NAME OF THE MEDICINAL PRODUCT AND PHARMACEUTICAL FORM - Iclusig 15 mg / 30 mg / 45 mg film-coated tablets

QUALITATIVE AND QUANTITATIVE COMPOSITION - Each film-coated tablet contains 15 mg, 30 mg, 45 mg of ponatinib (as hydrochloride). Excipients with known effect: Each film coated tablet contains 40 mg / 80 mg / 120 mg of lactose monohydrate.

Therapeutic indications - Iclusig is indicated in adult patients with

• chronic phase, accelerated phase, or blast phase chronic myeloid leukaemia (CML) who are resistant to dasatinib or nilotinib; who are intolerant to dasatinib or nilotinib and for whom subsequent treatment with imatinib is not clinically appropriate; or who have the T315I mutation
• Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph+ ALL) who are resistant to dasatinib; who are intolerant to dasatinib and for whom subsequent treatment with imatinib is not clinically appropriate; or who have the T315I mutation.

Posology and method of administration - Therapy should be initiated by a physician experienced in the diagnosis and treatment of patients with leukaemia. 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.

Posology: The recommended starting dose is 45 mg of ponatinib once daily. For the standard dose of 45 mg once daily, a 45 mg film-coated tablet is available. Treatment should be continued as long as the patient does not show evidence of disease progression or unacceptable toxicity. Patients should be monitored for response according to standard clinical guidelines. 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 Iclusig 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 response, and BCR-ABL transcript levels. If dose reduction is undertaken, close monitoring of response is recommended. In patients with loss of response the dose of Iclusig can be re-escalated to a previously tolerated dosage of 30 mg or 45 mg orally once daily.

Management of toxicities: Dose modifications or interruption of dosing should be considered for the management of haematological and non-haematological toxicities. In the case of severe adverse reactions, treatment should be withheld. For patients whose adverse reactions are resolved or attenuated in severity, Iclusig may be restarted and escalation of the dose back to the daily dose used prior to the adverse reaction may be considered, if clinically appropriate. For a dose of 30 mg or 15 mg once daily, 15 mg and 30 mg film-coated tablets are available

Myelosuppression - Dose modifications for neutropenia (ANC* < 1.0 x 109/L) and thrombocytopenia (platelet < 50 x 109/L) that are unrelated to leukaemia:

*ANC = absolute neutrophil count

Arterial occlusion and venous thromboembolism - In a patient suspected of developing an arterial occlusive event or a venous thromboembolism, Iclusig should be immediately interrupted. A benefit-risk consideration should guide a decision to restart Iclusig therapy after the event is resolved. Hypertension may contribute to risk of arterial occlusive events. Iclusig treatment should be temporarily interrupted if hypertension is not medically controlled.

Pancreatitis - Recommended modifications for pancreatic adverse reactions:

• Grade 2 pancreatitis and/or asymptomatic elevation of lipase/amylase: Iclusig 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: Iclusig should be withheld and resumed at 30 mg after recovery to ≤ Grade 1 (< 1.5 x IULN)
• Occurrence at 30 mg: Iclusig should be withheld and resumed at 15 mg after recovery to ≤ Grade 1 (< 1.5 x IULN)
• Occurrence at 15 mg: Iclusig discontinuation should be considered
• Grade 3 pancreatitis:
• Occurrence at 45 mg: Iclusig should be withheld and resumed at 30 mg after recovery to < Grade 2
• Occurrence at 30 mg: Iclusig should be withheld and resumed at 15 mg after recovery to < Grade 2
• Occurrence at 15 mg: Iclusig discontinuation should be considered
• Grade 4 pancreatitis: Iclusig should be discontinued

*IULN = institution upper limit of normal

Hepatic toxicity - Dose interruption or discontinuation may be required:

• Elevation of liver transaminase > 3 × ULN*, Persistent grade 2 (longer than 7 days), Grade 3 or higher;
• Occurrence at 45 mg: Iclusig should be interrupted and hepatic function should be monitored. Iclusig should be resumed at 30 mg after recovery to ≤ Grade 1 (< 3 × ULN), or recovery to pre-treatment grade
• Occurrence at 30 mg: Iclusig should be interrupted and resumed at 15 mg after recovery to ≤ Grade 1, or recovery to pre-treatment grade
• Occurrence at 15 mg: Iclusig should be discontinued
• Elevation of AST or ALT ≥ 3 × ULN concurrent with an elevation of bilirubin > 2 × ULN and alkaline phosphatase < 2 × ULN: Iclusig should be discontinued.

*ULN = Upper Limit of Normal for the lab

Elderly patients - Of the 449 patients in the clinical study of Iclusig, 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 Iclusig to patients with hepatic impairment.

