HSA would like to update healthcare professionals on the risk minimisation measures that will be implemented to mitigate the risk of dose-dependent QT interval prolongation with citalopram. These measures include new dosing and warning recommendations.
Background
Citalopram is a selective serotonin reuptake inhibitor (SSRI) indicated for the treatment of depression and prevention of relapse/recurrence, panic disorder with or without agoraphobia, and obsessive-compulsive disorder. Two citalopram-containing products are registered in Singapore, with Cipram® (LF Asia Pharmaceutical Division) registered since 1992, and Ciram (Drug Houses of Australia) in January 2012.
In August 2011, the US Food and Drug Administration (FDA) notified healthcare professionals and patients that citalopram should no longer be used at doses greater than 40mg per day due to the risk of dose-dependent QT interval prolongation.1 Studies also did not show a benefit in the treatment of depression at doses higher than 40mg per day.
The FDA evaluated the results of a thorough QT study* assessing the effects of 20mg and 60mg doses of citalopram against placebo on the QT intervals in adults (n=119). In the study, when compared to placebo, maximum mean prolongations in the individually corrected QT (QTc)** intervals were 8.5ms (90% CI 6.2–10.8) and 18.5ms (90% CI 16.0–21.0) for 20mg and 60mg citalopram, respectively. For 40mg citalopram, prolongation of the QTc interval was estimated to be 12.6ms (90% CI 10.9–14.3).
As a result of this thorough QT study and the FDA's analysis of post-marketing reports of QT interval prolongation and Torsade de Pointes associated with citalopram, the citalopram US product label was revised to include the new drug dosage and usage recommendations, as well as important safety information about the potential for QT interval prolongation and Torsade de Pointes.2 Please refer to the summary of the updated dosing and warning recommendations below:
- 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 40mg per day because such doses cause too large an effect on the QT interval and confer no additional benefit
- The maximum recommended dose is 20mg per day for patients with hepatic impairment, who are older than 60 years of age, who are CYP2C19 poor metabolisers, or who are taking concomitant cimetidine or other CYP2C19 inhibitors, because these factors lead to increased blood levels of citalopram, increasing the risk of QT interval prolongation and Torsade de Pointes
- Citalopram is not recommended for use in patients with congenital long QT syndrome, bradycardia, hypokalaemia or hypomagnesaemia, 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
- Consider more frequent electrocardiogram (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. Hypokalaemia and/or hypomagnaesemia 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 500ms
* A thorough QT study refers to a single trial intended to determine if a drug has a threshold pharmacologic effect on cardiac repolarisation, as detected by QT/QTc prolongation. Please refer to the following weblink for more information
http://www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm129357.pdf.
** As the QT interval has an inverse relationship to heart rate, the measured QT interval is routinely corrected by means of various formulae to a value known as the QTc interval which is less dependent on the heart rate.
Actions by other regulatory agencies
Other regulatory agencies, including the European Medicines Agency (EMA),3 Australia Therapeutic Goods Administration (TGA),4 UK Medicines and Healthcare products Regulatory Agency (MHRA)5 and Health Canada,6 have also issued new dosing recommendations for citalopram, with a maximum dose of 40mg daily in adults and 20mg daily in elderly and patients with reduced hepatic function. New warnings were also added to the product labels of citalopram-containing products.
Local situation
To date, HSA has not received any local reports of QT prolongation associated with use of citalopram.
Following the FDA announcement, HSA initiated an evidence-based review regarding the maximum dose for citalopram, including a review of the thorough QT study reports used by the FDA to support their regulatory decision, and determined that a reduction in maximum dose to 40mg daily is warranted. HSA has been working with the companies to update the local package insert for Cipram® and Ciram™ to reflect the new dosing and warning recommendations.
HSA's advisory
Healthcare professionals are advised to adhere to the new dosing and warning recommendations for citalopram. Patients should be advised to contact a healthcare professional immediately if they experience signs and symptoms of an abnormal heart rate or rhythm (eg, dizziness, palpitations or syncope) while taking citalopram. Healthcare professionals are also encouraged to report any suspected adverse reactions associated with the use of citalopram to the Vigilance Branch of HSA.
References
1.http://www.fda.gov/Drugs/DrugSafety/ucm269086.htm
2.http://www.fda.gov/Drugs/DrugSafety/ucm297391.htm
3.http://www.ema.europa.eu/docs/en_GB/document_library/Report/2011/10/WC500117061.pdf
4.http://www.tga.gov.au/safety/alerts-medicine-citalopram-111104.htm#hp
5.http://www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/CON137769
6.http://www.healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2012/14672a-eng.php