Source: European Medicines Agency (EU) Revision Year: 2026 Publisher: Incyte Biosciences Distribution B.V., Paasheuvelweg 25, 1105 BP Amsterdam, Netherlands
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Iclusig 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 (APCML) or blast phase CML (BPCML), or Ph+ ALL than in chronic phase CML (CPCML). 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 Iclusig temporarily or reducing the dose (see section 4.2).
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 Iclusig-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 (see sections 4.8 and 5.1).
Arterial occlusive adverse reactions including serious reactions, have occurred in the clinical development (see section 4.8). Some patients experienced more than 1 type of event.
Iclusig 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 (see sections 4.2 and 4.8).
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. Iclusig should be interrupted immediately in case of arterial occlusion. A benefit -risk consideration should guide a decision to restart Iclusig therapy (see sections 4.2 and 4.8).
Venous thromboembolic adverse reactions including serious reactions have occurred in the clinical development (see section 4.8).
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 (see sections 4.2 and 4.8).
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.
Hypertension may contribute to risk of arterial thrombotic events, including renal artery stenosis. During Iclusig treatment, blood pressure should be monitored and managed at each clinic visit and hypertension should be treated to normal. Iclusig treatment should be temporarily interrupted if hypertension is not medically controlled (see section 4.2).
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 Iclusig-treated patients. Patients may require urgent clinical intervention for hypertension associated with confusion, headache, chest pain, or shortness of breath.
The use of VEGF pathway inhibitors in patients with or without hypertension may promote the formation of aneurysms and/or artery dissections. Before initiating Iclusig, this risk should be carefully considered in patients with risk factors such as hypertension or history of aneurysm.
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 Iclusig. Discontinuation of ponatinib should be considered in patients who develop serious heart failure (see sections 4.2 and 4.8).
Iclusig 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, Iclusig should be withheld and patients evaluated for evidence of pancreatitis (see section 4.2). 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.
Iclusig 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. Hepatic function should be carefully monitored when ponatinib is used in combination with chemotherapy agents also known to be associated with hepatic dysfunction (see section 4.8).
Severe haemorrhage, including fatalities, occurred in Iclusig-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. Iclusig should be interrupted and patients evaluated for serious or severe haemorrhage.
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 Iclusig. 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 Iclusig should be closely monitored for signs and symptoms of active HBV infection throughout therapy and for several months following termination of therapy (see section 4.8).
Post-marketing cases of Posterior Reversible Encephalopathy Syndrome (PRES) have been reported in Iclusig-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 Iclusig treatment and resume treatment only once the event is resolved and if the benefit of continued treatment outweighs the risk of PRES.
Growth retardation has been observed in paediatric patients treated with BCR-ABL-targeted tyrosine kinase inhibitor (TKI). Given the plausible mechanism and the suspected association of TKIs with growth retardation, close monitoring of growth in paediatric patients under ponatinib treatment is recommended.
Caution should be exercised with concurrent use of Iclusig and moderate and strong CYP3A inhibitors and moderate and strong CYP3A inducers (see section 4.5). Close clinical surveillance is recommended when ponatinib is administered with substrates of P gp or BCRP (see section 4.5).
Concomitant use of ponatinib with anti-clotting agents should be approached with caution in patients who may be at risk of bleeding events (see "Myelosuppression" and "Haemorrhage"). Formal studies of ponatinib with anti-clotting medicinal products have not been conducted.
In patients with Ph+ ALL, when co-administering ponatinib with chemotherapy (see section 5.1) occurrence of adverse events i.e. hepatotoxicity, myelosuppression or others, may increase (see section 4.8). The use of ponatinib in combination with chemotherapy requires special precaution.
The QT interval prolongation potential of Iclusig was assessed in 39 leukaemia patients and no clinically significant QT prolongation was observed (see section 5.1). However, a thorough QT study has not been performed; therefore a clinically significant effect on QT cannot be excluded.
Patients with hepatic impairment may receive the recommended starting dose. Caution is recommended when administering Iclusig to patients with hepatic impairment (see sections 4.2 and 5.2).
Caution is recommended in when administering Iclusig to patients with estimated creatinine clearance of <50 mL/min or end-stage renal disease (see section 4.2).
This medicinal product contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
This medicinal product contains less than 1 mmol sodium (23 mg) per tablet or capsule, that is to say essentially 'sodium-free'.
Ponatinib is metabolized by CYP3A4.
Co-administration of a single 15 mg oral dose of Iclusig 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 Iclusig in adults 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.
For paediatric patients a reduction of the starting dose should be considered as described in section 4.2.
Co-administration of a single 45 mg dose of Iclusig 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.
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.
Interaction studies have only been performed in adults.
Women of childbearing age being treated with Iclusig should be advised not to become pregnant and men being treated with Iclusig 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.
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 (see section 5.3). Iclusig 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 Iclusig 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 Iclusig.
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 (see section 5.3). The clinical relevance of these findings to human fertility is unknown.
