Famotidine

Uses and Indications

Famotidine is indicated for the treatment of various gastrointestinal conditions in both adults and pediatric patients. The indications are as follows:

Adult Indications

• Active Duodenal Ulcer (DU): Short-term treatment; most adult patients heal within 4 weeks. Full dosage is rarely used for longer than 6 to 8 weeks.

• Active Gastric Ulcer (GU): Short-term treatment; most adult patients heal within 6 weeks. Safety or efficacy not assessed for periods longer than 8 weeks.

• Symptomatic Nonerosive Gastroesophageal Reflux Disease (GERD): Indicated for short-term treatment of patients with symptoms of GERD.

• Erosive Esophagitis due to GERD: Diagnosed by biopsy; indicated for short-term treatment.

• Pathological Hypersecretory Conditions: Treatment of conditions such as Zollinger-Ellison syndrome and multiple endocrine neoplasias.

• Reduction of the Risk of DU Recurrence: Maintenance therapy at reduced dosage after healing of an active ulcer; controlled studies have not extended beyond one year.

Pediatric Indications

• Active Duodenal Ulcer (DU): In pediatric patients 40 kg and greater.

• Active Gastric Ulcer (GU): In pediatric patients 40 kg and greater.

• Symptomatic Nonerosive Gastroesophageal Reflux Disease (GERD): In pediatric patients 40 kg and greater.

• Erosive Esophagitis due to GERD: Diagnosed by biopsy in pediatric patients 40 kg and greater.

• Peptic Ulcer: In pediatric patients 1 year of age and older.

• GERD with or without Esophagitis and Ulcerations: In pediatric patients 1 year of age and older.

• GERD: In pediatric patients from birth to less than 1 year of age.

Limitations of Use

• The safety of famotidine has not been assessed for uncomplicated active duodenal or gastric ulcers for periods longer than 8 weeks.

• Controlled studies in adults for maintenance therapy have not extended beyond one year.

Famotidine is available in various forms, including tablets, oral suspension, and injection, to accommodate different patient needs and conditions.

Dosage and Administration

The recommended dosage of Famotidine varies based on the indication and patient population.

Adult and Pediatric Patients (40 kg and greater):

• Active Duodenal Ulcer (DU): 40 mg once daily at bedtime or 20 mg twice daily.

• Active Gastric Ulcer (GU): 40 mg once daily.

• Gastroesophageal Reflux Disease (GERD): 20 mg twice daily.

• Erosive Esophagitis due to GERD: 20 mg twice daily or 40 mg twice daily.

• Pathological Hypersecretory Conditions: 20 mg every 6 hours, adjusted to patient needs, with a maximum of 160 mg every 6 hours.

• Risk Reduction of DU Recurrence: 20 mg once daily.

Pediatric Patients (1 year to less than 17 years):

• Peptic Ulcer Disease: Starting dosage of 0.5 mg/kg once daily or 0.25 mg/kg twice daily; may increase to 1 mg/kg once daily at bedtime or 0.5 mg/kg twice daily, with a maximum of 40 mg per day.

• GERD:

  • Birth to less than 3 months: Starting dosage of 0.5 mg/kg once daily; may increase to 1 mg/kg once daily.

  • 3 months to less than 1 year: Starting dosage of 0.5 mg/kg twice daily; may increase to 1 mg/kg twice daily, with a maximum of 40 mg per day.

  • GERD with or without esophagitis and ulcerations (1 year to less than 17 years): 0.5 mg/kg twice daily, with a maximum of 40 mg twice daily.

Administration: Famotidine should be taken once daily before bedtime or twice daily in the morning and before bedtime, with or without food.

Intravenous Administration: For hospitalized patients unable to take oral medication, Famotidine Injection may be administered. The recommended dosage for adults is 20 mg intravenously every 12 hours. For pediatric patients aged 1 to 16 years, the starting dose is 0.25 mg/kg intravenously every 12 hours, up to a maximum of 40 mg/day. Doses may be adjusted based on clinical response.

