Famotidine

Description

Famotidine is a histamine H2-receptor antagonist with the chemical name N’-(aminosulfonyl)-3-[[[2-(diaminomethylene)amino-4-thiazolyl]methyl]thio]propanimidamide. Its molecular formula is C8H15N7O2S3, and it has a molecular weight of 337.45 g/mol. Famotidine appears as a white to pale yellow crystalline compound. It is freely soluble in glacial acetic acid, slightly soluble in methanol, very slightly soluble in water, and practically insoluble in ethanol.

Each tablet for oral administration contains either 20 mg or 40 mg of famotidine, along with the following inactive ingredients: hydroxypropyl cellulose, hypromellose, magnesium stearate, microcrystalline cellulose, pregelatinized starch, talc, titanium dioxide, and polyethylene glycol. The 20 mg tablets also include iron oxides.

Uses and Indications

Famotidine tablets are indicated for the short-term treatment of active duodenal ulcer, with most adult patients healing within 4 weeks. It is recommended that famotidine not be used at full dosage for longer than 6 to 8 weeks, as studies have not assessed the safety of famotidine in uncomplicated active duodenal ulcer beyond this duration.

Additionally, famotidine is indicated for maintenance therapy in duodenal ulcer patients at a reduced dosage following the healing of an active ulcer; however, controlled studies in adults have not extended beyond one year.

The drug is also indicated for the short-term treatment of active benign gastric ulcer, with most adult patients healing within 6 weeks. Similar to duodenal ulcers, studies have not evaluated the safety or efficacy of famotidine in uncomplicated active benign gastric ulcer for periods exceeding 8 weeks.

Famotidine is indicated for the short-term treatment of gastroesophageal reflux disease (GERD) in patients presenting with symptoms, as well as for the short-term treatment of esophagitis due to GERD, including erosive or ulcerative disease diagnosed by endoscopy.

Furthermore, famotidine is indicated for the treatment of pathological hypersecretory conditions, such as Zollinger-Ellison Syndrome and multiple endocrine adenomas.

No teratogenic or nonteratogenic effects have been reported.

Dosage and Administration

The recommended adult oral dosage for the treatment of active duodenal ulcer is 40 mg once daily at bedtime. Most patients typically achieve healing within 4 weeks; however, there is generally no need to continue famotidine at the full dosage for longer than 6 to 8 weeks. An alternative regimen of 20 mg administered twice daily (b.i.d.) is also effective. For maintenance therapy, the recommended adult oral dose is 20 mg once daily at bedtime.

For the treatment of active benign gastric ulcer, the recommended adult oral dosage is 40 mg once daily at bedtime.

In adult patients with gastroesophageal reflux disease (GERD), the recommended oral dosage for symptomatic treatment is 20 mg b.i.d. for up to 6 weeks. For patients with esophagitis, including erosions and ulcerations due to GERD, the recommended oral dosage is either 20 mg or 40 mg b.i.d. for up to 12 weeks.

For pediatric patients under 1 year of age with GERD, the starting dose is 0.5 mg/kg per dose of famotidine oral suspension. This is to be administered once daily for up to 8 weeks in patients under 3 months of age, and twice daily in patients aged 3 months to less than 1 year.

In pediatric patients aged 1 to 16 years, the dosage for peptic ulcer is 0.5 mg/kg per day, administered orally at bedtime or divided b.i.d., with a maximum of 40 mg per day. For gastroesophageal reflux disease, with or without esophagitis including erosions and ulcerations, the dosage is 1.0 mg/kg per day, administered orally and divided b.i.d., with a maximum of 40 mg b.i.d.

For pathological hypersecretory conditions, such as Zollinger-Ellison Syndrome and Multiple Endocrine Adenomas, the recommended adult oral starting dose is 20 mg every 6 hours (q 6 h). Doses should be tailored to individual patient needs and may be continued as long as clinically indicated. In some adult patients with severe Zollinger-Ellison Syndrome, doses up to 160 mg q 6 h have been administered.

