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June 26, 2016

Citalopram and Escitalopram – Risk of QT interval prolongation

Products include: Cipramil/Bellcital/Ciprager/Ciprapine/Ciprotan/Citalopram Actavis/Citalopram Teva/ Citrol and Lexapro/Escipriex/Escitalpro/Escitomar

Citalopram and escitalopram are selective serotonin reuptake inhibitors (SSRIs) indicated in the treatment of depressive illness (see the Summaries of Product Characteristics (SPCs) for full details of licensed indications).

Following a review of the available information on the risk of QT prolongation with these medicines, the Pharmacovigilance Working Party (PhVWP) has recommended that the product information for citalopram and escitalopram be updated with new contraindications and warnings and a reduction in the maximum dose for use in the elderly for both active substances. For citalopram, there has additionally been a general reduction in the maximum dose and in the maximum dose for patients with impaired liver function.  This information was recently communicated to Healthcare Professionals by the marketing authorisation holder, in agreement with the IMB and is available on www.imb.ie.

Advice to Healthcare Professionals

• Citalopram and escitalopram have been found to cause a dose-dependent prolongation of the QT interval.

• Cases of ventricular arrhythmia including Torsade de Pointes (TdP) have been reported, predominantly in females, with hypokalaemia and with pre-existing QT interval prolongation or other cardiac diseases.

• Citalopram and escitalopram are now contraindicated in patients with known QT interval prolongation or congenital long QT syndrome.

• Co-administration with other medicinal products known to prolong the QT-interval is also contraindicated (e.g. Class IA and III antiarrythmics, antipsychotics, tricyclic antidepressants and some antimicrobial agents such as moxifloxacin).

• Caution is advised in patients at higher risk of developing TdP, e.g. those with congestive heart failure, myocardial infarction, bradyarrhythmias or a predisposition to hypokalaemia or hypomagnesaemia because of concomitant illness/medicines.

• Healthcare professionals are advised to review elderly patients taking citalopram or escitalopram at doses above the new recommended maximum dose, and gradually reduce the dose accordingly (the product information advises on how to minimise the risk of withdrawal symptoms).

Information on the data assessed

The new recommendations for citalopram-containing products follow an assessment of a QT-study which revealed a dose dependant increase of the QT-interval observed with ECG. In addition, review of data from spontaneous reports has identified cases of QT prolongation and ventricular arrhythmia including TdP.  Furthermore, studies have not shown an added benefit in the treatment of depression at doses higher than 40mg daily. The product information for citalopram-containing products will be revised to reflect the study findings and the following new dosage and usage recommendations:

• The recommended maximum dose of citalopram in adults has been lowered from 60mg to 40mg daily due to risk of QT interval prolongation with higher doses.

• The recommended maximum dose of citalopram in the elderly is accordingly lowered from 40mg to 20mg daily.

• The recommended maximum dose is lowered from 30mg to 20mg citalopram daily in patients with reduced hepatic function.

In addition to the data evaluated for citalopram, the PhVWP assessed the results of a QT-study undertaken in healthy volunteers given doses of 10mg and 30mg escitalopram and concluded that a dose dependent increase in QT interval was shown in this study, particularly with 30mg/day. The PhVWP also noted that cases of QT interval prolongation and ventricular arrhythmia including TdP were spontaneously reported, predominantly in female patients with hypokalaemia, pre-existing QT interval prolongation or other cardiac diseases. Most of the reported cases of TdP had a temporal relationship with starting treatment with escitalopram, or with the increase in dosing, and/or at the time of other risk situations, e.g. hypokalaemia. Recovery from the event was reported when escitalopram was discontinued in most of the reported cases. The data from spontaneous reporting indicates a signal for QT prolongation and the potential for under-reporting is recognised.

The PhVWP considered that it is not possible to conclude that there is a substantially lower risk for QT-prolongation with escitalopram than with citalopram, and therefore, the same risk minimisation measures should apply. In considering the appropriate risk minimisation strategy, the PhVWP also noted that elderly patients achieve higher systemic exposure than younger patients and made the following recommendations:

• In the elderly (> 65 years of age), the recommended maximum dose of escitalopram is now reduced to 10mg daily.

• The maximum dose of escitalopram for adults ≤ 65 years remains 20mg daily.

Patients treated with citalopram or escitalopram should be advised to contact a healthcare professional immediately if they experience symptoms of an abnormal heart rate or rhythm.  Patients should not stop taking these medicines or change or reduce the dose without first consulting their healthcare professional, as withdrawal symptoms may occur.  Cases of QT interval prolongation have been reported also in association with other SSRIs, for further information please refer to the respective SPCs.  Suspected adverse reactions associated with the use of citalopram or escitalopram, particularly cardiac disorders, should be reported to the IMB via the usual routes.

Key Message: Citalopram and escitalopram are associated with dose-dependent QT interval prolongation. Risk minimisation measures will be implemented including new contraindications and warnings and dosing recommendations.