Terfenadine, cisapride, astemizole … do you remember these drugs? They all were removed from the U.S. market subsequent to adverse outcomes related to QTc interval prolongation, including ventricular arrhythmias.1-3 Many drugs prolong the QTc interval, particularly if a drug is combined with others that affect its metabolism.
QTc interval prolongation can lead to torsades de pointes (TdP). Certain individuals are particularly predisposed to developing TdP, including: women, people with hypokalemia or hypomagnesemia, and those with a history of congenital or idiopathic QTc syndrome, cardiac arrest, syncope, congestive heart failure, bradycardia, baseline QT prolongation, renal failure, or cardiac failure.4 Some agents can prolong the QTc interval by five to 10 milliseconds and cause TdP, while others require a 50-millisecond increase or more.
Drugs that confer a risk of ventricular arrhythmias include: disopyramide, dofetilide, ibutilide, procainamide, quinidine, sotalol, and amiodarone (antiarrhythmic agents); clarithromycin, erythromycin, levofloxacin, gatifloxacin, gemifloxacin, moxifloxacin, telithromycin (anti-infectives); domperidone and droperidol antiemetics; chlorpromazine, haloperidol, mesoridazine, thioridazine, and pimozide (antipsychotics); amitriptyline, desipramine, doxepin, fluoxetine, imipramine, sertraline, and venlafaxine (antidepressants); fluconazole, itraconazole, and ketoconazole (antifungals); naratriptan, sumatriptan, and zolmitriptan; and methadone.4-8 Other related agents, such as voriconazole and ondansetron, have been reported to cause QTc prolongation.
Drugs of special concern are those that frequently inhibit the metabolism of other agents, including erythromycin, clarithromycin, ketoconazole, itraconazole, amiodarone, and quinidine, and many antidepressants and antiretroviral agents. Of the deaths associated with drug-induced QTc prolongation related to the prokinetic agent cisapride, many were due to drug interactions with an imidazole or macrolide antibiotic. In these cases, increased serum concentrations of cisapride occurred due to inhibition of the cytochrome P450 CYP3A4 isoenzyme.9
If treatment with a drug that has the potential for causing QTc prolongation is begun, tell your patient to report any “potential cardiac” symptoms, such as palpitations, syncope, or near-syncope with or without palpitations, to a member of the healthcare team. Always be on the lookout for any concomitant conditions or treatments that can cause hypokalemia (e.g., diuretic use, gastroenteritis, diarrhea, excessive vomiting), or other agents that inhibit drug metabolism.
Obtaining a complete medication history, including the use of herbal products and over-the-counter medications, can help identify and prevent QTc prolongation from a drug interaction. A routine, 12-lead electrocardiogram (EKG) should be utilized during treatment to detect asymptomatic QTc prolongation or abnormal postectopic QTc intervals. Additionally, any patient predisposed to QTc prolongation should have an EKG performed before commencing treatment as well as after treatment is complete. If a drug prolongs the QTc interval beyond normal limits, the benefit of continuing the drug should be weighed against the risk of serious adverse cardiac events.10 TH
Michele B Kaufman, PharmD, BSc, RPh, is a freelance medical writer based in New York City.
1. Kupec IF. Seldane and generic terfenadine withdrawn from market. Food and Drug Administration Web site. Available at: www.fda.gov/bbs/topics/answers/ ans00853.html. Accessed Nov. 7, 2008.
2. Zalewski JM. Cisapride withdrawal requires alternate therapy. Cleveland Clinic Web site. Available at: www.clevelandclinicmeded.com/medicalpubs/pharmacy/mayjune2000/cisapride.htm. Accessed Nov. 7, 2008.
3. Drugs removed from or restricted in the U.S. market because of drug interactions. Food and Drug Administration Web site. Available at: www.fda.gov/cder/drug/drugReactions/CERT%20Educational%20Module%201/sld013.htm. Updated Dec. 22, 2008. Accessed Nov. 7, 2008.
4. Roden DM. Drug-induced prolongation of the QT interval. N Engl J Med. 2004;350:1013-1022.
5. Pham CP, de Feiter PW, van der Kuy PHM, van Mook WN. Long QTc interval and torsades de pointes caused by fluconazole. Ann Pharmacother. 2006;40:1456-1461.
6. Nykamp DL, Blackmon CL, Schmidt PE, Roberson AG. QTc prolongation associated with combination therapy of levofloxacin, imipramine, and fluoxetine. Ann Pharmacother. 1005;39:543-546.
7. Philips JA, Marty FM, Stone RM et al. Torsades de pointes associated with voriconazole use. Transpl Infect Dis. 2007;9:33-36.
8. Charbit B, Alvarez JC, Dasque E, Abe E, Démolis JL, Funck-Brentano C. Droperidol and ondansetron-induced QT interval prolongation. Anesthesiol. 2008;109:206-212.
9. Yap YG, Camm AJ. Drug induced qt prolongation and torsades de pointes. Heart. 2003;89:1363-1372.
10. Jayasinghe R, Registrar S, Kovoor P. Drugs and the QTc interval. Aust Prescr. 2002;25:63-65.
11. Atacand HCT 32/25 mg gives patients and physicians more treatment flexibility. Available at: www.pharmacitelink.com/news/2008/08/14_az.pdf. Accessed Nov. 4, 2008.
12. FDA approves astellas’ vaprisol (conivaptan hydrochloride injection) premixed in 5% dextrose for the treatment of hyponatremia. Sandoz Web site. Available at: sandoz.yellowbrix.com/pages/sandoz/Story.nsp?story_id=122559939. Accessed Nov. 4, 2008.
13. U.S. FDA drug shortages. Available at: www.fda.gov/cder/drug/shortages/default.htm#Foscavir. Accessed Nov. 3, 2008.
14. FDA Drug Shortages. Food and Drug Administration Web site. Available at: www.fda.gov/cder/drug/ shortages/discontinuation.pdf. Accessed Nov. 6, 2008.
15. Waknine Y. FDA safety changes: mirena, zyvox, orencia. Medscape Web site. Available at: www.medscape.com/viewarticle/580101. Accessed Nov. 3, 2008.
16. MannKind and Pfizer announce collaboration for certain exubera patients to transition to Mannkind’s inhaled insulin therapy. Drugs.com Web site. Available at: www.drugs.com/news/mannkind-pfizer-announce-collaboration-certain-exubera-patients-transition-mannkind-s-inhaled-13677.html. Accessed Nov. 3, 2008.
17. MannKind reports positive data from a phase 3 clinical study of technosphere insulin in Type 1 diabetics. Drugs.com Web site. Available at: www.drugs.com/ clinical_trials/mannkind-reports-positive-data-phase-3-clinical-study-technosphere-insulin-type-1-diabetes-5554.html. Accessed Nov. 3, 2008.
18. Bratulic A. Sanofi-aventis to halt all Acomplia trials. FirstWord Web site. Available at: www.firstwordplus.com/Fws.do?articleid=34DAB2DC3D7A48939A1D24AB97204CB4&logRowId=263560. Accessed Nov. 6, 2008.