modification of dosage and/or dosing interval may be used to avoid excess accumulation of the drug in such patients.1 In adults with moderate (creatinine clearances less than 50 mL/minute) or severe (creatinine clearances less than 10 mL/minute) renal impairment, the manufacturer states that dosage of famotidine may be reduced to half the usual dosage or the dosing interval may be prolonged to 36-48 hours as necessary according to the patient's clinical response.1,114,115 Some clinicians have recommended that one-half the usual adult dosage be administered in adults with creatinine clearances of 30-60 mL/minute per 1.48 m² and that one-fourth the usual adult dosage be administered in those with creatinine clearances less than 30 mL/minute per 1.48 m².4,86

Based on the comparison of pharmacokinetic parameters of famotidine in adults and children, dosage adjustment also should be considered in children with moderate or severe renal impairment.1,240

Famotidine generally is well tolerated.1,4,5,6,12,13,14,15,17,18,20,22,93,94,140 A causal relationship between many adverse reactions and the drug has not been established but cannot be excluded.1,8,9,131,135 In some studies, the incidence of reported adverse effects was similar in patients receiving famotidine or placebo.1,5,9,16,93,114,131 The frequency of adverse effects of the drug does not appear to be affected by patient age in adults.94

Overall, the frequency of adverse effects produced by famotidine is similar to that produced by ranitidine.4,7,21,94,114,115,116,123,130,135 Famotidine does not appear to exhibit substantial antiandrogenic activity1,3,4,10,21,51,58,93 nor to substantially affect serum prolactin concentrations,1,4,44,46,65,71,74,81,114,118,135 and the drug also does not appear to affect hepatic clearance of other drugs.1,3,4,21,39,40,41,42,43,44,45,46,50,93,114,118,125 Adverse nervous system effects (e.g., headache, dizziness)1,4,5,7,130 and GI effects (e.g., constipation, diarrhea)1,4,5,7,9,13,22,123,130 occur most frequently during famotidine therapy. Although adverse effects of the drug generally are not severe,5,12,123,126 discontinuance of famotidine therapy has been necessary in up to 14% of patients.4,8,12,13,19,131,136 Adverse effects generally are similar when famotidine is administered orally or IV.1

Nervous System Effects

Headache1,4,5,7,9,11,16,19,22,94,114,123,130,131 and dizziness1,4,5,7,20,114 occur in about 5 and 1% of patients, respectively, receiving famotidine.1,5,114 Weakness (asthenia),1,7,114 fatigue,1,13,114 paresthesia,1,114 tonic-clonic (grand mal) seizure,1,114 insomnia,1,114 drowsiness,1,7,114 and reversible psychic disturbances such as depression,1,114 disorientation,9,131,136 confusion,1,94 anxiety,1,18,114 agitation,1 decreased libido,1,9,20,114,123 and hallucinations1,114 have been reported in 1% or less of patients receiving famotidine but have not been directly attributed to the drug in many cases.1,114 The risk of adverse CNS effects of famotidine may be greater in patients with impaired renal function. 1,240

GI Effects

Constipation1,4,5,9,12,13,16,22,114,123 and diarrhea1,4,5,7,9,13,16,18,19,94,114,123,130 occur in 1-2% of patients receiving famotidine.1,5,130 Nausea,1,9,13,16,114,123,139 vomiting,1,9,13,94,114 abdominal discomfort,1,7,13,114,135,136 flatulence,9,16,123 belching,9,136 anorexia,1,7,9,13,16,19,114,123 dry mouth,1,13,114 heartburn,9,10 and dysgeusia1,3,114 have been reported in 1% or less of patients receiving famotidine but have not been directly attributed to the drug in many cases.1,114

Dermatologic and Sensitivity Reactions

Adverse dermatologic effects occur in 1% or less of patients receiving famotidine, but a causal relationship to the drug has not been established.1 Dermatologic effects include acne,1,114 pruritus,1,114,123 urticaria,1 and dry skin.1,114 Rash also has been reported1,4,9,11,12,13,19,20,114,123 and occasionally has required discontinuance of the drug.12,19 Some of these adverse dermatologic effects appear to be hypersensitivity reactions.1 Anaphylaxis,1 angioedema,1 bronchospasm,1,114 orbital1,114 or facial1,13 edema, and conjunctival congestion1,114 also have been reported. Alopecia has occurred during famotidine therapy1,4,51,114 but was attributed to removal of the antiandrogenic effects of the previously administered high-dose cimetidine therapy.4,51 Toxic epidermal necrolysis has been reported very rarely with famotidine therapy.1 Transient irritation at the site of injection may occur following IV administration of famotidine.1,114

Renal Effects

Increases in BUN9,22,123 or serum creatinine concentrations9 and proteinuria9 have been reported occasionally during famotidine therapy. There is limited evidence that, unlike cimetidine,98,99,101,102 famotidine does not substantially inhibit renal tubular secretion of creatinine.46,53

Hepatic Effects

Increases in total serum bilirubin,4,8,9,13,18,22 and cholestatic jaundice1 have been reported rarely during famotidine therapy and have required discontinuance of the drug in some patients.4,8,13,22 Increases in serum aminotransferase (transaminase) (AST [SGOT] and ALT [SGPT])5,9,11,123,135 and alkaline phosphatase9,22,123 concentrations also have occurred, occasionally requiring discontinuance of the drug.1,5,114 Hepatomegaly was reported in one patient during famotidine therapy.22

