ICLUSIG 15mg film-coated tablets medication leaflet

Iclusig 15 mg film-coated tablets

Iclusig 30 mg film-coated tablets

Iclusig 45 mg film-coated tablets

Iclusig 15 mg film-coated tablets

Each film-coated tablet contains 15 mg of ponatinib (as hydrochloride).

Each film-coated tablet contains 40 mg of lactose monohydrate.

Iclusig 30 mg film-coated tablets

Each film-coated tablet contains 30 mg of ponatinib (as hydrochloride).

Each film-coated tablet contains 80 mg of lactose monohydrate.

Iclusig 45 mg film-coated tablets

Each film-coated tablet contains 45 mg of ponatinib (as hydrochloride).

Each film-coated tablet contains 120 mg of lactose monohydrate.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

Iclusig 15 mg film-coated tablets

White, biconvex, round film-coated tablet that is approximately 6 mm in diameter, with 'A5'debossed on one side.

Iclusig 30 mg film-coated tablets

White, biconvex, round film-coated tablet that is approximately 8 mm in diameter, with 'C7' debossedon one side.

Iclusig 45 mg film-coated tablets

White, biconvex, round film-coated tablet that is approximately 9 mm in diameter, with “AP4”debossed on one side.

Iclusig is indicated in adult patients with

* chronic phase, accelerated phase, or blast phase chronic myeloid leukaemia (CML) who areresistant to dasatinib or nilotinib; who are intolerant to dasatinib or nilotinib and for whomsubsequent treatment with imatinib is not clinically appropriate; or who have the T315Imutation

* Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph+ ALL) who are resistantto dasatinib; who are intolerant to dasatinib and for whom subsequent treatment with imatinib isnot clinically appropriate; or who have the T315I mutation.

See sections 4.2 for the assessment of cardiovascular status prior to start of therapy and 4.4 forsituations where an alternative treatment may be considered.

Therapy should be initiated by a physician experienced in the diagnosis and treatment of patients withleukaemia. Haematologic support such as platelet transfusion and haematopoietic growth factors canbe 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 activelymanaged. Cardiovascular status should continue to be monitored and medical and supportive therapyfor conditions that contribute to cardiovascular risk should be optimised during treatment withponatinib.

The recommended starting dose is 45 mg of ponatinib once daily. For the standard dose of 45 mg oncedaily, a 45 mg film-coated tablet is available. Treatment should be continued as long as the patientdoes 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 occurredby 3 months (90 days).

The risk of arterial occlusive events is likely to be dose-related. Reducing the dose of Iclusig to 15 mgshould be considered for CP-CML patients who have achieved a major cytogenetic response taking thefollowing factors into account in the individual patient assessment: cardiovascular risk, side effects ofponatinib therapy, time to response, and BCR-ABL transcript levels (see sections 4.4 and 5.1). If dosereduction is undertaken, close monitoring of response is recommended. In patients with loss ofresponse the dose of Iclusig can be re-escalated to a previously tolerated dosage of 30 mg or 45 mgorally once daily.

Management of toxicities

Dose modifications or interruption of dosing should be considered for the management ofhaematological and non-haematological toxicities. In the case of severe adverse reactions, treatmentshould be withheld.

For patients whose adverse reactions are resolved or attenuated in severity, Iclusig may be restartedand 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.

Dose modifications for neutropenia (ANC* < 1.0 x 109/L) and thrombocytopenia(platelet < 50 x 109/L) that are unrelated to leukaemia are summarized in Table 1.

Table 1 Dose modifications for myelosuppression

First occurrence:

* Iclusig should be withheld and resumed at the same doseafter recovery to ANC ≥ 1.5 x 109/L and platelet≥ 75 x 109/L

ANC* < 1.0 x 109/L Recurrence at 45 mg:

or * Iclusig should be withheld and resumed at 30 mg afterplatelet < 50 x 109/L recovery to

ANC ≥ 1.5 x 109/L and platelet ≥ 75 x 109/L

Recurrence at 30 mg:

* Iclusig should be withheld and resumed at 15 mg afterrecovery to

ANC ≥ 1.5 x 109/L and platelet ≥ 75 x 109/L

*ANC = absolute neutrophil count

Arterial occlusion and venous thromboembolism

In a patient suspected of developing an arterial occlusive event or a venous thromboembolism, Iclusigshould be immediately interrupted. A benefit-risk consideration should guide a decision to restart

Iclusig therapy (see sections 4.4 and 4.8) after the event is resolved.

Hypertension may contribute to risk of arterial occlusive events. Iclusig treatment should betemporarily interrupted if hypertension is not medically controlled.

Recommended modifications for pancreatic adverse reactions are summarized in Table 2.

Table 2 Dose modifications for pancreatitis and elevation of lipase/amylase

Grade 2 pancreatitis and/orasymptomatic elevation of Iclusig should be continued at the same doselipase/amylase

Occurrence at 45 mg:

* Iclusig should be withheld and resumed at 30 mg after

Grade 3 or 4 asymptomatic recovery to ≤ Grade 1 (< 1.5 x IULN)elevation of lipase/amylase Occurrence at 30 mg:

(> 2.0 x IULN*) only * Iclusig should be withheld and resumed at 15 mg afterrecovery to ≤ Grade 1 (< 1.5 x IULN)

Occurrence at 15 mg:

* Iclusig discontinuation should be considered

Occurrence at 45 mg:

* Iclusig should be withheld and resumed at 30 mg afterrecovery to < Grade 2

Grade 3 pancreatitis Occurrence at 30 mg:

* Iclusig should be withheld and resumed at 15 mg afterrecovery 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

Dose interruption or discontinuation may be required as described in Table 3.

Table 3 Recommended dose modifications for hepatic toxicity

Elevation of liver transaminase Occurrence at 45 mg:> 3 × ULN* * Iclusig should be interrupted and hepatic functionshould be monitored

Persistent grade 2 (longer than 7 days) * Iclusig should be resumed at 30 mg after recovery to≤ Grade 1 (< 3 × ULN), or recovery to pre-treatmentgrade

Grade 3 or higher Occurrence at 30 mg:

* Iclusig should be interrupted and resumed at 15 mgafter recovery to ≤ Grade 1, or recovery topre-treatment grade

Occurrence at 15 mg:

* Iclusig should be discontinued

Elevation of AST or ALT ≥ 3 × ULN Iclusig should be discontinuedconcurrent with an elevation ofbilirubin > 2 × ULN and alkalinephosphatase < 2 × ULN

*ULN = Upper Limit of Normal for the lab

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

Patients with hepatic impairment may receive the recommended starting dose. Caution isrecommended when administering Iclusig to patients with hepatic impairment (see sections 4.4 and5.2).

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

The safety and efficacy of Iclusig in patients less than 18 years of age have not been established. Nodata are available.

Iclusig is for oral use. The tablets should be swallowed whole. Patients should not crush or dissolvethe tablets. Iclusig may be taken with or without food.

Patients should be advised not to swallow the desiccant canister found in the bottle.

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

Important adverse reactions

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 or4 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 blastphase CML (BP-CML)/Ph+ ALL than in chronic phase CML (CP-CML). A complete blood countshould 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 temporarilyor reducing the dose (see section 4.2).

Arterial occlusion

Arterial occlusions, including fatal myocardial infarction, stroke, retinal arterial occlusions associatedin some cases with permanent visual impairment or vision loss, stenosis of large arterial vessels of thebrain, severe peripheral vascular disease, renal artery stenosis (associated with worsening, labile ortreatment-resistant hypertension), and the need for urgent revascularization procedures have occurredin Iclusig-treated patients. Patients with and without cardiovascular risk factors, including patients age50 years or younger, experienced these events. Arterial occlusion adverse events were more frequentwith increasing age and in patients with history of ischaemia, hypertension, diabetes, orhyperlipidaemia.

