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Executive Summary

UPJOHN's XANAX PANIC INDICATION: FDA APPROVED DOSING for alprazolam recommends starting treatment at a 0.5 mg three times daily regimen similar to existing dosing patterns for anxiety treatment. However, the upper dosage limits for the panic indication far exceed the anxiety schedule. In clinical trials, the mean panic dosing was between 5 mg and 6 mg daily. About 18% of the 1,700 patients in the panic clinical trials "received maximum Xanax dosages of greater than 7 mg/day," the labeling states. Xanax received a "3B" rating (modest therapeutic gain). The change in dosing levels for the panic indication, approved by FDA on Nov. 6, provided Upjohn with the opportunity to bring out a higher dosage form of the tablet. The company is introducing a new 2 mg tablet, double the dosage of the largest tab previously on the market. That new tab (white, oblong and multi-scored) could be useful in gaining the Upjohn brand some extended protection from competition in 1993 (when the patent on the original product expires) and should give the product a boost from a new price schedule. The original alprazolam patents expire in mid-September and mid-October 1993. The exclusive panic indication will run several weeks longer, until Nov. 6, 1993. Because the panic indication higher dosage exceeds the advised "lowest possible effective dose" recommendation for anxiety, there appears to be little rationale for the first generic versions to seek a dose above 0.25 mg or 0.5 mg. That could complicate the ANDA strategies for generic firms by creating a double set of ANDA filing requirements: the lower levels for initial approval for the anxiety indication and then a higher dosage for panic. After initial dosage build-up for anxiety treatment, the standard daily dose for Xanax is 4 mg in two daily doses. That indicates that the new Xanax dosage form could have a convenience factor for existing anxiety patients. The new indication and dosage form also allows Upjohn to change Xanax pricing: the trade cost for the new dosage is $98.69 per 100 tablets compared to the 0.5 mg tablet price of $43.50 per 100. The company is planning to announce the official launch of the product in January. The Xanax panic use has reportedly been well-known in the medical community prior to approval and some figures have put off-label uses of the drug in the 15% range. Upjohn estimates that 3 mil. people in the U.S., "between 1% and 2% of the population, will suffer from panic disorder in their lifetime." The company said, however, that only 25% of those diagnosed, or 750,000, are actually treated. Professional labeling for Xanax states the drug is indicated for the "treatment of panic disorder, with or without agoraphobia." In the labeling panic disorder is characterized as recurrent panic attacks which initially occur unexpectedly but later may become associated with certain situations such as driving a car or being in crowded places. "The diagnosis requires four such attacks within a four week period or one or more attacks followed by at least a month of persistent fear of having another attack," labeling specifies. Panic attacks must be characterized by at least four of the symptoms listed in the labeling. These include: smothering sensations; dizziness; palpitations or tachycardia; trembling or shaking; choking; nausea or abdominal distress; depersonalization or derealization; hot flashes or chills; chest pains; fear of dying; fear of going crazy or of doing something uncontrolled. Labeling notes that patients with panic disorder were treated for four to ten weeks in controlled clinical trials, and that "patients with panic disorder have been treated on an open basis for up to eight months without apparent loss of benefit." In clinical trials in 1,700 patients with panic disorder, 82% of alprazolam-treated patients had moderate improvement compared to 43% of placebo-receiving patients after four weeks of therapy. The number of patients free of panic attacks after four weeks was 50% for the Xanax group compared to 28% for placebo. Warnings are significantly expanded in the new labeling to highlight withdrawal symptoms associated with the drug, the most important of which is seizure. According to the labeling, eight patients of 1,980 patients with panic disorder experienced seizures when Xanax therapy was discontinued. Other withdrawal symptoms included impaired concentration, clouded sensorium, muscle cramps, muscle twitch, diarrhea, blurred vision, appetite decrease and weight loss. At a meeting of FDA's Psychopharmacological Drugs Advisory Committee in September 1989, the FDA medical reviewer for the Xanax application, 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. However, Graham's calculations were based on Xanax postmarketing data. In the clinical trials, the two groups had similar rates of seizures and the overall seizure rate was similar to other benzodiazepines. Upjohn has agreed to conduct postmarketing studies to investigate the withdrawal effects of Xanax in panic disorder. The company has also committed to addressing questions regarding acute dose response and chronic dose response. In its approval letter to Upjohn, FDA said that it will contact the company "shortly" to discuss study proposals. FDA also noted that Upjohn has agreed to work with the agency to develop a patient education program. The FDA advisory committee, which considered Xanax for the indication last year, recommended that the company provide a patient package insert upon marketing of the drug. The package insert should include rebound/relapse issues, difficulty of withdrawal from Xanax, the availability of alternative treatments, and the seizure/dose relationship, the committee decided, "so that patients can be informed at the outset of just exactly what they are [getting] into" ("The Pink Sheet" Sept. 25, 1989, p. 11).

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