RIMACTAZID Rifampicin / Isoniazid 450mg / 400mg Film-Coated Tablet 1's
RXDRUG-DRP-5099-1pc
Discreet Packaging
FDA-registered Products
FDA-licensed Pharmacies
Indications/Uses
All forms of pulmonary and extrapulmonary tuberculosis due to strains of Mycobacterium tuberculosis sensitive to rifampicin and INH.
Rifampicin is effective in cases resistant to other anti-tuberculosis agents and shows no cross-resistance outside the rifamycin group of drugs.
Rifampicin is effective in cases resistant to other anti-tuberculosis agents and shows no cross-resistance outside the rifamycin group of drugs.
Dosage/Direction for Use
Rimactazid-300: Adults: Continuous Therapy: Body weight ≥50 kg: 2 tabs Rimactazid-300 once daily (600 rifampicin + 300 mg INH).
Intermittent Therapy: For all body weights: 2 tabs Rimactazid-300 twice or 3 times weekly (600 mg rifampicin + 300 mg INH) 2 or 3 times a week. Rimactazid has to be supplemented with 150 mg INH for every 10 kg body weight >20 kg (ie, body weight 60 kg: 150 x 4 = 600 mg additional INH needed).
Rimactazid-450: As a general rule, 1 tab once a day, taken with meals. Rimactazid-450 is designed for use in patients with a body weight of ≤50 kg.
Duration of Treatment and Combined Medication: Total Duration: 9 months. For 2 months: Rimactazid-450 (according to weight) + ethambutol 1.2 g or streptomycin 1 g daily. For 7 months: Rimactazid-450 (according to weight).
Total Duration: 6 months. For 2 months: Rimactazid-450 (according to weight) + pyrazinamide 1.5-2.5 g + ethambutol 1.2 g or streptomycin 1 g daily. For 4 months: Rimactazid-450 (according to weight) daily.
CombiPack: A triple combination (blister strip) specifically designed for the daily therapy (use in 1 single intake 7 times a week) during the first 2 months of short-course chemotherapy of tuberculosis. After completion of the first 2 months therapy, treatment should be continued daily for 4-7 months with Rimactazid-450. The content of 1 blister strip provides a dosage of rifampicin 450 mg, INH 400 mg and pyrazinamide 1500 mg, which corresponds to the dosage used in common practice for the daily treatment of a patient of ≥50 kg body weight.
CombiPack: The chemotherapeutic agents usually employed today as combined therapy for tuberculosis are rifampicin (RMP), isoniazid (INH), pyrazinamide (PZA), ethambutol (EMB), streptomycin (STM).
The dosages recommended by the Centers for Disease Control and Prevention are as follows: See Table 2.
Intermittent Therapy: For all body weights: 2 tabs Rimactazid-300 twice or 3 times weekly (600 mg rifampicin + 300 mg INH) 2 or 3 times a week. Rimactazid has to be supplemented with 150 mg INH for every 10 kg body weight >20 kg (ie, body weight 60 kg: 150 x 4 = 600 mg additional INH needed).
Rimactazid-450: As a general rule, 1 tab once a day, taken with meals. Rimactazid-450 is designed for use in patients with a body weight of ≤50 kg.
Duration of Treatment and Combined Medication: Total Duration: 9 months. For 2 months: Rimactazid-450 (according to weight) + ethambutol 1.2 g or streptomycin 1 g daily. For 7 months: Rimactazid-450 (according to weight).
Total Duration: 6 months. For 2 months: Rimactazid-450 (according to weight) + pyrazinamide 1.5-2.5 g + ethambutol 1.2 g or streptomycin 1 g daily. For 4 months: Rimactazid-450 (according to weight) daily.
CombiPack: A triple combination (blister strip) specifically designed for the daily therapy (use in 1 single intake 7 times a week) during the first 2 months of short-course chemotherapy of tuberculosis. After completion of the first 2 months therapy, treatment should be continued daily for 4-7 months with Rimactazid-450. The content of 1 blister strip provides a dosage of rifampicin 450 mg, INH 400 mg and pyrazinamide 1500 mg, which corresponds to the dosage used in common practice for the daily treatment of a patient of ≥50 kg body weight.
CombiPack: The chemotherapeutic agents usually employed today as combined therapy for tuberculosis are rifampicin (RMP), isoniazid (INH), pyrazinamide (PZA), ethambutol (EMB), streptomycin (STM).
The dosages recommended by the Centers for Disease Control and Prevention are as follows: See Table 2.
For some drugs mentioned in the table, the dosages recommended by the CDC may differ from those recommended by WHO.
For the treatment of sputum-positive pulmonary tuberculosis, preference is nowadays given to the following regimens:
Continuous Therapy (7 times a week): Total duration 9 months: Initial phase for 2 months: RMP + INH + PZA + EMB or STM. Continuation phase for 7 months: RMP + INH.
A total duration of 9 months is recommended for tuberculosis with HIV infection, and for tuberculous meningitis, disseminated tuberculosis or spinal involvement with neurological complications.
Total duration 6 months: Initial phase for 2 months: RMP + INH + PZA + EMP or STM. Continuation phase for 4 months: RMP + INH.
Partially Intermittent Therapy: Total duration 6 months: Initial phase for 2 months: RMP + INH + PZA + EMB or STM daily. Continuation phase for 4 months: RMP + INH twice or 3 times a week.
Fully Intermittent Therapy: Total duration 6 months: RMP + INH + PZA + EMB or STM 3 times a week.
DOTS strategy (directly observed treatment, short-course ie, administration of the antituberculous agents under supervision) should be considered for all patients, irrespective of the treatment regimen they are receiving.
Dosage recommendations for sputum-negative pulmonary tuberculosis and extrapulmonary tuberculosis, and dosage recommendations for elderly and/or undernourished patients and those with severe liver damage can be found in the relevant literature.
To ensure optimum absorption, Rimactazid should preferably be taken on an empty stomach ie, at least ½ hr before a meal.
