Dear healthcare professionals letter on reminder on the Procoralan/Corlentor conditions of use for the symptomatic treatment of chronic stable angina pectoris to avoid potentially dangerous bradycardia

12.06.2014

Servier Pharma d.o.o., local representative of the marketing authorization holder, in collaboration with the Croatian Agency for Medicinal Products and Medical Devices, have sent a letter to healthcare professionals on the emerging safety issue for Procoralan/Corlentor (ivabradine). Preliminary results of the SIGNIFY study have shown a small but statistically significant increase in the combined risk of cardiovascular death and non-fatal myocardial infarction with ivabradine compared with placebo in a pre-specified subgroup of patients with symptomatic angina of CCS class II or more.

Initial data indicate that the adverse cardiovascular outcomes may be mostly associated with the target heart rate being below 60 bpm; however data from the SIGNIFY study are being further evaluated to fully understand its implications for the clinical use of ivabradine.

Summary:

Initial data indicate that the adverse cardiovascular outcomes observed in the SIGNIFY study may be mostly associated with a target heart rate below 60 bpm. Treatment must be discontinued if resting heart rate becomes too low or symptoms of bradycardia persist.
The usual recommended starting dose of ivabradine is 5 mg twice daily. The maintenance dose should not exceed 7.5 mg twice daily.
If resting heart rate decreases persistently or the patient experiences symptoms related to bradycardia, the dose must be down-titrated, including the possible dose of 2.5 mg twice daily.
The dose should only be increased to 7.5 mg twice daily after three to four weeks of treatment if the therapeutic response with 5 mg twice daily is insufficient and if the 5 mg dose is well tolerated. The effect of a dose increase on the heart rate should be carefully monitored.
Concomitant use of ivabradine with heart rate-reducing calcium channel blockers such as verapamil or diltiazem should be avoided.
While on treatment with ivabradine patients should be carefully monitored for the occurrence of too low resting heart rates or symptoms of bradycardia. Treatment of patients currently using ivabradine should be reviewed where appropriate.

In addition, health care professionals are reminded of the following:

Ivabradine is authorised for the symptomatic treatment of chronic stable angina pectoris in coronary artery disease adults with normal sinus rhythm.
Ivabradine is not a first-line treatment, but is indicated:
- in adults unable to tolerate or with a contra-indication to the use of beta-blockers
- or in combination with beta-blockers in patients inadequately controlled with an optimal beta- blocker dose and whose resting heart rate is > 60 bpm.

Further information on the preliminary findings from the SIGNIFY study:

The review was started in the EU after preliminary results from the SIGNIFY study were made available. This study was evaluating whether treatment with ivabradine in patients with coronary heart disease reduces the rate of cardiovascular events (such as heart attack) when compared with placebo. The results showed a small but significant increase in the combined risk of cardiovascular death or non-fatal heart attack with the medicine in a subgroup of patients who had symptomatic angina (Canadian Cardiovascular Society class II - IV). Patients in the study received up to 10 mg twice daily, which is higher than the currently authorised maximum daily dose (7.5 mg twice daily). The public and healthcare professionals will be informed on the outcome of the safety issue assessment in a timely manner.

Ivabradine is also indicated in chronic heart failure NYHA II to IV class with systolic dysfunction, in patients in sinus rhythm and whose resting heart rate is ≥ 75 bpm, in combination with standard therapy including beta-blocker therapy or when beta-blocker therapy is contraindicated or not tolerated.

Healthcare professionals should take note of the relevant precautions in the product information for this indication, especially in relation to heart rate.

So far, HALMED has received one suspected adverse reaction report of bradycardia (slow heart rate) with fatal outcome in 84 years old patient. In this patient, unfortunately, there were several important factors that contributed to such an outcome. These factors are: presence of the heart attack before of the introduction of ivabradie in the therapy (heart attack is a contra-indication to the use of this medicinal product), the use of the medicinal product with the aim of treating sinus tachycardia (increased heart rate, which is not approved indication for the use of this medicine) and that application of the dose that was not reduced according to the the patient's age.

In addition to these factors, it is considered possible that the use of the medicine contributed to the occurrence of side effect in this patient. In this case there was considerable. trifascicular block (difficulty in conducting electrical impulses to the heart), bradycardia (slow heart rate) and asystole (cessation of electrical activity of the heart), which has unfortunately led to a fatal outcome.

Based on this, HALMED encourages health care professionals to strictly adhere to the approved indication of ivabradine, as well as any restrictions on the use of ivabradine listed in the summary of product characteristics, until the outcomes of the assessment are known. In case of any concerns, patients who were treated with ivabradine should contact their doctor for advice.

We remind healthcare professionals that they should report any adverse reaction to HALMED, as well as quality defect. Patients who have developed any adverse reaction to medicinal product may report it directly to HALMED via form or on-line application, with recommendation regarding any adverse reaction they discover to consult with their doctor or pharmacist about the continuation of their therapy.