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In September, 2020, the FDA announced a new boxed warning for benzodiazepines. This is the timeline of how that warning came to be.

Benzodiazepine Information Coalition’s Call-to-Action

Background

  • In 2017, Benzodiazepine Information Coalition led a community-wide reporting drive through MedWatch, the FDA’s adverse event reporting program.
  • We hoped this drive would encourage the FDA to reexamine benzodiazepine safety.
  • We realized that the FDA’s prescribing literature failed to warn about the real risks of harm that patients are experiencing.
  • Patient support groups joined our call-to-action and urged their members to report their harm.
  • As a result, thousands of patients reported their adverse events.

Our FDA Call-To-Action Worked (Sort of)

  • In 2018, the FDA observed an increase in patient adverse event reports.
  • These reports described prolonged symptoms after benzodiazepine withdrawal and failed attempts at discontinuation.
  • The FDA found that this increase in reporting was likely due to our call-to-action.
  • They investigated and discovered several themes in the reports.

FDA Observed Themes

  • Lack of physician education/knowledge regarding benzodiazepine prescribing
  • Lack of patient education by the physician at the time of prescribing
  • Physician-directed tapering schedules that did not prevent withdrawal symptoms
  • In spite of this, the FDA only produced a memorandum, deciding that existing benzodiazepine warnings were sufficient and that the numerous reports required no regulatory action.

The FDA’s Second Look

The FDA Starts a Review

  • In 2019, shortly after reviewing our call-to-action, the FDA began a review of benzodiazepines.
  • They specifically wanted to explore if Xanax was associated with more abuse and dependence than other benzodiazepines.
  • The FDA reviewed 104 cases of adverse events selected from the roughly 300,000 MedWatch adverse event reports.

FDA Review Findings

  • Adverse benzodiazepine events occur with prescribed therapeutic use.
  • Physician education about benzodiazepine safety is lacking.
  • Withdrawal was longer than expected.
  • The median length of withdrawal symptoms was 9.5 months.
  • Physical dependence occurred within days or weeks.
  • Median onset time to physical dependence was 14 days.
  • Abrupt and over-rapid tapers are harming patients.
  • Protracted withdrawals can last 12 months or more post-cessation.
  • In the longest case in the 104-case series, withdrawal symptoms lasted 8 years and were still present.

The FDA Takes Action

  • In September, 2020, the FDA announced a new benzodiazepine boxed warning.
  • The Warning now includes the risks of:
    • abuse
    • addiction
    • physical dependence
    • withdrawal reactions
  • The FDA now recommends:
    • judicious benzodiazepine prescribing
    • gradual benzodiazepine tapering
    • standardized warning labels on all benzodiazepines
Old Benzodiazepine Boxed Warning
New Benzodiazepine Boxed Warning

Canada Takes Action

  • In October, 2020, following the FDA Boxed Warning announcement, Health Canada also took action and updated their safety labels for benzodiazepines and benzodiazepine-like drugs.
  • The update by Health Canada included warnings about the risks of: 
    • problematic use and substance use disorder
    • severe and life-threatening withdrawal symptoms
    • harm when taken with opioids, which may cause deep drowsiness, respiratory depression, coma and death
    • falls and fractures in specified populations

The Benzodiazepine Boxed Warning Remains an Incomplete Achievement

Unaddressed Problems Remain

  • Many problems were not addressed in the warning, including:
    • No help for harmed patients
    • No help for future patients
    • Most prescribers are unaware of the warning’s existence, with no strategy in place to inform them
    • No calls for smaller dosing for safer cessation
    • FDA seems unsure of how to safely taper and offers little guidance beyond “slow”
    • No awareness of the level of harm some patients are suffering
    • No warnings about withdrawal-induced akathisia or fluoroquinolone interactions

Why We Still Consider the FDA’s Boxed Warning a Victory for Patient Safety 

  • The FDA finally took a stance on benzodiazepines after more than 60 years of patient harm and regulator inaction.
  • The FDA officially recognized protracted withdrawal syndromes.
  • The FDA acknowledged the need to for slow tapering.
  • The FDA is an authority recognized by physicians, so patients and activists can cite their findings.
  • University’s Margolis Center for Health Policy held a public workshop, with FDA officials and other benzodiazepine-concerned professionals, to discuss possible solutions.
  • Our director spoke at Duke’s workshop about prescribed benzodiazepine harm:

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