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UPJOHN’s HALCION (TRIAZOLAM) SIDE EFFECTS BOX WARNINGS

Executive Summary

UPJOHN's HALCION (TRIAZOLAM) SIDE EFFECTS BOX WARNINGS addressing withdrawal seizures, aggressive behavior and amnesia are sought by Public Citizen's Health Research Group in an April 19 citizens petition to FDA Center for Drug Evaluation Director Carl Peck. The HRG petition specifically urges box warnings for both patients and physicians stating that Halcion causes the following side effects "considerably more often" than other products in its class: "amnesia of events occurring after Halcion is taken, anxiety, agitation, bizarre and aggressive behavior, confusion, delirium, depression, hallucinations, paranoia, and withdrawal seizures." FDA's Psychopharmacologic Drugs Advisory Committee recommended in September a relabeling of Halcion to suggest a greater possibility of amnesia than with other benzodiazepines ("The Pink Sheet" Sept. 25, p. 13). Referring to that decision, HRG commented that "unfortunately, the advisory committee disregarded the FDA's own evidence that triazolam is also reported to produce 8-34 times more agitation, psychosis, confusion, hostility/intentional injury and withdrawal seizures than temazepam, and voted against incorporating this into drug labeling." The internal discussions at FDA about Halcion make an enticing area for HRG publicity. Some internal FDA notes relating to the Neuropharmacologic Drug Division have been circulating outside of FDA. One congressional staff interested in drug approval decisions responded, "No comment," when asked about Halcion. HRG notes that the incidence of central nervous system side effects with Halcion compared to another benzodiazepine hypnotic, temazepam (Sandoz' Restoril), was determined by two studies conducted by FDA's Office of Epidemiology and Biostatistics. The studies were undertaken to analyze the high number of adverse reaction reports submitted since the drug's late 1982 launch in the U.S. Aside from amnesia, the greatest differences were reported for seizures, with an adverse reporting rate 34 times higher than for the other sleeping pills analyzed, and hostility or intentional injury, with a reporting rate 19 times higher. The figures are based on the number of adverse reports per one million prescriptions. A third study, conducted in 1987 by Bixler, et al., compared reports of adverse reactions to Halcion during its first year on the market to ADRs submitted for Restoril and Roche's Dalmane (flurazepam) in their first market years. That study showed six different types of CNS side effects -- hyperexcitability, amnesia, cognitive disturbances and psychotic symptoms, affective and behavioral disorders, withdrawal systems and other CNS effects -- were reported 2-47 times more frequently with triazolam. In addition, HRG continues, Halcion's efficacy is "substantially reduced" after two weeks of continuous use. "Although this is currently weakly acknowledged in the labeling, it needs to be emphasized by inclusion in a box warning, particularly since triazolam's side effects (e.g., daytime anxiety and rebound insomnia) may be falsely interpreted as symptomatology necessitating longer-term treatment with triazolam," the petition states. In an April 19 FDA "Talk Paper," the agency said it had not received HRG's petition, but commented generally: "Concern about the side effects of Halcion is not new and has been discussed publicly in detail." As discussed at the September advisory council meeting, "there are more reports of certain adverse psychological and behavioral side effects, such as anxiety, insomnia and hallucinations, with Halcion than other similar drugs. However, all of these same side effects occur with the other sleeping pills." Stressing that "all relevant data" in FDA's files were provided to the panel, the agency adds that the panel concluded that while "reporting rates for certain adverse reactions were higher for Halcion, it was not clear that the actual incidence of adverse reactions with Halcion was higher except for amnesia."
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