Preparation for Intravenous Use: To prepare intravenous solutions, aseptically dilute 2 mL of Famotidine Injection (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. For intravenous infusion solutions, aseptically dilute 2 mL of Famotidine Injection with 100 mL of Dextrose 5% or other compatible solution, and infuse over a 15 to 30 minute period.

Renal Impairment: In patients with moderate (creatinine clearance <50 mL/min) or severe (creatinine clearance <10 mL/min) renal insufficiency, the dose of Famotidine may be reduced to half the dose or the dosing interval may be prolonged to 36-48 hours as indicated by the patient's clinical response.

Contraindications

Famotidine is contraindicated in patients with a history of serious hypersensitivity reactions, including anaphylaxis, to famotidine or other H2 receptor antagonists. Cross-sensitivity among H2 receptor antagonists has been observed, thus famotidine should not be administered to individuals with such a history.

Warnings and Precautions

Central Nervous System (CNS) Adverse Reactions Elderly patients and those with renal impairment are at increased risk for CNS adverse reactions, including confusion, delirium, hallucinations, disorientation, agitation, seizures, and lethargy. Dosage adjustments are recommended for these populations to mitigate risks.

Gastrointestinal Malignancy The absence of gastrointestinal symptoms does not exclude the possibility of gastric malignancy. A thorough evaluation is necessary prior to initiating therapy with famotidine, especially in patients presenting with suboptimal responses or early symptomatic relapses after treatment.

Benzyl Alcohol Toxicity in Neonates Famotidine Injection in multiple dose vials contains benzyl alcohol, which has been associated with fatal 'gasping syndrome' in neonates (children less than one month of age). Symptoms may include gasping respiration, hypotension, bradycardia, and cardiovascular collapse. Therefore, famotidine injection should not be used in neonates or pregnant women.

Renal Insufficiency Precautions Patients with moderate or severe renal insufficiency may require longer intervals between doses or lower doses due to the longer elimination half-life of famotidine. Monitoring is essential to prevent CNS adverse effects in these patients.

General Precautions No specific general precautions or laboratory tests are explicitly listed in the provided data.

Emergency Medical Help No specific instructions for emergency medical help are provided.

Stop Taking and Call Your Doctor Instructions No specific instructions for stopping the medication and contacting a healthcare provider are provided.

Side Effects

Common adverse reactions reported in patients receiving famotidine include:

• Headache (4.7%)

• Dizziness (1.3%)

• Constipation (1.2%)

• Diarrhea (1.7%)

Other Adverse Reactions

Body as a Whole

• Fever

• Asthenia

• Fatigue

Cardiovascular

• Arrhythmia

• AV block

• Palpitations

• Prolonged QT interval (very rare, particularly in patients with impaired renal function)

Gastrointestinal

• Cholestatic jaundice

• Hepatitis

• Elevated liver enzymes

• 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

• Bronchospasm

Musculoskeletal

• Rhabdomyolysis

• Musculoskeletal pain including muscle cramps

• Arthralgia

Nervous System/Psychiatric

• Seizures

• Hallucinations

• Confusion

• Agitation

• Depression

• Anxiety

• Decreased libido

• Paresthesia

• Insomnia

• Somnolence

• Convulsions (very rare, particularly in patients with impaired renal function)

Respiratory

• Interstitial pneumonia

Skin

• Toxic epidermal necrolysis/Stevens-Johnson syndrome (very rare)

• Alopecia

• Acne

• Pruritus

• Dry skin

• Flushing

Special Senses

• Tinnitus

• Taste disorder

Other

• Rare cases of impotence

• Rare cases of gynecomastia (incidences not greater than those seen with placebo)

Central Nervous System (CNS) Adverse Reactions

Elderly patients and those with renal impairment are at increased risk for CNS adverse reactions, which may include confusion, delirium, hallucinations, disorientation, agitation, seizures, and lethargy. It is recommended to reduce the dosage in these populations.

Overdosage

The types of adverse reactions observed in cases of overdosage are similar to those encountered with the use of recommended dosages.

Pediatric Patients

In a clinical study involving 35 pediatric patients under 1 year of age with GERD symptoms, agitation was observed in 5 patients on famotidine, which resolved upon discontinuation of the medication.

