QTc Interval Prolongation

The Hospitalist. 2009 February;2009(02):

February 1, 2009|The Hospitalist

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.