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Executive Summary

Burroughs-Wellcome's antihistamine/decongestant combination product Semprex-D for symptomatic treatment of seasonal allergic rhinitis was recommended for approval by FDA's Pulmonary-Allergy Drugs Advisory Committee at its April 26 meeting. The committee recommended that the acrivastine 8 mg/pseudoephedrine HCl 60 mg capsule be indicated for use in people 12 years old and over at a regimen of four times a day. Burroughs-Wellcome was also seeking an indication for Semprex- D's use in treating perennial allergic rhinitis, but the advisory committee determined that the company's data do not support that indication. Summarizing the committee's conclusion, Chairman Richard Rosenthal, MD, Johns Hopkins School of Medicine, said "the committee is not fully convinced at this juncture." The committee, FDA and the company agreed that labeling for Semprex-D should carry a statement that the product has sedation potential. During his safety and efficacy review of the NDA, FDA Acting Pulmonary Group Leader John Jenkins, MD, noted that the incidence of somnolence "was 5%-6% greater for acrivastine and acrivastine plus pseudoephedrine versus placebo in clinical trials." Burroughs-Wellcome's Semprex-D project leader M.F. Frosolono, PhD, acknowledged that "the frequency of somnolence associated with Semprex-D warrants appropriate labeling to the patients and physicians." Jenkins stated: "I would not use the term 'nonsedating' for Semprex-D." Frosolono presented an efficacy summary of the NDA. The U.S. clinical development program for Semprex-D involved "almost 8,800 patients," a majority if whom were in controlled trials, Frosolono said. "In total, approximately 5,200 patients have received one or more doses of acrivastine either as a single entity or in combination with pseudoephedrine." The NDA was filed in December 1987. Semprex-D is approved in U.K, France, Denmark and Finland and marketed under the name Duact. The primary efficacy assessments used in the trials were diary symptom score indices, with which patients rated the severity of allergic rhinitis symptoms. Frosolono presented the results from two studies (P39C:16 and P39C:17) that compared Semprex-D, acrivastine, pseudoephedrine and placebo in patients with seasonal allergic rhinitis (SAR) at a regimen of four times a day (q.i.d.) for two weeks. "For each study the major comparisons show the same pattern of statistically significant favorable differences [for] Semprex-D," Frosolono said. The differences in antihistaminic efficacy "are significant and in favor of Semprex-D relative to pseudoephedrine." In support of a three times a day (t.i.d.) regimen of Semprex- D for seasonal allergic rhinitis, Frosolono referred to study P39C:17 and presented results from four additional studies. Frosolono noted that although Semprex-D was given q.i.d. in study P39C:17, efficacy evaluations that were done in the morning revealed scores that "strongly indicate that Semprex-D capsules [could] provide relief overnight, that is, for at least eight hours." Frosolono also discussed study P39:09, which was a 14-day trial of SAR patients comparing t.i.d. dosing of four treatments: Semprex-D, acrivastine, pseudoephedrine and placebo, and study P39C:10, a 14-day trial comparing Semprex-D, chlorpheniramine maleate 4 mg and pseudoephedrine 60 mg and placebo. Frosolono also said that a dosing study showed "favorable differences for acrivastine relative to placebo through eight hours." He then presented study H4754, a crossover study in which 40 patients were administered six days of each active treatment at t.i.d dosing and one day of placebo washout between active treatments. To support Semprex-D's use in perennial allergic rhinitis, Burroughs conducted two studies, P39C:09 and P39C:07. Study P39C:09 involved giving PAR patients q.i.d. dosing of Semprex-D, chlorpheniramine plus pseudoephedrine or placebo for 28 days. In the study "there was a trend in favor of Semprex-D compared to chlorpheniramine plus pseudoephedrine," Frosolono said. Study P39C:07 was a chronic administration study of q.i.d. or t.i.d. dosing of Semprex-D or chlorpheniramine plus pseudoephedrine for 52 weeks. Allergy symptom severity scores "are significantly lower than at baseline and there are no significant differences between the two active treatments," Frosolono said. "We believe that this study is an important indication that Semprex-D patients do not become tachyphylactic to the effects of Semprex-D capsules after chronic treatment of up to one year." Summarizing his conclusions about data in the NDA, FDA's Jenkins stated: "The sponsor has adequately demonstrated effectiveness in patients with seasonal allergic rhinitis throughout 15 days when administered [every] six hours, four times a day. The sponsor, however, in my opinion has not demonstrated effectiveness for [Semprex-D] in patients with perennial allergic rhinitis or when administered [every] eight hours or three times per day." Commenting on the design of studies in PAR patients, Jenkins said that in study P39C:09, "what the sponsor was able to show is that the Semprex-D and chlorpheniramine-D...were both better than placebo and no different from one another." He added that "the control groups pseudoephedrine and acrivastine were not included so...they haven't met the requirement that they demonstrate that each component has contributed to the study." Study P39C:07 "is not an adequate efficacy study," Jenkins said. "The design of the study was such that it was primarily a safety study." Jenkins pointed out that he has not looked at the data from study H4754 that Frosolono said supports t.i.d. dosing for SAR, which were not included in the briefing document sent to the committee, but would be happy to do so. The design of the t.i.d. SAR study, P39C:10, he called "inadequate to establish the contribution of the individual components," and P39:09, Jenkins noted, "included the appropriate control arms, [but] they were only able to demonstrate effectiveness for nonhistamine mediated symptoms of (SAR), i.e. they were able to show that the pseudoephedrine in Semprex-D worked." Burroughs-Wellcome Professional Services Division Senior Director T. L. Wenger, MD, said the company decided to look at acrivastine's effects on the cardiovascular system in the wake of the relabeling of the nonsedating antihistamines Seldane and Hismanal to warn of the potential for cardiovascular side effects. Summarizing cardiac studies, Wenger said "acrivastine has no effect on heart rate at therapeutic doses or single doses up to 100 mg -- that's 12-and-a-half times the therapeutic dose." He noted that "if you push it higher, to 50 to 100 times the therapeutic dose, there is an increase in heart rate of some 14 to 17 beats per minute." Also, acrivastine has "no other effect on the ECG, not on PR, QRS or QTc, even at massive ingestion doses." Jenkins said that "there have formal drug-drug interactions for other agents such as erythromycin, ketoconazole, etc., that I'm aware of for this agent." The advisory committee concluded that Burroughs provided an adequate database to support the cardiac safety of Semprex-D. Rosenthal commented that cardiac effects "seemed rather benign". The advisory committee did recommend that labeling for Semprex-D state that the serum concentration of the product increases in renally impaired patients.

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