Respiratory Effects

Community-acquired Pneumonia

Administration of gastric antisecretory agents (e.g., H₂-receptor antagonists, proton-pump inhibitors) has been associated with an increased risk for developing certain infections (e.g., community-acquired pneumonia).270 A possible association between chronic administration of gastric acid-suppressive drugs and occurrence of community-acquired pneumonia has been evaluated using a large Dutch database (Integrated Primary Care Information [IPCI]) containing information on approximately 500,000 patients, 364,683 of whom (average follow-up: 2.7 years) were selected for evaluating any such association.270 During the 8-year population-based, case-control study, gastric acid suppressants were first prescribed in 19,459 individuals (10,177 received H₂-receptor antagonists [mean duration of use: 2.8 months] and 12,337 received proton-pump inhibitors [mean duration of use: 5 months]; some individuals received both drugs).270 Most patients did not undergo endoscopy and were treated empirically for upper GI symptoms.270 In this study, first occurrence of pneumonia (confirmed by radiography or microbiologic testing in 18% of patients) was reported in 5551 individuals;270 development of pneumonia occurred in 185 individuals while receiving gastric acid suppressants and in 292 individuals who had discontinued such use.270

The adjusted relative risk for development of pneumonia (or the incidence rate) was 0.6, 2.3 and 2.5 per 100 person-years for individuals not receiving acid-suppressive drugs, for those receiving H₂-receptor antagonists, and for those receiving proton-pump inhibitors, respectively.270 Patients using gastric acid suppressants developed community-acquired pneumonia 4.5 (95% confidence interval of 3.8-5.1) times more often than those who never used such drugs.270 When evaluating use of all gastric acid suppressants, current use of the drugs was associated with a small (27%) overall increase in the risk of pneumonia (adjusted odds ratio 1.27 and 95% confidence interval of 1.06-1.54).270 Higher risks were observed for current users of H₂-receptor antagonists and proton-pump inhibitors;270 the adjusted relative risk for developing community-acquired pneumonia was 1.63 (95% confidence interval of 1.07-2.48) or 1.89 (95% confidence interval of 1.36-2.62), respectively, for these classes of drugs compared with those who discontinued using these agents.270 Estimates for developing pneumonia were higher (1.7 [95% confidence interval of 0.8-2.9] for H₂-receptor antagonists) and 2.2 [95% confidence interval of 1.4-3.5] for proton-pump inhibitors) when only laboratory-confirmed cases of pneumonia were considered for analysis.270

Although there was variation among individual H₂-receptor antagonists and individual proton-pump inhibitors, the numbers were small and the heterogeneity was not considered significant.270 For patients currrently receiving proton-pump inhibitors, a dose-response relationship for developing pneumonia was observed; individuals using more than one defined daily dose of these drugs had a 2.3-fold increased risk for developing pneumonia compared with those who discontinued gastric acid suppressants.270,271 Such a dose-response relationship for developing pneumonia was not observed in patients receiving H₂-receptor antagonists; however, dose variation of these drugs was limited.270 Among current users of H₂-receptor antagonists or proton-pump inhibitors, the risk for developing pneumonia was most pronounced among those who initiated such therapies within the past 30 days.270

Although the exact mechanism for development of community-acquired pneumonia in patients receiving gastric acid suppressants has not been fully elucidated, it has been suggested that reduction of gastric acid secretion by acid suppressive therapy and consequent increases of gastric pH may result in a favorable environment for the development of infection.270,271 Intragastric acidity constitutes a major nonspecific defense mechanism of the stomach to ingested pathogens; when gastric pH is less than 4, most pathogens are killed, while at higher gastric pH, pathogens may survive.270 Since for the effective management of upper GI symptoms, intragastric pH should be maintained above 4 for several hours, acid suppressive therapy may lead to insufficient elimination or, even, increased colonization of ingested pathogens.270 Some evidence indicates that acid-supressive therapy may result in nosocomial infections.270

It should be considered that certain patients (e.g., those with pleuritic chest pain, hypothermia, systolic hypotension, tachypnea, diabetes mellitus, neoplastic disease, neurologic disease, bacteremia, leukopenia, multilobar pulmonary infiltrate) are at increased risk for developing infections and in these individuals community-acquired pneumonia may be associated with increased mortality.270,272 270 Some clinicians state that gastric acid-suppressive drugs should be used in patients in whom community-acquired pneumonia may be severe (e.g., those with asthma or chronic obstructive lung disease, immunocompromised patients, pediatric or geriatric individuals) only when clearly needed and the lowest effective dose should be employed.270

Other Adverse Effects

Fever,1,114 hypertension,13 flushing,13,114 musculoskeletal pain (including muscle cramps),1,9,20,114,131,136,240 arthralgia,1,114 and tinnitus1,13,114 have been reported in 1% or less of patients receiving famotidine, but a causal relationship to the drug has not been established in many cases.1 An acute episode of gout occurred in one patient during therapy with the drug.9

Leukocytosis,9,10,22 leukopenia,1,10,123,140 neutropenia,123,140 pancytopenia,1 agranulocytosis,1 eosinophilia,123,140 prolonged erythrocyte sedimentation rate (ESR),9,22 and thrombocytopenia1,9,114,123,140 have occurred rarely in patients receiving famotidine. Changes in serum protein or cholesterol concentrations also have occurred.9

