Zolpidem at night may cause next-morning alertness impairment

Published in Health News and Evidence

Date published: About this date

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Summary

The US Food and Drug Administration (FDA) recently released a Drug Safety Communication announcement calling for a 50% reduction in bedtime doses of insomnia drug zolpidem, especially in women. Analysis of new safety data links bedtime doses with next-morning impairment of alertness sufficient to impair driving and other skills in some patients. For both men and women the FDA advise that controlled-release formulations of the drug are most likely to cause next-morning impairment after bedtime; women appear to be more susceptible to this risk because they eliminate zolpidem more slowly than men.

In Australia a number of sleep-related adverse events in people taking zolpidem have been reported to the Therapeutic Goods Administration (TGA), which continues to monitor the drug closely. In recent years safety warnings have been added to the product information (PI), and pack sizes have been reduced to 14 tablets in an attempt to reduce adverse events.

Key points

  • New data show that in some patients taking zolpidem at bedtime, blood levels of drug may be high enough the morning after to impair activities that require alertness.
  • The FDA recommends that bedtime doses for women should be lowered from 10 mg to 5 mg for immediate-release products and from 12.5 mg to 6.25 mg for extended-release products. The FDA is also urging prescribers to consider these lower doses for men.
  • The TGA determined in 2012 that while there is evidence of extreme side effects in some people, the medicine is of value to some patients.
  • Remind patients of the risks associated with hyponotics — including their use with alcohol — and report adverse events, including suspected cases, to the TGA. 

Bedtime zolpidem may impair next-morning alertness

New data show that in some patients blood levels of the insomnia drug zolpidem may be high enough after bedtime dosing to impair activities that require alertness the next morning.1 The FDA has recommended that the bedtime dose should be lowered in women, and considered for lowering in men, to reduce residual blood levels the next morning.1

In pharmacokinetic trials:1

  • 15% of women and 10% of men taking a bedtime dose of 10 mg immediate-release zolpidem had next-morning blood levels sufficient to impair driving
  • 33% of women and 25% of men taking a bedtime dose of 12.5 mg controlled-release zolpidem had next-morning blood levels sufficient to impair driving.

This new evidence, along with data from clinical trials, driving simulation studies and about 700 reports linking zolpidem to ‘impaired driving ability and/or road traffic accidents’2 has led to the new US warning and recommendations.1,2

The FDA is especially concerned about extended-release forms of zolpidem,3 which the new data show are associated with the highest risk of next-morning impairment1. Women appear to be more susceptible to this risk because they eliminate zolpidem more slowly than men.1

Fifty per cent reduction in bedtime dosing recommended

In the US, manufacturers of a number of zolpidem products will be required by the FDA to lower the recommended bedtime doses in order to lower drug levels in the blood the next morning.1 The FDA recommends that doses for women should be lowered from 10 mg to 5 mg for immediate-release products and from 12.5 mg to 6.25 mg for extended-release products.1 The FDA is also requiring label changes urging prescribers to consider these lower doses for men.1 Lower doses are already recommended for elderly patients and patients with hepatic impairment, and zolpidem is contraindicated in patients with severe hepatic impairment.

What are the implications in Australia?

A range of immediate-release and controlled-release zolpidem products is available in Australia (see Table 1).4

Table 1. Zolpidem products currently available in Australia

Brand name Presentation
Stilnox 10 mg (scored, white), 7 and 14 tabs per pack
Stilnox CR Controlled release
6.25 mg (pink), 14 tabs per pack
12.5 mg (blue), 14 tabs per pack
Dormizol
10 mg (scored, white), 14 tabs per pack
Zolpibell 10 mg (scored, white), 14 tabs per pack
Zolpidem 10 mg (scored, white), 7 and 14 tabs per pack
Stildem 10 mg (scored, white), 7 and 14 tabs per pack
Somidem 10 mg (scored, white), 7 tabs per pack

Sleep-related adverse events associated with zolpidem have been a concern in Australia for several years.5–9 In 2008 the National Drugs and Poisons Schedule Committee considered whether zoldipem should be reclassified as a schedule 8 drug in Australia in response to reported incidents of bizarre and sometimes dangerous sleep-related behaviours such as sleep walking and sleep driving in some users of the drug.7 The National Drugs and Poisons Schedule Committee considered that the current schedule 4 classification of zolpidem remained appropriate;7 however, the TGA imposed a boxed safety warning on the PI of all zolpidem-containing medicines:


