The “current prescribing information for benzodiazepines does not provide adequate warnings about [the] serious risks and harms associated with these medicines so they may be prescribed and used inappropriately.”
The FDA statement above was made regarding class labeling of benzodiazepines as the agency called for an update to the current Boxed Warning. The revised must include additional information on the risks of abuse, misuse, addiction, physical dependence and withdrawal reactions associated with this drug class.
The requirement for the update is the outcome of an FDA review of postmarketing databases and published literature on benzodiazepine use and these associated risks. The review evaluated 104 cases from the FDA Adverse Event Reporting System (FAERS) database from January 1, 1968 through June 30, 2019, which represented a small subset of FAER cases but identified the most descriptive reports of dependence or withdrawal:
- 80% of cases described benzodiazepine withdrawal, reported even when the drug was prescribed for therapeutic use
- Most cases reported use of the agents for months to years.
- Time to dependence after drug initiation ranged from days to weeks
- Withdrawal symptoms were found to last from weeks to years.
- Abrupt discontinuation vs dose tapering was described in some cases; most likely the cause of withdrawal symptoms.
To mitigate the potential for benzodiazepine-related adverse events, the Agency recommends the following:
• Assess the patient’s risk for abuse, misuse, and addiction before prescribing benzodiazepines. • Consider all therapeutic options to manage the patient’s condition. • Limit the dosage and duration to the minimum needed to achieve the clinical effect. • When prescribing benzodiazepines, use caution with opioids or other drugs that depress the central nervous system.
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• Medication management is imperative when benzodiazepines are used in combination with opioid addiction medications. • Patients should be alerted about the risks of abuse, misuse, addiction, dependence, and withdrawal with these drugs. • Follow-up should be done regularly.
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• Avoid abrupt cessation if possible; use a gradual taper to discontinue treatment or for dose reduction. • If a patient experiences withdrawal symptoms, it may be necessary to pause the taper or increase the dose and then proceed with a more gradual taper.
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• If very short-term agents (ie, diazepam injection, nasal spray, rectal gel; midazolam nasal spray, injection; lorazepam injection) are used inappropriately (long-term use), abrupt discontinuation or dose reduction can lead to acute withdrawal reactions.
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• Be aware of protracted withdrawal syndrome, which may persist beyond 4-6 weeks and initial benzodiazepine withdrawal. • Symptoms (ie, anxiety, cognitive impairment, depression, insomnia, formication, weakness, tremor, muscle twitches, paresthesia, tinnitus) may last weeks to months.
Adverse events should be reported to FDA’s MedWatch program.
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