DOSE OF MIDAZOLAM SHOULD BE REDUCED DURING DILTIAZEM AND VERAPAMIL TREATMENTS

1 The effects of diltiazem and verapamil on the pharmacokinetics and p harmacodynamics of midazolam were investigated in a double-blind rando mized cross-over study of three phases. 2 Nine healthy volunteers were given orally diltiazem (60 mg), verapamil (80 mg) or placebo three ti mes daily for 2 days. On the second day they received a 15 mg oral dos e of midazolam, after which plasma samples were collected and performa nce tests carried out for 17 h. 3 The area under the midazolam concent ration-time curve was increased from 12 +/- 1 mu g ml(-1) min to 45 +/ - 5 mu g ml(-1) min by diltiazem (P < 0.001) and to 35 +/- 5 mu g ml(- 1)diltiazem (P < 0.001) and to 35 +/- 5 mu g 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 di ltiazem and verapamil treatments. 4 These changes in the pharmacokinet ics of midazolam were also associated with profound and prolonged seda tive effects. 5 If the administration of midazolam cannot be avoided, the dose of midazolam should be reduced during concomitant treatment w ith diltiazem and verapamil.