The risk of arterial occlusive events is likely to be dose-related (see sections 4.2 and 5.1).

Arterial occlusive adverse reactions including serious reactions, have occurred in the PACE phase 2trial (see section 4.8). Some patients experienced more than 1 type of event.

The median time to onset of the first cardiovascular, cerebrovascular, and peripheral vascular arterialocclusive events was 351, 611, and 605 days, respectively.

Iclusig should not be used in patients with a history of myocardial infarction, prior revascularization orstroke, 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 withponatinib.

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 activelymanaged. Cardiovascular status should continue to be monitored and medical and supportive therapyfor conditions that contribute to cardiovascular risk should be optimised during treatment withponatinib.

Monitoring for evidence of arterial occlusion should be performed and if decreased vision or blurredvision occurs, an ophthalmic examination (including fundoscopy) should be performed. Iclusig shouldbe interrupted immediately in case of arterial occlusion. A benefit -risk consideration should guide adecision to restart Iclusig therapy (see sections 4.2 and 4.8).

Venous thromboembolic adverse reactions including serious reactions have occurred in the PACEphase 2 trial (see section 4.8).

Monitoring for evidence of thromboembolism should be performed. Iclusig should be interruptedimmediately in case of thromboembolism. A benefit -risk consideration should guide a decision torestart Iclusig therapy (see sections 4.2 and 4.8).

Retinal venous occlusions associated in some cases with permanent visual impairment or vision losshave occurred in Iclusig-treated patients. If decreased vision or blurred vision occurs, an ophthalmicexamination (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 andhypertension should be treated to normal. Iclusig treatment should be temporarily interrupted ifhypertension is not medically controlled (see section 4.2).

In the event of significant worsening, labile or treatment-resistant hypertension, treatment should beinterrupted 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 theformation of aneurysms and/or artery dissections. Before initiating Iclusig, this risk should becarefully 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 orsymptoms consistent with heart failure and they should be treated as clinically indicated, includinginterruption of Iclusig. Discontinuation of ponatinib should be considered in patients who developserious heart failure (see sections 4.2 and 4.8).

Pancreatitis and serum lipase

Iclusig is associated with pancreatitis. The frequency of pancreatitis is greater in the first 2 months ofuse. Check serum lipase every 2 weeks for the first 2 months and then periodically thereafter. Doseinterruption or reduction may be required. If lipase elevations are accompanied by abdominalsymptoms, Iclusig should be withheld and patients evaluated for evidence of pancreatitis (see section4.2). Caution is recommended in patients with a history of pancreatitis or alcohol abuse. Patients withsevere or very severe hypertriglyceridemia should be appropriately managed to reduce the risk ofpancreatitis.

Iclusig may result in elevation in ALT, AST, bilirubin, and alkaline phosphatase. Most patients whohad 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 totreatment initiation and monitored periodically, as clinically indicated.

Severe haemorrhage, including fatalities, occurred in Iclusig-treated patients. The incidence of severebleeding events was higher in patients with AP-CML, BP-CML and Ph+ ALL. Gastrointestinalhaemorrhage and subdural hematoma were the most commonly reported grade 3/4 bleeding events.

Most haemorrhagic events, but not all, occurred in patients with grade 3/4 thrombocytopenia. Iclusigshould 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 thesepatients received BCR-ABL tyrosine kinase inhibitors. Some cases resulted in acute hepatic failure orfulminant hepatitis leading to liver transplantation or a fatal outcome.

Patients should be tested for HBV infection before initiating treatment with Iclusig. Experts in liverdisease and in the treatment of hepatitis B should be consulted before treatment is initiated in patientswith positive hepatitis B serology (including those with active disease) and for patients who testpositive for HBV infection during treatment. Carriers of HBV who require treatment with Iclusigshould be closely monitored for signs and symptoms of active HBV infection throughout therapy andfor several months following termination of therapy (see section 4.8).

Posterior Reversible Encephalopathy Syndrome

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 neurologicaldisturbances.

If diagnosed, interrupt Iclusig treatment and resume treatment only once the event is resolved and ifthe benefit of continued treatment outweighs the risk of PRES.

Caution should be exercised with concurrent use of Iclusig and moderate and strong CYP3A inhibitorsand moderate and strong CYP3A inducers (see section 4.5).

Concomitant use of ponatinib with anti-clotting agents should be approached with caution in patientswho may be at risk of bleeding events (see “Myelosuppression” and “Haemorrhage”). Formal studiesof ponatinib with anti-clotting medicinal products have not been conducted.

The QT interval prolongation potential of Iclusig was assessed in 39 leukaemia patients and noclinically significant QT prolongation was observed (see section 5.1). However, a thorough QT studyhas not been performed; therefore a clinically significant effect on QT cannot be excluded.

Patients with hepatic impairment may receive the recommended starting dose. Caution isrecommended when administering Iclusig to patients with hepatic impairment (see sections 4.2 and5.2).

Caution is recommended in when administering Iclusig to patients with estimated creatinine clearanceof < 50 mL/min or end-stage renal disease (see section 4.2).

This medicinal product contains lactose monohydrate. Patients with rare hereditary problems ofgalactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not takethis medicinal product.

Substances that may increase ponatinib serum concentrations

Ponatinib is metabolized by CYP3A4.

Co-administration of a single 15 mg oral dose of Iclusig in the presence of ketoconazole (400 mgdaily), a strong CYP3A inhibitor, resulted in modest increases in ponatinib systemic exposure, withponatinib AUC0-∞ and Cmax values that were 78% and 47% higher, respectively, than those seen whenponatinib was administered alone.

Caution should be exercised and a reduction of the starting dose of Iclusig to 30 mg should beconsidered with concurrent use of strong CYP3A inhibitors such as clarithromycin, indinavir,itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin,troleandomycin, voriconazole, and grapefruit juice.

Substances that may decrease ponatinib serum concentrations

Co-administration of a single 45 mg dose of Iclusig in the presence of rifampin (600 mg daily), astrong 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 ponatinibunderexposure.

Substances that may have their serum concentrations altered by ponatinib

In vitro, ponatinib is an inhibitor of P-gp and BCRP. Therefore, ponatinib may have the potential toincrease plasma concentrations of co-administered substrates of P-gp (e.g., digoxin, dabigatran,colchicine, pravastatin) or BCRP (e.g., methotrexate, rosuvastatin, sulfasalazine) and may increasetheir therapeutic effect and adverse reactions. Close clinical surveillance is recommended whenponatinib 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 andmen being treated with Iclusig should be advised not to father a child during treatment. An effectivemethod of contraception should be used during treatment. It is unknown whether ponatinib affects theeffectiveness of systemic hormonal contraceptives. An alternative or additional method ofcontraception should be used.

There are no adequate data from the use of Iclusig in pregnant women. Studies in animals have shownreproductive toxicity (see section 5.3). The potential risk for humans is unknown. Iclusig should beused during pregnancy only when clearly necessary. If it is used during pregnancy, the patient must beinformed of the potential risk to the foetus.

It is unknown whether Iclusig is excreted in human milk. Available pharmacodynamic andtoxicological data cannot exclude potential excretion in human milk. Breast-feeding should be stoppedduring treatment with Iclusig.

No human data on the effect of ponatinib on fertility are available. In rats, treatment with ponatinibhas shown effects on female fertility and male fertility was not affected (see section 5.3). The clinicalrelevance of these findings to human fertility is unknown.

