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SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Isoniazid Tablets BP 50 mg.

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Isoniazid BP 50.00 mg per tablet.

3    PHARMACEUTICAL FORM

White, flat bevelled edge tablet engraved with a breakline.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

1.    As a prophylaxis for the prevention of tuberculosis in susceptible close contacts.

2.    Treatment of tuberculosis in combination with other antitubercular drugs.

4.2    Posology and method of administration

Recommended doses and dosage schedules:

Dose:

Prophylaxis:

Adults:300 mg daily usually for up to 12 months, although 6 months may be adequate.

It may be given with rifampicin.

Children: 5-10 mg/kg body-weight daily, although 10-14 mg/kg body-weight daily, up to 300 mg daily, is also recommended in certain overseas territories.

Treatment:

Pulmonary tuberculosis:

Adult: 300 mg as a single dose daily or (15 mg/kg bodyweight) twice or three times weekly.

Children 3-12 years: 10 mg/kg bodyweight daily or 15 mg/kg body-weight three times weekly.

Children 0-3 years: A liquid dosage form of this product is more appropriate.

Tuberculous meningitis: 10 mg/kg bodyweight daily.

Severe renal impairment: A maximum of 200mg daily.

Duration of treatment with Isoniazid depends on the combination of drugs employed in the initial phase.

Where Isoniazid and Rifampicin are administered daily throughout the treatment, a 9 months course is sufficient for patients with respiratory disease.

If pyrazinamide is included in the initial phase of treatment with Isoniazid and Rifampicin which are then used in the continuation phase, a total of 6 months therapy gives good results.

Route of administration: oral

4.3 Contraindications

1.    Hypersensitivity to Isoniazid or to any of the excipients.

2.    Previous experience of severe adverse reaction to Isoniazid including drug induced liver disease.

3.    Porphyria.

4.4 Special warnings and precautions for use

Caution should be exercised when administering isoniazid to patients suffering from convulsive disorders, malnutrition, diabetes mellitus, chronic alcoholism and history of psychosis, impaired hepatic and renal functions and to patients taking other potentially hepatotoxic drugs. In patients with liver disease it is recommended that liver function is monitored regularly and particularly frequently in the first 2 months.

If symptoms of hepatitis such as malaise, fatigue, anorexia and nausea develop, isoniazid should be discontinued immediately. There may be an increased risk of liver damage in patients receiving rifampicin and isoniazid concomitantly but liver enzymes are elevated only transiently. There is a risk of peripheral neuritis in patients with HIV infection, Patients, particularly those at risk from peripheral neuropathies, may require additional treatment with pyridoxine.

Patients at risk of developing metabolic bone disease may be administered vitamin D supplements.

Patients intolerant of ethionamide, pyrazinamide, niacin (nicotinic acid) or other chemically related medications may also be intolerant of this medication. Caution should also be exercised in patients over 50 years of age as this group has the highest incidence of hepatitis.

4.5 Interaction with other medicinal products and other forms of interaction

Concurrent use of glucocorticoids, especially prednisolone with isoniazid may increase the hepatic metabolism and/or excretion of isoniazid leading to decreased plasma concentrations and effectiveness of isomazid especially in patients who are rapid acetylators. Dosage adjustment of isoniazid is therefore required.

Concurrent daily use of alcohol with isoniazid may result in increased incidence of isoniazid induced hepatotoxicity and increased metabolism of isoniazid. Dosage adjustment of isoniazid may be necessary. Patients should be monitored closely for signs of hepatotoxicity and advised accordingly. Hepatoxicity of isoniazid is possibly potentiated by general anaesthetics. Chronic preoperative or perioperative use of isoniazid, an hepatic enzyme inhibitor, may decrease the plasma clearance and prolong the duration of action of alfentanil. Concurrent use of enflurane with isoniazid may increase the formation of potentially nephrotoxic inorganic fluoride metabolite.

