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Intermittent Therapy, Resumption of Therapy After Its Interruption: The presence of rifampicin means that, if treatment with Rimactazid is withdrawn for a while and then resumed again, or if the medication is not taken regularly, potentially serious side effects can occur (see Rifampicin under Adverse Reactions). For this reason, both temporary interruption of treatment and noncompliance (if the medication is not taken regularly) should if possible be avoided as potentially serious side effects can occur. Where temporary withdrawal of the medication is unavoidable, the components, rifampicin and INH, or with pyrazinamide should be administered separately when resuming the treatment, because rifampicin should then be given in an incremental dosage. A start should be made with approximately 75-150 mg rifampicin on the 1st day, and the desired therapeutic dose should be reached within 3-4 days. During this time, the patient's renal function should be closely monitored. Corticosteroids may prove useful in attenuating possible immunopathological reactions. INH should be given in its normal dosage from the 1st day onwards.
If severe acute hypersensitivity reactions set in eg, thrombocytopenia, purpura, hemolytic anemia, dyspnea, asthma-like attacks, shock or renal failure (these being side effects which rifampicin may provoke in exceptional cases). Rimactazid should be withdrawn at once. Inform the doctor if temporary withdrawal of the medication is unavoidable. Patients developing such complications should never again be treated with rifampicin.
If other signs of hypersensitivity appear eg, drug fever or skin reactions, Rimactazid/CombiPack should likewise be withdrawn. For safety reasons, treatment should not be continued with rifampicin; instead, another antituberculous agent should be prescribed.
Where INH is considered indispensable for combined medication and is therefore not withdrawn, treatment with it should be resumed in low doses and under strict surveillance.
Liver Disease, Undernourishment and Alcoholism: In patients with chronic liver disease, as well as in chronic alcoholics and undernourished patients, the therapeutic benefits of treatment with Rimactazid/CombiPack must be weighed against the possible risks. If the treatment is considered necessary, the dosage of both components must be correspondingly reduced; it is only possible to arrive at a correct adaptation of the dosage by administering rifampicin, INH and pyrazinamide separately.
Patients with current chronic liver disease or impaired liver function should be treated with caution and under strict medical supervision. Careful monitoring of liver function should be carried out and paid attention to possible prodromal symptoms of hepatitis eg, fatigue, weakness, malaise, anorexia, nausea and vomiting. If these symptoms appear or if signs suggestive of hepatic damage are detected, treatment should be discontinued promptly. The occurrence of severe and sometimes fatal hepatitis associated may develop even after many months of treatment.
Porphyria: Owing to its enzyme-inducing effect, rifampicin must be employed with extreme caution in patients with porphyria, because activation of δ-aminolaevulinic acid synthetase may lead to an acute manifestation of the porphyria.
Patients with Epilepsy: Owing to the neurotoxic action of INH, patients with epilepsy must be kept under special observation during treatment with Rimactazid/CombiPack (see Interactions).
Neuropathy: Pyridoxine (vitamin B6) may be useful for attenuating any neuropathy due to INH.
Alcohol: Patients should abstain from alcohol while under treatment with Rimactazid/CombiPack (see also Interactions).
Contraception: To preclude all possibility of pregnancy during treatment with Rimactazid/CombiPack, additional nonhormonal means of contraception must be employed (see Interactions).
Tests to be Performed: Blood counts and liver function tests (SGPT, SGOT) should be performed periodically (especially in prolonged treatment), and at baseline if possible.
Hyperuricemia, Gout: Special attention should be paid to patients with a history of hyperuricemia. Appropriate management of hyperuricemia should be undertaken (see also Interactions), or pyrazinamide should be discontinued, in the event of severe arthralgia or attacks of gout. In patients already displaying signs of liver damage prior to treatment as well as in severely undernourished patients, particular caution is indicated. CombiPack should be withdrawn and not reinstated if signs of hepatocellular damage occur.
Diabetes Mellitus: Pyrazinamide should be used with caution in patient with diabetes mellitus, as their management may become more difficult (see also Interactions).
Effects on the Ability to Drive or Operate Machinery: Isoniazid in high doses might possibly have an adverse effect.
Use in pregnancy & lactation: Rifampicin: In mice and rats, rifampicin proved teratogenic in daily doses of >150 mg/kg, insofar as an increased occurrence of spina bifida and cleft palate was observed. In rabbits, it had no teratogenic effect. In all 3 animal species, unspecific embryotoxic effects occurred after doses >150 mg/kg.
In humans, no significant increase in malformation rate was observed in the offspring of >300 women exposed to rifampicin during pregnancy.
Administration of rifampicin during the last few weeks of pregnancy can cause postnatal hemorrhage in the mother and newborn infant, which may necessitate treatment with vitamin K preparations.
Isoniazid: Teratogenic effects have been noted in animal models.
Nevertheless, isoniazid has been found to entail relatively little risk during pregnancy in humans. Congenital malformations are no greater than those expected for the normal population. Since it is theoretically possible that the drug might exert neurotoxic effects on the child, it is recommended that the mother should take pyridoxine during pregnancy.
Rimactazid/CombiPack should not be given during pregnancy unless the potential benefit justifies the potential risk to the fetus.
Although rifampicin and isoniazid pass into the breast milk, no adverse effects on breastfed infants have been observed. It is therefore not absolutely necessary to wean the infant. However, in view of the theoretical possibility of neurotoxic effects due to isoniazid, breastfed infants should be kept under careful surveillance. Prophylactic administration of pyridoxine to mother and child is recommended.
Pyrazinamide: There is no experience upon which to judge the safety of pyrazinamide in human pregnancy, nor is there evidence from animal work that it is free from either teratogenic potential or other adverse effects on the embryo and/or fetus relevant to the safety assessment of the product. It is unknown whether pyrazinamide passes through the placenta. Pyrazinamide also passes into the breast milk; the adverse effects on the infant are unknown. Therefore, the benefits and risks of nursing the infant should be carefully considered.