Iclusig has minor influence on the ability to drive and use machines. Adverse reactions such aslethargy, dizziness, and vision blurred have been associated with Iclusig. Therefore, caution should berecommended when driving or operating machines.

In the PACE phase 2 trial (see section 5.1) 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 arterialocclusive 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 failurecongestive (2.4%), cerebrovascular accident (2.4%), sepsis (2.4%), cellulitis (2.2%), acute kidneyinjury (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% ofpatients.

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-treatedpatients from the PACE phase 2 trial with a minimum 64 months follow-up, with serious adversereactions 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. Theincidence 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 discontinuationwere 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) 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 mgcohort) and serious adverse reactions occurring in 4.3% of patients (45 mg cohort). Arterialcardiovascular, cerebrovascular, and peripheral vascular occlusive adverse reactions(treatment-emergent frequencies) occurred in 4.3%, 2.1%, and 3.2% of Iclusig-treated patients (45 mgcohort), respectively. Of the 94 patients in the 45 mg cohort, 1 patient experienced a venousthromboembolic reaction.

The frequencies of adverse reactions are based on 449 CML and Ph+ALL patients exposed toponatinib in the PACE phase 2 trial. See section 5.1 for information on the main characteristics ofparticipants in the trial. Adverse reactions reported in all CML and Ph+ ALL patients are listed bysystem organ class and by frequency in Table 4. 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 eachfrequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 4 Adverse reactions observed in CML and Ph+ ALL patients - frequency reported byincidence of treatment emergent events

System organ class Frequency Adverse reactions

Infections and infestations Very common upper respiratory tract infection

Common pneumonia, sepsis, folliculitis, cellulitis

Very common anaemia, platelet count decreased,neutrophil count decreased

Blood and lymphatic systemdisorders pancytopenia, febrile neutropenia, white

Common blood cell count decreased, lymphocytecount decreased

Endocrine disorders Common hypothyroidism

System organ class Frequency Adverse reactions

Very common decreased appetitedehydration, fluid retention,

Metabolism and nutrition hypocalcaemia, hyperglycaemia,disorders Common hyperuricaemia, hypophosphataemia,hypertriglyceridaemia, hypokalaemia,weight decreased, hyponatraemia

Uncommon tumour lysis syndrome

Psychiatric disorders Very common insomnia

Very common headache, dizzinesscerebrovascular accident, cerebral

Common infarction, neuropathy peripheral, lethargy,migraine, hyperaesthesia, hypoaesthesia,

Nervous system disorders paraesthesia, transient ischaemic attackcerebral artery stenosis, cerebral

Uncommon haemorrhage, haemorrhage intracranial,posterior reversible encephalopathysyndrome *vision blurred, dry eye, periorbital oedema,

Common eyelid oedema, conjunctivitis, visual

Eye disorders impairment

Uncommon retinal vein thrombosis, retinal veinocclusion, retinal artery occlusioncardiac failure, myocardial infarction,cardiac failure congestive, coronary artery

Common disease, angina pectoris, pericardialeffusion, atrial fibrillation, ejection fraction

Cardiac disorders decreased, acute coronary syndrome, atrialfluttermyocardial ischemia, cardiac discomfort,

Uncommon ischemic cardiomyopathy, arteriospasmcoronary, left ventricular dysfunction,

Very common hypertensionperipheral arterial occlusive disease,

Common peripheral ischaemia, peripheral arterystenosis, intermittent claudication, deep

Vascular disorders vein thrombosis, hot flush, flushingpoor peripheral circulation, splenic

Uncommon infarction, embolism venous, venousthrombosis, hypertensive crisis, renal arterystenosis

Not known aneurysms and artery dissections

Very common dyspnoea, cough

Respiratory, thoracic and pulmonary embolism, pleural effusion,mediastinal disorders Common epistaxis, dysphonia, pulmonaryhypertension

Very common abdominal pain, diarrhoea, vomiting,constipation, nausea, lipase increasedpancreatitis, blood amylase increased,

Gastrointestinal disorders gastrooesophageal reflux disease,

Common stomatitis, dyspepsia, abdominal distension,abdominal discomfort, dry mouth, gastrichaemorrhage

Hepatobiliary disorders Very common alanine aminotransferase increased,aspartate aminotransferase increased

System organ class Frequency Adverse reactionsblood bilirubin increased, blood alkaline

Common phosphatase increased, gamma-glutamyltransferase increased

Uncommon hepatotoxicity, hepatic failure, jaundice

Very common rash, dry skin, pruritusrash pruritic, exfoliative rash, erythema,

Skin and subcutaneous tissue alopecia, skin exfoliation, night sweats,disorders Common hyperhidrosis, petechia, ecchymosis, painof skin, dermatitis exfoliative,hyperkeratosis, skin hyperpigmentation

Rare panniculitis (including erythema nodosum)bone pain, arthralgia, myalgia, pain in

Musculoskeletal and Very common extremity, back pain, muscle spasmsconnective tissue disorders Common musculoskeletal pain, neck pain,musculoskeletal chest pain

Reproductive system andbreast disorders Common erectile dysfunction

Very common fatigue, asthenia, oedema peripheral,

General disorders and pyrexia, painadministrative site conditions Common chills, influenza like illness, non-cardiacchest pain, mass, face oedema

* Spontaneous reports from post-marketing experience

Vascular occlusion (see section 4.2 and 4.4).

Serious vascular occlusion has occurred in patients treated with Iclusig, including cardiovascular,cerebrovascular and peripheral vascular events, and venous thrombotic events. Patients with andwithout cardiovascular risk factors, including patients age 50 years or younger, experienced theseevents. Arterial occlusive adverse events were more frequent with increasing age and in patients withhistory of ischaemia, hypertension, diabetes, or hyperlipidaemia.

In the PACE phase 2 trial (see section 5.1) with a minimum 64-month follow-up, arterialcardiovascular, 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-treatedpatients 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 firstcardiovascular, cerebrovascular, and peripheral vascular arterial occlusive events was 351, 611, and605 days, respectively in the PACE trial. Venous thromboembolic reactions (treatment-emergentfrequencies) occurred in 6% of patients.

In the OPTIC phase 2 trial (see section 5.1) with a median 31.1 months follow-up, arterialcardiovascular, cerebrovascular, and peripheral vascular occlusive adverse reactions(treatment-emergent frequencies) occurred in 4.3%, 2.1%, and 3.2% of Iclusig-treated patients (45 mgcohort), 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 peripheralvascular arterial occlusive events was 295, 379, and 23 days, respectively in the OPTIC trial. Of the 94patients in OPTIC (45 mg cohort), 1 patient experienced a venous thromboembolic reaction.

Myelosuppression was commonly reported in all patient populations. The frequency of Grade 3 or 4thrombocytopenia, neutropenia, and anaemia was higher in patients with AP-CML and

BP-CML/Ph+ ALL than in patients with CP-CML (see Table 5). Myelosuppression was reported inpatients with normal baseline laboratory values as well as in patients with pre-existing laboratoryabnormalities.

Discontinuation due to myelosuppression was infrequent (thrombocytopenia 4%, neutropenia andanaemia < 1% each).

Hepatitis B reactivation has been reported in association with BCR-ABL TKIs. Some cases resulted inacute hepatic failure or fulminant hepatitis leading to liver transplantation or a fatal outcome (seesection 4.4).

