1Experts recommend prolonged continuation phase (31 weeks) for patients with cavitation on initial chest radiograph and positive cultures at the end of the intensive treatment phase. 2May consider 5 days per week if needed for DOT. No studies compare 5 versus 7 doses per week, but extensive experience suggests efficacy of this regimen. DOT, directly observed therapy; EMB, ethambutol; HIV, human immunodeficiency virus; INH, isoniazid; PZA, pyrazinamide; RIF, rifampin.
preexisting hepatic insufficiency and should be guided by serum concentrations if a reduction in dose is contemplated. Isoniazid inhibits several cytochrome P450 enzymes, leading to increased concentrations of such medications as phenytoin, carbamazepine, and benzodiazepines. However, when used in combination with rifampin, a potent CYP enzyme inducer, the concentrations of these medications are usually decreased.
The typical dosage of isoniazid is 5 mg/kg/d; a typical adult dose is 300 mg given once daily. Up to 10 mg/kg/d may be used for serious infections or if malabsorption is a problem. A 15-mg/kg dose, or 900 mg, may be used in a twice to three times-weekly dosing regimen in combination with a second antituberculous agent (eg, rifampin, 600 mg). Pyridoxine, 25–50 mg/d, is recommended for those with conditions predisposing to neuropathy, an adverse effect of isoniazid. Isoniazid is usually given by mouth but can be given parenterally in the same dosage.
Isoniazid as a single agent is also indicated for treatment of latent tuberculosis. The dosage is 300 mg/d (5 mg/kg/d) or 900 mg twice weekly, and the duration is usually 9 months.
The incidence and severity of untoward reactions to isoniazid are related to dosage and duration of administration.
A. Immunologic Reactions
Fever and skin rashes are occasionally seen. Drug-induced systemic lupus erythematosus has been reported.
B. Direct Toxicity
Isoniazid-induced hepatitis is the most common major toxic effect. This is distinct from the minor increases in liver aminotransferases (up to three or four times normal), which do not require cessation of the drug and which are seen in 10–20% of patients, who usually are asymptomatic. Clinical hepatitis with loss of appetite, nausea, vomiting, jaundice, and right upper quadrant pain occurs in 1% of isoniazid recipients and can be fatal, particularly if the drug is not discontinued promptly. There is histologic evidence of hepatocellular damage and necrosis. The risk of hepatitis depends on age. It occurs rarely under age 20, in 0.3% of those age 21–35, 1.2% of those age 36–50, and 2.3% for those age 50 and above. The risk of hepatitis is greater in individuals with alcohol dependence and possibly during pregnancy and the postpartum period. Development of isoniazid hepatitis contraindicates further use of the drug.
Peripheral neuropathy is observed in 10–20% of patients given dosages greater than 5 mg/kg/d, but it is infrequently seen with the standard 300-mg adult dose. Peripheral neuropathy is more likely to occur in slow acetylators and patients with predisposing conditions such as malnutrition, alcoholism, diabetes, AIDS, and uremia. Neuropathy is due to a relative pyridoxine deficiency.