Iclusig

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 



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This medicinal product is subject to additional monitoring. This will allow quick identification of 
new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 
See section 4.8 for how to report adverse reactions. 
 
 
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" debossed 
on 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. 
 
 



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4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Iclusig is indicated in adult patients with 
 

 chronic phase, accelerated phase, or blast phase chronic myeloid leukaemia (CML) who are 
resistant to dasatinib or nilotinib; who are intolerant to dasatinib or nilotinib and for whom 
subsequent treatment with imatinib is not clinically appropriate; or who have the T315I 
mutation 

 Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph+ ALL) who are resistant 
to dasatinib; who are intolerant to dasatinib and for whom subsequent treatment with imatinib is 
not clinically appropriate; or who have the T315I mutation. 

 
See sections 4.2 for the assessment of cardiovascular status prior to start of therapy and 4.4 for 
situations 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 with 
leukaemia. Haematologic support such as platelet transfusion and haematopoietic growth factors can 
be used during treatment if clinically indicated. 
 
Before starting treatment with ponatinib, the cardiovascular status of the patient should be assessed, 
including history and physical examination, and cardiovascular risk factors should be actively 
managed. Cardiovascular status should continue to be monitored and medical and supportive therapy 
for conditions that contribute to cardiovascular risk should be optimised during treatment with 
ponatinib. 
 
Posology 
The recommended starting dose is 45 mg of ponatinib once daily. For the standard dose of 45 mg once 
daily, a 45 mg film-coated tablet is available. Treatment should be continued as long as the patient 
does not show evidence of disease progression or unacceptable toxicity. 
 
Patients should be monitored for response according to standard clinical guidelines.  
 
Discontinuing ponatinib should be considered if a complete haematologic response has not occurred 
by 3 months (90 days). 
 
The risk of arterial occlusive events is likely to be dose-related. Reducing the dose of Iclusig to 15 mg 
should be considered for CP-CML patients who have achieved a major cytogenetic response taking the 
following factors into account in the individual patient assessment: cardiovascular risk, side effects of 
ponatinib therapy, time to cytogenetic response, and BCR-ABL transcript levels (see sections 4.4 and 
5.1). If dose reduction is undertaken, close monitoring of response is recommended. 
 
Management of toxicities 
 
Dose modifications or interruption of dosing should be considered for the management of 
haematological and non-haematological toxicities. In the case of severe adverse reactions, treatment 
should be withheld. 
 
For patients whose adverse reactions are resolved or attenuated in severity, Iclusig may be restarted 
and escalation of the dose back to the daily dose used prior to the adverse reaction may be considered, 
if clinically appropriate. 
 
For a dose of 30 mg or 15 mg once daily, 15 mg and 30 mg film-coated tablets are available. 
 



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Myelosuppression 

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

ANC* < 1.0 x 109/L 
or 
platelet < 50 x 109/L 

First occurrence:  
 Iclusig should be withheld and resumed at the same dose after 

recovery to ANC ≥ 1.5 x 109/L and platelet ≥ 75 x 109/L 
Recurrence at 45 mg:  
 Iclusig should be withheld and resumed at 30 mg after 

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

Recurrence at 30 mg:  
 Iclusig should be withheld and resumed at 15 mg 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, Iclusig 
should 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 be 
temporarily interrupted if hypertension is not medically controlled. 
 
Pancreatitis 

Recommended modifications for pancreatic adverse reactions are summarized in Table 2. 
 
Table 2 Dose modifications for pancreatitis and elevation of lipase/amylase 
Grade 2 pancreatitis and/or 
asymptomatic elevation of 
lipase/amylase 

Iclusig should be continued at the same dose 

Grade 3 or 4 asymptomatic 
elevation of lipase/amylase 
(> 2.0 x IULN*) only 

Occurrence at 45 mg: 
 Iclusig should be withheld and resumed at 30 mg after 

recovery to ≤ Grade 1 (< 1.5 x IULN)  
Occurrence at 30 mg:  
 Iclusig should be withheld and resumed at 15 mg after 

recovery to ≤ Grade 1 (< 1.5 x IULN) 
Occurrence at 15 mg: 
 Iclusig discontinuation should be considered 

Grade 3 pancreatitis  

Occurrence at 45 mg: 
 Iclusig should be withheld and resumed at 30 mg after 

recovery to < Grade 2 
Occurrence at 30 mg: 
 Iclusig should be withheld and resumed at 15 mg after 

recovery to < Grade 2 
Occurrence at 15 mg: 
 Iclusig discontinuation should be considered 

Grade 4 pancreatitis Iclusig should be discontinued 
*IULN = institution upper limit of normal 
 
Hepatic toxicity 

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



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Table 3 Recommended dose modifications for hepatic toxicity 
Elevation of liver transaminase 
> 3 × ULN* 
 
Persistent grade 2 (longer 
than 7 days) 
 
Grade 3 or higher 

Occurrence at 45 mg: 
 Iclusig should be interrupted and hepatic function 

should be monitored 
 Iclusig should be resumed at 30 mg after recovery to 

≤ Grade 1 (< 3 × ULN), or recovery  to pre-treatment 
grade 

Occurrence at 30 mg: 
 Iclusig should be interrupted and resumed at 15 mg 

after recovery to ≤ Grade 1, or recovery to pre-
treatment grade 

Occurrence at 15 mg: 
 Iclusig should be discontinued 

Elevation of AST or ALT ≥ 3 × ULN 
concurrent with an elevation of 
bilirubin > 2 × ULN and alkaline 
phosphatase < 2 × ULN 

Iclusig should be discontinued 

*ULN = Upper Limit of Normal for the lab 
 

Elderly patients 

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

Patients with hepatic impairment may receive the recommended starting dose. Caution is 
recommended when administering Iclusig to patients with hepatic impairment (see sections 4.4 and 
5.2). 
 
Renal impairment 

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

The safety and efficacy of Iclusig in patients less than 18 years of age have not been established. No 
data are available. 
 
Method of administration 
Iclusig is for oral use. The tablets should be swallowed whole. Patients should not crush or dissolve 
the tablets. Iclusig may be taken with or without food. 
 
Patients should be advised not to swallow the desiccant canister found in the bottle. 
 
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 with grade 3 or 
4 platelet count decreased, anaemia or neutropenia, developed it within the first 3 months of treatment. 
The frequency of these events is greater in patients with accelerated phase CML (AP-CML) or blast 



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phase CML (BP-CML)/Ph+ ALL than in chronic phase CML (CP-CML). A complete blood count 
should be performed every 2 weeks for the first 3 months and then monthly or as clinically indicated. 
Myelosuppression was generally reversible and usually managed by withholding Iclusig temporarily 
or reducing the dose (see section 4.2). 
 