Unlike cimetidine,4,54,55,59,97,98,99,100 famotidine does not appear to exhibit substantial antiandrogenic activity.1,3,4,10,21,51,58,93,114 Famotidine did not produce gynecomastia,1,10,46,114 impotence,1,10,46,114 or decreased libido10,46 in one study in males with GI hypersecretory conditions who were receiving dosages of 80-640 mg daily for periods longer than 12 months,1,10,46,51,93,114 but such effects occasionally have been associated with therapy with the drug.1,9,10,20,123,131,136 The manufacturer states that in controlled studies the incidence of impotence in patients receiving famotidine was not greater than that in patients receiving placebo.1 Impotence and gynecomastia, which developed in one male during cimetidine therapy, continued during subsequent therapy with ranitidine and then with famotidine,10,132 but did not resolve following discontinuance of famotidine.10 In at least one patient, androgenic activity that had been inhibited by cimetidine appeared to become disinhibited (as evidenced by worsening of preexisting alopecia) when famotidine was substituted.4,51 Menstrual abnormalities have occurred in at least one woman receiving famotidine.13

Cardiac arrhythmias,1 palpitations,1,114 and AV block1 have been reported in 1% or less of patients receiving famotidine.1 There is limited evidence suggesting that famotidine may have a negative inotropic effect, but further study is necessary to confirm these preliminary findings.150

Precautions and Contraindications

Symptomatic response to famotidine should not be interpreted as precluding the presence of gastric malignancy.1

The possibility that gastric acid-suppressive therapy may increase the risk of community-acquired pneumonia should be considered. (See Respiratory Effects: Community-acquired Pneumonia, in Cautions.)

Adverse CNS effects have been reported in patients with moderate (i.e., creatinine clearance less than 50 mL/minute) or severe (i.e., creatinine clearance less than 10 mL/minute) renal impairment receiving famotidine, and the drug should be used with caution and dosage and/or frequency of administration reduced in such patients, since the drug is excreted principally by the kidneys.1,3,114,240

Unless otherwise directed by a clinician, patients receiving famotidine for self-medication should be advised to discontinue the drug and consult a clinician if symptoms of heartburn (pyrosis), acid indigestion (hyperchlorhydria), or sour stomach persist after 2 weeks of continuous use of the drug.238,260

Individuals with phenylketonuria (i.e., homozygous genetic deficiency of phenylalanine hydroxylase) and other individuals who must restrict their intake of phenylalnine should be warned that Pepcid AC^® chewable tablets and Pepcid RPD^® orally disintegrating tablets contain aspartame (NutraSweet^®), which is metabolized in the GI tract to phenylalanine following oral administration.1,238

Famotidine is contraindicated in patients with known hypersensitivity to the drug or any ingredient in the formulation.1 240 Since cross-sensitivity has been observed among H₂-receptor antagonists, famotidine should not be administered to patients with a history of hypersensitivity to other drugs in this class.1,240

Pediatric Precautions

Safety and efficacy of famotidine in children 1-16 years of age is supported by evidence from adequate and well-controlled studies in adults and by a limited number of studies in pediatric patients.1 In studies in a limited number of pediatric patients 1-15 years of age, clearance and area under the curve (AUC) were similar to those values reported in adults.1 Limited evidence also suggests that the relationship between serum concentration and acid suppression is similar in children 1-15 years of age as compared with adults.1 While uncontrolled studies suggest efficacy of famotidine in the treatment of gastroesophageal reflux disease and peptic ulcer, data in pediatric patients are insufficient to establish percent response with dose and duration of therapy.1 Therefore, treatment duration (initially based on adult duration recommendations) and dose should be individualized based on clinical response and/or pH determination (gastric or esophageal) and endoscopy.1 In uncontrolled clinical studies in pediatric patients, dosages of up to 1 mg/kg daily for peptic ulcer and 2 mg/kg daily for gastroesophageal reflux disease with or without esophagitis including erosions and ulcerations have been used.1 The manufacturer states that no pharmacokinetic or pharmacodynamic data for famotidine are available in children younger than 1 year of age.1 Famotidine should not be used for self-medication in children younger than 12 years of age unless directed by a clinician.238,239,260

Geriatric Precautions

Of almost 5000 patients in clinical studies of famotidine, 9.8% were 65 years of age or older, while 1.7% were older than 75 years of age.1,240 Although no overall differences in efficacy and safety were observed between geriatric and younger patients, the possibility that some older patients may exhibit increased sensitivity to the drug cannot be ruled out.1,240 Clinically important changes in the pharmacokinetics of famotidine have not been observed in geriatric individuals, and dosage of the drug does not need to be modified based on age alone.1,240 However, famotidine dosage should be selected carefully in geriatric patients because these individuals may have decreased renal function, and patients with renal impairment may be at increased risk of famotidine-induced toxicity.1,240 Monitoring of renal function may be useful for patients in this age group.1,240 Doses and/or frequency of administration of famotidine should be modified in geriatric patients with moderate (creatinine clearance less than 50 mL/minute) or severe (creatinine clearance less than 10 mL/minute) renal impairment.1,240

Mutagenicity and Carcinogenicity

No evidence of mutagenicity was observed in in vitro studies using famotidine concentrations up to 10 mg per plate in the Ames microbial mutagen test with or without metabolic activation and in in vivo studies in mice using a micronucleus test and a chromosomal aberration test.1,3,23,24,114

No evidence of carcinogenicity was seen in long-term studies in mice or rats receiving oral famotidine dosages up to 2 g/kg daily (approximately 2500 times the usual human dosage).1,3,23,24,114 Although famotidine did not produce changes in gastric mucosal cells in animals,4,24 long-term effects of the drug on human gastric mucosal morphology are not known,4 and the risk, if any, of gastric neoplasms and long-term therapy with an H₂-receptor antagonist remains controversial.98,109,110,111,112,113,116

