Dr. Julia Harder, PharmD, CGP
Two years ago, the FDA issued a warning that doses of citalopram (Celexa) exceeding 40 mg per day may cause prolongation of the cardiac QT interval, which can result in potentially fatal cardiac arrhythmias including Torsades de Pointes (please see our previous blog post on the FDA’s warning for more information). In addition, the maximum recommended dose of citalopram for patients greater than 60 years of age – most of the patients we treat in hospice – was reduced to 20 mg per day because of further increased risk of adverse cardiac outcomes in the geriatric population.
A recent study (see reference below) published in the American Journal of Psychiatry offers some evidence that contradicts the FDA’s warnings. In this study, doses of citalopram greater than 40 mg daily were not associated with increased risk of ventricular arrhythmia or all-cause mortality (cardiac and non-cardiac) as compared to lower doses.
This was a cohort study conducted using Veterans Health Administration data between 2004 and 2009. The study included almost a million depressed patients who were prescribed either citalopram (n = 618,450) or sertraline (n = 365,898). Sertraline was used as a comparison because it is also a selective serotonin reuptake inhibitor (SSRI), like citalopram, but does not have any warnings regarding adverse cardiac effects. Statistical analysis examined the association between antidepressant dosing and adverse outcomes including ventricular arrhythmia and all-cause (cardiac and non-cardiac) mortality.
The results were surprising in that higher doses of both antidepressants were actually associated with fewer adverse outcomes. Citalopram daily doses > 40 mg were associated with lower risks of ventricular arrhythmia (adjusted hazard ratio = 0.68, 95% CI = 0.61–0.76) and all-cause mortality (adjusted hazard ratio = 0.94, 95% CI = 0.90–0.99) compared with daily doses of 1–20 mg. Citalopram daily doses of 21–40 mg were associated with lower risks of ventricular arrhythmia (adjusted hazard ratio = 0.80, 95% CI = 0.74–0.86) compared with dosages of 1–20 mg/day but did not have significantly different risks of mortality. The sertraline cohort revealed similar findings, except there were no significant associations between daily dose and mortality. According to the authors, “these results raise questions regarding the continued merit of the FDA warning.”
The FDA’s warning was initially prompted by post-marketing reports of QT interval prolongation and Torsades de Pointes associated with citalopram. The FDA evaluated the results of a thorough QT study assessing the effects of 20 mg and 60 mg doses of citalopram on the QT interval in adults. In this randomized, multi-center, double-blind, placebo-controlled trial, 119 subjects received citalopram 20 mg per day, citalopram 60 mg per day, and placebo in a crossover fashion (meaning each individual received all three interventions for comparison).
Compared to placebo, maximum mean prolongations in the individually corrected QT intervals were 8.5 milliseconds (ms) for 20 mg citalopram and 18.5 ms for 60 mg citalopram. For 40 mg citalopram, prolongation of the corrected QT interval was estimated to be 12.6 ms. Let’s put these numbers in perspective. In adult males a QT interval greater than 450 ms is considered prolonged and between 430 and 450 ms is considered borderline. For females, a QT interval greater than 470 ms is considered prolonged and between 450 and 470 ms is considered borderline. So, you can see that a QT interval increase of nearly 20 ms (as may potentially be seen with the 60 mg dose) could be clinically significant.
As a result of this QT study, the FDA determined that citalopram causes dose-dependent QT interval prolongation and should no longer be used at doses above 40 mg per day. Safety information about the potential for QT interval prolongation and Torsades de Pointes with drug dosage and usage recommendations were added to the package inserts of Celexa and its generic equivalents.
How can we make sense of this conflicting data? While the recent Veterans Health Administration study looked at an incredibly large number of patients, it’s important to keep in mind that, as a cohort study, it can only demonstrate an association, not cause-and-effect. In other words, we cannot determine conclusively whether the antidepressant dose was the direct cause of the varying risks of arrhythmia and mortality, or whether other factors came into play. While the authors did attempt to correct for potentially confounding variables, it is impossible to completely do so with an observational study. Randomized controlled trials (RCTs), which more comprehensively account for confounding variables and are prospective (rather than retrospective) in nature, are considered superior forms of evidence to observational studies like cohort studies. The FDA’s study, though it looked at a much smaller number of patients, was an RCT using a crossover design to demonstrate conclusively the dose-dependent QT prolongation caused by citalopram. So, while the Veterans Health Administration data do raise questions, do not dismiss the FDA’s warnings about citalopram at this time. Especially in the hospice population, where many of our patients are already at an increased risk of QT prolongation and cardiac arrhythmia, it’s important to stick to the dosing limits currently included in citalopram drug labeling. For more comprehensive information about QT prolongation, including risk factors and which other medications may cause it, please see this blog post.
Zivin K, Pfeiffer PN, Bohnert ASB, et al. Evaluation of the FDA warning against prescribing citalopram at doses exceeding 40 mg. Am J Psychiatry. 2013; 170: 642-650.
