Leaflet ICLUSIG 30mg film-coated tablets

Product code:: W64972001
Quantity:: 30
Indicated for:: cancer
Route of administration:: oral
Substance:: ponatinib (tyrosine kinase inhibitor)
ATC: L01EA05 — Antineoplastic and immunomodulating agents | Protein kinase inhibitors | BCR-ABL tyrosine kinase inhibitors

Ponatinib is a tyrosine kinase inhibitor used in the treatment of chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL) with the T315I mutation. It works by blocking the activity of abnormal proteins that drive cancer cell growth.

The medication is taken orally, as directed by a doctor, usually once daily. It is important for patients to follow the treatment regimen and undergo regular tests to monitor the therapy's effects and potential side effects.

Patients should be aware of potential side effects, such as hypertension, skin rashes, or thrombosis. It is important to inform the doctor of any unusual symptoms.

Common side effects include hypertension, skin rashes, and fatigue. In rare cases, severe reactions such as heart failure, arterial thrombosis, or pancreatitis may occur. Patients should be informed of these risks before use.

General data about ICLUSIG 30mg

Substance:: ponatinib
Date of latest medicines list:: 01-12-2018
Product code:: W64972001
Concentration:: 30mg
Pharmaceutical form:: film-coated tablets
Quantity:: 30
Product type:: Original
Prescription status:: P-RF — Medicines dispensed with a medical prescription that is retained by the pharmacy and cannot be renewed.

Marketing authorisation

Manufacturer:: HAUPT PHARMA-AMAREG GMBH - GERMANIA
Holder:: INCYTE BIOSCIENCES DISTRIBUTION B.V. - OLANDA
Number:: 839/2013/06
Shelf life:: 3 years

Concentrations available for ponatinib

15mg
30mg
45mg

Official documents

EMA leaflet

Added to database:: 11/07/2013
Source record updated:: 31/07/2026

Precautions:

Fertility warning

This medicine may affect fertility.

Cytotoxic / special handling

Handle with special care.

Contraception required

Effective contraception is required during treatment.

Contraindicated during breastfeeding

Do not use this medicine while breastfeeding.

Contraindicated during pregnancy

Do not use this medicine during pregnancy.

Avoid grapefruit

Avoid grapefruit and grapefruit juice.

Hepatotoxicity

This medicine may affect the liver.

Major drug interactions

This medicine may have important interactions with other medicines.

Myelosuppression / agranulocytosis

This medicine may lower blood cell counts.

Additional monitoring

This medicine is subject to additional monitoring.

Requires periodic laboratory tests

Periodic laboratory tests may be required during treatment.

Severe skin reactions

Stop taking the medicine and seek urgent medical help if a severe rash occurs.

Cardiac risk / QT prolongation / arrhythmias

This medicine may increase the risk of heart rhythm disturbances.

Contents of the package leaflet for the medicine ICLUSIG 30mg film-coated tablets

Leaflet ICLUSIG 30mg

1. NAME OF THE MEDICINAL PRODUCT

Iclusig 15 mg film-coated tablets

Iclusig 30 mg film-coated tablets

Iclusig 45 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Iclusig 15 mg film-coated tablets

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

Excipients with known effect

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).

Excipients with known effect

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).

Excipients with known effect

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

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

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.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Iclusig is indicated as monotherapy 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.

Iclusig is indicated in combination with reduced-intensity chemotherapy in adult patients with newlydiagnosed Ph+ ALL (see section 5.1).

Iclusig is indicated as monotherapy in paediatric patients 6 years of age or older with

* chronic phase chronic myeloid leukaemia (CP-CML) who are resistant to dasatinib or nilotinib;who are intolerant to dasatinib or nilotinib 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.

4.2 Posology and method of administration

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.

Posology

Adult patients with CML and Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph+

ALL) previously treated with other tyrosine kinase inhibitors (TKIs) or who have the T315I mutation:

The recommended starting dose is 45 mg of ponatinib once daily. Treatment should be continued aslong 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 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 molecular response (MR2 i.e. ≤1%

BCR-ABL1IS) 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(see sections 4.4 and 5.1). If dose reduction is undertaken, close monitoring of response isrecommended. In patients with loss of response the dose of Iclusig can be re-escalated to a previouslytolerated dose of 30 mg or 45 mg orally once daily. Iclusig should be continued until loss of responseat the re escalated dose or unacceptable toxicity.

Adult patients with newly-diagnosed Ph+ ALL in combination with chemotherapy:

The recommended starting dose is 30 mg of ponatinib once daily in combination with chemotherapywith a dose reduction to 15 mg once daily upon achievement of Minimal Residual Disease (MRD)-negative complete response (≤0.01% BCR-ABL1) at the end of induction.

Patients with loss of MRD negativity can re-escalate the dose of ponatinib to a previously tolerateddose of up to 30 mg once daily. After completion of ponatinib in combination with chemotherapy,continue treatment with ponatinib as monotherapy until loss of response at the re-escalated dose orunacceptable toxicity (see section 5.1).

CNS prophylaxis or treatment, steroid induction, anti-CD20 therapy in CD20+ patients orchemotherapy as applicable should follow the respective Summaries of Product Characteristics andstandard clinical guidelines.

Discontinuing ponatinib should be considered if a complete molecular response has not occurred afterthe induction phase.

Paediatric patients with CP-CML:

Ponatinib is administered orally once daily in the form of either Iclusig film-coated tablets or Iclusighard capsules. The recommended starting dose is individualized for each paediatric patient on thebasis of body weight (see Table 1):

Table 1 Recommended starting dose and reduced dose after achieving a molecular responsefor paediatric patients with CP-CML

Body weight Recommended Recommendedstarting dose in reduced dose inmg (once daily) mg (once daily)> 45 kg 45 mg 15 mg> 30 kg to 45 kg 30 mg 10 mg15 to 30 kg 15 mg 5 mg

Treatment should be continued as long as the patient does not show evidence of disease progression orunacceptable toxicity.

Patients should be monitored for response according to standard clinical guidelines.

As in adults, the risk of arterial occlusive events is likely to be dose related. Reducing the dose of

Iclusig according to Table 1 should be considered for paediatric CP-CML patients who have achieveda molecular 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(see sections 4.4 and 5.1). If dose reduction is undertaken, close monitoring of response isrecommended. In patients with loss of response the dose of Iclusig can be re escalated to a previouslytolerated daily dose. Iclusig should be continued until loss of response at the re escalated dose orunacceptable toxicity.

Concurrent use of strong CYP3A inhibitors

With the concurrent use of strong CYP3A inhibitors a reduction of the starting dose of Iclusig shouldbe considered to 30 mg for adults and as per Table 2 below for paediatric patients (see section 4.4).