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 standard dose, or the dosing interval may be extended to 36-48 hours, depending on the patient's clinical response.

Contraindications

Use of this product is contraindicated in patients with a known hypersensitivity to any component of the formulation. Due to the potential for cross-sensitivity, famotidine should not be administered to individuals with a history of hypersensitivity to other H2-receptor antagonists.

Warnings and Precautions

Symptomatic response to therapy with famotidine does not exclude the possibility of gastric malignancy. Therefore, healthcare professionals should remain vigilant for signs of malignancy in patients receiving this treatment.

In patients with impaired renal function, particularly those with moderate or severe renal insufficiency, there is a risk of prolonged QT interval, which has been reported very rarely. It is essential to adjust the dose or dosing interval of famotidine appropriately in these patients to mitigate this risk. For individuals with moderate renal insufficiency (creatinine clearance <50 mL/min) or severe renal insufficiency (creatinine clearance <10 mL/min), longer intervals between doses or reduced doses may be necessary due to the longer elimination half-life of famotidine.

While no significant drug interactions have been identified with famotidine, it is important to note that studies conducted in humans, animal models, and in vitro have shown no substantial interference with the metabolism of compounds processed by hepatic microsomal enzymes. This information should be considered when evaluating potential drug regimens for patients.

Currently, there are no specific laboratory tests required or suggested for the safe use of famotidine. However, healthcare professionals should continue to monitor patients for any adverse effects, particularly those with renal insufficiency, to ensure safe and effective therapy.

Side Effects

Patients may experience a range of adverse reactions while using the medication. Common adverse reactions, occurring in at least 1% of participants, include headache (4.7%), diarrhea (1.7%), dizziness (1.3%), and constipation (1.2%).

Serious adverse reactions have been reported, although they are less frequent. These include cardiovascular events such as arrhythmia, AV block, palpitation, and a very rare occurrence of prolonged QT interval, particularly in patients with impaired renal function. Neurologically, patients may experience grand mal seizures and various psychic disturbances, which are reversible and may include hallucinations, confusion, agitation, depression, anxiety, decreased libido, and paresthesia. Convulsions have also been reported very rarely in patients with impaired renal function.

Other notable adverse reactions encompass a variety of systems. Gastrointestinal issues may include cholestatic jaundice, hepatitis, liver enzyme abnormalities, vomiting, nausea, abdominal discomfort, anorexia, and dry mouth. Hematologic reactions are rare but can include agranulocytosis, pancytopenia, leukopenia, and thrombocytopenia. Hypersensitivity reactions may manifest as anaphylaxis, angioedema, orbital or facial edema, urticaria, rash, and conjunctival injection.

Musculoskeletal complaints such as musculoskeletal pain, including muscle cramps and arthralgia, have also been reported. Respiratory adverse reactions include bronchospasm and interstitial pneumonia. Skin reactions may range from toxic epidermal necrolysis/Stevens-Johnson syndrome (very rare) to alopecia, acne, pruritus, dry skin, and flushing. Additionally, patients may experience tinnitus and taste disorders as part of the special senses reactions.

In clinical studies, particularly one involving 35 pediatric patients under 1 year of age with gastroesophageal reflux disease (GERD) symptoms, agitation was observed in 5 patients receiving famotidine, which resolved upon discontinuation of the medication. Other rare adverse reactions include impotence and gynecomastia, with incidences not exceeding those seen with placebo.

Drug Interactions

No drug interactions have been identified for the compound in question. Comprehensive studies, including those involving famotidine in humans, animal models, and in vitro assessments, have demonstrated that there is no significant interference with the metabolism of compounds processed by hepatic microsomal enzymes, specifically the cytochrome P450 system.

The compounds evaluated in these studies include warfarin, theophylline, phenytoin, diazepam, aminopyrine, and antipyrine, all of which showed no notable interactions. Additionally, the use of indocyanine green as an index for hepatic drug extraction has also indicated no significant effects. Therefore, no dosage adjustments or enhanced monitoring are necessary when co-administering these agents.

