Chemical formula: C₂₉H₂₇F₃N₆O Molecular mass: 532.56 g/mol PubChem compound: 24826799
Ponatinib interacts in the following cases:
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 AUC0-∞ and Cmax 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 of ponatinib to 30 mg 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.
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 AUC0-∞ and Cmax 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.
In the phase 2 trial (with a minimum of 64 months follow-up), venous thromboembolic adverse reactions have occurred in 6% of patients (treatment-emergent frequencies). Serious venous thromboembolic adverse reactions occurred in 5% of patients (treatment-emergent frequencies).
Monitoring for evidence of thromboembolism should be performed. Iclusig should be interrupted immediately in case of thromboembolism. A benefit-risk consideration should guide a decision to restart Iclusig therapy.
Retinal venous occlusions associated in some cases with permanent visual impairment or vision loss have occurred in Iclusig-treated patients. If decreased vision or blurred vision occurs, an ophthalmic examination (including fundoscopy) should be performed.
Severe haemorrhage, including fatalities, occurred in ponatinib-treated patients. The incidence of severe bleeding events was higher in patients with AP-CML, BP-CML and Ph+ ALL. Gastrointestinal haemorrhage and subdural hematoma were the most commonly reported grade ¾ bleeding events. Most haemorrhagic events, but not all, occurred in patients with grade ¾ thrombocytopenia. Ponatinib should be interrupted and patients evaluated for serious or severe haemorrhage.
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.
Treatment-emergent hypertension (including hypertensive crisis) occurred in ponatinib-treated patients. Patients may require urgent clinical intervention for hypertension associated with confusion, headache, chest pain, or shortness of breath.
Ponatinib is associated with pancreatitis. The frequency of pancreatitis is greater in the first 2 months of use. Check serum lipase every 2 weeks for the first 2 months and then periodically thereafter. Dose interruption or reduction may be required. If lipase elevations are accompanied by abdominal symptoms, ponatinib should be withheld and patients evaluated for evidence of 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.
Recommended modifications for pancreatic adverse reactions are summarized in the following table.
Dose modifications for pancreatitis and elevation of lipase/amylase:
| Grade 2 pancreatitis and/or asymptomatic elevation of lipase/amylase | Ponatinib should be continued at the same dose |
| Grade 3 or 4 asymptomatic elevation of lipase/amylase (>2.0 x IULN*) only | Occurrence at 45 mg: Ponatinib should be withheld and resumed at 30 mg after recovery to ≤ Grade 1 (<1.5 x IULN) |
| Occurrence at 30 mg: Ponatinib should be withheld and resumed at 15 mg after recovery to ≤ Grade 1 (<1.5 x IULN) | |
| Occurrence at 15 mg: Ponatinib discontinuation should be considered | |
| Grade 3 pancreatitis | Occurrence at 45 mg: Ponatinib should be withheld and resumed at 30 mg after recovery to < Grade 2 |
| Occurrence at 30 mg: Ponatinib should be withheld and resumed at 15 mg after recovery to < Grade 2 | |
| Occurrence at 15 mg: Ponatinib discontinuation should be considered | |
| Grade 4 pancreatitis | Ponatinib should be discontinued |
* IULN = institution upper limit of normal
Arterial occlusions, including fatal myocardial infarction, stroke, retinal arterial occlusions associated in some cases with permanent visual impairment or vision loss, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, renal artery stenosis (associated with worsening, labile or treatment-resistant hypertension), and the need for urgent revascularization procedures have occurred in ponatinib-treated patients. Patients with and without cardiovascular risk factors, including patients age 50 years or younger, experienced these events. Arterial occlusion adverse events were more frequent with increasing age and in patients with history of ischaemia, hypertension, diabetes, or hyperlipidaemia.
The risk of arterial occlusive events is likely to be dose-related.
In the phase 2 trial (with a minimum of 64 months follow-up), arterial occlusive adverse reactions have occurred in 25% of patients (treatment-emergent frequencies). Some patients experienced more than 1 type of event. Arterial cardiovascular, cerebrovascular, and peripheral vascular occlusive adverse reactions (treatment-emergent frequencies) occurred in 13%, 9%, and 11% of ponatinib-treated patients, respectively.
In the phase 2 trial, serious arterial occlusive adverse reactions occurred in 20% of patients (treatment-emergent frequencies). Serious arterial cardiovascular, cerebrovascular, and peripheral vascular occlusive adverse reactions (treatment-emergent frequencies) occurred in 10%, 7%, and 9% of ponatinib treated patients, respectively.