Table 2 Recommended starting dose in paediatric patients with concurrent use of strong

CYP3A inhibitors

Body weight Recommended startingdose in mg (once daily)> 45 kg 30 mg> 30 kg to 45 kg 20 mg15 to 30 kg 10 mg

Management of toxicities

Iclusig 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. When Iclusig is given in combination with chemotherapy, standard dosereductions for the chemotherapeutic medicinal products should be applied, see their respective

Summary of Product Characteristics and standard clinical guidelines.

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.

Myelosuppression

Dose modifications for neutropenia and thrombocytopenia that are unrelated to leukaemia aresummarized in Table 3 for adult patients and in Table 4 for paediatric patients.

Table 3 Dose modifications for myelosuppression for adult patients

Starting dose of First occurrence:ponatinib 45 mg once * Withhold and resume at the same dose afterdaily recovery to ANC ≥ 1.5 x 109/L and platelet≥ 75 x 109/L

Recurrence at 45 mg:

ANC* < 1.0 x 109/L * Withhold and resume at 30 mg afteror recovery toplatelet < 50 x 109/L ANC ≥ 1.5 x 109/L andplatelet ≥ 75 x 109/L

Recurrence at 30 mg:

* Withhold and resume at 15 mg afterrecovery to

ANC ≥ 1.5 x 109/L andplatelet ≥ 75 x 109/L

*ANC = absolute neutrophil count

Table 4 Dose modifications for myelosuppression for paediatric patients

Starting dose of First occurrence:ponatinib 45 mg once * Withhold and resume at the same dose afterdaily recovery to ANC ≥ 1.5 x 109/L and platelet≥ 75 x 109/L

Recurrence at 45 mg:

ANC* < 1.0 x 109/L * Withhold and resume at 30 mg afteror recovery toplatelet < 50 x 109/L ANC ≥ 1.5 x 109/L andplatelet ≥ 75 x 109/L

Recurrence at 30 mg:

* Withhold and resume at 15 mg afterrecovery to

ANC ≥ 1.5 x 109/L andplatelet ≥ 75 x 109/L

Starting dose of ANC* < 1.0 x 109/L First occurrence:ponatinib 30 mg once or Withhold and resume at the same dose afterdaily platelet < 50 x 109/L recovery to ANC ≥ 1.5 x 109/L and platelet≥ 75 x 109/L

Recurrence at 30 mg:

Withhold and resumed at 20 mg after recoveryto

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

Recurrence at 20 mg:

Withhold and resume at 10 mg after recovery to

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

Starting dose of ANC* < 1.0 x 109/L First occurrence:ponatinib 15 mg once or Withhold and resume at the same dose afterdaily platelet < 50 x 109/L recovery to ANC ≥ 1.5 x 109/L and platelet≥ 75 x 109/L

Recurrence at 15 mg:

Withhold and resume at 10 mg after recovery to

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

Recurrence at 10 mg:

Withhold and resume at 5 mg after recovery 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.

Pancreatitis

Recommended modifications for pancreatic adverse reactions are summarized in Table 5 for adultpatients and in Table 6 for paediatric patients.

Table 5 Dose modifications for pancreatitis and elevation of lipase for adults

Starting dose of Grade 2 pancreatitisponatinib 45 mg once and/or Grade 2daily elevation of lipase(> 1.5 - 2.0 x IULN or Continue at the same dose> 2.0 - 5.0 x IULN andasymptomatic)

Occurrence at 45 mg:

* Withhold and resume at 30 mg afterrecovery to ≤ Grade 1 (< 1.5 x IULN)

Grade 3 asymptomatic Occurrence at 30 mg:elevation of lipase * Withhold and resume at 15 mg after(> 5.0 x IULN*) recovery to ≤ Grade 1 (< 1.5 x IULN)

Occurrence at 15 mg:

* Iclusig discontinuation should beconsidered

Occurrence at 45 mg:

* Withhold until complete resolution ofsymptoms and after recovery of lipaseelevation to < Grade 2 and resume at

Grade 3 pancreatitis or 30 mg

Grade 3 symptomatic Occurrence at 30 mg:

elevation of lipase * Withhold until complete resolution of(> 2.0 - 5.0 x IULN) symptoms and after recovery of lipaseelevation to < Grade 2 and resume at15 mg

Occurrence at 15 mg:

* Iclusig discontinuation should beconsidered

Grade 4 pancreatitis or

Grade 4 elevation oflipase (> 5.0 x IULN Discontinueand symptomatic)

*IULN = institution upper limit of normal

Table 6 Dose modifications for pancreatitis and elevation of lipase for paediatric patients

Starting dose of Grade 2 pancreatitisponatinib 45 mg once and/or Grade 2 elevationdaily oflipase(> 1.5 - 2.0 x IULN Continue at the same doseor > 2.0 - 5.0 x IULNand asymptomatic)

Occurrence at 45 mg:

* Withhold and resume at 30 mg afterrecovery to ≤ Grade 1 (< 1.5 x IULN)

Grade 3 asymptomatic Occurrence at 30 mg:elevation of lipase * Withhold and resume at 15 mg after(> 5.0 x IULN*) recovery to ≤ Grade 1 (< 1.5 x IULN)

Occurrence at 15 mg:

* Iclusig discontinuation should beconsidered

Occurrence at 45 mg:

* Withhold until complete resolution ofsymptoms and after recovery of lipaseelevation to < Grade 2 and resume at

Grade 3 pancreatitis or 30 mg

Grade 3 symptomatic Occurrence at 30 mg:

elevation of lipase * Withhold until complete resolution of(> 2.0 - 5.0 x IULN) symptoms and after recovery of lipaseelevation to < Grade 2 and resume at15 mg

Occurrence at 15 mg:

* Iclusig discontinuation should beconsidered

Grade 4 pancreatitis or

Grade 4 elevation oflipase (> 5.0 x IULN and Discontinuesymptomatic)

Starting dose of Grade 2 pancreatitisponatinib 30 mg once and/or Grade 2 elevationdaily of lipase(> 1.5 - 2.0 x IULN or Continue at the same dose> 2.0 - 5.0 x IULN andasymptomatic)

Occurrence at 30 mg:

* Withhold and resume at 20 mg after

Grade 3 asymptomatic recovery to ≤ Grade 1 (< 1.5 x IULN)elevation of lipase Occurrence at 20 mg:

(> 5.0 x IULN*) * Withhold and resume at 10 mg afterrecovery to ≤ Grade 1 (< 1.5 x IULN)

Occurrence at 10 mg:

Iclusig discontinuation should be considered

Occurrence at 30 mg:

Grade 3 pancreatitis or * Withhold until complete resolution of

Grade 3 symptomatic symptoms and after recovery of lipaseelevation of lipase elevation to < Grade 2 and resume at(> 2.0 - 5.0 x IULN) 20 mg

Occurrence at 20 mg:

Starting dose of Grade 2 pancreatitisponatinib 45 mg once and/or Grade 2 elevationdaily oflipase(> 1.5 - 2.0 x IULN Continue at the same doseor > 2.0 - 5.0 x IULNand asymptomatic)

