Isoniazid

Isoniazid oral solution is recommended for all forms of tuberculosis in which organisms are susceptible. However, active tuberculosis must be treated with multiple concomitant anti-tuberculosis medications to prevent the emergence of drug resistance. Single-drug treatment of active tuberculosis with isoniazid or any other medication is inadequate therapy. Isoniazid oral solution is recommended as preventive therapy for the following groups, regardless of age. (Note: the criterion for a positive reaction to a skin test (in millimeters of induration) for each group is given in parentheses): Persons with human immunodeficiency virus (HIV) infection (greater than or equal to 5 mm) and persons with risk factors for HIV infection whose HIV infection status is unknown but who are suspected of having HIV infection. Preventive therapy may be considered for HIV infected persons who are tuberculin-negative but belong to groups in which the prevalence of tuberculosis infection is high. Candidates for preventive therapy who have HIV infection should have a minimum of 12 months of therapy. Close contacts of persons with newly diagnosed infectious tuberculosis (greater than or equal to 5 mm). In addition, tuberculin-negative (less than 5 mm) children and adolescents who have been close contacts of infectious persons within the past 3 months are candidates for preventive therapy until a repeat tuberculin skin test is done 12 weeks after contact with the infectious source. If the repeat skin test is positive (greater than 5 mm), therapy should be continued. Recent converters, as indicated by a tuberculin skin test (greater than or equal to 10 mm increase within a 2-year period for those less than 35 years old; greater than or equal to 15 mm increase for those greater than or equal to 35 years of age). All infants and children younger than 4 years of age with a greater than 10 mm skin test are included in this category. Persons with abnormal chest radiographs that show fibrotic lesions likely to represent old healed tuberculosis (greater than or equal to 5 mm). Candidates for preventive therapy who have fibrotic pulmonary lesions consistent with healed tuberculosis or who have pulmonary silicosis should have 12 months of isoniazid or 4 months of isoniazid and rifampin, concomitantly. Intravenous drug users known to be HIV-seronegative (greater than 10 mm). Persons with the following medical conditions that have been reported to increase the risk of tuberculosis (greater than or equal to 10 mm): silicosis; diabetes mellitus; prolonged therapy with adrenocorticosteroids; immunosuppressive therapy; some hematologic and reticuloendothelial diseases, such as leukemia or Hodgkin's disease; end-stage renal disease; clinical situations associated with substantial rapid weight loss or chronic undernutrition (including: intestinal bypass surgery for obesity, the postgastrectomy state [with or without weight loss], chronic peptic ulcer disease, chronic malabsorption syndromes and carcinomas of the oropharynx and upper gastrointestinal tract that prevent adequate nutritional intake). Candidates for preventive therapy who have fibrotic pulmonary lesions consistent with healed tuberculosis or who have pulmonary silicosis should have 12 months of isoniazid or 4 months of isoniazid and rifampin, concomitantly. Additionally, in the absence of any of the above risk factors, persons under the age of 35 with a tuberculin skin test reaction of 10 mm or more are also appropriate candidates for preventive therapy if they are a member of any of the following high-incidence groups: Foreign-born persons from high-prevalence countries who never received BCG vaccine. Medically underserved low-income populations, including high-risk racial or ethnic minority populations, especially blacks, Hispanics and Native Americans. Residents of facilities for long-term care (e.g., correctional institutions, nursing homes and mental institutions). Children who are less than 4 years old are candidates for isoniazid preventive therapy if they have greater than 10 mm induration from a PPD Mantoux tuberculin skin test. Finally, persons under the age of 35 who a) have none of the above risk factors (1 to 6); b) belong to none of the high-incidence groups; and c) have a tuberculin skin test reaction of 15 mm or more, are appropriate candidates for preventive therapy. The risk of hepatitis must be weighed against the risk of tuberculosis in positive tuberculin reactors over the age of 35. However, the use of isoniazid is recommended for those with the additional risk factors listed above (1 to 6) and on an individual basis in situations where there is likelihood of serious consequences to contacts who may become infected.

Isoniazid is contraindicated in patients who develop severe hypersensitivity reactions, including drug-induced hepatitis; previous isoniazid-associated hepatic injury; severe adverse reactions to isoniazid such as drug fever, chills, arthritis; and acute liver disease of any etiology.

See the boxed warning.

