NPC Archive Item: MHRA Drug Safety Update December 2011 — important information for prescribers

The Drug Safety Update is an NHS Evidence accredited provider.

21 December 2011

The MHRA and CHM have published the December edition of Drug Safety Update. This edition includes articles on:

• dose-dependent QT interval prolongation associated with citalopram and escitalopram (including new maximum dose restrictions)
• the risk of serious haemorrhage and need for renal function testing with dabigatran▼
• angiotensin-2 receptor antagonists (A2RAs) — evidence does not suggest any link with cancer.

Action
Drug Safety Update is an essential read for everyone whose professional practice involves medicines. It is published every month in electronic format only. Health professionals should follow the advice given in the Drug Safety Update, the key messages of which are given below.

Citalopram and escitalopram: QT interval prolongation

Contraindications and cautions for use
Citalopram and escitalopram are associated with dose-dependent QT interval prolongation and should not be used in:

• patients with congenital long QT syndrome or known pre-existing QT interval prolongation
• combination with other medicines known to prolong the QT interval (see below).

The balance of benefits and risks of citalopram and escitalopram should be considered carefully, particularly at higher doses, in patients with pre-existing risk factors for QT interval prolongation — including patients with significant bradycardia; recent acute myocardial infarction; or decompensated heart failure.

New maximum daily doses
New restrictions on the maximum daily dose of citalopram and escitalopram now apply (see Table below). Patients who currently take doses higher than the new recommended daily maximum should have their treatment reviewed.

Table. Maximum daily doses of citalopram and escitalopram

*New (restricted) maximum daily dose.

Monitoring recommendations
In patients with cardiac disease, an ECG review should be considered before treatment with citalopram and escitalopram. Electrolyte disturbances (e.g. hypokalaemia, hypomagnesaemia) should be corrected before treatment with citalopram and escitalopram. Monitoring of serum magnesium is advised, particularly in elderly patients, who may be taking diuretics or proton pump inhibitors.

If cardiovascular symptoms, such as palpitations, vertigo, syncope, or seizures develop during treatment, cardiac evaluation including an ECG should be undertaken to exclude a possible malignant cardiac arrhythmia.

• If QTc interval is >500 milliseconds, treatment should be withdrawn gradually.
• If QTc interval duration is between 480 milliseconds and 500 milliseconds, the balance of benefits and risks of continued treatment should be carefully considered, alongside options for dose reduction or gradual withdrawal.

Drug interactions
Citalopram and escitalopram may have an additive effect to other drugs that prolong the QT interval. Coadministration of citalopram and escitalopram with medicines that prolong the QT interval is therefore contraindicated. These include:

• class IA and III antiarrhythmics (e.g. amiodarone, dronedarone, quinidine)
• antipsychotics (e.g. fentiazine derivatives, pimozide, haloperidol)
• tricyclic antidepressants
• some antimicrobial agents (e.g. sparfloxacin, moxifloxacin, erythromycin IV, pentamidine, antimalaria treatment — particularly halofantrine)
• some antihistamines (astemizole, mizolastine)
• some antiretrovirals (e.g. ritonavir, saquinavir, lopinavir)

Patients taking concomitant medications known to increase plasma levels of escitalopram and citalopram may require a dose reduction in light of these most recent QT data. These include some antiretroviral medications, omeprazole and cimetidine. See individual Summaries of Product Characteristics (SPCs) for more information.

Dabigatran▼: risk of serious haemorrhage and need for renal function testing
While haemorrhage is a well recognised and common adverse reaction with dabigatran, a number of cases of serious and fatal haemorrhage have been reported in elderly patients with renal impairment, resulting in a strengthening of the advice for prescribers.

New advice
Do not start dabigatran in any patient with severe renal impairment (creatinine clearance <30 mL/min). A dose reduction and close clinical surveillance should be considered in patients older than 75 years, or those with moderate renal impairment (creatinine clearance 30–50 mL/min), particularly in those at increased risk of bleeding. See the SPC for more details.

Assess renal function:

• in all patients before starting dabigatran
• when a decline in renal function is suspected during treatment (e.g. hypovolaemia, dehydration, or with some comedications)
• at least annually in patients older than 75 years
• at least annually in patients with renal impairment.

Check for signs of bleeding or anaemia and stop treatment if severe bleeding occurs.

A2RAs: evidence does not suggest any link with cancer
In 2010, a meta-analysis by Sipahi and colleagues found a small but significant association between use of A2RAs and new cancer occurrence. Further meta-analyses and observational studies have been reassuring and suggested no association with cancer. Following a Europe-wide review, the European Medicines Agency has now concluded that the evidence does not support any increased risk of cancer in patients who use A2RAs. This is consistent with the findings of an FDA review.

Further information can be found on NHS Evidence and in the CNS and mental health and cardiovascular e-learning sections of the NPC website.

Please comment on this Rapid Review using our feedback form.

Make sure you are signed up to NPC Email updates — the free email alerting system that keeps you up to date with the NPC news and outputs relevant to you.