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Executive Summary

Marion Merrell Dow's Seldane (terfenadine) will carry a new boxed warning contraindicating its use in patients who are being treated with the antibiotic erythromycin or the antifungal ketoconazole (Janssen's Nizoral). New labeling for Seldane and the company's antihistamine decongestant product Seldane-D (terfenadine/pseudoephedrine) will begin with the boxed statement: "Warning -- QT interval prolongation/ventricular arrhythmia." The warning adds: "Terfenadine is contraindicated in patients taking ketoconazole or erythromycin and in patients with significant hepatic dysfunction. Do not exceed recommended dose." The warning continues that "rare cases of serious cardiovascular adverse events, including death, cardiac arrest, torsades de pointes, and other ventricular arrhythmias have been observed in the following clinical settings, frequently in association with increased terfenadine levels which lead to electrocardiographic QT prolongation: concomitant administration of ketoconazole (Nizoral); overdose, including single doses as low as 360 mg; concomitant administration of erythromycin; and significant hepatic dysfunction." Because erythromycin is frequently used for treatment of upper respiratory tract infections, that contraindication may have a significant impact on Seldane. Erythromycin, marketed by Abbott, Parke-Davis and a number of generic firms, is one of the most widely prescribed antibiotic products in the U.S.: the National Prescription Audit, for example, puts 1990 prescriptions of the drug at 36 mil. Seldane is the number one prescription antihistamine product in the U.S. with over 50 mil. scripts dispensed annually. Changes in the labeling of the erythromycin products on the market to conform with the Seldane relabeling are reportedly under consideration at FDA. However, the agency is requiring the immediate relabeling of ketoconazole to include a boxed warning that spells out the potential risks of the drug's interaction with terfenadine. Ketoconazole manufacturer Janssen sent letters on July 7 to 400,000 physicians and pharmacists reminding them of the "potentially fatal labeled drug interaction" between Seldane and Nizoral. Ketoconazole labeling already carries a boxed warning for hepatotoxicity. The relabeling of Seldane and Nizoral expands warnings included in the drugs' labeling since August 1990. Following a June 1990 meeting of the Pulmonary-Allergy Drugs Advisory Committee convened to review reports of cardiovascular side effects potentially associated with Seldane, FDA asked the companies to include precautions about drug interactions in labeling. At the recommendation of the committee, the company also was required to send out "Dear Doctor" letters. FDA plans to take Seldane before the Pulmonary-Allergy Committee again; its next meeting is expected to occur in September. In the meantime, the agency said it will consult with experts in the field about Seldane and potential drug interactions with other antibiotics. In addition to its adverse reporting system and its own pharmacokinetic studies, FDA may be able to collect data from companies with recently approved macrolide antibiotics. When FDA approved Abbott's Biaxin (clarithromycin) and Pfizer's Zithromax (azithromycin) in the fall of 1991, it asked the companies to conduct Phase IV drug interaction studies with terfenadine ("The Pink Sheet" Nov. 11, p. 8). The close attention to the Seldane interactions at FDA may derive in part from the experience of Center for Drug Evaluation and Research Director Carl Peck, MD. Peck was personally involved in seeing one of the first cases of terfenadine drug interaction. Peck was a consultant to the University of Uniformed Health Services in 1989 when it recorded an incident of fainting and irregular heartbeat in a woman who was taking Seldane and ketoconazole. While the new Seldane labeling is in the process of being printed, Marion Merrell Dow has moved quickly to address FDA's concerns. The firm sent "Dear Doctor" letters to 600,000 physicians nationwide by mailgram on July 7, a little more than a week after a pivotal meeting with the agency. The letter informs physicians of the expanded contraindications and provides a toll-free "800" number for further information. The company sent an additional 300,000 letters to pharmacists, nurse practitioners, and other health professionals by regular mail. According to FDA, as of June 30 there have been about 70 reports of serious cardiovascular events in patient being treated with Seldane since the introduction of the nonsedating antihistamine in 1985. Ten of the patients with cardiac complications have died. FDA cautioned, however, that the case reports do not always yield conclusive information about the role of Seldane to the adverse events. On the other hand, FDA said, serious cardiovascular events associated with Seldane therapy could be underreported. In the July 7 letter, MMD reports that rare cases of serious cardiovascular events have been received "in apparently normal individuals without identifiable risk factors." One report involving an apparently normal individual provided the impetus for FDA to initiate its action requesting the boxed warning and "Dear Doctor" letters. In May, the agency received the report of a case of a 29-year- old Maryland woman who had been taking Seldane for allergies and was started on ketoconazole therapy for a nail fungus. After a short time on therapy, she experienced irregular heartbeats and visited a hospital emergency room. Following an evaluation by physicians, she was released and died two days later. The agency has since received another report of a death of a patient being treated with terfenadine and ketoconazole. MMD maintained in its letter to physicians that "there is not conclusive evidence of a causal relationship of these events with terfenadine. Although in rare cases there was measurable