Pregnancy, Fertility, and Lactation

Pregnancy

Reproduction studies in rats and rabbits using oral famotidine dosages up to 2 (approximately 2500 times the maximum human dosage)1,3,24,26,27,28,114 and 0.5 g/kg1,24,29 daily, respectively, or IV dosages up to 0.2 (approximately 250 times the maximum human dosage)1,3,24,25,114 and 0.1 g/kg30 daily, respectively, have not revealed evidence of harm to the fetus.1,3,24,25,26,27,28,29,30,114 Oral dosages of 2 g/kg daily inhibited weight gain in pregnant rats,24,26,27 and those of 0.5 and/or 2 g/kg daily on days 7-17 of gestation decreased fetal weight24,26 and delayed sternal ossification in the offspring.24 Decreased food intake and decreased weight gain also occurred in offspring of rats receiving these dosages from days 10-28 post partum.24,28 Death and locomotor dysfunction were observed in pregnant rats receiving IV famotidine dosages of 100 or 200 mg/kg daily.24,25 IV dosages of 100 or 200 mg/kg daily in rats have decreased pup body weight during the post-weaning period.24,25 Although no direct fetotoxic effects have been observed, sporadic abortions and decreases in fetal weight occurred secondary to substantial decreases in food intake in pregnant rabbits receiving oral dosages of 200 mg/kg (250 times the usual human dosage) or more daily.1,24,29 Decreased number of sacrocaudal vertebrae and delayed ossification have occurred in rabbits receiving oral famotidine dosages of 0.5 g/kg daily.29 There are no adequate and controlled studies to date using famotidine in pregnant women, and the drug should be used during pregnancy only when clearly needed.1,3 Women who are pregnant or nursing should seek the advice of a health professional before using famotidine for self-medication .238

Fertility

Reproduction studies in rats and rabbits using oral famotidine dosages up to 2 (approximately 2500 times the maximum human dosage)1,3,24,26,27,28,114 and 0.5 g/kg1,24,29 daily, respectively, or IV dosages up to 0.2 (approximately 250 times the maximum human dosage)1,3,24,25,114 and 0.1 g/kg30 daily, respectively, have not revealed evidence of impaired fertility.1,3,24,25,26,27,28,29,30,114

Lactation

Famotidine is distributed into milk in humans and in animals.1 The drug has produced transient growth depression in the offspring of lactating rats receiving dosages at least 600 times the usual human dosage.1 Because of the potential for serious adverse reactions to famotidine in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.1

Food and Antacids

Food appears to slightly enhance, and antacids appear to slightly decrease, the bioavailability of famotidine, but these effects do not appear to be clinically important.1,3,47,114 Famotidine can be administered concomitantly with antacids.1,4,6,7,16,18,19,47,49,94

In one study following concomitant administration of food and a single oral 40-mg dose of famotidine, mean peak plasma concentration, fraction of the dose excreted in urine, bioavailability, and renal clearance of famotidine increased slightly; however, area under the plasma concentration-time curve (AUC) and time to reach the peak were decreased slightly.47 In the same study following concomitant administration of 10 mL of an aluminum and magnesium hydroxides antacid (Mylanta-II^®) and 40 mg of famotidine orally, the mean peak plasma concentration decreased from 81 to 60 ng/mL, and the mean AUC decreased from 443 to 355 mcg/hour per L.47 The time to reach the peak and the fraction of the dose excreted in urine also decreased slightly, and renal clearance increased slightly.47

Effects on Hepatic Clearance of Drugs

Unlike cimetidine4,32,34,35,36,37,41,46,53,98,99,114,127 or ranitidine,4,33,99 famotidine does not appear to inhibit the metabolism of drugs, including warfarin,1,3,46,93,114,118,125 theophylline,1,3,4,39,46,93,114,118,125 phenytoin,1,3,4,43,46,93,114,118,125 diazepam,1,3,4,40,42,46,93,114,118,125 or procainamide,4,42,46,114,118 by the hepatic cytochrome P-450 (microsomal) enzyme system.1,3,4,21,39,40,41,45,46,114,118,125,127 Metabolism of aminopyrine1,3,114,118 or antipyrine1,3,4,46,50,114,118 and clearance and/or half-life of the drugs4,44,46,50,114,125 also do not appear to be affected substantially by famotidine therapy. However, minimal effects of the drug on cytochrome P-450 enzymes have been suggested,45,125,126 and additional experience with long-term therapy and with relatively high dosages is necessary to determine the potential, if any, for clinically important effects.45 Famotidine does not appear to affect elimination of indocyanine green.1,3,43,119,124

Acute Toxicity

There has been no experience to date with acute overdosage of famotidine.1,2,3

Pathogenesis

The oral and IV LD₅₀s of famotidine have been reported to be greater than 3000 and 254-563 mg/kg, respectively, in both mice and rats,1,2,3,24,31,114 and the intraperitoneal and subcutaneous LD₅₀s have been reported to be greater than 778 and greater than 800 mg/kg, respectively, in these animals.3,24,31,114 The minimum acute oral and IV lethal doses have been reported to be greater than 20001 and about 300 mg/kg, respectively, in dogs.1,2 In rabbits, oral famotidine dosages of 200 mg/kg or more daily produce substantial anorexia and growth retardation;1 however, no evidence of toxicity was observed following high oral dosages in dogs and rats.1,3 In dogs, IV dosages of 5-200 mg/kg daily produce vomiting; restlessness; pallor of the mucous membranes or redness of the mouth and ears; and cardiovascular effects, including hypotension, tachycardia, and collapse.1,24,114

Oral dosages up to 800 mg of famotidine daily produced no evidence of serious toxicity when the drug was used in patients with pathologic GI hypersecretory conditions.1,2,3,4,10,51,132

Treatment

In acute famotidine overdose, usual measures to remove unabsorbed drug from the GI tract and clinical monitoring should be employed.1,3 Supportive and symptomatic treatment should be initiated.1,3

