FDA Drug Safety Communication: Revised recommendations for Celexa (citalopram hydrobromide) related to a potential risk of abnormal heart rhythms with high doses

This update provides additional information related to a previous FDA Drug Safety Communication (posted 8/24/2011)¹: Abnormal heart rhythms associated with high doses of Celexa (citalopram hydrobromide).

Safety Announcement
Additional Information for Patients
Additional Information for Healthcare Professionals
Data Summary

Safety Announcement

[3-28-2012] The U.S. Food and Drug Administration (FDA) is clarifying dosing and warning recommendations for the antidepressant Celexa (citalopram hydrobromide; also available in generic form). In August 2011², FDA issued a Drug Safety Communication (DSC) stating that citalopram should no longer be used at doses greater than 40 mg per day because it could cause potentially dangerous abnormalities in the electrical activity of the heart.

Citalopram use at any dose is discouraged in patients with certain conditions because of the risk of QT prolongation, but because it may be important for some of those patients to use citalopram, the drug label has been changed to describe the particular caution that needs to be taken when citalopram is used in such patients. The revised drug label also describes lower doses that should be used in patients over 60 years of age.
Changes in the electrical activity of the heart (specifically, prolongation of the QT interval of the electrocardiogram [ECG]) can lead to a risk of an abnormal heart rhythm called Torsade de Pointes, which can be fatal. Patients at particular risk for developing prolongation of the QT interval include those with underlying heart conditions and those who are predisposed to having low levels of potassium and magnesium in the blood.

The citalopram drug label was revised on August 12, 2011 and again on March 27, 2012, to include new warnings about the potential for QT interval prolongation and Torsade de Pointes, as well as new drug dosage and usage recommendations. (See Additional Information for Healthcare Professionals).

The following changes have now been made to the citalopram drug label as of 3/27/12:

Recognition that although citalopram use should be avoided, if possible, in patients with certain conditions because of the risk of QT prolongation, ECG monitoring and/or electrolyte monitoring should be performed if citalopram must be used in such patients.
Patients with congenital long QT syndrome are at particular risk of Torsade de Pointes, ventricular tachycardia, and sudden death when given drugs that prolong the QT interval. Nevertheless, the labeling recommendation for patients with congenital long QT syndrome has been changed from “contraindicated” to “not recommended,” because it is recognized that there may be some patients with this condition who could benefit from a low dose of citalopram and who lack viable alternatives.
The maximum recommended dose of citalopram is 20 mg per day for patients older than 60 years of age.
Citalopram should be discontinued in patients who are found to have persistent QTc measurements greater than 500 ms.

Additional Information for Patients (updated from 8/24/2011)

Do not stop taking citalopram or change your dose without talking to your healthcare professional. Stopping citalopram suddenly can cause withdrawal effects.
If you are currently taking a citalopram dose greater than 40 mg per day, talk to your healthcare professional.
Seek immediate care if you experience an irregular heartbeat, shortness of breath, dizziness, or fainting while taking citalopram.
If you are taking citalopram, your healthcare professional may occasionally order an electrocardiogram (ECG, EKG) to monitor your heart rate and rhythm.
Your healthcare professional may also order tests to check levels of potassium and magnesium in your blood.
Read the Medication Guide for citalopram carefully and discuss any questions you have with your healthcare professional.
Report any side effects you experience to the FDA MedWatch program using the information in the “Contact FDA” box at the bottom of the page.

Additional Information for Healthcare Professionals (updated from 8/24/2011)