Packaging & NDC

The table below lists all NDC Code configurations of Famotidine, the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

Pediatric patients under 1 year of age require careful dosing of famotidine for the treatment of gastroesophageal reflux disease (GERD). The recommended starting dose is 0.5 mg/kg/dose once daily for patients less than 3 months of age, and 0.5 mg/kg/dose twice daily for those aged 3 months to less than 1 year. The safety and efficacy of famotidine treatment beyond 4 weeks in this age group have not been established, and conservative measures, such as thickened feedings, should be employed concurrently.

For pediatric patients aged 1 to 16 years, the recommended starting doses vary based on the condition being treated. For peptic ulcers, the dose is 0.5 mg/kg/day orally at bedtime or divided twice daily, up to a maximum of 40 mg/day. For GERD, with or without esophagitis, the recommended dose is 1.0 mg/kg/day orally, divided twice daily, also up to 40 mg twice daily. Treatment duration and dosing should be individualized based on clinical response, pH determination, and endoscopy findings. Uncontrolled studies indicate that doses up to 1 mg/kg/day for peptic ulcers and 2 mg/kg/day for GERD may be effective.

Pharmacokinetic data indicate that clearance of famotidine in pediatric patients aged 3 months to 1 year is comparable to that of older pediatric patients and adults. However, patients aged 0 to 3 months exhibit clearance values that are 2- to 4-fold lower than those in older pediatric patients and adults. The mean bioavailability of famotidine in patients under 1 year of age after oral dosing is similar to that observed in older pediatric patients and adults.

In terms of pharmacodynamics, the duration of acid suppression is longer in pediatric patients less than 1 month of age, which aligns with the longer half-life of famotidine in this age group.

Adverse reactions have been noted in pediatric patients, particularly in a study involving 35 patients under 1 year of age with GERD, where agitation was reported in 5 patients receiving famotidine. This agitation resolved upon discontinuation of the medication.

Geriatric Use

In clinical studies involving 4,966 subjects treated with famotidine, 488 subjects (9.8%) were aged 65 years and older, while 88 subjects (1.7%) were over 75 years of age. No overall differences in safety or effectiveness were observed between these elderly patients and their younger counterparts. However, it is important to note that greater sensitivity to the drug may be present in some older individuals.

No dosage adjustment is required based solely on age. Nevertheless, famotidine is substantially excreted by the kidneys, which raises the potential risk of toxic reactions in patients with impaired renal function. Given that elderly patients are more likely to experience decreased renal function, careful consideration should be given during dose selection. Monitoring of renal function may be beneficial in this population.

In cases of moderate or severe renal impairment, dosage adjustments are necessary to mitigate the risk of adverse effects. Healthcare providers should remain vigilant in assessing renal function and adjusting the dosage accordingly to ensure the safety and efficacy of famotidine in geriatric patients.

Pregnancy

Pregnant patients should be aware that this medication is classified as Pregnancy Category B. Reproductive studies conducted in rats and rabbits at oral doses of up to 2000 mg/kg/day and 500 mg/kg/day, respectively, as well as intravenous doses of up to 200 mg/kg/day, have not demonstrated significant evidence of impaired fertility or fetal harm associated with famotidine.

While no direct fetotoxic effects have been observed, it is important to note that sporadic abortions were reported in some rabbits that exhibited marked decreased food intake when administered oral doses of 200 mg/kg/day (which is approximately 250 times the usual human dose) or higher.

Despite these findings, there are no adequate or well-controlled studies in pregnant women. Therefore, due to the limitations of animal reproductive studies in predicting human outcomes, this medication should be used during pregnancy only if clearly needed. Healthcare professionals are advised to weigh the potential benefits against the risks when considering this treatment for pregnant patients.

Lactation

Famotidine is secreted into breast milk, as demonstrated in studies performed in lactating rats. It is also detectable in human milk. In animal studies, transient growth depression was observed in young rats suckling from mothers treated with maternotoxic doses of at least 600 times the usual human dose. Due to the potential for serious adverse reactions in breastfed infants, healthcare professionals should consider whether to discontinue nursing or discontinue famotidine, weighing the importance of the medication to the mother against the risks to the nursing infant.