Occurrence at 45 mg:

* Withhold and resume at 30 mg afterrecovery to ≤ Grade 1 (< 1.5 x IULN)

Grade 3 asymptomatic Occurrence at 30 mg:elevation of lipase * Withhold and resume at 15 mg after(> 5.0 x IULN*) recovery to ≤ Grade 1 (< 1.5 x IULN)

Occurrence at 15 mg:

* Iclusig discontinuation should beconsidered

Occurrence at 45 mg:

* Withhold until complete resolution ofsymptoms and after recovery of lipaseelevation to < Grade 2 and resume at

Grade 3 pancreatitis or 30 mg

Grade 3 symptomatic Occurrence at 30 mg:

elevation of lipase * Withhold until complete resolution of(> 2.0 - 5.0 x IULN) symptoms and after recovery of lipaseelevation to < Grade 2 and resume at15 mg

Occurrence at 15 mg:

* Iclusig discontinuation should beconsidered

Grade 4 pancreatitis or

Grade 4 elevation oflipase (> 5.0 x IULN and Discontinuesymptomatic)

* Withhold until complete resolution ofsymptoms and after recovery of lipaseelevation to < Grade 2 and resume at10 mg

Occurrence at 10 mg:

Iclusig discontinuation should be considered

Grade 4 pancreatitis or

Grade 4 elevation oflipase (> 5.0 x IULN and Discontinuesymptomatic)

Starting dose of Grade 2 pancreatitisponatinib 15 mg once and/or Grade 2 elevationdaily of lipase(> 1.5 - 2.0 x IULN or Continue at the same dose> 2.0 - 5.0 x IULN andasymptomatic)

Occurrence at 15 mg:

* Withhold and resume at 10 mg after

Grade 3 asymptomatic recovery to ≤ Grade 1 (< 1.5 x IULN)elevation of lipase Occurrence at 10 mg:

(> 5.0 x IULN*) * Withhold and resume at 5 mg afterrecovery to ≤ Grade 1 (< 1.5 x IULN)

Occurrence at 5 mg:

Iclusig discontinuation should be considered

Starting dose of Grade 2 pancreatitisponatinib 45 mg once and/or Grade 2 elevationdaily oflipase(> 1.5 - 2.0 x IULN Continue at the same doseor > 2.0 - 5.0 x IULNand asymptomatic)

Occurrence at 45 mg:

* Withhold and resume at 30 mg afterrecovery to ≤ Grade 1 (< 1.5 x IULN)

Grade 3 asymptomatic Occurrence at 30 mg:elevation of lipase * Withhold and resume at 15 mg after(> 5.0 x IULN*) recovery to ≤ Grade 1 (< 1.5 x IULN)

Occurrence at 15 mg:

* Iclusig discontinuation should beconsidered

Occurrence at 45 mg:

* Withhold until complete resolution ofsymptoms and after recovery of lipaseelevation to < Grade 2 and resume at

Grade 3 pancreatitis or 30 mg

Grade 3 symptomatic Occurrence at 30 mg:

elevation of lipase * Withhold until complete resolution of(> 2.0 - 5.0 x IULN) symptoms and after recovery of lipaseelevation to < Grade 2 and resume at15 mg

Occurrence at 15 mg:

* Iclusig discontinuation should beconsidered

Grade 4 pancreatitis or

Grade 4 elevation oflipase (> 5.0 x IULN and Discontinuesymptomatic)

Occurrence at 15 mg:

* Withhold until complete resolution ofsymptoms and after recovery of lipase

Grade 3 pancreatitis or elevation to < Grade 2 and resume at 10

Grade 3 symptomatic mgelevation of lipase Occurrence at 10 mg:

(> 2.0 - 5.0 x IULN) * Withhold until complete resolution ofsymptoms and after recovery of lipaseelevation to < Grade 2 and resume at 5 mg

Occurrence at 5 mg:

Iclusig discontinuation should be considered

Grade 4 pancreatitis or

Grade 4 elevation oflipase (> 5.0 x IULN and Iclusig should be discontinuedsymptomatic)

*IULN = institution upper limit of normal

Hepatic toxicity

Dose interruption or discontinuation may be required as described in Table 7 for adult patients and in

Table 8 for paediatric patients.

Table 7 Recommended dose modifications for hepatic toxicity for adults

Starting dose of ponatinib Elevation of liver Occurrence at 45 mg:45 mg once daily transaminase > 3 × ULN* * Withhold Iclusig and monitor thehepatic function

Persistent Grade 2 (longer * Resume at 30 mg after recovery tothan 7 days) ≤ Grade 1 (< 3 × ULN), orrecovery to pre-treatment grade

Occurrence at 30 mg:

Grade 3 or higher * Withhold and resumeat 15 mg afterrecovery to ≤ Grade 1, or recoveryto pre-treatment grade

Occurrence at 15 mg:

* Discontinue

Elevation of AST or ALT Discontinue≥ 3 × ULN concurrentwith an elevation ofbilirubin > 2 × ULN andalkaline phosphatase< 2 × ULN

*ULN = Upper Limit of Normal for the lab

Table 8 Recommended dose modifications for hepatic toxicity for paediatric patients

Starting dose of ponatinib Elevation of liver Occurrence at 45 mg:45 mg once daily transaminase > 3 × ULN* * Withhold Iclusig and monitorhepatic function

Persistent Grade 2 (longer * Resume at 30 mg after recoverythan 7 days) to ≤ Grade 1 (< 3 × ULN), orrecovery to pre-treatment grade

Occurrence at 30 mg:

Grade 3 or higher * Withhold and resume at 15 mgafter recovery to ≤ Grade 1, orrecovery to pre-treatment grade

Occurrence at 15 mg:

* Discontinue

Elevation of AST or ALT Discontinue≥ 3 × ULN concurrentwith an elevation ofbilirubin > 2 × ULN andalkaline phosphatase< 2 × ULN

Starting dose of ponatinib Elevation of liver Occurrence at 30 mg:30 mg once daily transaminase > 3 × ULN* * Withhold Iclusig and monitorhepatic function

Persistent Grade 2 (longer * Resume at 20 mg after recoverythan 7 days) to ≤ Grade 1 (< 3 × ULN), orrecovery to pre-treatment grade

Occurrence at 20 mg:

Grade 3 or higher * Withhold and resume at 10 mgafter recovery to ≤ Grade 1, orrecovery to pre-treatment grade

Occurrence at 10 mg:

Discontinue

Starting dose of ponatinib Elevation of liver Occurrence at 45 mg:45 mg once daily transaminase > 3 × ULN* * Withhold Iclusig and monitorhepatic function

Persistent Grade 2 (longer * Resume at 30 mg after recoverythan 7 days) to ≤ Grade 1 (< 3 × ULN), orrecovery to pre-treatment grade

Occurrence at 30 mg:

Grade 3 or higher * Withhold and resume at 15 mgafter recovery to ≤ Grade 1, orrecovery to pre-treatment grade

Occurrence at 15 mg:

* Discontinue

Elevation of AST or ALT Discontinue≥ 3 × ULN concurrentwith an elevation ofbilirubin > 2 × ULN andalkaline phosphatase< 2 × ULN

Starting dose of ponatinib Elevation of liver Occurrence at 15 mg:15 mg once daily transaminase > 3 × ULN* * Withhold Iclusig and monitorhepatic function

Persistent grade 2 (longer * Resume at 10 mg after recoverythan 7 days) to ≤ Grade 1 (< 3 × ULN), orrecovery to pre-treatment grade

Occurrence at 10 mg:

Grade 3 or higher * Resume at 5 mg after recoveryto ≤ Grade 1 (< 3 × ULN), orrecovery to pre-treatment grade

Occurrence at 5 mg:

Discontinue

Elevation of AST or ALT Discontinue≥ 3 × ULN concurrentwith an elevation ofbilirubin > 2 × ULN andalkaline phosphatase< 2 × ULN

*ULN = Upper Limit of Normal for the lab

Elderly patients

Of the 732 patients in the PACE and OPTIC clinical studies of Iclusig, 191 (26%) were ≥ 65 years ofage. Compared to patients < 65 years, older patients are more likely to experience adverse reactions.

No dose adjustment is required in patients aged 65 years or above.

Hepatic impairment

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 impairment

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.

Paediatric population

The safety and efficacy of Iclusig monotherapy in children below 6 years has not been established.

The safety and efficacy of Iclusig in combination with chemotherapy in children has not beenestablished (see section 5.1).

Method of administration

Iclusig is for oral use. It may be taken with or without food.

Iclusig is available as film-coated tablets and hard capsules.

The tablets should be swallowed whole. The tablets should not be crushed or dissolved.

For doses that cannot be achieved by using the film-coated tablets, or for paediatric patients who areunable to swallow film-coated tablets, the 5 mg hard capsules are available. The hard capsules can beswallowed whole, but for the patients who are unable to swallow them, they can be opened and thecontent can be dispersed in soft food (applesauce or yogurt) and taken immediately.

4.3 Contraindications

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

4.4 Special warnings and precautions for use

Important adverse reactions

Myelosuppression

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 withgrade 3 or 4 platelet count decreased, anaemia or neutropenia, developed it within the first 3 months oftreatment. 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 bloodcount should be performed every 2 weeks for the first 3 months and then monthly or as clinicallyindicated. Myelosuppression was generally reversible and usually managed by withholding Iclusigtemporarily or 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 4.8 and 5.1).

Arterial occlusive adverse reactions including serious reactions, have occurred in the clinicaldevelopment (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 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.

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 thromboembolism

Venous thromboembolic adverse reactions including serious reactions have occurred in the clinicaldevelopment (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

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.

Aneurysms and artery dissections

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.

Congestive heart failure

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.

Hepatotoxicity

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. Hepatic function should becarefully monitored when ponatinib is used in combination with chemotherapy agents also known tobe associated with hepatic dysfunction (see section 4.8).

Haemorrhage

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.

Hepatitis B reactivation

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.

Paediatric population:

Growth retardation has been observed in paediatric patients treated with BCR-ABL-targeted tyrosinekinase inhibitor (TKI). Given the plausible mechanism and the suspected association of TKIs withgrowth retardation, close monitoring of growth in paediatric patients under ponatinib treatment isrecommended.

Medicinal product interactions

Caution should be exercised with concurrent use of Iclusig and moderate and strong CYP3A inhibitorsand 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 patientswho may be at risk of bleeding events (see “Myelosuppression” and “Haemorrhage”). Formal studiesof 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 section4.8). The use of ponatinib in combination with chemotherapy requires special precaution.

QT prolongation

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.

Special populations
Hepatic impairment

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).

Renal impairment

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).

Lactose

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

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet or capsule, that is to sayessentially ‘sodium-free’.

4.5 Interaction with other medicinal products and other forms of interaction

Substances that may increase ponatinib serum concentrations

CYP3A inhibitors

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 in adults to 30 mg shouldbe 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 section4.2.

Substances that may decrease ponatinib serum concentrations

CYP3A inducers

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

Transporter substrates

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.

Paediatric population

Interaction studies have only been performed in adults.

4.6 Fertility, pregnancy and lactation

Women of childbearing potential/Contraception in males and females

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.

Pregnancy

Based on limited human data (less than 50 known pregnancy outcomes), cases of congenitalmegacolon (Hirschsprung’s disease) have been reported in children born to women exposed toponatinib during the first trimester. Studies in animals have shown reproductive toxicity (see section5.3). Iclusig should not be used during pregnancy unless the clinical condition of the woman requirestreatment with ponatinib. If it is used during pregnancy, the patient must be informed of the potentialrisk to the foetus.

Breast-feeding

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.

Fertility

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.

4.7 Effects on ability to drive and use machines

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.

4.8 Undesirable effects

Summary of the safety profile

Patients with previously treated CML or Ph+ ALL or who have the T315I mutation (PACE Study)

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 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.

Previously treated CP-CML (OPTIC Study)

In the OPTIC phase 2 trial (see section 5.1) overall arterial occlusive adverse reactions have occurredin 13.8% of Iclusig-treated patients (45 mg cohort) including 2 of which were fatal, and seriousadverse 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%, pct. 4.3%, and 4.3% of Iclusig-treated patients (45 mg cohort), respectively. Of the94 patients in the 45 mg cohort, 1 patient experienced a venous thromboembolic reaction (Grade 1retinal vein occlusion).

Patients with newly diagnosed Ph+ ALL (PhALLCON Study)

Myelosuppression events were reported in 83 % of ponatinib-treated patients in PhALLCON. Themost frequently reported adverse drug reactions were thrombocytopenia (47%), neutropenia (44%)and anaemia (44%). Events of hepatotoxicity occurred in 64 % of patients. Overall a higher incidenceof myelosuppression associated with chemotherapy (febrile neutropenia, pyrexia, pneumonia andsepsis) as well as peripheral sensory neuropathy and stomatitis was observed as compared to the use ofponatinib alone.

Tabulated lists of adverse reactions

The frequencies of adverse reactions of Iclusig monotherapy are listed in Table 9 and are based on449 CML and Ph+ ALL patients exposed to ponatinib in the PACE phase 2 trial and the94 CML patients exposed to ponatinib (45 mg starting dose) in the OPTIC phase 2 trial with a medianduration 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 incombination with reduced-intensity chemotherapy followed by continued treatment with Iclusig asmonotherapy in the PhALLCON phase 3 trial.