Children: In Rimactazid, the rifampicin and INH are present in a ratio which makes it hardly possible for both components to be administered in a dosage appropriate for children. Rimactazid is therefore not suitable for pediatric use.
For the treatment of sputum-positive pulmonary tuberculosis, preference is nowadays given to the following regimens:
Continuous Therapy (7 times a week): Total duration 9 months: Initial phase for 2 months: RMP + INH + PZA + EMB or STM. Continuation phase for 7 months: RMP + INH.
A total duration of 9 months is recommended for tuberculosis with HIV infection, and for tuberculous meningitis, disseminated tuberculosis or spinal involvement with neurological complications.
Total duration 6 months: Initial phase for 2 months: RMP + INH + PZA + EMP or STM. Continuation phase for 4 months: RMP + INH.
Partially Intermittent Therapy: Total duration 6 months: Initial phase for 2 months: RMP + INH + PZA + EMB or STM daily. Continuation phase for 4 months: RMP + INH twice or 3 times a week.
Fully Intermittent Therapy: Total duration 6 months: RMP + INH + PZA + EMB or STM 3 times a week.
DOTS strategy (directly observed treatment, short-course ie, administration of the antituberculous agents under supervision) should be considered for all patients, irrespective of the treatment regimen they are receiving.
Dosage recommendations for sputum-negative pulmonary tuberculosis and extrapulmonary tuberculosis, and dosage recommendations for elderly and/or undernourished patients and those with severe liver damage can be found in the relevant literature.
To ensure optimum absorption, Rimactazid should preferably be taken on an empty stomach ie, at least ½ hr before a meal.
Children: In Rimactazid, the rifampicin and INH are present in a ratio which makes it hardly possible for both components to be administered in a dosage appropriate for children. Rimactazid is therefore not suitable for pediatric use.
Overdosage
Symptoms: Rifampicin: Reddish-brown or orange discoloration of the skin, urine, saliva, lacrimal fluid, sweat, feces ("red man syndrome"); nausea, vomiting, abdominal pains; enlargement of the liver, jaundice, elevated liver enzyme levels; possibly acute pulmonary edema, lethargy, clouding of consciousness, convulsions, generalized pruritus.
Isoniazid: Early manifestations (within 30 min to 3 hrs): Nausea, vomiting, dizziness, slurring of speech, blurring of vision and visual hallucinations. Mild Poisoning: Ataxia, symptoms of polyneuritis, disturbed articulation, swimming before the eyes. Severe Poisoning: Hallucinations, epileptiform tonic-clonic attacks, respiratory depression, coma, severe metabolic acidosis, hyperglycemia, acetonuria.
Pyrazinamide: Acute liver damage and hyperuricemia have been reported.
Treatment: General supportive measures to maintain vital functions; IV administration of anticonvulsants and pyridoxine in large doses; control of metabolic acidosis; gastric lavage together with the administration of an activated charcoal suspension via the stomach tube; forced diuresis; hemodialysis; peritoneal dialysis; fluid intake and output monitoring; in the presence of severe liver damage, bile drainage may be indicated.
Gastric lavage is advised within the 1st 2-3 hrs after ingestion, but it should not be attempted until convulsions are under control.
Isoniazid: Early manifestations (within 30 min to 3 hrs): Nausea, vomiting, dizziness, slurring of speech, blurring of vision and visual hallucinations. Mild Poisoning: Ataxia, symptoms of polyneuritis, disturbed articulation, swimming before the eyes. Severe Poisoning: Hallucinations, epileptiform tonic-clonic attacks, respiratory depression, coma, severe metabolic acidosis, hyperglycemia, acetonuria.
Pyrazinamide: Acute liver damage and hyperuricemia have been reported.
Treatment: General supportive measures to maintain vital functions; IV administration of anticonvulsants and pyridoxine in large doses; control of metabolic acidosis; gastric lavage together with the administration of an activated charcoal suspension via the stomach tube; forced diuresis; hemodialysis; peritoneal dialysis; fluid intake and output monitoring; in the presence of severe liver damage, bile drainage may be indicated.
Gastric lavage is advised within the 1st 2-3 hrs after ingestion, but it should not be attempted until convulsions are under control.
Administration
Should be taken on an empty stomach: Take at least 30 min before or 2 hr after meals.
Contraindications
Known or suspected hypersensitivity to rifamycins and/or to INH, and/or to any of the excipients including a history of drug-induced hepatitis; acute liver diseases, regardless of their origin; peripheral neuritis.
Special Precautions
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.
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.
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.
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.
Adverse Reactions
Frequency Estimates: Frequent: >10%, occasional: 1-10%, rare: 0.001-1%, isolated cases: <0.001%.
Rifampicin: Rifampicin may cause reddish discoloration of body fluids and occasionally other body secretions eg, urine, sputum, lacrimal fluid, feces, saliva, sweat. It may permanently discolor soft contact lenses.
Unwanted Effects which may Occur During Continuous Daily or Intermittent Therapy: Skin and Appendages: Occasional: Flushing, itching with or without skin rash, urticaria and reddening of the eyes. Isolated Cases: Severe signs and symptoms eg, exudative conjunctivitis or generalized hypersensitivity reactions involving the skin (eg, exfoliative dermatitis, Lyell's syndrome) and pemphigoid reactions.
Gastrointestinal Tract: Occasional: Anorexia, nausea, abdominal pains, gaseous distention. Rarely: Vomiting or diarrhea. Isolated Cases: Erosive gastritis and pseudomembranous colitis.
Liver: Frequently, an asymptomatic increase in liver enzymes. Rarely: Hepatitis or jaundice. Isolated Cases: Induction of porphyria.
Central and Peripheral Nervous System: Occasional: Tiredness, drowsiness, headache, lightheadedness and dizziness. Rarely: Ataxia and mental confusion. Isolated Cases: Muscular weakness and visual disturbances.
Blood: Isolated Cases: Transient leukopenia; eosinophilia, thrombocytopenia and thrombocytopenic purpura are encountered more frequently under intermittent therapy than on continuous daily treatment, during which they occur only in isolated cases.
