Isoniazid with carbamazepine

Rifampicin is an enzyme inducer and can increase the incidence and severity of isoniazid-induced hepatitis. Carbamazepine is an enzyme induction agent and interacts with isoniazid, increasing its hepatotoxicity. Isoniazid toxicity is associated with fast acetylator genotype. Although his phenotype was unknown, the interaction with carbamazepine increases risk of this toxicity. 

Increased effect with isoniazid, nicotinamide, phenytoin Decreased effect with carbamazepine, ethosuximide... 

Why should concurrent therapy with carbamazepine and isoniazid be monitored closely ... 

Anti-infective drugs Ciprofloxacin can greatly increase the risk of seizure induction in patients taking anticonvulsants. Erythromycin produces a rapid 100-200% rise in carbamazepine levels. There is a possibility of reduced plasma levels of the protease inhibitors indinavir and saquinavir with carbamazepine. Isoniazid increases carbamazepine serum levels, and leads to the possible emergence of toxicity (disorientation and aggression). Mefloquine may antagonize the anticonvulsant effect of carbamazepine. Ritonavir, a protease inhibitor, may cause toxicity by raising carbamazepine plasma levels. 

Drugs that may interact with isoniazid include acetaminophen, carbamazepine, chlorzoxazone, disulfiram, enflurane, hydantoins, ketoconazole, rifampin, and theophylline. 

Only a few well-documented drug combinations with phenytoin may necessitate dosage adjustment. Coadministration of the following drugs can result in elevations of plasma phenytoin levels in most patients cimetidine, chloramphenicol, disulfiram, sulthiame, and isoniazid (in slow acetylators). Phenytoin often causes a decline in plasma carbamazepine levels if these two drugs are given concomitantly. 

Ethosuximide Ethosuximide interacts with isoniazid, phenytoin, phenobarbi-tone, carbamazepine, valproic acid, antipsychotics, and antidepressants.193... 

Isoniazid can cause convulsions and therefore should be prescribed with caution in patients with epilepsy. Isoniazid is an enzyme inhibitor and may increase carbamazepine levels. Rifampicin is an enzyme inducer and may decrease carbamazepine levels. 

Valsalan VC, Cooper GL. Carbamazepine intoxication caused by interaction with isoniazid. BMJ (Clin Res Ed) 1982 285(6337) 261-2. 

Clinically important, potentially hazardous interactions with aluminum, aminophylline, carbamazepine, carbimazole, cyclosporine, daclizumab, diuretics, etoposide, etretinate, grapefruit juice, indomethacin, isoniazid, itraconazole, ketoconazole, licorice, live vaccines, methotrexate, naproxen, oral contraceptives, pancuronium, phenobarbital, phenytoin, rifampicin, troleandomycin... 

The following drugs have been commonly associated with inducing, aggravating or unmasking SLE beta-blockers, carbamazepine, chlorpromazine, estrogens, griseofulvin, hydralazine, isoniazid (INH), lithium, methyldopa, minoxidil, oral contraceptives, penicillamine, phenytoin (diphenylhydantoin), procainamide, propylthiouracil, quinidine, and testosterone. 

Carbamazepine is metabolized to an active 10,11-epoxide metabolite, thus medications that inhibit 3A4 isoenzymes may result in carbamazepine toxicity (e.g., cimetidine, dUtiazem, erythromycin, fluoxetine, fluvoxamine, isoniazid, itraconazole, ketoconazole, nefa-zodone, propoxyphene, and verapamil). " When carbamazepine is combined with valproate, the carbamazepine dose should be reduced because valproate displaces carbamazepine from protein binding sites, thus increasing free levels." Combining clozapine and carbamazepine is not recommended because of the possibdity of bone marrow suppression with both agents. ... 

Transient elevations of the serum transaminases occur in 12% to 15% of patients receiving isoniazid and usually occur within the first 8 to 12 weeks of therapy. Overt hep ato toxicity, however, occurs in only 1% of cases. Risk factors for hepatotoxicity include patient age, preexisting liver disease, excessive alcohol intake, pregnancy, and the postpartum state. Isoniazid also may result in neurotoxicity, most frequently presenting as peripheral neuropathy or, in overdose, as seizures and coma. Patients with pyridox-ine deficiency, such as pregnant women, alcoholics, children, and the malnourished, are at increased risk. Isoniazid may inhibit the metabolism of phenytoin, carbamazepine, primidone, and warfarin." Patients who are being treated with these agents should be monitored closely, and appropriate dose adjustments should be made when necessary. 

Conversely, the steady-state carbamazepine levels of 7 epileptic patients receiving long-term treatment remained unaltered when they were given cimetidine 1 g daily for a week. Another study also showed a lack of an interaction in 11 epileptic patients. However, an 89-year-old woman taking carbamazepine 600 mg daily developed symptoms of carbamazepine toxicity within 2 days of starting to take cimetidine 400 mg daily, and had a rise in serum carbamazepine levels, which fell when the cimetidine was withdrawn. The effects of cimetidine may be additive with those of iso-niazid, see Carbamazepine + Isoniazid or Rifampicin (Rifampin) , below. 

Isoniazid-induced fulminant liver failure occurred in a 16-year-old girl taking carbamazepine and clonazepam, within 5 days of starting isoniazid, rifampicin and pyrazinamide. She recovered with supportive measures and later tolerated the antiepileptics with concurrent rifampicin and pyrazinamide. Isoniazid hepatotoxicity has also occurred in a 74-year-old woman and a 10-year-old boy" taking carbamazepine, shortly after treatment with isoniazid, rifampicin, and ethambutol, with or without pyrazinamide, was started. 

It seems probable that isoniazid inhibits the activity of the cytochrome P450 isoenzyme CYP3A4, which is concerned with the metabolism of carbamazepine, causing it to accumulate in the body. Rifampicin is a potent enzyme inducer, and would be expected to negate the effects of isoniazid, and to induce the metabolism of carbamazepine. This is supported by one report, but not another. 

Dold and Reichenmiller (1969) saw elevations of liver-specific enzymes, especially under the combination of isoniazid and antiepileptic drugs (diphenylhydan-toin or carbamazepine). Greenberg et al. (1972) describe a case of severe lupus erythematosus with tamponade of the pericardium after administration of isoniazid. 

Drug interactions anticonvulsants (phenytoin, barbiturates, carbamazepine) increase the risk of hepatotoxicity by increasing conversion of acetaminophen to toxic metabolites. Isoniazide also increases risk of acetaminophen hepatotoxicity. Acetaminophen may enhance the anticoagulant effect of warfarin with daily doses > 1.3 g for > 1 week. Phenothiazines may increase risk of severe hypothermia with acetaminophen. Cholestyramine resin may decrease the absorption of acetaminophen. 

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