Darunavir × Zolpidem

Hepatic enzymes clear zolpidem, mainly CYP3A4 with a contribution from CYP1A2. Darunavir is always given with a booster, ritonavir or cobicistat, and the boosted combination strongly inhibits CYP3A4, so zolpidem concentration rises. The darunavir label lists zolpidem among sedatives/hypnotics that are 'extensively metabolised by CYP3A' and warns that their concentration may rise substantially. The pair itself was not studied. The zolpidem label confirms the direction: ketoconazole, a potent CYP3A4 inhibitor, raised zolpidem exposure 1.83-fold, prolonged its half-life and increased sedation. Zolpidem is not among the hypnotics contraindicated with darunavir; that list contains only triazolam and oral midazolam.

Expect a stronger and longer zolpidem effect: deeper drowsiness, slowed reactions, impaired attention and coordination, including the next morning and while driving. The risk of falls, confusion, amnesia and complex sleep behaviours rises: sleep-walking, sleep-driving, eating or phone calls with no memory of them. Alcohol, opioids and other central nervous system (CNS) depressants add to the sedation, and with opioids the risk of respiratory depression grows.

The combination is not banned. Among hypnotics, only triazolam and oral midazolam are contraindicated with darunavir, and zolpidem is not on that list (darunavir label, EMA, 4.3). The EMA label recommends clinical monitoring and asks to consider a lower zolpidem dose (darunavir label, EMA, 4.5). The FDA label says the same: titration, a lower dose and monitoring for adverse events (darunavir label FDA, 7). The documents name no specific reduced dose. The zolpidem label has two doses: the usual 10 mg, and 5 mg for elderly or debilitated patients and in hepatic impairment, with a ceiling of 10 mg per night (zolpidem label, 4.2). It does not require a systematic dose reduction with potent CYP3A4 inhibitors but asks to warn the patient about stronger sedation (zolpidem label, 4.5); the FDA label suggests considering a lower zolpidem dose (zolpidem label FDA, 7.2). Zolpidem is taken once, right before bedtime, with no repeat dose the same night, and at least 8 hours should pass before driving or other work that needs alertness (zolpidem label, 4.4). Alcohol and other central nervous system (CNS) depressants are avoided; with opioids the dose and duration are limited (zolpidem label, 4.4 and 4.5). Complex sleep behaviours such as sleep-walking, sleep-driving or eating with no memory of it mean zolpidem is stopped at once (zolpidem label, 4.4). The zolpidem course is kept short: a few days to two weeks, four weeks at most including tapering (zolpidem label, 4.2).