Endocrine Reactions: Rarely, disturbances in the menstrual cycle; induction of a crisis in Addison patients (see Interactions).
Unwanted Effects Chiefly Occurring During Intermittent Therapy or Upon Resumption of Treatment After Temporary Interruption: In patients taking rifampicin other than daily or in those resuming treatment with the drug after a temporary interruption, an influenza-like syndrome ("flu syndrome") may set in, this being very probably of immunopathological origin. It is characterized by fever, shivering and possibly headache, dizziness and pain in the limbs. In rare cases, the "flu syndrome" may be followed by thrombocytopenia, purpura, dyspnea, asthma-like attacks, hemolytic anemia, shock and acute renal failure. These serious complications may, however, also set in suddenly with no preceding "flu syndrome", chiefly when treatment is resumed after a temporary interruption or when rifampicin is given only once a week in high doses (≥25 mg/kg). When rifampicin is administered in lower doses (600 mg) 2-3 times a week, the syndrome is only rarely encountered, its incidence then being comparable to that observed during daily medication.
Isoniazid: Central and Peripheral Nervous System: Frequently, peripheral neuropathy (usually preceded by paresthesias of feet and hands, dose-dependent and more common in undernourished patients, in alcoholics and in diabetics); rarely, damage to the optic nerve, convulsions, psychoses, dizziness, lightheadedness, headache. Isolated Cases: Toxic encephalopathy. High doses may increase the frequency of seizures in epileptics.
Gastrointestinal Tract: Occasionally, nausea, vomiting, epigastric distress.
Liver: Frequently, disturbances of liver function (usually transient); rarely, hepatitis, which in isolated instances may be severe; the frequency of hepatitis rises with increasing age.
The common prodromal symptoms of severe hepatitis are anorexia, nausea, vomiting, fatigue, malaise and weakness. The frequency of progressive liver damage increases with age.
It is rare in persons <20, but occurs in up to 2.3% of those >50 years.
Hematological Reactions: Isolated cases of agranulocytosis, eosinophilia, thrombocytopenia, anemia (hemolytic, hypoplastic).
Allergic and Miscellaneous Reactions: Occasional: Drug rash and fever. Rarely: Dryness of the mouth, heartburn, disorders of micturition, rheumatic syndrome, lupus erythematosus-like signs and symptoms, pellagra. Isolated Cases: Gynecomastia and vasculitis, lymphadenopathy, hyperglycemia, metabolic acidosis.
Pyrazinamide: Liver: The liver toxicity of pyrazinamide depends on the dosage, the duration of treatment and concomitant therapy. It can vary from occasional mild liver disorders eg, a transient increase in serum transaminase levels to isolated cases of acute yellow atrophy of the liver. Rarely, attacks of porphyria.
Gastrointestinal Tract: Nausea, anorexia, vomiting, diarrhea and abdominal pain may occur. Aggravation of peptic ulcer.
Urogenital System: Decreased renal excretion of uric acid, resulting in hyperuricemia, may occur with pyrazinamide in dosages exceeding 2 g/day.
Occasionally, arthralgia and rarely, attacks of gout have been reported; these always proved reversible after the drug had been withdrawn or the dosage decreased and appropriate therapy given.
Blood: Rarely, sideroblastic anemia, thrombocytopenia.
Central Nervous System: Mild fever and malaise may occur.
Skin: Allergic skin reactions, including urticaria, rash, flushing, pruritus, burning sensations and photosensitization have been observed.
Rifampicin: Rifampicin may cause reddish discoloration of body fluids and occasionally other body secretions eg, urine, sputum, lacrimal fluid, feces, saliva, sweat. It may permanently discolor soft contact lenses.
Unwanted Effects which may Occur During Continuous Daily or Intermittent Therapy: Skin and Appendages: Occasional: Flushing, itching with or without skin rash, urticaria and reddening of the eyes. Isolated Cases: Severe signs and symptoms eg, exudative conjunctivitis or generalized hypersensitivity reactions involving the skin (eg, exfoliative dermatitis, Lyell's syndrome) and pemphigoid reactions.
Gastrointestinal Tract: Occasional: Anorexia, nausea, abdominal pains, gaseous distention. Rarely: Vomiting or diarrhea. Isolated Cases: Erosive gastritis and pseudomembranous colitis.
Liver: Frequently, an asymptomatic increase in liver enzymes. Rarely: Hepatitis or jaundice. Isolated Cases: Induction of porphyria.
Central and Peripheral Nervous System: Occasional: Tiredness, drowsiness, headache, lightheadedness and dizziness. Rarely: Ataxia and mental confusion. Isolated Cases: Muscular weakness and visual disturbances.
Blood: Isolated Cases: Transient leukopenia; eosinophilia, thrombocytopenia and thrombocytopenic purpura are encountered more frequently under intermittent therapy than on continuous daily treatment, during which they occur only in isolated cases.
Endocrine Reactions: Rarely, disturbances in the menstrual cycle; induction of a crisis in Addison patients (see Interactions).
Unwanted Effects Chiefly Occurring During Intermittent Therapy or Upon Resumption of Treatment After Temporary Interruption: In patients taking rifampicin other than daily or in those resuming treatment with the drug after a temporary interruption, an influenza-like syndrome ("flu syndrome") may set in, this being very probably of immunopathological origin. It is characterized by fever, shivering and possibly headache, dizziness and pain in the limbs. In rare cases, the "flu syndrome" may be followed by thrombocytopenia, purpura, dyspnea, asthma-like attacks, hemolytic anemia, shock and acute renal failure. These serious complications may, however, also set in suddenly with no preceding "flu syndrome", chiefly when treatment is resumed after a temporary interruption or when rifampicin is given only once a week in high doses (≥25 mg/kg). When rifampicin is administered in lower doses (600 mg) 2-3 times a week, the syndrome is only rarely encountered, its incidence then being comparable to that observed during daily medication.
