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QTc Interval Prolongation

From: The Hospitalist, February 2009

Know your patient’s history, drug combinations before starting a new treatment

by By Michele B. Kaufman, PharmD, BSc, RPh

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.

Market watch

New Generics

  • Dorzolamide/timolol ophthalmic solution (generic: Cosopt)
  • Galantamine extended-release capsules (generic: Razadyne ER)

New Drugs, Indications and Dosage Forms

  • Candesartan cilexetil/hydrochlorothiazide (Atacand HCT), approved by the FDA for treating hypertension, is available in a new, fixed combination of 32-mg candesartan and 25-mg HCT. Other strengths include 16/12.5 mg and 32/12.5 mg.11
  • Conivaptan hydrochloride injection (Vaprisol), originally approved in an ampule, is now available as 20-mg conivaptan premixed in D5W for the treatment of hyponatremia.12 Conivaptan also has an extended expiration date of 24 months. Conivaptan is an arginine vasopressin receptor antagonist approved to treat euvolemic and hypervolemic hyponatremia in hospitalized patients.

Drug Discontinuations

  • AstraZeneca Pharmaceuticals will discontinue distribution of branded Foscavir (foscarnet sodium injection) by April 30. Generic foscarnet will be available.13
  • Bayer Pharmaceuticals has discontinued nimodipine (Nimotop) capsules for treatment of subarachnoid hemorrhage due to diminished market demand and alternate available treatments.14

New Warnings

In June, the FDA and Pfizer approved updated safety labeling for linezolid (Zyvox) regarding contraindications with concomitant monoamine oxidase inhibitors, serotonergic agents, and other drugs that might increase blood pressure.15 The FDA has received post-marketing reports of cases of serotonin syndrome in patients using linezolid within two weeks of receiving serotonergic agents. Any patients being evaluated for linezolid therapy must have a careful medication history to rule out the current use, or use within two weeks, of selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, triptans, meperidine, or buspirone. Due to potential blood-pressure increases, the use of linezolid in patients with uncontrolled hypertension, pheochromocytoma, and thyrotoxicosis, as well as in those receiving sympathomimetic agents, vasopressors, or dopaminergic agents, should be discontinued.

In the Pipeline

  • Pfizer and MannKind entered into a collaborative agreement for certain patients needing to continue inhaled insulin treatment. The patients will be switched from Pfizer’s product (which was removed from the U.S. market in 2007) and placed on MannKind’s Technosphere product, which is in Phase Three trials.16 A recent study in Type 1 diabetics showed prandial inhaled insulin compared with insulin aspart along with insulin glargine led to comparable A1c levels and comparable numbers of patients reaching predefined A1c goals, weight loss versus weight gain, fewer patients with hypoglycemic events, better fasting blood-glucose levels, and no adverse pulmonary effects.17
  • The clinical trial program for the experimental weight-loss drug rimonabant has been discontinued due to safety concerns. Approved in Europe but discontinued there in October 2008, the drug generated sales of $70 million in early 2008.18

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 QTc prolongation is begun, tell your patient to report any “potential cardiac” symptoms to a member of the healthcare team.

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.

References

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.


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