SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Teva Nizatidine 300 mg Capsules

2.    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each hard capsule contains 300 mg of nizatidine For excipients, see 6.1.

3. PHARMACEUTICAL FORM

Hard capsule.

No. 1 white / caramel hard gelatine capsule imprinted axial “NTD” on the cap and “300” on the body with 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 Mild to moderate forms of reflux oesophagitis

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. Treatment may be continued if necessary up to one year.

For the treatment of mild to moderate forms of oesophageal reflux, the recommended dosage is from 150 mg twice daily, up to 300 mg twice daily. Therapy for 6 weeks, or up to 12 weeks, if necessary, 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 and adolescents under 16 years of age: 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 Renal Impairment
600 mg	150 mg twice daily	150 mg daily
300 mg	150 mg in the evening	150 mg on alternate days
150 mg	150 mg on alternate days	150 mg every third day

Contraindications

Hypersensitivity to nizatidine, other H₂-receptor antagonists or to any of the excipients.

4.4 Special warnings and special 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 ‘Posology and Method of Administration' section.)

The 300 mg strength is not suitable for the treatment of patients with renal impairment (see section 4.2).

In patients with ulcer disease, the H. pylori status should be determined. For H. pylori positive patients, removal of the H. pylori bacteria by means of eradication therapy should be striven for whenever possible.

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

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. Approximately 35 per cent of nizatidine is bound to plasma protein.

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

The pH-dependent absorption of certain active substances, such as ketaconazole or itraconazole, may be reduced.

Urobilinogen tests with Multistix® have yielded false-positive results in patients receiving nizatidine.

4.6 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, nizatidine 150 mg and 300 mg capsules should be administered to nursing mothers only if considered absolutely necessary.

4.7 Effects on ability to drive and use machines

An influence of nizatidine on the ability to drive or use machines will not be expected due to the pharmacological properties of the substance. However, studies on this possible influence have not been performed and side effects such as somnolence and dizziness may impair these abilities in rare cases.

4.8 Undesirable effects

The following undesirable effects were observed in large scale clinical trials:

Psychiatric disorders

Abnormal dreams

Nervous system disorders

Somnolence, headache, dizziness

Respiratory, thoracic and mediastinal disorders

Thoracic pain, common cold, cough, pharyngitis

Hepato-biliary disorders

Mild, transient, asymptomatic elevations of transaminases or alkaline phosphatase

Rarely (>0,01 - <0,1 %), marked elevations (>500 iu/l) or transaminases or alkaline phosphatase

All abnormalities were reversible after discontinuation of nizatidine.

Skin and subcutaneous tissue disorders Sweating, urticaria, itching

Musculoskeletal, connective tissue and bone disorders Myalgia

The following undesirable effects have been reported in clinical practice:

Blood and lymphatic system disorders

Rarely (>0,01 - <0,1 %), anaemia, hyperuricaemia

Very rarely (< 0,01 %, including isolated reports), thrombocytopenia

Endocrine disorders

Increased dihydrotestosterone levels

Psychiatric disorders

Very rarely (< 0,01 %, including isolated reports), reversible mental confusion, reduced libido

Vascular disorders

Rarely (>0,01 - <0,1 %), vasculitis

Very rarely (< 0,01 %, including isolated reports), thrombocytopenic purpura Gastrointestinal disorders

Very rarely (< 0,01 %, including isolated reports), nausea

Hepato-biliary disorders Hepatitis, jaundice

Rarely (>0,01 - <0,1 %), increases in transaminases, alkaline phosphatase and bilirubin (partly with histomorphological -cholestatic or mixed hepatocellular - changes of the liver)

Very rarely (< 0,01 %, including isolated reports), cholestatic jaundice These abnormalities were observed to reverse after discontinuation of nizatidine.

Skin and subcutaneous tissue disorders

Rarely (>0,01 - <0,1 %), sweating, exfoliative dermatitis

Musculoskeletal, connective tissue and bone disorders Rarely (>0,01 - <0,1 %), arthralgia, myalgia

Renal and urinary disorders Altered creatinine levels

Reproductive system and breast disorders

Very rarely (< 0,01 %, including isolated reports), gynaecomastia, impotence

General disorders and administration site conditions Rarely (>0,01 - <0,1 %), hypersensitivity reactions (urticaria, pruritus, exanthema, oedema, laryngeal oedema, bronchospasm, anaphylaxis, eosinophilia), serum sickness

Very rarely (< 0,01 %, including isolated reports), fever.

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. Nizatidine absorption may be reduced with activated charcoal, or by emptying the stomach, for example by gastric lavage. 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

Pharmacotherapeutic group:H₂-receptor antagonists ATC Code: A02BA04

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.

There is evidence that nizatidine dose-dependently decreases cardiac rate and output in healthy volunteers. The clinical significance of this effect is unknown.

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%. The elimination half-life is approximately 1.6 hours, but increases significantly in the presence of moderate to severe renal impairment, ranging from 3.5 to 14 hours in functionally anephric patients.. 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, but decreases in patients with moderate to severe renal impairment, ranging from approximately 117 to 233 ml/min in functionally anephric individuals. 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

There are no preclinical data of relevance to the prescriber in addition to that summarised in other sections of the Summary of Product Characteristics.

6.    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Capsule contents:

Pregelatinised starch

Dimeticone

Povidone

Magnesium stearate

Capsule shell:

Gelatin

Red iron oxide E172 Titanium dioxide E171 Yellow iron oxide E172

Printing ink:

Shellac Soya lecithin Antifoam DC 1510 Black iron oxide (E172)

6.2 Incompatibilities

Not applicable.

Shelflife

6.4 Special precautions for storage

Store in the original container.

6.5 Nature and content of container

Aluminium foil, PVC/PVdC heat sealable 31.5 pm thick (aluminium 20.0 pm thick), PVC/PVdC transparent foil (PVC: 250 pm thick, PVdC coating: 60 g/m2)

Aluminium foil, PVC/PVdC heat sealable 31.5 pm thick (aluminium 20.0 pm thick), PVC/PVdC white opaque foil (PVC: 250 pm thick, PVdC coating: 60 g/m2)

Aluminium foil, PVC/PVdC heat sealable 31.5 pm thick (aluminium 20.0 pm thick), PVC/PVdC white opaque foil (PVC: 250 pm thick, PVdC coating: 40 g/m2)

Blister in cardboard boxes containing 10, 15, 20, 28, 30, 50, 100 capsules.

Not all pack sizes may be marketed.

6.6 Instructions for use and handling

No special requirements.

7.    MARKETING AUTHORISATION HOLDER

Teva UK Limited Brampton Road, Hampden Park Eastbourne BN22 9AG United Kingdom

8.    MARKETING AUTHORISATION NUMBER(S)

PL 00289/0397

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

DATE OF REVISION OF THE TEXT

11/08/2009