4.1. Therapeutic indications

For the treatment of the following diseases where reduction of gastric acid is indicated:

1) Duodenal ulcer

2) Benign gastric ulcer

3) Prevention of duodenal or benign gastric ulcer recurrence

4) Gastric oesophageal reflux disease (including erosions, ulcerations and associated heartburn)

5) Gastric and/or duodenal ulcer associated with concomitant use of non-steroidal anti-inflammatory drugs

4.2. Posology and method of administration

Posology

1) Adults: For treatment of duodenal ulcer, the recommended daily dose is 300 mg in the evening. Treatment should continue for four weeks, although this period may be reduced if healing is confirmed earlier by endoscopy. Most ulcers will heal within four weeks, but if complete ulcer healing has not occurred after four weeks therapy, patients should continue therapy for a further four weeks.

2) For the treatment of benign gastric ulcer: the recommended daily dose is 300 mg in the evening for four or, if necessary, eight weeks. Prior to treatment with nizatidine, care should be taken to exclude the possibility of gastric cancer.

If preferred, the 300 mg daily dose for the treatment of duodenal or benign gastric ulcer may be given as two divided doses of 150 mg in the morning and evening.

3) For the prevention of duodenal or benign gastric ulcer recurrence (prophylactic maintenance therapy): the recommended daily dose is 150 mg in the evening.

4) For the treatment of gastric oesophageal reflux disease: the recommended dosage is from 150 mg twice daily up to 300 mg twice daily. Therapy for up to 12 weeks is indicated for erosions, ulcerations and associated heartburn.

5) For the treatment of gastric and/or duodenal ulcer associated with concomitant use of non-steroidal anti-inflammatory drugs: the recommended daily dose is 300 mg daily (either 300 mg at bedtime or 150 mg twice daily, in the morning and in the evening) for up to 8 weeks. In most patients, the ulcers will heal within 4 weeks. During treatment, the use of non-steroidal anti-inflammatory drugs may continue.

The elderly: Age does not significantly influence efficacy or safety. Normally dosage modification is not required except in patients who have moderate to severe renal impairment (creatinine clearance less than 50 ml/min).

Paediatric population: The safety and efficacy of nizatidine in children have not been established. No data are available.

Patients with impaired renal function: For patients who have moderate renal impairment (creatinine clearance less than 50 ml/min) or patients who have severe renal impairment (creatinine clearance less than 20 ml/min), the dosage should be reduced as follows:

DOSAGE RECOMMENDED

Indications

Moderate Renal Impairment

Severe Renal Impairment

Duodenal ulcer

150 mg in the evening

150 mg on alternate days

Benign gastric ulcer

150 mg in the evening

150 mg on alternate days

Prevention of duodenal or benign gastric ulcer recurrence

150 mg in the evening on alternate days

150 mg in the evening every third day

Gastric oesophageal reflux disease

From 150 mg daily, up to 150 mg twice daily

From 150 mg on alternate days, up to 150 mg daily

Gastric and/or duodenal ulcer associated with concomitant use of non-steroidal anti-inflammatory drugs

150 mg in the evening

150 mg on alternate days

Method of administration

For oral administration.

4.3. Contraindications

Hypersensitivity to the active substance, any other H2-receptor antagonists or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

As nizatidine is partially metabolised by the liver and principally excreted by the kidneys, patients with impaired liver or kidney function should be treated with caution. (see section 4.2.)

Symptomatic response to nizatidine therapy does not preclude the presence of gastric malignancy.

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

There is evidence that oral nizatidine does not affect the serum levels of concomitantly-administered aminophylline, theophylline, chlordiazepoxide, diazepam, lidocaine, phenytoin, ibuprofen, metoprolol, warfarin or lorazepam.

Nizatidine does not inhibit the hepatic cytochrome P450-linked drug metabolising enzyme system, but may increase absorption of salicylates when they are used in very high dosage. However, nizatidine and other histamine H2-receptor antagonists can reduce the gastric absorption of drugs whose absorption is dependent on an acidic gastric pH. Approximately 35% of nizatidine is bound to plasma protein. Warfarin, diazepam, paracetamol, propantheline, phenobarbitone, and propranolol did not affect plasma protein binding of nizatidine in vitro.

Absorption of nizatidine is not clinically significantly affected by food intake, anticholinergic agents, or antacids.

4.6. Fertility, pregnancy and lactation

Pregnancy

The safety of nizatidine for use during pregnancy has not been established. Animal studies have shown no evidence of impaired fertility or teratogenicity attributable to nizatidine. Nizatidine should only be used in pregnant women, or in those planning pregnancy, if considered absolutely necessary, and then with caution.

Breast-feeding

Studies conducted in lactating women have shown that 0.1% of the administered oral dose of nizatidine is secreted in human milk in proportion to plasma concentrations. Because of the growth depression in pups reared by lactating rats treated with nizatidine, it should be administered to nursing mothers only if considered absolutely necessary.

4.7. Effects on ability to drive and use machines

There is no influence of nizatidine on the ability to drive or use machines.

4.8. Undesirable effects

In large scale clinical trials, sweating and urticaria were significantly more common in nizatidine-treated patients when compared with placebo. In these trials, 1.9% of treated patients experienced somnolence, compared to 1.6% of placebo patients (non-significant).

In the same trials, patients treated with both nizatidine and placebo had mild, transient, asymptomatic elevations of transaminases or alkaline phosphatase; rare instances of marked elevations (> 500 iu/l) occurred in nizatidine-treated patients. The overall rate of occurrences of elevated liver enzymes and elevations to 3 times the upper limit of normal, however, did not differ significantly from placebo. All abnormalities were reversible after discontinuation of nizatidine. Hepatitis and jaundice have been reported. Rare cases of cholestatic or mixed hepatocellular and cholestatic injury with jaundice have also been reported, with reversal of the abnormalities after discontinuation.

The following effects have also been rarely reported, thrombocytopenic purpura, fatal thrombocytopenia, leucopenia, agranulocytosis, anaemia, exfoliative dermatitis, vasculitis, arthralgia, myalgia, gynaecomastia, impotence, hyperuricaemia, fever, nausea and reversible mental confusion.

Rare episodes of hypersensitivity reactions (eg, bronchospasm, laryngeal oedema, rash, pruritus and eosinophilia), serum sickness and anaphylaxis have been reported.

The frequency of following effects are not known (cannot be estimated from the available data); headache and diarrhoea.

Reporting of suspected adverse reactionsReporting 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.

4.9. Overdose

Symptoms

There is little experience of overdose in humans. Tested at very high doses in animals, nizatidine has been shown to be relatively non-toxic. Animal studies suggest that cholinergic-type effects, including lacrimation, salivation, emesis, miosis and diarrhoea, may occur following very large oral doses.

Treatment

Symptomatic and supportive therapy is recommended. Activated charcoal, emesis or lavage may reduce nizatidine absorption. The ability of haemodialysis to remove nizatidine from the body has not been conclusively demonstrated. However, this method is not expected to be efficient, since nizatidine has a large volume of distribution.