Isoniazid: Central and Peripheral Nervous System: Frequently, peripheral neuropathy (usually preceded by paresthesias of feet and hands, dose-dependent and more common in undernourished patients, in alcoholics and in diabetics); rarely, damage to the optic nerve, convulsions, psychoses, dizziness, lightheadedness, headache. Isolated Cases: Toxic encephalopathy. High doses may increase the frequency of seizures in epileptics.
Gastrointestinal Tract: Occasionally, nausea, vomiting, epigastric distress.
Liver: Frequently, disturbances of liver function (usually transient); rarely, hepatitis, which in isolated instances may be severe; the frequency of hepatitis rises with increasing age.
The common prodromal symptoms of severe hepatitis are anorexia, nausea, vomiting, fatigue, malaise and weakness. The frequency of progressive liver damage increases with age.
It is rare in persons <20, but occurs in up to 2.3% of those >50 years.
Hematological Reactions: Isolated cases of agranulocytosis, eosinophilia, thrombocytopenia, anemia (hemolytic, hypoplastic).
Allergic and Miscellaneous Reactions: Occasional: Drug rash and fever. Rarely: Dryness of the mouth, heartburn, disorders of micturition, rheumatic syndrome, lupus erythematosus-like signs and symptoms, pellagra. Isolated Cases: Gynecomastia and vasculitis, lymphadenopathy, hyperglycemia, metabolic acidosis.
Pyrazinamide: Liver: The liver toxicity of pyrazinamide depends on the dosage, the duration of treatment and concomitant therapy. It can vary from occasional mild liver disorders eg, a transient increase in serum transaminase levels to isolated cases of acute yellow atrophy of the liver. Rarely, attacks of porphyria.
Gastrointestinal Tract: Nausea, anorexia, vomiting, diarrhea and abdominal pain may occur. Aggravation of peptic ulcer.
Urogenital System: Decreased renal excretion of uric acid, resulting in hyperuricemia, may occur with pyrazinamide in dosages exceeding 2 g/day.
Occasionally, arthralgia and rarely, attacks of gout have been reported; these always proved reversible after the drug had been withdrawn or the dosage decreased and appropriate therapy given.
Blood: Rarely, sideroblastic anemia, thrombocytopenia.
Central Nervous System: Mild fever and malaise may occur.
Skin: Allergic skin reactions, including urticaria, rash, flushing, pruritus, burning sensations and photosensitization have been observed.
Drug Interactions
Rifampicin: Antacids, opiates and anticholinergic drugs reduce the bioavailability of rifampicin when it is given concomitantly by mouth. The same applies to PAS preparations containing bentonite. To avoid this interaction, rifampicin must be administered a few hours before these preparations.
Owing to its enzyme-inducing effect, rifampicin accelerates the metabolism of many concomitantly administered drugs, whose activity may thus be reduced and the success of treatment with them jeopardized.
The activity of the following drugs may be impaired, and their dosage must therefore be re-assessed during and after treatment with rifampicin:
Oral anticoagulants; oral antidiabetic agents; digitalis preparations; antiarrhythmic agents (disopyramide, pirmenol, quinidine; mexiletine, tocainide; lorcainide, propafenone); methadone (withdrawal signs may set in); hydantoins [phenytoins (see also under isoniazid), ethotoin, mephenytoin]; hexobarbital; nortriptyline; benzodiazepines; corticosteroids (Addison patients may develop a crisis; exacerbation of pemphigus may occur; treatment for corticoid-dependent asthma may become more difficult or impossible); sex hormones (menstrual disorders may appear); oral contraceptives (their effect can no longer be relied upon); theophylline; dapsone; chloramphenicol; antifungal agents (ketoconazole; itraconazole), cyclosporin A, azathioprine (transplants may be rejected); β-blockers; calcium-channel blockers (nifedipine, verapamil); enalapril, cimetidine.
Although concurrent use of isoniazid, pyrazinamide and rifampicin is common and therapeutically valuable, hepatic toxicity may be increased.
Rifampicin can delay the biliary excretion of contrast media employed in the x-ray of the gallbladder.
Microbiological techniques for assaying folic acid and vitamin B12 in the serum are unsuitable for use during treatment with Rimactazid. Rifampicin causes temporary competitive inhibition of bromsulphthalein excretion. To guard against false-positive results, the bromsulphthalein test should be performed in the morning before administration of Rimactazid.
Isoniazid: The absorption of isoniazid is reduced by antacids. Isoniazid retards the metabolism of various concomitantly administered drugs, whose toxicity thus becomes increased. Clinically relevant interactions of this kind can occur with hydantoins (phenytoin, ethotoin, mephenytoin), carbamazepine, primidone and valproic acid, the dosages of which may have to be reduced. Concurrent administration of disulfiram may lead to mental disturbances; the mechanism underlying this interaction has not been clarified. It is not advisable to employ disulfiram concomitantly with isoniazid.
Concomitant use of halothane and isoniazid (and possibly rifampicin) may increase the risk of hepatotoxic reactions.
As alcohol tolerance is decreased under isoniazid, the consumption of alcoholic beverages should be avoided. The metabolism of isoniazid is increased in chronic alcoholics.
Pyrazinamide: The effect of uricosuric drugs eg, probenecid and sulfinpyrazone is antagonized by pyrazinamide, and the elimination half-life of probenecid is increased. Allopurinol increases the plasma concentration of pyrazinoic acid which is directly responsible for the inhibition of renal urate secretion. It should be used with caution in patients with diabetes mellitus as their management may become more difficult. Pyrazinamide may interfere with the Acetest and Ketostix urine tests for Ketones.
Incompatibilities: Not applicable.
Owing to its enzyme-inducing effect, rifampicin accelerates the metabolism of many concomitantly administered drugs, whose activity may thus be reduced and the success of treatment with them jeopardized.
