ethambutol hydrochloride + isoniazid + pyrazinamide + rifampicin: clinical use

Prescribing considerations

• Initiate and supervise through a clinician trained in tuberculosis management.
• Confirm that the fixed component ratio is appropriate; use separate components when individual adjustment is required.
• Review susceptibility information, previous tuberculosis treatment, adherence risks, hepatic and renal function, gout, diabetes, epilepsy, nutritional status, alcohol use, neuropathy and pre-existing visual impairment.
• Do not use this fixed combination to resume therapy after an interruption; specialist reassessment and separate components are required.
• Consider pyridoxine for patients at increased risk of isoniazid-associated neuropathy.
• Perform a comprehensive interaction review because rifampicin is a potent enzyme and transporter inducer.

Contraindications and cautions

• Hypersensitivity to rifamycins, isoniazid, pyrazinamide, ethambutol or an excipient
• History of drug-induced hepatitis or current acute liver disease
• Porphyria
• Acute gouty arthritis
• Severe renal impairment
• Concomitant voriconazole or specified strongly affected antiviral, antiretroviral or psychiatric medicines listed in the current product information

Monitoring

• Full blood count, liver function, renal function and serum uric acid before treatment and regularly thereafter
• Visual acuity, colour discrimination and visual fields before and during ethambutol exposure; ask about vision at every review
• Clinical signs of hepatitis, hypersensitivity, severe skin reactions, neuropathy, gout and haematological toxicity
• Adherence, emerging tuberculosis symptoms, microbiology and clinical response
• Concentrations, effects or toxicity of susceptible interacting medicines during treatment and after rifampicin withdrawal

Clinical pharmacology

Rifampicin inhibits bacterial DNA-dependent RNA polymerase; isoniazid inhibits mycolic-acid synthesis and is most active against rapidly dividing bacilli; pyrazinamide has activity in acidic conditions; and ethambutol suppresses multiplication of actively dividing mycobacteria. Rifampicin is also a potent metabolic enzyme and transporter inducer, whereas isoniazid inhibits metabolism of selected medicines.

Formulation and product differences

• Rimstar and Voractiv refer to the same brown, oval, biconvex fixed-combination film-coated tablet described in the product information.
• The fixed combination is unsuitable when component amounts require independent adjustment.
• The formulation is unsuitable below the stated body-weight threshold and is not recommended for young children because of aspiration risk and difficulty detecting visual toxicity.
• It is essentially sodium-free according to the product information.