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Executive Summary

Direct-to-consumer ads for nicotine replacement products are an "appropriate" means of promoting smoking cessation, members of FDA's Drug Abuse Advisory Committee suggested at a July 14 meeting. Committee member George Bigelow, PhD, Johns Hopkins University Medical Center, said he believes that "direct-to-consumer advertising is an appropriate thing to do with these [nicotine replacement] products. We have thought over the years that it is best to do anything to promote smoking cessation among smokers and [that is] one of the things that advertising has done." To ban the ads, he decided, "would be a mistake." The FDA advisory committee met to discuss several issues concerning nicotine patches and nicotine gum, including a petition from Public Citizen's Health Research Group asking FDA to add a "boxed warning" to product labeling. The boxed warning would include a caution against smoking while using nicotine patches and gum and a statement that the products only work when used as part of a comprehensive smoking- cessation program. Both statements are currently included in both the package insert and patient instructions but not in boxed format. Under FDA regulations, the addition of a boxed warning would prohibit TV ads for the products. Print ads with the full product labeling would not be banned. The HRG citizen's petition was filed with FDA on April 30 ("The Pink Sheet" May 4, T&G-4). Bigelow's statement echoed the view expressed by FDAers and other committee members that consumer ads for nicotine replacement products, particularly the widely-viewed TV ads, should be allowed to continue because they encourage smokers to try to quit smoking. FDA Medical Officer Curtis Wright, MD, commented: "We have probably had more people try and quit smoking following the introduction of these products than after any other public health intervention that I can think of. The message that -- 'there is something new so you can quit smoking and it is not going to be that hard to do' -- may not be a bad message." The same argument was voiced by the four companies with approvals to market nicotine replacement products in the U.S. -- Ciba-Geigy (Habitrol), Marion Merrell Dow (Nicoderm and Nicorette), Lederle (ProStep) and Warner-Lambert (Nicotrol). "Direct to consumer ads for nicotine patches are meant to let smokers know that there is a potential aid to quitting smoking which might be useful to them; and to encourage them to see their physician and to consider quitting smoking," Ciba-Geigy Executive Director of Clinical Research, CNS Drug Development, Charles Gorodetzky, MD, said in a statement prepared by all four companies. Committee members also expressed concern that a boxed warning could discourage smokers from trying to quit. Theodore Cicero, PhD, Washington University School of Medicine, commented: "If someone sees a box up on the top [of product labeling], you are going to be scaring people away, which is the wrong message to send." FDA Pilot Drug Staff Director John Harter, MD, agreed that "if you frighten people very much, they might decide to stick with the devil they know, which is their two packs a day." Invited guest Reese Jones, MD, University of California-Los Angeles, questioned whether TV reminder ads give smokers "enough information," commenting: "If it takes written ads to present the message, then so be it." Jones also objected to the TV reminder ads on the grounds that they are "medicalizing -- it is a quick fix, saying 'go to the doctor and get this pill' when the real message, the public health message, should be 'you have got a behavioral problem that maybe will require medication.'" The committee also addressed recent reports of adverse cardiovascular events, including myocardial infarction, in connection with concomitant smoking and nicotine patch use. The issue was added to the meeting agenda based on five reports of heart attacks at Sturdy Memorial Hospital in Attleboro, Mass. in patients who were using nicotine patches and smoking ("The Pink Sheet" July 6, T&G-1). FDA said that a total of 33 cardiac adverse events have been reported with patients using nicotine patches. Gorodetzky said that the three companies with patches on the market, Ciba-Geigy, Marion Merrell Dow, and Lederle, estimate that approximately 3 mil. patients in the U.S. have used the transdermal products. Richard Shea, MD, Sturdy Memorial Hospital, told the committee that the heart attacks at his institution led him to conclude that "concomitant cigarette usage with the patch appeared to carry with it a risk of cardiac events that was not shared by the people using the product as intended." Invited panel member Michael Winniford, MD, University of Iowa, concurred, saying: "It seems almost certain and quite reasonable to speculate that there will be a higher risk of adverse cardiovascular events in patients who use the patch and smoke even half-a-pack a day than in patients who don't smoke." However, Winniford further stated that "it is...unclear why smoking a little bit...while wearing the patch would be somehow more dangerous and cause a greater risk of cardiac events than smoking a lot of cigarettes without wearing the patch." He theorized that, due to the lower dose and steady administration of nicotine from the patch, "smoking a little bit while wearing the patch should be less risky than smoking a lot without wearing the patch." He concluded that "what we really need is more studies." The committee considered evidence that the route of administration of nicotine may make a difference in its potential to cause adverse cardiovascular effects. David Sachs, MD, Palo Alto Center of Pulmonary Disease Prevention, said that smoking results in arterial blood nicotine levels that "can easily be 10 times or greater higher than the concomitant maximum venous blood level." Nicotine patches and gum deliver drug mostly to the veins, he explained. The higher arterial blood nicotine levels "is the end blood level that the coronary arteries see" and "that is what has a much bigger potential for producing arrhythmias or sudden acute MI." Acting Committee Chairman Richard Meisch, MD/PhD, University of Texas Mental Sciences Institute, Houston, outlined "a hierarchy: wearing the patch is not so bad, the intermediate situation is wearing the patch and smoking, and the worst situation is with no treatment, no patch and regular smoking." Winniford agreed: "That is the hierarchy I would construct, given what we have heard about so far [about] the nicotine bolus." FDA's Harter concluded that the association of nicotine substitution products with cardiovascular events "is a very complex question that would need a large epidemiological study to answer." Ciba-Geigy is conducting a study of patch use in Israeli patients with coronary artery disease and plans to sponsor a study in the U.S. The results of the Israeli study should be available next summer, the company said. The committee reached no conclusions as to how cardiovascular risks should be assessed. The committee also reached a consensus that labeling for Nicorette and Nicoderm should include a statement that prescribers apprise pregnant patients of the risks involved in nicotine replacement therapy. Nicoderm is labeled for pregnancy category D, which indicates that there is evidence of fetal risk associated with the drug; however "potential benefits" from the use of the drug "may be acceptable" despite potential risk. The designation requires prescribers to tell pregnant women of the potential risks. Nicorette 2 mg gum, however, is in category X, "contraindicated in pregnant women." A 4 mg version of Nicorette was approved in November 1991 and FDA proposes to label it category C ("human fetal risk is unknown"). The agency also has proposed changing the labeling for the 2 mg Nicorette to category C. Marion Merrell Dow said the 4 mg Nicorette has not been launched pending the outcome of discussions with the agency. An FDA position paper states that the proposed change in labeling is based on single-dose studies that demonstrate "that the use of nicotine gum results in lower blood levels of nicotine and less effect (or no effect) on the the fetal cardiorespiratory function than smoking." No such studies have been performed with nicotine patches -- hence the category D designation. MMD Director of Regulatory Affairs Elaine Waller said the company wanted to eliminate "inconsistencies in labeling for products with the same active ingredients." However, she added, MMD still wants labeling that "requires physicians to inform pregnant patients of the potential risks of nicotine therapy irregardless of the pregnancy category." Harter said he "would have no problems with putting something similar to that in labeling."

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