Benzodiazepines

Background

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Chlordiazepoxide was synthesized in 1955 and the first BZD was brought to market in 1960 as chlordiazepoxide (Librium). Multiple other products with various molecular modifications followed. This class of medications quickly gained favor over the barbiturates because of their more favorable safety profile yet comparable efficacy as an anxiolytic and for reducing sleep onset latency.

Compared with barbiturates, BZDs result in less respiratory depression and a higher therapeutic index. Moreover, BZDs were thought to have less potential for misuse and dependence. BZDs were also found to have other clinical applications (eg, as a muscle relaxant, an anticonvulsant, a preanesthetic). By the mid-1970s they were among the most frequently prescribed medications.

In the 1980s, the similar nonbenzodiazepines or “Z drugs” (eg, zolpidem) were marketed for insomnia. These have all but completely taken the place of the BZDs as the drugs of choice in treating sleep onset latency problems.

In 2019, an estimated 92 million benzodiazepine prescriptions were dispensed from U.S. pharmacies with alprazolam – commonly known by its brand name Xanax – making up 38% of those prescriptions, according to the FDA.

Treatment / Use

Benzodiazepines are widely used to treat anxiety, insomnia, seizures, and other conditions, often for extended periods of time.

They are one of the most widely prescribed medications in the United States, particularly among older patients.

Benzodiazepines have qualities that can help to reduce anxiety and seizures, relax the muscles, and induce sleep.

According to the FDA, in 2019, an estimated 92 million benzodiazepine prescriptions were dispensed from US outpatient pharmacies, most commonly alprazolam (Xanax), clonazepam (Klonopin), and lorazepam (Ativan).

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Injuries / Complications / Concerns

Data from 2018 show that roughly 5.4 million people in the United States aged 12 years and older abused or misused benzodiazepines in the previous year.

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Although the precise risk of benzodiazepine addiction remains unclear, population data "clearly indicate that both primary benzodiazepine use disorders and polysubstance addiction involving benzodiazepines do occur," the FDA said.

Data from the National Survey on Drug Use and Health from 2015 to 2016 suggests that a half million community-dwelling US adults were estimated to have a benzodiazepine use disorder.

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Overdose deaths involving benzodiazepines jumped from 1298 in 2010 to 11,537 in 2017 — an increase of more 780%. Most of these deaths involved benzodiazepines taken with prescription opioids.  Before prescribing a benzodiazepine and during treatment, a patient's risk for abuse, misuse, and addiction should be assessed, the FDA said.

They urge particular caution when prescribing benzodiazepines with opioids and other central nervous system depressants, "which has resulted in serious side effects, including severe respiratory depression and death.”

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The FDA reviewed postmarketing databases and the published literature on the use of benzodiazepines and associated abuse, misuse, addiction, and physical dependence. In 2019, an estimated 92 million benzodiazepine prescriptions were dispensed from U.S outpatient pharmacies, with alprazolam (38%) being the most common followed by clonazepam (24%) and lorazepam (20%). In 2018, an estimated 50% of patients who were dispensed oral benzodiazepines received them for a duration of two months or longer.

Postmarketing data suggest that benzodiazepine abuse and misuse are common and that associated harms are substantial but occur primarily when people use benzodiazepines in combination with other drugs. In 2018, an estimated 5.4 million U.S. individuals 12 years and older abused or misused benzodiazepines in the previous year.

In 2016, the nationally estimated number of emergency department (ED) visits due to nonmedical use of benzodiazepines (n=167,845) was higher than the corresponding estimate for prescription opioids (n=129,863). A relatively smaller proportion involved benzodiazepines alone – 14% (n=23,335) compared to 31% (n=40,499) of visits due to prescription opioid nonmedical use. Similarly, among the 8,761 U.S. poison control center calls involving benzodiazepine misuse or abuse in 2017, 63% involved multiple substances – most commonly prescription opioids, alcohol or stimulants – and medical outcomes in these cases were more severe than in cases involving benzodiazepines alone.

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Benzodiazepine-involved overdose deaths increased from 1,298 in 2010 to 11,537 in 2017.6 The proportion of these reported deaths documenting involvement of only benzodiazepines alone was small and decreased over this period, from 3.7% in 2010 to 2.7% in 2017. From 2013-2017, 55% of benzodiazepine-involved overdose deaths also documented involvement of prescription opioids.

The exact risk of addiction associated with benzodiazepine use is uncertain; however, population data clearly indicate that both primary benzodiazepine use disorders and polysubstance addiction involving benzodiazepines do occur. In one published analysis of National Survey on Drug Use and Health data from 2015 to 2016, a half million community-dwelling U.S. adults were estimated to have a benzodiazepine use disorder.7 In 2017, approximately 1% (n=10,316) of admissions to publicly-funded substance use disorder treatment programs indicated that benzodiazepines were the primary drug of abuse; however, an additional 7% and 10% of admissions indicated benzodiazepines were the secondary and tertiary drug of abuse, respectively.8 For context, the primary drug of abuse was prescription opioids in approximately 3.6% of admissions, and the majority of admissions listed the primary drug of abuse as a non-pharmaceutical substance such as alcohol (33%), heroin (31%), marijuana/hashish (12%), and methamphetamine/speed (6.3%).