Antacids may delay and decrease the absorption and serum concentration of orally administered isoniazid. Concurrent use should be avoided or patients advised to take oral isoniazid at least 1 hour before antacids.

Concurrent use of anticoagulants, coumarin or indandione-derivatives or warfarin with isoniazid may result in increased anticoagulant effect because of the inhibition of enzymatic metabolism of anticoagulants.

Concurrent use of acetaminophen with isoniazid may increase the potential for hepatotoxicity and, possibly nephrotoxicity. A significant decrease in ketoconazole serum concentration has been reported when isoniazid was given concurrently with ketoconazole and 12 hours before ketoconazole.

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 inhibit the elimination of diazepam or triazolam when administered concurrently with these drugs.

Concurrent use of isoniazid with ethionamide may intensify the side effects of isoniazid.

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

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.

Concurrent use of phenytoin with isoniazid inhibits parahydroxylation of phenytoin resulting in increased phenytoin serum concentrations and toxicity. Phenytoin dosage adjustment maybe necessary during and after isoniazid therapy especially in slow acetylators of isoniazid.

The metabolism of carbamazepine, primidone and ethosuximide is also inhibited as a result of concurrent administration of isoniazid.

Concurrent use of rifampicin with isoniazid may increase the risk of hepatotoxicity, especially in patients with pre-existing hepatic impairment and/or in fast acetylators of isoniazid, patients should be monitored closely for signs of hepatotoxicity during the first 3 months of therapy.

Broad spectrum antibiotics may reduce the contraceptive effect of oestrogens, although the risk is probably small.

4.6 Pregnancy and lactation

Isoniazid crosses the placenta, resulting in foetal serum concentrations that may exceed maternal serum concentrations.

Problems in humans have not been documented. Studies conducted in rats and rabbits have shown it to be embryocidal.

However studies have not shown isoniazid to be teratogenic in mice, rats and rabbits.

Isoniazid is excreted in breast milk in concentration comparable to maternal serum concentration. Infants should not be breast fed by patients receiving isoniazid. Isoniazid tablets should not be administered to pregnant women or nursing mothers unless in the physicians judgement the potential benefit justifies the potential risk.

4.7 Effects on ability to drive and use machines

None.

4.8 Undesirable effects

Isoniazid has low toxicity. High doses of isoniazid are more likely to cause adverse effect.

Hypersensitivity reactions include various types of skin eruptions, fever, lymphadenopathy and vasculitis. Patients who are slow inactivators experience greater incidence of toxicity.

Peripheral neuropathy may be common if pyridoxine is not administered concurrently.

Other adverse effects include nausea, vomiting and gastrointestinal effects, dry mouth, hyperglycaemia and metabolic acidosis have also occurred. Blood disorders resulting from the use of isoniazid include haemolytic, aplastic and sideroblastic anaemias, agranulocytosis, thrombocytopaenia and eosinophilia. Occasionally lupus like reactions, a rheumatic syndrome and gynaecomastia has been reported.

Rarely pellagra due to isoniazid induced pyridoxine deficiency has been reported. Optic neuritis and atrophy has also been reported rarely. Transient elevations of liver enzymes commonly occur during the first few months of therapy, and return to normal despite continued treatment. However severe progressive liver damage sometimes occurs especially in patients over the age of 35 and in those consuming alcohol regularly. Fatalities have occurred following liver necrosis.

Urinary retention may occur in the elderly and there have been reports of convulsions and psychotic reactions, especially in patients with history of these conditions. Some patients may experience slight euphoria during therapy. Vertigo and hyperreflexia have also been reported.

4.9 Overdose

Symptoms of overdose with isoniazid are slurred speech, metabolic acidosis, hyperglycaemia, hallucinations, respiratory and central nervous system depression, convulsions and coma. Treatments of isoniazid overdose include gastric lavage which should be performed within 2-3 hours following isoniazid ingestion. Maintenance of patent airway and respiratory exchange should be carried out.

