SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Isoniazid 100 mg Tablets

2    QUALITATIVE AND QUANTITATIVE    COMPOSITION

Each tablet contains

100 mg of the active ingredient, Isoniazid.

For a full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Tablets

White, circular, biconvex, uncoated tablets having plain surface on both the sides.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Isoniazid 100 mg Tablets are indicated for the treatment of all forms of pulmonary and extra-pulmonary tuberculosis.

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

4.2    Posology and method of administration

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.

Isoniazid 100 mg tablets should be taken preferably on an empty stomach, i.e. at least 30 minutes before a meal or 2 hours after a meal. Tablets must be swallowed whole and not chewed.

Adults:

The dose of isoniazid for the treatment of tuberculosis is commonly 4 to 5 mg per kilogram bodyweight daily given by mouth in single or divided doses up to a maximum of 300 mg daily. Up to 10 mg per kilogram body-weight daily may be given particularly during the first 1 to 2 weeks of treatment of tuberculous meningitis. A dose of 15 mg 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.

Children:

The usual daily dose for children is from 5 up to 20 mg per kilogram body-weight daily in single or divided doses up to a maximum of 300mg/daily.

4.3 Contraindications

Patients who are known to be hypersensitive to isoniazid or any of the excipients. (see section 4.5).

Previous experience of severe adverse reaction to Isoniazid including drug induced liver disease. (See section 4.4).

4.4 Special warnings and precautions for use

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 If serum AST rises to more than three times normal, or there is any increase in bilirubin, treatment should be withdrawn.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, preexisting 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.

4.5 Interaction with other medicinal products and other forms of interaction

When isoniazid is given to patients who inactivate it slowly or to patients receiving paraminosalicyclic acid concurrently, tissue concentrations may be enhanced and adverse effects are more likely to appear. There may be an increased risk of liver damage in patients receiving rifampicin and isoniazid but liver enzymes are raised only transiently.

Concurrent use of other hepatotoxic medications with isoniazid may increase the potential for hepatotoxicity.

Isoniazid can inhibit the hepatic metabolism of a number of drugs, in some cases leading to increased toxicity. These include the antiepileptics carbamazepine, primidone, and phenytoin, the benzodiazepines diazepam and triazolam, chlorzoxazone, and disulfiram. Concomitant benzodiazepine (diazepam, triazolam) and isoniazid therapy has been reported to result in an increased risk of benzodiazepine toxicity (sedation, respiratory depression).

Isoniazid has been reported to cause substantial elevations of serum concentrations of carbamazepine and symptoms of carbamazepine toxicity at isoniazid doses of 200 mg daily or more. The concurrent used is not recommended unless the effects can be closely monitored and suitable downward dosage adjustments made (a reduction between one-half or one-third was reported effective).

Phenytoin dosage adjustment maybe necessary during and after isoniazid therapy especially in slow acetylators of isoniazid.

Isoniazid may increase renal excretion of pyridoxine; requirements for pyridoxine may be increased in patients receiving isoniazid concurrently. Concurrent use of isoniazid may reduce the metabolism of theophylline, increasing theophylline plasma concentrations. Propranolol has been reported to cause a significant reduction in the clearance of concurrently administered isoniazid. Concurrent use of cycloserine with isoniazid results in increased incidence of central nervous system effects such as dizziness or drowsiness, dosage adjustment may be necessary and patients should be monitored closely for signs or central nervous system toxicity especially if performing tasks requiring alertness.

Isoniazid may reduce the therapeutic effects of levodopa.

Concomitant administration of isoniazid with itraconazole may result in significant decreases in itraconazole serum concentrations and therapeutic failure. Coadministration is not recommended. Isoniazid may decrease ketoconazole serum levels. Concurrent use should be well monitored and dosage increases made if necessary.

Because the clearance of isoniazid was found doubled when zalcitabine was given in HIV positive patients, concurrent use of isoniazid and zalcitabine should be monitored to ensure isoniazid effectiveness.

There may be an increased risk of distal sensory neuropathy when isoniazid is used in patients taking stavudine (d4T).

Concurrent use of isoniazid with other neurotoxic medication may produce additive neurotoxicity.

Isoniazid may cause niacin deficiency by inhibiting niacin incorporation into nicotinamide adenine dinucleotide.

There may be a potential interaction between isoniazid and foods containing histamine or tyramine.

4.6 Fertility, pregnancy and lactation

Animal studies show there is a teratogenic risk to the embryo. There is limited experience in humans but without evidence of a clinically relevant risk (trimester 1)

Isoniazid passes into breast milk. As the effects on the infant are unknown, your doctor may advise you discontinue breast feeding whilst being treated with Isoniazid.

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed.

4.8 Undesirable effects

Hypersensitivity reactions: Fever, anaphylactic reactions.