Arterial occlusion 

Arterial occlusions, including fatal myocardial infarction, stroke, retinal arterial occlusions associated 
in some cases with permanent visual impairment or vision loss, stenosis of large arterial vessels of the 
brain, severe peripheral vascular disease, renal artery stenosis (associated with worsening, labile or 
treatment-resistant hypertension), and the need for urgent revascularization procedures have occurred 
in Iclusig-treated patients. Patients with and without cardiovascular risk factors, including patients age 
50 years or younger, experienced these events. Arterial occlusion adverse events were more frequent 
with increasing age and in patients with history of ischaemia, hypertension, diabetes, or 
hyperlipidaemia.  
 
The risk of arterial occlusive events is likely to be dose-related (see sections 4.2 and 5.1). 
 
In the phase 2 trial (with a minimum of 64 months follow-up), arterial occlusive adverse reactions 
have occurred in 25% of patients (treatment-emergent frequencies). Some patients experienced more 
than 1 type of event. Arterial cardiovascular, cerebrovascular, and peripheral vascular occlusive 
adverse reactions (treatment-emergent frequencies) occurred in 13%, 9%, and 11% of Iclusig-treated 
patients, respectively.  
 
In the phase 2 trial, serious arterial occlusive adverse reactions occurred in 20% of patients 
(treatment-emergent frequencies). Serious arterial cardiovascular, cerebrovascular, and peripheral 
vascular occlusive adverse reactions (treatment-emergent frequencies) occurred in 10%, 7%, and 9% 
of Iclusig treated patients, respectively (see section 4.8). 
 
The median time to onset of the first cardiovascular, cerebrovascular, and peripheral vascular arterial 
occlusive events was 351, 611, and 605 days, respectively. 
 
Iclusig should not be used in patients with a history of myocardial infarction, prior revascularization or 
stroke, unless the potential benefit of treatment outweighs the potential risk (see sections 4.2 and 4.8). 
In these patients, alternative treatment options should also be considered before starting treatment with 
ponatinib. 
 
Before starting treatment with ponatinib, the cardiovascular status of the patient should be assessed, 
including history and physical examination, and cardiovascular risk factors should be actively 
managed. Cardiovascular status should continue to be monitored and medical and supportive therapy 
for conditions that contribute to cardiovascular risk should be optimised during treatment with 
ponatinib. 
 
Monitoring for evidence of arterial occlusion should be performed and if decreased vision or blurred 
vision occurs, an ophthalmic examination (including fundoscopy) should be performed. Iclusig should 
be interrupted immediately in case of arterial occlusion. A benefit -risk consideration should guide a 
decision to restart Iclusig therapy (see sections 4.2 and 4.8). 
 
Venous thromboembolism  

In the phase 2 trial (with a minimum of 64 months follow-up), venous thromboembolic adverse 
reactions have occurred in 6% of patients (treatment-emergent frequencies). Serious venous 
thromboembolic adverse reactions occurred in 5% of patients (treatment-emergent frequencies) (see 
section 4.8). 
 
Monitoring for evidence of thromboembolism should be performed. Iclusig should be interrupted 
immediately in case of thromboembolism. A benefit -risk consideration should guide a decision to 
restart Iclusig therapy (see sections 4.2 and 4.8). 
 



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Retinal venous occlusions associated in some cases with permanent visual impairment or vision loss 
have occurred in Iclusig-treated patients. If decreased vision or blurred vision occurs, an ophthalmic 
examination (including fundoscopy) should be performed. 
 

Hypertension  

Hypertension may contribute to risk of arterial thrombotic events, including renal artery stenosis. 
During Iclusig treatment, blood pressure should be monitored and managed at each clinic visit and 
hypertension should be treated to normal. Iclusig treatment should be temporarily interrupted if 
hypertension is not medically controlled (see section 4.2). 
 
In the event of significant worsening, labile or treatment-resistant hypertension, treatment should be 
interrupted and evaluation for renal artery stenosis should be considered. 
 
Treatment-emergent hypertension (including hypertensive crisis) occurred in Iclusig-treated patients. 
Patients may require urgent clinical intervention for hypertension associated with confusion, headache, 
chest pain, or shortness of breath. 
 

Aneurysms and artery dissections 

The use of VEGF pathway inhibitors in patients with or without hypertension may promote the 
formation of aneurysms and/or artery dissections. Before initiating Iclusig, this risk should be 
carefully considered in patients with risk factors such as hypertension or history of aneurysm. 
 
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 or 
symptoms consistent with heart failure and they should be treated as clinically indicated, including 
interruption of Iclusig. Discontinuation of ponatinib should be considered in patients who develop 
serious heart failure (see sections 4.2 and 4.8). 
 
Pancreatitis and serum lipase 

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

Iclusig may result in elevation in ALT, AST, bilirubin, and alkaline phosphatase. Most patients who 
had an event of hepatotoxicity had their first event during the first year of treatment. Hepatic failure 
(including fatal outcome) has been observed. Liver function tests should be performed prior to 
treatment initiation and monitored periodically, as clinically indicated. 
 
Haemorrhage 

Severe haemorrhage, including fatalities, occurred in Iclusig-treated patients. The incidence of severe 
bleeding events was higher in patients with AP-CML, BP-CML and Ph+ ALL. Gastrointestinal 
haemorrhage and subdural hematoma were the most commonly reported grade 3/4 bleeding events. 
Most haemorrhagic events, but not all, occurred in patients with grade 3/4 thrombocytopenia. Iclusig 
should 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 these 
patients received BCR-ABL tyrosine kinase inhibitors. Some cases resulted in acute hepatic failure or 
fulminant hepatitis leading to liver transplantation or a fatal outcome. 
Patients should be tested for HBV infection before initiating treatment with Iclusig. Experts in liver 
disease and in the treatment of hepatitis B should be consulted before treatment is initiated in patients 



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with positive hepatitis B serology (including those with active disease) and for patients who test 
positive for HBV infection during treatment. Carriers of HBV who require treatment with Iclusig 
should be closely monitored for signs and symptoms of active HBV infection throughout therapy and 
for several months following termination of therapy (see section 4.8). 
 
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 neurological 
disturbances. 
If diagnosed, interrupt Iclusig treatment and resume treatment only once the event is resolved and if 
the benefit of continued treatment outweighs the risk of PRES. 
 
Medicinal product interactions 
Caution should be exercised with concurrent use of Iclusig and moderate and strong CYP3A inhibitors 
and moderate and strong CYP3A inducers (see section 4.5).  
 
Concomitant use of ponatinib with anti-clotting agents should be approached with caution in patients 
who may be at risk of bleeding events (see “Myelosuppression” and “Haemorrhage”). Formal studies 
of ponatinib with anti-clotting medicinal products have not been conducted. 
 
