The Missing Message: New FDA Boxed Warning for Z-drugs

OPINION

When the FDA released its latest warning on Z-drugs, I quickly wrote up a blog post on the subject and even published it. But, before I posted it on Facebook, I re-read it as I often do, and something concerned me. I immediately removed the post and decided to re-write it in a different context.

Here’s the recent announcement from the FDA on Z-drugs. I’ll follow with my opinion.

New FDA Boxed Warning for Z-drugs

On April 30th, 2019, the U.S. Food and Drug Administration (FDA) issued a safety announcement which stated that they will require a “Boxed Warning” on several drugs in the nonbenzodiazepine (Z-drug) class.

A Boxed Warning is the FDA’s most prominent warning and will be added to the prescribing information and the patient medication guides. This warning is based on evidence that “rare but serious injuries have happened with certain common prescription insomnia medicines because of sleep behaviors, including sleepwalking, sleep driving, and engaging in other activities while not fully awake.” Some of these sleep behaviors have resulted in death.

Serious injuries and death from complex sleep behaviors have occurred in patients with and without a history of such behaviors, even at the lowest recommended doses, and the behaviors can occur after just one dose. — U.S. Food and Drug Administration (FDA)

These “complex sleep behaviors” are more common in three specific nonbenzodiazepines which include zolpidem (Ambien), eszopiclone (Lunesta), and zaleplon (Sonata). The FDA identified 66 cases of this type of behavior linked to these drugs that resulted in serious injuries or death. The announcement cautions that these numbers only include reports submitted to the FDA or found in medical literature, so the real number may be higher.

According to an article in Monthly Prescribing Reference (MPR) regarding this announcement, the author, Diana Ernst, noted that “adverse events reported in these cases included falls, self-injuries, accidental overdoses, hypothermia, suicide attempts, apparent completed suicides, fatal motor vehicle accidents, gunshot wounds, carbon monoxide poisoning, drowning or near drowning, burns, and homicide.” These behaviors can occur in patients who have taken Z-drugs both with, and without, other central nervous depressants such as alcohol, opioids, or anti-anxiety medications.

This isn’t the first time Z-drugs have been under scrutiny by the FDA. In 2013, the FDA released a safety announcement about zolpidem (Ambien), recommending the reduction of evening doses because blood levels in some patients might still be significant enough in the morning to impair certain activities which require alertness. This announcement also required the manufacturers of Ambien, Ambien CR, Edluar, and Zolpimist to lower the recommended dose on their labeling.

The FDA issued this warning because they believe there is enough evidence to modify dosing recommendations. Thus, it needs to be taken seriously and if you are concerned, please speak with your doctor.

What are Z-drugs?

Nonbenzodiazepines, also known as Z-drugs, were released in the late 1980s as an alternative to benzodiazepines (anti-anxiety medication). They have entirely different chemical structures to benzodiazepines, and yet have very similar effects, and side effects. This includes the potential for physiological dependence, tolerance, and severe withdrawal complications.

The British National Formulary (BNF) guidelines state that benzodiazepines and Z-drugs (BZD) should not be prescribed for longer than four weeks. A study published in 2017 in the British Journal of General Practice on long-term use of both classes of drugs stated, “As there is evidence that long-term use of BZDs causes adverse physiological and neurological effects, and protracted withdrawal (with associated complications), this represents a serious public health problem.”

Do We Need a Warning on the Warning?

Many of us whose lives have been adversely affected by benzodiazepines and Z-drugs believe that our message is clear, and often wonder why it is not universally shared. We grind our teeth when we see media cover opioid addiction every hour of every day, but completely ignore benzos. Or if they do report on benzos, it’s in the context of overdose and street use, and rarely will a journalist mention the struggles of iatrogenic, physiological dependence which affects millions around the world.

Now, some of that is changing and new articles are starting to appear which cover the narrative of patients’ battles with dependence and withdrawal. But still, the message is often lacking some very basic information many of us want to relay to the public. And sometimes, it’s not just the media. Government’s regulatory agencies can contribute to the confusing message about these drugs.

There are two specific points I would like to make in the opinion part of this article:

1) FDA Announcement Instructions

In this recent Safety Announcement from the FDA, the following instructions were provided for people who find themselves having sleep behavior problems:

Patients should stop taking your insomnia medicine and contact your health care professional right away if you experience a complex sleep behavior… — U.S. FOOD AND DRUG ADMINISTRATION (FDA)

For most of us who have had personal experiences with these drugs, this statement appears to have a flaw. Nonbenzodiazepines (Z-drugs), much like benzodiazepines, create physiological dependence with long-term use. Most experts agree that the abrupt cessation of these drugs can create serious complications. Even if these patients did contact their healthcare professional immediately after stopping the drug, it might have been days, even weeks before they could schedule an appointment, during which time the patient might be experiencing the dramatic, and dangerous, effects of cold turkey withdrawal.

