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

This drug is indicated for the short-term treatment of active duodenal ulcers. Most adult patients typically achieve healing within 4 weeks; however, there is rarely a need to administer famotidine at full dosage for longer than 6 to 8 weeks. The safety of famotidine has not been evaluated in uncomplicated active duodenal ulcers for durations exceeding eight weeks.

Additionally, this drug is indicated for maintenance therapy in patients with duodenal ulcers at a reduced dosage following the healing of an active ulcer. Controlled studies in adults have not extended beyond one year for this indication.

Famotidine is also indicated for the short-term treatment of active benign gastric ulcers, with most adult patients healing within 6 weeks. The safety and efficacy of famotidine in uncomplicated active benign gastric ulcers have not been assessed for periods longer than 8 weeks.

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

Lastly, 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 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). In certain patients, a higher starting dose may be necessary. Dosing should be tailored to individual patient needs and may continue as long as clinically indicated, with doses up to 160 mg q 6 h having been administered to some adults with severe Zollinger-Ellison Syndrome.

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. Healthcare professionals should remain vigilant for signs of malignancy in patients presenting with gastrointestinal symptoms, even if they exhibit improvement with famotidine treatment.

Prolonged QT interval has been reported very rarely in patients with impaired renal function. It is crucial to ensure that the dose and dosing interval of famotidine are appropriately adjusted in these patients to mitigate this risk.

Patients with moderate or severe renal insufficiency may require longer intervals between doses or lower doses due to the extended elimination half-life of famotidine. Careful consideration should be given to dose selection in elderly patients, who are more likely to have decreased renal function and may be at increased risk for adverse effects.

While no specific laboratory tests are required or suggested for the safe use of famotidine, healthcare providers should monitor renal function in patients with known renal insufficiency to ensure appropriate dosing and minimize the risk of complications.

Side Effects

Patients receiving treatment may experience a range of adverse reactions, which can be categorized by frequency and seriousness.

Common adverse reactions observed in clinical trials include headache (4.7%), dizziness (1.3%), diarrhea (1.7%), and constipation (1.2%).

In addition to these common reactions, other adverse reactions have been reported across various systems:

Body as a Whole: Patients may experience fever, asthenia, and fatigue.

Cardiovascular: Adverse reactions may include arrhythmia, AV block, palpitations, and very rarely, prolonged QT interval, particularly in patients with impaired renal function.

Gastrointestinal: Reactions such as cholestatic jaundice, hepatitis, liver enzyme abnormalities, vomiting, nausea, abdominal discomfort, anorexia, and dry mouth have been noted.

Hematologic: Rare cases of agranulocytosis, pancytopenia, leukopenia, and thrombocytopenia have been reported.

Hypersensitivity: Serious reactions can include anaphylaxis, angioedema, orbital or facial edema, urticaria, rash, and conjunctival injection.

Musculoskeletal: Patients may report musculoskeletal pain, including muscle cramps and arthralgia.

Nervous System/Psychiatric: Serious adverse reactions may include grand mal seizures and reversible psychic disturbances such as hallucinations, confusion, agitation, depression, anxiety, decreased libido, paresthesia, insomnia, and somnolence. Convulsions have been reported very rarely, particularly in patients with impaired renal function.

Respiratory: Bronchospasm and interstitial pneumonia have been observed.

Skin: Very rare cases of toxic epidermal necrolysis or Stevens-Johnson syndrome have been reported, along with alopecia, acne, pruritus, dry skin, and flushing.

Special Senses: Patients may experience tinnitus and taste disorders.

Other: Rare occurrences of impotence and gynecomastia have been noted, with incidences not exceeding those seen with placebo.

In pediatric patients, agitation was observed in five patients under one year of age, which resolved upon discontinuation of famotidine.

Healthcare professionals should monitor for these adverse reactions and manage them appropriately.

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 following compounds have been evaluated in clinical studies without evidence of interaction:

• Warfarin

• Theophylline

• Phenytoin

• Diazepam

• Aminopyrine

• Antipyrine

Additionally, the use of indocyanine green as an index for hepatic drug extraction has also shown no significant effects. Therefore, no dosage adjustments or enhanced monitoring are necessary when co-administering these agents with the compound.

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 may be treated with famotidine, as supported by studies. For 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 it is advised that patients also receive conservative measures, such as thickened feedings.

In pediatric patients aged 1 to 16 years, famotidine use is also supported by clinical studies. The starting doses for treatment are 0.5 mg/kg/day orally at bedtime or divided twice daily for peptic ulcers, up to a maximum of 40 mg/day. For GERD, with or without esophagitis, the starting 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. Published studies have utilized doses up to 1 mg/kg/day for peptic ulcers and 2 mg/kg/day for GERD with or without esophagitis.

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. The data indicated no overall differences in safety or effectiveness between these elderly patients and their younger counterparts. However, it is important to note that greater sensitivity to the drug may be observed in some older individuals.

No dosage adjustment is required based solely on age. Nevertheless, famotidine is substantially excreted by the kidneys, which raises concerns regarding the 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 to dose selection in this population. Monitoring of renal function may be beneficial to ensure safety and efficacy.

