Benzodiazepines

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Manufacturer 

 

Pfizer                                                $202.16 Billion
Xanax (Alprazolam)  
Xanax XR
Halcion (Triazolam)
Seizalam (Midazolam)

 

FDA Approval 

 

Xanax                                  NDA 018276 - October 16, 1981
Xanax XR                            NDA 021434 - January 17, 2003
Generic Xanax                   Multiple (First) - October 31, 1993
Generic Xanax XR             Multiple (First)  - January 27, 2006
Halcion                               NDA 017892 - November 15, 1982
Generic Halcion                HICKMA - June 1, 1994
Seizalam                            NDA 209566 - September 14, 2018
Generic Seizalam             None

MDL Information 

 

No information at this time

Manufacturer 

 

Sunovion Pharmaceuticals               $202.16 Billion
 
Lunesta
(Eszopiclone)

 

FDA Approval 

 
Lunesta                             NDA 021476              December 15, 2004
Generic Lunesta              Multiple (First)           April 15, 2014

MDL Information 

 

No information at this time

Manufacturer 

 

Roche Laboratories                $299.12 Billion
Valium
(Diazepam)
Klonopin
(Clonazepam)

 

FDA Approval 

 
Klonopin                             NDA 017533 - June 4, 1975
Generic Klonopin              Multiple (First) - October 31, 1996
Valium                                 NDA 013263 - November 15, 1963
Generic Valium                  Multiple - November 1, 1985

MDL Information 

 

No information at this time

Manufacturer 

 

Bausch (1 of 2)                          $5.77 Billion
(Valeant Pharmaceuticals)  
 
Librax (Chlordiazepoxide HCI/Clidinium Bromide)
Librium (Chlordiazepoxide HCI)
Diastat (Diazepam)
Diastat AcuDial (Diazepam)

FDA Approval 

 
Librax                                    NDA 012750  September 1, 1966
Generic Librax                     Multiple  July 7, 2020 
Librium                                 NDA 012249  February 24, 1960
Generic Librium                  Teva  June 10, 1976
Diastat                                  NDA 020648  July 29, 1997
Generic Diastat                   Teva  September 2010

MDL Information 

 

No information at this time

Manufacturer 

 
Bausch (2 of 2)                       $5.77 Billion
(Valeant Pharmaceuticals)  
 
Ativan (Lorazepam)
Dalmane (Flurazepam)

FDA Approval 

 
Ativan                                      NDA 017794  September 30, 1977
Generic Ativan                       Multiple  April 21, 1987
Dalmane                                 NDA 016721  April 7, 1970
Generic Dalmane                  Mylan  June 2, 1985

MDL Information 

 

No information at this time
Manufacturer
 
Heritage Pharmaceuticals      Private
(Avet Pharmaceuticals)  
 
 
Limbitrol
(Chlordiazepoxide HCI/Amitriptyline HCI)
Limbitrol DS

FDA Approval 

 
Limbitrol                                    NDA 016949 - December 23, 1977
Generic Limbitrol

MDL Information 

No information at this time

Manufacturer 

 
Lundbeck Pharmaceuticals        N/A
Onfi
(Clobazam)
 
 

FDA Approval 

 
Onfi                                     NDA 202067 - October 21, 2011
                                            NDA 203993 - December 14, 2012
Generic Onfi                      Breckenridge - October 23, 2018 
 

MDL Information 

 
No information at this time

Manufacturer 

 

Recordati Rare Diseases Group  $9.86 Billion
 
 
Tranxene
(Clorazepate)
 
 

FDA Approval 

 
Tranxene                       NDA 017105  - June 23, 1972
Generic Tranxene        Multiple - July 17, 1987 
 

MDL Information 

 
No information at this time

Manufacturer 

 

GALT Pharmaceuticals  $154.01 Million
 
Doral
(Quazepam)
 
 

FDA Approval 

 
Doral                             NDA 018708 - December 27, 1985
Generic Doral              None
 

MDL Information 

 
No information at this time

Manufacturer 

 
SpecGx LLC                       $80.51 Million
(Mallinckrodt) 
 
Restoril
(Temazepam)
 
 

FDA Approval 

 
Restoril                                 NDA 018163 - February 27, 1981
Generic Restoril                  Multiple - July 7, 1986
 
MDL Information 
 
No information at this time

Manufacturer 

 
Proximagen                        Private
(Upsher-Smith) 
 
Nayzilam
(Midazolam)
 
 

FDA Approval 

 
Nayzilam                                 NDA 211321  May 17, 2019
Generic Nayzilam                  None
 
 

MDL Information 

 
No information at this time

Manufacturer 

 
Neurelis                                 Private
 
Valtoco
(Diazepam)
 
 

FDA Approval 

 
Valtoco                                  NDA 211635 - January 10, 2020
Generic Valtoco                   None
 
 

MDL Information 

 
No information at this time

Background

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).

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.
 
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.
 
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.”
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.
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%).
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).
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.
 
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.
According to the release by the FDA, the following are included in the new warning:

Information on the Topic of Benzodiazepines

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

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/

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

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

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

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