Nervous system: Vertigo; polyneuritis, presenting as paraesthesia, muscle weakness, loss of tendon reflexes, hyperreflexia. Other neurotoxic effects are convulsions, toxic encephalopathy, optic neuritis and atrophy, diplopia, strabismus, sensory disturbances, headache, dizziness, tremors, memory impairment, depression and psychosis (maniform, catatonic or paranoid) as well as irritability, anxiety, lack of concentration. The incidence is higher in "slow acetylators”.

The possibility that the frequency of seizures may be increased in patients with epilepsy should be borne in mind.

Cutaneous: Rash, acne, Stevens-Johnson syndrome, exfoliative dermatitis and pemphigus, pellagra, photosensitivity, erythema multiforme, vasculitis

Hematologic: Eosinophilia, granulocytopaenia, agranulocytosis, thrombocytopenia, anaemia, aplastic anaemia and haemolytic anaemia, panmyelopathy, clotting disorders

Gastrointestinal: Pancreatitis, constipation, dry mouth, nausea, vomiting, diarrhoea, and epigastric distress.

Hepatic: increased transaminases, hepatitis including severe and sometimes fatal hepatitis

Investigations: anti-nuclear antibodies

Metabolism and Nutrition Disorders: hyperglycaemia, hypoglycaemia Renal and bladder: urinary retention

Endocrine system: Usually reversible hyperactivity of the adrenal cortex (Cushing's syndrome) and pituitary disorders in women with menstrual disorders and gonadotropic / gynaecomastia

Cardiovascular system: Heart rhythm disturbances, blood pressure dysregulation with vertigo

Respiratory system: asthma

Miscellaneous: systemic lupus erythematosus-like syndrome, fatigue, purpura 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.

4.9 Overdose

Symptoms of overdose with isoniazid are slurred speech, metabolic acidosis, hyperglycaemia, hallucinations, respiratory and central nervous system depression, vertigo, convulsions and coma.

Treatment of overdosage may include gastric lavage following intubation and the control of convulsions by anti-convulsants given intravenously as well as the intravenous injection of large doses of pyridoxine. Metabolic acidosis is corrected with sodium bicarbonate. Forced diuresis may be tried and haemodialysis or peritoneal dialysis has been used.

5 PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: Antimycobacterial ATC code: J04AC01

Isoniazid has no significant antibacterial action against any micro-organisms except the Mycobacteria; It is believed to act by inhibition of mycolic acid synthesis and disruption of cell wall in susceptible organisms. It is primarily active against actively dividing mycobacteria and considered bacteriostatic against semidormant organisms.

Isoniazid is used mainly in the treatment of pulmonary tuberculosis but it appears to be effective also in the treatment of extrapulmonary lesions, including meningitis and genito-urinary disease.

5.2    Pharmacokinetic properties

Absorption

Readily and completely absorbed after oral administration.

Distribution

Readily diffuses into all tissues and fluids including the cerebrospinal fluid. Isoniazid is retained in the skin and in infected tissue; it crosses the placenta and is secreted in the milk of lactating mothers.

Protein binding

Isoniazid does not appear to be bound in the blood.

Half-life

Plasma elimination half-life, in rapid acetylators about 1.2 hours and in slow acetylators about 3.5 hours.

Metabolic reactions

Acetylation, hydrolysis and glycine conjugation, hydrazone formation, and n-methylation; acetylation is polymorphic and two groups of acetylators have been identified, rapid and slow acetylators. The rate of hydrolysis is more rapid in the rapid acetylators than in the slow ones. The metabolites formed include acetyl isoniazid, isonicotinic acid, isonicotinuric acid, isonicotinoylhydrazones of pyruvic and glutaric acids, and n-methylisoniazid.

Excretion

Over 90% of a dose is excreted in the urine in 24 hours, most being excreted in the first 12 hours, 4-32% is unchanged, but no more than 10% of a dose is excreted in the faeces.

5.3 Preclinical safety data

Not applicable since isoniazid tablets have been used in clinical practice for many years and its effects in man are well known.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Calcium Hydrogen Phosphate Maize Starch (dried)

Purified Talc

Colloidal Anhydrous Silica Magnesium stearate

6.2 Incompatibilities

Not applicable

Shelf life

36 months

6.4    Special precautions for storage

Store below 25°C.

6.5    Nature and contents of container

White opaque PVC/PVdC/Aluminium blisters available in pack sizes of 7, 10, 14, 20, 28, 30, 56, 60, 84, 90, 100 and 112 tablets.

Not all pack sizes may be marketed.

6.6    Special precautions for disposal

No special requirements

7    MARKETING AUTHORISATION HOLDER

Morningside Healthcare Ltd 115 Narborough Road Leicester LE30PA United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 20117/0233

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

17/07/2014

10    DATE OF REVISION OF THE TEXT

17/07/2014