Citalopram causes dose-dependent QT interval prolongation, which can cause Torsades de Pointes, ventricular tachycardia, and sudden death.
Citalopram is not recommended for use at doses greater than 40 mg per day because such doses cause too large an effect on the QT interval and confer no additional benefit.
Citalopram is not recommended for use in patients with congenital long QT syndrome, bradycardia, hypokalemia, or hypomagnesemia, recent acute myocardial infarction, or uncompensated heart failure. Citalopram use is also not recommended in patients who are taking other drugs that prolong the QT interval.
The maximum recommended dose of citalopram is 20 mg per day for patients with hepatic impairment, patients who are older than 60 years of age, patients who are CYP 2C19 poor metabolizers, or patients who are taking concomitant cimetidine (Tagamet®) or another CYP2C19 inhibitor, because these factors lead to increased blood levels of citalopram, increasing the risk of QT interval prolongation and Torsade de Pointes.
Electrolyte and/or ECG monitoring is recommended in certain circumstances
- Consider more frequent ECG monitoring in patients for whom citalopram use is not recommended, but is, nevertheless, considered essential.
- Patients at risk for significant electrolyte disturbances should have baseline serum potassium and magnesium measurement, with periodic monitoring. Hypokalemia and/or hypomagnesemia may increase the risk of QTc prolongation and arrhythmia and should be corrected prior to initiation of treatment with periodic monitoring.
Citalopram should be discontinued in patients found to have persistent QTc measurements greater than 500 ms.
Advise patients on citalopram to contact a healthcare professional immediately if they experience signs and symptoms of an abnormal heart rate or rhythm (e.g., dizziness, palpitations, or syncope). If patients experience symptoms, the prescriber should initiate further evaluation, including cardiac monitoring.
Report adverse events involving citalopram to the FDA MedWatch program, using the information in the “Contact FDA” box at the bottom of the page.

Data Summary

FDA has received post-marketing reports of QT interval prolongation and Torsade de Pointes associated with Celexa (citalopram) and its generic equivalents. FDA evaluated the results of thorough QT studies assessing the effects of doses of citalopram and its active S-isomer escitalopram (Lexapro) on the QT interval in adults. Both studies are randomized, double-blind, placebo-controlled, crossover studies. In the citalopram study, 119 subjects received citalopram 20 mg/day and 60 mg/day, moxifloxacin 400 mg/day, and placebo. In the escitalopram study, 113 subjects received escitalopram 10 mg/day and 30 mg/day, moxifloxacin 400 mg/day, and placebo.
The summary of findings is presented in Table 1. As of March 27, 2012, this table has been updated to provide comparative information for escitalopram. Citalopram is a racemic mixture of S- and R-isomers. Escitalopram is the S-isomer of citalopram. The antidepressant activity of citalopram is limited to the S-isomer; therefore, each row of Table 1 shows equally effective doses of citalopram and escitalopram. The maximum recommended dose of escitalopram is 20 mg once daily.
Table 1: Citalopram and Escitalopram: Dose-dependent Change in Corrected QT Interval (QTc) [revised 3/27/2012 to include escitalopram]

Citalopram		Escitalopram
Dose	Change in QTc (90% Confidence Interval) (ms)	Dose	Change in QTc (90% Confidence Interval) (ms)
20 mg 40 mg* 60 mg Moxifloxacin 400 mg	8.5 (6.2, 10.8) 12.6 (10.9, 14.3) 18.5 (16.0, 21.0) 13.4 (10.9, 15.9)	10 mg 20 mg* 30 mg Moxifloxacin 400 mg	4.5 (2.5, 6.4) 6.6 (5.3, 7.9) 10.7 (8.7, 12.7) 9.0 (7.3, 10.8)

* Estimate based on the relationship between citalopram (and escitalopram) blood concentrations and QT interval
Although the antidepressant effects of the drugs are known to be limited to the S-isomer, the difference between the effects of citalopram racemate and escitalopram on the QT interval presumably means that the QT effects are not specific to the S-isomer.
These studies show that citalopram causes dose-dependent QT interval prolongation that is clinically significant with the 60 mg daily dose. In addition, clinical trials do not show any added effectiveness of citalopram at 60 mg/day compared to 40 mg/day. Therefore, citalopram should not be used at doses above 40 mg per day. Important safety information about the potential for QT interval prolongation and Torsade de Pointes with updated drug dosage and usage recommendations have been added to the citalopram drug label. Given that these findings were not observed with escitalopram, there are no changes planned for escitalopram at this time.
References
1. IMS, Vector One®: National (VONA). Year 2011. Extracted February 2012.
2. IMS, Vector One®: Total Patient Tracker (TPT). Year 2011. Extracted February 2012.
3. SDI, Physician Drug and Diagnosis Audit (PDDA). Year 2011. Extracted February 2012.