Cilostazol-containing medicines - referral
Current status
Referral
Human
On 22 March 2013, the European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) recommended that the use of cilostazol-containing medicines in the treatment of intermittent claudication – a condition where poor blood supply to the leg muscles causes pain and affects the ability to walk – should be restricted with a range of new measures aimed at targeting a patient population in which there are clinical benefits, and at the same time minimising important risks.
The recommendations followed a review of current evidence, which indicated that the modest benefits of these medicines, i.e. their ability to increase the distance patients are able to walk, are only greater than their risks, in particular the risks of side effects affecting the heart or serious bleeding, in a limited subgroup of patients.
Cilostazol-containing medicines are available in the European Union (EU) under the names Pletal and Ekistol.
The Committee recommended that cilostazol should only be used in patients whose symptoms have not improved despite prior lifestyle changes such as exercise, healthy diet and stopping smoking. In addition, cilostazol-containing medicines should not be used in patients who have suffered severe tachyarrhythmia (fast, abnormal heart rhythm), or recent unstable angina, heart attack or bypass surgery, or who take two or more antiplatelet or anticoagulant medicines such as aspirin and clopidogrel.
Doctors should review their patients at their next routine appointment and assess the continued suitability of cilostazol treatment.
Detailed recommendations for patients and healthcare professionals are available below.
The Spanish Agency for Medicines and Health Products (AEMPS) asked the CHMP to carry out a review of these medicines following a number of reports of serious suspected side effects, in particular affecting the heart, as well as cases of serious bleeding.
The CHMP examined available clinical-trial data on the benefits and risks of the medicines provided by the companies that market these medicines, as well as data from scientific literature, reports of suspected side effects, post-marketing studies and experimental studies before making its recommendations. More information on the studies and the CHMP's conclusions is available below.
The CHMP recommendation was sent to the European Commission, which endorsed it and adopted a legally-binding decision throughout the EU on 24 June 2013.
Healthcare professionals should follow these recommendations:
For the full changes to information for doctors and patients, see under the 'all documents' tab.
The Agency's recommendations are based on a review by the Committee for Medicinal Products for Human Use (CHMP), which looked at available data on the benefits and risks of cilostazol.
In conclusion, the CHMP considered that, although on average the efficacy of cilostazol is modest, there is a small group of patients in whom it is of clinical relevance, not least in helping them to begin exercise programmes. Although suspected adverse-drug-reaction reports have raised some safety concerns, these have not been substantiated in the clinical trial data (including the CASTLE study), and it remains possible to exclude high-risk patients in clinical practice. CHMP therefore recommended a number of measures aimed at targeting use of cilostazol to the population most likely to benefit, and in whom the risk of side effects is low.
Reference
1Hiatt WR, Money SR, Brass EP. Long-term safety of cilostazol in patients with peripheral artery disease: the CASTLE study (Cilostazol: A Study in Long-term Effects). J Vasc Surg 2008; 47: 330-336.
Cilostazol is a medicine that is used to improve walking distance in patients who have intermittent claudication due to peripheral arterial obstructive disease (obstruction and narrowing of the arteries of the limbs, leading to reduced blood flow).
Medicines containing cilostazol have been approved in the EU through national procedures since 2000 and are available in France, Germany, Italy, Spain, Sweden and the United Kingdom under the invented names Pletal and Ekistol.
Cilostazol works by blocking an enzyme called phosphodiesterase type 3, which is found in the walls of arteries and is involved in various processes affecting circulation, including aggregation (clumping together) of blood platelets and narrowing of the arteries. Blocking the enzyme reduces these actions and blood flow is improved, allowing patients to walk further without disabling pain.
The review of cilostazol was initiated at the request of Spain, under Article 31 of Directive 2001/83/EC.
The Spanish Agency for Medicines and Health Products (AEMPS) asked the CHMP to carry out a full assessment of the benefit-risk balance of cilostazol and to issue an opinion on whether the marketing authorisations for products containing cilostazol should be maintained, varied, suspended or withdrawn across the EU.
The request followed reports to the Spanish agency of serious adverse effects affecting the heart including fatal heart attacks, angina and arrhythmias (irregular heartbeat) as well as cases of serious bleeding including bleeding in the brain. Many of the patients who were prescribed the medicine were much older, and taking more medicines, than those in whom it was originally tested before marketing, which may explain the increased risk of side effects. There was evidence that many of these patients had to stop taking the medicine. In addition, the benefits of treatment were modest.
The CHMP opinion was forwarded to the European Commission, which issued a final decision endorsing the opinion on 24 June 2013.
This type of referral is triggered when the interest of the Union is involved, following concerns relating to the quality, safety or efficacy of a medicine or a class of medicines.
Description of documents published
Please note that some of the listed documents apply only to certain procedures.
Note that older documents may have different titles.