The activity of the following drugs may be impaired, and their dosage must therefore be re-assessed during and after treatment with rifampicin:
Oral anticoagulants; oral antidiabetic agents; digitalis preparations; antiarrhythmic agents (disopyramide, pirmenol, quinidine; mexiletine, tocainide; lorcainide, propafenone); methadone (withdrawal signs may set in); hydantoins [phenytoins (see also under isoniazid), ethotoin, mephenytoin]; hexobarbital; nortriptyline; benzodiazepines; corticosteroids (Addison patients may develop a crisis; exacerbation of pemphigus may occur; treatment for corticoid-dependent asthma may become more difficult or impossible); sex hormones (menstrual disorders may appear); oral contraceptives (their effect can no longer be relied upon); theophylline; dapsone; chloramphenicol; antifungal agents (ketoconazole; itraconazole), cyclosporin A, azathioprine (transplants may be rejected); β-blockers; calcium-channel blockers (nifedipine, verapamil); enalapril, cimetidine.
Although concurrent use of isoniazid, pyrazinamide and rifampicin is common and therapeutically valuable, hepatic toxicity may be increased.
Rifampicin can delay the biliary excretion of contrast media employed in the x-ray of the gallbladder.
Microbiological techniques for assaying folic acid and vitamin B12 in the serum are unsuitable for use during treatment with Rimactazid. Rifampicin causes temporary competitive inhibition of bromsulphthalein excretion. To guard against false-positive results, the bromsulphthalein test should be performed in the morning before administration of Rimactazid.
Isoniazid: The absorption of isoniazid is reduced by antacids. Isoniazid retards the metabolism of various concomitantly administered drugs, whose toxicity thus becomes increased. Clinically relevant interactions of this kind can occur with hydantoins (phenytoin, ethotoin, mephenytoin), carbamazepine, primidone and valproic acid, the dosages of which may have to be reduced. Concurrent administration of disulfiram may lead to mental disturbances; the mechanism underlying this interaction has not been clarified. It is not advisable to employ disulfiram concomitantly with isoniazid.
Concomitant use of halothane and isoniazid (and possibly rifampicin) may increase the risk of hepatotoxic reactions.
As alcohol tolerance is decreased under isoniazid, the consumption of alcoholic beverages should be avoided. The metabolism of isoniazid is increased in chronic alcoholics.
Pyrazinamide: The effect of uricosuric drugs eg, probenecid and sulfinpyrazone is antagonized by pyrazinamide, and the elimination half-life of probenecid is increased. Allopurinol increases the plasma concentration of pyrazinoic acid which is directly responsible for the inhibition of renal urate secretion. It should be used with caution in patients with diabetes mellitus as their management may become more difficult. Pyrazinamide may interfere with the Acetest and Ketostix urine tests for Ketones.
Incompatibilities: Not applicable.
Storage
Protect from heat and moisture (store at temperatures not exceeding 30°C).
Action
Rimactazid is a fixed combination for the treatment of tuberculosis.
Pharmacology: Rifampicin is a rifamycin antibiotic which in vivo has a bactericidal effect on strains of Mycobacterium tuberculosis located not only in the extracellular spaces but also intracellularly. Of particular clinical significance in the treatment of tuberculosis is its rapid onset of action, which results in a sterilizing effect. Rifampicin has a high sterilizing activity.
Rifampicin inhibits the DNA-dependent RNA polymerase of sensitive bacterial strains, but without affecting the corresponding mammalian enzyme.
Isoniazid is a specific antituberculous agent exerting a strong bactericidal effect mainly on rapidly growing populations of Mycobacterium tuberculosis. Its mechanism of action is probably based chiefly on inhibition of mycolic acid synthesis, mycolic acid being an important constituent of the mycobacterial cell wall.
Pyrazinamide is highly specific and bactericidal for M. tuberculosis hominis at an acidic pH and has potent sterilizing activity. The minimal inhibitory concentration at pH 5.5 in vitro is 20-50 mcg/mL. Clinically, pyrazinamide has been shown to be especially effective against mycobacteria growing slowly in an acidic environment eg, caseous foci, pulmonary cavities. Primary resistance of M. tuberculosis hominis to pyrazinamide is very rare.
There seems to be no cross-resistance with other major antituberculous agents eg, rifampicin, isoniazid, streptomycin and ethambutol.
The combination of these 3 agents exerts a bactericidal and sterilizing action on all fractions of the bacterial population.
Pharmacokinetics: The bioavailability of both active ingredients, rifampicin and isoniazid, is the same when administered as a fixed combination or when given separately. Neither component interferes with the pharmacokinetics of the other when administered simultaneously.
Absorption: After oral administration of the fixed combination on an empty stomach, the 2 active substances are well absorbed.
Rifampicin, following a single dose of 600 mg, reaches mean peak plasma concentrations of 9.4 mcg/mL after 2-3 hrs.
Isoniazid, following a single dose of 300 mg, reaches mean peak plasma concentrations of 6.1 mcg/mL after 0.5-2 hrs. However, plasma concentrations vary interindividually, depending on the acetylator status of the patient.
Concomitant intake of food reduces the absorption of the active components.
Distribution: Rifampicin: The apparent distribution volume is 1.6 L/kg in adults and 1.1 L/kg in children. Binding to serum proteins amounts to 84-91%.
Isoniazid: The apparent distribution volume is 0.61 L/kg. Isoniazid is not appreciably bound to serum proteins.
Rifampicin and isoniazid penetrate rapidly into various body fluids and tissues, including bone tissue (rifampicin) and cerebrospinal fluid, in therapeutically active concentrations. Rifampicin crosses the blood-brain barrier in the case of inflamed meninges only, but concentrations in the cerebrospinal fluid may remain above the MIC for Mycobacterium tuberculosis for up to 2 months with continuous therapy of 600 mg/day orally.
Rifampicin and isoniazid cross the human placenta and are secreted in human breast milk. Isoniazid attains the highest levels, but a breastfed infant would receive no more than 20%, and in the case of rifampicin, <1% of the usual therapeutic dose.