See section 5.1 for information on the main characteristics of participants in the trials. Adversereactions 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 T315Imutation - frequency reported by incidence of treatment emergent events

System organ class Frequency Adverse reactions

Very common Upper respiratory tract infection

Pneumonia

Infections and infestations Sepsis

Common Folliculitis

Cellulitis

Herpes zoster

Anaemia

Very common Platelet count decreased

Neutrophil count decreased

Pancytopenia

Blood and lymphatic system Febrile neutropeniadisorders White blood cell count decreased

Common Lymphocyte count decreased

Eosinophilia

Neutrophil count increased

Myelosuppression

Endocrine disorders Common Hypothyroidisma

System organ class Frequency Adverse reactions

Decreased appetite

Very common Hypertriglyceridaemia

Hypercholesterolaemia

Dehydration

Fluid retention

Hypocalcaemia
Hyperglycaemia

Metabolism and nutrition Hyperuricaemiadisorders Hypophosphataemia

Common Hypokalaemia

Weight decreased

Hyponatraemia

Dyslipidaemia

Glucose tolerance impaired

Low density lipoprotein increased

Weight increase

Tumour lysis syndrome

Very common Insomnia

Psychiatric disorders Common Anxiety

Very common Headache

Dizziness

Cerebrovascular accident

Cerebral infarction

Neuropathy peripheral

Lethargy

Migraine

Common Hyperaesthesia

Nervous system disorders Hypoaesthesia

Paraesthesia

Transient ischaemic attack

Facial nerve disorder

Carotid artery stenosis

Cerebral artery stenosis

Cerebral haemorrhage

Uncommon Haemorrhage intracranial

Posterior reversible encephalopathysyndrome *

Vision blurred

Dry eye

Periorbital oedema

Eyelid oedema

Common Conjunctivitis

Eye disorders Visual impairment

Blepharitis

Eye pain

Ocular hyperaemia

Retinal vein occlusion

Uncommon Retinal vein thrombosis

Retinal artery occlusion

System organ class Frequency Adverse reactions

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

Common Tachycardia

Cardiac disorders Left ventricular dysfunction

Left ventricular hypertrophy

Sinus bradycardia

N-terminal prohormone brain natriureticpeptide increased

Angina unstable

Myocardial ischaemia

Supraventricular extrasystoles

Ventricular extrasystoles

Electrocardiogram QT prolonged

Cardiac failure chronic

Brain natriuretic peptide increased

Cardiac discomfort

Uncommon Ischemic cardiomyopathy

Arteriospasm coronary

Very common Hypertension

Peripheral arterial occlusive disease

Peripheral ischaemia

Peripheral artery stenosis

Common Intermittent claudication

Deep vein thrombosis

Hot flush

Vascular disorders Flushing

Hypertensive crisis

Poor peripheral circulation

Splenic infarction

Uncommon Embolism venous

Venous thrombosis

Renal artery stenosis

Not known Aneurysms

Artery dissections

System organ class Frequency Adverse reactions

Very common Dyspnoea

Cough

Pulmonary embolism

Respiratory, thoracic and Pleural effusionmediastinal disorders Epistaxis

Common Dysphonia

Pulmonary hypertension

Oropharyngeal pain

Productive cough

Abdominal pain

Diarrhoea

Very common Vomiting

Constipation

Nausea

Lipase increased

Pancreatitis

Blood amylase increased

Gastrooesophageal reflux disease

Gastrointestinal disorders Stomatitis

Dyspepsia

Abdominal distension

Common Abdominal discomfort

Dry mouth

Gastric haemorrhage

Gastritis

Oropharyngeal pain

Gastric ulcer

Gingival bleeding

Alanine aminotransferase increased

Very common Aspartate aminotransferase increased

Transaminases increased

Hepatotoxicity

Hepatobiliary disorders Blood bilirubin increased

Common Blood alkaline phosphatase increased

Gamma-glutamyl transferase increased

Hypertransaminasaemia

Uncommon Hepatic failure

Jaundice

Skin and subcutaneous tissue Rashdisorders Very common Dry skin

Pruritus

System organ class Frequency Adverse reactions

Rash pruritic

Exfoliative rash

Erythema

Alopecia

Skin exfoliation

Night sweats

Hyperhidrosis

Petechia

Ecchymosis

Pain of skin

Dermatitis exfoliative

Hyperkeratosis

Skin hyperpigmentation

Acne

Common 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

Bone pain

Arthralgia

Very common Myalgia

Pain in extremity

Back pain

Muscle spasms

Musculoskeletal and Musculoskeletal painconnective tissue disorders Neck pain

Musculoskeletal chest pain

Common Chest pain

Muscular weakness

Musculoskeletal stiffness

Spinal pain

Tendonitis

Renal and urinary disorders Common Proteinuria

Reproductive system and Common Erectile dysfunctionbreast disorders Amenorrhoea

Fatigue

General disorders and Astheniaadministrative site conditions Very common Oedema peripheral

Pyrexia
Pain

System organ class Frequency Adverse reactions

Chills

Influenza like illness

Common Non-cardiac chest pain

Mass

Face oedema

Investigations Common C-reactive protein increased

Hypoalbuminaemia

* Spontaneous reports from post-marketing experiencea 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

Ponatinib in combination with reduced-

System Organ Class Frequency intensity chemotherapy

Adverse reactions

Pneumonia

Conjunctivitis

Infections and infestations Common Sepsis

Septic shock

Neutropenic infection

Thrombocytopenia

Anemia

Very common Neutropenia

Febrile neutropenia

Blood and lymphatic system Leukopeniadisorders Leukocytosis

Myelosuppression

Common Lymphopenia

Cytopenia

Agranulocytosis

Hypokalaemia
Hyperglycaemia

Very common Hypocalcaemia

Hypophosphataemia

Hyperuricaemia

Metabolism and nutrition Decreased appetitedisorders Hypertriglyceridaemia

Hyponatraemia

Common Hypoalbuminaemia

Hypercholesterolaemia

Dyslipidaemia

Fluid retention

Psychiatric disorders Very common Insomnia

Headache

Neuropathy peripheral

Very common Paraesthesia

Nervous system disorders Peripheral sensory neuropathy

Dizziness

Common Hypoaesthesia

Common Conjunctival hemorrhage

Eye disorders

Uncommon Retinal vein occlusion

Ponatinib in combination with reduced-

System Organ Class Frequency intensity chemotherapy

Adverse reactions

Tachycardia

Palpitations

Common Pericardial effusion

Atrial fibrillation

Cardiac disorders Sinus bradycardia

Angina pectoris

Cardiac failure

Uncommon Acute myocardial infarction

Cardiac failure congestive

Very common Hypertension

Deep vein thrombosis

Common Superficial vein thrombosis

Vascular disorders Embolism

Peripheral arterial occlusive disease

Uncommon Peripheral coldness

Thrombosis

Very common Cough

Dyspnoea

Respiratory, thoracic and Oropharyngeal painmediastinal disorders Common Pleural effusion