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Epidemiologic data on benzodiazepine dependence and withdrawal are scarce. A small number of published longitudinal studies identified female sex, older age, mental health conditions and concomitant use of certain medications (e.g., antidepressants) as possible risk factors for long-term or high-dose benzodiazepine use or dependence.9-11

We evaluated 104 cases from the FDA Adverse Event Reporting System (FAERS) database of abuse, dependence, or withdrawal involving a benzodiazepine as a single drug substance reported by patients or health care professionals directly to FDA from January 1, 1968, through June 30, 2019. While this is a small subset of FAERS cases received for benzodiazepines as a whole, we selected a focused case series to identify the most descriptive reports of dependence or withdrawal. Most patients reported that dependence and subsequent withdrawal symptoms developed even when the benzodiazepine (clonazepam, alprazolam, lorazepam, diazepam, triazolam, or oxazepam) was prescribed for therapeutic use. However, patients or others using these medications are unlikely to report directly to FDA about abuse or illicit uses. Approximately 80% of the FAERS cases described benzodiazepine withdrawal, including CNS effects (e.g., insomnia, increased anxiety or panic attacks, memory impairment, depression), cardiovascular effects (e.g., heart rate or rhythm fluctuations), and gastrointestinal effects (e.g., abdominal pain, nausea, diarrhea).

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These cases reported a wide range of time to dependence, with some describing the onset as early as days to weeks after the start of a benzodiazepine. Similarly, there were variations in the duration of the withdrawal symptoms that lasted from weeks to years. Most of the FAERS cases reported use of the benzodiazepine for months to years. In some cases, the patient reported that the prescriber abruptly discontinued the benzodiazepine rather than prescribing a taper to mitigate withdrawal symptoms. An important limitation in the assessment of these cases was the difficulty in differentiating withdrawal symptoms from potential re-emergence or continuation of symptoms for which the benzodiazepine was being used.

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Based upon this information, we believe the injuries and complications involved in the warning label change include overdose, death due to overdose, addiction to benzodiazepines and other illicit drugs, and withdrawal symptoms that include cardiovascular effects such as heart rate or rhythm fluctuations, gastrointestinal effects such as abdominal pain and diarrhea.

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According to the release by the FDA, the following are included in the new warning:

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Information on the Topic of Benzodiazepines

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FDA Requires Stronger Warning Label for Xanax, Valium and Other Similar Benzodiazepine Drugs (9-24-2020)

https://www.usatoday.com/story/news/health/2020/09/24/fda-requires-stronger-warning-label-xanax-valium-similar-drugs-benzodiazepine/3516126001/

FDA Orders Stronger Warnings on Benzodiazepines (9-24-2020)

https://www.medscape.com/viewarticle/937997

FDA Requiring Labeling Changes for Benzodiazepines (9-23-2020)

https://www.fda.gov/news-events/press-announcements/fda-requiring-labeling-changes-benzodiazepines

FDA Requiring Boxed Warning Updated to Improve Safe Use of Benzodiazepine Drug Class (9-23-2020)

https://www.fda.gov/drugs/drug-safety-and-availability/fda-requiring-boxed-warning-updated-improve-safe-use-benzodiazepine-drug-class

FDA Requires Stronger Warning Label for Xanax and Similar Drugs (9-23-2020)

https://www.nytimes.com/2020/09/23/health/benzodiazepines-fda-warning.html

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Benzodiazepines to Carry Abuse, Addiction Warnings (9-23-2020)

https://www.medpagetoday.com/publichealthpolicy/fdageneral/88782?xid=nl_mpt_DHE_2020-09-24&eun=g1234948d0r&utm_source=Sailthru&utm_medium=email&utm_campaign=Daily%20Headlines%20Top%20Cat%20HeC%20%202020-09-24&utm_term=NL_Daily_DHE_dual-gmail-definition

Understanding Benzodiazepines: Commonly Prescribed but Caution Advised

(4-20-2020)

https://www.psychiatrictimes.com/view/understanding-benzodiazepines-commonly-prescribed-caution-advised

Who Discovered Xanax? (3-13-20)

https://www.therecoveryvillage.com/xanax-addiction/who-discovered-xanax/

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Halcion Prescribing Information (10-2019)

https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/017892s050lbl.pdf

Generic Clobazam (Onfi) Tablets Granted FDA Approval (10-24-2018)

https://www.pharmacytimes.com/news/generic-clobazam-tablets-granted-fda-approval

Doral Prescribing Information (10-2016)

https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/018708s023lbl.pdf

Limbitrol Medication Guide (9-2016)

https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/016949s040lbl.pdf#page=12

Drug Approval Package – Xanax XR (1-17-2003)

https://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/21-434_Xanax_Approv.pdf

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Drug Approval Package – Ativan

https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=017794

Drug Approval Package – Diastat

https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&varApplNo=020648

Drug Approval Package – Doral

https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=018708

Drug Approval Package – Halcion

https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=017892

Drug Approval Package – Klonopin

https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=017533

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Drug Approval Package – NDA 012750 – Librax

https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=012750

Drug Approval Package – Librium

https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=012249

Drug Approval Package – Limbitrol

https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=016949

Drug Approval Package – Nayzilam

https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211321Orig1s000TOC.cfm

Drug Approval Package – Restoril

https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=018163

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Drug Approval Package – Seizalam

https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/209566Orig1s000TOC.cfm

Drug Approval Package – Tranxene

https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=017105

Drug Approval Package - Valtoco

https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=211635

Valtoco Prescribing Information

https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/211635s000lbl.pdf

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