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

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

Method of administration - Iclusig is for oral use. The tablets should be swallowed whole. Patients should not crush or dissolve the tablets. Iclusig may be taken with or without food. Patients should be advised not to swallow the desiccant canister found in the bottle.

Contraindications - Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Undesirable effects

Summary of the safety profile: In the PACE phase 2 trial 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 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 with a median duration of follow-up of 31.1 months, overall arterial occlusive adverse reactions have occurred in 10% of Iclusig-treated patients (45 mg cohort) and serious adverse reactions occurring in 4.3% of patients (45 mg cohort). Arterial cardiovascular, cerebrovascular, and peripheral vascular occlusive adverse reactions (treatment-emergent frequencies) occurred in 4.3%, 2.1%, and 3.2% of Iclusig-treated patients (45 mg cohort), respectively. Of the 94 patients in the 45 mg cohort, 1 patient experienced a venous thromboembolic reaction.

List of adverse reactions: The frequencies of adverse reactions are based on 449 CML and Ph+ALL patients exposed to ponatinib in the PACE phase 2 trial. Adverse reactions reported in all CML and Ph+ ALL patients 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.

Infections and infestations: Very common: upper respiratory tract infection. Common: pneumonia, sepsis, folliculitis, cellulitis. 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. Endocrine disorders: Common: hypothyroidism. Metabolism and nutrition disorders: Very common: decreased appetite. Common: dehydration, fluid retention, hypocalcaemia, hyperglycaemia, hyperuricaemia, hypophosphataemia, hypertriglyceridaemia, hypokalaemia, weight decreased, hyponatraemia. Uncommon: tumour lysis syndrome. Psychiatric disorders: Very common: insomnia. Nervous system disorders: 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 *. Eye disorders: Common: vision blurred, dry eye, periorbital oedema, eyelid oedema, conjunctivitis, visual impairment. Uncommon: retinal vein thrombosis, retinal vein occlusion, 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. Uncommon: myocardial ischemia, cardiac discomfort, ischemic cardiomyopathy, arteriospasm coronary, left ventricular dysfunction. Vascular disorders: 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. Respiratory, thoracic and mediastinal disorders: Very common: dyspnoea, cough. Common: pulmonary embolism, pleural effusion, epistaxis, dysphonia, pulmonary hypertension. 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. Hepatobiliary disorders: Very common: alanine aminotransferase increased, aspartate aminotransferase increased. Common: blood bilirubin increased, blood alkaline phosphatase increased, gamma-glutamyl transferase increased. Uncommon: hepatotoxicity, 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. Rare: panniculitis (including erythema nodosum). 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. Reproductive system and breast disorders: Common: erectile dysfunction. 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. * Spontaneous reports from post-marketing experience.

Description of selected adverse reactions

Vascular occlusion: 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 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 with a median 31.1 months follow-up, arterial cardiovascular, cerebrovascular, and peripheral vascular occlusive adverse reactions (treatment-emergent frequencies) occurred in 4.3%, 2.1%, and 3.2% of Iclusig-treated patients (45 mg cohort), respectively. Overall, arterial occlusive adverse reactions have occurred in 10% of Iclusig-treated patients (45 mg cohort) with serious adverse reactions occurring in 4.3% of patients (45 mg cohort). The median time to onset of the first cardiovascular, cerebrovascular, and peripheral vascular arterial occlusive events was 295, 379, and 23 days, respectively in the OPTIC trial. Of the 94 patients in OPTIC (45 mg cohort), 1 patient experienced a venous thromboembolic reaction.

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. 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.

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.

Laboratory abnormalities: see table 5 in the section ‘Undesirable effects’ of the SPC - 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.

Reporting of suspected adverse reactions

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: Federal Agency for Medicines and Health Products, Vigilance Department, Postbus 97, B-1000 Brussel Madou - Website: www.eenbijwerkingmelden.be - e-mail: adr@fagg.be.

Marketing Authorisation Holder - Incyte Biosciences Distribution B.V., Paasheuvelweg 25, 1105 BP Amsterdam, Netherlands

Marketing Authorisation Numbers

Iclusig 15 mg film-coated tablets: EU/1/13/839/001 (60 tablets), EU/1/13/839/002 (180 tablets), EU/1/13/839/005 (30 tablets)

Iclusig 30 mg film-coated tablets: EU/1/13/839/006 (30 tablets)

Iclusig 45 mg film-coated tablets: EU/1/13/839/003 (30 tablets), EU/1/13/839/004 (90 tablets)

General classification for supply

On medical prescription.

Date of revision on the text – 24 march 2022

Detailed information on this medicinal product is available on the website of the European Medicines Agency https://www.ema.europa.eu.