ISONIAZID

Official guidance should always be consulted when selecting the dose regimens to be used for adults and children (according to age and body weight), the duration of therapy and the total content of the combination treatment regimen.

Posology Adults The dose of isoniazid for the treatment of tuberculosis is commonly 4 to 5mg per kilogram body-weight daily given by mouth in single or divided doses up to a maximum of 300mg daily. Up to 10mg per kilogram body-weight daily may be given particularly during the first 1 to 2 weeks of treatment of tuberculous meningitis.

A dose of 15mg per kilogram has been given two or three times weekly in intermittent treatment regimens. Elderly No dosage reduction is necessary in the elderly, but caution should be exercised due to the possible decrease in renal and hepatic function.

Paediatric population The usual daily dose for children aged three months and above is from 10 up to 15mg per kilogram body-weight daily in single or divided doses. Isoniazid should not be used in children aged 0 to 3 months because of the lack of specific data.

e. at least 30 minutes before a meal or 2 hours after a meal.

Undesirable effects are listed by MedDRA System Organ Classes.

Assessment of undesirable effects is based on the following frequency groupings:

Very common: ≥1/10 Common: ≥1/100 to <1/10 Uncommon: ≥1/1,000 to <1/100 Rare: ≥1/10,000 to <1/1,000 Very rare: <1/10,000 Frequency not known: cannot be estimated from the available data The frequency of the reactions described below cannot be determined from the data available.

Blood and lymphatic system disorders Frequency not known:

Agranulocytosis, Aplastic anaemia, Haemolytic anaemia Ear and labyrinth disorders Frequency not known: Deafness, Tinnitus, Vertigo These have been reported in patients with end stage renal impairment Vertigo may be troublesome with doses of 10mg per kg body weight Gastrointestinal disorders Frequency not known: Constipation, Dry mouth Nausea, Pancreatitis acute, Vomiting and other gastrointestinal effects General disorders and administration site conditions Frequency not known: Pyrexia Hepatobiliary disorders Frequency uncommon: Hepatitis Frequency not known: Acute hepatic failure, Liver injury, Jaundice The risk of these undesirable effects increases with age, especially over the age of 35; it may be serious and sometimes fatal with the development of necrosis.

Investigations Frequency not known:

Hepatic enzyme increased Metabolism and nutrition disorders Frequency not known: Acidosis, Hypoglycaemia, Nicotinic acid deficiency Nicotinic acid deficiency may be related to an isoniazid-induced pyridoxine deficiency which affects the conversion of tryptophan to nicotinic acid.

Musculoskeletal and connective tissue disorders Frequency not known:

Systemic lupus erythematosus, lupus-like syndrome Nervous system disorders Frequency not known: Neuropathy peripheral, Optic neuritis, Seizure Hyperreflexia may be troublesome with doses of 10mg per kg body weight Psychiatric disorders Frequency not known: Elevated mood, Psychotic disorder Although isoniazid usually has a mood elevating effect, mental disturbances, ranging from minor personality changes to major mental derangement have been reported; these are usually reversed on withdrawal of the drug Renal and urinary disorders Frequency not known: Dysuria Reproductive system and breast disorders Frequency not known: Gynaecomastia Respiratory, thoracic and mediastinal disorders Frequency not known: Interstitial lung disease Skin and subcutaneous tissue disorders Frequency rare: Toxic epidermal necrolysis, eosinophilia systemic symptoms, Frequency not known: Erythema multiforme, Stevens-Johnson syndrome, acute generalised exanthematous pustulosis Vascular disorders Frequency not known: Vasculitis Miscellaneous Withdrawal symptoms, which may occur on the cessation of the treatment, include headache, insomnia, excessive dreaming, irritability and nervousness.

All patients should have baseline liver function tests performed and repeated at regular intervals during treatment. If serum AST rises to more than three times normal, or there is any increase in bilirubin, treatment should be withdrawn.

Special precautions are required in patients with impaired liver function. Any deterioration in liver function in these patients is an indication for stopping treatment. Isoniazid should not be given to patients who have experience severe adverse reactions including drug-induced liver disease.

Care should be taken in giving isoniazid to patients suffering from convulsive disorders, diabetes mellitus, chronic alcoholism, or impaired liver or kidney function or to patients taking other potentially hepatoxic agents. If symptoms of hepatitis such as malaise, fatigue, anorexia, and nausea develop isoniazid should be discontinued immediately.

Isoniazid should be used with caution in patients with a history of psychosis. Advanced age, female gender, slow acetylators, malnutrition, HIV infection, pre- existing liver disease, and extra-pulmonary tuberculosis were identified as risk factors for isoniazid-induced hepatotoxicity.

Patients who are at risk of neuropathy or pyridoxine deficiency, including those who are diabetic, alcoholic, malnourished, uraemic, pregnant, or infected with HIV, should be given pyridoxine. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Severe cutaneous adverse reactions (SCARs) such as:

Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) and acute generalised exanthematous pustulosis (AGEP), which can be life-threatening or fatal, have been reported in association with isoniazid treatment.

Patients who are known to be hypersensitive to isoniazid or drug-induced liver disease.