EMA’s Pharmacovigilance Risk Assessment Committee Recommends Further Measures to Minimise Risk of Thrombosis and Occlusion of Blood Vessels With Ponatinib

The recommendations to be considered by EMA’s Committee for Medicinal Products for Human Use for Final Opinion

The European Medicines Agency’s (EMA’s) Pharmacovigilance Risk Assessment committee (PRAC) has completed a review of the benefits and risks of ponatinib (Iclusig), a medicine used for the treatment of leukaemia. The aim of this review was to examine the risk of arterial and vein thrombosis or occlusion and to assess whether further measures were needed to minimise this risk.

Ponatinib is authorised for use in patients with chronic myeloid leukaemia (CML) and acute lymphoblastic leukaemia (ALL) who cannot take or tolerate several other medicines of the same class, known as tyrosine-kinase inhibitors. The PRAC considered that the benefits of ponatinib continue to outweigh its risks; however, the Committee recommended that the product information for patients and healthcare professionals should be updated with strengthened warnings, particularly about the risk of thrombosis and occlusion in the arteries.

The PRAC assessed the available data on the nature, frequency and severity of thrombosis or occlusion of the arteries or veins. Although the Committee noted that this risk is likely to be dose-related, there are insufficient data to formally recommend the use of lower doses of ponatinib, and there is a risk that lower doses might not be as effective in all patients and in long-term treatment.

The PRAC therefore considered that the recommended starting dose of ponatinib should remain 45 mg once a day. However, updates to the product information are recommended to provide healthcare professionals with the latest evidence, in case they wish to consider reducing the dose in patients with chronic phase CML who are responding well to treatment, and who might be at particular risk of blood vessel occlusion. In addition, healthcare professionals should stop ponatinib if there has been no response after three months of treatment, and monitor patients for high blood pressure or signs of heart problems.

A new study on the safety and benefits of ponatinib is planned to help clarify if lower doses of the medicine carry a lower risk of thrombosis or occlusion of the blood vessels while still having a beneficial effect in patients with chronic phase CML.

The PRAC recommendation will now be forwarded to the Committee for Medicinal Products for Human Use (CHMP), which will adopt the EMA’s final opinion.

More about ponatinib

Ponatinib is a cancer medicine used to treat adults with the following types of leukaemia:

  • chronic myeloid leukaemia (CML)
  • acute lymphoblastic leukaemia (ALL) in patients who are Philadelphia-chromosome positive (Ph+)

Ponatinib is used in patients who cannot tolerate or do not respond to dasatinib or nilotinib and for whom subsequent treatment with imatinib is not considered appropriate. It is also used in patients who have a T315I mutation which makes them resistant to treatment with imatinib, dasatinib or nilotinib.

The active substance in Iclusig, ponatinib, belongs to a group of medicines called tyrosine-kinase inhibitors. Ponatinib works by blocking a tyrosine kinase Bcr-Abl, which is found in some receptors on the surface of the cancer cells where it is involved in stimulating the cells to divide uncontrollably. By blocking Bcr-Abl, ponatinib helps to control the growth and spread of leukaemia cells.

Ponatinib was authorised as an orphan medicine (a medicine to treat rare diseases) in the EU in July 2013.

More about the procedure

The review of ponatinib was initiated on 27 November 2013 at the request of the European Commission, under Article 20 of Regulation (EC) No 726/2004.

This follows an initial assessment of clinical trial data with ponatinib, conducted in November 2013, indicating that cases of blood thrombosis and occlusion in the arteries or veins were occurring at a higher rate than was observed at the time of the medicine’s initial authorisation.

At the time, the EMA recommended a number of measures to help minimise this risk, which included additional warnings (e.g. against use in patients who have had a heart attack or stroke in the past). Since a number of issues required further investigation, including a better understanding of the nature, frequency and severity of events obstructing the arteries or veins, the potential mechanism through which the medicine leads to these side effects and whether there was a need to revise the dosing recommendation of ponatinib, the European Commission asked to Agency to perform an in-depth review.

The current review has been carried out by the Pharmacovigilance Risk Assessment Committee, the Committee responsible for the evaluation of safety issues for human medicines, which has made a set of recommendations. As ponatinib is a centrally authorised medicine, the PRAC recommendations will now be forwarded to the CHMP, responsible for questions concerning medicines for human use, which will adopt a final opinion. This will then be sent to the European Commission, which will issue a final legally binding decision valid throughout the EU in due course.