### Effect of Concomitant Use of Benzodiazepines and Opioids

The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression because of actions at different receptor sites in the CNS that control respiration. Benzodiazepines interact at GABAA sites, and opioids interact primarily at mu receptors. When benzodiazepines and opioids are combined, the potential for benzodiazepines to significantly worsen opioid-related respiratory depression exists. Monitor patients closely for respiratory depression and sedation.

### Other CNS Depressants

One case was reported of inadequate sedation with chloral hydrate and later with oral midazolam due to a possible interaction with methylphenidate administered chronically in a 2-year-old boy with a history of Williams syndrome. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate.

The sedative effect of midazolam HCl syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly opioids (e.g., morphine, meperidine, and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of midazolam HCl syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response [see DOSAGE AND ADMINISTRATION].

No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed.

### Inhibitors of CYP3A4 Isozymes

Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as diltiazem, erythromycin, fluconazole, itraconazole, ketoconazole, saquinavir, and verapamil were shown to significantly increase the Cmax and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when midazolam HCl syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated [see CLINICAL PHARMACOLOGY: Pharmacokinetics: Special Populations: Drug-Drug Interactions].

### Inducers of CYP3A4 Isozymes

Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and cause a markedly decreased Cmax and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering midazolam to patients receiving these medications and if necessary dose adjustments should be considered.