Famotidine

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT FAMOTIDINE (FAMOTIDINE)

Composition:

Active substance: famotidine;

One tablet contains famotidine equivalent to 100% substance 20 mg;

Excipients: lactose monohydrate; potato starch; povidone; calcium stearate; silicon dioxide, colloidal anhydrous.

Pharmaceutical form. Tablets.

Main physicochemical properties: tablets are white or white with a creamy shade, round-shaped, flat-surfaced, with a bevelled edge.

Pharmacotherapeutic group. Drugs for treatment of peptic ulcer and gastroesophageal reflux disease. H₂-receptor antagonists.

ATC code A02B A03.

Pharmacological Properties

Pharmacodynamics

Famotidine is a potent competitive H2-histamine receptor antagonist. The primary clinically significant pharmacological effect of famotidine is the inhibition of gastric acid secretion. Famotidine reduces both the concentration of acid and the volume of gastric secretion, while pepsin production remains proportional to the volume of gastric juice secreted.

Famotidine suppresses basal and nocturnal gastric secretion, as well as secretion stimulated by pentagastrin, betazole, caffeine, insulin, and the physiological reflex of the vagus nerve.

The duration of acid secretion inhibition after doses of 20 mg and 40 mg lasts from 10 to 12 hours.

A single evening oral dose of 20 mg or 40 mg effectively inhibits basal and nocturnal acid secretion.

Nocturnal hydrochloric acid secretion is suppressed by 86–94% for at least 10 hours. The same doses taken in the morning reduce food-stimulated acid secretion. This inhibition amounts to 76–84% of initial secretion 3–5 hours after administration and 25% and 30% at 8 and 10 hours after food intake, respectively.

Famotidine has almost no effect on fasting or postprandial serum gastrin levels. The drug does not influence gastric emptying, exocrine pancreatic function, hepatic blood flow, or portal circulation.

Pharmacokinetics

The kinetics of famotidine are linear in nature.

Absorption. Famotidine is rapidly absorbed. Oral bioavailability ranges from 40% to 45%. Bioavailability is not affected by food content in the stomach, although it is slightly reduced when antacids are co-administered.

Clinically significant age-related changes in the bioavailability of famotidine have not been observed in elderly patients.

First-pass metabolism in the liver has only a minimal effect on the drug's bioavailability.

Distribution. After oral administration, peak plasma concentrations are reached within 1–3 hours. Repeated dosing does not result in cumulative effects. Plasma protein binding is relatively low, ranging from 15% to 20%.

The elimination half-life is 2.3–3.5 hours. In patients with severe renal impairment, the elimination half-life of famotidine may exceed 20 hours.

The drug is metabolized in the liver. The only metabolite identified in humans is the sulfoxide.

Famotidine is eliminated primarily via the kidneys (65–70%) and through metabolism (30–35%). Renal clearance ranges from 250 to 450 ml/min, indicating some degree of tubular excretion. 25–30% of an orally administered dose and 65–70% of an intravenously administered dose are excreted unchanged in urine. A small portion of the administered dose may be excreted as the sulfoxide metabolite.

Clinical characteristics.

Indications.

• Benign gastric ulcer.
• Duodenal peptic ulcer (treatment and prevention of recurrences).
• Hypersecretory conditions, such as Zollinger–Ellison syndrome.
• Treatment of gastroesophageal reflux disease (reflux esophagitis).
• Prevention of symptoms and of erosion or ulcer formation associated with gastroesophageal reflux disease.

Contraindications.

Hypersensitivity to any component of the drug or to other H2-histamine receptor antagonists.

Paediatric age, pregnancy or lactation (due to lack of adequate clinical experience).

Interaction with other medicinal products and other forms of interaction.

The absorption of certain medicinal products (e.g., ketoconazole, amoxicillin, iron preparations) depends on gastric juice acidity.

Therefore, famotidine should be taken at least 2 hours after administration of such medicinal products.

All medicinal products that inhibit gastric juice secretion may alter the bioavailability and rate of absorption of certain drugs, leading to reduced atazanavir absorption due to changes in gastric pH. Because of increased gastric pH, famotidine may reduce the absorption of ketoconazole and itraconazole when used concomitantly. Therefore, ketoconazole should be taken at least 2 hours before taking famotidine tablets.