The median time to onset of the first cardiovascular, cerebrovascular, and peripheral vascular arterial occlusive events was 351, 611, and 605 days, respectively.
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.
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.
Ponatinib is associated with severe (National Cancer Institute Common Terminology Criteria for Adverse Events grade 3 or 4) thrombocytopenia, neutropenia, and anaemia. Most of the patients with grade 3 or 4 platelet count decreased, anaemia or neutropenia, developed it within the first 3 months of treatment. The frequency of these events is greater in patients with accelerated phase CML (AP-CML) or blast phase CML (BP-CML)/Ph+ ALL than in chronic phase CML (CP-CML). A complete blood count should be performed every 2 weeks for the first 3 months and then monthly or as clinically indicated. Myelosuppression was generally reversible and usually managed by withholding ponatinib temporarily or reducing the dose.
Dose modifications for neutropenia (ANC* <1.0 × 109/L) and thrombocytopenia (platelet <50 × 109/L) that are unrelated to leukaemia are summarized in the following table.
Dose modifications for myelosuppression:
| ANC* <1,0 × 109/L or platelet <50 × 109/L | First occurrence: Ponatinib should be withheld and resumed at the same dose after recovery to ANC ≥1.5 × 109/L and platelet ≥75 × 109/L |
| Recurrence at 45 mg: Ponatinib should be withheld and resumed at 30 mg after recovery to ANC ≥1.5 × 109/L and platelet ≥75 × 109/L | |
| Recurrence at 30 mg: Ponatinib should be withheld and resumed at 15 mg after recovery to ANC ≥1.5 × 109/L and platelet ≥75 × 109/L |
* ANC = absolute neutrophil count
Fatal and serious heart failure or left ventricular dysfunction occurred in Iclusig-treated patients, including events related to prior vascular occlusive events. Patients should be monitored for signs or symptoms consistent with heart failure and they should be treated as clinically indicated, including interruption of ponatinib. Discontinuation of ponatinib should be considered in patients who develop serious heart failure.
Ponatinib may result in elevation in ALT, AST, bilirubin, and alkaline phosphatase. Most patients who had an event of hepatotoxicity had their first event during the first year of treatment. Hepatic failure (including fatal outcome) has been observed. Liver function tests should be performed prior to treatment initiation and monitored periodically, as clinically indicated.
Dose interruption or discontinuation may be required as described in the following table.
Recommended dose modifications for hepatic toxicity:
| Elevation of liver transaminase >3 × ULN* | Occurrence at 45 mg: Ponatinib should be interrupted and hepatic function should be monitored. Ponatinib should be resumed at 30 mg after recovery to ≤ Grade 1 (<3 × ULN), or recovery to pre-treatment grade |
| Persistent grade 2 (longer than 7 days) | Occurrence at 30 mg: Ponatinib should be interrupted and resumed at 15 mg after recovery to ≤ Grade 1, or recovery to pretreatment grade |
| Grade 3 or higher | Occurrence at 15 mg: Ponatinib should be discontinued |
| Elevation of AST or ALT ≥3 × ULN concurrent with an elevation of bilirubin >2 × ULN and alkaline phosphatase <2 × ULN | Ponatinib should be discontinued |
* ULN = Upper Limit of Normal for the lab
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.
Post-marketing cases of Posterior Reversible Encephalopathy Syndrome (PRES) have been reported in ponatinib-treated patients.
PRES is a neurological disorder that can present with signs and symptoms such as seizure, headache, decreased alertness, altered mental functioning, vision loss, and other visual and neurological disturbances.
If diagnosed, interrupt ponatinib treatment and resume treatment only once the event is resolved and if the benefit of continued treatment outweighs the risk of PRES.
There are no adequate data from the use of ponatinib in pregnant women. Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown. Ponatinib should be used during pregnancy only when clearly necessary. 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 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.
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.
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 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 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 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 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.
Adverse reactions reported in all CML and Ph+ ALL patients are presented in list below. 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.
