4.1. Therapeutic indications

Duodenal ulcers and prevention of relapses of duodenal ulceration.

Benign gastric ulcers.

Zollinger-Ellison syndrome.

Symptomatic treatment of mild to moderate reflux oesophagitis.

4.2. Posology and method of administration

Posology

Adults

Duodenal ulcers - The initial recommended dose is 40 mg of famotidine to be taken at night. Healing generally occurs in most patients within 4 weeks. This period, however, may be shortened if an endoscopic examination reveals that the ulcer has healed. However, in those patients whose ulcers have not healed within this 4 week period, treatment should continue for a further 4 weeks.

Prevention of relapses of duodenal ulceration - To prevent ulcers from reoccurring the recommended dose is 20 mg of famotidine to be taken at night.

Benign gastric ulcers - The recommended dose of 40 mg of famotidine to be taken at night. Treatment should continue for between 4-8 weeks unless earlier healing is revealed by endoscopy.

Zollinger-Ellison syndrome - Patients who are not receiving any antisecretory therapy should be started on a dose of 20 mg of famotidine every 6 hours. The dosage should then be adjusted to individual response. Doses up to 800 mg daily have been used up to one year without the development of significant adverse effects or tachyphylaxis.

If the desired inhibition of acid secretion cannot be attained with a daily dosage of 800 mg, alternative treatment should be considered to regulate acid secretion, since no long term experience with dosages of more than 800 mg of famotidine/day have been recorded.

Treatment should be continued for as long as necessary. Patients who have been receiving other H2-receptor antagonist treatment may be switched directly to famotidine treatment at a higher dosage than the initial dosage that is usually recommended. The starting dosage will depend on the severity of the condition and the size of the last dose of H2-antagonist previously used.

Symptomatic treatment of mild to moderate oesophagitis - The recommended dose in case of mild oesophagitis is 20 mg of famotidine twice daily. In case of mild to moderate oesophagitis, the recommended dose is 40 mg twice daily. Generally treatment should be conducted for 6 weeks. If the condition has not improved, treatment should be continued for a further 6 weeks.

Renal impairment:

Famotidine is primarily eliminated via the kidneys. For patients with impaired renal function in whom creatinine clearance is less than 30 ml/min, the daily dose of famotidine should be reduced by 50%. Caution is advised in patients with renal impairment.

Dialysis patients should also take dosages that are reduced by 50%. Famotidine 20 mg tablets should be administered at the end of dialysis or thereafter since some of the active ingredient is removed by dialysis.

Elderly:

The dosage regimen recommended for elderly patients is the same as for adults.

Paediatric population:

The efficacy and safety of famotidine in children have not been established.

Method of administration

For oral use. Famotidine tablets can be taken with or without food (see section 5.2).

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Cross sensitivity in this class of compounds has been observed. Therefore, Famotidine should not be administered to patients with a history of hypersensitivity to other H2-receptor antagonists.

4.4. Special warnings and precautions for use

Gastric neoplasm

The presence of gastric malignancy should be excluded prior to the use of famotidine for the treatment of gastric ulcers. Symptomatic responses of gastric ulcers following treatment with famotidine do not preclude the presence of gastric malignancy.

Renal insufficiency

As famotidine is excreted primarily via the kidneys, caution should be exercised when treating patients who are suffering from impaired renal function. A reduction in the daily dose to 20 mg at night should be considered if creatinine clearance falls below 10ml/min (see section 4.2).

Paediatric population

The safety and efficacy for the use of Famotidine in children has not been established.

Use in the elderly

When famotidine was administered to elderly patients in clinical trials, no increase in the incidence or change in the type of drug-related side effects was observed. No dosage adjustment is required based on age alone.

General

In case of long-term treatment with high dosage, monitoring of blood count and liver function is recommended.

In case of long-standing ulcer disease, abrupt withdrawal after symptom relief should be avoided.

This medicine contains less than 1 mmol (23mg) sodium per tablet, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

No clinically important drug interactions have been identified.

Famotidine does not interact with the cytochrome P450 drug metabolising enzyme system. Compounds metabolised by this system, which have been tested in man have included warfarin, theophylline, phenytoin, diazepam, propranolol, aminopyrine and antipyrine.

Indocyanide green as an index of hepatic blood flow and/or hepatic drug extraction has been tested and no significant effects have been found.

Studies in patients stabilised on phenprocoumon therapy have shown no pharmacokinetic interaction with famotidine and no effect on the pharmacokinetic or anticoagulant activity of phenprocoumon.

In addition, studies with famotidine have shown no augmentation of expected blood alcohol levels resulting from alcohol ingestion.

Alterations of gastric pH may affect the bioavailability of certain drugs, resulting in a decrease in the absorption of atazanavir. The absorption of ketoconazole and itraconazole could be reduced. Ketoconazole should be administered two hours before famotidine.