QT prolongation 
The QT interval prolongation potential of Iclusig was assessed in 39 leukaemia patients and no 
clinically significant QT prolongation was observed (see section 5.1). However, a thorough QT study 
has not been performed; therefore a clinically significant effect on QT cannot be excluded. 
 
Special populations 
 

Hepatic impairment 

Patients with hepatic impairment may receive the recommended starting dose. Caution is 
recommended when administering Iclusig to patients with hepatic impairment (see sections 4.2 and 
5.2). 
 
Renal impairment 

Caution is recommended in when administering Iclusig to patients with estimated creatinine clearance 
of < 50 mL/min or end-stage renal disease (see section 4.2). 
 
Lactose 
This medicinal product contains lactose monohydrate. Patients with rare hereditary problems of 
galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take 
this medicinal product. 
 
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 mg 
daily), a strong CYP3A inhibitor, resulted in modest increases in ponatinib systemic exposure, with 
ponatinib AUC0-∞ and Cmax values that were 78% and 47% higher, respectively, than those seen when 
ponatinib was administered alone.  
 
Caution should be exercised and a reduction of the starting dose of Iclusig to 30 mg should be 
considered with concurrent use of strong CYP3A inhibitors such as clarithromycin, indinavir, 



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itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, 
troleandomycin, voriconazole, and grapefruit juice. 
 
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), a 
strong CYP3A inducer, to 19 healthy volunteers, decreased the AUC0-∞ and Cmax of ponatinib by 62% 
and 42%, respectively, when compared to administration of ponatinib alone. 
 
Co-administration of strong CYP3A4 inducers such as carbamazepine, phenobarbital, phenytoin, 
rifabutin, rifampicin, and St. John’s Wort with ponatinib should be avoided, and alternatives to the 
CYP3A4 inducer should be sought, unless the benefit outweighs the possible risk of ponatinib 
underexposure. 
 
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 to 
increase plasma concentrations of co-administered substrates of P-gp (e.g., digoxin, dabigatran, 
colchicine, pravastatin) or BCRP (e.g., methotrexate, rosuvastatin, sulfasalazine) and may increase 
their therapeutic effect and adverse reactions. Close clinical surveillance is recommended when 
ponatinib is administered with these medicinal products.  
 
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 and 
men being treated with Iclusig should be advised not to father a child during treatment. An effective 
method of contraception should be used during treatment. It is unknown whether ponatinib affects the 
effectiveness of systemic hormonal contraceptives. An alternative or additional method of 
contraception should be used.  
 
Pregnancy 
There are no adequate data from the use of Iclusig in pregnant women. Studies in animals have shown 
reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Iclusig should be 
used during pregnancy only when clearly necessary. If it is used during pregnancy, the patient must be 
informed of the potential risk to the foetus. 
 
Breast-feeding 
It is unknown whether Iclusig is excreted in human milk. Available pharmacodynamic and 
toxicological data cannot exclude potential excretion in human milk. Breast-feeding should be stopped 
during treatment with Iclusig. 
 
Fertility 
No human data on the effect of ponatinib on fertility are available. In rats, treatment with ponatinib 
has shown effects on female fertility and male fertility was not affected (see section 5.3). The clinical 
relevance of these findings to human fertility is unknown. 
 
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 as 
lethargy, dizziness, and vision blurred have been associated with Iclusig. Therefore, caution should be 
recommended when driving or operating machines. 



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4.8 Undesirable effects 
 
Summary of the safety profile 
The adverse reactions described in this section were identified in a single-arm, open-label, 
international, multicenter trial in 449 CML and Ph+ ALL patients who were resistant or intolerant to 
prior TKI therapy including those with a BCR-ABL T315I mutation. All patients received 45 mg 
Iclusig once daily. Dose adjustments to 30 mg once daily or 15 mg once daily were allowed for the 
management of treatment toxicity. Additionally, after approximately 2 years of follow-up, all patients 
who were still taking a 45 mg daily dose were recommended to undergo a dose reduction, even in the 
absence of adverse events, in response to the continued occurrence of vascular occlusive events in the 
clinical trial. At the time of reporting, all ongoing patients had a minimum follow-up of 64 months. 
The median duration of treatment with Iclusig was 32.2 months in CP-CML patients, 19.4 months in 
AP-CML patients, and 2.9 months in BP-CML/Ph+ ALL patients. The median dose intensity was 
28 mg/day in CP-CML patients or, 63% of the expected 45 mg dose; median dose intensity was 
greater in advanced disease states (32 mg/day in the AP-CML patients and 44 mg/day in the BP 
CML/Ph+ ALL patients).  
 
The most common serious adverse reactions >2% (treatment-emergent frequencies) were pneumonia 
(7.3%), pancreatitis (5.8%), abdominal pain (4.7%), atrial fibrillation (4.5%), pyrexia (4.5%), 
myocardial infarction (4.0%), peripheral arterial occlusive disease (3.8%), anaemia (3.8%), angina 
pectoris (3.3%), platelet count decreased (3.1%), febrile neutropenia (2.9%), hypertension (2.9%), 
coronary artery disease (2.7%), cardiac failure congestive (2.4%), cerebrovascular accident (2.4%), 
sepsis (2.4%), cellulitis (2.2%), acute kidney injury (2.0%), urinary tract infection (2.0%) and lipase 
increased (2.0%). 
 
Serious arterial cardiovascular, cerebrovascular, and peripheral vascular occlusive adverse reactions 
(treatment-emergent frequencies) occurred in 10%, 7%, and 9% of Iclusig treated patients, 
respectively. Serious venous occlusive reactions (treatment-emergent frequencies) occurred in 5% of 
patients.  
 
Arterial cardiovascular, cerebrovascular, and peripheral vascular occlusive adverse reactions 
(treatment-emergent frequencies) occurred in 13%, 9%, and 11% of Iclusig-treated patients, 
respectively. Overall arterial occlusive adverse reactions have occurred in 25% of Iclusig-treated 
patients from the phase 2 trial, with serious adverse reactions occurring in 20% of patients. Some 
patients experienced more than one type of event. 
 
Venous thromboembolic reactions (treatment-emergent frequencies) occurred in 6% of patients. The 
incidence of thromboembolic events is higher in patients with Ph+ ALL or BP-CML than those with 
AP-CML or CP-CML. No venous occlusive events were fatal. 
 
After a minimum follow-up of 64 months, the rates of adverse reactions resulting in discontinuation 
were 20% in CP-CML, 11% in AP-CML, 15% in BP-CML and 9% in Ph+ ALL.  
 