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

Laboratory test All CP-CML AP-CML BP-CML/Ph+patients (N = 270) (N = 85) ALL (N = 94)(N = 449) (%) (%) (%)(%)

Thrombocytopenia (platelet count 40 35 49 46decreased)

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.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Isolated reports of unintentional overdose with Iclusig were reported in clinical trials. Single doses of165 mg and an estimated 540 mg in two patients did not result in any clinically significant adversereactions. Multiple doses of 90 mg per day for 12 days in a patient resulted in pneumonia, systemicinflammatory response, atrial fibrillation, and asymptomatic, moderate pericardial effusion. Treatmentwas interrupted, the events resolved, and Iclusig was restarted at 45 mg, once daily. In the event of anoverdose of Iclusig, the patient should be observed and appropriate supportive treatment given.

Pharmacotherapeutic group: antineoplastic agents, protein kinase inhibitors, ATC code: L01EA05

Ponatinib is a potent pan BCR-ABL inhibitor with structural elements, including a carbon-carbontriple-bond, that enable high affinity binding to native BCR-ABL and mutant forms of the ABLkinase. Ponatinib inhibits the tyrosine kinase activity of ABL and T315I mutant ABL with IC50 valuesof 0.4 and 2.0 nM, respectively. In cellular assays, ponatinib was able to overcome imatinib, dasatinib,and nilotinib resistance mediated by BCR-ABL kinase domain mutations. In preclinical mutagenesisstudies, 40 nM was determined as the concentration of ponatinib sufficient to inhibit viability of cellsexpressing all tested BCR-ABL mutants by > 50% (including T315I) and suppress the emergence ofmutant clones. In a cell-based accelerated mutagenesis assay, no mutation in BCR-ABL was detectedthat could confer resistance to 40 nM ponatinib.

Ponatinib elicited tumour shrinkage and prolonged survival in mice bearing tumours expressing nativeor T315I mutant BCR-ABL.

At doses of 30 mg or greater plasma steady state trough concentrations of ponatinib typically exceed21 ng/mL (40 nM). At doses of 15 mg or greater, 32 of 34 patients (94%) demonstrated a ≥ 50%reduction of CRK-like (CRKL) phosphorylation, a biomarker of BCR-ABL inhibition, in peripheralblood mononuclear cells.

Ponatinib inhibits the activity of other clinically relevant kinases with IC50 values below 20 nM andhas demonstrated cellular activity against RET, FLT3, and KIT and members of the FGFR, PDGFR,and VEGFR families of kinases.

PACE Trial

The safety and efficacy of Iclusig in CML and Ph+ ALL patients who were resistant or intolerant toprior tyrosine kinase inhibitor (TKI) therapy were evaluated in a single-arm, open-label, international,multicenter trial. All patients were administered 45 mg of Iclusig once-daily with the possibility ofdose de-escalations and dose interruptions followed by dose resumption and re-escalation. Patientswere assigned to one of six cohorts based on disease phase (CP-CML; AP-CML; or

BP-CML/Ph+ ALL), resistance or intolerance (R/I) to dasatinib or nilotinib, and the presence of the

T315I mutation.

Resistance in CP-CML was defined as failure to achieve either a complete haematological response(by 3 months), a minor cytogenetic response (by 6 months), or a major cytogenetic response (by12 months) while on dasatinib or nilotinib. CP-CML patients who experienced a loss of response ordevelopment of a kinase domain mutation in the absence of a complete cytogenetic response orprogression to AP-CML or BP-CML at any time on dasatinib or nilotinib were also consideredresistant. Resistance in AP-CML and BP-CML/Ph+ ALL was defined as failure to achieve either amajor haematological response (AP-CML by 3 months, BP-CML/Ph+ ALL by 1 month), loss of majorhaematological response (at any time), or development of kinase domain mutation in the absence of amajor haematological response while on dasatinib or nilotinib.

Intolerance was defined as the discontinuation of dasatinib or nilotinib due to toxicities despite optimalmanagement in the absence of a complete cytogenetic response for CP CML patients or majorhaematological response for AP CML, BP CML, or Ph+ ALL patients.

The primary efficacy endpoint in CP-CML was major cytogenetic response (MCyR), which includedcomplete and partial cytogenetic responses (CCyR and PCyR) by 12 months. The secondary efficacyendpoints in CP-CML were complete haematological response (CHR) and major molecular response(MMR).

The primary efficacy endpoint in AP-CML and BP-CML/Ph+ ALL was major haematologicalresponse (MaHR), defined as either a complete haematological response (CHR) or no evidence ofleukaemia (NEL). The secondary efficacy endpoints in AP-CML and BP-CML/Ph+ ALL were MCyRand MMR.

For all patients, additional secondary efficacy endpoints included: confirmed MCyR, time to response,duration of response, progression free survival, and overall survival. Also, post-hoc analyses to assessthe relationship of shorter-term cytogenetic (MCyR) and molecular (MMR) response outcomes withlonger-term outcomes of PFS and OS, maintenance of response (MCyR and MMR) after dosereductions, and PFS and OS by Arterial Occlusive Event status were conducted.

The trial enrolled 449 patients of which 444 were eligible for analysis: 267 CP-CML patients (R/I

Cohort: n = 203, T315I Cohort: n = 64), 83 AP-CML patients (R/I Cohort: n = 65, T315I Cohort:n = 18), 62 BP-CML (R/I Cohort: n = 38, T315I Cohort: n = 24), and 32 Ph+ ALL patients (R/I

Cohort: n = 10, T315I Cohort: n = 22). A prior MCyR or better (MCyR, MMR, or CMR) to dasatinibor nilotinib was only achieved in 26 % patients with CP-CML and a prior MaHR or better (MaHR,

MCyR, MMR, or CMR) was only achieved in 21 %, and 24 % of AP-CML, and BP-CML/Ph+ALLpatients, respectively. Baseline demographic characteristics are described in Table 6 below.

Table 6 Demographics and disease characteristics for the PACE trial

Patient characteristics at entry Total safety population

N = 449

Median, years (range) 59 (18 - 94)

Gender, n (%)

Male 238 (53%)

Race, n (%)

Asian 59 (13%)

Black/African American 25 (6%)

White 352 (78%)

Other 13 (3%)

ECOG Performance Status, n (%)

ECOG = 0 or 1 414 (92%)

Disease history

Median time from diagnosis to first dose, years (range) 6.09 (0.33 - 28.47)

Resistant to Prior TKI Therapy a *, n (%) 374 (88%)

Prior TKI therapy- number of regimens, n (%)1 32 (7%)2 155 (35%)≥ 3 262 (58%)

BCR-ABL mutation detected at entry, n (%)b

None 198 (44%)1 192 (43%)≥ 2 54 (12%)

Patient characteristics at entry Total safety population

N = 449

Comorbidities

Hypertension 159 (35%)

Diabetes 57 (13%)

Hypercholesterolemia 100 (22%)

History of ischemic heart disease 67 (15%)a* of 427 patients reporting prior TKI therapy with dasatinib or nilotinibb Of the patients with one or more BCR-ABL kinase domain mutations detected at entry, 37 unique mutationswere detected.

Overall, 55% of patients had one or more BCR-ABL kinase domain mutation at entry with the mostfrequent being: T315I (29%), F317L (8%), E255K (4%) and F359V (4%). In 67% of CP-CMLpatients in the R/I cohort, no mutations were detected at study entry.

Efficacy results are summarized in Table 7, Table 8, and Table 9.

