Bitub

For all forms of pulmonary and extra-pulmonary tuberculosis.

Bitub 50 mg/2 ml Solution for Injection is for intramuscular, intravenous, intrapleural, or intrathecal injection.

Adults and children

The usual intramuscular or intravenous dose for adults is 200 to 300 mg as a single daily dose, for children 100 to 300 mg daily (10 - 20 mg/kg), but doses much larger than these are sometimes given, especially in conditions such as tuberculous meningitis. It is recommended to give an intravenous dose slowly as an undiluted bolus injection, although other methods may be employed.

Neonates

The recommended intravenous or intramuscular dose for neonates is 3-5 mg/kg with a maximum of 10 mg/kg daily. Bitub may be present in the milk of lactating mothers.

The elderly

No dosage reduction is necessary in the elderly.

Intrapleural use

50 to 250 mg may be instilled intrapleurally after aspiration of pus, the dosage of oral Bitub on that day being correspondingly reduced. The ampoule solution is also used for the local treatment of tuberculous ulcers, for irrigation of fistulae, etc.

Intrathecal use:

It should be noted that CSF concentrations of Bitub are approximately 90% of plasma concentrations. Where intrathecal use is required, 25 - 50 mg daily has been given to adults and 10 - 20 mg daily for children, according to age.

It is usual to give Bitub together with other antituberculous therapy, as determined by current practice and/or sensitivity testing.

It is recommended that pyridoxine be given during Bitub therapy to minimise adverse reactions, especially in malnourished patients and those predisposed to neuropathy (eg. diabetics and alcoholics).

Patients with renal impairment

No dosage reduction of Bitub is necessary when given to patients with mild renal failure. Patients with severe renal failure (glomerular filtration rate of less than 10 ml/minute) and slow acetylator status might require a dose reduction of about 100mg to maintain trough plasma levels at less than 1 mcg/ml.

Isonaizid is removed by both haemodialysis and peritoneal dialysis therefore Bitub should be administered immediately after dialysis.

Patients with hepatic impairment

The possible risks of administration of Bitub to patients with pre-existing non-tuberculous hepatic disease should be balanced against the benefits expected from treating tuberculosis.

Care is required in chronic alcoholism and when prescribing Bitub for patients with pre-existing hepatitis. Convulsions and psychotic reactions have occurred , especially in patients with a previous history of these conditions. These manifestations usually subside rapidly when the drug is withdrawn. Bitub should therefore be given with caution to patients with convulsive disorders and should be avoided in those with manic or hypomanic psychoses.

Bitub is metabolised by acetylation, which is subject to genetic variation. The 'slow acetylators' may be more susceptible to drug-induced peripheral neuropathy. However, dose adjustment is not normally required.

In patients with porphyria, Bitub should only be used where no safer alternative is available. Precautions should be considered in these patients.

It is recommended if Bitub-induced pancreatitis is proven that the drug should be permanently avoided.

Bitub, especially if given with rifampicin, may induce abnormalities in liver function, particularly in patients with pre-existing liver disorders, in the elderly, the very young and the malnourished. Monthly review is suggested to detect and limit the severity of this side-effect by stopping treatment if plasma transaminases exceed three times the upper limit of normal.

Patients should be warned of the possibility of convulsions, psychosis and optic neuritis.

Side-effects have been reported mainly in association with high doses or in slow acetylators who develop higher blood levels of the drug.

Tabulated list of adverse reactions

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

Not known: cannot be estimated from the available data

Description of selected adverse reactions

Bitub, especially if given with rifampicin, may induce abnormalities in liver function, particularly in patients with pre-existing liver disorders, in the elderly, the very young and the malnourished.

Peripheral neuropathy may be preventable with pyridoxine.

Severe and sometimes fatal hepatitis may occur with Bitub therapy.

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, Website: www.mhra.gov.uk/yellowcard.

In severe poisoning the main risk is of epileptiform convulsions.

The benefit of gastric decontamination is uncertain. Consider activated charcoal if the patient presents within 1 hour of ingestion of more than 20 mg/kg.

Consider gastric aspiration/lavage in adults within 1 hour of a potentially life-threatening overdose, providing the airway can be protected.

Treatment should be directed to the control of convulsions. Control convulsions initially with intravenous diazepam or lorazepam. Phenytoin is ineffective and not advised as Bitub inhibits the metabolism of phenytoin. Large doses of pyridoxine may limit the occurrence of other adverse effects. Metabolic acidosis may require sodium bicarbonate infusion. The drug is removed by dialysis.

Pharmacotherapeutic group: Combinations of drugs for treatment of tuberculosis

ATC code: J04AM

Bitub is a highly active tuberculostatic drug, and at high concentrations it is bactericidal to mycobacterium tuberculosis, possibly acting by interference with the synthesis of mycolic acid (a constituent of the bacterial cell wall).

Bitub is not appreciably protein-bound and diffuses readily throughout the body. It affects intracellular as well as extracellular bacilli. The primary metabolic route involves acetylation the rate of which is determined genetically.

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

None known.

None.