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Regulatory News | 22 February 2016 | By Zachary Brennan
Concerns over the risks of co-prescribing benzodiazepine and opioid drugs has 41 state health officials petitioning the US Food and Drug Administration (FDA) to place a new black box warning on both classes of pharmaceuticals to warn patients and doctors of the potential risks with concomitant use.
“Only a few labels and medication guides contain specific information on the dangers of concurrent use of these two classes of medications; none contain black box warnings,” the officials write in their petition submitted Monday, calling for all labels for opioids to read:
“WARNING: CONCURRENT USE WITH BENZODIAZEPINES [replace with OPIOIDS on benzodiazepine labels] REDUCES THE MARGIN OF SAFETY FOR RESPIRATORY DEPRESSION AND CONTRIBUTES TO THE RISK OF FATAL OVERDOSE, PARTICULARLY IN THE SETTING OF MISUSE.”
The petition comes as a recently published six-year study of US veterans nationwide analyzing the relationship between history of benzodiazepine prescription, dose, type, and schedule and the associated risk of death from a drug overdose among those receiving opioid analgesics from the Veterans Health Administration, found that significantly, the risk of death from drug overdose increased in a synergistic, dose-response fashion as daily benzodiazepine dose increased.
The officials are also calling for FDA to require medication guides for both classes of medications that specifically warn patients of the potential dangers of combined use of opioids and benzodiazepines.
The daily use of a combination of drugs from both classes has steadily increased, the officials warned, also noting that during the month prior to treatment admission, of patients admitted for co-use of opioids and benzodiazepines, 57.1% and 45.5% reported daily use of opioids and benzodiazepines, respectively.
Guidance on Warnings
FDA guidance says a black box warning is appropriate when: “There is an adverse reaction so serious in proportion to the potential benefit from the drug (e.g., a fatal, life-threatening, or permanently disabling adverse reaction) that it is essential that it be considered in assessing the risks and benefits of using the drug;” OR “There is a serious adverse reaction that can be prevented or reduced in severity by appropriate use of the drug (e.g., patient selection, careful monitoring, avoiding certain concomitant therapy, addition of another drug or managing patients in a specific manner, avoiding use in a specific clinical situation).”
The state health officials said both of these conditions for a black box warning are met in this case and the warnings can be added under the authority granted to FDA from the Food and Drug Administration Amendments Act of 2007 (“FDAAA”), which allows the agency to mandate postapproval safety-related labeling changes for both individual drugs and classes of drugs.
“Clinicians should consider the serious adverse reaction of fatal overdose when assessing the risks and benefits of co-prescribing benzodiazepines and opioids,” according to the petition. “Moreover, clinicians can prevent fatal overdose by reducing rates of co-prescribing these classes of medications.”
And as far as objections from those who say all possible combinations between opioids and benzodiazepines have not been fully studied, the officials said: “It is our view that the basic science and epidemiology support class effects that obviate the need for additional research. Moreover, clinicians and patients should generally be aware of the dangers; a strong black box warning will provide a clear general message to improve care and save lives.”
Tags: opioids, benzodiazepine, black box warning, boxed warning