General All drugs should be stopped and an evaluation made at the first sign of a hypersensitivity reaction. If isoniazid therapy must be reinstituted, the drug should be given only after symptoms 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 hypersensitivity reaction. Use of isoniazid should be carefully monitored in the following: Daily users of alcohol. Daily ingestion of alcohol may be associated with a higher incidence of + isoniazid hepatitis. Patients with active chronic liver disease or severe renal dysfunction. Age greater than 35. Concurrent use of any chronically administered medication. History of previous discontinuation of isoniazid. Existence of peripheral neuropathy or conditions predisposing to neuropathy. Pregnancy. Injection drug use. Women belonging to minority groups, particularly in the postpartum period. HIV seropositive patients. Laboratory Tests Because there is a higher frequency of isoniazid associated hepatitis among certain patient groups, including Age greater than 35, daily users of alcohol, chronic liver disease, injection drug use and women belonging to minority groups, particularly in the post-partum period, transaminase measurements should be obtained prior to starting and monthly during preventative therapy or more frequently as needed. If any of the values exceed three to five times the upper limit of normal, isoniazid should be temporarily discontinued and consideration given to restarting therapy. Drug Interactions Food Isoniazid should not be administered with food. Studies have shown that the bioavailability of isoniazid is reduced significantly when administered with food. Tyramine- and histamine-containing foods should be avoided in patients receiving isoniazid. Because isoniazid has some monoamine oxidase inhibiting activity, an interaction with tyramine-containing foods (cheese, red wine) may occur. Diamine oxidase may also be inhibited, causing exaggerated response (e.g., headache, sweating, palpitations, flushing, hypotension) to foods containing histamine (e.g., skipjack, tuna, other tropical fish). Acetaminophen A report of severe acetaminophen toxicity was reported in a patient receiving Isoniazid. It is believed that the toxicity may have resulted from a previously unrecognized interaction between isoniazid and acetaminophen and a molecular basis for this interaction has been proposed. However, current evidence suggests that isoniazid does induce P-450IIE1, a mixed-function oxidase enzyme that appears to generate the toxic metabolites, in the liver. Furthermore it has been proposed that isoniazid resulted in induction of P-450IIE1 in the patient's liver which, in turn, resulted in a greater proportion of the ingested acetaminophen being converted to the toxic metabolites. Studies have demonstrated that pretreatment with isoniazid potentiates acetaminophen hepatotoxicity in rats 1,2 . Carbamazepine Isoniazid is known to slow the metabolism of carbamazepine and increase its serum levels. Carbamazepine levels should be determined prior to concurrent administration with isoniazid, signs and symptoms of carbamazepine toxicity should be monitored closely and appropriate dosage adjustment of the anticonvulsant should be made 3 . Ketoconazole Potential interaction of ketoconazole and isoniazid may exist. When ketoconazole is given in combination with isoniazid and rifampin the AUC of ketoconazole is decreased by as much as 88 percent after 5 months of concurrent isoniazid and rifampin therapy 4 . Phenytoin Isoniazid may increase serum levels of phenytoin. To avoid phenytoin intoxication, appropriate adjustment of the anticonvulsant should be made 5,6 . Theophylline A recent study has shown that concomitant administration of isoniazid and theophylline may cause elevated plasma levels of theophylline and in some instances a slight decrease in the elimination of isoniazid. Since the therapeutic range of theophylline is narrow, theophylline serum levels should be monitored closely and appropriate dosage adjustments of theophylline should be made 7 . Valproate A recent case study has shown a possible increase in the plasma level of valproate when co-administered with isoniazid. Plasma valproate concentration should be monitored when isoniazid and valproate are co-administered and appropriate dosage adjustments of valproate should be made 5 . Carcinogenesis and Mutagenesis Isoniazid has been shown to induce pulmonary tumors in a number of strains of mice. Isoniazid has not been shown to be carcinogenic in humans. (Note: a diagnosis of mesothelioma in a child with prenatal exposure to isoniazid and no other apparent risk factors has been reported). Isoniazid has been found to be weakly mutagenic in strains TA 100 and TA 1535 of Salmonella typhimurium (Ames assay) without metabolic activation. Pregnancy . Teratogenic Effects Isoniazid has been shown to have an embryocidal effect in rats and rabbits when given orally during pregnancy. Isoniazid was not teratogenic in reproduction studies in mice, rats and rabbits. There are no adequate and well-controlled studies in pregnant women. Isoniazid should be used as a treatment for active tuberculosis during pregnancy because the benefit justifies the potential risk to the fetus. The benefit of preventive therapy also should be weighed against a possible risk to the fetus. Preventive therapy generally should be started after delivery to prevent putting the fetus at risk of exposure; the low levels of isoniazid in breast milk do not threaten the neonate. Since isoniazid is known to cross the placental barrier, neonates of isoniazid treated mothers should be carefully observed for any evidence of adverse effects. Nonteratogenic Effects Since isoniazid is known to cross the placental barrier, neonates of isoniazid-treated mothers should be carefully observed for any evidence of adverse effects. Nursing Mothers . The small concentrations of isoniazid in breast milk do not produce toxicity in the nursing newborn; therefore, breast feeding should not be discouraged. However, because levels of isoniazid are so low in breast milk, they cannot be relied upon for prophylaxis or therapy of nursing infants.

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 most often in the malnourished and in those predisposed to neuritis (e.g., alcoholics and diabetics) and is usually preceded 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. Hepatic Reactions See boxed warning . Elevated serum transaminase (SGOT; SGPT), bilirubinemia, bilirubinuria, jaundice and occasionally severe and sometimes fatal hepatitis. The common prodromal symptoms of hepatitis are anorexia, nausea, vomiting, fatigue, malaise and weakness. Mild hepatic dysfunction, evidenced by mild and transient elevation of serum transaminase levels occurs in 10 to 20 percent of patients taking isoniazid. This abnormality usually appears in the first 1 to 3 months of treatment but can occur at any time during therapy. In most instances, enzyme levels return to normal, and generally, there is no necessity to discontinue medication during the period of mild serum transaminase elevation. In occasional instances, progressive liver damage occurs, with accompanying symptoms. If the SGOT value exceeds three to five times the upper limit of normal, discontinuation of the isoniazid should be strongly considered. The frequency of progressive liver damage increases with age. It is rare in persons under 20, but occurs in up to 2.3 percent of those over 50 years of age. Gastrointestinal Reactions Nausea, vomiting, epigastric distress, and pancreatitis. Hematologic Reactions Agranulocytosis; hemolytic, sideroblastic or aplastic anemia, thrombocytopenia; and eosinophilia. Hypersensitivity Reactions Fever, skin eruptions (morbilliform, maculopapular, purpuric or exfoliative), lymphadenopathy, vasculitis, toxic epidermal necrolysis, and drug reaction with eosinophilia syndrome (DRESS). Metabolic and Endocrine Reactions Pyridoxine deficiency, pellagra, hyperglycemia, metabolic acidosis and gynecomastia. Miscellaneous Reactions Rheumatic syndrome and systemic lupus erythematosus-like syndrome. To report SUSPECTED ADVERSE REACTIONS, contact Chartwell RX, LLC. at 1-845-232-1683 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.