Ponatinib

Patients with hepatic impairment may receive the recommended starting dose. Caution is recommended when administering ponatinib to patients with hepatic impairment.

In vitro, ponatinib is an inhibitor of P-gp and BCRP. Therefore, ponatinib may have the potential to increase plasma concentrations of co-administered substrates of P-gp (e.g., digoxin, dabigatran, colchicine, pravastatin) or BCRP (e.g., methotrexate, rosuvastatin, sulfasalazine) and may increase their therapeutic effect and adverse reactions. Close clinical surveillance is recommended when ponatinib is administered with these medicinal products.

Ponatinib is metabolized by CYP3A4.

Co-administration of a single 15 mg oral dose of ponatinib in the presence of ketoconazole (400 mg daily), a strong CYP3A inhibitor, resulted in modest increases in ponatinib systemic exposure, with ponatinib AUC_0-∞ and C_max values that were 78% and 47% higher, respectively, than those seen when ponatinib was administered alone.

Caution should be exercised and a reduction of the starting dose should be considered with concurrent use of strong CYP3A inhibitors such as clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, voriconazole, and grapefruit juice.

With the concurrent use of strong CYP3A inhibitors a reduction of the starting dose of ponatinib should be considered to 30 mg for adults and as per table below for paediatric patients.

Recommended starting dose in paediatric patients with concurrent use of strong CYP3A inhibitors:

Co-administration of a single 45 mg dose of ponatinib in the presence of rifampin (600 mg daily), a strong CYP3A inducer, to 19 healthy volunteers, decreased the AUC_0-∞ and C_max of ponatinib by 62% and 42%, respectively, when compared to administration of ponatinib alone.

Co-administration of strong CYP3A4 inducers such as carbamazepine, phenobarbital, phenytoin, rifabutin, rifampicin, and St. John's Wort with ponatinib should be avoided, and alternatives to the CYP3A4 inducer should be sought, unless the benefit outweighs the possible risk of ponatinib underexposure.

Caution is recommended in when administering ponatinib to patients with estimated creatinine clearance of <50 mL/min or end-stage renal disease.

No human data on the effect of ponatinib on fertility are available. In rats, treatment with ponatinib has shown effects on female fertility and male fertility was not affected. The clinical relevance of these findings to human fertility is unknown.

Hypertension may contribute to risk of arterial thrombotic events, including renal artery stenosis. During ponatinib treatment, blood pressure should be monitored and managed at each clinic visit and hypertension should be treated to normal. Ponatinib treatment should be temporarily interrupted if hypertension is not medically controlled.

In the event of significant worsening, labile or treatment-resistant hypertension, treatment should be interrupted and evaluation for renal artery stenosis should be considered.

Ponatinib should not be used in patients with a history of myocardial infarction, prior revascularization or stroke, unless the potential benefit of treatment outweighs the potential risk. In these patients, alternative treatment options should also be considered before starting treatment with ponatinib.

Before starting treatment with ponatinib, the cardiovascular status of the patient should be assessed, including history and physical examination, and cardiovascular risk factors should be actively managed. Cardiovascular status should continue to be monitored and medical and supportive therapy for conditions that contribute to cardiovascular risk should be optimised during treatment with ponatinib. The safety of ponatinib treatment has not been studied in patients with atrial fibrillation.

Monitoring for evidence of arterial occlusion should be performed and if decreased vision or blurred vision occurs, an ophthalmic examination (including fundoscopy) should be performed. Ponatinib should be interrupted immediately in case of arterial occlusion. A benefit-risk consideration should guide a decision to restart ponatinib therapy.

The use of VEGF pathway inhibitors in patients with or without hypertension may promote the formation of aneurysms and/or artery dissections. Before initiating ponatinib, this risk should be carefully considered in patients with risk factors such as hypertension or history of aneurysm.

Reactivation of hepatitis B in patients who are chronic carriers of this virus has occurred after these patients received BCR-ABL tyrosine kinase inhibitors. Some cases resulted in acute hepatic failure or fulminant hepatitis leading to liver transplantation or a fatal outcome.

