The Zolpidem Paradigm Shift -- Why Now?

Matthew D. Johnson, PharmD


AccessMedicine from McGraw-Hill 

Zolpidem (AMBIEN, AMBIEN CR, EDLUAR, INTERMEZZO, ZOLPIMIST) is a benzodiazepine receptor agonist, approved for the management of insomnia. The FDA recently lowered the recommended starting dose for females, and strengthened the warnings about the risk of next-day driving.[1,2,3,4] The question is, why now, more than 20 years after the original FDA approval of zolpidem?

The zolpidem labeling changes were prompted by data that first came to light during clinical trials of a sublingual tablet formulation, INTERMEZZO. These data demonstrated that average blood levels four hours after administration can be above the threshold (50 ng/mL) now thought to cause significant impairment of activities requiring mental alertness.[3,5] An earlier pharmacokinetic evaluation of a controlled-release formulation of zolpidem (AMBIEN CR) also showed zolpidem levels in excess of 50 ng/mL eight hours after administration in up to one-third (33%) of study subjects, but at the time, the correlation between impaired driving and zolpidem plasma levels had not been established.[3,6]

In addition to the finding that next day impairment appears to last longer than previously thought, a significant gender difference in systemic exposure has also been detected (see Table I ).[3,5] Overall, average plasma zolpidem levels run approximately 50% higher in women than in men at any given time (see Figure 1),[3] and contrary to previous assumptions, the effect has proven to be independent of body weight.[5] This disparity in drug elimination was probably not detected at the time of the original 1992 approval for zolpidem, because prior to 1993 women were often under-represented in the pharmacokinetic assessments of new drugs.[7,8,9] Correcting the original pharmacokinetic data for body weight and other early study limitations may also have masked detection of the difference between the genders.[10]

Figure 1.

Frequency of Specific Plasma Zolpidem Levels 8 hours After a 10 mg Dose of Zolpidem in Women (left) and Men (right)5

The underlying reason for the gender difference remains unproven, but a small body of literature points to activation of cytochrome P450 3A4 (CYP3A4) by testosterone as a possible explanation.[11,12] Zolpidem is extensively metabolized through the liver, mainly by CYP3A4 (~60%).[13] If testosterone enhances the metabolism of zolpidem, then an inference can be made that the recent rapid growth in the testosterone replacement therapy market in the US over the past five-plus years may have magnified the population effect to an extent that allowed FDA to pick up the signal of a gender difference in the next-day impairment risk.[14]

Until the gender differences are more fully elucidated, healthcare professionals should caution patients, particularly women and the elderly, to use the lowest effective dose of zolpidem, and to allow sufficient time for the drug effects to clear before engaging in activities that require mental alertness. It is clear that zolpidem can impair driving for up to a full day following administration. While the available data for zolpidem is insufficient to precisely identify the mechanism underlying this paradigm shift, the FDA is continuing to evaluate the possibility of a class effect for other agents approved for use as sedative-hypnotics.