phenytoin and rifampicin

Rifampicin is a potent inducer of hepatic cytochrome P450 enzymes, particularly CYP2C9 and CYP2C19, which are the main enzymes responsible for the metabolism of phenytoin. Induction increases the rate of phenytoin metabolism, leading to a significant decrease in its plasma concentrations.

Co-administration can cause a marked reduction in phenytoin serum levels, potentially leading to loss of seizure control and breakthrough seizures. The effect may develop within days to weeks of starting rifampicin and persist for a similar period after its discontinuation.

Avoid the combination if possible. If co-administration is necessary, closely monitor phenytoin plasma concentrations and observe for signs of reduced efficacy. Phenytoin dosage may need substantial upward adjustment, often by two- to three-fold, based on therapeutic drug monitoring. After stopping rifampicin, phenytoin levels may rise, requiring dose reduction to avoid toxicity. Consider alternative antiepileptics or anti-tuberculosis drugs when feasible.

This interaction is well established in clinical practice and supported by numerous case reports and pharmacokinetic studies.