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The U.S. Food and Drug Administration has approved a revised U.S. Prescribing Information (USPI) and Risk Evaluation and Mitigation Strategy (REMS) for the leukemia drug Iclusig (ponatinib). In addition, the agency has asked Ariad Pharmaceuticals, the drug's manufacturer, to conduct postmarket investigations to further characterize ponatinib's safety and dosing.

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These required safety measures include:


* Label changes to narrow the indication;


* Providing additional warnings and precautions about the risk of blood clots and severe narrowing of blood vessels;


* Revising the recommendations about the dosage and administration; and


* Updating the patient Medication Guide.



Once these measures are met, the agency said, sales and marketing of the drug are expected to resume in the U.S.


Ponatinib's marketing and sales were suspended in October after longer follow-up data to the Phase I and II trials found high risks of life-threatening blood clots and severe narrowing of blood vessels (OT 12/25/13 issue).


The objective of the REMS program is to inform prescribers of (1) the risk of the vascular events associated with the drug and (2) the revised indications. The program was set to be initiated within 15 days after the REMS approval date. The expectation was that the new safety measures would be in place by the end of this month, allowing sales and marketing of the drug to resume.


The new safety measures include the following:


* The indications for use are limited to:


* 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); or


* 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 (including a description of the observed arterial and venous thrombosis and occlusions that have occurred in at least 27 percent of patients treated with the drug).


* The Dosage and Administration recommendations are revised to state that the optimal dose 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.


* Revisions of the patient Medication Guide to include additional safety information consistent with the safety information in the revised drug label.


* The Iclusig REMS, the FDA said, 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 letter to health care professionals who are known or likely to prescribe Iclusig;


* A letter for professional societies to be distributed to their members;


* A fact sheet for health care professionals;


* A public statement to be published quarterly for one year in several professional journals;


* Information to be prominently displayed at scientific meetings; and


* An Iclusig REMS website to provide access to all REMS materials for the duration of the program.


* Ariad's postmarket investigations, the FDA said, will further evaluate dose selection, drug exposure, treatment response, and toxicity of Iclusig therapy.



The FDA also noted that from the time of the October suspension through the date of the announcement of the plan to make it possible for the suspension to be rescinded, that the agency had granted 350 single-patient investigational new drug (IND) applications for patients to have access to Iclusig.