The leukemia drug ponatinib is expected to return to market once the drug’s manufacturer has implemented measures to address the recently discovered safety risks.
The US Food and Drug Administration (FDA) is requiring that a number of safety measures be adopted, including changes to ponatinib’s label to narrow the drug’s indication and the addition of warnings about the increased risk of thrombosis and venous occlusion associated with ponatinib use.
In addition, dosing and administration recommendations must be revised, the patient medication guide must be updated, a risk evaluation and mitigation strategy (REMS) must be implemented, and postmarket investigations must be conducted to further characterize the drug’s safety and dosing.
Ponatinib was approved by the FDA in December 2012 to treat adults with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) that is resistant to or intolerant of other tyrosine kinase inhibitors (TKIs).
But in October 2013, follow-up results of the phase 2 PACE trial suggested ponatinib can increase a patient’s risk of arterial and venous thrombotic events. So all trials of the drug were placed on partial clinical hold, with the exception of the phase 3 EPIC trial, which was discontinued.
Then, the FDA suspended sales and marketing of ponatinib, pending results of a safety evaluation. Now, the agency has decided ponatinib can return to the market if the new safety measures are implemented.
Safety measures in detail
The FDA is requiring that ponatinib use be restricted to:
- Adults with T315I-positive CML (chronic phase, accelerated phase, or blast phase)
- Adults with T315I-positive Ph+ ALL
- Adults with CML (chronic phase, accelerated phase, or blast phase) who cannot receive another TKI
- Adults with Ph+ ALL who cannot receive another TKI.
The Warnings and Precautions section of the drug’s label must be revised to include a description of the arterial and venous thrombosis and occlusions that have occurred in at least 27%—more than 1 in every 4—of patients treated with ponatinib.
The Dosage and Administration recommendations must be 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.
The patient Medication Guide must be revised to include additional safety information consistent with the safety information in the revised drug label.
The ponatinib REMS must inform prescribers about the approved indications for use and the serious risk of vascular occlusion and thromboembolism associated with the drug. The REMS must include 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 healthcare professionals
- Public statement to be published quarterly for 1 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.
And postmarket investigations must further evaluate the dose selection, drug exposure, treatment response, and toxicity of ponatinib.
For more information, see the FDA’s safety communication.
