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FDA Approval for Ponatinib Hydrochloride

Brand name(s): Iclusig

Full prescribing information is available, including clinical trial information, safety, dosing, drug-drug interactions, and contraindications.

Safety Announcement

On October 31, 2013, the Food and Drug Administration (FDA) requested and the manufacturer, ARIAD Pharmaceuticals, agreed to voluntarily suspend marketing of the leukemia drug ponatinib (Iclusig). This 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 ponatinib, 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.

On December 20, 2013, FDA began requiring several new safety measures for ponatinib to address the risk of life-threatening blood clots and severe narrowing of blood vessels. Once these new safety measures were in place, ARIAD Pharmaceuticals was expected to resume marketing to appropriate patients.  Health care professionals were advised to review these additional safety measures and carefully consider them when evaluating the risks and benefits of ponatinib 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 ponatinib, and update the patient Medication Guide. FDA also required a risk evaluation and mitigation strategy (REMS). In addition, ARIAD Pharmaceuticals must conduct postmarket investigations to further characterize the drug’s safety and dosing.

ARIAD Pharmaceuticals resumed marketing ponatinib in January 2014.

The new safety measures for ponatinib 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).
    • 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 ponatinib.
  • The Dosage and Administration recommendations are revised to state that the optimal dose of ponatinib 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 ponatinib 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:
    • REMS letter to healthcare professionals who are known or likely to prescribe ponatinib
    • REMS letter for professional societies to be distributed to their members
    • REMS fact sheet for health care professionals
    • Public statement to be published quarterly for one year in several professional journals
    • Information to be prominently displayed at scientific meetings
    • Ponatinib REMS website to provide access to all REMS materials for the duration of the REMS
  • ARIAD Pharmaceuticals' postmarket investigations will further evaluate dose selection, drug exposure, treatment response, and toxicity of ponatinib therapy.

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Approved for chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia

On December 14, 2012, the Food and Drug Administration (FDA) granted accelerated approval to ponatinib hydrochloride (Iclusig™ tablets, made by ARIAD Pharmaceuticals, Inc.) for the treatment of adult patients with chronic-phase (CP), accelerated-phase (AP), or blast-phase (BP) chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy.  

The approval was based on the results of the PACE trial, a multicenter international single-arm clinical trial of 449 patients with disease that was resistant or intolerant to prior tyrosine kinase inhibitor therapy. The primary endpoints were major cytogenetic response (MCyR), for patients with CP-CML, and major hematologic response (MaHR), for patients with AP-CML, BP-CML or Ph+ALL. FDA required that the sponsor commit to submit 24-month follow-up data for all patients as a condition for the accelerated approval.

The efficacy results demonstrated a 54 percent MCyR rate in patients with CP-CML. Seventy percent of patients with CP-CML with the T315I mutation in BCR-ABL achieved MCyR. The median duration of MCyR had not yet been reached at the time of analysis. The MaHR rate was 52 percent in patients with AP-CML, 31 percent in patients with BP-CML, and 41 percent in patients with Ph+ ALL. The median duration of MaHR was 9.5 months in patients with AP-CML, 4.7 months in patients with BP-CML, and 3.2 months in patients with Ph+ ALL.

Ponatinib hydrochloride is being approved with a Boxed Warning alerting patients and healthcare professionals that arterial thrombosis and liver toxicity have occurred in patients treated with ponatinib hydrochloride. The most common side effects reported in the clinical trial include hypertension, rash, abdominal pain, fatigue, headache, dry skin, constipation, fever, joint pain, and nausea.

The recommended dose and schedule for ponatinib hydrochloride is 45 mg taken orally once daily with or without food.

This summary was provided by Richard Pazdur, M.D., director of the FDA's Office of Hematology and Oncology Products.

The FDA is the division of the U.S. Department of Health and Human Services charged with ensuring the safety and effectiveness of new drugs and other products. (See "Learn How Drugs and Devices Get Approved.") The FDA's mission is to promote and protect the public health by helping safe and effective products to reach the market in a timely way, and monitoring products for continued safety after they are in use.

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  • Updated: March 12, 2014