Iclusig has minor influence on the ability to drive and use machines. Adverse reactions such as lethargy, dizziness, and vision blurred have been associated with Iclusig. Therefore, caution should be recommended when driving or operating machines.
In the PACE phase 2 trial (see section 5.1) 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 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 Iclusig-treated patients, respectively. Overall arterial occlusive adverse reactions have occurred in 25% of Iclusig-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.
In the OPTIC phase 2 trial (see section 5.1) overall arterial occlusive adverse reactions have occurred in 13.8% of Iclusig-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 Iclusig-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).
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.
The frequencies of adverse reactions of Iclusig monotherapy are listed in Table 9 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 Iclusig in combination with chemotherapy are listed in Table 10 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 Iclusig as monotherapy in the PhALLCON phase 3 trial.
See section 5.1 for information on the main characteristics of participants in the trials. 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 9. Adverse reactions observed in CML and Ph+ ALL patients or who have the T315I mutation – frequency reported by incidence of treatment emergent events:
| System organ class | Frequency | Adverse reactions |
| Infections and infestations | Very common | Upper respiratory tract infection |
| Common | Pneumonia Sepsis Folliculitis Cellulitis Herpes zoster | |
| Blood and lymphatic system disorders | Very common | Anaemia Platelet count decreased Neutrophil count decreased |
| Common | Pancytopenia Febrile neutropenia White blood cell count decreased Lymphocyte count decreased Eosinophilia Neutrophil count increased Myelosuppression | |
| Endocrine disorders | Common | Hypothyroidisma |
| Metabolism and nutrition disorders | Very common | Decreased appetite Hypertriglyceridaemia Hypercholesterolaemia |
| Common | Dehydration Fluid retention Hypocalcaemia Hyperglycaemia Hyperuricaemia Hypophosphataemia Hypokalaemia Weight decreased Hyponatraemia Dyslipidaemia Glucose tolerance impaired Low density lipoprotein increased Weight increase Tumour lysis syndrome | |
| Psychiatric disorders | Very common | Insomnia |
| Common | Anxiety | |
| Nervous system disorders | Very common | Headache Dizziness |
| Common | Cerebrovascular accident Cerebral infarction Neuropathy peripheral Lethargy Migraine Hyperaesthesia Hypoaesthesia Paraesthesia Transient ischaemic attack Facial nerve disorder Carotid artery stenosis | |
| Uncommon | Cerebral artery stenosis Cerebral haemorrhage Haemorrhage intracranial Posterior reversible encephalopathy syndrome* | |
| Eye disorders | Common | Vision blurred Dry eye Periorbital oedema Eyelid oedema Conjunctivitis Visual impairment Blepharitis Eye pain Ocular hyperaemia Retinal vein occlusion |
| Uncommon | Retinal vein thrombosis Retinal artery occlusion | |
| Cardiac disorders | 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 Bradycardia Palpitations Tachycardia Left ventricular dysfunction Left ventricular hypertrophy Sinus bradycardia N-terminal prohormone brain natriuretic peptide increased Angina unstable Myocardial ischaemia Supraventricular extrasystoles Ventricular extrasystoles Electrocardiogram QT prolonged Cardiac failure chronic Brain natriuretic peptide increased |
| Uncommon | Cardiac discomfort Ischemic cardiomyopathy Arteriospasm coronary | |
| Vascular disorders | Very common | Hypertension |
| Common | Peripheral arterial occlusive disease Peripheral ischaemia Peripheral artery stenosis Intermittent claudication Deep vein thrombosis Hot flush Flushing Hypertensive crisis | |
| Uncommon | Poor peripheral circulation Splenic infarction Embolism venous Venous thrombosis Renal artery stenosis | |
| Not known | Aneurysms Artery dissections | |
| Respiratory, thoracic and mediastinal disorders | Very common | Dyspnoea Cough |
| Common | Pulmonary embolism Pleural effusion Epistaxis Dysphonia Pulmonary hypertension Oropharyngeal pain Productive cough | |
| Gastrointestinal disorders | 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 Gastritis Oropharyngeal pain Gastric ulcer Gingival bleeding | |
| Hepatobiliary disorders | Very common | Alanine aminotransferase increased Aspartate aminotransferase increased Transaminases increased Hepatotoxicity |
| Common | Blood bilirubin increased Blood alkaline phosphatase increased Gamma-glutamyl transferase increased Hypertransaminasaemia | |
| Uncommon | Hepatic failure Jaundice | |
| Skin and subcutaneous tissue disorders | 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 Acne Dermatitis acneiform Eczema Keratosis pilaris Rash macular Rash maculo-papular Contusion Pityriasis rubra pilaris Rash erythematous Rash pustular Panniculitis (including erythema nodosum) Dermatitis Rash papular Erythema multiforme Dermatitis allergic Skin papilloma Dermatitis psoriasiform | |
| Musculoskeletal and connective tissue disorders | Very common | Bone pain Arthralgia Myalgia Pain in extremity Back pain Muscle spasms |
| Common | Musculoskeletal pain Neck pain Musculoskeletal chest pain Chest pain Muscular weakness Musculoskeletal stiffness Spinal pain Tendonitis | |