Tabulated list of adverse reactions 
Adverse reactions reported in all CML and Ph+ ALL patients are presented in Table 4. Frequency 
categories are very common (≥ 1/10), common (≥ 1/100 to < 1/10) and uncommon (≥ 1/1,000 to 
< 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), and not known (cannot be estimated 
from the available data). Within each frequency grouping, undesirable effects are presented in order of 
decreasing seriousness. 
 



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Table 4 Adverse reactions observed in CML and Ph+ ALL patients – frequency reported by 
incidence of treatment emergent events 

System organ class Frequency Adverse reactions 

Infections and infestations Very common upper respiratory tract infection Common pneumonia, sepsis, folliculitis, cellulitis 

Blood and lymphatic system 
disorders 

Very common anaemia, platelet count decreased, neutrophil count decreased 

Common 
pancytopenia, febrile neutropenia, white 
blood cell count decreased, lymphocyte 
count decreased 

Endocrine disorders Common hypothyroidism 

Metabolism and nutrition 
disorders 

Very common decreased appetite 

Common 

dehydration, fluid retention, hypocalcaemia, 
hyperglycaemia, hyperuricaemia, 
hypophosphataemia, hypertriglyceridaemia, 
hypokalaemia, weight decreased, 
hyponatraemia 

Uncommon tumour lysis syndrome 
Psychiatric disorders Very common insomnia 

Nervous system disorders 

Very common headache, dizziness 

Common 

cerebrovascular accident, cerebral infarction, 
neuropathy peripheral, lethargy, migraine, 
hyperaesthesia, hypoaesthesia, paraesthesia, 
transient ischaemic attack 

Uncommon 

cerebral artery stenosis, cerebral 
haemorrhage, haemorrhage intracranial, 
posterior reversible encephalopathy 
syndrome * 

Eye disorders 
Common 

vision blurred, dry eye, periorbital oedema, 
eyelid oedema, conjunctivitis, visual 
impairment 

Uncommon retinal vein thrombosis, retinal vein occlusion, retinal artery occlusion 

Cardiac disorders 

Common 

cardiac failure, myocardial infarction, 
cardiac failure congestive, coronary artery 
disease, angina pectoris, pericardial effusion, 
atrial fibrillation, ejection fraction decreased, 
acute coronary syndrome, atrial flutter 

Uncommon 
myocardial ischemia, cardiac discomfort, 
ischemic cardiomyopathy, arteriospasm 
coronary, left ventricular dysfunction, 

Vascular disorders 

Very common hypertension 

Common 

peripheral arterial occlusive disease, 
peripheral ischaemia, peripheral artery 
stenosis, intermittent claudication, deep vein 
thrombosis, hot flush, flushing 

Uncommon 

poor peripheral circulation, splenic 
infarction, embolism venous, venous 
thrombosis, hypertensive crisis, renal artery 
stenosis 

Not known aneurysms and artery dissections 



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System organ class Frequency Adverse reactions 

Respiratory, thoracic and 
mediastinal disorders 

Very common dyspnoea, cough 

Common 
pulmonary embolism, pleural effusion, 
epistaxis, dysphonia, pulmonary 
hypertension 

Gastrointestinal disorders 

Very common abdominal pain, diarrhoea, vomiting, constipation, nausea, lipase increased 

Common 

pancreatitis, blood amylase increased, 
gastrooesophageal reflux disease, stomatitis, 
dyspepsia, abdominal distension, abdominal 
discomfort, dry mouth, gastric haemorrhage  

Hepatobiliary disorders 

Very common alanine aminotransferase increased, aspartate aminotransferase increased 

Common 
blood bilirubin increased, blood alkaline 
phosphatase increased,  
gamma-glutamyltransferase increased 

Uncommon hepatotoxicity, hepatic failure, jaundice 

Skin and subcutaneous tissue 
disorders  

Very common rash, dry skin, pruritus 

Common 

rash pruritic, exfoliative rash, erythema, 
alopecia, skin exfoliation, night sweats, 
hyperhidrosis, petechia, ecchymosis, pain of 
skin, dermatitis exfoliative, hyperkeratosis, 
skin hyperpigmentation 

Musculoskeletal and 
connective tissue disorders 

Very common bone pain, arthralgia, myalgia, pain in extremity, back pain, muscle spasms 

Common musculoskeletal pain, neck pain, musculoskeletal chest pain 
Reproductive system and 
breast disorders Common erectile dysfunction 

General disorders and 
administrative site conditions 

Very common fatigue, asthenia, oedema peripheral, pyrexia, pain 

Common chills, influenza like illness, non-cardiac chest pain, mass, face oedema 
* Spontaneous reports from post-marketing experience 
 
Description of selected adverse reactions 
 

Vascular occlusion (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 and 
without cardiovascular risk factors, including patients age 50 years or younger, experienced these 
events. Arterial occlusive adverse events were more frequent with increasing age and in patients with 
history of ischaemia, hypertension, diabetes, or hyperlipidaemia. 
 
Myelosuppression 

Myelosuppression was commonly reported in all patient populations. The frequency of Grade 3 or 4 
thrombocytopenia, neutropenia, and anaemia was higher in patients with AP-CML and BP-
CML/Ph+ ALL than in patients with CP-CML (see Table 5). Myelosuppression was reported in 
patients with normal baseline laboratory values as well as in patients with pre-existing laboratory 
abnormalities.  
 
Discontinuation due to myelosuppression was infrequent (thrombocytopenia 4%, neutropenia and 
anaemia < 1% each). 
 



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Hepatitis B reactivation  
Hepatitis B reactivation has been reported in association with BCR-ABL TKIs. Some cases resulted in 
acute hepatic failure or fulminant hepatitis leading to liver transplantation or a fatal outcome (see 
section 4.4). 
 
Severe Cutaneous Adverse Reactions (SCARs) 

Severe skin reactions (such as Stevens-Johnson Syndrome) have been reported with some BCR-ABL 
Tyrosine Kinase Inhibitors. Patients should be warned to immediately report suspected skin reactions, 
especially if associated with blistering, peeling, mucosal involvement or systemic symptoms. 
 