Patients should be tested for HBV infection before initiating treatment with ponatinib. Experts in liver disease and in the treatment of hepatitis B should be consulted before treatment is initiated in patients with positive hepatitis B serology (including those with active disease) and for patients who test positive for HBV infection during treatment. Carriers of HBV who require treatment with ponatinib should be closely monitored for signs and symptoms of active HBV infection throughout therapy and for several months following termination of therapy.

Ponatinib is associated with pancreatitis. Caution is recommended in patients with a history of pancreatitis or alcohol abuse. Patients with severe or very severe hypertriglyceridemia should be appropriately managed to reduce the risk of pancreatitis.

Based on limited human data (less than 50 known pregnancy outcomes), cases of congenital megacolon (Hirschsprung's disease) have been reported in children born to women exposed to ponatinib during the first trimester. Studies in animals have shown reproductive toxicity. Ponatinib should not be used during pregnancy unless the clinical condition of the woman requires treatment with ponatinib. If it is used during pregnancy, the patient must be informed of the potential risk to the foetus.

It is unknown whether ponatinib is excreted in human milk. Available pharmacodynamic and toxicological data cannot exclude potential excretion in human milk. Breast-feeding should be stopped during treatment with ponatinib.

Women of childbearing potential / Contraception in males and females

Women of childbearing age being treated with ponatinib should be advised not to become pregnant and men being treated with ponatinib should be advised not to father a child during treatment. An effective method of contraception should be used during treatment. It is unknown whether ponatinib affects the effectiveness of systemic hormonal contraceptives. An alternative or additional method of contraception should be used.

Fertility

No human data on the effect of ponatinib on fertility are available. In rats, treatment with ponatinib has shown effects on female fertility and male fertility was not affected. The clinical relevance of these findings to human fertility is unknown.

Ponatinib has minor influence on the ability to drive and use machines. Adverse reactions such as lethargy, dizziness, and vision blurred have been associated with ponatinib. Therefore, caution should be recommended when driving or operating machines.

Summary of the safety profile

Patients with previously treated CML or Ph+ ALL or who have the T315I mutation (PACE Study)

In the PACE phase 2 trial the most common serious adverse reactions (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-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-treated patients, respectively. Overall arterial occlusive adverse reactions have occurred in 25% of ponatinib-treated patients from the PACE phase 2 trial with a minimum 64 months follow-up, 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.

Previously treated CP-CML (OPTIC Study)

In the OPTIC phase 2 trial overall arterial occlusive adverse reactions have occurred in 13.8% of ponatinib-treated patients (45 mg cohort) including 2 of which were fatal, and serious adverse reactions occurred in 8.5% of patients (45 mg cohort). Arterial cardiovascular, cerebrovascular, and peripheral vascular occlusive adverse reactions (treatment-emergent frequencies) occurred in 5.3%, 4.3%, and 4.3% of ponatinib-treated patients (45 mg cohort), respectively. Of the 94 patients in the 45 mg cohort, 1 patient experienced a venous thromboembolic reaction (Grade 1 retinal vein occlusion).

Patients with newly diagnosed Ph+ ALL (PhALLCON Study)

Myelosuppression events were reported in 83% of ponatinib-treated patients in PhALLCON. The most frequently reported adverse drug reactions were thrombocytopenia (47%), neutropenia (44%) and anaemia (44%). Events of hepatotoxicity occurred in 64% of patients. Overall a higher incidence of myelosuppression associated with chemotherapy (febrile neutropenia, pyrexia, pneumonia and sepsis) as well as peripheral sensory neuropathy and stomatitis was observed as compared to the use of ponatinib alone.

Tabulated lists of adverse reactions

The frequencies of adverse reactions of ponatinib monotherapy are listed in Table 1 and are based on 449 CML and Ph+ ALL patients exposed to ponatinib in the PACE phase 2 trial and the 94 CML patients exposed to ponatinib (45 mg starting dose) in the OPTIC phase 2 trial with a median duration of follow up of 77.93 months.