Warnings

Famotidine Injection contains benzyl alcohol, which has been associated with fatal ‘gasping syndrome’ in neonates. Symptoms include gasping respiration, hypotension, bradycardia, and cardiovascular collapse. Therefore, famotidine injection from multiple dose vials containing benzyl alcohol should not be used in neonates and pregnant women.

Important Notes

• The absence of gastrointestinal symptoms does not preclude the presence of gastric malignancy; evaluation is recommended prior to initiating therapy.

• History of serious hypersensitivity reactions (e.g., anaphylaxis) to famotidine or other H2 receptor antagonists should be noted.

Drug Interactions

Systemic exposure of concomitant drugs that depend on gastric pH for absorption may be significantly reduced when administered with famotidine, potentially leading to a loss of efficacy. It is advised to consult the full prescribing information for a comprehensive list of these interacting drugs.

Famotidine is also a weak inhibitor of the CYP1A2 enzyme. Concomitant use of tizanidine, a substrate of CYP1A2, may result in substantial increases in blood concentrations of tizanidine. This can lead to adverse effects such as hypotension, bradycardia, or excessive drowsiness. Therefore, it is recommended to avoid the concomitant use of famotidine and tizanidine if possible. If their use together is clinically necessary, careful monitoring for these adverse effects is advised.

In clinical studies, famotidine has not shown significant interference with the metabolism of drugs processed by the hepatic microsomal enzymes, including the cytochrome P450 system. Compounds tested include warfarin, theophylline, phenytoin, diazepam, aminopyrine, and antipyrine, with no significant effects observed. Indocyanine green, used as an index of hepatic drug extraction, has also shown no significant effects when tested.

Overall, while famotidine has potential interactions with drugs dependent on gastric pH and with tizanidine, it has not demonstrated significant interactions with other drugs metabolized by the liver.

Pediatric Use

The safety and effectiveness of famotidine have been established in pediatric patients for the treatment of peptic ulcer disease (including duodenal and gastric ulcers) and gastroesophageal reflux disease (GERD), which encompasses symptomatic nonerosive GERD and erosive esophagitis as diagnosed by endoscopy.

Pediatric Patients 1 Year to Less Than 17 Years of Age

• Famotidine for oral suspension has been shown to be effective for treating peptic ulcer disease and GERD, with or without esophagitis and ulcerations. This use is supported by evidence from adequate and well-controlled studies in adults, along with pharmacokinetic and pharmacodynamic data in this age group.

• The recommended starting dose for peptic ulcer treatment is 0.5 mg/kg/day orally at bedtime or divided twice daily, up to a maximum of 40 mg/day. For GERD, the starting dose is 1 mg/kg/day orally, divided twice daily, also up to 40 mg.

• Treatment duration and dosage should be individualized based on clinical response and/or pH determination and endoscopy.

Pediatric Patients Less Than 1 Year of Age

• The safety and effectiveness of famotidine for oral suspension have been established for the treatment of GERD in patients from birth to less than 1 year of age. This use is supported by studies in both adults and pediatric patients in this age group.

• A starting dose of 0.5 mg/kg/dose is recommended for GERD treatment, administered once daily for patients less than 3 months of age and twice daily for those aged 3 months to less than 1 year. The safety and benefit of treatment beyond 4 weeks have not been established.

• Famotidine should be considered only if conservative measures (e.g., thickened feedings) are used concurrently and if the potential benefit outweighs the risk.

General Considerations

• The safety and effectiveness of famotidine for the treatment of pathological hypersecretory conditions and the reduction of the risk of duodenal ulcer recurrence have not been established in pediatric patients.

• A safe and effective dosage has not been established in pediatric patients with renal impairment.

• Famotidine 20 mg and 40 mg tablets are not recommended for use in pediatric patients weighing less than 40 kg, as these strengths exceed the recommended dose for this population. Alternative formulations, such as oral suspension or lower dose tablets, should be considered for these patients.

