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The arrhythmogenic potential of 5-HT3 antagonists: A cause for concern
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Drugs that prolong the QT interval may increase the risk for developing torsades de pointes (TdP). A variety of cardiac and noncardiac medications can cause QT interval prolongation, including antiarrythymics (eg, quinidine, sotalol, dofetilide [Tikosyn, Pfizer]; ibutilide amiodarone; dronedarone [Multaq, Sanofi-Aventis]); antipsychotics (eg, ziprasidone, paliperidone [Invega, Janssen Pharmaceuticals]; iloperidone [Fanapt, Novartis]), antibiotics (eg, macrolides, fluoroquinolones, trimethoprim-sulfamethoxazole, voriconazole); antidepressants (eg, citalopram, amitriptyline) and methadone.
QT interval prolongation has been the most cited reason for a drug being withdrawn from the market, being restricted or acquiring a black box warning from the FDA. One class of drugs that has brought recent concern to the FDA for potentially causing QT interval prolongation and TdP are the serotonin 5-HT3 antagonists. These agents are popular antiemetics for patients undergoing surgery or receiving cancer chemotherapy. This class includes ondansetron (Zofran, GlaxoSmithKline), dolasetron (Anzemet, Sanofi-Aventis), palonosetron (Aloxi, Eisai) and granisetron (Kytril, Genentech). Based on animal studies, 5-HT3 antagonists appear to prolong the QT interval by blocking IKr channels. In addition, these drugs block the cardiac sodium channels leading to QRS interval widening, which consequently prolongs cardiac depolarization and further lengthens the QT interval and can subsequently lead to TdP.
Chris Domenico
Cynthia Sanoski
Effects of prolongation
The 5-HT3 antagonists have been touted as safe and effective alternatives to droperidol. Many switched from droperidol to the 5-HT3 antagonists for management of nausea and vomiting after concerns over droperidol’s potential proarrythmic effects were raised, believing they were safer alternatives.
However, several recent reports have questioned the safety of the 5-HT3 antagonists. In late 2010, data from a phase 4 study demonstrated that single 100 mg and 300 mg IV doses of dolasetron prolonged the QT interval by 14.1 msec and 36.6 msec, respectively, when used for prevention of chemotherapy-induced nausea and vomiting (CINV). These results prompted the FDA to recommend that the IV formulation should no longer be used for prevention of CINV. A subsequent warning was added to the dolasetron labeling that emphasized the risk of QT interval prolongation and stated that the drug should be avoided in patients with congenital long QT syndrome, hypokalemia or hypomagnesemia. However, IV dolasetron may still be used for prevention and treatment of postoperative nausea and vomiting (PONV) because the lower dose (12.5 mg IV) is less likely to cause QT interval prolongation.
In September 2011, the FDA asked GlaxoSmithKline to conduct studies to evaluate the prevalence of QT interval prolongation with ondansetron. The FDA also recommended adding new warnings to the ondansetron label stating that the drug should be avoided in patients at risk for TdP, including those with congenital long QT syndrome. Recently, preliminary results from the requested studies with ondansetron demonstrated that a single 32-mg IV dose increased the QT interval by 20 msec. These results prompted several changes to the ondansetron labeling, including the removal of the single 32-mg IV dosing regimen and a revision of the dosing recommendations for the IV formulation for the management of CINV. According to the revisions, the recommended dose of IV ondansetron for adults and children with CINV is 0.15 mg/kg every 4 hours for up to three doses, with no dose exceeding 16 mg. However, no changes were made to the oral or IV dosing recommendations for the prevention of PONV.
The FDA has also asked Roche to conduct studies to evaluate the prevalence of QT interval prolongation with granisetron; these studies are to be completed by April 2016.
QT interval prolongation and the risk for TdP may potentially be adverse effects that are associated with all of the 5-HT3 antagonists, and clinicians should be aware of these risks.
Clinical recommendations
The primary question is how these findings might affect clinical use of the 5-HT3 antagonists. Although there is reasonable evidence that 5-HT3 antagonists prolong the QT interval, there are very few published reports of associated TdP.
Two important parameters to consider when deciding on whether to use a 5-HT3 antagonist are potential drug interactions and risk factors for TdP.
With regard to drug interactions, extreme caution should be observed when prescribing 5-HT3 antagonists in patients concomitantly receiving drugs that prolong the QT interval or inhibit cytochrome P450 enzymes. The 5-HT3 antagonists are metabolized primarily by CYP3A4 and CYP2D6, and to a lesser extent by CYP1A2. Concomitant use of inhibitors of these enzymes, such as aprepitant, diltiazem, verapamil, amiodarone and quinidine, can increase the plasma concentration of the 5-HT3 antagonists and subsequently increase the risk for QT interval prolongation.
A patient’s risk factors for TdP should also be evaluated before making the decision to use a 5-HT3 antagonist. Electrolyte abnormalities, especially hypokalemia and hypomagnesemia, should be corrected before these drugs are administered. The FDA recommends that 5-HT3 antagonists should be avoided in patients with congenital long QT syndrome and that ECG monitoring should be performed in patients with HF, bradycardia, underlying heart disease, electrolyte abnormalities or renal impairment, as well as in those who are elderly or receiving drugs that prolong the QT interval. If a 5-HT3 antagonist is administered in the inpatient setting, patients with at least two risk factors for TdP should be monitored via telemetry for 1 to 2 hours after drug administration. If a patient has risk factors for TdP, consideration may be given to using palonosetron as an alternative since it is the only drug in the 5-HT3 antagonist class that has not been associated with significant QT interval prolongation.
Unlike other 5-HT3 antagonists, palonosetron does not contain a warning or precaution in its labeling regarding risk for QT interval prolongation or TdP. However, a potential drawback with palonosetron is that a generic formulation is not yet available, and thus, it is a more expensive option. Because most reports evaluating risk for 5-HT3 antagonist-induced QT interval prolongation involved IV administration, it is difficult to determine whether similar risk is associated with oral formulations. It is important to remember that alternative antiemetic options can also cause QT prolongation (droperidol) or other serious adverse effects (phenothiazines).
As always, clinicians must weigh the risks vs. the benefits before using the 5-HT3 antagonists as antiemetic agents.
Chris Domenico is a PharmD candidate and Cynthia Sanoski, PharmD, BCPS, FCCP, is chair and associate professor, both at Jefferson School of Pharmacy, Thomas Jefferson University, Philadelphia.
Rhonda M. Cooper-DeHoff, PharmD, MS, is associate professor in the department of pharmacotherapy and translational research, College of Pharmacy, and division of cardiovascular medicine, College of Medicine, University of Florida, Gainesville. Dr. Cooper-DeHoff is Cardiology Today’s Pharmacology Consult column editor and a member of the CHD and Prevention section of the Editorial Board. For suggestions for future topics for this column, contact her at dehoff@cop.ufl.edu.
For more information:
- Charbit B. Anesthesiology. 2005;102:1094-1100.
- Charbit B. Anesthesiology. 2008;109:206-212.
- Hafermann MJ. Drug Healthc Patient Saf. 2011;3:53-58.
Disclosures:
- Mr. Domenico and Dr. Sanoski report no relevant financial disclosures.