Zolpidem

Additional information

Pharmacokinetics and dosing

Zolpidem has a short half-life, 2.4 h. Pharmacokinetic studies of zolpidem in healthy young men and women show that men had significantly higher apparent clearance than women. After correction for body weight, the sex difference in clearance was still statistically significant in four of the studies [3-8]. Pooled mean apparent clearance corrected for body weight was 25% lower in women than in men (3.75 vs. 4.98 ml/min/kg, p<0.002) [8].

Women appear to eliminate zolpidem slower than men but the mechanism behind this sex difference is not established. In 2013, the U.S. Food and Drug Administration (FDA) recommended a 50% lower initial dose of zolpidem to women [9, 10]. However, this action has been criticized for the lack of available scientific evidence to support the recommendation of reduced dosage to women [8].

Effect

A few studies have evaluated sex differences in the relation between zolpidem pharmacokinetics or plasma concentrations and pharmacodynamic responses. The pharmacodynamics of a single dose zolpidem (1.0, 1.75, or 3.5 mg) or placebo was studied in healthy volunteers in a small double-blind study (13 men, 11 women). In men, zolpidem dose reduced self-rated sedation, while in women the dose impaired performance of digit symbol substitution test, choice reaction test, and symbol copying test. The authors suggested that the observed pharmacodynamic effects in women was explained by the higher plasma concentrations and increased intrinsic sensitivity among women [5]. In another study where healthy adults received a single dose 10 mg zolpidem (10 men, 8 women), women reported higher “self-rated sedation”, while no sex differences were seen for other pharmacodynamic effects [3]. However, the digit symbol substitution test has been criticized to have insufficient predictive validity of actual on-road driving [11].

Zolpidem increases sleep spindle activity and reduces low frequency EEG (electroencephalogram) activity. A randomized, double-blind, placebo-controlled trial recorded brain activity after intake of 10 mg zolpidem in healthy volunteers (45 women, 36 men) using EEG. Women had a greater increase in sleep spindle activity in Non Rapid Eye Movement sleep (beta activity, stage 2 sleep), but no sex differences were seen in the suppression of delta and theta activity (deep or slow-wave sleep, stage 3 sleep) [12]. However, measuring EEG activity has been criticized to have insufficient predictive validity of actual on-road driving [11].

Post hoc analyses of data from clinical trials evaluating the efficacy of zolpidem in adult patients with primary insomnia have shown similar efficacy in men and women [13, 14]. In the first study, patients (24 men, 58 women) were randomized to receive either zolpidem 1.75 mg, zolpidem 3.5 mg, or placebo in the middle of the night in a sleep laboratory setting [13]. In the second study, patients (94 men, 201 women), were randomized to receive either zolpidem 3.5 mg or placebo in the middle of the night for 4 weeks [13]. In the third study, patients (37 men, 52 women) were randomized to receive either zolpidem 10 mg or placebo before bedtime for 12 months [14]. There were no sex differences in efficacy of zolpidem on time to return to sleep, digit symbol substitution test [13], in short-term, long-term, or next-day sleepiness [14]. However, the trials were not originally designed to detect sex differences in efficacy and thus interpreting of results is limited [13, 14].

Adverse effects

A post-hoc analysis analyzing sex differences in driving performance showed that 4 hours after middle-of-the-night administration of 10 mg zolpidem to healthy volunteers (15 men, 15 women), women drove worse than men and reported drowsiness and dizziness more often than men. There were no sex differences in driving performance after the 20 mg dose [15, 16]. However, plasma zolpidem concentrations were not measured in men and women in the study described above because lack of method for therapeutic drug monitoring at the time of the study [15]. Thus, there is no evidence that impaired driving capacity in women receiving zolpidem is explained by higher plasma concentrations. Furthermore, zolpidem is not recommended for middle-of-the-night-administration and thus the clinical relevance of impaired driving ability 4 hours after administration of zolpidem is questionable.Zolpidem blood levels > 50 ng/ml has been associated with increased risk of driving impairment. Eight hours after the administration of a 10 mg zolpidem tablet, an estimated 15% of the women and 3% of the men will have zolpidem blood concentration levels that could affect their driving [17].In a study of driving capacity after medication with sleeping pills (9 men, 14 women) zopiclone 7.5 mg, but not zolpidem 10 mg, was found to increase the number of collisions in a driving simulator compared to placebo. No analysis based on patient’s sex was performed probably due to the low number of study participants [1]. Also another study showed that zopiclone 7.5 mg, but not zolpidem 3.5 mg (administered 3 hours before driving), impaired next-day driving, but with no differences between men and women [2].

Reproductive health issues

Zolpidem might interact with oral contraceptive preparations, but it is not likely to be of clinical importance. Regarding drug-drug interactions aspects, please consult Janusmed Interactions (in Swedish, Janusmed interaktioner).

Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).

Other information

Two large register-based studies analyzing utilization of zopiclone in men and women (aged ≥75 years) in Sweden showed that men were more likely than women to dispense zolpidem [18, 19]. In large register studies from Denmark and Norway, women dispensed more prescriptions of zopiclone and zolpidem in the years 2004 and 2006, respectively [20, 21].

A few studies have evaluated the impact of the FDA recommendations of lowering initial dose in women on zolpidem prescribing to women. Prescription data from University of Colorado Health System (n=400 in total) showed that the proportion of patients with a first-time low-dose zolpidem prescription increased after the labeling change, but was only significant for young women (42% vs 70%) [22]. Data on dispensed prescriptions from the Optum Clinformatics research database between 2011 and 2013 showed that the number of women with high dose zolpidem decreased and with low-dose zolpidem increased after the FDA Drug Safety Communications. Similar patterns were observed in men [23].