BRISTOL-MYER's BUSPAR (BUSPIRONE) WILL BE LAUNCHED IN EARLY DECEMBER; APPROVED LABELING CALLS DRUG "LESS SEDATING", "NO POTENTIAL FOR ABUSE"

Mead Johnson will launch BuSpar (buspirone) in the U.S. in December with labeling which strongly differentiates the drug from existing anxiolytics. The FDA-approved labeling for the anxiolytic declares that the drug is "an antianxiety agent that is not chemically or pharmacologically related to the benzodiazepines, barbiturates, or other sedative/anxiolytic drugs." FDA approved the product on Sept. 29. BuSpar "lacks the prominent sedative side effect that is associated with more typical anxiolytics," labeling states. Studies "indicate that BuSpar is less sedating than other anxiolytics and that it does not produce significant functional impairment." In contrast to the blanket caution in benzodiazepine labeling against operating an automobile or complex machinery, BuSpar's labeling cautions against those functions "until [patients] are reasonably certain that buspirone treatment does not affect them adversely." Mead Johnson took almost four years to get FDA approval for BuSpar; however, the products is emerging from the regulatory clearance process with a relatively clean label. Bristol-Myers filed for NDA approval in December 1982. The product was favorably reviewed by an advisory committee less than a year later, in September 1983. The long three-year wait after the advisory committee review was apparently required to get the clean label. BuSpar is not a controlled substance. Labeling prominently states that "in human and animal studies, BuSpar has shown no potential for abuse or diversion and there is no evidence that it causes tolerance, or either physical or psychological dependence." In a press release announcing the drug's approval, Bristol-Myers maintained that "unlike the benzodiazepines, BuSpar does not cause the euphoric or sedative effects which can often lead to abuse." Labeling notes that the drug was tested in "human volunteers with a history of recreational drug or alcohol usage" and "none of the [trial] subjects were able to distinguish between BuSpar and placebo." The labeling compares the lack of response to BuSpar as a drug of abuse directly to two other other anxiolytics. "By contrast," it says, "subjects showed a statistically significant preference for methaqualone and diazepam." The company also noted that "in clinical trials, patients receiving BuSpar have not exhibited a withdrawal syndrome, even when therapy was abruptly discontinued." Bristol-Myers indirectly estimated the target population for BuSpar by citing a National Institutes of Mental Health study that indicated that roughly 8% of the U.S. population "could be expected to suffer from an anxiety disorder" during a six-month period. Labeling, however, does carry a warning against abruptly changing patients on CNS active drugs. "Because BuSpar does not exhibit cross-tolerance with benzodiazepines and other common sedative/hypnotic drugs, it will not block withdrawal syndrome often seen with cessation of therapy with these drugs. Therefore, before starting therapy with BuSpar, it is advisable to withdraw patients gradually . . . from their prior treatment." To protect against adverse effects from rapid shifts to BuSpar, FDA's approval is contingent upon a Phase IV post-marketing study "to determine to what degree prior exposure to benzodiazepine treatment affects the clinical efficacy of BuSpar." The approved labeling indicates that FDA will also watch for signs of neuroleptic-like activity in the expanding patient population after marketing begins. Under a section labeled, "Possible Concerns Related to Buspirone's Binding to Dopamine Receptors," the labeling notes that "clinical experience in controlled trials has failed to identify any significant neuroleptic-like activity; however, a syndrome of restlessness, appearing shortly after initiation of treatment, has been reported in some small fraction of buspirone treated patients." The labeling notes that some questions have been raised about the drug's "potential to cause acute and chronic changes in dopamine mediated neurological function." The labeling concludes that "generally, long-term sequelae of any drug's use can be identified only after several years of marketing." In a separate section, labeling notes that foreign use has shown no unexpected incidence of adverse reactions. FDA expects Mead Johnson to perform a multiple dose bioavailability study on the 5 mg and 10 mg ovoid-rectangular tablets and a reference oral solution. The drug is formulated in ovoid (pillow-shaped) white tabs with three embossed marks: MJ logo, the strength, and the tradename, BuSpar. The labeling will include bioavailability data on the ovoid tablets rather than round tablets. FDA agreed to allow labeling to discuss the ovoid formulation on the condition that Mead Johnson agreed "to update the bioavailability/pharmacokinetic information in labeling when the Phase IV steady state bioavilability study is completed. The recommended initial dose is 15 mg (three 5 mg tabs daily). Labeling suggests increasing the dosage by 5 mg per day "at intervals of 2 to 3 days" to "achieve an optimal therapeutic response." The maximum daily dose is 60 mg per day. The product is indicated for short-term use: efficacy was not shown for more than three to four weeks. Labeling notes, however, that patients have been treated with BuSpar for several months without ill effect. Because of its different qualities from other anxiolytics, BuSpar carries slightly more limited indications. For example, it does not carry an indication as a muscle relaxant or for convulsive disorders. The approved labeling defines anxiety according to the American Psychiatric Association's Diagnostic and Statistical Manual III, and includes four sets of symptoms to identify anxiety suitable for drug treatment. While BuSpar does not carry a specific indication for use in the elderly, the drug's labeling notes that "several hundred elderly patients have participated in clinical studies . . . and no unusual adverse age related phenomena have been identified." The model total daily dose for elderly patients (where the information was available) matched the figure for the total sample of clinical trial patients. Mead Johnson already has experience in the psychopharmacologic drug class with Desyrel (trazodone), an antidepressant marketed for four years. The company is planning an extensive educational/promotion campaign for the launch, aimed toward health care professionals. The firm said a "simulcast" conference on the drug is tentatively scheduled for January. The simulcast, which will be broadcast via satellite to hospitals and clinics across the country, will feature informational presentations on the new anxiolytic and will allow viewer participation. Mead Johnson said it is also planning a series of educational seminars at various locations across the country prior to the simulcast.