Table 5 Incidence of clinically relevant grade 3/4* laboratory abnormalities in ≥ 2% of 

patients in any disease group from the Phase 2 Trial (N=449): minimum follow-up of 
64 month for all ongoing patients 

Laboratory test All patients 
(N=449) 

(%) 

CP-CML  
(N=270) 

(%) 

AP-CML  
(N=85) 

(%)  

BP-CML/Ph+ 
ALL (N=94)  

(%) 
Haematology 

Thrombocytopenia (platelet count 
decreased) 

40 35 49 46 

Neutropenia (ANC decreased) 34 23 52 52 
Leukopenia (WBC decreased) 25 12 37 53 
Anaemia (Hgb decreased) 20 8 31 46 
Lymphopenia 17 10 25 28 

Biochemistry 

Lipase increased 14 14 13 14 
Phosphorus decreased 10 10 13 9 
Glucose increased 7 8 13 1 
ALT increased 6 4 8 7 
Sodium decreased 5 6 6 2 
AST increased 4 3 5 3 
Amylase increased 4 4 4 3 
Potassium decreased 2 < 1 6 2 
Potassium increased 2 2 1 3 
Alkaline phosphatase increased 2 2 4 2 
Bilirubin 1 < 1 2 1 
Calcium decreased 1 < 1 2 1 

ALT=alanine aminotransferase, ANC=absolute neutrophil count, AST=aspartate aminotransferase, 
Hgb=haemoglobin, WBC=white blood cell count.  
*Reported using National Cancer Institute Common Terminology Criteria for Adverse Events version 
4.0. 
 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
Isolated reports of unintentional overdose with Iclusig were reported in clinical trials. Single doses of 
165 mg and an estimated 540 mg in two patients did not result in any clinically significant adverse 
reactions. Multiple doses of 90 mg per day for 12 days in a patient resulted in pneumonia, systemic 
inflammatory response, atrial fibrillation, and asymptomatic, moderate pericardial effusion. Treatment 
was interrupted, the events resolved, and Iclusig was restarted at 45 mg, once daily. In the event of an 
overdose of Iclusig, the patient should be observed and appropriate supportive treatment given. 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


14 

 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: antineoplastic agents, protein kinase inhibitors, ATC code: L01XE24 
 
Ponatinib is a potent pan BCR-ABL inhibitor with structural elements, including a carbon-carbon 
triple-bond, that enable high affinity binding to native BCR-ABL and mutant forms of the ABL 
kinase. Ponatinib inhibits the tyrosine kinase activity of ABL and T315I mutant ABL with IC50 values 
of 0.4 and 2.0 nM, respectively. In cellular assays, ponatinib was able to overcome imatinib, dasatinib, 
and nilotinib resistance mediated by BCR-ABL kinase domain mutations. In preclinical mutagenesis 
studies, 40 nM was determined as the concentration of ponatinib sufficient to inhibit viability of cells 
expressing all tested BCR-ABL mutants by > 50% (including T315I) and suppress the emergence of 
mutant clones. In a cell-based accelerated mutagenesis assay, no mutation in BCR-ABL was detected 
that could confer resistance to 40 nM ponatinib.  
Ponatinib elicited tumour shrinkage and prolonged survival in mice bearing tumours expressing native 
or T315I mutant BCR-ABL.  
At doses of 30 mg or greater plasma steady state trough concentrations of ponatinib typically exceed 
21 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 peripheral 
blood mononuclear cells.  
Ponatinib inhibits the activity of other clinically relevant kinases with IC50 values below 20 nM and 
has demonstrated cellular activity against RET, FLT3, and KIT and members of the FGFR, PDGFR, 
and VEGFR families of kinases.  
 
Clinical efficacy and safety 
The safety and efficacy of Iclusig in CML and Ph+ ALL patients who were resistant or intolerant to 
prior 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 of 
dose de-escalations and dose interruptions followed by dose resumption and re-escalation. Patients 
were 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. The trial is ongoing. 
 
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 (by 
12 months) while on dasatinib or nilotinib. CP-CML patients who experienced a loss of response or 
development of a kinase domain mutation in the absence of a complete cytogenetic response or 
progression to AP-CML or BP-CML at any time on dasatinib or nilotinib were also considered 
resistant. Resistance in AP-CML and BP-CML/Ph+ ALL was defined as failure to achieve either a 
major haematological response (AP-CML by 3 months, BP-CML/Ph+ ALL by 1 month), loss of major 
haematological response (at any time), or development of kinase domain mutation in the absence of a 
major haematological response while on dasatinib or nilotinib.  
 
Intolerance was defined as the discontinuation of dasatinib or nilotinib due to toxicities despite optimal 
management in the absence of a complete cytogenetic response for CP CML patients or major 
haematological response for AP CML, BP CML, or Ph+ ALL patients. 
 
The primary efficacy endpoint in CP-CML was major cytogenetic response (MCyR), which included 
complete and partial cytogenetic responses (CCyR and PCyR). The secondary efficacy endpoints 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 haematological 
response (MaHR), defined as either a complete haematological response (CHR) or no evidence of 
leukaemia (NEL). The secondary efficacy endpoints in AP-CML and BP-CML/Ph+ ALL were MCyR 
and MMR. 



15 

 
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 assess 
the relationship of shorter-term cytogenetic (MCyR) and molecular (MMR) response outcomes with 
longer-term outcomes of PFS and OS, maintenance of response (MCyR and MMR) after dose 
reductions, 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 dasatinib or 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+ALL patients, respectively. 
Baseline demographic characteristics are described in Table 6 below. 
 
Table 6 Demographics and disease characteristics 

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%) 
  BCR-ABL mutation detected at entry, n (%)b  
     None 198 (44%) 
     1 192 (43%) 
     ≥ 2 54 (12%) 
a* of 427 patients reporting prior TKI therapy with dasatinib or nilotinib 
b Of the patients with one or more BCR-ABL kinase domain mutations detected at entry, 37 unique 
mutations were  detected. 
 
Overall, 55% of patients had one or more BCR-ABL kinase domain mutation at entry with the most 
frequent being: T315I (29%), F317L (8%), E255K (4%) and E359V (4%). In 67% of CP-CML 
patients in the R/I cohort, no mutations were detected at study entry. 
 
Efficacy results are summarized in Table 7, Table 8, and Table 9. 
 



16 

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

(N=267) 
Resistant or Intolerant 

R/I  
Cohort 
(N=203) 

T315I 
Cohort 
(N=64) 

Cytogenetic Response     
  Major (MCyR) a  
  %  
  (95% CI) 

 
55% 

(49-62) 

 
51% 

(44-58) 

 
70% 

(58-81) 
     Complete (CCyR)  
     % 
     (95% CI) 

 
46% 

(40-52) 

 
40% 

(33-47) 

 
66% 

(53-77) 
Major Molecular Response b 
%  
(95% CI) 

 
40% 

(35-47) 

 
35% 

(28-42) 

 
58% 

(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), 
in peripheral 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, and 
molecular 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. 
 
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 was 
achieved following treatment with Iclusig. 
 
In CP-CML patients who achieved MCyR, the median time to MCyR was 2.8 months (range: 1.6 to 
11.3 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 patients 
of 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 and 
61% (95% CI: [51%- 70%]) of CP-CML patients who achieved a MMR are projected to maintain that 
response at 36 months. The probability of all patients with CP CML maintaining MCyR and MMR did 
not 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 experienced 
transformation 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-CML disease 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. 
 