Biotransformation: Rifampicin is metabolized in the liver, the principal metabolite being 25-O-deacetylrifampicin, which is microbiologically active and like rifampicin, subject to enterohepatic circulation. Rifampicin induces its own metabolism.
Isoniazid is acetylated and hydrolyzed in the liver. Acetylation is the most important metabolic pathway and is subject to genetic predisposition (fast and slow acetylators).
Elimination/Excretion: Rifampicin: The plasma elimination half-life increases with increasing doses, and amounts to 2.5, 3-4 and about 5 hrs after single doses of 300, 600 and 900 mg, respectively. After a few days of repeated daily administration, the bioavailability of rifampicin diminishes, and the half-life value following repeated doses of 600 mg falls to 1-2 hrs. Owing to its enzyme-inducing effect in the liver, rifampicin accelerates its own metabolism, with the result that its systemic clearance, which amounts to approximately 6 L/hr after the 1st dose, rises to approximately 9 L/hr after repeated dosing.
Although the bulk of the drug is eliminated in the bile, 80% of the quantity excreted being accounted for by the deacetylrifampicin metabolite, rifampicin also appears in the urine.
In a dosage range of 150-900 mg, 4-18% of a dose is excreted dose-dependently in the urine in unchanged form.
Isoniazid: The plasma elimination t½ is 0.6-1.8 hrs in fast acetylators and 1.8-6.7 hrs in slow acetylators.
Within 24 hrs, 75-95% of the dose administered is excreted in the urine, mainly as metabolites. N-acetylisoniazid is eliminated in the urine together with other metabolites. The quantity appearing in the urine as unchanged isoniazid is equivalent to 12% of the dose in fast acetylators and to 27% in slow acetylators.
Characteristics in Patients: Rifampicin: In elderly patients, plasma concentrations are similar to those in young patients.
With impaired renal function, the elimination half-life becomes prolonged only at doses exceeding 600 mg daily. Provided that hepatic excretory function is normal, the dosage in patients with impaired renal function does not need to be reduced.
Rifampicin is eliminated by peritoneal or hemodialysis. Dosage adjustment is not necessary during dialysis.
In patients with impaired liver function, the plasma concentrations are raised and the elimination half-life prolonged. In the presence of severe hepatic dysfunction, the dosage may have to be adjusted accordingly.
Elderly Patients: In fast acetylators, old age has no significant influence on the rate at which isoniazid is eliminated. However, clearance and elimination half-life vary significantly in elderly slow acetylators, so that it might be necessary to adjust the dosage accordingly.
In slow acetylators with severely impaired renal function, accumulation of isoniazid may occur. In such cases, the serum concentration of isoniazid should be monitored and, if necessary, the dosage reduced.
In the presence of impaired liver function, the elimination half-life of isoniazid is prolonged. To avoid unwanted effects, it may therefore be necessary to adapt the dosage accordingly.
Pyrazinamide, following a single dose of 1.5 g, reaches mean peak plasma concentrations of 30 mcg/mL in volunteers and about 40 mcg/mL in patients following doses of 2.5 g in volunteers, maximum plasma concentrations of 50 mcg/mL are attained after 1-2 hrs.
Peak plasma concentrations of pyrazinamide show a linear correlation in a dose range of 0.5-3 g.
During repeated administration for 60 days, the peak plasma concentrations after dosing are slightly raised on day 15. However, no further accumulative effect is seen thereafter. The apparent distribution volume is 1.65 L/kg. In vitro, protein-binding of pyrazinamide to human whole plasma is approximately 40%. Its levels in CSF may reach 100% of the serum levels when given in combination with other tuberculostatics. It is extensively metabolized, first to pyrazinoic acid, the main metabolite, which is subsequently oxidized to 5-hydroxypyrazinoic acid by xanthine oxidase and 5-hydroxypyrazinamide. Maximum plasma concentrations of pyrazinoic acid are achieved within 4-8 hrs after administration of pyrazinamide. Pyrazinamide is eliminated from plasma with a t½ of 8-12 hrs in individual cases, when calculating the value in a strictly multiphasic way, a terminal elimination t½ of 23 hrs has been observed. It is mainly excreted in urine. Within 24 hrs, ≤4% appears as unchanged drug, the remainder as metabolites. Pyrazinoic acid constitutes about 40%, 5-hydroxypyrazinoic acid about 10% and 5-hydroxypyrazinamide about 15% of the dose. During hemodialysis, approximately 73% of the total isoniazid dose is removed.
Therapeutic Efficacy: Concentrations of 20-25 mcg/mL or higher are necessary to achieve optimum therapeutic efficacy. These levels can be maintained >6 hrs after daily therapeutic doses of 1-3 g and may last for up to 12 hrs. Impaired renal function has only negligible influence on the elimination of pyrazinamide and its metabolites are extracted during hemodialysis to a marked degree. Provided that pyrazinamide is given at the end of a hemodialysis session, it is unnecessary to reduce the usual dose in such patients. In the presence of hepatic cirrhotic insufficiency, the metabolic clearance is drastically diminished, resulting in a reduction of the total clearance by about ½, and in a considerable prolongation of the elimination half-life of pyrazinamide. For pyrazinoic acid, the main metabolite, AUC values are nearly 3 times higher and the elimination half-life is twice as long compared with healthy controls, resulting in markedly increased plasma concentrations. The dose must be reduced by about ½ and the biologic hepatic parameters closely monitored, together with the renal excretion of uric acid.
Carcinogenicity: Preclinical Safety Data: Rifampicin: There is only limited evidence as to the carcinogenicity potential of rifampicin in animals. After oral administration to 2 mouse strains, a significant increase in benign and malignant liver-cell tumors was observed after 1 year of treatment with rifampicin in quantities equivalent to 2-10 times the maximum clinical doses in female animals of 1 strain (known to be susceptible to hepatomas) only. No evidence of carcinogenicity was observed in females of the other strain or in male animals of both strains, as well as in rats of both sexes treated for 2 years.