Renal Impairment

In patients with severe renal insufficiency (creatinine clearance <10 mL/min), the elimination half-life of famotidine may exceed 20 hours, which necessitates adjustments in dose or dosing intervals. For those with moderate renal insufficiency (creatinine clearance <50 mL/min) or severe renal insufficiency, it is recommended that the dose of famotidine be reduced to half the usual dose or that the dosing interval be extended to 36-48 hours, depending on the clinical response.

CNS adverse effects have been reported in patients with moderate and severe renal insufficiency; therefore, careful monitoring and appropriate dose adjustments are essential. Additionally, a prolonged QT interval has been reported very rarely in patients with impaired renal function when the dose or dosing interval of famotidine has not been adjusted accordingly.

In pediatric patients with moderate or severe renal insufficiency, dosage adjustments should be considered based on pharmacokinetic parameters. The recommended adult oral dosage for patients with moderate renal insufficiency is to reduce the dose or extend the dosing interval to prevent excess accumulation of the drug.

Hepatic Impairment

Patients with hepatic impairment do not require specific dosage adjustments. However, caution is advised when administering famotidine to this population due to the potential for altered drug metabolism. It is recommended that liver function tests be considered for monitoring in patients with compromised liver function. Additionally, no significant interference with the disposition of compounds metabolized by hepatic microsomal enzymes has been identified, suggesting that famotidine does not adversely affect the metabolism of other drugs processed by the liver.

Overdosage

In cases of overdosage, the adverse reactions observed are consistent with those typically encountered during normal clinical use. While oral doses of up to 640 mg/day have been administered to adult patients suffering from pathological hypersecretory conditions without any serious adverse effects, caution is still warranted.

Management of Overdosage

In the event of an overdosage, treatment should be primarily symptomatic and supportive. It is essential to remove any unabsorbed material from the gastrointestinal tract. Continuous monitoring of the patient is recommended, alongside the implementation of supportive therapy as needed.

Toxicological Data

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. Notably, famotidine does not produce overt effects at high oral doses in various species, including mice, rats, cats, and dogs. However, significant anorexia and growth depression have been observed in rabbits at doses starting from 200 mg/kg/day.

For intravenous administration, the LD50 for famotidine in mice and rats ranges from 254 to 563 mg/kg, with the minimum lethal single intravenous dose in dogs being approximately 300 mg/kg. Signs of acute intoxication in dogs treated intravenously may include emesis, restlessness, pallor of mucous membranes or redness of the mouth and ears, hypotension, tachycardia, and potential collapse.

Healthcare professionals should remain vigilant for these symptoms and manage the patient accordingly.

Nonclinical Toxicology

Reproductive studies conducted in rats and rabbits at oral doses of up to 2000 mg/kg/day and 500 mg/kg/day, respectively, as well as intravenous doses of up to 200 mg/kg/day in both species, have shown no significant evidence of impaired fertility or fetal harm associated with famotidine. Although no direct fetotoxic effects were noted, sporadic abortions were observed in some rabbits at oral doses of 200 mg/kg/day (250 times the usual human dose) or higher, but these occurrences were linked to marked decreases in food intake in the mothers.

There are no adequate or well-controlled studies in pregnant women. Given that animal reproductive studies may not always predict human responses, famotidine should be used during pregnancy only if clearly needed.

In a 106-week study in rats and a 92-week study in mice receiving oral doses of up to 2000 mg/kg/day (approximately 2500 times the recommended human dose for active duodenal ulcer), no evidence of carcinogenic potential for famotidine was observed. Additionally, famotidine was found to be negative in the microbial mutagen test (Ames test) using Salmonella typhimurium and Escherichia coli, both with and without rat liver enzyme activation, at concentrations up to 10,000 mcg/plate. In vivo studies in mice, including a micronucleus test and a chromosomal aberration test, also revealed no evidence of mutagenic effects.