Table 7 Efficacy of Iclusig in resistant or intolerant chronic phase CML patients

Overall Resistant or Intolerant(N = 267) R/I T315I

Cohort Cohort(N = 203) (N = 64)

Cytogenetic Response

Major (MCyR) a% 55% 51% 70%(95% CI) (49-62) (44-58) (58-81)

Complete (CCyR)% 46% 40% 66%(95% CI) (40-52) (33-47) (53-77)

Major Molecular Response b% 40% 35% 58%(95% CI) (35-47) (28-42) (45-70)a Primary endpoint for CP-CML Cohorts was MCyR, which combines both complete (No detectable Ph+cells) and partial (1% to 35% Ph+ cells) cytogenetic responses.b Measured in peripheral blood. Defined as a ≤ 0.1% ratio of BCR-ABL to ABL transcripts on the

International Scale (IS) (ie, ≤ 0.1% BCR-ABLIS; patients must have the b2a2/b3a2 (p210) transcript), inperipheral blood measured by quantitative reverse transcriptase polymerase chain reaction (qRT PCR).

Database cutoff date 06 February 2017.

CP-CML patients who received fewer prior TKIs attained higher cytogenetic, haematological, andmolecular responses. Of the CP-CML patients previously treated with one, two, three or four prior

TKIs, 75% (12/16), 68% (66/97), 44% (63/142), and 58% (7/12)) achieved a MCyR while on Iclusig,respectively. The median dose intensity was 28 mg/day or, 63% of the expected 45 mg dose.

Of the CP-CML patients with no mutation detected at entry, 49% (66/136) achieved a MCyR.

For every BCR-ABL mutation detected in more than one CP-CML patient at entry, a MCyR wasachieved following treatment with Iclusig.

In CP-CML patients who achieved MCyR, the median time to MCyR was 2.8 months (range: 1.6 to11.3 months) and in patients who achieved MMR, the median time to MMR was 5.5 months (range:1.8 to 55.5 months). At the time of updated reporting with minimum follow-up for all ongoing patientsof 64 months, the median durations of MCyR and MMR had not yet been reached. Based on the

Kaplan-Meier estimates, 82% (95% CI: [74%-88%]) of CP-CML (median duration of treatment:32.2 months) patients who achieved a MCyR are projected to maintain that response at 48 months and61% (95% CI: [51%- 70%]) of CP-CML patients who achieved a MMR are projected to maintain thatresponse at 36 months. The probability of all patients with CP-CML maintaining MCyR and MMR didnot change further when the analysis was extended out to 5 years.

With a minimum follow-up of 64 months, 3.4% (9/267) of CP-CML patients experiencedtransformation of their disease to AP-CML or BP-CML.

For CP-CML patients overall (N = 267), as well as for CP-CML R/I Cohort A patients (N = 203) and

T315I Cohort B patients (N = 64), the median OS has not yet been reached. For the overall CP-CMLdisease group, the probability of survival at 2, 3, 4, and 5 years is estimated as 86.0%, 81.2%, 76.9%,and 73.3%, respectively, as shown in Figure 1.

Figure 1- Kaplan-Meier estimates for overall survival in the CP-CML population (Treated

Population)

CP-CML patients who achieved MCyR or MMR response within the first year of treatment hadstatistically significantly improved progression-free (PFS) and overall survival (OS) compared tothose patients who did not meet the treatment milestones. A MCyR at the 3-month landmarkcorrelated strongly and statistically significantly with PFS and OS (p< 0.0001 and p = 0.0006,respectively). Statistical significance was achieved in the correlation of PFS and OS with a MCyR atthe 12-month landmark (p = < 0.0001 and p = 0.0012, respectively).

Table 8 Efficacy of Iclusig in resistant or intolerant advanced phase CML patients

Accelerated Phase CML Blast Phase CML

Overall Resistant or Overall Resistant or(N = 83) Intolerant (N = 62) Intolerant

R/I T315I R/I T315I

Cohort Cohort Cohort Cohort(N = 65) (N = 18) (N = 38) (N = 24)

Haematological Response

Rate

Majora (MaHR)% 57% 57% 56% 31% 32% 29%(95% CI) (45-68) (44-69) (31-79) (20-44) (18-49) (13-51)

Completeb (CHR)% 51% 49% 56% 21% 24% 17%(95% CI) (39-62) (37-62) (31-79) (12-33) (11-40) (5-37)

Major Cytogenetic

Responsec% 39% 34% 56% 23% 18% 29%(95% CI) (28-50) (23-47) (31-79) (13-35) (8-34) (13-51)a Primary endpoint for AP-CML and BP-CML/Ph+ ALL Cohorts was MaHR, which combines completehaematological responses and no evidence of leukaemia.b CHR: WBC ≤ institutional ULN, ANC ≥ 1,000/mm3, platelets ≥ 100,000/mm3, no blasts or promyelocytes inperipheral blood, bone marrow blasts ≤ 5%, < 5% myelocytes plus metamyelocytes in peripheral blood,basophils < 5% in peripheral blood, No extramedullary involvement (including no hepatomegaly orsplenomegaly).c MCyR combines both complete (No detectable Ph+ cells) and partial (1% to 35% Ph+ cells) cytogeneticresponses.

Database cutoff date 06 February 2017

The median dose intensity was 32 mg/day in the AP-CML patients.

Table 9 Efficacy of Iclusig in resistant or intolerant Ph+ ALL patients

Overall Resistant or Intolerant(N = 32) R/I T315I

Cohort Cohort(N = 10) (N = 22)

Haematological Response

Rate

Majora (MaHR)% 41% 50% 36%(95% CI) (24-59) (19-81) (17-59)

Completeb (CHR)% 34% 40% 32%(95% CI) (19-53) (12-74) (14-55)

Major Cytogenetic

Responsec% 47% 60% 41%(95% CI) (29-65) (26-88) (21-64)a Primary endpoint for AP-CML and BP-CML/Ph+ ALL Cohorts was MaHR, which combines completehaematological responses and no evidence of leukaemia.b CHR: WBC ≤ institutional ULN, ANC ≥ 1,000/mm3, platelets ≥ 100,000/mm3, no blasts or promyelocytesin peripheral blood, bone marrow blasts ≤ 5%, < 5% myelocytes plus metamyelocytes in peripheral blood,basophils < 5% in peripheral blood, No extramedullary involvement (including no hepatomegaly orsplenomegaly).c MCyR combines both complete (No detectable Ph+ cells) and partial (1% to 35% Ph+ cells) cytogeneticresponses.

Database cutoff date 06 February 2017

The median dose intensity was 44 mg/day in the BP CML/Ph+ ALL patients.

The median time to MaHR in patients with AP-CML, BP-CML, and Ph+ ALL was 0.7 months (range:0.4 to 5.8 months), 1.0 months (range: 0.4 to 3.7 months), and 0.7 months (range: 0.4 to 5.5 months),respectively. At the time of updated reporting with minimum follow-up for all ongoing patients of64 months, the median duration of MaHR for AP-CML (median duration of treatment: 19.4 months)

BP-CML (median duration of treatment: 2.9 months), and Ph+ ALL (median duration of treatment:2.7 months) patients was estimated as 12.9 months (range: 1.2 to 68.4 months), 6.0 months (range:1.8 to 59.6 months), and 3.2 months (range: 1.8 to 12.8 months), respectively.

For all patients in the PACE phase 2 trial, the dose intensity-safety relationship indicated that there aresignificant increases in grade ≥ 3 adverse events (cardiac failure, arterial thrombosis, hypertension,thrombocytopenia, pancreatitis, neutropenia, rash, ALT increase, AST increase, lipase increase,myelosuppression, arthralgia) over the dose range of 15 to 45 mg once-daily.

The analysis of the dose intensity-safety relationship in the PACE phase 2 trial concluded that afteradjusting for covariates, the overall dose intensity is significantly associated with an increased risk ofarterial occlusion, with an odds ratio of approximately 1.6 for each 15 mg increase. In addition, resultsfrom logistic regression analyses of data from patients in the phase 1 trial, suggest a relationshipbetween systemic exposure (AUC) and occurrence of arterial thrombotic events. A reduction in dose istherefore expected to reduce the risk of vascular occlusive events, however, the analysis suggested thatthere may be a ‘carry over’ effect of higher doses such that it might take up to several months before adose reduction manifests in risk reduction. Other covariates that show a statistically significantassociation with the occurrence of vascular occlusive events in this analysis are medical history ofischemia and age.

