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This article was originally published in The Tan Sheet

Executive Summary

OTC ZOVIRAX PATIENT EDUCATION PROGRAM WILL BE PIVOTAL TO Rx- TO-OTC SWITCH of Burroughs Wellcome's herpes product, A Antiviral Drug Products Division Medical Officer Heidi Jolson, MD, told physicians attending the Interscience Conference on Antimicrobial Agents and Chemotherapy Oct. 19 in New Orleans. Jolson suggested that "what will ultimately be acceptable in patient education [for OTC acyclovir] is something we have started discussing with the industry because we think it is an important component to ultimate approval or disapproval." After two years of preparation, Burroughs Wellcome submitted an NDA for OTC acyclovir in August for the management of recurrent genital herpes via a dosage regimen of two 200 mg tablets twice daily. If approved, OTC acyclovir will be marketed by a joint venture between Warner-Lambert and Burroughs Wellcome formed in late July ("The Tan Sheet" Aug. 2, p. 1). Burroughs Wellcome Senior Clinical Research Scientist Gray Davis, MD, acknowledged that for the Zovirax OTC switch to be successful, the company "will need to mount an extensive educational campaign so that patients will be aware of genital herpes, go to their doctor for diagnosis and initiate appropriate action." The company has begun to review several vehicles for delivering educational information on genital herpes and sexually transmitted diseases in general. "For high school kids one of the things we have already evaluated is a rap song about STDS, not just genital herpes," she noted. For college students, Davis said the firm has met with representatives of the American College Health Association and is "reviewing some videos that they already have available on all STDs." The company plans to initiate a number of educational projects targeting adults including TV commercials discussing herpes, "not about acyclovir, but about herpes," Davis emphasized. Over six months ago, Burroughs Wellcome put in place its first educational program for the genital herpes patient called Wellcome Dialog. Through the physician, patients may obtain materials describing the cause of herpes, recurrences, treatment, how to reduce the risk of transmission, how to inform a partner, and about herpes and pregnancy. The company has sent out over 400,000 of these "information organizers." Responding to a question about the similarity of the OTC switch for the vaginal antifungal clotrimazole to the acyclovir situation, FDA's Jolson said the agency is "certainly looking at the experience [with clotrimazole] and some of the issues . . . but, in comparison, I think the issues [surrounding acyclovir] will be more complicated because of the nature of the treatment of an STD versus vaginal candidiasis." In addition, she pointed out that acyclovir is a systemic product while clotrimazole is a topical product. "I think [vaginal antifungals] broke some ground," Jolson commented, "but we keep finding that [acyclovir] is so much more complex." The organizers of the special ICAAC session, Stephen Strauss, MD, National Institute of Allergy and Infectious Diseases, and Richard Whitley, MD, University of Alabama, said the forum was arranged "so that the infectious disease community can participate in the discussion about [the] concept [of OTC acyclovir] and the issues relevant to it." Whitely noted that "a lot of the questions [during the session] seem to focus on the educational issue, which seems to be a real concern to everyone here." Davis said the company is addressing the issue of self- diagnosis among patients with recurrent genital herpes. Davis reported that data from two clinical trials show that "patients who were previously diagnosed were able to recognize symptoms of a recurrence over 97% of the time." In addition, "over 50% of patients with previously unrecognized lesions can with instructions be taught to recognize lesions of the disease," Davis maintained. To address the risk of misdiagnosis in patients who have other ulcerative diseases, such as syphilis or chancroid, the company has initiated a trial in public health clinics to determine whether patients are able to recognize the symptoms of other diseases. Davis noted that "the pilot study has been completed and all patients with syphilis in this small trial correctly identified their disease with the exception of one patient who actually did have both syphilis and genital herpes." Davis suggested that recurrent genital herpes can be managed "by treating it five times a day for five days" or suppress an outbreak with "400 mg twice a day" via 200 mg capsules. For the OTC application, the company has amassed safety data on 7,500 patients from clinical trials, with the most common side effects being nausea and vomiting, diarrhea, headache and malaise, and evaluated over 55,000 patent exposures from its postmarketing surveillance trials with "no evidence of safety risk," Davis said. In addition to the large safety database, Davis said that acyclovir fulfills at least six other criteria of FDA Office of OTC Drug Evaluation Director Michael Weintraub's "switch principles." Davis said the drug has a predictable time course of action that results in a reduction in the frequency of genital herpes recurrences in 95% of patients on suppression therapy; the dosing regimen is simple -- 400 mg twice daily; the pharmacokinetics are not complex -- the drug has a bioavailability of 10-20% and a half-life of 2.5 to 3.2 hours, both of which decrease the likelihood of adverse events or overdosing; adverse events are infrequent and minor; and the drug has no food, drug or disease interactions. One of the most common concerns about OTC acyclovir is that "with more widespread use is the potential of increased viral resistance in the general population," Davis said, echoing some of the infectious disease physicians' concerns. To allay this fear, the company has looked at data on viral resistance prior to the availability of acyclovir from a six-year suppression trial and from patients in clinical trials. The rates of resistance were 2.6%, 3.5%, and 3%, respectively. "No matter how you compare the results between these three groups, there is no statistical difference," Davis said. Acyclovir clinical investigator Lawrence Corey, MD, University of Washington, emphasized that information on viral shedding will be important for OTC use of acyclovir because "a large segment of patients take this with the intent that they are going to decrease transmission." He asked: "How do we get that message out to the user who takes OTC acyclovir [that] there are limited data on acyclovir's effect on suppression of subclinical shedding and none on reducing transmission?" Davis estimated that 21.7% of the U.S. population aged 15 to 74 years is seropositive for the herpes simplex-2 virus, meaning that approximately 55 mil. are infected. Since 1978, there has been a 32% increase in the prevalence of HSV-2, Davis noted. Incidences for the most highly infected segments of the population are: 26% for white women aged 30-39; 19% for white males 30-39; 81% for black women 60-74; and 61% for black males 60-74. Davis reported that 87% of the 20 mil. Zovirax prescriptions dispensed in the U.S. since 1985 have been for genital herpes.

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