plasma terfenadine, the implications of this finding with respect to the variability of terfenadine metabolism in the normal population cannot be assessed without further study." MMD said that it is undertaking studies to "further evaluate these observations." New pharmacokinetic data have bolstered the previous evidence that concurrent terfenadine and ketoconazole use results in "abnormal terfenadine metabolism, elevated terfenadine levels, and prolongation of the electrocardiographic QT interval," the MMD letter states. Preliminary data on concurrent erythromycin administration and hepatic dysfunction show "a similar metabolic effect," the letter notes; however, the company adds that "further evaluation of these latter risk factors is in progress." In addition to avoiding the concomitant use of Seldane and ketoconazole, the letter advises physicians to inform patients of the potential risk of serious cardiovascular events with Seldane therapy and discuss with them specific risk factors. FDA issued a press release on July 7 advising patients "who experience fainting, dizziness, palpitations or any other unusual symptoms while taking Seldane to contact their doctor." However, the agency added that it believes that "patients who have not had serious adverse reactions to Seldane in the past are not likely to have them now, provided they consult a doctor before taking it with other medications." The American Academy of Allergy and Immunology issued a memo to its 4,500 members stating that the academy "considers these medications [Seldane and Seldane-D] to be safe when properly prescribed and when not used with ketoconazole, erythromycin (and possibly other macrolide antibiotics) or in the presence of significant liver disease." In a letter attached to the memo, the academy tells allergists to show the memo to patients because "providing the information on AAAI letterhead, signed by the president, might lend added credibility in allaying patient concerns." MMD is undertaking its own consumer information program to warn patients of the potential risks of Seldane therapy. In a July 7 press release, the company said it will be preparing a patient pamphlet and unit-of-use packaging to be distributed in doctor's offices and pharmacies. In addition, MMD intends to highlight the contraindications for Seldane in direct-to-consumer print advertising. Marion Merrell Dow has put its OTC submission for Seldane on hold pending a review of interactions between Seldane and ketoconazole and erythromycin. "The company has decided to re-evaluate the submission of a new drug application for an over-the counter version of Seldane in the U.S.," MMD said. In April, MMD was still talking about a second quarter resubmission of the Seldane OTC application, which the company withdrew following the 1990 advisory committee meeting and subsequent product relabeling ("The Pink Sheet" April 6, p. 16). MMD has been in negotiations with several major pharmaceutical and consumer products firms, reportedly including Proctor & Gamble, for the marketing of OTC Seldane. Taking Seldane OTC could have doubled or tripled the current $500 mil. per year in sales for the nonsedating antihistamine. MMD had been targeting the April 1994 patent expiration for terfenadine for its OTC launch. An OTC Seldane would receive three years of exclusivity. While the incidence of serious adverse events is low, 70 cases out of over 200 mil. patients treated, it is questionable whether a drug with a boxed warning could ever gain OTC status. FDA requires that OTC drugs demonstrate a "high level" of safety and a boxed warning concerning serious adverse events appears inconsistent with that goal. FDA is currently looking at all antihistamine products to determine whether they may pose similar drug interactions. Antihistamines in general have received heightened attention by FDA due to criticisms on Capitol Hill that the agency has allowed efficacy claims for antihistamines in the treatment of cold symptoms without supporting evidence ("The Pink Sheet" April 13, p. 6). The pending Rx-to-OTC switch for Sandoz' Tavist (clemastine fumarate) may indicate the extent of any fallout effect beyond terfenadine. Sandoz' Tavist-1 was recommended in March for an Rx-to-OTC switch by the Pulmonary-Allergy Committee ("The Pink Sheet" March 30, p. 4). If Tavist makes it to the OTC market soon, Sandoz may have a long period during which it can establish a new market position after the switch. Although labeling for Janssen's nonsedating prescription antihistamine Hismanal (astemizole) reports cases of serious ventricular arrhythmias including torsades de pointes, FDA has never brought the drug before an advisory committee. The agency reportedly has reviewed internally some of the adverse events associated with Hismanal but has not been able to document side effects of the same severity or frequency as those related to Seldane therapy. In response to Seldane publicity, Warner-Lambert issued a press release on July 8 stating that its brand "Benadryl, the leading OTC allergy brand, was not affected by the FDA announcement, and continues to be an appropriate choice for people wishing to treat their allergy symptoms." Warner-Lambert has instituted a toll-free hotline number for consumers to call if they have any questions. The American Pharmaceutical Association issued a July 10 press release contending the Seldane case supports its longstanding argument for a three-class drug system. "The recent warning by FDA on the use of Seldane emphasizes the value of pharmacists monitoring patient medication [and] underscores certain inadequacies in the current two-class drug system in the U.S.," APhA said. Concerns with overuse of Seldane or its concomitant use with erythromycin or ketoconazole "could be dealt with by a pharmacist monitoring program that would be required with the transition class of drugs," APhA maintained.

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