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International Drug Information Notes DRUG WITHDRAWALS AND PROPOSED WITHDRAWALS IN THE US AND UK Larry D. Sasich* and Sana R. Sukkari "2" TERFENADINE |
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| The FDA has proposed to withdraw the marketing approval of drug products containing terfenadine on January 14, 1997. Terfenadine is an antihistamine, indicated for the relief of symptoms associated with seasonal allergic rhinitis such as sneezing, rhinorrhea, pruritus, and lacrimation. Terfenadine was the first antihistamine approved in the U.S that was not associated with more somnolence than placebo in clinical trials. The absence of an increased risk of somnolence over placebo is an important safety advantage to many people who use antihistamines. Terfenadine 60 mg with the decongestant pseudoephedrine hydrochloride 120 mg was approved on August 19, 1991. Other antihistamines now available in the United States that were not associated with more somnolence than placebo in clinical trials are astemizole and loratadine, approved on December 29, 1988, and April 12, 1993 respectively. Most significant to the withdrawal of terfenadine was the FDA's approval of fexofenadine hydrochloride 60 mg capsules on July 25, 1996. Fexofenadine is the metabolite of terfenadine responsible for its antihistamine efficacy. Fexofenadine hydrochloride was also not associated with more somnolence than placebo in clinical trials. After the approval of terfenadine in 1985, there began to be reports of certain serious cardiac adverse events associated with terfenadine use in patients taking certain antimicrobials or with significant liver dysfunction. Very little parent terfenadine normally circulates in the plasma because orally administered terfenadine undergoes extensive first pass metabolism by a specific cytochrome P-450 isoenzyme (CYP3A4). This metabolic pathway may be impaired in patients with liver dysfunction (e.g., alcoholic cirrhosis) or who are taking drugs such as ketoconazole, itraconazole, or macrolide antimicrobials (e.g., clarithromycin, erythromycin, or troleandomycin). These drugs are all inhibitors of the cytochrome P-450 isoenzyme. Interference with the normal metabolism of terfenadine can lead to elevated plasma terfenadine levels. At these elevated levels, terfenadine can delay cardiac repolarization (prolong the electrocardiographic QT interval) because of its effects on cardiac potassium channels. The delayed cardiac repolarization increases the risk of serious ventricular tachyarrhythmias, most characteristically a kind of ventricular tachycardia called torsades de pointes. This arrhythmia can cause dizziness and syncope when it is short-lived, but it may persist and degenerate into unstable ventricular tachycardia or ventricular fibrillation. Ventricular fibrillation is fatal if not promptly reversed. These serious and possibly fatal events can occur at the recommended dose of terfenadine if it is taken along with other medications that interfere with its metabolism or if it is administered to someone with significant hepatic dysfunction. In an effort to inform the medical and patient communities about the serious and potentially fatal cardiac adverse effects associated with inappropriate use of terfenadine, the labeling for terfenadine and terfenadine with pseudoephedrine have been revised many times. In 1992, terfenadine labeling was revised to include a prominent boxed warning cautioning against its use in certain settings, particularly with the drugs that inhibit its metabolism. In addition, "Dear Health Care Professional" letters warning health care practitioners of the serious risk of inappropriate use of terfenadine were issued by the manufacturer in 1990, 1992, and 1996. Although the released labeling and "Dear Health Care Professional" letters have significantly reduced the inappropriate prescribing of terfenadine together with the drugs that block its metabolism, such prescribing and dispensing has not been eliminated and may not be possible. Three recently published studies indicate that co-prescription and co-dispensing of medications contraindicated with terfenadine continues to occur. The Cavuto study also demonstrates that the computerized drug-interaction screening programs used by many pharmacists, who are the last line of defense against prescribing errors, do not completely prevent prescribing and filling of prescriptions for potentially dangerous combinations of terfenadine and contraindicated drugs. Terfenadine is an antihistamine that is intended to be used when symptoms of seasonal allergic rhinitis occur. Patients often do not consume all of the tablets they receive in a prescription of terfenadine for a single episode of seasonal allergic rhinitis, and may keep the remaining pills