FDA Warns About Sleeping Pills and Sleep Driving

The March 14, 2007 FDA warning about the dangers of "sedative-hypnotics" may do more to create confusion than it does to increase patient safety, but it certainly reveals flaws in the agency's categorization of drugs as well as evidence of how little FDA approval really means. The FDA Press Release lists the following drugs (Comments in parentheses are mine.):

• Ambien and Ambien CR (already carry the warning!)
• Butisol sodium (Does anyone still prescribe this dinosaur?!)
• Carbrital (pentobarbital and carbromal) (Do they really still manufacture this stuff?!)
• Dalmane (a benzodiazepine)
• Doral (a benzodiazepine)
• Halcion (a benzodiazepine)
• Lunesta
• Placidyl (Does anyone still prescribe this dinosaur?!)
• Prosom (a benzodiazepine)
• Restoril (a benzodiazepine)
• Rozerem (probably acts like melatonin, a hormone)
• Seconal (Does anyone still prescribe this dinosaur?!)
• Sonata

What do these drugs have in common? Apparently they have all been approved by the FDA for treatment of insomnia. (Just try to find a copy of the official label to confirm this!) Although the warning refers to "sedative-hypnotics," drugs used to combat insomnia are usually categorized as soporifics or hypnotics. The "sedative" in "sedative-hypnotics" addresses the fact that most drugs so classified produce sedation or calming as well as assist in falling asleep or staying asleep. Although it might be considered a hypnotic, Rozerem would not be classified or used as a sedative. In the past benzodiazepines like Dalmane and diazepam have been separated from other sedative-hypnotic drugs, like Placidyl and pentobarbital (a barbiturate) because of the different chemical structure, different properties, and relatively better safety record of the benzodiazepines. Not surprisingly drugs like Ambien and Dalmane are included along with several other central nervous system depressants. It is surprising, however, that they have also included Rozerem, the only drug on the list that is neither a central nervous system depressant nor a controlled substance, and is thought to act on the melatonin receptor. While one might expect all of the central nervous system depressant drugs to share the adverse effect that prompted the warning, one might not expect Rozerem to cause this phenomenon. Unless there is clear evidence that it does this might unfortunately discourage physicians from prescribing what might be one of the few drugs, if not the only drug, that might be safer.
Even more confusing and potentially dangerous than the inclusion of Rozerem is the exclusion of a number of other central nervous system depressants and other sedating drugs which are often used to aid sleep. Of greatest concern is the omission of all the other benzodiazepines, sedative hypnotics, including even barbiturates, that are not explicitly approved for treating insomnia, despite the fact that these might be the drugs one would most likely expect to be associated with this phenomenon. Drugs frequently prescribed for insomnia such as quetiapine, mirtazapine, trazodone, and sedating antihistamines, such as diphenhydramine are conspicuously absent. Of course melatonin is omitted even though ramelteon is included, despite the fact that they probably share the same mechanism of action, presumably because melatonin, a hormone, is regulated by the FDA as a dietary supplement while Rozerem is regulated as a prescription pharmaceutical. The omission of sodium oxybate might be related to the tight control over its use.
The FDA overvalues its approval designations to the extent that they appear to consider approved indication to determine clinical class. This approach risks creation of increased confusion and potential for ill advised switching to drugs that might be even less safe. For example, a physician might switch a patient from Ambien to diazepam despite the drug's similarity to Halcion, eschewing Rozerem, which might not be associated with this effect, simply because Rozerem is included in the warning.
The FDA should adopt a more rational application of categories that does not depend solely on approved indication. Drug categories frequently overlap and may be based on different properties. The class of "benzodiazepines" is based on the similarities in chemical structure among the drugs in the class. The class of "hypnotics" is based on the drugs' effectiveness in induction of sleep. The class of serotonin reuptake inhibitors is based on the drugs' common mechanism of action. Approval is driven by the marketing choices of the company that holds the patent on the drug. Obtaining approval for a spcific indication requires evidence of safety and effectiveness, and the process costs the company millions of dollars with no guarantee of ultimate approval. The FDA should develop a more uniform and rational approach to approval as well as categorization. All drugs effective for treating insomnia should be approved for that indication and classified as hypnotics regardless of the business goals of the company that markets the entity, but only the drugs for which there is compelling evidence of a given adverse effect should carry the appropriate warning.