... zolpidem may be associated with potentially complex sleep-related behaviours which may include sleep walking, sleep driving and other bizarre behaviours. Zolpidem is not to be taken with alcohol. Caution is needed with other CNS depressant drugs. Limit use to 4 weeks maximum under close medical supervision.5

In addition to the warning, from December 2007 pack sizes have been limited to no more than 14 tablets.6

In Australia 1338 adverse events involving zolpidem medicines had been reported to the TGA by October 2012.10 These events include 392 abnormal sleep-related events, 25 deaths and 20 road traffic accidents.10 Between January 2009 and April 2012 zolpidem medicines were linked to 15% of road traffic accidents reported to the TGA.9

The TGA reports that the annual number of adverse events is decreasing since the introduction of the new warning in the PI.8 In July 2012 the TGA published a statement explaining:


... while there is evidence of some extreme side effects in some people, the TGA has determined that [when] used properly this is a medicine of value to some patients, particularly with severe insomnia, and should remain available in Australia.

and that ‘There is no specific new safety signal of concern to the TGA that would require the TGA to take further action at this time’.8

Prescribing tips

  • Consider reduced doses of zolpidem at bedtime to avoid next-morning impairment of alertness.
  • Advise patients that drowsiness may persist the following day after using zolpidem and that they should avoid driving or operating heavy equipment until they know how they will react.4
  • Advise patients of the contraindications and precautions listed in the PI, and of the spectrum of potential adverse effects.9
  • Non-drug treatments are first line for insomnia.11
  • When considering zolpidem, prescribe the lowest effective dose for the shortest time possible.1,6
  • Prescribers are encouraged not to prescribe, and pharmacists are encouraged not to dispense, more than one pack at a time.6
  • Advise patients taking zolpidem to avoid alcohol.
References 
  1. US Food and Drug Administration. FDA Drug Safety Communication: Risk of next-morning impairment after use of insomnia drugs; FDA requires lower recommended doses for certain drugs containing zolpidem (Ambien, Ambien CR, Edluar, and Zolpimist). 2013. http://www.fda.gov/downloads/Drugs/DrugSafety/UCM335007.pdf (accessed 11 January 2013).
  2. US Food and Drug Administration. Questions and Answers: Risk of next-morning impairment after use of insomnia drugs; FDA requires lower recommended doses for certain drugs containing zolpidem (Ambien, Ambien CR, Edluar, and Zolpimist). 2013. http://www.fda.gov/Drugs/DrugSafety/ucm334041.htm (accessed 11 January 2013).
  3. US Food and Drug Administration. Some Sleep Drugs Can Impair Driving. 2013. http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm322743.htm (accessed 11 January 2013).
  4. Rossi S, (ed). Australian Medicines Handbook, 2012. Adelaide: Australian Medicines Handbook, 2012.
  5. Australian Government Department of Health and Ageing, Therapeutic Goods Administration. Medicine regulator places boxed warning on Stilnox. 2008. http://www.tga.gov.au/newsroom/media-2008-stilnox-080221.htm (accessed 11 January 2013).
  6. Australian Government Department of Health and Ageing Therapeutic Goods Administration. Zolpidem ('Stilnox'). 2008. http://www.tga.gov.au/safety/alerts-medicine-zolpidem-071127.htm (accessed 11 January 2013).
  7. Australian Government Department of Health and Ageing Therapeutic Goods Administration. Scheduling of zolpidem (Stilnox). 2008. http://www.tga.gov.au/archive/committees-ndpsc-zolpidem-080221.htm (accessed 11 January 2013).
  8. Australian Government Department of Health and Ageing Therapeutic Goods Administration. Why hasn't the TGA taken Stilnox off the market? 2012. http://www.tga.gov.au/newsroom/btn-stilnox-120706.htm (accessed 11 January 2013).
  9. Australian Government Department of Health and Ageing Therapeutic Goods Administration. Medicines Safety Update, Volume 3, Number 3, June 2012. http://www.tga.gov.au/hp/msu-2012-03.htm#zolpidem (accessed 11 January 2013).
  10. Australian Government Department of Health and Ageing, Therapeutic Goods Administration. Database of Adverse Event Notifications. 2013. http://www.tga.gov.au/hp/msu-2012-03.htm#zolpidem (accessed 11 January 2013).
  11. eTG complete [online]. Therapeutic Guidelines: Insomnia: pharmacological management, 2013. http://etg.hcn.net.au (accessed 13 January 2013).