From the Guidelines
Zolpidem dosing differs between men and women due to sex-related variations in drug metabolism, with women requiring lower doses to minimize the risk of adverse effects, such as next-morning impairment and increased risk of accidents 1. The primary reason for this difference is that women metabolize zolpidem more slowly than men, resulting in higher blood concentrations and increased risk of side effects.
- The recommended starting dose for women is 5 mg of immediate-release zolpidem or 6.25 mg of extended-release formulation, while men can start with 10 mg immediate-release or 12.5 mg extended-release.
- This difference is due to women having lower activity of certain liver enzymes that break down zolpidem, particularly CYP3A4, as well as differences in body composition, such as a higher percentage of body fat, which can affect drug distribution.
- The FDA mandated these sex-specific dosing recommendations in 2013 after studies showed women had nearly 50% higher blood levels of zolpidem compared to men when given the same dose, resulting in increased morning drowsiness and impaired driving ability 1.
- Elderly patients of both sexes should also receive the lower dose due to similar concerns about slower drug clearance, as highlighted in studies assessing the pharmacologic treatment of insomnia disorder 1. These dosing differences help optimize the safety profile while maintaining efficacy for insomnia treatment, and are supported by recent studies, such as those published in the Journal of Clinical Sleep Medicine 1.
From the FDA Drug Label
Women clear zolpidem tartrate from the body at a lower rate than men. Cmax and AUC parameters of zolpidem were approximately 45% higher at the same dose in female subjects compared with male subjects The recommended initial dose of zolpidem tartrate for adult women is 5 mg, and the recommended dose for adult men is 5 or 10 mg.
The different dosing for men and women is due to the gender difference in pharmacokinetics, where women have a lower clearance rate of zolpidem compared to men, resulting in higher blood levels at the same dose. This leads to a recommended initial dose of 5 mg for women and 5 or 10 mg for men 2. The dose difference is intended to minimize adverse effects related to the higher blood levels in women 2.
From the Research
Zolpidem Dosing for Men and Women
- The reasoning for different zolpidem dosing for men and women is based on the fact that women have higher morning serum zolpidem concentrations than men after taking an evening dose, potentially leading to increased risk of harm 3.
- A study found that women had a non-significantly higher mean plasma concentration than men after 8 hours for the 10mg IR (28 vs. 20 ng/mL) and the 12.5mg MR (33 vs. 28ng/mL) 4.
- The FDA has recommended an initial dose of no greater than 5 mg (immediate release) or 6.25 mg (controlled release) per night in women due to the increased risk of harm 3.
- A study compared prescribing practices before and after the 2013 zolpidem labeling change and found that the percentage of patients prescribed low-dose zolpidem increased from 44% to 58% after the labeling change, with a significant increase in young women (42%-70%, p = 0.0045) 3.
Pharmacokinetics and Pharmacodynamics
- Zolpidem has a faster sleep-induction effect, but its efficacy in sleep maintenance is similar to other formulations 5.
- The pharmacokinetic profile of zolpidem shows that it has a rapid onset of action, but its duration of action can vary depending on the formulation and dose 5.
Clinical Implications
- The different dosing recommendations for men and women highlight the importance of considering individual factors, such as sex, when prescribing zolpidem 3.
- Clinicians should be aware of the potential risks and benefits of zolpidem and adjust the dose accordingly to minimize adverse effects 4, 3.
- Further research is needed to fully understand the effects of zolpidem on men and women and to determine the optimal dosing strategy for each sex 6.