The frequencies of adverse reactions of ponatinib in combination with chemotherapy are listed in Table 2 and are based on 163 newly diagnosed patients with Ph+ ALL exposed to ponatinib in combination with reduced-intensity chemotherapy followed by continued treatment with ponatinib as monotherapy in the PhALLCON phase 3 trial.

Adverse reactions are listed by system organ class and by frequency. 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.

Table 1. Adverse reactions observed in CML and Ph+ ALL patients or who have the T315I mutation – frequency reported by incidence of treatment emergent events:

^* Spontaneous reports from post-marketing experience
^a hypothyroidism includes hypothyroidism, and primary hypothyroidism

Table 2. Adverse Reactions observed in newly diagnosed Ph+ ALL patients in PhALLCON Study – frequency reported by incidence of treatment emergent events:

Description of selected adverse reactions

Vascular occlusion

Serious vascular occlusion has occurred in patients treated with ponatinib, 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.

In the PACE phase 2 trial with a minimum 64-month follow-up, arterial cardiovascular, cerebrovascular, and peripheral vascular occlusive adverse reactions (treatment-emergent frequencies) occurred in 13%, 9%, and 11% of ponatinib-treated patients, respectively. Overall, arterial occlusive adverse reactions have occurred in 25% of ponatinib-treated patients from the PACE phase 2 trial, with serious adverse reactions occurring in 20% of patients. Some patients experienced more than one type of event. The median time to onset of the first cardiovascular, cerebrovascular, and peripheral vascular arterial occlusive events was 351, 611, and 605 days, respectively in the PACE trial. Venous thromboembolic reactions (treatment-emergent frequencies) occurred in 6% of patients.

In the OPTIC phase 2 trial with a median 77.9 months follow-up, arterial cardiovascular, cerebrovascular, and peripheral vascular occlusive adverse reactions (treatment-emergent frequencies) occurred in 5.3%, 4.3%, and 4.3% of ponatinib-treated patients (45 mg cohort), respectively. Overall, arterial occlusive adverse reactions have occurred in 13.8% of ponatinib-treated patients (45 mg cohort) with serious adverse reactions occurring in 8.5% of patients (45 mg cohort). The median time to onset of the first cardiovascular, cerebrovascular, and peripheral vascular arterial occlusive events was 473, 356, and 108 days, respectively in the OPTIC trial. Of the 94 patients in OPTIC (45 mg cohort), 1 patient experienced a venous thromboembolic reaction.

In the PhALLCON phase 3 trial with a median 20.43 months follow up, arterial cardiovascular, cerebrovascular, and peripheral vascular occlusive adverse reactions (treatment emergent frequencies) occurred in 1.2%, 0.6%, and 0.6% of patients treated with ponatinib in combination with chemotherapy, respectively. Venous thromboembolic events occurred in 12% of patients who have received ponatinib in combination with chemotherapy in PhALLCON.

Myelosuppression

In the PACE Study, 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 3). 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).

Myelosuppression events were reported in 83% of ponatinib-treated patients in PhALLCON, 63% of ponatinib-treated patients in OPTIC (45 mg cohort) and in 60% of ponatinib-treated patients in PACE.

Hepatotoxicity

Events of hepatotoxicity occurred in 64% of patients who have received ponatinib in combination with chemotherapy in PhALLCON, 28% of ponatinib-treated patients in OPTIC (45 mg cohort) and in 30% of ponatinib-treated patients in PACE.

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.

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.

Table 3. Incidence of clinically relevant grade 3/4* laboratory abnormalities in ≥2% of patients in any disease group from the Phase 2 Trial (N=449): minimum follow-up of 64 months for all ongoing patients:

ALT = alanine aminotransferase, ANC = absolute neutrophil count, AST = aspartate aminotransferase, Hgb = haemoglobin, WBC = white blood cell count.
^* Reported using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.

Paediatric population

The safety of ponatinib monotherapy in paediatric patients has been evaluated in a phase ½ open-label, single-arm study that included 61 paediatric participants (≥1 to <18 years old) with recurrent or refractory leukaemias, lymphomas, or solid tumours. The observed safety profile of ponatinib monotherapy in paediatric patients has been generally consistent with the one observed in adults.