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BENZODIAZEPINE SLEEP AID RELABELING SHOULD INCLUDE UNIFORM INDICATION

Executive Summary

BENZODIAZEPINE SLEEP AID RELABELING SHOULD INCLUDE UNIFORM INDICATION "that emphasizes the importance of short-term use and the careful evaluation of patients," a letter from FDA to manufacturers of short-acting benzodiazepine hypnotics says. "We ask that you adopt this language verbatim . . .: (BRACKET)drug name(BRACKET) is indicated for the short-term treatment of insomnia (generally 7-10 days). Use for more than 2-3 weeks requires complete reevaluation of the patient (See Warnings). Prescriptions for (BRACKET)drug name(BRACKET) should be written for short-term use (7-10 days) and it should not be prescribed in quantities exceeding a 1-month supply." The letters, signed by Neuropharmacological Drug Products Division Director Paul Leber, MD, were sent Dec. 3. FDA said Nov. 20 that it would seek benzodiazepine class relabeling after its agreement with Upjohn to relabel Halcion (triazolam) in the wake of European regulatory action ("The Pink Sheet" Nov. 25, p. 11). Europe's CPMP on Dec. 11 also decided to expand its Halcion review to include all similar drugs (see preceding T&G). "There has been much concern recently about the misuse of benzodiazepine hypnotics," the letter says, "particularly the use of these drugs for longer durations than is appropriate and their use in patients not adequately evaluated for the presence of underlying psychiatric or physical disorders that are manifested by insomnia. Consequently, we are asking the manufacturers of benzodiazepine products marketed specifically as hypnotics to: "make a series of changes in the text of their professional product labeling"; "provide supplies of their product intended for distribution to ambulatory, non-institutionalized patients in unit of use packages containing no more than 10 night's supply"; "attach a patient package insert (PPI) to these units-of-use packages." The letter provides standardized warnings and a patient package insert identical to the revised Halcion label. Benzodiazepine manufacturers "should immediately undertake to manufacture unit-of-use packaging . . . that will provide for no more than a 10-day supply," the letter says. "We recognize that some time may elapse before the unit of use packaging can be implemented; in the interim, the PPI should be distributed to retail pharmacies for distribution to patients," the letter advises. "Finally," FDA requested that "Dear Doctor" letters "announcing these changes be issued." Other drugs in Halcion's class include: temazepam (Sandoz' Restoril and generics), quazepam (Baker-Cummins' Doral, marketed by Carter-Wallace), flurazepam (Roche's Dalmane and generics) and estazolam (Abbott's ProSom). Roche and Abbott both said they have received the letter and are formulating responses. Manufacturers may resist the agency's assertion that the various drugs are similar enough to support class labeling. ProSom, for example, was launched only this year and has the benefit of comparative data to Halcion ("The Pink Sheet" Jan. 7, p. 13). The company may ask FDA for means of differentiating its product in the new label. In the Dec. 12 New England Journal of Medicine, a series of letters responding to a June 13 article on the use of triazolam in the elderly indicated a division of opinion in the medical community as to whether Halcion's side effect profile is unique. Anthony Kales, MD, Pennsylvania State University, who has submitted a citizen petition calling for FDA to withdraw Halcion, argued that "three serious types of adverse reactions are unique to triazolam or, at a minimum, that their rates are much more frequent than the rates with other benzodiazepines." Frank Ayd, MD, who chaired a committee organized by Upjohn to evaluate adverse reaction reports on Halcion in 1979, wrote that "subsequent studies and clinical reports have indicated that triazolam has major side effects that would not necessarily have been detected in the early studies." He argued that Halcion may lose its efficacy after repeated use more quickly than other benzodiazepines. The authors of the original article, led by David Greenblatt, MD, Tufts University School of Medicine, responded that "the weight of medical and scientific evidence does not support the conclusion that triazolam has unique or unusual properties." Another concern manufacturers may have with the relabeling effort is the call for a patient package insert. Drug companies traditionally oppose PPIs as costly and unwieldy. FDA has announced a new voluntary patient information initiative that implicitly rejects PPIs for general use in all drug classes.

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