Isoniazid: Limited evidence in animals shows that isoniazid produces lung tumors in mice after various modes of administration. Available evidence of human exposure has not suggested that isoniazid is carcinogenic in man at doses applicable to treatment and prophylaxis of tuberculosis.
Pyrazinamide: In a lifetime bioassay, pyrazinamide was not carcinogenic in rats or male mice, and no conclusion was possible for female mice due to the poor survival and small size of the matching control group.
Mutagenicity: In various short-term in vitro and in vivo tests in animals, rifampicin did not induce mutagenic effects. A slight increase in the occurrence of chromosome aberrations may be seen in human blood cell cultures, according to the evaluation method used.
Isoniazid, besides having weak direct genotoxic activity, is a promutagen in the sense that formation of the toxic metabolites, hydrazine and acetylhydrazine, is the 1st step in metabolic activation. In lymphocytes of patients treated with isoniazid, no chromosomal aberrations could be detected, whereas in a study comparing the effects of combination treatment, an increased frequency of chromosomal aberrations was observed.
There was an increase in chromosomal aberrations in lymphocytes of tuberculosis patients after treatment with a combination of rifampicin-isoniazid-pyrazinamide and in lymphocyte cultures exposed to pyrazinamide alone from normal subjects.
Pharmacology: Rifampicin is a rifamycin antibiotic which in vivo has a bactericidal effect on strains of Mycobacterium tuberculosis located not only in the extracellular spaces but also intracellularly. Of particular clinical significance in the treatment of tuberculosis is its rapid onset of action, which results in a sterilizing effect. Rifampicin has a high sterilizing activity.
Rifampicin inhibits the DNA-dependent RNA polymerase of sensitive bacterial strains, but without affecting the corresponding mammalian enzyme.
Isoniazid is a specific antituberculous agent exerting a strong bactericidal effect mainly on rapidly growing populations of Mycobacterium tuberculosis. Its mechanism of action is probably based chiefly on inhibition of mycolic acid synthesis, mycolic acid being an important constituent of the mycobacterial cell wall.
Pyrazinamide is highly specific and bactericidal for M. tuberculosis hominis at an acidic pH and has potent sterilizing activity. The minimal inhibitory concentration at pH 5.5 in vitro is 20-50 mcg/mL. Clinically, pyrazinamide has been shown to be especially effective against mycobacteria growing slowly in an acidic environment eg, caseous foci, pulmonary cavities. Primary resistance of M. tuberculosis hominis to pyrazinamide is very rare.
There seems to be no cross-resistance with other major antituberculous agents eg, rifampicin, isoniazid, streptomycin and ethambutol.
The combination of these 3 agents exerts a bactericidal and sterilizing action on all fractions of the bacterial population.
Pharmacokinetics: The bioavailability of both active ingredients, rifampicin and isoniazid, is the same when administered as a fixed combination or when given separately. Neither component interferes with the pharmacokinetics of the other when administered simultaneously.
Absorption: After oral administration of the fixed combination on an empty stomach, the 2 active substances are well absorbed.
Rifampicin, following a single dose of 600 mg, reaches mean peak plasma concentrations of 9.4 mcg/mL after 2-3 hrs.
Isoniazid, following a single dose of 300 mg, reaches mean peak plasma concentrations of 6.1 mcg/mL after 0.5-2 hrs. However, plasma concentrations vary interindividually, depending on the acetylator status of the patient.
Concomitant intake of food reduces the absorption of the active components.
Distribution: Rifampicin: The apparent distribution volume is 1.6 L/kg in adults and 1.1 L/kg in children. Binding to serum proteins amounts to 84-91%.
Isoniazid: The apparent distribution volume is 0.61 L/kg. Isoniazid is not appreciably bound to serum proteins.
Rifampicin and isoniazid penetrate rapidly into various body fluids and tissues, including bone tissue (rifampicin) and cerebrospinal fluid, in therapeutically active concentrations. Rifampicin crosses the blood-brain barrier in the case of inflamed meninges only, but concentrations in the cerebrospinal fluid may remain above the MIC for Mycobacterium tuberculosis for up to 2 months with continuous therapy of 600 mg/day orally.
Rifampicin and isoniazid cross the human placenta and are secreted in human breast milk. Isoniazid attains the highest levels, but a breastfed infant would receive no more than 20%, and in the case of rifampicin, <1% of the usual therapeutic dose.
Biotransformation: Rifampicin is metabolized in the liver, the principal metabolite being 25-O-deacetylrifampicin, which is microbiologically active and like rifampicin, subject to enterohepatic circulation. Rifampicin induces its own metabolism.
Isoniazid is acetylated and hydrolyzed in the liver. Acetylation is the most important metabolic pathway and is subject to genetic predisposition (fast and slow acetylators).
Elimination/Excretion: Rifampicin: The plasma elimination half-life increases with increasing doses, and amounts to 2.5, 3-4 and about 5 hrs after single doses of 300, 600 and 900 mg, respectively. After a few days of repeated daily administration, the bioavailability of rifampicin diminishes, and the half-life value following repeated doses of 600 mg falls to 1-2 hrs. Owing to its enzyme-inducing effect in the liver, rifampicin accelerates its own metabolism, with the result that its systemic clearance, which amounts to approximately 6 L/hr after the 1st dose, rises to approximately 9 L/hr after repeated dosing.
Although the bulk of the drug is eliminated in the bile, 80% of the quantity excreted being accounted for by the deacetylrifampicin metabolite, rifampicin also appears in the urine.
In a dosage range of 150-900 mg, 4-18% of a dose is excreted dose-dependently in the urine in unchanged form.
Isoniazid: The plasma elimination t½ is 0.6-1.8 hrs in fast acetylators and 1.8-6.7 hrs in slow acetylators.
Within 24 hrs, 75-95% of the dose administered is excreted in the urine, mainly as metabolites. N-acetylisoniazid is eliminated in the urine together with other metabolites. The quantity appearing in the urine as unchanged isoniazid is equivalent to 12% of the dose in fast acetylators and to 27% in slow acetylators.
