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The Food and Drug Administration has asked the manufacturer of ponatinib to suspend sales and marketing of the leukemia drug because of the risk of "life-threatening blood clots and severe narrowing of blood vessels" associated with the drug, the agency announced Oct. 31.
The request comes less than a year since the expedited approval of ponatinib for the treatment of chronic phase, accelerated phase, or blast phase chronic myeloid leukemia (CML) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy, or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy.
Ponatinib is a kinase inhibitor, marketed as Iclusig by ARIAD Pharmaceuticals. A recent FDA investigation determined that, since the drug was approved in December 2012, blood clots and narrowing of blood vessels have increased, according to the FDA statement. At the time of approval, 14% of patients on the drug experienced these events, according to an agency spokesperson. Two of the company’s clinical trials are now showing rates of 24% and 48%.
Patients who are not responding to treatment should be taken off the drug immediately and discuss alternative treatment with their clinicians, the agency has advised. In addition, patients who are responding to treatment, "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, the statement said.
About 24% of patients treated with ponatinib over a median of 1.3 years in a phase II study and about 48% of the patients in a phase I study treated for a median of 2.7 years have had serious adverse vascular events, which include fatal and life-threatening MIs, 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," the statement said. These events have been reported in patients with and without cardiovascular risk factors. In studies, 67% of treated patients have developed hypertension; and 8% have developed heart failure, including fatal cases.
The prescribing information for the drug includes a boxed warning about the risk of arterial thrombosis and hepatotoxicity associated with treatment.
"We will continue to evaluate the drug to further understand its risks and potential patient populations in which the benefits of the drug may outweigh the risks," the FDA noted.
In a separate Oct. 31 statement, ARIAD confirmed that it was temporarily suspending sales and marketing of ponatinib. The company "believes that Iclusig is an important medicine for patients with resistant or intolerant Philadelphia-positive leukemias and is actively working with the FDA on actions to achieve the resumption of marketing of Iclusig," the company stated.
The prescribing information for the drug includes a boxed warning about the risk of arterial thrombosis and hepatotoxicity associated with treatment.
Serious adverse events associated with ponatinib should be reported online to the FDA or by phone, 800-332-0178. Information about the IND program is available online.