Geriatric Use

In clinical studies involving famotidine, approximately 10% of the 4,966 patients treated were aged 65 and older, with a subset of 1.7% being over 75 years of age. No significant differences in safety or effectiveness were observed between elderly and younger patients. However, greater sensitivity in some older individuals cannot be ruled out.

Famotidine is primarily excreted by the kidneys, which raises concerns regarding the risk of adverse reactions, particularly in elderly patients with impaired renal function. In postmarketing experience, central nervous system (CNS) adverse reactions have been reported in elderly patients, both with and without renal impairment. Therefore, it is recommended to use the lowest effective dose of famotidine for elderly patients and to closely monitor renal function.

While no dosage adjustment is required based solely on age, caution should be exercised in dose selection due to the likelihood of decreased renal function in elderly patients. Dosage adjustments are necessary for those with moderate to severe renal impairment. Regular monitoring of renal function is advised to mitigate potential risks associated with famotidine use in this population.

Pregnancy

Available data regarding the use of famotidine, an H2-receptor antagonist, in pregnant patients are insufficient to establish a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, no adverse developmental effects were observed with oral administration of famotidine at doses up to approximately 243 and 122 times, respectively, the recommended human dose of 80 mg per day for the treatment of erosive esophagitis.

The estimated background risk for major birth defects and miscarriage in the general population is unknown; however, all pregnancies carry a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the background risk of major birth defects and miscarriage in clinically recognized pregnancies is approximately 2 to 4% and 15 to 20%, respectively.

Reproductive studies conducted in rats and rabbits at oral doses of up to 2000 and 500 mg/kg/day, respectively, and in both species at intravenous doses of up to 200 mg/kg/day, 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 were noted in some rabbits at oral doses of 200 mg/kg/day (about 49 times the recommended human dose), occurring only in mothers displaying marked decreased food intake.

There are, however, no adequate or well-controlled studies in pregnant women. Because animal reproductive studies are not always predictive of human response, famotidine should be used during pregnancy only if clearly needed.

Lactation

There are limited data available on the presence of famotidine in human breast milk. Studies indicate that famotidine is detectable in human milk, and it has been shown to be secreted into the milk of lactating rats. However, there were no observed effects on breastfed infants in the available data.

The developmental and health benefits of breastfeeding should be weighed against the mother's clinical need for famotidine and any potential adverse effects on the breastfed child. Notably, transient growth depression was observed in young rats suckling from mothers treated with maternotoxic doses of famotidine, which were at least 600 times the usual human dose.

Due to the potential for serious adverse reactions in nursing infants, healthcare providers should consider whether to discontinue nursing or the medication, taking into account the importance of famotidine to the mother’s health. There are no data available regarding the effects of famotidine on milk production.

Renal Impairment

Patients with renal impairment are at an increased risk for adverse effects when treated with famotidine. It is recommended that the dosage be reduced for these patients, particularly for those with moderate or severe renal impairment, defined as having a creatinine clearance of less than 60 mL/minute. In patients with mild renal impairment (creatinine clearance greater than or equal to 60 mL/minute), no dosage adjustment is necessary.

For patients with severe renal insufficiency (creatinine clearance <10 mL/min), the elimination half-life of famotidine may exceed 20 hours, which may necessitate further adjustments in dosing intervals or dosages. To avoid excess accumulation of the drug, a reduction to half the usual dose or an extension of the dosing interval to 36 to 48 hours may be warranted based on the patient's clinical response.

CNS adverse reactions, including confusion, delirium, and prolonged QT intervals, have been reported in patients with moderate and severe renal impairment. Therefore, careful monitoring of renal function is advised, especially in elderly patients, who may also experience decreased clearance of famotidine.

Data regarding the safe and effective dosage of famotidine in pediatric patients with renal impairment are not available, and caution should be exercised when prescribing to this population.

Hepatic Impairment

Patients with hepatic impairment do not require specific dosage adjustments when using Famotidine in any of its formulations, including tablets, powder for suspension, and injections. The available data indicates that hepatic metabolism of Famotidine is minimal, and there have been no significant effects on hepatic drug extraction reported.

