Coadministration is contraindicated because competition for CYP3A4 by efavirenz could result in inhibition of metabolism and create the potential for serious and/or life-threatening events (for example, prolonged sedation or respiratory depression).

The effect of a single dose of efavirenz (400 mg) on midazolam clearance following oral or intravenous administration was studied in 12 healthy subjects. Twelve hours after efavirenz administration, midazolam apparent oral clearance significantly increased by 70% and systemic clearance after intravenous administration significantly increased by 27%. Similar effects were still present on day 6, after which midazolam clearances slowly returned to baseline on day 22. At least on day 1, the midazolam clearance increase is consistent with the in vitro observed CYP3A activation. The onset of an efavirenz treatment will almost immediately result in enhanced elimination of CYP3A substrates.