Convulsions should be controlled by administering intravenous diazepam and intravenous pyridoxine (approximately 1 mg for each mg of isoniazid ingested).

Convulsions should be controlled prior to attempting gastric lavage.

Metabolic acidosis is treated with sodium bicarbonate. Significant quantities have been removed by haemodialysis and peritoneal dialysis.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: HYDRAZIDES ATC Code: J04A C

Isoniazid is a synthetic bactericidal anti-tubercular agent being highly active against mycobacterium tuberculosis. It is primarily active against those mycobacteria which are actively dividing and considered only bacteriostatic against semidormant organisms.

It is believed to act by inhibition of mycolic acid synthesis and disruption of cell wall in susceptible organisms.

Isoniazid appears to be highly effective in preventing emergence of resistance to other anti-tubercular agents. Isoniazid may have some activity against some strains of other mycobacteria including M. Kansasil the incidence of primary drug resistance is generally low in developed countries, mycobacteria rapidly becomes resistant to isoniazid when used alone. Therefore isoniazid is usually administered in conjunction with other anti-tubercular drugs except in prophylaxis.

5.2 Pharmacokinetic properties

Isoniazid (INH) is readily absorbed from the gastrointestinal tract. Peak concentrations are attained within 1-2 hours following oral administration. Protein binding is low. It is widely distributed to all body fluids and tissues including cerebrospinal fluid, pleural and ascitic fluids and caseous tissues. Isoniazid crosses the placenta and appears in foetal blood when administered during pregnancy. It also appears in the milk of nursing mothers. The primary metabolic route is the acetylation of isoniazid to acetylisoniazid by N-acetyl transferase found in the liver and small intestine. Acetylisoniazid is then hydrolysed to isonicotinic acid and monoacetylhydrazine. Isonicotinic acid is conjugated with glycine to isonicotinyl glycine (isonicotinic acid) and monoacetylhydrazine is further acetylated to diacetyihydrazine. Some unacetylated isoniazid is also conjugated to hydrazones. The metabolites of isoniazid have no tuberculostatic activity and apart possibly from monoacetyihydrazine they are also less toxic.

The rate of acetylation of INH and monoacetylhydrazine is genetically determined and there is bimodal distribution of persons who acetylate them either slowly or rapidly. Rapid acetylators have been reported to acetylate LNH about 5 times more rapidly than slow acetylators. The half life of isoniazid has been reported to be 0.5-1.5 hours in rapid acetylators and 2 or more hours in slow acetylators.

Elimination of isoniazid depends on the rate of acetylation. In patients with normal renal function approximately 70% of a dose appears in urine in 24 hours mostly as inactive metabolites; of this amount 93% of INH as excreted in urine may occur as the acetylated form in fast acetylators and 63% is slow acetylators, 7% of the 11411 excreted in the urine may occur as the free or conjugated form in fast acetylators and 37% in slow acetylators.

It is also excreted in the breast milk. Small quantities are excreted in saliva, sputum and faeces.

5.3 Preclinical safety data

Not applicable.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Calcium hydrogen phosphate Maize Starch

Pregelatinised maize starch Potable water Sodium lauryl sulphate Magnesium stearate Sodium starch glycollate

6.2 Incompatibilities

None reported.

6.3 Shelf life

36 months in plastic containers and 24 months in blister packs

6.4 Special precautions for storage

Store in the original package

6.5 Nature and contents of container

1.    Opaque plastic containers (securitainers) fitted with plastic cap in all pack sizes (9, 10, 14, 15, 20, 21, 28, 30, 50, 56, 84, 100, 250, 500, and 1000 tablets).

2.    Opaque plastic container composed of high density polypropylene with a tamper evident or child resistant tamper evident closure composed of high density polyethylene for all pack sizes. Packaging inclusion: standard polyether foam or polyethylene or polypropylene made filler in all pack sizes (9, 10, 14, 15, 20, 21, 28, 30, 50, 56, 84, 100, 250, 500, and 1000 tablets).