Pharmacology

GI Effects

Famotidine competitively inhibits the action of histamine on the H₂ receptors of parietal cells,1,3,4,23,46,52,63,79,81,114,118 reducing gastric acid secretion1,4,46,60,61,62,63,65,66,77,81,118,128,134 and concentration under daytime1,4,46,60,61,62,63,65,66,71,81,118,128 and nocturnal basal conditions1,4,11,56,61,62,65,66,69,71,72,73,77,81,114,118,128 and also when stimulated by food,1,4,61,62,73,81,114,118,128 histamine,4,81 or pentagastrin.1,4,48,63,65,71,81 The H₂-receptor antagonist activity of famotidine reportedly is slowly reversible,23,68,81,114 since the drug dissociates slowly from the H₂ receptor.68 Famotidine has been shown to be 20-150 or 3-20 times as potent on a molar basis as cimetidine4,5,10,21,51,60,75,81,114,118,132 or ranitidine,4,5,10,21,51,69,75,81 respectively, in inhibiting stimulated gastric acid secretion.

The degree of inhibition of gastric acid secretion by famotidine is similar to that observed following equipotent doses of cimetidine10,63,65,81 or ranitidine.10 A 5-mg dose of famotidine appears to produce inhibition of gastric acid secretion similar in degree to that produced by a 300-mg dose of cimetidine.48,63,65,81,114 The degree of inhibition of gastric acid secretion (especially nocturnal or food-stimulated) by famotidine is directly related to the dose1,4,11,46,48,60,61,62,63,65,81,114,118,130 and the time of administration of the drug.4,56,65,73,76,81,114 In one study in healthy individuals who were hypersecretors of gastric acid (basal gastric acid output of 5 or more mEq/hour), the total volume of gastric acid secretion was decreased 55-65% following single 20-mg oral or 10- or 20-mg IV doses of the drug, but the largest decrease was observed following the 20-mg IV dose.11,114 In another study in healthy individuals, a single 40-mg evening dose of famotidine inhibited 9556,77 and 32%56 of nocturnal and daytime gastric acid secretion, respectively; 24-hour gastric acid secretion was inhibited about 70%.56

Evening (bedtime) doses produce maximal inhibitory effects on nocturnal or breakfast-stimulated gastric acid secretion, but produce minimal inhibition of lunch- or dinner-stimulated secretion;4,56,65,67,73,81,114 administration of famotidine twice daily before meals produces substantial inhibition of meal-stimulated gastric acid secretion.4,65,73,114

Basal and nocturnal gastric acid secretion appear to be inhibited to a greater extent than are food- or pentagastrin-stimulated gastric acid secretion following a given dose of famotidine in both healthy individuals and patients with duodenal ulcer or GI hypersecretory conditions.1,4,48,61,62 Following oral administration of a single 20-1 or 40-mg1,77 evening dose of famotidine, 86 or 94% of nocturnal gastric acid secretion, respectively, is inhibited for at least 10 hours.1,77 Following oral administration of a single 20- or 40-mg morning dose, 76 or 84% of food-stimulated gastric acid secretion, respectively, is inhibited for up to 3-5 hours and 25 or 30%, respectively, for up to 8-10 hours.1,46 However, inhibition of food-stimulated gastric acid secretion disappeared within 6-8 hours following administration of a 20-mg dose in some individuals.1,4,81 Following oral administration of a single 40-mg bedtime dose of the drug, basal or pentagastrin-stimulated gastric acid secretion is inhibited by 70 or 30%, respectively, for 12 hours and by 55 or 9%, respectively, for 20 hours.4,71

The inhibitory effects of famotidine on gastric acid secretion do not appear to be cumulative following repeated administration of the drug,1,73 and tolerance to the drug's effects does not develop rapidly.51

The increases in gastric pH that occur secondary to inhibition of gastric acid secretion by famotidine also are dose dependent.11,48,61,62 Nocturnal gastric pH increased to a mean of 5 or 6.4 following oral administration of a single 20- or 40-mg evening dose of famotidine, respectively,1,61,62,114 and basal gastric pH increased to about 5 for 3-8 hours after a single 20- or 40-mg morning (after breakfast) dose of the drug.1 Following administration of a single evening dose of 20 mg orally, 10 mg IV, 20 mg IV, or placebo, nocturnal gastric pH averaged 4.4, 5.5, 6.2, or 1.7, respectively, 2 hours after the dose; nocturnal gastric pH averaged 6, 5.4, and 4.4 at 7, 8, and 10 hours after the 20-mg IV dose or 4, 3.3, and 3 at 7, 8, and 10 hours after the 10-mg IV dose.11 Gastric pH for a 24-hour period (measured every 5 seconds) was greater than 6 about half the time during continuous IV infusion of famotidine dosages of 3.2 or 4 mg/hour in patients with duodenal ulcer; however, during postprandial periods of the day, pH exceeded 6 only 10% of the time.128

Famotidine indirectly causes a dose-dependent reduction in pepsin secretion by decreasing the volume of gastric acid secretion.1,4,60,63,66,81,114 The drug appears to have minimal effects on fasting and postprandial serum gastrin concentrations.1,3,4,10,64,118,135 Serum gastrin concentrations have increased in some patients during famotidine therapy but remained within the normal range.4,23,114 Famotidine may protect the gastric mucosa from the irritant effects caused by certain drugs (e.g., aspirin, nonsteroidal anti-inflammatory agents).4,70,78,80

Famotidine does not appear to affect gastric emptying,1,3,5,46,114,117,118 lower esophageal sphincter pressure,115,116 or biliary secretion.115,116,119