| Renal and urinary disorders | Common | Proteinuria |
| Reproductive system and breast disorders | Common | Erectile dysfunction Amenorrhoea |
| General disorders and administrative site conditions | Very common | Fatigue Asthenia Oedema peripheral Pyrexia Pain |
| Common | Chills Influenza like illness Non-cardiac chest pain Mass Face oedema | |
| Investigations | Common | C-reactive protein increased Hypoalbuminaemia |
* Spontaneous reports from post-marketing experience
a hypothyroidism includes hypothyroidism, and primary hypothyroidism
Table 10. Adverse Reactions observed in newly diagnosed Ph+ ALL patients in PhALLCON Study – frequency reported by incidence of treatment emergent events:
| System Organ Class | Frequency | Ponatinib in combination with reduced- intensity chemotherapy Adverse reactions |
| Infections and infestations | Common | Pneumonia Conjunctivitis Sepsis Septic shock Neutropenic infection |
| Blood and lymphatic system disorders | Very common | Thrombocytopenia Anemia Neutropenia Febrile neutropenia Leukopenia Leukocytosis |
| Common | Myelosuppression Lymphopenia Cytopenia Agranulocytosis | |
| Metabolism and nutrition disorders | Very common | Hypokalaemia Hyperglycaemia Hypocalcaemia Hypophosphataemia Hyperuricaemia |
| Common | Decreased appetite Hypertriglyceridaemia Hyponatraemia Hypoalbuminaemia Hypercholesterolaemia Dyslipidaemia Fluid retention | |
| Psychiatric disorders | Very common | Insomnia |
| Nervous system disorders | Very common | Headache Neuropathy peripheral Paraesthesia Peripheral sensory neuropathy Dizziness |
| Common | Hypoaesthesia | |
| Eye disorders | Common | Conjunctival hemorrhage |
| Uncommon | Retinal vein occlusion | |
| Cardiac disorders | Common | Tachycardia Palpitations Pericardial effusion Atrial fibrillation Sinus bradycardia Angina pectoris |
| Uncommon | Cardiac failure Acute myocardial infarction Cardiac failure congestive | |
| Vascular disorders | Very common | Hypertension |
| Common | Deep vein thrombosis Superficial vein thrombosis Embolism | |
| Uncommon | Peripheral arterial occlusive disease Peripheral coldness Thrombosis | |
| Respiratory, thoracic and mediastinal disorders | Very common | Cough |
| Common | Dyspnoea Oropharyngeal pain Pleural effusion Dysphonia Pulmonary embolism | |
| Gastrointestinal disorders | Very common | Constipation Nausea Vomiting Stomatitis Diarrhoea Abdominal pain Abdominal pain upper |
| Common | Dyspepsia Abdominal distension Abdominal discomfort Pancreatitis Gastritis Pancreatitis acute | |
| Uncommon | Mouth haemorrhage | |
| Hepatobiliary disorders | Common | Hepatotoxicity Hyperbilirubinaemia Hypertransaminasaemia Hepatitis toxic |
| Uncommon | Drug-induced liver injury Hepatobilliary disease Liver injury | |
| Skin and subcutaneous tissue disorders | Very common | Rash Dry skin |
| Common | Pruritus Alopecia Rash maculo-papular | |
| Musculoskeletal and connective tissue disorders | Very common | Back pain Pain in extremity Arthralgia Myalgia |
| Common | Bone pain Neck pain Muscle spasms | |
| General disorders and administration site conditions | Very common | Pyrexia Fatigue Asthenia Oedema peripheral |
| Common | Chest pain Pain | |
| Investigations | Very common | Alanine aminotransferase increased Lipase increased Aspartate aminotransferase increased Gamma-glutamyltransferase increased Blood lactate dehydrogenase increased Amylase increased |
| Common | Blood alkaline phosphatase increased Blood creatinine increased Blood fibrinogen decreased C-reactive protein increased Neutrophil count increased Protein total decreased Platelet count increased Brain natriuretic peptide increased Troponin I increased Uncommon Ejection fraction decreased | |
| Injury, poisoning and procedural complications | Uncommon | Subdural hematoma |
Serious vascular occlusion has occurred in patients treated with 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.
In the PACE phase 2 trial (see section 5.1) 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 Iclusig-treated patients, respectively. Overall, arterial occlusive adverse reactions have occurred in 25% of Iclusig-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 (see section 5.1) 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 Iclusig-treated patients (45 mg cohort), respectively. Overall, arterial occlusive adverse reactions have occurred in 13.8% of Iclusig-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 (see section 5.1) 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.
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 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).
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.
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 (see section 4.4).
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 section 4.4).
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 11. 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:
| 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.
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 (see section 5.1). The observed safety profile of ponatinib monotherapy in paediatric patients has been generally consistent with the one observed in adults.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
Not applicable.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.