UPJOHN XANAX PANIC DISORDER INDICATION SHOULD BE ACCOMPANIED BY PATIENT PACKAGE INSERT ON WITHDRAWAL REACTIONS, FDA ADVISORY COMMITTEE RECOMMENDS

Upjohn's Xanax (alprazolam) should be approved for panic disorder with the understanding that the company provide a patient package insert describing potential adverse reactions associated with withdrawal from the drug, FDA's Psychopharmacological Drugs Advisory Committee recommended at its Sept. 21 meeting. The committee unanimously recommended approval of the new indication and voted six-to-one in favor of a motion that "Upjohn, in collaboration with the FDA, prepare a patient package insert for voluntary distribution" by health care professionals. The patient package insert suggestion was raised by committee member James Claghorn, MD, Clinical Research Associates, Houston, Texas, who commented: "I think its very important that there be some clear labeling changes . . . that include a patient package listing, which would indicate the rebound/relapse issues, the difficulty in some patients with successfully withdrawing, the availability of alternative treatments, and the seizure/dose relationship, so the patients can be informed at the outset of just exactly what they're ]getting[ into." FDA Neuropharmacological Drugs Division Director Paul Leber, MD, indicated that the agency endorses the patient package insert idea, but also recognizes that it is not in keeping with approval requirements for other benzodiazepines. "In this particular instance," Leber said, "the physician, no matter how careful he is, will not have instantaneous data on the observation of a patient. An informed patient may be able to seek the physician out and . . . the alerted physician and patient together may enhance the safety." FDA "wouldn't do this ordinarily," Leber explained, "but I think having heard the discussion today, ]there is a consensus[ that there be some level of safety net offered by enhancing the sensitivity." However, he added, "I think it singles out this drug." Leber also alluded to the possibility that a patient package insert could provide liability protection. He noted that in the U.K. there "is an enormous class action suit being brought against companies, the Department of Health and the CSM ]Committee for Safety of Medicines[ for failure to advise for risk, dependency and use of benzodiazepines." Leber remarked that "it is not unusual for things to move across the Atlantic rather rapidly." The patient package insert recommendation arose, in part, out of the committee's conclusion that the existing data base on Xanax is inadequate to accurately characterize its risks, particularly at the higher dose and longer treatment regimen proposed by Upjohn. The firm is seeking a dosage of up to 10 mg/day for the panic indication. In addition, Upjohn would like to include a statement in the labeling that patients in clinical trials have received the drug for up to eight months. Xanax' current labeling for anxiety recommends a maximum daily dose of 4 mg, and notes that efficacy has not been established for longer than four months. Based on both efficacy and safety issues, the committee recommended that Xanax labeling not specify a maximum dose or duration of therapy, but instead describe clinical experience with the drug in the treatment of panic disorder. FDA identified three studies in Upjohn's supplemental NDA as pivotol trials in support of the panic disorder indication. Agency reviewers agreed that all three support efficacy of the drug. The largest of the three studies randomized 526 patients with panic disorder to Xanax or placebo for eight weeks of therapy. After four weeks of treatment, patients receiving alprazolam experienced 3.3 less panic attacks a week than at baseline, while placebo-treated patients experienced 1.6 fewer panic attacks. Reductions from baseline at week eight were 3.6 for the Xanax group and 1.7 for the placebo groups. Results were highly significant at both time points: p = .001 at week four, and p = .002 at week eight. Approximately 270 patients received Xanax in the study. Roughly 35% (93) of those patients received an alprazolam dose of less than 4 mg/day, while 33% (87) got between 4.1 mg and 6 mg, 21% (55) between 6.1 mg and 8 mg and 12% (31) got over 8 mg. Upjohn's Carl Lewis, MD, reported that most of the dropouts in the study were in the lower dose groups. Eighteen patients in the less than 4 mg/day group dropped out, 12 because of side effects; a total of 13 patients dropped out in the 4.1-6 mg group (nine dropouts) and 6.1-8 mg group (four dropouts), nine because of lack of efficacy; none of the 31 patients in the 8 mg-plus group dropped out. The eight-center study also evaluated long-term efficacy at four centers. Three of the centers continued patients on therapy in a double-blind fashion for up to eight months. A total of 85 patients at the three centers continued on to the long-term phase -- 69 of the 100 originally randomized to receive Xanax and 16 of the 95 originally randomized to get placebo. A fourth center moved into an open label phase where 31 of 50 Xanax-treated patients went on to receive drug for up to eight months and 18 of 48 placebo-treated patients were switched to Xanax. An additional 76 patients received Xanax for up to year in an open label continuation of a comparative study. In total, 194 patients entered the long-term studies, with 98 completing eight months of treatment with alprazolam. The committee's concerns about the safety of higher doses and longer durations of therapy stemmed mostly from an FDA analysis of data from its spontaneous adverse drug reaction reporting system. Based on the post-marketing reports, FDA reviewer David Graham, MD, calculated that the risk of experiencing withdrawal seizures may be 39 times greater for patients receiving doses greater than 4 mg a day than for patients receiving less than 4 mg. Patients taking the drug for more than 120 days, according to Graham's calculations, may be four times more likely to have withdrawal seizures. The postmarketing data, however, is somewhat at odds with clinical trial results, which found a similar rate of seizures in low and high dose groups. In the clinical trials, three seizures were seen in the approximately 600 patients receiving Xanax doses less than 4 mg, while four seizures were seen in the roughly 700 patients receiving doses above 4 mg. The overall seizure rate in the trials was .5%, which Leber noted is similar to other benzodiazepines. Commenting on the dose/safety issue, FDA Psychopharmacologic Drugs Group Leader Thomas Laughren, MD, noted that only 3% of the patients got a dose of alprazolam above 7 mg, which "is a fairly small number upon which to base a maximum recommended dose of 10 mg." Laughren acknowledged that the post-marketing data only provides a "reporting rate ratio," and not an estimate of incidence of withdrawal traumas. However, he said, "I do think they give a very strong signal for an increased risk of various withdrawal trauma at a dose greater than 4 mg compared to less than 4 mg, and a somewhat less strong signal for greater that 120 days ]of treatment[ compared to less than 120 days." Regarding efficacy of long-term treatment, Laughren pointed out that the data supporting approval of the panic indication is based on short-term data, but Upjohn's proposed labeling statement that the drug has been used for up to eight months "tends to imply" that efficacy has been established for long-term treatment.