Dose reduction in CP-CML patients

In the PACE phase 2 trial, dose reductions were recommended following adverse events. Additionalrecommendations for prospective dose reduction in all CP-CML patients in the absence of adverseevents were introduced in this trial with the aim of reducing the risk of vascular occlusive events.

With a minimum follow-up of 48 months, and approximately 2 years after the recommendation forprospective dose reduction, there were 110 CP-CML patients ongoing. A majority of these ongoingpatients (82/110 patients; 75%) were reported to be receiving 15 mg at the last dose, while24/110 patients (22%) were receiving 30 mg, and 4/110 (4%) were receiving 45 mg. At the time ofstudy closure initiation (minimum follow-up of 64 months, and more than 3 years after therecommendation for prospective dose reduction), 99 CP-CML patients were ongoing and 77 (78%) ofthese patients received 15 mg as their last dose on study.

Safety

In the PACE phase 2 trial, 86 CP-CML patients achieved MCyR at a dose of 45 mg, 45 CP-CMLpatients achieved MCyR after a dose reduction to 30 mg, mostly for adverse events.

Vascular occlusive events occurred in 44 of these 131 patients. Most of these events occurred at thedose at which the patient achieved MCyR; fewer events occurred after dose reduction.

Table 10 Vascular occlusive first adverse events in CP-CML patients who achieved MCyR at45 mg or 30 mg (data extraction 7 April 2014)

Most recent dose at onset of first vascular occlusive Event45 mg 30 mg 15 mg

Achieved MCyR at 45 mg(N = 86) 19 6 0

Achieved MCyR at 30 mg(N = 45) 1 13 5

The median time to onset of the first cardiovascular, cerebrovascular, and peripheral vascular arterialocclusive events was 351, 611, and 605 days, respectively. When adjusted for exposure, the incidenceof first arterial occlusive events was greatest in the first two years of follow-up and declined withdecreasing daily dose intensity (following recommendation for prospective dose reduction). Factorsother than dose may also contribute to this risk of arterial occlusion.

Data from the PACE phase 2 trial are available for the maintenance of response (MCyR and MMR) inall CP-CML patients who underwent dose reduction for any reason. Table 11 shows these data forpatients who achieved MCyR and MMR at 45 mg; similar data are available for patients who achieved

MCyR and MMR at 30 mg.

The majority of patients who underwent dose reduction maintained response (MCyR and MMR) forthe duration of currently available follow-up. A proportion of patients did not undergo any dosereduction, based on an individual benefit-risk assessment.

Table 11 Maintenance of response in CP-CML patients who achieved MCyR or MMR at45 mg dose (data extraction 6 February 2017)

Achieved MCyR Achieved MMRat 45 mg (N = 86) at 45 mg (N = 63)

Number of Maintained Number of Maintainedpatients MCyR patients MMR

No dose reduction 19 13 (68%) 18 11 (61%)

Dose reduction to 30 mg only 15 13 (87%) 5 3 (60%)≥ 3 month reduction at 30 mg 12 10 (83%) 3 2 (67%)≥ 6 month reduction at 30 mg 11 9 (82%) 3 2 (67%)≥ 12 month reduction at 30 mg 8 7 (88%) 3 2 (67%)≥ 18 month reduction at30 mg 7 6 (86%) 2 2 (100%)≥ 24 month reduction at30 mg 6 6 (100%) 2 2 (100%)≥ 36 month reduction at30 mg 1 1 (100%) -- --

Any dose reduction to 15 mg 52 51 (98%) 40 36 (90%)≥ 3 month reduction at 15 mg 49 49 (100%) 39 36 (92%)≥ 6 month reduction at 15 mg 47 47 (100%) 37 35 (95%)≥ 12 month reduction at 15 mg 44 44 (100%) 34 33 (97%)≥ 18 month day reduction at15 mg 38 38 (100%) 29 29 (100%)≥ 24 month reduction at15 mg 32 32 (100%) 23 23 (100%)≥ 36 month reduction at15 mg 8 8 (100%) 4 4 (100%)

The anti-leukaemic activity of Iclusig was also evaluated in a phase 1 dose escalation study thatincluded 65 CML and Ph+ ALL patients; the study is completed. Of 43 CP-CML patients, 31

CP-CML patients achieved a MCyR with a median duration of follow-up of 55.5 months (range: 1.7 to91.4 months). At the time of reporting, 25 CP-CML patients were in MCyR (median duration of

MCyR had not been reached).

OPTIC Open-label randomized Phase 2 Trial

The safety and efficacy of Iclusig was evaluated in the OPTIC phase 2 trial, a dose-optimization trial.

Eligible patients had CP-CML whose disease was considered to be resistant to at least 2 prior kinaseinhibitors or who have the T315I mutation. Resistance in CP-CML while on a prior kinase inhibitorwas defined as failure to achieve either a complete hematologic response (by 3 months), a minorcytogenetic response (by 6 months), or a major cytogenetic response (by 12 months), or developmentof a new BCR-ABL1 kinase domain mutation or new clonal evolution. Patients were required to have> 1% BCR-ABL1IS (by real-time polymerase chain reaction) at trial entry. Patients received one ofthree starting dosages: 45 mg orally once daily, 30 mg orally once daily, or 15 mg orally once daily.

Patients who received a starting dose of 45 mg or 30 mg had a mandatory dose reduction to 15 mgonce daily upon achieving ≤ 1% BCR-ABL1IS. The primary efficacy endpoint was a molecularresponse based on the achievement of ≤ 1% BCR-ABL1IS at 12 months. All patients reached the12-month time point (primary endpoint) by the primary analysis data cut-off. The median duration offollow-up for the 45 mg cohort (N = 94) was 31.1 months (95% CI: 24.1, 36.0). Only the efficacyresults for the recommended starting dose of 45 mg are described below. A total of 282 patientsreceived Iclusig: 94 received a starting dose of 45 mg, 94 received a starting dose of 30 mg, and 94received a starting dose of 15 mg. Baseline demographic characteristics are described in Table 12 forpatients who received a starting dose of 45 mg.

Table 12 Demographic and Disease Characteristics for the OPTIC trial

Iclusig

Patient Characteristics at Entry 45 mg → 15 mg(N = 94)

Median years (range) 46 (19 to 81)

Sex, n (%)

Male 50 (53 %)

Race, n (%)

White 73 (78%)

Asian 16 (17%)

Other/Unknown 4 (4%)

Black or African American 1 (1%)

ECOG Performance Status, n (%)

ECOG 0 or 1 93 (99%)

Disease History

Median time from diagnosis to first dose, years (range) 5.5 (1 to 21)

Resistant to Prior Kinase Inhibitor, n (%) 92 (98%)

Presence of one or more BCR-ABL kinase domain mutations, n (%) 41 (44%)

Number of Prior Kinase Inhibitors, n (%)1 1 (1%)2 43 (46%)≥ 3 50 (53%)

T315I mutation at baseline 25 (27%)

Comorbidities

Hypertension 29 (31%)

Diabetes 5 (5%)

Hypercholesterolemia 3 (3%)

History of ischemic heart disease 3 (3%)

Efficacy results are summarised in Table 13.

The primary endpoint was met in patients who received a starting dose of 45 mg.