Probenecid inhibits the renal tubular secretion of famotidine and has been shown to cause a 50% increase in famotidine plasma concentrations. Therefore, concomitant use of probenecid and famotidine should be avoided.

Concomitant use of famotidine and antacids could reduce the famotidine absorption and lead to lower plasma levels of famotidine. Therefore, famotidine should be administered 1-2 hours before taking an antacid.

Concomitant use of sucralfate inhibits the absorption of famotidine. Therefore, sucralfate should not be administered within 2 hours of the famotidine dose.

Risk of loss of efficacy of calcium carbonate when co-administered as phosphate binder with famotidine in haemodialysis patients.

Co-administration of posaconazole oral-suspension with famotidine should be avoided if possible, since famotidine may reduce the absorption of posaconazole oral-suspension during concomitant use.

Co– administration of famotidine with the tyrosine kinase inhibitors (TKIs) dasatinib, erlotinib, gefitinib, pazopanib may decrease plasma concentrations of TKIs resulting in lower efficacy, therefore co-administration of famotidine with these TKIs is not recommended. For further specific recommendations please refer to the product information of individual TKI medicinal products.

4.6. Fertility, pregnancy and lactation

Pregnancy:

Famotidine is not recommended for use in pregnancy, and should be prescribed only if clearly needed. Before a decision is made to use famotidine during pregnancy, the physician should weigh the potential benefits from the drug against the possible risks involved.

Breast-feeding:

Famotidine is excreted in human breast milk. Therefore breast-feeding mothers should either stop taking famotidine or stop breast-feeding.

4.7. Effects on ability to drive and use machines

Some patients have experienced adverse reactions such as dizziness and headache while taking famotidine. Patients should be informed that they should avoid driving vehicles or operating machinery or doing activities which require prompt vigilance if they experience these symptoms (see section 4.8).

4.8. Undesirable effects

Famotidine has been demonstrated to be generally well-tolerated.

Adverse reactions are ranked under the heading of frequency, the most frequent first, using the following convention:

Very Common (>1/10), Common (>1/100, <1/10), Uncommon (>1/1000, <1/100), Rare (>1/10,000, <1/1,000), Very Rare (<1/10,000), including isolated cases not known (cannot be estimated from the available data).

System Organ Class

Frequency: Adverse drug reactions

Blood and lymphatic system disorders

Very rare: Thrombocytopenia, Leukopenia, Agranulocytosis, Pancytopenia, Neutropenia

Immune system disorders

Very rare: Hypersensitivity reactions (angioneurotic oedema, anaphylaxis, bronchospasm)

Metabolism and nutrition disorders

Uncommon: Loss of appetite (anorexia)

Psychiatric disorders

Very rare: Reversible psychological disturbances including:

• Hallucinations

• Disorientation

• Confusion

• Anxiety disorders

• Agitation

• Depression

• Reduced libido

• Insomnia

Nervous system disorders

Common: Headache, Dizziness

Uncommon: Taste disorder

Very rare: Paraesthesia, Somnolence, Convulsions, Grand mal seizures (particularly in patients with impaired renal function)

Cardiac disorders

Very rare: AV block with H2-receptor antagonists administered intravenously, Arrhythmias, QT prolongation(especially in patients with impaired renal function)

Respiratory, thoracic and mediastinal disorders

Very rare: Interstitial pneumonia, sometimes fatal

Gastrointestinal disorders

Common: Constipation, Diarrhoea

Uncommon: Nausea and or vomiting, Abdominal discomfort or distension, Flatulence, Dry mouth

Hepato-biliary disorders

Very rare: Hepatitis, Cholestatic jaundice, Liver enzyme abnormalities, Isolated cases of worsening of existing hepatic disease

Skin and subcutaneous tissue disorders

Uncommon: Rash, Pruritus, Urticaria

Very rare: Alopecia, Stevens Johnson syndrome/toxic epidermal necrolysis sometimes fatal

Musculoskeletal and connective tissue disorders

Very rare: Muscle cramps, Arthralgia

Reproductive system and breast disorders

Very rare: Impotence

General disorders and administration site conditions

Uncommon: Fatigue

Very rare: Chest tightness

Investigations

Rare: Increase in laboratory values (transaminases, gamma GT, alkaline phosphatase, bilirubin)

Adverse Effects - Causal Relationship

Unknown: Rare cases of gynecomastia have been reported, however, in controlled clinical trials the incidences were not greater than those seen with placebo.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

The adverse reactions in overdose cases are similar to the adverse reactions encountered in normal clinical experience (see section 4.8).

In the event of overdose the usual measures to remove unabsorbed material from the gastrointestinal tract, clinical monitoring and supportive therapy should be employed.

Patients suffering from Zollinger-Ellison syndrome have tolerated doses of up to 800 mg/day. These patients have been treated for more than a year without the development of any significant adverse effects.