Dysphonia

Pulmonary embolism

Constipation

Nausea

Vomiting

Very common Stomatitis

Diarrhoea

Abdominal pain

Gastrointestinal disorders Abdominal pain upper

Dyspepsia

Abdominal distension

Common Abdominal discomfort

Pancreatitis

Gastritis

Pancreatitis acute

Uncommon Mouth haemorrhage

Hepatotoxicity

Common Hyperbilirubinaemia

Hypertransaminasaemia

Hepatobiliary disorders Hepatitis toxic

Drug-induced liver injury

Uncommon Hepatobilliary disease

Liver injury

Very common Rash

Skin and subcutaneous tissue Dry skindisorders Pruritus

Common Alopecia

Rash maculo-papular

Back pain

Musculoskeletal andconnective tissue disorders Very common Pain in extremity

Arthralgia

Myalgia

Ponatinib in combination with reduced-

System Organ Class Frequency intensity chemotherapy

Adverse reactions

Bone pain

Common Neck pain

Muscle spasms

Pyrexia
Fatigue

General disorders and Very common Astheniaadministration site conditions Oedema peripheral

Common Chest pain

Pain

Alanine aminotransferase increased

Lipase increased

Very common Aspartate aminotransferase increased

Gamma-glutamyltransferase increased

Blood lactate dehydrogenase increased

Amylase increased

Blood alkaline phosphatase increased

Blood creatinine increased

Investigations Blood fibrinogen decreased

C-reactive protein increased

Common Neutrophil count increased

Protein total decreased

Platelet count increased

Brain natriuretic peptide increased

Troponin I increased

Uncommon Ejection fraction decreased

Injury, poisoning andprocedural complications Uncommon Subdural hematoma

Description of selected adverse reactions

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 77.9 months follow-up, arterialcardiovascular, cerebrovascular, and peripheral vascular occlusive adverse reactions(treatment-emergent frequencies) occurred in 5.3%, pct. 4.3%, and 4.3% of Iclusig-treated patients (45 mgcohort), 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 peripheralvascular arterial occlusive events was 473, 356, and 108 days, respectively in the OPTIC trial. Of the94 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, arterialcardiovascular, cerebrovascular, and peripheral vascular occlusive adverse reactions (treatmentemergent frequencies) occurred in 1.2%, 0.6%, and 0.6% of patients treated with ponatinib incombination with chemotherapy, respectively. Venous thromboembolic events occurred in 12% ofpatients who have received ponatinib in combination with chemotherapy in PhALLCON.

Myelosuppression

In the PACE Study, myelosuppression was commonly reported in all patient populations. Thefrequency 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). Myelosuppressionwas reported in patients with normal baseline laboratory values as well as in patients with pre-existinglaboratory abnormalities.

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

Myelosuppression events were reported in 83% of ponatinib-treated patients in PhALLCON, 63% ofponatinib-treated patients in OPTIC (45 mg cohort) and in 60% of ponatinib-treated patients in PACE.

Hepatotoxicity

Events of hepatotoxicity occurred in 64% of patients who have received ponatinib in combination withchemotherapy 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

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 11 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 months for all ongoing patients

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

Haematology

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.

Paediatric population

The safety of ponatinib monotherapy in paediatric patients has been evaluated in a phase◦1/2 open-label, single-arm study that included 61 paediatric participants (≥◦1 to <◦18◦years old) with recurrentor refractory leukaemias, lymphomas, or solid tumours (see section 5.1).The observed safety profile ofponatinib monotherapy in paediatric patients has been generally consistent with the one observed inadults

Reporting of suspected adverse reactions

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.

4.9 Overdose

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.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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

Mechanism of action

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.

Pharmacodynamic effects

Ponatinib inhibits the tyrosine kinase activity of ABL and T315I mutant ABL with IC50 values of 0.4and 2.0 nM, respectively. In cellular assays, ponatinib was able to overcome imatinib, dasatinib, andnilotinib 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.

Cardiac electrophysiology

The QT interval prolongation potential of Iclusig was assessed in 39 patients with leukaemia whoreceived 30 mg, 45 mg, or 60 mg Iclusig once daily. Serial ECGs in triplicate were collected atbaseline and at steady state to evaluate the effect of ponatinib on QT intervals. No clinicallysignificant changes in the mean QTc interval (i.e., > 20 ms) from baseline were detected in the study.

In addition, the pharmacokinetic-pharmacodynamic models show no exposure-effect relationship, withan estimated QTcF mean change of -6.4 ms (upper confidence interval -0.9 ms) at Cmax for the 60 mggroup.

Clinical efficacy and safety

Patients with CML and Ph+ ALL previously treated with other tyrosine kinase inhibitors (TKIs) orwho have the T315I mutation.

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 12 below.

Table 12 Demographics and disease characteristics for the PACE trial

Patient characteristics at entry Total safety population

N = 449

Age

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%)

Patient characteristics at entry Total safety population

N = 449

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

None 198 (44%)1 192 (43%)≥ 2 54 (12%)

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 13, Table 14, and Table 15.

Table 13 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 14 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 15 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 16 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.

Efficacy

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 17 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 a 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 17 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 77.9 months (95% CI: 72.4, 84.0). 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 18 forpatients who received a starting dose of 45 mg.

Table 18 Demographic and disease characteristics for the OPTIC trial

Iclusig

Patient characteristics at entry 45 mg → 15 mg(N = 94)

Age

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 19.

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 19below). No mutations were detected at study entry for 54% of the patients who received the startingdose of 45 mg.

With a median follow up of 6.5 years among patients with CP-CML, the proportion of patientsexperiencing transformation of their disease to either AP-CML or BP-CML was 11.7% and 3.2%respectively.

Table 19 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). Additional assessment included the rates of molecular response at each patientvisit at 3-month intervals for 36 months based on the achievement of ≤ 1% BCR-ABL1IS.

* At 12 months, 34% (32/93) and 17% (16/93) of patients achieved CCyR, and MMR, respectively.

At 24 months, 34% (18/75) of patients achieved MMR. The median duration of MMR had not yetbeen reached.

* The median duration of ponatinib treatment was 31 months.

* Of the 45 patients who had a dose reduction from 45 mg to 15 mg after achieving ≤ 1%

BCR-ABL1IS, 25 patients (55.6%) maintained their response at the reduced dose for at least oneyear. Of these 25 patients, 16 patients (64%) maintained the response at 15 mg for greater than60 months. Median duration of response (MR2) was not reached. The probabilities of maintaining

MR2 at 60 months was 68.8% (95% CI, 53.9, 79.8).

* The molecular response rates (≤1% BCR-ABLIS) by 60 months was 64.0% (95% CI 42.5, 82.0) inpatients with T315I mutation and 59.1% (95% CI, 46.3, 71.0) in patients without T315I mutation.

* The molecular response rates (≤ 1% BCR-ABL1IS) at 12 months were lower among patients whohad received treatment with ≤ 2 prior TKIs compared with patients who had received ≥ 3 prior

TKIs (40% vs 48%), respectively).