Famotidine concentrations ranging from 128-1024 mcg/mL are necessary to inhibit growth of various strains of Helicobacter pylori (formerly Campylobacter pylori or C. pyloridis ),95 an organism possibly contributing to the etiology of duodenal and gastric ulcers.107,108,120,121,180,181,182,183,184,185,186,187,188,189 The MIC₅₀ and MIC₉₀ of famotidine for susceptible strains of H. pylori are reportedly 512 and greater than 1024 mcg/mL, respectively.95

Endocrine and Gonadal Effects

Famotidine has been shown to have little, if any, effect on serum prolactin concentrations.1,4,44,46,65,71,74,81,114,118,135 Although changes in serum prolactin concentrations occurred following a 20-mg IV dose of the drug in some healthy individuals and patients with duodenal ulcer, these changes were considered within normal physiologic variations.4,46,64,114 Serum prolactin concentrations remained unchanged following single IV doses of 20 mg1,3,46 or following oral dosages of 80-640 mg daily for periods longer than 12 months.1,3,46,51

Famotidine does not appear to have substantial antiandrogenic effects.1,3,4,10,21,51,58,93 Unlike cimetidine4,54,55,59,98,99 but like ranitidine,4,54,55,59,74,99 famotidine has been shown to have little, if any, effect on serum concentrations of testosterone,1,4,44,46,64,71,74,114,118,135 luteinizing hormone (LH),4,46,64,74,114 follicle-stimulating hormone (FSH),4,46,64,74,114 estradiol,4,64 parathyroid hormone (PTH),44 cortisol,1,44,46,74,118,135 insulin,44,46,118 glucagon,44,46,118 thyrotropin (TSH),44,74,135 thyroxine (T₄),1,44,74,135 triiodothyronine (T₃),44,74,135 or thyroxine-binding globulin (TBG).44

Other Effects

Famotidine has been shown to produce few, if any, CNS,1,3,114 cardiovascular,1,3,5,46,114,118 or respiratory effects.1,3 The drug does not appear to affect hepatic43,115,116,119,124 or portal blood flow124 in healthy individuals43,124 or patients with chronic liver disease.124 Unlike cimetidine,50 famotidine does not inhibit hepatic metabolism of antipyrine.1,3,4,46,50,114,118 Famotidine does not appear to affect the volume or bicarbonate or amylase content of exocrine pancreatic secretions.1,3,5,46,114,117,118

In animals, famotidine did not inhibit immediate hypersensitivity reactions involving antigen-induced mediator release from mast cells or cellular and humoral immune responses.57

Pharmacokinetics

Absorption

Famotidine is incompletely absorbed from the GI tract following oral administration,1,3,4,11,46,85,93,114,118 and the drug reportedly undergoes minimal first-pass metabolism.1,3,114,118 The oral bioavailability of famotidine in adults is about 40-50%.1,3,4,11,46,85,114,118 Studies in a limited number of children 11-15 years of age indicate a similar oral bioavailability of famotidine (mean bioavailability: 50%).1 The film-coated tablets, oral suspension, and orally disintegrating tablets of famotidine reportedly are bioequivalent.1,2,3,114 Food may slightly enhance and antacids may slightly decrease the bioavailability of famotidine, but these alterations do not appear to be clinically important.1,3,47,114

Following IV injection of a single 20-mg dose of famotidine, peak plasma concentrations of 272 ng/mL occur within 20 minutes and decrease to 163, 98, 64, 25, and 11 ng/mL 1, 2, 4, 8, and 12 hours, respectively, after the dose.2 Following oral administration of a 5-, 10-, 20-, or 40-mg dose of famotidine, peak plasma concentrations of 17-22,4,48,65 29-39,4,48,65 40-71,2,4,11,48,65,83 or 78-132 ng/mL,2,4,65 respectively, occur within 1-4 hours.1,2,3,4,11,61,81,83,85,93,114,118

Plasma famotidine concentrations necessary to inhibit 50% of tetragastrin-stimulated gastric acid secretion (IC₅₀) are estimated to be 13 ng/mL.4,60 Plasma famotidine concentrations greater than 50 ng/mL result in inhibition of more than 80% of gastric acid secretion; however, inhibition generally appears to diminish at lower concentrations.11 Data are conflicting regarding the relationship between plasma famotidine concentrations and a given therapeutic effect of acid inhibition.11,60,61,66,118 However, in one study, the decline in the degree of inhibition of gastric acid secretion appeared to be proportional to decreases in plasma famotidine concentrations.60

Inhibition of gastric acid secretion is apparent within 1 hour following IV or oral administration of famotidine.1,2,11,118 Peak inhibition occurs within 0.5-3 or 1-4 hours following IV1,11,114,118 or oral1,10,11,46,51,114 administration, respectively. The duration of inhibition of gastric acid secretion and maximal inhibition produced by famotidine are dose dependent.1,4,11,46,48,60,61,62,63,65,81,118 The duration of inhibition of basal and nocturnal secretion following a single 20-1,2,11,61,62,63,81 or 40-mg1,2,46,61,62 oral dose of the drug reportedly is 10-12 hours.1,2,11,46,61,62,63,81,93,114,118 Inhibition of food-stimulated secretion generally persists for 8-10 hours when these doses are administered in the morning, but this inhibition may dissipate within 6-8 hours after a 20-mg oral dose in some patients.1,4,81 Following equipotent doses of famotidine (60 mg), cimetidine (1.9 g), or ranitidine (530 mg) in one study in patients with GI hypersecretory conditions, gastric acid secretion 12 hours after discontinuance of the drugs was reduced by 58, 27, or 38%, respectively, compared with basal secretion, and the time required for secretion to return to 20 mEq/hour averaged 12, 9, or 10 hours, respectively, following discontinuance of the drugs.10,51 The duration of inhibition of nocturnal gastric acid secretion is 10-15 hours following a single 10- or 20-mg IV famotidine dose.1,2,11 In one study in healthy individuals who were hypersecretors of gastric acid (basal gastric acid output of 5 or more mEq/hour), maximal inhibition of gastric acid secretion was 97.4, 99.7, or 99.4% 2-4 hours and 73.8, 77.2, or 83.3% 12 hours following a single famotidine dose of 10 or 20 mg IV or 20 mg orally, respectively.11

