Interactions between midazolam-hydrochloride(midazolam) and Atazanavir (atazanavir)
midazolam and atazanavir (Major Drug-Drug)
CONTRAINDICATED: Coadministration with protease inhibitors (PIs) may significantly increase the plasma concentrations and pharmacologic effects of orally administered midazolam and triazolam. The mechanism is PI inhibition of intestinal and hepatic CYP450 3A4, the isoenzyme primarily responsible for the metabolic clearance of these benzodiazepines. Within the class, ritonavir is the most potent CYP450 3A4 inhibitor, while saquinavir is considered one of the weaker ones. In six healthy volunteers, ritonavir (200 mg twice a day for 2 days) nearly doubled the peak plasma concentration (Cmax) of triazolam (0.125 mg single dose) and increased its systemic exposure (AUC) and elimination half-life by 20- and 14-fold, respectively, compared to placebo. Ritonavir also decreased triazolam clearance to less than 4% of control values. In 12 healthy volunteers, the Cmax and AUC of oral midazolam (7.5 mg single dose) increased by more than 2- and 5-fold, respectively, during coadministration with saquinavir (soft gelatin capsule 1200 mg three times a day for 5 days) relative to placebo, while oral bioavailability increased from 41% to 90%. The AUC of intravenous midazolam (0.05 mg/kg single dose) increased 2.4-fold, and mean plasma clearance decreased by 56%. In both studies, the pharmacokinetic changes were accompanied by increased sedation and impairment of psychomotor performance.
MANAGEMENT: Given the potential for prolonged and/or increased sedation and respiratory depression associated with excessive benzodiazepine blood levels, concomitant use of oral midazolam or triazolam with protease inhibitors is considered contraindicated. Caution and close clinical monitoring are recommended when administering parenteral midazolam in combination with protease inhibitors. Appropriate medical management should be readily available in case of respiratory depression and/or prolonged sedation. Dosage adjustment for midazolam may be appropriate, especially if more than a single dose of midazolam is administered.
