Isoniazid + Pyrazinamide + Rifampicin

Indications

Isoniazid + Pyrazinamide + Rifampicin is used for: Tuberculosis

Adult Dose

Oral Tuberculosis Adult: Isoniazid + Pyrazinamide + Rifampicin Initial Phase 2 months 30-37 kg: 2 tab daily; 38-54 kg: 3 tab daily; 55-70 kg: 4 tab daily; >71 kg: 5 tab daily. then Continuation Phase 4 months Isoniazid + Rifampicin 30-37 kg: 2 tab daily; 38-54 kg: 3 tab daily; 55-70 kg: 4 tab daily; >71 kg: 5 tab daily. Total Dosage Requirement: Rifampicin: 10 (8-12) mg/kg body mass/day. Isoniazid: 5 (4-6) mg/kg body mass/day. Pyrazinamide: 25 (20-30) mg/kg body mass/day.

Child Dose

Oral Tuberculosis Adult: Isoniazid + Pyrazinamide + Rifampicin Initial Phase 2 months upto 7 kg: 1 tab daily; 8-9 kg: 1.5 tab daily; 10-14 kg: 2 tab daily; 15-19 kg: 3 tab daily. 20-24 kg: 4 tab daily. 25-29 kg: 5 tab daily. then Continuation Phase 4 months Isoniazid + Rifampicin upto 7 kg: 1 tab daily; 8-9 kg: 1.5 tab daily; 10-14 kg: 2 tab daily; 15-19 kg: 3 tab daily. 20-24 kg: 4 tab daily. 25-29 kg: 5 tab daily.

Renal Dose

Administration

Should be taken on an empty stomach. Take on an empty stomach 1 hr before or 2 hr after meals. Avoid antacids w/in 1 hr of intake.

Contra Indications

Known or suspected hypersensitivity to rifamycins and/or to isoniazid and to pyrazinamide and/or to any of the excipients including a history of drug-induced hepatitis, acute liver diseases regardless of their origin, and peripheral neuritis.

Precautions

Caution is advised in patients with impaired renal or liver function, diabetes mellitus, chronic alcoholism and undernourished patients, patients with a history of gout and patients suffering from convulsive disorders and acute porphyria. Precautions need to be taken: Blood counts and liver function tests (SGPT, SGOT) should be performed periodically (especially in prolonged treatment) and at baseline, if possible. 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 attention should be paid to possible prodromal symptoms of hepatitis eg, fatigue, weakness, malaise, anorexia, nausea or 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.

Pregnancy-Lactation

Pregnancy Isoniazid: Embryocidal effects reported in both rats and rabbits, although no congenital abnormalities observed in mammalian offspring when given during pregnancy Pyrazinamide: Animal reproductive studies have not been conducted Rifampin No adequate and well-controlled studies have been performed in pregnant women; has been shown to be teratogenic in rodents Rifampin has been reported to cross the placental barrier and appear in cord blood When administered during the last few weeks of pregnancy, rifampin can cause postnatal hemorrhages in the mother and infant for which treatment with vitamin K may be indicated Use during pregnancy only if the potential benefit justifies the potential risk to the fetus Animal studies Congenital malformations, primarily spina bifida, were increased in offspring of pregnant rats given rifampin during organogenesis at oral doses of 150-250 mg/kg/day (~1-2 times the maximum recommended human dose [MRHD] based on body surface area comparisons) Cleft palate was increased in a dose-dependent fashion in fetuses of pregnant mice treated at oral doses of 50-200 mg/kg (~0.2-0.8 times MRHD) Imperfect osteogenesis and embryotoxicity were also reported in pregnant rabbits given rifampin at oral doses up to 200 mg/kg/day (~3 times MRHD) Lactation Isoniazid is known to be secreted into breast milk Because of potential for tumorigenicity shown for rifampin in animal studies, a decision should be made whether to discontinue nursing or discontinue drug, taking into account importance of drug to mother

Interactions

Rifampicin may reduce effectivity of hormonal contraceptives, ACE inhibitors (e.g. enalapril, imidapril), antiemetics (e.g. aprepitant), antineoplastics (e.g. imatinib), diuretics (e.g. eplerenone), drugs for erectile dysfunction (e.g. tadalafil), oral hypoglycaemics (e.g. nateglinide, repaglinide), NSAIDs (e.g. etoricoxib). Rifampicin may reduce serum levels of atovaquone, ketoconazole. Antacids may reduce absorption of rifampicin. Anaesthetics and halothane may increase risk for hepatotoxicity w/ rifampicin and isoniazid. Isoniazid may increase serum levels of phenytoin and theophylline; and may decrease carbamazepine metabolism. Stavudine may increase risk of distal sensory neuropathy w/ isoniazid. Antacids may reduce isoniazid absorption. May increase plasma levels of isoniazid w/ para-aminosalicylic acid. Increased risk of CNS toxicity when isoniazid is used concomitantly w/ cycloserine. Pyrazinamide antagonizes the effects of probenecid and sulfinpyrazone. Potentially Fatal: Concominant use w/ saquinavir/ritonavir may increase risk of severe hepatotoxicity. May reduce antiviral efficacy of atazanavir, darunavir, fosamprenavir, saquinavir, or tipranavir

Adverse Effects

Side effects of Isoniazid + Pyrazinamide + Rifampicin : Unwanted effects which may occur during continuous daily or intermittent therapy: Rifampicin: Rifampicin may cause reddish discolouration of body fluids and occasionally other body secretions eg, urine, sputum, lacrimal fluid, faeces, saliva and sweat. It may permanently discolour soft contact lenses. Hepatic Effects: Very common (>10%) is an asymptomatic increase in liver enzymes; severe life-threatening hepatic reactions eg, hepatic failure and acute fulminant hepatitis are uncommon (>0.1% and <1%). In isolated cases (<0.01%), a fatal outcome was observed. Renal Effects: Elevations of BUN and serum uric acid, haemolysis, haematuria, interstitial nephritis, renal insufficiency. Gastrointestinal Effects: Nausea, abdominal pains, vomiting or diarrhoea, pseudomembranous colitis. Central and Peripheral Nervous System Effects: Tiredness, drowsiness, headache, dizziness, ataxia, mental confusion, muscular weakness, visual disturbances. Haematological Changes: Leucopenia, eosinophilia, thrombocytopenia and thrombocytopenic purpura. Effects on Skin and Appendages: Flushing, itching with or without skin rash, urticaria, reddening of the eyes, exudative conjunctivitis or generalised hypersensitivity reactions involving the skin eg, exfoliative dermatitis, Lyell's syndrome and pemphigoid reactions. Endocrine Effects: Disturbances in the menstrual cycle, induction of crisis in Addison patients. Unwanted effects chiefly occurring during intermittent therapy or upon resumption of treatment after temporary interruption:

Mechanism of Action

Rifampicin, isoniazid and pyrazinamide are all active bactericidal antituberculosis drugs. Rifampicin and isoniazid are particularly active against the rapidly growing extracellular organisms and have an intracellular bactericidal activity. Rifampicin also inhibits DNA-dependent RNA polymerase activity in susceptible cells and it has activity against slow and intermittently-growing M tuberculosis. Pyrazinamide, particularly in the acid pH environment of macrophages is active against intracellular organisms. Combination of these agents covers activity against the 3 different bacterial populations.