Distribution

Distribution of famotidine into human body tissues and fluids has not been fully characterized.4 The apparent volume of distribution of the drug is reported to be 1.1-1.4 L/kg in adults and does not appear to be altered substantially in patients with renal dysfunction.4,86 In children 1-15 years of age, a volume of distribution of 1.5-2.07 L/kg has been reported.1,240 Following oral or IV administration in rats, famotidine is widely distributed, appearing in highest concentrations in the kidney, liver, pancreas, and submandibular gland.4,84 The drug is 15-20% protein bound.1,3,4,114,118

In rats, famotidine appears to distribute only minimally into the CNS,2,3,84,114 and does not cross the placenta.2 It is not known whether the drug crosses the placenta in humans.2 Famotidine is distributed into milk in rats; however, it is not known whether the drug is distributed into milk in humans.1,2,3

Elimination

The elimination half-life of famotidine averages 2.5-4 hours in adults with normal renal function.1,3,4,11,65,81,83,85,86,93,118 An elimination half-life of 2.3-3.38 hours has been reported in children 1-15 years of age.1,240 The elimination of famotidine does not appear to be affected substantially by age in adults,1,3,114 but is prolonged in patients with renal impairment;1,4,86,118,1 adjustment of dosage or dosing interval may be necessary to avoid excess accumulation of the drug in patients with moderate or severe renal impairment.1 In adults with creatinine clearances of 10 mL or less per minute, the elimination half-life of the drug may exceed 20 hours,1,3,4,86,114 with an elimination half-life of about 24 hours in anuric patients.1 There is some evidence that plasma concentrations of famotidine decline in a biphasic manner.86 In adults with normal renal function and those with creatinine clearances of 60-90, 30-60, or less than 30 mL/minute per 1.48 m², the plasma half-life in the distribution phase (t_½α) was not affected substantially by renal function, averaging 0.18, 0.23, 0.25, or 0.24 hours, respectively; the half-life in the terminal elimination phase (t_½β) averaged 2.6, 2.9, 4.7, or 12 hours, respectively.4,86

Famotidine is metabolized in the liver115 to famotidine S -oxide ( S -famotidine).1,2,3,82,84,114 The metabolite does not appear to inhibit gastric acid secretion.2,3,114 Orally administered famotidine undergoes minimal metabolism on first pass through the liver.1,3,114,118

Famotidine is excreted principally in urine1,2,3,4,86,114,118 via glomerular filtration and tubular secretion.1,3,4,53,86,114,118 Approximately 25-301,2,3,4,65,81,83,114 or 65-80%1,2,3,4,85,86,114 of a dose is excreted unchanged in urine within 24 hours following oral or IV administration, respectively,1,2,3,4,83,85,86 and approximately 13-49 or 52-82% of a single 40-mg oral or IV dose, respectively, is excreted within 72 hours.2 The cumulative renal excretion of famotidine is decreased in patients with renal dysfunction,4,86,114 with 72, 69, 65, or 21% of an administered dose excreted in individuals with normal renal function or those with creatinine clearances of 60-90, 30-60, or less than 30 mL/minute per 1.48 m², respectively.4,86 A small fraction of an orally administered dose is excreted in urine as famotidine S -oxide.4,83 The remainder of an orally administered dose is eliminated in feces.4 Nonrenal excretion of famotidine did not show a compensatory increase in patients with severe renal impairment, but rather decreased by about 40% in these patients.4,86 Interindividual variation in the metabolism and excretion of famotidine has been reported.4,83,118 Following oral administration of a 20-mg dose, 24-56 or 28-79% of the administered dose reportedly was excreted in urine or feces, respectively.83

Total body clearance of famotidine from plasma averages 381-483 mL/minute,4,86 and renal clearance of the drug averages 250-450 mL/minute.1,2,3,4,65,81,86 Total body and renal clearances are decreased in patients with renal dysfunction.4,86,114 In patients with creatinine clearances of 30-60 or less than 30 mL/minute per 1.48 m², total body clearance from plasma averaged 241 or 71-83 mL/minute, respectively, and renal clearance averaged 157 or 9.5-21 mL/minute, respectively.4,86

Famotidine does not appear to be removed by hemodialysis.4

Chemistry and Stability

Chemistry

Famotidine is a histamine H₂-receptor antagonist.1,3,4,6,23,46,48,114 Unlike the earlier histamine H₂-receptor antagonists, burimamide and metiamide, which are not commercially available,49,114 and cimetidine and ranitidine, famotidine contains a guanidine-substituted46,48,114 thiazole ring rather than an imidazole or furan ring.1,3,4,6,16,46,49,51,114

Famotidine occurs as a white to pale yellow, odorless,115 crystalline powder1,2,3,114 having a moderately bitter taste.115 Famotidine has solubilities of 740 mcg/mL in water and 360 mcg/mL in alcohol2,3,114 at 20°C.115 The drug has a pK_a of 7.1 in water at 25°C.3