By: Jim Joyner, Pharm.D., C.G.P
The commonly used antibiotic, Azithromycin (Z-Pak, Zithromax), was recently discussed in the medical news due to a report of increased risk for serious cardiac adverse effects associated with its use. This incidence of risk is quite low, but due to the potentially serious nature it has resulted in an advisory memorandum by the FDA. Specifically, there is a small risk of prolongation of the QT interval on the ECG which may progress to a serious cardiac arrhythmia known as Torsades des Pointes (TdP). TdP can lead to ventricular fibrillation and sudden death. In light of this recent focus on the issue of drug-induced QTc prolongation, this seems like an appropriate time to review and discuss other medications which also have the potential to cause this problem, especially since some of them are encountered frequently in the medication regimens for hospice patients.
There are 34 specific medications available for use in the U.S. which have substantial evidence that supports the conclusion that they may prolong the QT interval and have a risk of TdP when used as directed according to approved labeling.(1) The list encompasses certain drugs from a variety of different pharmacologic classes including:
8 different antiarrhythmic drugs,
2 antinausea drugs,
2 antidepressant drugs,
2 anticancer drugs,
2 non-sedating antihistamines,
2 antimalarial drugs,
1 antiangina drug,
1 cholesterol lowering drug,
1 GI stimulant drug
For a complete listing of all of the medications, and detailed information about drug-induced QT prolongation check out this link:
Five of the drugs on this list are quite commonly used in hospice to provide palliative management of a variety of symptoms. Those drugs include: Chlorpromazine (Thorazine), Citalopram (Celexa), Escitalopram (Lexapro), Haloperidol (Haldol), and Methadone (Dolophine).
The incidence of this adverse cardiac effect has not been established for any of these drugs and the majority of patients take these drugs without any problem of a prolonged QT interval or arrhythmia. It is also possible that some patients may have a prolonged QT interval while taking these drugs and exhibit no negative symptoms or effects. In those cases this event would go unnoticed unless an ECG was done. This adverse effect appears to be dose-related and has been associated with patients receiving higher dosages.
Awareness of the following risk factors for QT prolongation and TdP may help reduce the risks for this adverse effect when considering the use of these drugs(2) :
• Cardiac disease (MI, CHF, cardiomyopathy, congenital long QT syndrome, bradycardia)
• Low potassium or magnesium levels (may occur with diuretic usage)
• High drug doses (i.e.; methadone > 200mg/day)
• Combined use of multiple drugs which can prolong QT
• Clinically significant drug interactions that can result in excessively elevated blood levels of a drug identified as having QT prolongation potential
There are reports of several other drugs, commonly used in hospice ( not on the list above) where substantial evidence supports the conclusion that these drugs may also cause QT prolongation but will only present a risk of causing TdP in certain conditions such as over-dosage, significant drug interaction, or in a patient with pre-existing cardiac disease risk factors.(1,2)
The drugs listed below can prolong QT but do not have the higher level of risk for causing TdP as the list of 34 drugs above: Amitriptyline (Elavil), Diphenhydramine (Benadryl), Doxepin (Sinequan), Fluoxetine,(Prozac) Nortriptyline (Pamelor), Paroxetine (Paxil), Mirtazapine (Remeron), Olanzapine (Zyprexa), Quetiapine (Seroquel), Risperidone (Risperdal), and Ziprasidone (Geodon).
In conclusion, the risks and benefits of using these drugs must be assessed on a case by case basis. There is no general guideline, nor consensus about when to stop therapy or decrease a dosage with one of these drugs if one is concerned about prolonged QT or TdP. A reasonable approach to the problem in hospice care would include the following:
• Avoid the use of a drug known to cause TdP in a patient with the risk factors described above, unless there is no reasonable alternative available
• Reduce correctable risk factors if possible (low potassium or magnesium)
• Exercise caution when using multiple drugs known to cause TdP or prolonged QT, and utilize doses at the lower end of the therapeutic range when combining these drugs
• Exercise caution when using high doses of drugs known to cause TdP (methadone in doses > 200mg/day)
• Avoid clinically significant drug interactions which may result in significantly elevated levels of the drugs identified with a potential for prolonged QT and TdP
(1.) Arizona Center for Education and Research on Therapeutics
University of Arizona. www.azcert.org
(2.) Yap, Camm: Heart. 2003 November; 89(11): 1363–1372
Based on post-marketing surveillance and a recently conducted QT study, the FDA has determined that the antidepressant citalopram (Celexa) should no longer be used at doses greater than 40 mg per day because it causes dose-dependent prolongation of the cardiac QT interval. Previously, the citalopram drug label stated that certain patients may require a dose of 60 mg per day, even though studies did not show a benefit in the treatment of depression at doses higher than 40 mg per day.
For these patients, citalopram should be used with caution. Consider limiting the dose to 20 mg per day or more frequent EKG monitoring.
Furthermore, 20 mg per day is the maximum recommended dose for patients with hepatic impairment, who are greater than 60 years of age, or who are taking concomitant cimetidine (Tagamet), because these factors lead to increased blood levels of citalopram. Citalopram should not be used at all in patients with congenital long QT syndrome.
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