Enhanced sedation or respiratory and cardiovascular depression may occur if Midazolam are given with other drugs that have CNS depressant properties such as alcohol antidepressants, antihistamines, antipsychotic, general anesthetics, other hypnotics or sedatives, and opioid analgesics.
Analgesics: Aspirin shortens the time to induce anesthetics with Midazolam possibly due to competition for plasma protein binding sites. Opioid analgesics maybe used with Midazolam in anesthetic or analgesics regimens. An additive sedative effect is to be expected but there are also reports of severe respiratory depression with Midazolam and fentayl or sudden hypotension with Midazolam and fentayl or sufentanil. The clearance of Midazolam appears to be reduced by fentanyl. Careful monitoring is required during concomitant administration of Midazolam with opioid and the dose of both drugs may need to be reduced. Synergic potentiation of the induction of anaesthesia has been reported between Midazolam and fentanyl, but Midazolam can diminish the analgesic effects of sufentanil.
Antibacterials: An increase in peak plasma concentrations of Midazolam with profound and prolonged sedation have been reported following administration of erythromycin. The use of Midazolam with erythromycin should be avoided or the dose of Midazolam reduced to 50 to 75%. Roxithromycin has some effects on the pharmacokinetics and pharmacodynamics of Midazolam but these changes were not clinically relevant. However, it was recommended that as a precaution the lowest possible dose of Midazolam should be used when given with roxithromycin. Ciprofloxacin can cause a significant rise in steady-state blood- Midazolam concentration. Rifampicin can decrease the half-life of Midazolam.
Antifungals: Ketoconazole and itraconazole can produce marked pharmacokinetic interactions with Midazolam and greatly increase the intensity and duration of action of the drug. It is recommended that the concomitant use of these antifungals and benzodiazepines should be avoided or the dose of benzodiazepines should be greatly reduced. Similarly, a less pronounced interaction occurs between fluconazole and Midazolam, but the dosage of the Midazolam should be reduced during concomitant use.
Antivirals: Concomitant use of Midazolam with HIV-protease inhibitors should be avoided.
Calcium-channel blockers: Peak plasma concentrations of Midazolam were doubled and the elimination half-life of Midazolam prolonged when Midazolam was administered to healthy subjects receiving diltiazem or verapamil. Concomitant use should be avoided or the dose of Midazolam reduced.
Clozapine: Cardiorespiratory collapse has been observed in patients taking both Clozapine and benzodiazepines. Hypersalivation associated with Clozapine and benzodiazepines may be exacerbated when these drugs are used together.
Gastrointestinal Drugs: Simultaneous administration of cimetidine (but not ranitidine) has been reported to reduce clearance of Midazolam. The sedative effect of benzodiazepines is enhanced by cisapride.
General Anaesthetics: A synergistic interaction has been demonstrated for the hypnotic effects of Midazolam and thiopental. Similar synergistic have been observed between Midazolam and both methohexital and propofol. Midazolam has also been reported to be able to produce a marked reduction in the concentration of halothane required for anaesthesia. The effects of Midazolam can be reversed by the benzodiazepines antagonist flumazenil.