Famotidine is commercially available for oral administration as film-coated, chewable, gelatin-coated, or orally disintegrating tablets and as a powder for oral suspension.1,238,260 Some famotidine chewable tablet preparations (Pepcid^® AC)238 and famotidine orally disintegrating tablets (Pepcid RPD^®) contain aspartame (Nutrasweet^®).1 Following metabolism of aspartame in the GI tract, each 20- or 40-mg orally disintegrating tablet provides 1.05 or 2.1 mg, respectively, of phenylalanine.1

Famotidine powder for suspension occurs as a white to off-white powder.1,3 When reconstituted as directed, oral suspensions of the drug occur as smooth, mobile, off-white homogenous suspensions1,3 and have a pH of 6.5-7.5.2

Famotidine concentrate for injection is a clear, colorless, sterile solution of the drug in water for injection.1,3 The concentrate also contains mannitol; multiple-dose vials also contain benzyl alcohol as a preservative.1,3 Famotidine concentrate for injection has a pH of 5-5.6.2 The preservative-free injection has an osmolarity of 217 mOsm/L, and the injection preserved with benzyl alcohol has an osmolarity of 290 mOsm/L.115 Famotidine injection that is commercially available as a diluted solution in 0.9% sodium chloride is iso-osmotic and has a pH of 5.7-6.4.240 This injection contains approximately 7.8 mEq of sodium per 50 mL.240

Stability

Commercially available famotidine film-coated tablets (Pepcid^®) should be stored in well-closed, light-resistant containers152 at 25°C, but may be exposed to temperatures ranging from 15-30°C.1,2,3 These tablets have an expiration date of 30 months following the date of manufacture when stored under these conditions.2,3 Famotidine orally disintegrating tablets (Pepcid RPD^®) should be stored at 25°C, but may be exposed to temperatures ranging from 15-30°C.1 Famotidine tablets and chewable tablets for self-medication (Pepcid^® AC, Pepcid^® Complete) should be stored at a temperature between 25-30°C and protected from moisture.238,267,268

Commercially available famotidine powder for oral suspension should be stored in tight containers at 25°C, but may be exposed to temperatures ranging from 15-30°C.1,2,3 The powder for oral suspension has an expiration date of 18 months following the date of manufacture when stored at a temperature less than 40°C.2,3 Following reconstitution, oral suspensions of the drug should be stored at a temperature less than 30°C and, although not necessary, may be refrigerated;115 freezing should be avoided.1,2,3 Any unused suspension should be discarded after 30 days.1,2,3

Commercially available famotidine concentrate for injection should be refrigerated at 2-8°C1,2 and has an expiration date of 24 months following the date of manufacture when stored at this temperature.2,3 If freezing occurs, the injection should be thawed at room temperature1,3 or by warming it in a water bath or under running hot tap water,115 allowing sufficient time for dissolution of all ingredients.1,3 The injection should not be thawed by exposure to microwave radiation because of the potential hazard of rapidly increased temperature and vapor pressure in a closed system.115 When diluted with most commonly used IV solutions (e.g., 0.9% sodium chloride injection, 5 or 10% dextrose injection, lactated Ringer's, water for injection), famotidine solutions are stable for 7 days at room temperature.240 However, the manufacturer states that data on the maintenance of sterility of these solutions after dilution are unavailable.240 Therefore, the manufacturer recommends that solutions prepared by dilution of famotidine concentrate for injection, if not used immediately after dilution, should be refrigerated and used within 48 hours.240

Famotidine injection that is commercially available as a diluted solution in 0.9% sodium chloride should be stored at room temperature (25°C) and is stable for 15 months when stored as recommended.241 Brief exposure to temperatures up to 35°C will not adversely affect the stability of the solution, but240 the solution should be protected from exposure to excessive heat.240 The commercially available injection of famotidine in 0.9% sodium chloride is provided in a plastic container fabricated from specially designed multilayered plastic PL 2501 (Galaxy^® container). Solutions in contact with the plastic can leach out some of its chemical components in very small amounts within the expiration period of the injection; however, safety of the plastic has been confirmed in tests in animals according to USP biological tests for plastic containers as well as by tissue culture toxicity studies.240

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

1. Merck. Pepcid® (famotidine) tablets, Pepcid® (famotidine) for oral suspension, and Pepcid RPD® (famotidine) orally disintegrating tablets prescribing information (dated 2001 Mar). In: Physicians' desk reference. 56th ed. Montvale, NJ: Medical Economics Company Inc; 2002:2150-3.

2. Merck Sharp & Dohme. Pepcid^® product information form for American Hospital Formulary Service. West Point, PA; 1986 Oct.

3. Merck Sharp & Dohme. Pepcid^® product information summary. West Point, PA; 1986 Oct.

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74. Dammann HG, Burkhardt F, Muller P et al. Effect of intravenous famotidine and ranitidine on intragastric pH and hormone levels in critical care patients. Dig Dis Sci . 1985; 30:372.

75. Dicenta C, Cook T, Pierzchala PA. Results of a double-blind multicentric trial with a new H₂-antagonist: famotidine in gastric ulcers. Gastroenterology . 1985; 88:1366.

76. Evans DF, Clark AG, Hardcastle JD. The effect of oral famotidine on 24 hour ambulatory gastric pH in normal subjects. Gastroenterology . 1985; 88:1376.

77. Savarino V, Mela GS, Scalabrini P et al. Famotidine and ranitidine control of 24 h intragastric acidity after single bedtime administration: a study using continuous pH monitoring. Br J Clin Pharmacol . 1986; 22:749-50. [PubMed 3567023]

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