for later use when needed, as patients often do with over-the-counter antihistamines. Because of the nature of seasonal allergies, a long period of time (e.g., from early fall to spring) can elapse between the time the drug and any associated warning from a health care practitioner or pharmacist is received and the time terfenadine is used. Such intermittent dosing of terfenadine increases the probability that some patients may be taking one of the contraindicated medications, such as one of the frequently prescribed antimicrobials listed above, at the same time the patient self-diagnoses his or her seasonal allergy symptoms and takes the remaining terfenadine. This problem of concomitant use is further compounded by the growing list of medications known to inhibit the metabolism of terfenadine, many of which are taken for chronic medical conditions and may be prescribed by health care practitioners other than the practitioner who prescribed the terfenadine. Labeling changes and even perfect performance by prescribers and close attention by pharmacists, therefore, cannot completely eliminate the risks of serious cardiac adverse events associated with the inappropriate use of terfenadine. Very low to undetectable blood levels of parent terfenadine are found in patients taking the recommended dose of terfenadine. For this reason, parent terfenadine appears to have very little, if any, impact on the therapeutic efficacy that is associated with terfenadine use. The discovery of terfenadine's ability to delay cardiac repolarization and its associations with serious and sometimes fatal cardiac adverse events when used inappropriately led to evaluation of its principal active metabolite as a potentially safer alternative antihistamine. It was discovered that the metabolite that is responsible for the desired therapeutic effect of terfenadine, fexofenadine, does not affect cardiac potassium channels. The FDA encouraged the manufacturer to initiate the development of a drug product with only the active metabolite fexofenadine as the active antihistamine. Even at doses considerably in excess of those recommended for use, fexofenadine hydrochloride has not been shown to prolong the QT interval. It therefore should not have, and has not been shown to have, the serious cardiovascular adverse events potentially associated with unmetabolized terfenadine. No new adverse reaction, not already associated with terfenadine, would be expected because the many people who have taken terfenadine have been, in fact, exposed primarily to fexofenadine. Fexofenadine hydrochloride was approved by the FDA on July 25, 1996 and after 5 months of marketing of this product in the U.S there have not been reports of serious cardiac arrhythmia's. The FDA has announced new drug interaction labeling warnings for terfenadine and terfenadine with pseudoephedrine when taken in combination with a number of newer drugs. These include mibefradil, another calcium channel blocker approved for hypertension and the HIV protease inhibitors such as indinavir (Crixivan), ritonavir (Norvir), saquinavir (Invirase) and nelfinavir (Viracept) for AIDS, and selective serotonin reuptake inhibitor (SSRI) antidepressants such as fluxamine (Luvox), sertraline (Zoloft), nefazodone (Serzone), along with the additional medications zileuton (Zyflo) to prevent asthma attacks, cisapride (Propulside), and the fluroquinolone antibiotic sparfloxacin (Zagam). Additionally, the new warnings specify that patients with kidney problems should not take more than one terfenadine with pseudoephedrine tablet daily and that terfenadine products should not be taken with grapefruit juice. Hoechst Marion Roussel, the US maker of terfenadine, can delay the drug's withdrawal for years in the courts, while it sells both its new drug fexofenadine, and keeps the public at risk by continuing to sell terfenadine. Terfenadine was finally withdrawn in 1998. References: 1. Department of Health and Human Services, Food and Drug Administration. Hoechst Marion Roussel, Inc., and Baker Norton Pharmaceuticals, Inc.; Terfenadine; Proposal To Withdraw Approval of Two New Drug Applications and One Abbreviated New Drug Application; Opportunity for a Hearing Federal Register January 14, 1997; 62(9):1889-1892. 2. Thompson D, Oster G. Use of terfenadine and contraindicated drugs. JAMA 1996; 275:1339-1341. 3. Cavuto NJ, Woosley R L, Sale M. Pharmacies and prevention or potentially fatal drug interactions. JAMA 1996; 275:1086-1087. 4. Carlson A M, Morris LS. Coprescription of terfenadine and erythromycin and ketoconazole: an assessment of potential harm. J A, Pharm A 1996; NS36:263-269. 5. Department of Health and Human Services. Food and Drug Administration. Se;dane Labeling Changes. September 24, 1997. From Saudi Pharmaceutical Journal, Vol 6, No. 1, January 1998 |