FDA Belatedly Requires Abuse-Related Black-Box Warnings for Benzodiazepines

Benzodiazepines are a commonly overprescribed class of sedative, hypnotic medications approved by the Food and Drug Administration (FDA) to treat, depending on the drug, generalized anxiety disorder, insomnia, seizures, social phobia and panic disorder (see Table, below, for a list of oral formulations of these drugs).[1],[2]

In September 2020, the FDA issued a drug safety communication announcing that it had required the manufacturers of all benzodiazepines to update the black-box warning (the strongest warning that the agency can require) for these drugs to describe risks of abuse, addiction and other related adverse reactions.[3] The new warnings in the labeling were not implemented until February 2021.

Public Citizen’s Health Research Group has cautioned about these risks for many years.[4],[5],[6] We also had previously designated all benzodiazepines as Do Not Use for insomnia, anxiety disorders or any other uses, except for alprazolam (XANAX), which we designated as Do Not Use Except For Panic Disorder, and clonazepam (KLONOPIN), which is approved by the FDA only for certain types of seizures and panic disorder.

List of Oral Benzodiazepines Approved in the U.S.*

*All are designated by Worst Pills, Best Pills News as Do Not Use except for alprazolam (which is designated as Do Not Use Except For Panic Disorder) and clonazepam (which is approved only for certain types of seizures and panic disorder).
†Combination with another drug

Black-box warnings

The FDA previously required a black-box warning in the labeling of all benzodiazepines in 2016 to highlight the risk of using them concomitantly (together) with opioids.[7]

According to the new FDA announcement, the agency required expanding the black-box warnings for benzodiazepines to include the following risks:

• abuse
• addiction (physical inability to stop consuming these drugs)
• misuse (when the drugs are taken at higher-than-recommended doses or taken by someone to whom they were not prescribed)
• physical dependence (needing to use increasingly higher doses of these drugs)
• withdrawal reactions (due to sudden discontinuation or significant dose reduction of benzodiazepines).[8]

The updated changes also instruct that benzodiazepines should be used at the lowest effective dose for the shortest possible duration of time and that users of these drugs should be monitored for the newly updated risks.

FDA review of safety data

The FDA required the new changes after it reviewed reports of adverse events associated with benzodiazepine use that had been submitted to the agency and other published data. It found that in 2019, an estimated 92 million benzodiazepine prescriptions had been filled in the U.S.

The agency noted that benzodiazepine abuse and misuse are common and that they result in substantial harm. For example, approximately 5.4 million Americans abused or misused benzodiazepines in 2018. That year, benzodiazepines were either the only drug involved or were co-involved with other drugs or substances (mainly alcohol, marijuana and opioids) in 18% of admissions to publicly funded substance use disorder treatment programs. Additionally, half a million American adults had a benzodiazepine use disorder (addiction) in 2016.

The FDA evaluated 104 cases that had been reported directly to the agency by consumers or health care professionals in which a benzodiazepine was the single drug associated with abuse, dependence or withdrawal adverse reactions.

Most of the dependence and withdrawal reactions in these cases involved patients who were taking benzodiazepines for therapeutic uses. The withdrawal reactions involved central nervous system symptoms (including depression, increased anxiety or panic attacks, insomnia and memory impairment) and heart rate or rhythm changes as well as gastrointestinal symptoms (including abdominal pain, diarrhea and nausea).

Most of the cases reported to the FDA involved using benzodiazepines for months to years. Among the reported cases, dependence occurred as early as days to weeks after starting benzodiazepines and withdrawal symptoms lasted from weeks to years.

What You Can Do

Due to their serious risks, it is best not to start taking benzodiazepines except alprazolam (for panic attacks) and clonazepam (for panic attacks or seizures). If you are currently taking one of these drugs, do not stop it abruptly to avoid having serious withdrawal symptoms. Instead, develop a schedule with your doctor to safely taper your dose gradually.
 

References

[1] Drug profile: benzodiazepines. Last reviewed July 31, 2020. https://www.worstpills.org/monographs/view/83. Accessed March 15, 2021.

[2] Food and Drug Administration. FDA drug safety communication: FDA requiring boxed warning updated to improve safe use of benzodiazepine drug class Includes potential for abuse, addiction, and other serious risks. September 23, 2020. https://www.fda.gov/media/142368/download. Accessed March 15, 2021.

[3] Ibid.

[4] Drug profile: benzodiazepines. Last reviewed July 31, 2020. https://www.worstpills.org/monographs/view/83. Accessed March 15, 2021.

[5] New study shows increased risk of death with sleeping pills and tranquilizers. Worst Pills, Best Pills News. July 2014. https://www.worstpills.org/newsletters/view/907. Accessed March 15, 2021.

[6] Sleeping pills and tranquilizers. November 5, 2004. https://www.worstpills.org/chapters/view/20. Accessed March 15, 2021.

[7] Food and Drug Administration. FDA drug safety communication: FDA warns about serious risks and death when combining opioid pain or cough medicines with benzodiazepines; requires its strongest warning. August 31, 2016. https://www.fda.gov/media/99761/download. Accessed March 15, 2021.

[8] Food and Drug Administration. FDA drug safety communication: FDA requiring boxed warning updated to improve safe use of benzodiazepine drug class Includes potential for abuse, addiction, and other serious risks. September 23, 2020. https://www.fda.gov/media/142368/download. Accessed March 15, 2021.