Overall, 44% of patients had one or more BCR-ABL kinase domain mutations at study entry with themost frequent being T315I (27%). The subgroup analysis based on baseline T315I mutation statusshowed similar ≤ 1% BCR-ABL1IS rates at 2 months in patients with and without T315I (see Table 13below). No mutations were detected at study entry for 54% of the patients who received the startingdose of 45 mg.

With a minimum follow up of two years among patients with CP-CML, the proportion of patientsexperiencing transformation of their disease to either AP-CML or BP-CML was 10.6% and 3.2%respectively.

Table 13 Efficacy Results in Patients with CP-CML Who Received Iclusig at Starting Dose of45 mg in the OPTIC Phase 2 Trial

Iclusig45 mg → 15 mg(N = 93)(a)

Molecular Response at 12 months(b)

Overall ≤ 1% BCR-ABL1IS Rate% (n/N) 44% (41/93)(98.3% CI)(c) (32%, 57%)

Patients with T315I mutation% (n/N) 44% (11/25)(95% CI) (24%, 65%)

Patients without T315I mutation% (n/N) 44% (29/66)(d)(95% CI) (32%, 57%)

Cytogenetic Response at 12 months

Major (MCyR)(e)% (n/N) 48% (44/91)(f)(95% CI) (38%, 59%)

Patients with T315I mutation% (n/N) 52% (13/25)(95% CI) (31%, 72%)

Patients without T315I mutation% (n/N) 46% (30/65)(g)(95% CI) (34%, 59%)(a) ITT population (N = 93) defined as patients who had b2a2/b3a2 BCR ABL1 transcripts.(b) Primary endpoint was ≤ 1% BCR-ABL1IS rate at 12 months. Defined as a ≤ 1% ratio of BCR ABL to ABLtranscripts on the International Scale (IS) (i.e., ≤ 1% BCR-ABLIS; patients must have the b2a2/b3a2 (p210)transcript), in peripheral blood measured by quantitative reverse transcriptase polymerase chain reaction (qRT

PCR).(c) 98.3% CI is calculated using the binomial exact (Clopper-Pearson) method.(d) Of the 93 patients, two patients did not have a baseline mutation assessment and were excluded from theresponse by mutation analysis.(e) Secondary endpoint was MCyR by 12 months which combines both complete (no detectable Ph+ cells) andpartial (1% to 35% Ph+ cells in at least 20 metaphases) cytogenetic responses.(f) Analysis is based on ITT cytogenetic population (N = 91) defined as patients who had a cytogeneticassessment at baseline with at least 20 metaphases examined. One patient who had a complete cytogeneticresponse at baseline was excluded from the analysis.(g) Of the 91 patients, one patient did not have a baseline mutation assessment and was excluded from theresponse by mutation analysis.

The secondary efficacy endpoints included complete cytogenetic response (CCyR) at 12 months,major molecular response (MMR) at 12 and 24 months, complete hematologic response at 3 months,time to response, duration of response, maintenance of response, progression free survival (PFS), andoverall survival (OS). In addition, additional assessment included the rates of molecular response ateach patient visit at 3-month intervals for 36 months based on the achievement of ≤ 1% BCR-ABL1IS.

* At 12 months, 34% (31/91) and 17% (16/93) of patients achieved CCyR, and MMR, respectively.

At 24 months, 24% (18/75) of patients achieved MMR. The median duration of MMR had not yetbeen reached.

* The median duration of ponatinib treatment was 21 months.

* Of the 45 patients who had a dose reduction after achieving ≤ 1% BCR-ABL1IS, 28 patients(62%) maintained their response at the reduced dose for at least 90 days. Of the 28 patients, 18patients (64%) maintained the response for at least one year. Median duration of response (MR2)was not reached. The probabilities of maintaining MR2 at 12 months and at 24 months were79.13% and 73.17% respectively.

* The molecular response rates (measured by achievement of ≤ 1% BCR-ABL1IS) at 12 monthswas lower among patients who had received treatment with ≤ 2 prior TKIs compared withpatients who had received ≥ 3 prior TKIs (40% vs 48%), respectively).

The QT interval prolongation potential of Iclusig was assessed in 39 leukaemia patients who received30 mg, 45 mg, or 60 mg Iclusig once daily. Serial ECGs in triplicate were collected at baseline and atsteady state to evaluate the effect of ponatinib on QT intervals. No clinically significant changes in themean QTc interval (i.e., > 20 ms) from baseline were detected in the study. In addition, thepharmacokinetic-pharmacodynamic models show no exposure-effect relationship, with an estimated

QTcF mean change of -6.4 ms (upper confidence interval -0.9 ms) at Cmax for the 60 mg group.

The European Medicines Agency has waived the obligation to submit the results of studies with

Iclusig in children from birth to less than 1 year in CML and Ph+ ALL. The European Medicines

Agency has deferred the obligation to submit the results of studies with Iclusig in paediatric patientsfrom 1 year to less than 18 years in CML and Ph+ ALL (see section 4.2 for information on paediatricuse).

Peak concentrations of ponatinib are observed approximately 4 hours after oral administration. Withinthe range of clinically relevant doses evaluated in patients (15 mg to 60 mg), ponatinib exhibited doseproportional increases in both Cmax and AUC. The geometric mean (CV%) Cmax and AUC(0-τ)exposures achieved for ponatinib 45 mg daily at steady state were 77 ng/mL (50%) and1296 ng*hr/mL (48%), respectively. Following either a high-fat and low-fat meal, plasma ponatinibexposures (Cmax and AUC) were not different versus fasting conditions. Iclusig may be administeredwith or without food. Co-administration of Iclusig with a potent inhibitor of gastric acid secretionresulted in a minor reduction in ponatinib Cmax without a reduction in AUC0-∞.

Ponatinib is highly bound (> 99%) to plasma proteins in vitro. The blood/plasma ratio of ponatinib is0.96. Ponatinib is not displaced by concomitant administration of ibuprofen, nifedipine, propranolol,salicylic acid, or warfarin. At daily doses of 45 mg, the geometric mean (CV%) apparent steady statevolume of distribution is 1101 L (94%) suggesting that ponatinib is extensively distributed in theextravascular space. In vitro studies suggested that ponatinib is either not a substrate or is a weaksubstrate for both P-gp and breast cancer resistance protein BCRP. Ponatinib is not a substrate for thehuman organic anion transporting polypeptides OATP1B1, OATP1B3 and the organic cationtransporter OCT-1.

Ponatinib is metabolized to an inactive carboxylic acid by esterases and/or amidases, and metabolizedby CYP3A4 to an N-desmethyl metabolite that is 4 times less active than ponatinib. The carboxylicacid and the N-desmethyl metabolite comprise 58% and 2% of the circulating levels of ponatinib,respectively.

At therapeutic serum concentrations, ponatinib did not inhibit OATP1B1 or OATP1B3, OCT1 or

OCT2, organic anion transporters OAT1 or OAT3, or bile salt export pump (BSEP) in vitro.

Therefore, clinical medicinal product interactions are unlikely to occur as a result ofponatinib-mediated inhibition of substrates for these transporters. In vitro studies indicate that clinicalmedicinal product interactions are unlikely to occur as a result of ponatinib-mediated inhibition of themetabolism of substrates for CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP3A or CYP2D6.

An in vitro study in human hepatocytes indicated that clinical medicinal product interactions are alsounlikely to occur as a result of ponatinib-mediated induction of the metabolism of substrates for

CYP1A2, CYP2B6, or CYP3A.

Following single and multiple 45 mg doses of Iclusig, the terminal elimination half-life of ponatinibwas 22 hours, and steady state conditions are typically achieved within 1 week of continuous dosing.