Concomitant administration of sucralfate should be avoided within two hours before and after taking famotidine.

Whenever possible, concomitant use of posaconazole oral suspension and famotidine should be avoided, as famotidine may reduce the absorption of posaconazole in oral suspension form when administered together.

Concomitant use of famotidine with tyrosine kinase inhibitors (TKIs), such as dasatinib, erlotinib, gefitinib, and pazopanib, may lead to decreased plasma concentrations of TKIs and, consequently, reduced efficacy. Therefore, concomitant use of famotidine with these TKIs is not recommended. For further additional recommendations, please refer to the instructions for medical use of individual medicinal products containing TKIs.

Concomitant use with other H2-receptor antagonists may significantly reduce the effectiveness of tolazoline. Although there are no confirmed interactions between famotidine and tolazoline, the likelihood of such interactions is sufficiently high; therefore, the effect of tolazoline should be monitored at the beginning and after completion of concomitant therapy. If the effect of tolazoline decreases, its dose should be gradually increased or famotidine treatment discontinued.

The absorption of famotidine tablets may be reduced when medicinal products that counteract or neutralize gastric acidity (antacids) are used, which may lead to decreased plasma concentrations of famotidine. Therefore, antacids should be taken 1–2 hours after administration of famotidine tablets.

Famotidine does not affect the hepatic cytochrome P450 oxidase system; therefore, the metabolism of oral anticoagulants, antipyrine, aminopyrine, theophylline, phenytoin, diazepam, ethanol, and propranolol remains unchanged.

Probenecid may slow the elimination of famotidine.

In a test using indocyanine green as an indicator of hepatic blood flow and/or hepatic drug extraction, no significant effect was observed.

Studies involving patients receiving concomitant phenprocoumon therapy showed no pharmacokinetic interaction with famotidine and no effect on the anticoagulant activity of phenprocoumon.

Furthermore, studies with famotidine did not show an increased expected blood alcohol level following alcohol consumption.

Special precautions for use

Famotidine should be used with caution and in low doses in patients with hepatic insufficiency.

Since cross-sensitivity among H2-receptor antagonists has been reported, famotidine is contraindicated in patients with known hypersensitivity to other H2-receptor antagonists.

Prior to initiating treatment with famotidine, malignancies of the stomach and duodenum must be excluded. Treatment with this drug may mask symptoms of gastric carcinoma. Symptomatic relief of gastric ulcer due to famotidine therapy does not exclude the presence of malignant gastric tumors.

Since famotidine is primarily excreted by the kidneys, it should be used with caution in patients with impaired renal function.

Famotidine treatment must not be initiated without a physician's prescription or appropriate medical evaluation if:

• the patient has kidney or liver disease (in elderly patients or patients with impaired hepatic or renal function, psychiatric disorders (confusion) may occur, requiring dose reduction);
• the patient has concomitant diseases or is taking other medications simultaneously;
• a middle-aged or elderly patient experiences new-onset digestive complaints or changes in previous symptoms;
• the patient has gastric complaints and has experienced weight loss;
• the patient has black-colored stools;
• the patient has swallowing difficulties or chronic abdominal pain.

The drug should be used with caution in patients with acute porphyria (including in medical history) or immunodeficiency.

With prolonged use of high doses of the drug, regular monitoring of complete blood count and liver function is recommended.

Symptoms of duodenal ulcer may resolve within 1–2 weeks, but treatment should be continued until healing is confirmed by endoscopic or radiological examination.

Regular monitoring is required for patients (especially elderly patients and those with a history of gastric and/or duodenal ulcer) who are using the drug in combination with nonsteroidal anti-inflammatory drugs (NSAIDs).

When used concomitantly with antacids, the interval between administration of famotidine and antacids should be at least 1–2 hours.

If a dose is missed, it should be taken as soon as possible; however, the dose should not be doubled if it is time for the next scheduled dose.

Famotidine treatment should not be initiated without prior appropriate medical evaluation in elderly patients presenting with heartburn, symptoms of hyperacidity, stomach pain, or hyperacidity after meals.