Patients with newly diagnosed Ph+ ALL

PhALLCON Trial

The efficacy of Iclusig in combination with reduced-intensity chemotherapy followed by continuedtreatment with Iclusig as a single agent was evaluated in PhALLCON, a randomized, activecontrolled, multicenter, open label trial.

Eligible patients had newly diagnosed Ph+ALL. Randomization was stratified by age at the time ofinduction therapy (18 to <45 years; ≥45 to <60 years; and ≥60 years). Patients were randomized (2:1)to receive either Iclusig 30 mg orally once daily or imatinib 600 mg orally once daily in combinationwith 20 cycles of the chemotherapy regimen, followed by Iclusig or imatinib as monotherapy. The

Iclusig dose was reduced to 15 mg once daily after completion of the induction phase and achievementof MRD negative CR. If a patient lost MRD negativity at any time after a response-based dosereduction to 15 mg, re-escalation to 30 mg once daily was allowed. Only patients who achieved CR orincomplete complete remission (CRi) with MRD negativity at the end of induction could continuestudy treatment at the investigator’s discretion.

Study Phases and Regimens

* Induction Phase: Patients received three 28-day cycles of Iclusig starting dose of 30 mg orallyonce daily or imatinib starting dose of 600 mg orally once daily; administered from Day 1 to

Day 28 of Cycles 1 to 3 of the treatment regimen in combination with:o Vincristine: 1.4 mg/m2, IV, Days 1 and 14; capped at 2 mg ando Dexamethasone: Patients <60 years old received 40 mg, orally, Days 1 to 4 and

Days 11 to 14. Patients ≥60 years old: 20 mg, orally, Days 1 to 4 and Days 11 to 14.

* Consolidation Phase (alternating methotrexate and cytarabine): Patients received six 28-day cycles of Iclusig starting with the last induction phase dose; modified dose based on

MRD negative CR results or imatinib starting with the last induction phase dose; administeredfrom Day 1 to Day 28 of Cycles 4 to 9 of treatment regimen in combination with:o Methotrexate: Patients <60 years old received 1 000 mg/m2, IV, Day 1, 24-hour infusion.

Patients ≥60 years old received 250 mg/m2, IV, Day 1, 24-hour infusion. Rescue: folinicacid. Study Cycles 4, 6, and 8.

o Cytarabine: Patients <60 years old received 1 000 mg/m2 every 12 hours IV, Days 1, 3,and 5, 2-hour infusion. Patients ≥60 years old received 250 mg/m2 every 12 hours IV,

Days 1, 3, and 5, 2-hour infusion. Study Cycles 5, 7, and 9.

* Maintenance Phase: Patients received eleven 28-day cycles of Iclusig starting with the lastconsolidation phase dose; modified dose based on MRD negative CR results or imatinibstarting with the last consolidation phase dose; administered from Day 1 to Day 28 of

Cycles 10 to 20 of treatment regimen in combination with:o Vincristine: 1.4 mg/m2, IV, injected over 1 minute on Day 1 of each maintenance phasecycle, 1 injection/month; capped at 2 mg ando Prednisone: Patients <60 years old: 200 mg/d, orally, on Days 1 to 5. Patients ≥60 to69 years old: 100 mg/d, orally, on Days 1 to 5. Patients ≥70 years old: 50 mg/d, orally, on

Days 1 to 5.

Following 20 cycles of Iclusig or imatinib in combination with the chemotherapy, patients continuedto receive Iclusig (21%) or imatinib (9%) as single-agent therapy until relapse from completeremission (CR), progressive disease (PD), proceeded to HSCT, proceeded to alternative therapy, orunacceptable toxicity. Baseline demographic characteristics of the randomized population aredescribed in Table 20.

Table 20 Demographic and disease characteristics for PhALLCON

Iclusig Imatinib

Patient characteristics at entry 30 mg → 15 mg 600 mgwith chemotherapy with chemotherapy(N = 164) (N = 81)

Age (years)

Median, years (range) 54 (19 to 82) 52 (19 to 75)

Age Category(a), n (%)18 to <45 years 58 (35%) 29 (36%)45 to <60 years 45 (27%) 22 (27%)≥60 years 61 (37%) 30 (37%)

Sex, n (%)

Female 90 (55%) 43 (53%)

Race, n (%)

White 104 (63%) 62 (77%)

Not reported 28 (17%) 2 (3%)

Asian 20 (12%) 11 (14%)

Black or African American 9 (5%) 4 (5%)

ECOG Performance Status, n (%)0 72 (44%) 33 (41%)1 85 (52%) 43 (53%)2 7 (4%) 5 (6%)

Disease History

Presence of BCR-ABL1 dominant variants ofp190 or p210, n (%) 154 (94%) 78 (96%)

Without extramedullary disease, n (%) 154 (94%) 78 (96%)

Median, white blood cell count(b) (range) 4.37 (0.4 to 197) 3.21 (0.2 to 81)

Median, bone marrow leukemic blasts (%) 80% 75%

Comorbidities, n (%)

Hypertension 58 (35%) 30 (37%)

Diabetes 39 (24%) 24 (30%)

Dyslipidemia 29 (18%) 23 (28%)(a) Randomization was stratified by age (18 through <45 years; ≥45 through <60 years; and ≥60 years)(b) White blood cell count based on 10^9/L

The major efficacy outcome measure was MRD negative CR at the end of induction. MRD negativitywas defined as ≤0.01% BCR-ABL1 as determined by central laboratory tests. CR status was definedas having <5% blasts in the bone marrow and no extramedullary disease with hematologic recoveryfor at least 4 weeks as assessed by the investigator.

The patient population for analysis of MRD negative CR and molecular response included232 randomized patients who had a baseline BCR-ABL1 dominant variant of p190 or p210 asdetermined by central laboratory tests (154 patients in the Iclusig arm and 78 in the imatinib arm).

The key secondary efficacy outcome measure of event-free survival (EFS) was defined as the timefrom randomization to the first occurrence of any of the following events: failure to achieve CR by theend of induction, relapse from CR, or death due to any cause. The patient population for EFS wasbased on 245 randomized patients in the ITT population with 164 randomized patients in the

Iclusig arm (including 1 patient who died due to COVID before receiving the first dose) and81 randomized patients in the imatinib arm, unless otherwise specified.

The overall rate of HSCT was 34% (56/164) in the Iclusig arm versus 48% (39/81) in theimatinib arm.

The median duration of follow-up for overall survival was 20.43 months (95% CI: 18.39, 23.93) in the

Iclusig arm and 18.14 months (95% CI: 13.86, 24.25) in the imatinib arm.

The study demonstrated a statistically significant higher MRD negative CR rate at the end of inductionfor patients randomized to the Iclusig arm compared to the imatinib arm.

At the data cutoff point, the results for the key secondary efficacy outcome measure of EFS were notmature, with 33.5% of the required events for final analysis (34/164 events in the Iclusig arm and24/81 events in the imatinib arm).