17 

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 had 
statistically significantly improved progression-free (PFS) and overall survival (OS) compared to 
those patients who did not meet the treatment milestones. A MCyR at the 3-month landmark 
correlated 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 at 
the 12-month landmark (p=<0.0001 and p=0.0012, respectively). 
 



18 

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

Overall 
(N=83) 

Resistant or 
Intolerant 

Overall 
(N=62) 

Resistant or 
Intolerant 

R/I 
Cohort 
(N=65) 

T315I 
Cohort 
(N=18) 

R/I 
Cohort 
(N=38) 

T315I 
Cohort 
(N=24) 

Haematological Response 
Rate       

Majora (MaHR)  
% 
(95% CI) 

57% 
(45-68) 

57% 
(44-69) 

56% 
(31-79) 

31% 
(20–44) 

32% 
(18–49) 

29% 
(13–51) 

Completeb (CHR) 
%  
(95% CI) 

51% 
(39-62) 

 
49% 

(37-62) 
56% 

(31-79) 
21% 

(12-33) 
24% 

(11-40) 
17% 

(5-37) 
Major Cytogenetic Responsec  
%  
(95% CI) 

39% 
(28-50) 

34% 
(23-47) 

56% 
(31-79) 

23% 
(13-35) 

18% 
(8-34) 

29% 
(13-51) 

a Primary endpoint for AP-CML and BP-CML/Ph+ ALL Cohorts was MaHR, which combines 
complete haematological responses and no evidence of leukaemia.  
b CHR: WBC ≤ institutional ULN, ANC ≥ 1,000/mm3, platelets ≥ 100,000/mm3, no blasts or 
promyelocytes in peripheral blood, bone marrow blasts ≤ 5%, < 5% myelocytes plus metamyelocytes 
in peripheral blood, basophils < 5% in peripheral blood, No extramedullary involvement (including no 
hepatomegaly or splenomegaly).  
c MCyR combines both complete (No detectable Ph+ cells) and partial (1% to 35% Ph+ cells) 
cytogenetic responses. 
Database cutoff date 06 February 2017 
 
Table 9 Efficacy of Iclusig in resistant or intolerant Ph+ ALL patients 

 Overall 
(N=32) 

Resistant or Intolerant 
R/I 

Cohort 
(N=10) 

T315I 
Cohort 
(N=22) 

Haematological Response 
Rate    

Majora (MaHR)  
% 
(95% CI) 

41% 
(24-59) 

50% 
(19-81) 

36% 
(17-59) 

Completeb (CHR) 
%  
(95% CI) 

34% 
(19-53) 

 
40% 

(12-74) 
32% 

(14-55) 
Major Cytogenetic Responsec  
%  
(95% CI) 

47% 
(29-65) 

60% 
(26-88) 

41% 
(21-64) 

a Primary endpoint for AP-CML and BP-CML/Ph+ ALL Cohorts was MaHR, which combines 
complete haematological responses and no evidence of leukaemia.  
b CHR: WBC ≤ institutional ULN, ANC ≥ 1,000/mm3, platelets ≥ 100,000/mm3, no blasts or 
promyelocytes in peripheral blood, bone marrow blasts ≤ 5%, < 5% myelocytes plus metamyelocytes 
in peripheral blood, basophils < 5% in peripheral blood, No extramedullary involvement (including no 
hepatomegaly or splenomegaly).  
c MCyR combines both complete (No detectable Ph+ cells) and partial (1% to 35% Ph+ cells) 
cytogenetic responses. 
Database cutoff date 06 February 2017 
 
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), 



19 

respectively. At the time of updated reporting with minimum follow-up for all ongoing patients of 
64  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 phase 2 trial, the dose intensity-safety relationship indicated that there are 
significant 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 phase 2 trial concluded that after adjusting 
for covariates, the overall dose intensity is significantly associated with an increased risk of vascular 
occlusion, with an odds ratio of approximately 1.6 for each 15 mg increase. In addition, results from 
logistic regression analyses of data from patients in the phase 1 trial, suggest a relationship between 
systemic exposure (AUC) and occurrence of arterial thrombotic events. A reduction in dose is 
therefore expected to reduce the risk of vascular occlusive events, however, the analysis suggested that 
there may be a ‘carry over’ effect of higher doses such that it might take up to several months before a 
dose reduction manifests in risk reduction. Other covariates that show a statistically significant 
association with the occurrence of vascular occlusive events in this analysis are medical history of 
ischemia and age. 
 
Dose reduction in CP-CML patients 
 
In the phase 2 trial, dose reductions were recommended following adverse events; in addition in 
October 2013 new recommendations for prospective dose reduction in all CP-CML patients in the 
absence of adverse events 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 for 
prospective dose reduction, there were 110 CP-CML patients ongoing. A majority of these ongoing 
patients (82/110 patients; 75%) were reported to be receiving 15 mg at the last dose, while 
24/110 patients (22%) were receiving 30 mg, and 4/110 (4%) were receiving 45 mg. At the time of 
study closure initiation (minimum follow-up of 64 months, and more than 3 years after the 
recommendation for prospective dose reduction), 99 CP-CML patients were ongoing and 77 (78%) of 
these patients received 15 mg as their last dose on study. 
 
Safety 

In the phase 2 trial, 86 CP-CML patients achieved MCyR at a dose of 45 mg, 45 CP-CML patients 
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 the 
dose at which the patient achieved MCyR; fewer events occurred after dose reduction. 
 
Table 10 Vascular occlusive first adverse events in CP-CML patients who achieved MCyR at 

45 mg or 30 mg (data extraction 7 April 2014) 
 Most recent dose at onset of first vascular occlusive Event 

45 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 arterial 
occlusive events was 351, 611, and 605 days, respectively.  When adjusted for exposure, the incidence 
of first arterial occlusive events was greatest in the first two years of follow-up and declined with 
decreasing daily dose intensity (following recommendation for prospective dose reduction). Factors 
other than dose may also contribute to this risk of arterial occlusion. 
 



20 

Efficacy 

Data from the phase 2 trial are available on the maintenance of response (MCyR and MMR) in all CP-
CML patients who underwent dose reduction for any reason. Table 11 shows these data for patients 
who achieved MCyR and MMR at 45 mg; similar data are available for patients who achieved MCyR 
and MMR at 30 mg.  
The majority of patients who underwent dose reduction maintained response (MCyR and MMR) for 
the duration of currently available follow-up. A proportion of patients did not undergo any dose 
reduction, based on an individual benefit-risk assessment. 
 
