The U.S. Food and Drug Administration (FDA) has asked the manufacturer of the tyrosine kinase inhibitor ponatinib (Iclusig) to suspend marketing and sales of the drug because of the risk of life-threatening blood clots and severe narrowing of blood vessels. Ariad Pharmaceuticals has agreed to suspend marketing and sales while the safety of the drug continues to be evaluated.
Serious Adverse Events
Ponatinib is indicated for the treatment of patients with chronic-phase, accelerated-phase, or blast-phase chronic myeloid leukemia of Philadelphia chromosome–positive acute lymphoblastic leukemia, who are no longer benefiting from previous treatment or who did not tolerate treatment.
FDA’s recent investigation of ponatinib revealed an increased frequency of blood clots and narrowing of blood vessels since the drug was approved in December 2012. In phase I and II clinical trials, approximately 48% and 24% of patients, respectively, have experienced serious adverse vascular events, including fatal and life-threatening heart attack, stroke, loss of blood flow to the extremities resulting in tissue death, and severe narrowing of blood vessels in the extremities, heart, and brain requiring urgent surgical procedures to restore blood flow.
In the phase II clinical trial, adverse events affecting the blood vessels that supply the heart, brain, and extremities were observed in 12%, 6%, and 8% of patients, respectively; patients with and without cardiovascular risk factors, including patients in their 20s, have experienced these events. High blood pressure occurred in 67% of patients, and heart failure, including fatalities, occurred in 8% of patients treated with ponatinib. In addition, serious adverse reactions involving the eyes, which lead to blindness or blurred vision, occurred in ponatinib-treated patients.
In some patients, fatal and serious adverse events have occurred as early as 2 weeks after starting ponatinib therapy. The relationship of these adverse events to ponatinib has not been determined, but the increasing rate and pattern of the events strongly suggests that many are drug-related. At this time, FDA cannot identify a dose level or exposure duration that is safe.
The FDA will continue to evaluate the drug to further understand its risks and to identify potential patient populations in which the benefits of the drug may outweigh the risks. Patients currently receiving ponatinib should discuss with their health-care professionals the risks and benefits of continuing treatment with the drug.
At this time, patients and health-care professionals should follow FDA’s new recommendations for the drug:
Patients currently taking ponatinib who are not responding to the drug should immediately discontinue treatment and discuss alternative treatment options with their health-care professionals.
Patients who are currently taking ponatinib and responding to the drug and whose health-care professionals determine that the potential benefits outweigh the risks should be treated under a single-patient Investigational New Drug (IND) application or expanded access registry program while FDA’s safety investigation continues.
Health-care professionals should not start treating new patients with ponatinib unless no other treatment options are available and all other available therapies have failed. Upon the determination of their health-care professional, these patients can be considered for treatment under an IND or expanded access registry program.
Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System. ■
See comments from Brian J. Druker, MD here.