FDA label 0675dfb3-cc96-4401-8168-bdda5dbdb6c5

WARNING Severe and sometimes fatal hepatitis associated with isoniazid therapy may occur and may develop even after many months of treatment. The risk of developing hepatitis is age related. Approximate case rates by age are: 0 per 1,000 for persons under 20 years of age, 3 per 1,000 for persons in the 20-34 year age group, 12 per 1,000 for persons in the 35-49 year age group, 23 per 1,000 for persons in the 50-64 year age group, and 8 per 1,000 for persons over 65 years of age. The risk of hepatitis is increased with daily consumption of alcohol. Precise data to provide a fatality rate for isoniazid-related hepatitis is not available; however, in a U.S. Public Health Service Surveillance Study of 13,838 persons taking isoniazid, there were 8 deaths among 174 cases of hepatitis. Therefore, patients given isoniazid should be carefully monitored and interviewed at monthly intervals. Serum transaminase concentration becomes elevated in about 10-20 percent of patients, usually during the first few months of therapy, but it can occur at any time. Usually enzyme levels return to normal despite continuance of drug, but in some cases progressive liver dysfunction occurs. Patients should be instructed to report immediately any of the prodromal symptoms of hepatitis, such as fatigue, weakness, malaise, anorexia, nausea, or vomiting. If these symptoms appear or if signs suggestive of hepatic damage are detected, isoniazid should be discontinued promptly, since continued use of the drug in these cases has been reported to cause a more severe form of liver damage. Patients with tuberculosis should be given appropriate treatment with alternative drugs. If isoniazid must be reinstituted, it should be reinstituted only after symptoms and laboratory abnormalities have cleared. The drug should be restarted in very small and gradually increasing doses and should be withdrawn immediately if there is any indication of recurrent liver involvement. Treatment should be deferred in persons with acute hepatic diseases.

WARNINGS Rifampin and isoniazid capsules are a combination of two drugs, each of which has been associated with liverdysfunction. Liver function tests should be performed prior to therapy with rifampin/isoniazid and periodicallyduring treatment. Rifampin Rifampin has been shown to produce liver dysfunction. There have been fatalities associated with jaundice inpatients with liver disease or receiving rifampin concomitantly with other hepatoxic agents. Since an increased riskmay exist for individuals with liver disease, benefits must be weighed carefully against the risk of further liver damage. Several studies of tumorigenicity potential have been done in rodents. In one strain of mice known to be particularlysusceptible to the spontaneous development of hepatomas, rifampin given at a level 2-10 times the maximumdosage used clinically resulted in a significant increase in the occurrence of hepatomas in female mice of this strainafter one year of administration. There was no evidence of tumorigenicity in the males of this strain, in males or females of another mouse strain, orin rats. Isoniazid See the boxed warning .

ADVERSE REACTIONS Rifampin Nervous system reactions: headache, drowsiness, fatigue, ataxia, dizziness, inability to concentrate, mental confusion,visual disturbances, muscular weakness, pain in extremities, and generalized numbness. Gastrointestinal disturbances: in some patients heartburn, epigastric distress, anorexia, nausea, vomiting, gas,cramps, and diarrhea. Hepatic reactions: transient abnormalities in liver function tests (e.g., elevations in serum bilirubin, BSP, alkalinephosphatase, serum transaminases) have been observed. Rarely, hepatitis or a shock-like syndrome with hepaticinvolvement and abnormal liver function tests. Renal reactions: elevations in BUN and serum uric acid have been reported. Rarely, hemolysis, hemoglobinuria, hematuria, interstitial nephritis, renal insufficiency, and acute renal failure have been noted. These are generallyconsidered to be hypersensitivity reactions. They usually occur during intermittent therapy or when treatment isresumed following intentional or accidental interruption of a daily dosage regimen, and are reversible when rifampinis discontinued and appropriate therapy instituted. Hematologic reactions: thrombocytopenia, transient leukopenia, hemolytic anemia; eosinophilia, and decreasedhemoglobin have been observed. Thrombocytopenia has occurred when rifampin and ethambutol were administeredconcomitantly according to an intermittent dose schedule twice weekly and in high doses. Allergic and immunological reactions: occasionally pruritus, urticaria, rash, pemphigoid reaction, eosinophilia,sore mouth, sore tongue, and exudative conjunctivitis. Rarely, hemolysis, hemoglobinuria, hematuria, renal insufficiencyor acute renal failure, have been reported which are generally considered to be hypersensitivity reactions.These have usually occurred during intermittent therapy or when treatment was resumed following intentional oraccidental interruption of a daily dosage regimen and were reversible when rifampin was discontinued and appropriatetherapy instituted. Although rifampin has been reported to have an immunosuppressive effect in some animal experiments, availablehuman data indicate that this has no clinical significance. Metabolic reactions: elevations in BUN and serum uric acid have occurred. Miscellaneous reactions: fever and menstrual disturbances have been noted. Isoniazid The most frequent reactions are those affecting the nervous system and the liver. Nervous system reactions: peripheral neuropathy is the most common toxic effect. It is dose-related; occurs mostoften in the malnourished and in those predisposed to neuritis (e.g., alcoholics and diabetics); and is usuallypreceded by paresthesias of the feet and hands. The incidence is higher in "slow inactivators." Other neurotoxic effects, which are uncommon with conventional doses are convulsions, toxic encephalopathy,optic neuritis and atrophy, memory impairment, and toxic psychosis. Gastrointestinal reactions: nausea, vomiting, and epigastric distress. Hepatic reactions: elevated serum transaminases (SGOT; SGPT), bilirubinemia, bilirubinuria, jaundice, andoccasionally severe and sometimes fatal hepatitis. The common prodromal symptoms are anorexia, nausea, vomiting, fatigue, malaise, and weakness. Mild and transient elevations of serum transaminase levels occur in 10 to 20percent of persons taking isoniazid. The abnormality usually occurs in the first 4 to 6 months of treatment but canoccur at any time during therapy. In most instances, enzyme levels return to normal with no necessity to discontinuemedication. In occasional instances, progressive liver damage occurs, with accompanying symptoms. In thesecases, the drug should be discontinued immediately. The frequency of progressive liver damage increases withage. It is rare in persons under 20, but occurs in up to 2.3 percent of those over 50 years of age. Hematologic reactions: agranulocytosis, hemolytic sideroblastic or aplastic anemia, thrombocytopenia, andeosinophilia. Hypersensitivity reactions: fever, skin eruptions (morbilliform, maculopapular, purpuric, or exfoliative), lymphadenopathy,and vasculitis. Metabolic and endocrine reactions: pyridoxine deficiency, pellagra, hyperglycemia, metabolic acidosis, andgynecomastia. Miscellaneous reactions: rheumatic syndrome and systemic lupus erythematosus-like syndrome.