Efficacy results are summarized in Table 21.

Table 21 Efficacy results in patients with Ph+ ALL in PhALLCON(a)

Iclusig Imatinib30 mg → 15 mg 600 mgwith with chemotherapychemotherapy (N = 78)(N = 154)

MRD-negative CR(b) at End of Induction

Achieved at the end of induction % (n/N) 34.4% (53/154) 16.7% (13/78)

Risk difference (95% CI)(c) 0.18 (0.06, 0.29)p-value(d) 0.0021

Relative risk (95% CI)(e) 2.06 (1.19, 3.56)

MRD: minimal residual disease; CR: complete response; MR: molecular response; BCR-ABL1: breakpoint clusterregion-Abelson.(a) Based on 232 randomized patients who had a BCR-ABL1 dominant variant of p190 or p210 as determined bycentral laboratory tests at baseline.(b) MRD-negative CR rate is defined as the proportion of patients who achieved MRD-negative CR (≤0.01%

BCR-ABL1/ABL1 or undetectable BCR-ABL1 transcripts in cDNA with ≥10,000 ABL1 transcripts, and meetingcriteria for CR).(c) Difference and 95% CI: adjusted risk ICLUSIG - adjusted risk imatinib, and its 95% CI.(d) p-value is based on Cochran-Mantel-Haenszel (CMH) chi-square test, with stratification according torandomization strata (age): 18 through <45 years, ≥45 through <60 years, and ≥60 years(e) Adjusted Relative Risk and its 95% CI based on CMH method as defined in Footnote [d].

Paediatric population

CP-CML

A phase◦1/2 open-label, single-arm study (Study 102) in paediatric population has evaluated thetolerability, safety, PK/pharmacodynamics, and efficacy of oral ponatinib in 61 paediatric participants(≥◦1 to <◦18◦years old) with recurrent or refractory leukemias, lymphomas, or solid tumors, with a CP-

CML expansion cohort.

A total of 10 patients from 6 to <18 years of age with CP-CML who were resistant to or intolerant ofat least 1 prior BCR-ABL-targeted TKI therapy or who had the kinase domain mutation T315Ireceived ponatinib treatment.

In participants with CP-CML, the median exposure to ponatinib was 533 days (range: 72, 1 100) andthe median average daily dose was 40.59 mg.

The primary efficacy endpoint for participants with CP-CML was MCyR by 12 months assessed byconventional cytogenetics or FISH. The secondary endpoints were CHR at 6 months, CCyR at12 months, Major molecular response (MMR) at 12 months, TTR, DoR, PFS, and OS.

All participants (100%) with CP-CML had received prior BCR-ABL TKI treatment.

In those participants, Major Cytogenetic Response Rate (MCyR) by 12 months was 90.0%. The

Complete hematologic response (CHR) at 6 months was 90%. the median time to CyR was 1 monthand to MR 2.83 months. The clinical efficacy and safety profile of ponatinib in the paediatric CP-CMLpopulation was consistent with the profile observed in the adult CP-CML population.

Ph+ALL

A phase 1/2, single-arm, open-label, multicenter study (Study 1501) in 11 paediatric participants aged9-17 years has evaluated the safety, tolerability, PK, and efficacy of ponatinib when administered incombination with multiagent chemotherapy, for the treatment of Ph+ ALL in children with Ph+ ALL,

Ph+ MPAL, or Ph-like ALL disease that had relapsed or was resistant or intolerant to at least 1 prior

BCR-ABL TKI-containing therapy, or with Ph+ ALL disease with T315I mutation.

The study in paediatric participants with R/R Ph+ ALL treated with ponatinib in combination with anintensive, 4-agent induction chemotherapy regimen (PEG-asparaginase, daunorubicin, dexamethasone,and vincristine) demonstrated that the combination of ponatinib once a day with an intensive, 4-agentchemotherapy regimen is not tolerated in those patients.

5.2 Pharmacokinetic properties

Absorption

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-∞.

Distribution

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.

Biotransformation

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.

Elimination

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.

Renal impairment

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).

Hepatic impairment

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.

Paediatric population

Following administration of ponatinib in 61 paediatric patients using a weight-based approach oncedaily, steady-state exposure of ponatinib were found to be comparable to adult patients treated with45 mg once daily. The pharmacokinetic exposure of ponatinib following multiple doses appeared to becomparable between paediatric patients from 6 years to <12 years and from ≥12 years to <18 years.

5.3 Preclinical safety data

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.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core

Lactose monohydrate

Microcrystalline cellulose

Sodium starch glycolate

Colloidal anhydrous silica

Magnesium stearate

Tablet coating

Talc

Macrogol

Poly(vinyl alcohol)

Titanium dioxide (E171)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

4 years.

6.4 Special precautions for storage

Store in the original container in order to protect from moisture.The bottle contains one sealed canistercontaining a molecular sieve desiccant. Keep the canister in the bottle.

6.5 Nature and contents of container

Iclusig 15 mg film-coated tablets

High density polyethylene (HDPE) bottles with screw-top closures, containing either 30, 60 or180 film-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.

6.6 Special precautions for disposal and other handling

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

7. MARKETING AUTHORISATION HOLDER

Incyte Biosciences Distribution B.V.

Paasheuvelweg 251105 BP Amsterdam

Netherlands

8. MARKETING AUTHORISATION NUMBER(S)

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

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 1 July 2013

Date of latest renewal: 8 February 2018

10. DATE OF REVISION OF THE TEXT

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

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

Back to contents

General data about ICLUSIG 30mg

Marketing authorisation

Concentrations available for ponatinib

Other substances similar to ponatinib

Official documents

Precautions:

Fertility warning

Cytotoxic / special handling

Contraception required

Contraindicated during breastfeeding

Contraindicated during pregnancy

Avoid grapefruit

Hepatotoxicity

Major drug interactions

Myelosuppression / agranulocytosis

Additional monitoring

Requires periodic laboratory tests

Severe skin reactions

Cardiac risk / QT prolongation / arrhythmias

Contents of the package leaflet for the medicine ICLUSIG 30mg film-coated tablets

1. NAME OF THE MEDICINAL PRODUCT

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

3. PHARMACEUTICAL FORM

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

4.2 Posology and method of administration

4.3 Contraindications

4.4 Special warnings and precautions for use

4.5 Interaction with other medicinal products and other forms of interaction

4.6 Fertility, pregnancy and lactation

4.7 Effects on ability to drive and use machines

4.8 Undesirable effects

4.9 Overdose

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

5.2 Pharmacokinetic properties

5.3 Preclinical safety data

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

6.2 Incompatibilities

6.3 Shelf life

6.4 Special precautions for storage

6.5 Nature and contents of container

6.6 Special precautions for disposal and other handling

7. MARKETING AUTHORISATION HOLDER

8. MARKETING AUTHORISATION NUMBER(S)

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

10. DATE OF REVISION OF THE TEXT