Characteristics in Patients: Rifampicin: In elderly patients, plasma concentrations are similar to those in young patients.
With impaired renal function, the elimination half-life becomes prolonged only at doses exceeding 600 mg daily. Provided that hepatic excretory function is normal, the dosage in patients with impaired renal function does not need to be reduced.
Rifampicin is eliminated by peritoneal or hemodialysis. Dosage adjustment is not necessary during dialysis.
In patients with impaired liver function, the plasma concentrations are raised and the elimination half-life prolonged. In the presence of severe hepatic dysfunction, the dosage may have to be adjusted accordingly.
Elderly Patients: In fast acetylators, old age has no significant influence on the rate at which isoniazid is eliminated. However, clearance and elimination half-life vary significantly in elderly slow acetylators, so that it might be necessary to adjust the dosage accordingly.
In slow acetylators with severely impaired renal function, accumulation of isoniazid may occur. In such cases, the serum concentration of isoniazid should be monitored and, if necessary, the dosage reduced.
In the presence of impaired liver function, the elimination half-life of isoniazid is prolonged. To avoid unwanted effects, it may therefore be necessary to adapt the dosage accordingly.
Pyrazinamide, following a single dose of 1.5 g, reaches mean peak plasma concentrations of 30 mcg/mL in volunteers and about 40 mcg/mL in patients following doses of 2.5 g in volunteers, maximum plasma concentrations of 50 mcg/mL are attained after 1-2 hrs.
Peak plasma concentrations of pyrazinamide show a linear correlation in a dose range of 0.5-3 g.
During repeated administration for 60 days, the peak plasma concentrations after dosing are slightly raised on day 15. However, no further accumulative effect is seen thereafter. The apparent distribution volume is 1.65 L/kg. In vitro, protein-binding of pyrazinamide to human whole plasma is approximately 40%. Its levels in CSF may reach 100% of the serum levels when given in combination with other tuberculostatics. It is extensively metabolized, first to pyrazinoic acid, the main metabolite, which is subsequently oxidized to 5-hydroxypyrazinoic acid by xanthine oxidase and 5-hydroxypyrazinamide. Maximum plasma concentrations of pyrazinoic acid are achieved within 4-8 hrs after administration of pyrazinamide. Pyrazinamide is eliminated from plasma with a t½ of 8-12 hrs in individual cases, when calculating the value in a strictly multiphasic way, a terminal elimination t½ of 23 hrs has been observed. It is mainly excreted in urine. Within 24 hrs, ≤4% appears as unchanged drug, the remainder as metabolites. Pyrazinoic acid constitutes about 40%, 5-hydroxypyrazinoic acid about 10% and 5-hydroxypyrazinamide about 15% of the dose. During hemodialysis, approximately 73% of the total isoniazid dose is removed.
Therapeutic Efficacy: Concentrations of 20-25 mcg/mL or higher are necessary to achieve optimum therapeutic efficacy. These levels can be maintained >6 hrs after daily therapeutic doses of 1-3 g and may last for up to 12 hrs. Impaired renal function has only negligible influence on the elimination of pyrazinamide and its metabolites are extracted during hemodialysis to a marked degree. Provided that pyrazinamide is given at the end of a hemodialysis session, it is unnecessary to reduce the usual dose in such patients. In the presence of hepatic cirrhotic insufficiency, the metabolic clearance is drastically diminished, resulting in a reduction of the total clearance by about ½, and in a considerable prolongation of the elimination half-life of pyrazinamide. For pyrazinoic acid, the main metabolite, AUC values are nearly 3 times higher and the elimination half-life is twice as long compared with healthy controls, resulting in markedly increased plasma concentrations. The dose must be reduced by about ½ and the biologic hepatic parameters closely monitored, together with the renal excretion of uric acid.
Carcinogenicity: Preclinical Safety Data: Rifampicin: There is only limited evidence as to the carcinogenicity potential of rifampicin in animals. After oral administration to 2 mouse strains, a significant increase in benign and malignant liver-cell tumors was observed after 1 year of treatment with rifampicin in quantities equivalent to 2-10 times the maximum clinical doses in female animals of 1 strain (known to be susceptible to hepatomas) only. No evidence of carcinogenicity was observed in females of the other strain or in male animals of both strains, as well as in rats of both sexes treated for 2 years.
Isoniazid: Limited evidence in animals shows that isoniazid produces lung tumors in mice after various modes of administration. Available evidence of human exposure has not suggested that isoniazid is carcinogenic in man at doses applicable to treatment and prophylaxis of tuberculosis.
Pyrazinamide: In a lifetime bioassay, pyrazinamide was not carcinogenic in rats or male mice, and no conclusion was possible for female mice due to the poor survival and small size of the matching control group.
Mutagenicity: In various short-term in vitro and in vivo tests in animals, rifampicin did not induce mutagenic effects. A slight increase in the occurrence of chromosome aberrations may be seen in human blood cell cultures, according to the evaluation method used.
Isoniazid, besides having weak direct genotoxic activity, is a promutagen in the sense that formation of the toxic metabolites, hydrazine and acetylhydrazine, is the 1st step in metabolic activation. In lymphocytes of patients treated with isoniazid, no chromosomal aberrations could be detected, whereas in a study comparing the effects of combination treatment, an increased frequency of chromosomal aberrations was observed.
There was an increase in chromosomal aberrations in lymphocytes of tuberculosis patients after treatment with a combination of rifampicin-isoniazid-pyrazinamide and in lymphocyte cultures exposed to pyrazinamide alone from normal subjects.
MedsGo Class
Anti-TB Agents
Features
Brand
Rimactazid
Full Details
Dosage Strength
450mg / 400mg
Drug Ingredients
- Isoniazid
- Rifampicin
Drug Packaging
Film-Coated Tablet 1's
Generic Name
Isoniazid / Rifampicin
Dosage Form
Film-Coated Tablet
Registration Number
DRP-5099
Drug Classification
Prescription Drug (RX)
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