Dose of midazolam should be reduced during diltiazem and verapamil treatments

Abstract

1. The effects of diltiazem and verapamil on the pharmacokinetics and pharmacodynamics of midazolam were investigated in a double-blind randomized cross-over study of three phases. 2. Nine healthy volunteers were given orally diltiazem (60 mg), verapamil (80 mg) or placebo three times daily for 2 days. On the second day they received a 15 mg oral dose of midazolam, after which plasma samples were collected and performance tests carried out for 17 h. 3. The area under the midazolam concentration-time curve was increased from 12 +/- 1 microgram ml-1 min to 45 +/- 5 micrograms ml-1 min by diltiazem (P < 0.001) and to 35 +/- 5 micrograms ml-1 min by verapamil (P < 0.001). The peak midazolam concentration was doubled (P < 0.01) and the elimination half-life of midazolam prolonged (P < 0.05) by both diltiazem and verapamil treatments. 4. These changes in the pharmacokinetics of midazolam were also associated with profound and prolonged sedative effects. 5. If the administration of midazolam cannot be avoided, the dose of midazolam should be reduced during concomitant treatment with diltiazem and verapamil.