Table 11 Maintenance of response in CP-CML patients who achieved MCyR or MMR at 

45 mg dose (data extraction 6 February 2017) 
 Achieved MCyR  

at 45 mg (N=86) 
Achieved MMR 
at 45 mg (N=63) 

 Number of 
patients 

Maintained 
MCyR 

Number of 
patients 

Maintained 
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 at 30 mg 7 6 (86%) 2 2 (100%) 
 ≥ 24 month reduction at 30 mg 6 6 (100%) 2 2 (100%) 
 ≥ 36 month reduction at 30 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 at 
15 mg 38 38 (100%) 29 29 (100%) 

≥ 24 month reduction at 15 mg 32 32 (100%) 23 23 (100%) 
≥ 36 month reduction at 15 mg 8 8 (100%) 4 4 (100%) 

 
The anti-leukaemic activity of Iclusig was also evaluated in a phase 1 dose escalation study that 
included 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 to 
91.4 months). At the time of reporting, 25 CP-CML patients were in MCyR (median duration of 
MCyR had not been reached). 
 
Cardiac electrophysiology 
The QT interval prolongation potential of Iclusig was assessed in 39 leukaemia patients who received 
30 mg, 45 mg, or 60 mg Iclusig once daily. Serial ECGs in triplicate were collected at baseline and at 
steady state to evaluate the effect of ponatinib on QT intervals. No clinically significant 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, with an estimated 
QTcF mean change of –6.4 ms (upper confidence interval –0.9 ms) at Cmax for the 60 mg group.  
 
Paediatric population 
The European Medicines Agency has waived the obligation to submit the results of studies with 
Iclusig in children from birth to less than 1 year in CML and Ph+ ALL. The European Medicines 
Agency has deferred the obligation to submit the results of studies with Iclusig in paediatric patients 
from 1 year to less than 18 years in CML and Ph+ ALL (see section 4.2 for information on paediatric 
use). 
 



21 

5.2 Pharmacokinetic properties 
 
Absorption 
Peak concentrations of ponatinib are observed approximately 4 hours after oral administration. Within 
the range of clinically relevant doses evaluated in patients (15 mg to 60 mg), ponatinib exhibited dose 
proportional 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%) and 
1296 ng•hr/mL (48%), respectively. Following either a high-fat and low-fat meal, plasma ponatinib 
exposures (Cmax and AUC) were not different versus fasting conditions. Iclusig may be administered 
with or without food. Co-administration of Iclusig with a potent inhibitor of gastric acid secretion 
resulted 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 is 
0.96. 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 state 
volume of distribution is 1101 L (94%) suggesting that ponatinib is extensively distributed in the 
extravascular space. In vitro studies suggested that ponatinib is either not a substrate or is a weak 
substrate for both P-gp and breast cancer resistance protein BCRP. Ponatinib is not a substrate for the 
human organic anion transporting polypeptides OATP1B1, OATP1B3 and the organic cation 
transporter OCT-1. 
 
Biotransformation 
Ponatinib is metabolized to an inactive carboxylic acid by esterases and/or amidases, and metabolized 
by CYP3A4 to an N-desmethyl metabolite that is 4 times less active than ponatinib. The carboxylic 
acid 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 of  
ponatinib-mediated inhibition of substrates for these transporters. In vitro studies indicate that clinical 
medicinal product interactions are unlikely to occur as a result of ponatinib-mediated inhibition of the 
metabolism 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 also 
unlikely 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 ponatinib 
was 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-fold 
between first dose and steady state conditions. Although plasma ponatinib exposures increased to 
steady-state levels with continuous dosing, a population pharmacokinetic analysis predicts a limited 
increase in apparent oral clearance within the first two weeks of continuous dosing, which is not 
considered clinically relevant. Ponatinib is mainly eliminated via faeces. Following a single oral dose 
of [14C]-labeled ponatinib, approximately 87% of the radioactive dose is recovered in the faeces and 
approximately 5% in the urine. Unchanged ponatinib accounted for 24% and < 1% of the administered 
dose 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 major 
route of ponatinib elimination, the potential for moderate or severe renal impairment to affect hepatic 
elimination has not been determined (see section 4.2). 
 



22 

Hepatic impairment  
A single dose of 30 mg ponatinib was administered to patients with mild, moderate, or severe hepatic 
impairment and to healthy volunteers with normal hepatic function. Ponatinib Cmax was comparable in 
patients with mild hepatic impairment and healthy volunteers with normal hepatic function. In patients 
with moderate or severe hepatic impairment, ponatinib Cmax and AUC0-∞ were lower and ponatinib 
plasma elimination half-life was longer in patients with mild, moderate, and severe hepatic impairment 
but 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 subjects 
and hepatically impaired (mild, moderate and severe) subjects. Compared to healthy volunteers with 
normal liver function, no major differences in ponatinib PK were observed in patients with varying 
degrees of hepatic impairment. A reduction of the starting dose of Iclusig in patients with hepatic 
impairment is not necessary (see sections 4.2 and 4.4). 
 
Caution is recommended when administering Iclusig to patients with hepatic impairment (see sections 
4.2 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 weight 
on ponatinib pharmacokinetics. An integrated population pharmacokinetic analysis completed for 
ponatinib 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 pharmacokinetic 
intersubject variability. 
 
5.3 Preclinical safety data 
 
Iclusig has been evaluated in safety pharmacology, repeat-dose toxicity, genotoxicity, reproductive 
toxicity, phototoxicity and carcinogenicity studies. 
 
Ponatinib did not exhibit genotoxic properties when evaluated in the standard in vitro and in vivo 
systems. 
 
Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to 
clinical 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 cynomolgus 
monkeys. 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 toxicity 
studies in rats. 
 
In rats, inflammatory changes accompanied by increases in neutrophils, monocytes, eosinophils, and 
fibrinogen 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 in 
cynomolgus 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 in 
the lenticular epithelium suggestive of a mild phototoxic reaction were observed in animals treated 
with 5 and 10 mg/kg ponatinib.  
 
In cynomolgus monkeys, systolic heart murmurs with no macroscopic or microscopic correlates were 
noted in individual animals treated with 5 and 45 mg/kg in the single dose toxicity study and at 1, 2.5 



23 

and 5 mg/kg in the 4-week repeat-dose toxicity study. The clinical relevance of this finding is 
unknown.  
 
In cynomolgus monkeys, thyroid gland follicular atrophy mostly accompanied by a reduction in T3 
levels and a tendency toward increased TSH levels were observed in the 4-week repeat-dose toxicity 
study in cynomolgus monkeys.  
 
Ponatinib-related microscopic findings in the ovaries (increased follicular atresia) and testes (minimal 
germ cell degeneration) in animals treated with 5 mg/kg ponatinib were noted in repeat-dose toxicity 
studies in cynomolgus monkeys. 
 
