FDA Approves Suvorexant, Latest Dangerous Sleep Drug

In today’s overworked and highly stressed population, chronic sleep deprivation is endemic. Between 50 million and 70 million Americans have been diagnosed with a sleep disorder.[1]

Insomnia has deeply rooted psychological and physical causes and is rarely the result of a single, identifiable biological problem. However, this has not stopped drug companies from marketing, and making billions of dollars on, medications as a quick fix for Americans’ sleep troubles.

In August, the Food and Drug Administration (FDA) approved suvorexant (BELSOMRA),[2] the latest in a long line of sleep medicines. Suvorexant was approved in four doses: 5 milligrams (mg), 10 mg, 15 mg and 20 mg nightly. However, the two lowest doses were never tested in large clinical studies, a standard requirement for all modern medication and dosage approvals. And as with previous sleep drugs, the two higher doses were found to have life- threatening risks — both to individual users and to the public at large — with only marginal benefits on sleep.

Public health risks

Suvorexant is the first of a new class of sleep aids, called orexin receptor antagonists.[3] All other sleep drugs fall into two categories: benzodiazepines and nonbenzodiazepine “Z-drugs.”

Benzodiazepines were the first generation of sleeping aids to be marketed, and they are still sometimes used to help patients sleep. However, they were found to be habit-forming, and their potent and generally longer-lasting sedative effects were associated with an increase in traffic accidents.[4],[5],[6] These severe side effects caused benzodiazepines to be gradually phased out in favor of Z-drugs, whose introduction generated hope of improved sleep without such adverse effects.

Zolpidem (AMBIEN) was the first Z-drug approved in the U.S. and is still the most widely used.[7] At the time of the drug’s approval in 1992, there was no indication that it caused significant next-day impairment of motor or mental function.[8]

In the two decades since zolpidem’s approval, however, evidence has accumulated that the drug does, in fact, dangerously impair patients on the day after a nighttime dose. A 2008 study of 3.1 million Norwegians ages 18 to 69 found the risk of road traffic accidents doubled in the week after prescription of the Z-drugs zolpidem or zopiclone (not available in the U.S.).[9] A 2011 study of more than 70,000 drivers involved in road traffic accidents in France found that the risk of causing a traffic accident more than doubled in those dispensed more than one pill of zolpidem a day during the five months before the crash.[10]

By 2013, the FDA’s Adverse Event Reporting System had reportedly received approximately 700 reports of “driving mishaps” associated with zolpidem use.[11]

These data prompted the agency to issue a safety communication in May 2013 warning patients not to drive or engage in “other activities that require complete mental alertness” the day after taking extended-release zolpidem (AMBIEN CR) “because zolpidem levels can remain high enough the next day to impair these activities.”[12]

It is therefore noteworthy, given the FDA’s sound reasoning, that suvorexant remains in the body almost five times longer than zolpidem.[13]

Suvorexant and driving impairment

Zolpidem and other Z-drugs’ association with car accidents led to a series of preapproval tests assessing the effects of suvorexant on next-day driving ability. Subjects participated in supervised, hourlong road tests the morning after a bedtime dose of the drug. The results indicated that the 20 mg dose of suvorexant caused driving impairment, with drivers deviating toward the edges of their lanes significantly more than subjects given a placebo.[14] The level of lane deviation was similar to that seen in people with a blood alcohol level more than half the legal limit in most states.[15],[16]

The head of the FDA’s division responsible for approving sleep medicines concluded that the studies “demonstrate that suvorexant can cause significant impairment in driving the morning after dosing.”[17]

How would these findings translate to the real world? The preapproval driving studies measured performance in supervised, hourlong increments, and subjects had been explicitly warned of potential impairment.[18] In everyday life, sleepy patients would surely demonstrate worse impairment when alone at the wheel and on drives longer than an hour.

In addition, the risk of falling asleep at the wheel, which is much more dangerous than slight lane deviation, could not be measured in these studies. Subjects on suvorexant simply stopped the test at the first sign of sleepiness, something most people, in all likelihood, would not be able or willing to do on their morning commute to work.[19]

The FDA opted to address suvorexant’s next-day risks using the ineffective approaches it has pursued with Z-drugs, namely through insufficient warnings in the drug’s medication guide alerting patients not to drive or “do other dangerous activities” the day after taking the drug until they feel “fully awake.”[20] Aside from the fact that many patients will not read the medication guide, such instructions rely on people’s subjective judgment as to when they feel fully awake.

Indeed, the FDA’s recommendations are unrealistic even for those aware of their impairment. Suvorexant is indicated for use on a daily — and indefinite — basis, meaning that patients on the drug long-term would need to stop driving for a prolonged time period. However, relatively few people have other commuting options, and it is unlikely that even those with a public-transportation alternative would indefinitely upend their daily routines for the sake of an impairment of which they are, in all likelihood, unaware.

Other side effects

In addition to driving impairment, the results of preapproval studies of suvorexant pointed to an increase in suicidal thoughts, even in some subjects who had never before experienced such thoughts.[21]

Suvorexant also increased blood cholesterol levels at all doses administered during the preapproval trials.[22]

Finally, although Merck and Co., the manufacturer of suvorexant, maintained that the drug is not habit-forming like some of its predecessors, the data suggested otherwise. Almost half of subjects on high-dose suvorexant experienced even worse sleep disturbances after stopping the drug than they endured before taking it, a phenomenon known as rebound insomnia.[23] Such rebound effects may cause dependence on the drug over time.