Studies involving rats administered oral doses of up to 2000 mg/kg/day or intravenous doses of up to 200 mg/kg/day indicated that fertility and reproductive performance were not adversely affected. No specific details regarding animal pharmacology and toxicology beyond the studies mentioned in this section were provided.

Postmarketing Experience

Adverse reactions reported in postmarketing experience include those observed in clinical trials and voluntary reports. In controlled clinical trials, the following adverse reactions occurred in more than 1% of patients receiving famotidine: headache (4.7%), diarrhea (1.7%), dizziness (1.3%), and constipation (1.2%).

Other adverse reactions have been reported infrequently, with the relationship to famotidine therapy remaining unclear in many instances. These reactions are categorized as follows:

Body as a Whole: Fever, asthenia, fatigue. Cardiovascular: Arrhythmia, AV block, palpitation. Prolonged QT interval has been reported very rarely in patients with impaired renal function. Gastrointestinal: Cholestatic jaundice, hepatitis, liver enzyme abnormalities, vomiting, nausea, abdominal discomfort, anorexia, dry mouth. Hematologic: Rare cases of agranulocytosis, pancytopenia, leukopenia, and thrombocytopenia. Hypersensitivity: Anaphylaxis, angioedema, orbital or facial edema, urticaria, rash, conjunctival injection. Musculoskeletal: Musculoskeletal pain, including muscle cramps and arthralgia. Nervous System/Psychiatric: Grand mal seizure; psychic disturbances, which were reversible in cases with follow-up, including hallucinations, confusion, agitation, depression, anxiety, decreased libido; paresthesia; insomnia; somnolence. Convulsions have been reported very rarely in patients with impaired renal function. Respiratory: Bronchospasm, 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 and gynecomastia have been reported; however, incidences in controlled clinical trials were not greater than those seen with placebo.

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

Patient Counseling

Patients should be informed that a symptomatic response to therapy with famotidine does not exclude the possibility of gastric malignancy. It is important for healthcare providers to emphasize this point to ensure patients understand the need for further evaluation if symptoms persist.

For patients with moderate or severe renal insufficiency, healthcare providers should advise that longer intervals between doses or lower doses may be necessary due to the prolonged elimination half-life of famotidine. Additionally, patients should be made aware that central nervous system (CNS) adverse effects have been reported in individuals with moderate and severe renal insufficiency, and they should be monitored accordingly.

Patients should also be informed that famotidine is secreted into breast milk. A discussion should be held regarding the decision to either discontinue nursing or discontinue the medication, weighing the importance of famotidine to the mother against the potential risks to the infant.

In pediatric patients under one year of age, famotidine should only be administered if conservative measures, such as thickened feedings, are used concurrently and if the potential benefits outweigh the risks. Healthcare providers should advise parents and caregivers to monitor for any adverse reactions, including agitation, which has been observed in some pediatric patients treated with famotidine.

Finally, patients should be instructed to report any signs of hypersensitivity, such as rash, itching, or difficulty breathing, as these may indicate an allergic reaction to famotidine. It is crucial for healthcare providers to ensure that patients understand these potential reactions and the importance of timely reporting.

Storage and Handling

The product is supplied in a well-closed, light-resistant container. It should be stored at a temperature range of 20°-25°C (68°-77°F), in accordance with USP Controlled Room Temperature guidelines. Proper storage conditions are essential to maintain the integrity of the product.

Additional Clinical Information

Famotidine is administered orally. Clinicians should counsel patients that a symptomatic response to famotidine therapy does not rule out the possibility of gastric malignancy. For patients with moderate to severe renal insufficiency, it may be necessary to adjust the dosing interval or reduce the dose due to the prolonged elimination half-life of the drug. Additionally, nursing mothers should be informed that famotidine is excreted in breast milk, and they should weigh the potential risks of serious adverse reactions in nursing infants.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Famotidine as submitted by Aidarex Pharmaceuticals LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)