The adverse reactions described in this section were identified in a single-arm, open-label, international, multicenter trial in 449 CML and Ph+ ALL patients who were resistant or intolerant to prior TKI therapy including those with a BCR-ABL T315I mutation. All patients received 45 mg Ponatinib (Iclusig) once daily. Dose adjustments to 30 mg once daily or 15 mg once daily were allowed for the management of treatment toxicity. Additionally, after approximately 2 years of follow-up, all patients who were still taking a 45 mg daily dose were recommended to undergo a dose reduction, even in the absence of adverse events, in response to the continued occurrence of vascular occlusive events in the clinical trial. At the time of reporting, all ongoing patients had a minimum follow-up of 64 months. The median duration of treatment with Ponatinib (Iclusig) was 32.2 months in CP-CML patients, 19.4 months in AP-CML patients, and 2.9 months in BP-CML/Ph+ ALL patients. The median dose intensity was 28 mg/day in CP-CML patients or, 63% of the expected 45 mg dose; median dose intensity was greater in advanced disease states (32 mg/day in the AP-CML patients and 44 mg/day in the BP CML/Ph+ ALL patients).
The most common serious adverse reactions >2% (treatment-emergent frequencies) were pneumonia (7.3%), pancreatitis (5.8%), abdominal pain (4.7%), atrial fibrillation (4.5%), pyrexia (4.5%), myocardial infarction (4.0%), peripheral arterial occlusive disease (3.8%), anaemia (3.8%), angina pectoris (3.3%), platelet count decreased (3.1%), febrile neutropenia (2.9%), hypertension (2.9%), coronary artery disease (2.7%), cardiac failure congestive (2.4%), cerebrovascular accident (2.4%), sepsis (2.4%), cellulitis (2.2%), acute kidney injury (2.0%), urinary tract infection (2.0%) and lipase increased (2.0%).
Serious arterial cardiovascular, cerebrovascular, and peripheral vascular occlusive adverse reactions (treatment-emergent frequencies) occurred in 10%, 7%, and 9% of Ponatinib (Iclusig) treated patients, respectively. Serious venous occlusive reactions (treatment-emergent frequencies) occurred in 5% of patients.
Arterial cardiovascular, cerebrovascular, and peripheral vascular occlusive adverse reactions (treatment-emergent frequencies) occurred in 13%, 9%, and 11% of Ponatinib (Iclusig)-treated patients, respectively. Overall arterial occlusive adverse reactions have occurred in 25% of Ponatinib (Iclusig)-treated patients from the phase 2 trial, with serious adverse reactions occurring in 20% of patients. Some patients experienced more than one type of event.
Venous thromboembolic reactions (treatment-emergent frequencies) occurred in 6% of patients. The incidence of thromboembolic events is higher in patients with Ph+ ALL or BP-CML than those with AP-CML or CP-CML. No venous occlusive events were fatal.
After a minimum follow-up of 64 months, the rates of adverse reactions resulting in discontinuation were 20% in CP-CML, 11% in AP-CML, 15% in BP-CML and 9% in Ph+ ALL.
Tabulated list of adverse reactions: Adverse reactions reported in all CML and Ph+ ALL patients are presented in Table 10. Frequency categories are very common (≥ 1/10), common (≥ 1/100 to < 1/10) and uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), and not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. (See Table 10.)
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Description of selected adverse reactions: Vascular occlusion (see Precautions): Serious vascular occlusion has occurred in patients treated with Ponatinib (Iclusig), including cardiovascular, cerebrovascular and peripheral vascular events, and venous thrombotic events. Patients with and without cardiovascular risk factors, including patients age 50 years or younger, experienced these events. Arterial occlusive adverse events were more frequent with increasing age and in patients with history of ischaemia, hypertension, diabetes, or hyperlipidaemia.
Myelosuppression: Myelosuppression was commonly reported in all patient populations. The frequency of Grade 3 or 4 thrombocytopenia, neutropenia, and anaemia was higher in patients with AP-CML and BP-CML/Ph+ ALL than in patients with CP-CML (see Table 11). Myelosuppression was reported in patients with normal baseline laboratory values as well as in patients with pre-existing laboratory abnormalities.
Discontinuation due to myelosuppression was infrequent (thrombocytopenia 4%, neutropenia and anaemia <1% each).
Hepatitis B reactivation: Hepatitis B reactivation has been reported in association with BCR-ABL TKIs. Some cases resulted in acute hepatic failure or fulminant hepatitis leading to liver transplantation or a fatal outcome (see Precautions).
Severe Cutaneous Adverse Reactions (SCARs): Severe skin reactions (such as Stevens-Johnson Syndrome) have been reported with some BCR-ABL Tyrosine Kinase Inhibitors. Patients should be warned to immediately report suspected skin reactions, especially if associated with blistering, peeling, mucosal involvement or systemic symptoms. (See Table 11.)
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