Isoniazid warnings and precautions

Isoniazid
ISONIAZID® FDA Package Insert
Description
Clinical Pharmacology
Microbiology
Indications and Usage
Contraindications
Warnings and Precautions
Adverse Reactions
Overdosage
Dosage and Administration
How Supplied

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Chetan Lokhande, M.B.B.S [2]

Warnings

WARNING Severe and sometimes fatal hepatitis associated with isoniazid therapy has been reported and may occur or may develop even after many months of treatment. The risk of developing hepatitis is age related. Approximate case rates by age are: less than 1 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. For persons 35 and older, in addition to monthly symptom reviews, hepatic enzymes (specifically, AST and ALT (formerly SGOT and SGPT, respectively)) should be measured prior to starting isoniazid therapy and periodically throughout treatment. Isoniazid-associated hepatitis usually occurs during the first three months of treatment. Usually, enzyme levels return to normal despite continuance of drug, but in some cases progressive liver dysfunction occurs. Other factors associated with an increased risk of hepatitis include daily use of alcohol, chronic liver disease and injection drug use. A recent report suggests an increased risk of fatal hepatitis associated with isoniazid among women, particularly black and Hispanic women. The risk may also be increased during the post-partum period. More careful monitoring should be considered in these groups, possibly including more frequent laboratory monitoring. If abnormalities of liver function exceed three to five times the upper limit of normal, discontinuation of isoniazid should be strongly considered. Liver function tests are not a substitute for a clinical evaluation at monthly intervals or for the prompt assessment of signs or symptoms of adverse reactions occurring between regularly scheduled evaluations. Patients should be instructed to immediately report signs or symptoms consistent with liver damage or other adverse effects. These include any of the following: unexplained anorexia, nausea, vomiting, dark urine, icterus, rash, persistent paresthesias of the hands and feet, persistant fatigue, weakness or fever of greater than 3 days duration and/or abdominal tenderness, especially right upper quadrant discomfort. 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 who have hepatitis attributed to isoniazid 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. Preventive treatment should be deferred in persons with acute hepatic diseases.

Precautions

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 > 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 post-partum period.
• HIV seropositive patients.

Laboratory Tests

Because there is a higher frequency of isoniazid associated hepatitis among certain patient groups, including age > 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.

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 rats1,2.

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 made3.

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% after 5 months of concurrent isoniazid and rifampin therapy4.

Phenytoin

Isoniazid may increase serum levels of phenytoin. To avoid phenytoin intoxication, appropriate adjustment of the anticonvulsant should be made5,6.

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 made7.

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 made8.

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: Pregnancy Category C

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 can not be relied upon for prophylaxis or therapy of nursing infants.

References

Adapted from the FDA Package Insert.