Phenytoin and Midazolam Injection: Interaction Details

a) Carbamazepine and phenytoin greatly reduce the bioavailability of a single oral dose of midazolam. One study analyzed 6 patients with epilepsy and 7 healthy control subjects to determine the effects of carbamazepine and phenytoin on an oral dose of midazolam. Patients with epilepsy had been receiving either carbamazepine (dose range 700 mg to 900 mg daily), phenytoin (dose range 150 mg to 300 mg daily), or both drugs twice daily for at least 2 months. The control subjects were not receiving any enzyme-inducing agents. All study participants were administered a single oral dose of midazolam 15 mg. In the patient group, the mean midazolam AUC was only 5.7% (0.60 mcg/min/mL vs 10.5 mcg/min/mL) and the Cmax was 7.4% (5.2 nanograms/mL vs 70.4 nanograms/mL) of the control values. In one patient, only traces of midazolam (less than 0.1 nanograms/mL) were detectable in the plasma. The t(1/2) of midazolam was reduced to 1.3 hours in the patient group compared to 3.1 hours in the controls. There was no difference in Tmax (1 hour) between the two groups. As expected from the reduced serum concentrations of midazolam, the majority of the patient group did not report any sedation. All of the subjects from the control group experienced sedative effects which lasted from 2 to 4 hours. The low midazolam plasma concentrations, decreased elimination half-life, and lack of sedative effects are most likely the result of CYP3A enzyme induction by carbamazepine and phenytoin, since midazolam is extensively metabolized by CYP3A enzymes during first-pass and elimination phases ¹.