FDA Drug Safety Communication

The U.S. Food and Drug Administration (FDA) is requiring several new safety measures for the leukemia drug Iclusig (ponatinib) to address the risk of life-threatening blood clots and severe narrowing of blood vessels. Once these new safety measures are in place, the manufacturer of Iclusig is expected to resume marketing to appropriate patients. Health care professionals should review these additional safety measures and carefully consider them when evaluating the risks and benefits of Iclusig for each patient.

The required safety measures involve label changes to narrow the indication, provide additional warnings and precautions about the risk of blood clots and severe narrowing of blood vessels, revise recommendations about dosage and administration of Iclusig, and update the patient Medication Guide. We are also requiring a risk evaluation and mitigation strategy (REMS). In addition, the manufacturer of Iclusig, ARIAD Pharmaceuticals, must conduct postmarket investigations to further characterize the drug's safety and dosing.

On October 31, 2013, FDA requested and ARIAD agreed to voluntarily suspend marketing of Iclusig. FDA's request resulted from FDA's investigation, which revealed a steady increase in the number of serious vascular occlusion events identified through continued safety monitoring of the drug. This observation represented a significant change in the safety profile of Iclusig as the proportion of patients on the drug experiencing vascular occlusion events such as blood clots and severe narrowing of blood vessels was significantly greater than the proportion reported at the time of its approval in December 2012.

During the marketing suspension, Iclusig treatment has been available through single patient or emergency investigational new drug applications (INDs). Patients should continue to receive Iclusig under their authorized IND until marketing of Iclusig is resumed. FDA is working closely with ARIAD on the new safety measures and anticipates these will be in place by the end of January 2014. Once that process is complete, patients being treated under these INDs can be transitioned back to receiving the marketed Iclusig product.

In more detail, the new safety measures for Iclusig include the following:

- The indications for use are limited to:

a. Treatment of adult patients with T315I-positive chronic myeloid leukemia (chronic phase, accelerated phase, or blast phase) or T315I-positive Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL).

b. Treatment of adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia or Ph+ ALL for whom no other tyrosine kinase inhibitor (TKI) therapy is indicated.

- The Warnings and Precautions in the label are revised to describe the vascular occlusion events. This includes a description of the observed arterial and venous thrombosis and occlusions that have occurred in at least 27% - more than one in every four - of patients treated with Iclusig.

- The Dosage and Administration recommendations are revised to state that the optimal dose of Iclusig has not been identified. The recommended starting dose remains 45 mg administered orally once daily with or without food; however, additional information is included regarding dose decreases and discontinuations.

- The patient Medication Guide is revised to include additional safety information consistent with the safety information in the revised drug label.

- The Iclusig REMS will inform prescribers about the approved indications for use and the serious risk of vascular occlusion and thromboembolism associated with the drug. The REMS includes the following:

a. REMS letter to healthcare professionals who are known or likely to prescribe Iclusig

b. REMS letter for professional societies to be distributed to their members

c. REMS fact sheet for health care professionals

d. Public statement to be published quarterly for one year in several professional journals

e. Information to be prominently displayed at scientific meetings

f. Iclusig REMS Web site to provide access to all REMS materials for the duration of the REMS

- ARIAD's postmarket investigations will further evaluate dose selection, drug exposure, treatment response, and toxicity of Iclusig therapy.

View the full FDA Drug Safety Communication on FDA.gov