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Executive Summary

Pfizer's once-daily oral macrolide antibiotic Zithromax (azithromycin) is safe and effective for use against streptococcal pharyngitis and chlamydial cervicitis and urethritis, FDA's Anti- Infective Drugs Advisory Committee unanimously agreed at its July 18 meeting. "Satisfactory efficacy has been established for the use of azithromycin in a five-day regimen for treatment of Group A streptococcus pharyngitis in adults," committee Chairman Thomas Beam, MD, Buffalo VA Medical Center, stated. The regimen for Zithromax for strep throat is a five-day course in which patients receive one 500 mg dose on the first day and 250 mg once a day for the following four days. In its presentation to the committee, Pfizer stressed the drug's long half-life in tissue -- 70 hours compared to the 12-hour half-life of penicillin -- which allows the product to be effective in a once-daily dose for a shorter course of therapy than most standard antibiotic treatments. Penicillin and erythromycin, for example, require 7-10 day courses of therapy and must be taken 3-4 times daily. In support of the streptococcal indication, Pfizer presented pooled data from two pivotal U.S. trials for Zithromax in approximately 850 evaluable patients with streptococcal infections of the pharynx. Azithromycin was administered in the five day, once-daily regimen. Penicillin B, given in four daily doses of 250 mg for 10 days, was the control for both studies. Eradication of infection for the azithromycin arm was 91% compared to 94% in the penicillin arm, a difference that was not considered statistically significant. For streptococcal infections of the throat, Zithromax is to be indicated as a second-line therapy for use in adults. The product labeling will contain a statement that "penicillin is the drug of choice for treatment and prevention of streptococcal infections including prophylaxis of rheumatic fever. Zithromax is generally effective in eradication of streptococcus from the pharynx. However, as with all antibiotics besides penicillin, data establishing the efficacy of Zithromax in the subsequent prevention of rheumatic fever are not available." The product labeling for erythromycin products carrying an indication for streptococcus pharyngitis contains a similarly-worded statement. The agency asked the committee for its advice on establishing a recommended follow-up period in which patients should return for doctors to establish complete eradication of strep throat infection. Azithromyin's long half-life in tonsillar tissue makes proper follow up a concern, the agency indicated, since a diagnosis of complete cure cannot be made unless the infection remains absent after the antibiotic is no longer present. "Our recommendation would be that an appropriate time for follow up can be established," chairman Beam stated. However, the committee did not recommend a specific time frame. Invited guest and former committee member Floyd Denny, MD, University of North Carolina, suggested a follow-up period of between 90 days and six months after completion of therapy. The verdict for the chlamydial indication was summed up by FDA reviewer Debra Bowen and unanimously assented to by the panel: "Treatment of chlamydia by a single gram oral dose of azithromycin compares favorably to a seven-day course of doxycycline and meets standard 95% confidence intervals in both male and female populations." Data on 326 patients treated with Zithromax for the chlamydial indications for infections of the cervix and urethra were described by Pfizer in the second half of its presentation. The data included five randomized studies in 18 sites in Europe and a single large U.S. randomized trial at 21 centers. In all the studies, patients with chlamydia were treated with a single 1 g dose given once, while controls received the standard therapy of doxycycline twice daily for seven days. The studies found that azithromycin was equivalent in efficacy to doxycycline. Zithromax's one-time, one-dose regimen for chlamydia may effect a "long awaited change" to treatment of sexually transmitted disease, where treatment compliance is a significant concern, Beam stated in summing up committee discussion. In a recent study of chlamydia in adolescents in Indianapolis, only 58% of men and 48% of women complied with a seven-day regimen of antibiotics, STD researcher Robert Johnson, University of Indiana, told the committee in presenting azithromycin data. Pfizer Group Director of Clinical Research Jeff Stritar also told the committee that azithromycin has a superior safety profile to currently standard antibiotic therapies for the two indications: in head-to-head studies with erythromycin, Stritar said, only 7.02% patients on azithromycin reported side effects compared to 21% of erythromycin patients, including significantly fewer gastrointestinal side effects. The rate of discontinuation of therapy due to side effects for erythromycin was 5.3% compared to 0.2% for Zithromax. The NDA for azithromycin was filed in early 1990. Pfizer also plans to seek approval of the anti-infective for the treatment of Haemophilus influenzae. The data for that use is currently at an "advanced stage," Pfizer told the committee. Zithromax has been given to 4,949 patients in clinical trials of the drug in a number of indications, including skin and skin structure infections and upper and lower respiratory tract infections. The drug is awaiting approval in 24 countries and has received preliminary approvals in Italy and the U.K. Azithromycin is also marketed in Eastern Europe, and approximately a half- million people have been treated since the drug was first launched in Europe, with no unusual or unexpected adverse reactions reported, Pfizer says. Separate clinicals for Zithromax for strep throat in children are currently underway. At a 1990 analysts' meeting prior to the NDA filing, Pfizer predicted that as it picked up indications, Zithromax would compete against doxycycline, amoxicillin and Abbott's clarithromycin ("The Pink Sheet" Jan. 24, 1990, p. 15).

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