Chronic Myeloid Leukemia (CML): Ponatinib is indicated for adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia (CML) who are resistant or intolerant to dasatinib or nilotinib, and for whom further treatment with imatinib is not clinically appropriate, or who carry the T315I mutation.

Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL): Ponatinib is indicated for adult patients with Ph+ ALL who are resistant or intolerant to dasatinib and for whom imatinib is not appropriate, or who have the T315I mutation.

Ponatinib is a kinase inhibitor. It inhibits the tyrosine kinase activity of ABL and T315I mutant ABL with IC₅₀ values of 0.4 nM and 2.0 nM, respectively. It also inhibits multiple other kinases including VEGFR, PDGFR, FGFR, EPH receptor family, SRC family, KIT, RET, TIE2, and FLT3 with IC₅₀ values ranging from 0.1 to 20 nM. Ponatinib inhibits the viability of cells expressing native or mutant BCR-ABL, including T315I mutation. In mouse models, it reduces tumor size expressing both native and T315I mutant BCR-ABL compared to control.

Therapy should be initiated by a physician experienced in the diagnosis and treatment of patients with leukemia. Haematologic support such as platelet transfusion and haematopoietic growth factors can be used during treatment if clinically indicated. 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.

Recommended dosage: The recommended starting dose is 45 mg of ponatinib once daily. Treatment should be continued as long as the patient does not show evidence of disease progression or unacceptable toxicity. Discontinuing ponatinib should be considered if a complete haematologic response has not occurred by 3 months (90 days). The risk of arterial occlusive events is likely to be dose-related. Reducing the dose of ponatinib to 15 mg should be considered for CP-CML patients who have achieved a major cytogenetic response taking the following factors into account in the individual patient assessment: cardiovascular risk, side effects of ponatinib therapy, time to cytogenetic response, and BCR-ABL transcript levels. If dose reduction is undertaken, close monitoring of response is recommended.

Elderly patients: Of the 449 patients in the clinical study of ponatinib, 155 (35%) were >65 years of age. Compared to patients < 65 years, older patients are more likely to experience adverse reactions.

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

Renal impairment: Renal excretion is not a major route of ponatinib elimination. Ponatinib has not been studied in patients with renal impairment. Patients with estimated creatinine clearance of > 50 mL/min should be able to safely receive ponatinib with no dosage adjustment. Caution is recommended when administering ponatinib to patients with estimated creatinine clearance of < 50 mL/min, or end-stage renal disease.

Paediatric population: The safety and efficacy of ponatinib in patients less than 18 years of age have not been established. No data are available.

CYP3A inhibitors: Ponatinib is metabolized by CYP3A4. Caution is required when co-administered with strong CYP3A inhibitors such as clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, voriconazole, and grapefruit juice. In such cases, reduction of the starting dose of ponatinib to 30 mg should be considered.

CYP3A inducers: Strong CYP3A4 inducers such as carbamazepine, phenobarbital, phenytoin, rifabutin, rifampicin, and St. John’s Wort may reduce ponatinib plasma levels. Concomitant use should be avoided, or suitable alternatives should be considered unless benefit outweighs risk of reduced exposure.

Hypersensitivity to ponatinib or to any of the excipients.

The most common serious adverse reactions (>2%) include pneumonia, pancreatitis, abdominal pain, atrial fibrillation, pyrexia, myocardial infarction, peripheral arterial occlusive disease, anaemia, angina pectoris, thrombocytopenia, febrile neutropenia, hypertension, coronary artery disease, congestive heart failure, cerebrovascular accident, sepsis, cellulitis, acute kidney injury, urinary tract infection, and increased lipase.

Pregnancy: There are no adequate data in pregnant women. Animal studies show reproductive toxicity. Ponatinib should be used during pregnancy only if clearly necessary, and patients must be informed of potential fetal risk.

Lactation: It is unknown whether ponatinib is excreted in human milk. Because of potential serious adverse effects in infants, breastfeeding should be discontinued during treatment.

Fertility: No human fertility data are available. Animal studies showed effects on female fertility, while male fertility was not affected; clinical relevance is unknown.

Myelosuppression: Severe thrombocytopenia, neutropenia, and anaemia may occur, mostly within the first 3 months. Complete blood counts should be monitored every 2 weeks for the first 3 months, then monthly or as clinically indicated. Dose interruption or reduction may be required.

Arterial occlusion: Serious and sometimes fatal arterial thrombotic events (myocardial infarction, stroke, retinal occlusion, and peripheral vascular disease) have been reported. Risk increases with age and cardiovascular risk factors.

Venous thromboembolism: Patients should be monitored and therapy interrupted if thromboembolism occurs. Restarting should be based on risk–benefit evaluation.

Hypertension: Blood pressure should be regularly monitored and treated. Therapy may need temporary interruption if uncontrolled.

Heart failure: Serious or fatal cardiac failure may occur. Patients should be monitored and treatment interrupted or discontinued if necessary.

Hepatotoxicity: Elevation of liver enzymes may occur; rare cases of hepatic failure reported. Liver function should be monitored before and during treatment.

Haemorrhage: Severe and fatal bleeding has occurred; treatment should be interrupted in serious cases.

Hepatitis B reactivation: Patients should be screened before treatment and monitored during and after therapy in HBV carriers.

Overdose cases have been reported, including ingestion of high doses leading to QT prolongation, fatigue, chest pain, pneumonia, sepsis, atrial fibrillation, and pericardial effusion. No specific antidote exists. Treatment involves stopping ponatinib and providing supportive care and monitoring.

Tyrosine kinase inhibitor

Store in a cool, dry place below 30°C. Avoid exposure above 40°C. Keep out of reach and sight of children.