Minimal benefits

Are the benefits of suvorexant worth all of these risks? In the preapproval trials, subjects given the 20 mg dose of suvorexant fell asleep anywhere from 0.3 to eight minutes more quickly after three months of treatment, but these marginal benefits were, with one exception, statistically uncertain or insignificant.[24] Suvorexant was better at keeping people asleep, increasing total sleep time by 16 minutes and reducing nighttime awakenings by 23 minutes.[25]

Examined in the context of an eight-hour night, these findings are in line with the trend seen with other sleep medicines. A 2012 analysis of all preapproval clinical studies conducted on currently marketed sleep drugs found that the medicines reduced the time to fall asleep by an average of only 22 minutes. The medicines, as a group, did not increase total sleep time or decrease nighttime awakenings.[26]

Ultimately, the effectiveness of an insomnia treatment should be judged based on how well-rested and well-functioning a patient is while awake, not on its effects on a patient’s time to fall asleep or total sleep time. Can a sleeping pill that, in far too many cases, worsens the next-day drowsiness that necessitated treatment in the first place be deemed effective? The answer seems clear enough, but not, unfortunately, to the FDA.

What You Can Do

Given the risks, and the unpredictability as to who will be most affected, we recommend that you not use suvorexant or any other currently marketed sleep medication.

Instead, try nondrug approaches to help resolve sleep problems. Avoid the use of caffeine, nicotine and alcohol, especially after noon. Establish a routine for getting ready to go to bed, including relaxation techniques. Pursue regular physical activity, such as walking or gardening, but avoid vigorous exercise too close to bedtime.

Always talk to your doctor before starting or stopping any medication. Because of the possibility of withdrawal reactions, you should never abruptly discontinue any sleep medication.

References

[1] Centers for Disease Control and Prevention. Insufficient Sleep Is a Public Health Epidemic. http://www.cdc.gov/features/dssleep/index.html. Accessed September 12, 2014.

[2] Food and Drug Administration. FDA approves new type of sleep drug, Belsomra. August 13, 2014. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm409950.htm. Accessed September 12, 2014.

[3] Food and Drug Administration. FDA approves new type of sleep drug, Belsomra. August 13, 2014. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm409950.htm. Accessed September 12, 2014.

[4] Engeland A, Skurtveit S, Mørland J. Risk of road traffic accidents associated with the prescription of drugs: A registry-based cohort study. Ann Epidemiol. August 2007;17(8):597-602.

[5] Barbone F, McMahon AD, Davey PG, et al. Association of road-traffic accidents with benzodiazepine use. Lancet. October 24, 1998;352(9137):1331-6.

[6] Hemmelgarn B, Suissa S, Huang A, et al. Benzodiazepine use and the risk of motor vehicle crash in the elderly. JAMA. July 2, 1997;278(1):27-31.

[7] Tavernise S. Drug agency recommends lower doses of sleep aids for women. New York Times. January 10, 2013. http://www.nytimes.com/2013/01/11/health/fda-requires-cuts-to-dosages-of-ambien-and-other-sleep-drugs.html. Accessed May 29, 2013.

[8] Zolpidem Medical Review, p. 39, 41. Drugs@FDA. http://www.accessdata.fda.gov/drugsatfda_docs/nda/pre96/019908_S000_MOR.pdf. Accessed May 29, 2013.

[9] Gustavsen I, Bramness JG, Skurtveit S, et al. Road traffic accident risk related to prescriptions of the hypnotics zopiclone, zolpidem, flunitrazepam and nitrazepam. Sleep Med. December 2008;9(8):818-822.

[10] Orriols L, Philip P, Moore N, et al. Benzodiazepine-like hypnotics and the associated risk of road traffic accidents. Clin Pharmacol Ther. April 2011;89(4):595-601.

[11] Tavernise S. Drug agency recommends lower doses of sleep aids for women. The New York Times. January 10, 2013. http://www.nytimes.com/2013/01/11/health/fda-requires-cuts-to-dosages-of-ambien-and-other-sleep-drugs.html. Accessed June 4, 2013.

[12] Food and Drug Administration. FDA Drug Safety Communication: FDA approves new label changes and dosing for zolpidem products and a recommendation to avoid driving the day after using Ambien CR. May 14, 2013. http://www.fda.gov/Drugs/DrugSafety/ucm352085.htm. Accessed May 28, 2013.

[13] Public Citizen. Letter to the FDA Opposing Approval of the Sleep Medicine Suvorexant. June 17, 2013. http://www.citizen.org/documents/2136.pdf. Accessed September 22, 2014.

[14] FDA Briefing Document, p. 26-29, 33-34.

[15] FDA Briefing Document, p. 26.

[16] Progressive Auto Insurance. Blood Alcohol Concentration Limits by State. http://www.progressive.com/vehicle-resources/blood-alcohol-calculator/. Accessed September 12, 2014.

[17] FDA Briefing Document, p. 33.

[18] FDA Briefing Document, p. 405.

[19] FDA Briefing Document, p. 264.

[20] Food and Drug Administration. Suvorexant Medication Guide. August 2014. http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/204569s000lbledt.pdf. Accessed September 22, 2014.

[21] FDA Briefing Document, p. 205-207.

[22] FDA Briefing Document, p. 248.

[23] FDA Briefing Document, p. 279.

[24] FDA Briefing Document, p. 7-10.

[25] FDA Briefing Document, p. 134.

[26] Huedo-Medina TB, Kirsch I, Middlemass J, et al. Effectiveness of non-benzodiazepine hypnotics in treatment of adult insomnia: Meta-analysis of data submitted to the Food and Drug Administration. BMJ. December 17, 2012;345:e8343.