While no special monitoring or precautions are explicitly outlined for patients with liver problems, it is noted that adverse reactions such as hepatitis and liver enzyme abnormalities have been reported infrequently in clinical trials and post-marketing experiences. Therefore, it may be prudent to monitor liver function tests periodically in patients with pre-existing liver conditions, although this is not a mandated requirement.

Overall, the lack of significant drug interactions with hepatic microsomal enzymes, such as the cytochrome P450 system, further supports the safety profile of Famotidine in this patient population.

Overdosage

In cases of overdosage with famotidine, the adverse reactions are similar to those observed with recommended dosages. Treatment should be symptomatic and supportive. It is essential to remove unabsorbed material from the gastrointestinal tract, and the patient should be closely monitored throughout the management process. Supportive therapy should be employed as necessary.

Due to famotidine's low binding to plasma proteins, it can be eliminated by hemodialysis; however, there is limited experience regarding the effectiveness of hemodialysis as a treatment for famotidine overdosage.

Oral doses of up to 640 mg/day have been administered to adult patients with pathological hypersecretory conditions without serious adverse effects. The oral LD50 of famotidine in male and female rats and mice exceeds 3000 mg/kg, while the minimum lethal acute oral dose in dogs is greater than 2000 mg/kg. In intravenous studies, the LD50 for mice and rats ranges from 254 to 563 mg/kg, with a minimum lethal single IV dose in dogs approximately 300 mg/kg.

Signs of acute intoxication in IV-treated dogs may include emesis, restlessness, pallor of mucous membranes or redness of the mouth and ears, hypotension, tachycardia, and collapse. In non-lethal cases, famotidine has not produced overt effects at high oral doses in various animal species, although significant anorexia and growth depression were noted in rabbits starting at 200 mg/kg/day orally.

For additional management recommendations, it may be prudent to contact a medical toxicologist or the Poison Help line at 1-800-222-1222.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

The carcinogenic potential of famotidine was evaluated in a 106-week oral carcinogenicity study in rats and a 92-week oral carcinogenicity study in mice. In these studies, famotidine was administered at oral doses of up to 2000 mg/kg/day, which is approximately 243 times and 122 times the recommended human dose of 80 mg per day for the treatment of erosive esophagitis, based on body surface area. The results indicated no evidence of carcinogenic potential for famotidine.

Famotidine was also assessed for mutagenic potential using the microbial mutagen test (Ames test) with Salmonella typhimurium and Escherichia coli, both with and without rat liver enzyme activation, at concentrations up to 10,000 mcg/plate. The findings from these tests, along with in vivo studies in mice that included a micronucleus test and a chromosomal aberration test, showed no evidence of mutagenic effects.

In terms of reproductive toxicity, studies conducted with rats receiving oral doses of up to 2000 mg/kg/day (approximately 243 times the recommended human dose) demonstrated that fertility and reproductive performance were not adversely affected.

Storage and Handling

Famotidine is supplied in various forms, including tablets, film-coated tablets, powders for suspension, and injections.

Tablets and Film-Coated Tablets

• Store at 20°C to 25°C (68°F to 77°F) See USP Controlled Room Temperature.

• Excursions permitted between 15°C to 30°C (59°F to 86°F).

• Dispense in a USP tight, light-resistant container.

• Avoid storage at temperatures above 40°C (104°F).

Powder for Suspension

• Store famotidine for oral suspension dry powder and constituted suspension at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

• Protect from freezing.

• Discard unused constituted suspension after 30 days.

• Dispense in a USP tight, light-resistant container.

Injection

• Store Famotidine Injection at 2°C to 8°C (36°F to 46°F).

• If solution freezes, bring to room temperature; allow sufficient time to solubilize all components.

• Although diluted Famotidine Injection has been shown to be physically and chemically stable for 7 days at room temperature, it is recommended that if not used immediately after preparation, diluted solutions should be refrigerated and used within 48 hours.

• Protect from light and retain in carton until time of use.

All forms of famotidine should be handled with care, ensuring proper storage conditions to maintain product integrity and efficacy.