Isoniazid Valproate

Drugs that can increase carbamazepine serum levels include cimetidine, danazol, diltiazem, erythromycin, felbamate, clarithromycin, fluoxetine, isoniazid, niacinamide, propoxyphene, ketaconazole, itraconazole, verapamil, valproate, troleandomycin, loratadine, nicotinamide, tricyclic antidepressants, SSRIs, nefazodone, protease inhibitors. 

Drugs that inhibit phenytoin metabolism (causing its plasma concentration to rise) include sodium valproate, cimetidine, co-trimoxazole, isoniazid, chloramphenicol, some NSAIDs, disulfiram. There is a considerable body of mediocre and contradictory data, the lesson of which is that possible interaction should be borne in mind wherever other drugs are prescribed to a patient taking phenytoin. 

Acute hepatocellular necrosis. This reaction varies from a transient disturbance of liver function tests to acute hepatitis. It can be induced by several drugs including general anaesthetics (halothane), antiepileptics (carbamazepine, phenytoin, sodium valproate, phenobarbital), antidepressants (MAO inhibitors), antiinflammatory drugs (indomethacin, ibuprofen), antimicrobials (isoniazid, sulphonamides, nitrofurantoin) and cardiovascular drugs (methyldopa, hydralazine). 

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. ... 

Therefore, plasma concentrations for drugs metabolized by these isoforms will be affected (see Chapter 10). Thus, the addition of phenytoin to an AED regimen can reduce their plasma levels by inducing their CYP3A4 metabolism for carbamazepine, felbamate, lamotrigine, oxcarbazepine, tiagabine, valproate, and zonisamide. Other drugs for which metabolism is induced by phenytoin include methadone, theophylline, warfarin, and oral contraceptives. On the other hand, plasma phenytoin levels are increased by carbamazepine, felbamate, cimetidine, warfarin, chloramphenicol, isoniazid, and disulfiram. Plasma phenytoin levels are decreased by rifampin, antacids, and valproate (free phenytoin levels remain the same). 

An isolated report describes the development of raised serum valproate levels and toxicity in a child given isoniazid while taking valproate. Another report describes raised hepatic enzymes and drowsiness in a patient taking both drugs. 

Another child who had been treated with valproate for several years was prescribed isoniazid for the treatment of tuberculosis. At the same time, seizures recurred, and the valproate was stopped and primidone 750 mg daily started. Seven months later seizures persisted, and she was admitted to hospital. Liver enzyme values were normal. Valproate 300 mg daily increased to 600 mg daily was added, and within 2 days she was vomiting and drowsy. After 5 days she had increased liver enzymes and her prothrombin time had fallen, so the valproate was stopped. Valproate levels were 81 micrograms/mL. It was speculated that the CNS effects and hepatic impairment were due to an interaction between the valproate and isoniazid. ... 

Jonville AP, Gauchez AS, Autret E, Billard C, Barbier P, Nsabiyumva F, Breteau M, Interaction between isoniazid and valproate a case of valproate overdosage. EurJ Clin Pharmacol (1991) 40,197-8. 

Stewart JT, Nesmith MW, Mattox KM. A case of valproate toxicity related to isoniazid. J Clin Psychopharmacol December 2012 32(6) 840-1. 

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