With once-daily dosing, plasma exposures of ponatinib are increased by approximately 1.5-foldbetween first dose and steady state conditions. Although plasma ponatinib exposures increased tosteady-state levels with continuous dosing, a population pharmacokinetic analysis predicts a limitedincrease in apparent oral clearance within the first two weeks of continuous dosing, which is notconsidered clinically relevant. Ponatinib is mainly eliminated via faeces. Following a single oral doseof [14C]-labeled ponatinib, approximately 87% of the radioactive dose is recovered in the faeces andapproximately 5% in the urine. Unchanged ponatinib accounted for 24% and < 1% of the administereddose in faeces and urine, respectively, with the remainder of the dose comprising metabolites.

Iclusig has not been studied in patients with renal impairment. Although renal excretion is not a majorroute of ponatinib elimination, the potential for moderate or severe renal impairment to affect hepaticelimination has not been determined (see section 4.2).

A single dose of 30 mg ponatinib was administered to patients with mild, moderate, or severe hepaticimpairment and to healthy volunteers with normal hepatic function. Ponatinib Cmax was comparable inpatients with mild hepatic impairment and healthy volunteers with normal hepatic function. In patientswith moderate or severe hepatic impairment, ponatinib Cmax and AUC0-∞ were lower and ponatinibplasma elimination half-life was longer in patients with mild, moderate, and severe hepatic impairmentbut not clinically significantly different than in healthy volunteers with normal hepatic function.

In vitro data showed no difference in plasma protein binding in plasma samples of healthy subjectsand hepatically impaired (mild, moderate and severe) subjects. Compared to healthy volunteers withnormal liver function, no major differences in ponatinib PK were observed in patients with varyingdegrees of hepatic impairment. A reduction of the starting dose of Iclusig in patients with hepaticimpairment is not necessary (see sections 4.2 and 4.4).

Caution is recommended when administering Iclusig to patients with hepatic impairment (see sections4.2 and 4.4).

Iclusig has not been studied at doses above 30 mg in patients with hepatic impairment (Childs-Pugh

Classes A, B & C).

Intrinsic factors affecting ponatinib pharmacokinetics

No specific studies have been performed to evaluate the effects of gender, age, race, and body weighton ponatinib pharmacokinetics. An integrated population pharmacokinetic analysis completed forponatinib suggests that age may be predictive of variability for ponatinib apparent oral clearance(CL/F). Gender, race and body weight were not predictive in explaining ponatinib pharmacokineticintersubject variability.

Iclusig has been evaluated in safety pharmacology, repeat-dose toxicity, genotoxicity, reproductivetoxicity, phototoxicity and carcinogenicity studies.

Ponatinib did not exhibit genotoxic properties when evaluated in the standard in vitro and in vivosystems.

Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar toclinical exposure levels and with possible relevance to clinical use are described below.

Depletion of lymphoid organs was observed in repeat-dose toxicity studies in rats and cynomolgusmonkeys. The effects were shown to be reversible after withdrawal of the treatment.

Hyper-/hypoplastic changes of the chondrocytes in the physis were noted in repeat-dose toxicitystudies in rats.

In rats, inflammatory changes accompanied by increases in neutrophils, monocytes, eosinophils, andfibrinogen levels were found in the preputial and clitoral glands following chronic dosing.

Skin changes in the form of crusts, hyperkeratosis, or erythema were observed in toxicity studies incynomolgus monkeys. Dry flaky skin was observed in toxicity studies in rats.

In a study in rats, diffuse corneal edema with neutrophilic cell infiltration, and hyperplastic changes inthe lenticular epithelium suggestive of a mild phototoxic reaction were observed in animals treatedwith 5 and 10 mg/kg ponatinib.

In cynomolgus monkeys, systolic heart murmurs with no macroscopic or microscopic correlates werenoted in individual animals treated with 5 and 45 mg/kg in the single dose toxicity study and at 1, 2.5and 5 mg/kg in the 4-week repeat-dose toxicity study. The clinical relevance of this finding isunknown.

In cynomolgus monkeys, thyroid gland follicular atrophy mostly accompanied by a reduction in T3levels and a tendency toward increased TSH levels were observed in the 4-week repeat-dose toxicitystudy in cynomolgus monkeys.

Ponatinib-related microscopic findings in the ovaries (increased follicular atresia) and testes (minimalgerm cell degeneration) in animals treated with 5 mg/kg ponatinib were noted in repeat-dose toxicitystudies in cynomolgus monkeys.

Ponatinib at doses of 3, 10, and 30 mg/kg produced increases in urine output and electrolyte excretionsand caused a decrease in gastric emptying in safety pharmacology studies in rats.

In rats, embryo-foetal toxicity in the form of post-implantation loss, reduced foetal body weight, andmultiple soft tissue and skeletal alterations were observed at maternal toxic dosages. Multiple foetalsoft tissue and skeletal alterations were also observed at maternal nontoxic dosages.

In a fertility study in male and female rats, female fertility parameters were reduced at dose levelscorresponding to human clinical exposures. Evidence for pre- and post-implantation loss of embryoswas reported in female rats and ponatinib may therefore impair female fertility. There were no effectson male rat fertility parameters. The clinical relevance of these findings on human fertility isunknown.

In juvenile rats, mortality related to inflammatory effects was observed in animals treated with3 mg/kg/day, and reductions in body weight gain were observed at doses of 0.75, 1.5 and 3 mg/kg/dayduring the pre-weaning and early post-weaning treatment phases. Ponatinib did not adversely affectimportant developmental parameters in the juvenile toxicity study.

In a two-year carcinogenicity study in male and female rats, oral administration of ponatinib at 0.05,0.1 and 0.2 mg/kg/day in males and at 0.2 and 0.4 mg/kg/day in females did not result in anytumorigenic effects. The 0.8 mg/kg/day dose in females resulted in a plasma exposure level generallylower or equivalent to the human exposure at the range of dose from 15 mg to 45 mg daily. Astatistically significant increased incidence of squamous cell carcinoma of the clitoral gland wasobserved at that dose. The clinical relevance of this finding for humans is not known.

Lactose monohydrate

Microcrystalline cellulose

Sodium starch glycolate

Colloidal anhydrous silica

Magnesium stearate

Talc

Macrogol 4000

Poly(vinyl alcohol)

Titanium dioxide (E171)

Not applicable.

4 years.

Store in the original container in order to protect from light.

The bottle contains one sealed canister containing a molecular sieve desiccant. Keep the canister in thebottle.

Iclusig 15 mg film-coated tablets

High density polyethylene (HDPE) bottles with screw-top closures, containing either 30, 60 or 180film-coated tablets, together with one plastic canister containing a molecular sieve desiccant.

Iclusig 30 mg film-coated tablets

High density polyethylene (HDPE) bottles with screw-top closures, containing 30 film-coated tablets,together with one plastic canister containing a molecular sieve desiccant.

Iclusig 45 mg film-coated tablets

High density polyethylene (HDPE) bottles with screw-top closures, containing either 30 or90 film-coated tablets, together with one plastic canister containing a molecular sieve desiccant.

Not all pack sizes may be marketed.

No special requirements for disposal.

Incyte Biosciences Distribution B.V.

Paasheuvelweg 251105 BP Amsterdam

Netherlands

Iclusig 15 mg film-coated tablets

EU/1/13/839/001

EU/1/13/839/002

EU/1/13/839/005

Iclusig 30 mg film-coated tablets

EU/1/13/839/006

Iclusig 45 mg film-coated tablets

EU/1/13/839/003

EU/1/13/839/004

Date of first authorisation: 1 July 2013

Date of latest renewal: 8 February 2018

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.