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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Axid

Nizatidine Capsules 300mg

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains 300 mg of Nizatidine

3 PHARMACEUTICAL FORM

Size 1 capsule with an opaque brown cap and opaque pale yellow body, imprinted with ‘Flynn 3145’ in black ink.

4.    CLINICAL PARTICULARS

4.1    Therapeutic indications

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

Duodenal ulcer Benign gastric ulcer

Prevention of duodenal or benign gastric ulcer recurrence Gastric oesophageal reflux disease (including erosions, ulcerations and associated heartburn) Gastric and/or duodenal ulcer associated with concomitant use of non-steroidal anti-inflammatory drugs

4.2 Posology and method of administration

For oral administration.

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.

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.

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

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 and ulcerations, and associated heartburn.

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).

Children: Not recommended, as safety and efficacy have not been established.

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
No Renal Impairment	Moderate Renal Impairment	Severe Impairment	Renal
600 mg	150 mg twice daily	150 mg daily
300 mg	150 mg in the evening	150 mg on days	alternate

150 mg	150 mg on alternate days	150 mg every third
		day

4.3 Contraindications

Known hypersensitivity to H2-receptor antagonists.

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, lignocaine, 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

Usage in 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. Usage in lactation: 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, the product should be administered to nursing mothers only if considered absolutely necessary.

4.7 Effects on ability to drive and use machines

None stated.

4.8. Undesirable effects

In large scale clinical trials, sweating and urticaria were significantly more common in patients treated with oral nizatidine 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 (>500iu/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. Since introduction, hepatitis and jaundice have been reported. Rare cases of cholestatic or mixed hepatocellular and cholestatic injury with jaundice have 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.

4.9 Overdose

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.

5.    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Nizatidine is a potent, selective, competitive and fully reversible histamine H₂ receptor antagonist. Nizatidine significantly decreased basal and stimulated gastric acid and pepsin concentration, in addition to the volume of gastric secretion.

In various clinical trials, nizatidine, administered as either a single daily dose (at bedtime) or in two divided doses (morning and evening), significantly inhibited gastric acid secretion, and ulcer pain was usually rapidly abolished.

Nizatidine has no significant effect on the serum concentrations of gastrin, gonadotrophins, prolactin, growth hormone, antidiuretic hormone, cortisol, testosterone, 5-alpha-dihydrotestosterone or oestradiol.

Nizatidine has no antiandrogenic action.

5.2 Pharmacokinetic properties

Absorption of nizatidine after oral administration is rapid and peak plasma concentrations (700 - 1800 ng/ml after 150 mg; 1400 - 3600 ng/ml after 300 mg dose) are usually achieved within two hours of administration (range 0.5 -3 hours). Oral bioavailability exceeds 70%, and the elimination half life is approximately 1.6 hours. Minor (6%) first pass hepatic metabolism occurs, but nizatidine is principally excreted via the kidneys, about 60% as unchanged drug, renal clearance is about 500 ml/min. Metabolites include desmethyl nizatidine (7%), sulphoxide (6%) and N-oxide (5%). Desmethyl nizatidine is an active metabolite of limited potency. More than 90% of an oral dose of nizatidine (including metabolites) is excreted in the urine within 12 hours.

5.3 Preclinical safety data

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Starch flowable powder Starch

Silicone fluid 350 cs Povidone

Carboxymethyl cellulose sodium cross-linked Talc

Capsule shell:

Yellow iron oxide Red iron oxide Titanium dioxide Gelatin

Black ink (SW-9008), including Shellac

Black iron oxide Propylene glycol

6.2 Incompatibilities

None known.

6.3 Shelf life

24 months unopened.

6.4 Special precautions for storage

Do not store above 25 °C.

6.5 Nature and contents of container

Opaque or transparent PVC/aluminium foil blisters. Packs contain 28 or 30 capsules.

6.6 Instructions for use/handling

None.

7 MARKETING AUTHORISATION HOLDER

Flynn Pharma Limited Alton House 4 Herbert Street Dublin Ireland

8. MARKETING AUTHORISATION NUMBER

PL 13621/0028

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

17/08/2005

10 DATE OF REVISION OF THE TEXT

28/10/2008