Adverse reactions observed in CML and Ph+ ALL patients – frequency reported by incidence of treatment emergent events:
Very common: upper respiratory tract infection
Common: pneumonia, sepsis, folliculitis, cellulitis
Very common: anaemia, platelet count decreased, neutrophil count decreased
Common: pancytopenia, febrile neutropenia, white blood cell count decreased, lymphocyte count decreased
Common: hypothyroidism
Very common: decreased appetite
Common: dehydration, fluid retention, hypocalcaemia, hyperglycaemia, hyperuricaemia, hypophosphataemia, hypertriglyceridaemia, hypokalaemia, weight decreased, hyponatraemia
Uncommon: tumour lysis syndrome
Very common: insomnia
Very common: headache, dizziness
Common: cerebrovascular accident, cerebral infarction, neuropathy peripheral, lethargy, migraine, hyperaesthesia, hypoaesthesia, paraesthesia, transient ischaemic attack
Uncommon: cerebral artery stenosis, cerebral haemorrhage, haemorrhage intracranial, posterior reversible encephalopathy syndrome*
Common: vision blurred, dry eye, periorbital oedema, eyelid oedema, conjunctivitis, visual impairment
Uncommon: retinal vein thrombosis, retinal vein occlusion, retinal artery occlusion
Common: cardiac failure, myocardial infarction, cardiac failure congestive, coronary artery disease, angina pectoris, pericardial effusion, atrial fibrillation, ejection fraction decreased, acute coronary syndrome, atrial flutter
Uncommon: myocardial ischemia, cardiac discomfort, ischemic cardiomyopathy, arteriospasm coronary, left ventricular dysfunction,
Very common: hypertension
Common: peripheral arterial occlusive disease, peripheral ischaemia, peripheral artery stenosis, intermittent claudication, deep vein thrombosis, hot flush, flushing
Uncommon: poor peripheral circulation, splenic infarction, embolism venous, venous thrombosis, hypertensive crisis, renal artery stenosis
Not known: aneurysms and artery dissections
Very common: dyspnoea, cough
Common: pulmonary embolism, pleural effusion, epistaxis, dysphonia, pulmonary hypertension
Very common: abdominal pain, diarrhoea, vomiting, constipation, nausea, lipase increased
Common: pancreatitis, blood amylase increased, gastrooesophageal reflux disease, stomatitis, dyspepsia, abdominal distension, abdominal discomfort, dry mouth, gastric haemorrhage
Very common: alanine aminotransferase increased, aspartate aminotransferase increased
Common: blood bilirubin increased, blood alkaline phosphatase increased, gamma-glutamyltransferase increased
Uncommon: hepatotoxicity, hepatic failure, jaundice
Very common: rash, dry skin, pruritus
Common: rash pruritic, exfoliative rash, erythema, alopecia, skin exfoliation, night sweats, hyperhidrosis, petechia, ecchymosis, pain of skin, dermatitis exfoliative, hyperkeratosis, skin hyperpigmentation
Very common: bone pain, arthralgia, myalgia, pain in extremity, back pain, muscle spasms
Common: musculoskeletal pain, neck pain, musculoskeletal chest pain
Common: erectile dysfunction
Very common: fatigue, asthenia, oedema peripheral, pyrexia, pain
Common: chills, influenza like illness, non-cardiac chest pain, mass, face oedema
* Spontaneous reports from post-marketing experience
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.
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 BPCML/Ph+ ALL than in patients with CP-CML. 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 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 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.
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 month for all ongoing patients:
| Laboratory test | All patients (N=449)(%) | CP-CML (N=270)(%) | AP-CML (N=85)(%) | BP-CML/Ph+ ALL (N=94)(%) |
|---|---|---|---|---|
| Haematology | ||||
| Thrombocytopenia (platelet count decreased) | 40 | 35 | 49 | 46 |
| Neutropenia (ANC decreased) | 34 | 23 | 52 | 52 |
| Leukopenia (WBC decreased) | 25 | 12 | 37 | 53 |
| Anaemia (Hgb decreased) | 20 | 8 | 31 | 46 |
| Lymphopenia | 17 | 10 | 25 | 28 |
| Biochemistry | ||||
| Lipase increased | 14 | 14 | 13 | 14 |
| Phosphorus decreased | 10 | 10 | 13 | 9 |
| Glucose increased | 7 | 8 | 13 | 1 |
| ALT increased | 6 | 4 | 8 | 7 |
| Sodium decreased | 5 | 6 | 6 | 2 |
| AST increased | 4 | 3 | 5 | 3 |
| Amylase increased | 4 | 4 | 4 | 3 |
| Potassium decreased | 2 | <1 | 6 | 2 |
| Potassium increased | 2 | 2 | 1 | 3 |
| Alkaline phosphatase increased | 2 | 2 | 4 | 2 |
| Bilirubin | 1 | <1 | 2 | 1 |
| Calcium decreased | 1 | <1 | 2 | 1 |
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
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