Patients should be informed that one 20 mg tablet of famotidine contains lactose; therefore, patients with galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medication.

Use during pregnancy or breastfeeding

Fertility. Controlled studies in pregnant women have not been conducted.

Pregnancy. Animal studies have shown that famotidine crosses the placenta. Controlled studies in pregnant women to confirm this have not been conducted. Famotidine is not recommended during pregnancy.

Breastfeeding period

Famotidine passes into human breast milk; therefore, breastfeeding women should either discontinue the drug or stop breastfeeding.

Ability to affect reaction speed when driving or operating machinery

Some patients have experienced dizziness and headache while taking famotidine. Patients should be advised to avoid driving, operating machinery, or engaging in other activities requiring heightened attention if these symptoms occur (see section "Adverse reactions").

Dosage and Administration

The drug is most effective when taken in the evening before bedtime. When famotidine is taken twice daily, one dose should be taken in the morning and the other in the evening before bedtime.

Peptic ulcer of the duodenum and stomach (benign)

40 mg once daily in the evening before bedtime for 4–8 weeks.

Prevention of duodenal ulcer relapse

For prevention of relapses after achieving therapeutic effect, the drug should be administered at a maintenance dose: 20 mg once nightly for 1–4 weeks.

Gastroesophageal reflux disease (reflux esophagitis)

20 mg or 40 mg (depending on disease severity) twice daily for 6–12 weeks.

For gastroesophageal reflux disease associated with erosive esophagitis or ulceration: 40 mg twice daily for 6–12 weeks.

For prevention of symptom relapse and recurrence of erosions or ulceration associated with gastroesophageal reflux disease (maintenance therapy).

Administer 20 mg twice daily.

Zollinger–Ellison syndrome

The dosage should be individually adjusted. For patients who have not previously received antisecretory drugs, initiate treatment with 20 mg four times daily (every 6 hours). For patients previously treated with other H2-receptor antagonists, a higher initial dose may be immediately initiated—40 mg every 6 hours. The dose should then be adjusted based on gastric juice secretion levels and the patient's clinical condition. Treatment should continue as long as clinical symptoms of the disease persist.

If necessary, the daily dose may be gradually increased according to individual requirements until an optimal dose is achieved.

According to published data, the highest doses of famotidine administered to patients with severe disease reached up to 160 mg every 6 hours.

Dosing in renal impairment

If creatinine clearance is less than 30 mL/min or serum creatinine level exceeds 3 mg/100 mL, the daily dose should be reduced to 20 mg or the dosing interval should be extended to 36–48 hours.

The drug should be discontinued gradually due to the risk of rebound syndrome following abrupt discontinuation.

Dosing in elderly patients

Dosage adjustment is not required for elderly patients, except for those with renal impairment.

Children

This drug should not be prescribed to children due to lack of experience with its use in this patient population.

Overdose

Adverse reactions in overdose are similar to those observed in usual clinical practice (see section "Adverse Reactions"). In patients with Zollinger–Ellison syndrome who received oral famotidine at doses of 800 mg daily for more than 1 year, no serious adverse effects were observed.

Symptoms: vomiting, psychomotor agitation, tremor, decreased arterial pressure, tachycardia, and collapse may occur.

Treatment: discontinue the drug, induce vomiting and/or perform gastric lavage.

If necessary, appropriate symptomatic and supportive treatment may be administered: intravenous diazepam in case of seizures, atropine in case of bradycardia, and lidocaine in case of ventricular arrhythmia. Hemodialysis is effective.

Adverse reactions.

Famotidine is generally well tolerated.

The adverse reactions listed below have been reported very rarely or rarely. However, in many cases, a causal relationship to famotidine administration has not been established.

* Gynecomastia is very rare and reversible upon discontinuation of treatment.

If any serious adverse reactions occur, treatment with Famotidine must be discontinued.

After marketing authorization, reporting of suspected adverse reactions is important. This enables ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions.

Shelf life. 4 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging. 10 tablets in a blister pack, 2 blisters per carton.

Prescription status. Prescription only.

Manufacturer. JSC "Kyivmedpreparat".

Manufacturer's address and place of business.

139 Saksaganskogo Street, Kyiv, 01032, Ukraine.