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 for 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

Studies performed in lactating rats have shown that famotidine is secreted into breast milk. Famotidine is also detectable in human milk. Transient growth depression was observed in young rats suckling from mothers treated with maternotoxic doses of at least 600 times the usual human dose. Due to the potential for serious adverse reactions in nursing infants from famotidine, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

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 dose or dosing interval adjustments. For those with moderate renal insufficiency (creatinine clearance <50 mL/min) or severe renal insufficiency, longer intervals between doses or lower doses may be required to account for the prolonged elimination half-life of famotidine.

To prevent excess accumulation of the drug in patients with moderate or severe 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. It is important to note that 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 appropriately adjusted.

In elderly patients with decreased renal function, the clearance of famotidine may be further reduced, necessitating careful consideration in dose selection. Additionally, dosage adjustments in pediatric patients with moderate or severe renal insufficiency should also be considered to ensure safety and efficacy.

Hepatic Impairment

Patients with hepatic impairment do not require specific dosage adjustments. There is no significant interference with the disposition of compounds metabolized by hepatic microsomal enzymes, including the cytochrome P450 system, indicating that drug interactions are unlikely to affect patients with compromised liver function.

However, liver-related adverse reactions have been reported in this population, including cholestatic jaundice, hepatitis, and liver enzyme abnormalities. It is advisable for healthcare providers to monitor liver function parameters in patients with hepatic impairment to detect any potential abnormalities early.

Additionally, it is important to note that a prolonged QT interval has been reported very rarely in patients with impaired renal function, which may also be relevant for patients with hepatic impairment. Therefore, careful monitoring of cardiac function may be warranted in these patients.

Overdosage

In cases of overdosage, the adverse reactions observed are consistent with those reported during normal clinical use (refer to the ADVERSE REACTIONS section for further details). Clinical experience indicates that oral doses of up to 640 mg/day have been administered to adult patients suffering from pathological hypersecretory conditions without any serious adverse effects.

Management of overdosage 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 studies have established that the oral LD50 of famotidine in both 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 elicit overt effects at high oral doses in various species, including mice, rats, cats, and dogs. However, significant adverse effects such as anorexia and growth depression have been observed in rabbits at doses starting from 200 mg/kg/day.

For intravenous administration, the LD50 of famotidine in mice and rats ranges from 254 to 563 mg/kg, with the minimum lethal single intravenous dose in dogs estimated to be 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.

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 teratogenic effects associated with famotidine. Although no direct fetotoxic effects were observed, sporadic abortions were noted in some rabbits at oral doses of 200 mg/kg/day (250 times the usual human dose) or higher, occurring only in mothers exhibiting marked decreased food intake.

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 long-term studies, famotidine demonstrated no evidence of carcinogenic potential in a 106-week study in rats and a 92-week study in mice at oral doses of up to 2000 mg/kg/day (approximately 2500 times the recommended human dose for active duodenal ulcer). 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. Furthermore, 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.

Animal studies have not revealed significant adverse effects at high doses; however, significant anorexia and growth depression were observed in rabbits starting at an oral dose of 200 mg/kg/day. The oral LD50 of famotidine in male and female rats and mice was greater than 3000 mg/kg, while the minimum lethal acute oral dose in dogs exceeded 2000 mg/kg. The intravenous LD50 for mice and rats ranged from 254 to 563 mg/kg, and the minimum lethal single intravenous dose in dogs was approximately 300 mg/kg. Signs of acute intoxication in dogs treated intravenously included emesis, restlessness, pallor of mucous membranes or redness of the mouth and ears, hypotension, tachycardia, and collapse.

Postmarketing Experience

Adverse reactions reported in postmarketing experience include a range of events that have occurred in patients receiving famotidine therapy. In controlled clinical trials, the following adverse reactions were observed in more than 1% of patients: headache (4.7%), diarrhea (1.7%), dizziness (1.3%), and constipation (1.2%).

Infrequent adverse reactions reported in clinical trials or post-marketing include:

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 advised 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, it is crucial to inform them that they may require longer intervals between doses or lower doses of famotidine. This adjustment is necessary due to the longer elimination half-life of the medication in this population.

Patients should also be made aware 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 implemented concurrently and if the potential benefits are deemed to outweigh the risks. Healthcare providers should ensure that parents or guardians are fully informed of these considerations.

Additionally, patients should be instructed to report any signs of agitation, particularly in pediatric patients, as this has been observed in some individuals treated with famotidine.

Finally, patients should be advised to monitor for any adverse reactions while on famotidine and to report these reactions to their healthcare provider promptly. This proactive approach will help ensure patient safety and effective management of their treatment.

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. Additionally, patients with moderate to severe renal insufficiency may need to adjust their dosing schedule, either by extending the intervals between doses or reducing the dose, due to the drug's prolonged elimination half-life. Nursing mothers are advised to weigh the potential for serious adverse reactions in nursing infants against the decision to continue breastfeeding or to discontinue the medication.

FDA Insert (PDF)

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

View full prescribing information (PDF)