I am not a medical professional and this article is strictly my opinion, but I do have concerns about an FDA announcement which advises patients to “stop taking your insomnia medication” even with the follow-up instructions to “contact your health care provider.” While I recognize the dangers continuation of this medication may cause — and these concerns need to be taken seriously and limitations on a person’s activities may be required — abrupt cessation may be worse.

2) No Mention of Dependence or Withdrawal

Another concern I had with this announcement, and others like it, was the lack of certain language. I realize that the context of this Safety Announcement from the FDA was on side effects during use, especially those related to complex sleeping behavior. But I find it surprising, and even a bit disheartening, to note that not once in the over 650 words of this document did the FDA ever mention “dependence” or “withdrawal.”

Perhaps I’m being too harsh on the FDA, but since this is a significant complication of these drugs, I would think it should garner at least a passing mention.

Recognition of Benzo Dependence and Withdrawal

If you do a search for the word “benzodiazepine” within the U.S. Food & Drug Administration’s website, you will find 544 items. Of the top 20 results, 19 are focused on the dangers of combining benzodiazepines with opioids. No mention of withdrawal. The other one was a resume for a doctor who had studied benzos.

Now, this investigation of mine was far from scientific, as can clearly be seen. I’ll admit it is anecdotal at best. Still, I did other searches and found little to no information on benzo dependence and withdrawal on the site. I wish I could say that this surprised me, but it didn’t.

I don’t want to be too judgmental here. Nor am I trying to disparage the FDA or any other regulatory agency. Unfortunately, recognition of physiological dependence from benzodiazepines and nonbenzodiazepines is still in debate within many circles of the medical community. Many patients who have sought medical support for their taper know this all too well.

But, what frustrates so many of us is that this is not a new message. Not by a long shot. Warnings about these drugs started in 1960, soon after they were first released, by the likes of medical experts such as Prof. Malcolm Lader and others. Since then, other medical professionals and organizational leaders have worked diligently to help us find support and raise awareness. If it wasn’t for them, I would not have found the Ashton Manual which guided me to a successful withdrawal from 12 years of clonazepam.

All we want to know is this. What will it take for us to get our message through? More research? Well, that is costly but we are working on it. Better media coverage? Again, costly, but we’re making strides. Litigation? Legislation? Much is being done on many fronts, but it’s an uphill battle to be sure.

In the end, it might just be the grassroots efforts of each and every person who has battled the demon of withdrawal to tell their story, whenever and wherever they can. If we do that, I am hopeful that our message will start to be heard. Perhaps it already is.

Thanks for listening to me ramble, D :)

Disclaimer

This article is for informational purposes only. The author of this article is not a medical professional nor is he providing medical advice in any way. Do not substitute any information in this article for medical advice, nor delay in seeking it. If you have any further questions, please see our complete disclaimer on our website.

References

1. Davies, J., T.C. Rae, and L. Montagu. “Long-term benzodiazepine and Z-drugs use in England: a survey of general practice.” British Journal of General Practice 67(662)(September 2017):e609-13. Accessed May 3, 2019. https://www.ncbi.nlm.nih.gov/pubmed/28716996.

2. Ernst, Diana. “FDA: Boxed Warning, Contraindication Added to Several Insomnia Medications.” MPR. April 30, 2019. Accessed May 1, 2019. https://www.empr.com/home/news/fda-boxed-warning-contraindication-added-to-several-insomnia-medications.

3. Foster, D E. Benzo Free: The World of Anti-Anxiety Drugs and the Reality of Withdrawal. Erie, Colorado: Denim Mountain Press, 2018. https://easinganxiety.com/book.

4. U.S. Food & Drug Administration (FDA). “FDA adds Boxed Warning for risk of serious injuries caused by sleepwalking with certain prescription insomnia medicines.” FDA Drug Safety Communication: Safety Announcement (April 30, 2019). Accessed May 1, 2019. https://www.fda.gov/drugs/drug-safety-and-availability/fda-adds-boxed-warning-risk-serious-injuries-caused-sleepwalking-certain-prescription-insomnia.

5. U.S. Food & Drug Administration (FDA). “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).” FDA Drug Safety Communication: Safety Announcement (January 10, 20013). Accessed May 1, 2019. https://wayback.archive-it.org/7993/20170404172106/https:/www.fda.gov/Drugs/DrugSafety/ucm334033.htm