Ponatinib at doses of 3, 10, and 30 mg/kg produced increases in urine output and electrolyte excretions 
and 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, and 
multiple soft tissue and skeletal alterations were observed at maternal toxic dosages. Multiple foetal 
soft 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 levels 
corresponding to human clinical exposures. Evidence for pre- and post-implantation loss of embryos 
was reported in female rats and ponatinib may therefore impair female fertility. There were no effects 
on male rat fertility parameters. The clinical relevance of these findings on human fertility is 
unknown. 
 
In juvenile rats, mortality related to inflammatory effects was observed in animals treated with 
3 mg/kg/day, and reductions in body weight gain were observed at doses of 0.75, 1.5 and 3 mg/kg/day 
during the pre-weaning and early post-weaning treatment phases. Ponatinib did not adversely affect 
important 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 any 
tumorigenic effects. The 0.8 mg/kg/day dose in females resulted in a plasma exposure level generally 
lower or equivalent to the human exposure at the range of dose from 15 mg to 45 mg daily. A 
statistically significant increased incidence of squamous cell carcinoma of the clitoral gland was 
observed 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 4000 
Poly(vinyl alcohol) 
Titanium dioxide (E171) 
 
6.2 Incompatibilities 
 
Not applicable.  



24 

 
6.3 Shelf life 
 
3 years. 
 
6.4 Special precautions for storage 
 
Store in the original container in order to protect from light.  
 
The bottle contains one sealed canister containing a molecular sieve desiccant. Keep the canister in 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 or 180 
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 or 
90 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 
 
Disposal 
 
No special requirements for disposal. 
 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Incyte Biosciences Distribution B.V. 
Paasheuvelweg 25 
1105 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 



25 

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

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


26 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURERS RESPONSIBLE FOR BATCH 
RELEASE 

 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE 

MARKETING AUTHORISATION 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT 

 

 



27 

A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturers responsible for batch release 
 
Haupt Pharma - AMAREG GmbH 
Donaustaufer Strasse 378 
93055 Regensburg 
Germany 
 
Incyte Biosciences Distribution B.V. 
Paasheuvelweg 25 
1105 BP Amsterdam 
Netherlands 
 
Tjoapack Netherlands B.V. 
Nieuwe Donk 9 
4879 AC Etten-Leur 
Netherlands 
 
The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch. 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION  
 
 Periodic safety update reports  
 
The requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent updates published on the European medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
 Risk Management Plan (RMP) 
 
The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 
agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent 
updates of the RMP. 
 
An updated RMP should be submitted: 
• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result 
of an important (pharmacovigilance or risk minimisation) milestone being reached.  

 



28 

 Obligation to conduct post-authorisation measures 
 
The MAH shall complete, within the stated timeframe, the below measures: 
Description Due date 

In order to determine the optimal starting dose of Iclusig and characterise the 
safety and efficacy of Iclusig following dose reductions after achieving MCyR in 
patients with CP-CML, the MAH should conduct and submit the results of a dose-
ranging study.  

August 2021 

 



29 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
 

 



30 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
 
 

 
 
 



31 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING 
 
OUTER CARTON AND BOTTLE LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Iclusig 15 mg film-coated tablets 
ponatinib 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 15 mg ponatinib (as hydrochloride). 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. See the package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
30 tablets 
60 tablets 
180 tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Outer Carton: 
Do not swallow the desiccant canister found in the bottle. 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in the original container in order to protect from light. 



32 

 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 

Incyte Biosciences Distribution B.V. 
Paasheuvelweg 25 
1105 BP Amsterdam 
Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/13/839/001  60 film-coated tablets 
EU/1/13/839/002  180 film-coated tablets 
EU/1/13/839/005  30 film-coated tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 

 
16. INFORMATION IN BRAILLE 
 
Outer Carton: 
Iclusig 15 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:   
NN:   
 



33 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING 
 
OUTER CARTON AND BOTTLE LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Iclusig 30 mg film-coated tablets 
ponatinib 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 30 mg ponatinib (as hydrochloride). 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. See the package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
30 tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Outer Carton: 
Do not swallow the desiccant canister found in the bottle. 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in the original container in order to protect from light. 
 



34 

 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 

Incyte Biosciences Distribution B.V. 
Paasheuvelweg 25 
1105 BP Amsterdam 
Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/13/839/006 30 film-coated tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 

 
16. INFORMATION IN BRAILLE 
 
Outer Carton: 
Iclusig 30 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:   
SN:   
NN:   
 



35 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING 
 
OUTER CARTON AND BOTTLE LABEL  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Iclusig 45 mg film-coated tablets 
ponatinib 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 45 mg ponatinib (as hydrochloride). 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. See the package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
30 tablets 
90 tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Outer Carton: 
Do not swallow the desiccant canister found in the bottle. 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in the original container in order to protect from light. 
 



36 

 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 

Incyte Biosciences Distribution B.V. 
Paasheuvelweg 25 
1105 BP Amsterdam 
Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/13/839/003  30 film-coated tablets 
EU/1/13/839/004  90 film-coated tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 

 
16. INFORMATION IN BRAILLE 
 
Outer Carton: 
Iclusig 45 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:   
SN:   
NN:   
 



37 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



38 

Package leaflet: Information for the patient 
 

Iclusig 15 mg film-coated tablets 
Iclusig 30 mg film-coated tablets 
Iclusig 45 mg film-coated tablets 

ponatinib 
 

This medicine is subject to additional monitoring. This will allow quick identification of new 
safety information. You can help by reporting any side effects you may get. See the end of section 4 
for how to report side effects. 
 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
 Keep this leaflet. You may need to read it again. 
 If you have any further questions, ask your doctor or pharmacist. 
 This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
 If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What Iclusig is and what it is used for  
2. What you need to know before you take Iclusig  
3. How to take Iclusig  
4. Possible side effects  
5. How to store Iclusig 
6. Contents of the pack and other information 
 
 
1. What Iclusig is and what it is used for 
 
Iclusig is used to treat adults with the following leukaemia types who are no longer benefiting from 
treatment with other medicines, or have a certain genetic difference known as a T315I mutation: 
 chronic myeloid leukaemia (CML): a blood cancer involving too many abnormal white blood 

cells in the blood and the bone marrow (where blood cells are formed). 
 Philadelphia-chromosome positive acute lymphoblastic leukaemia (Ph+ ALL): a type of 

leukaemia involving too many immature white blood cells in the blood and blood forming bone 
marrow. In this kind of leukaemia, some of the DNA (genetic material) has become rearranged 
to form an abnormal chromosome, the Philadelphia chromosome. 

 
Iclusig belongs to a group of medicines called tyrosine kinase inhibitors. In patients with CML and 
Ph+ ALL, changes in the DNA trigger a signal that tells the body to produce abnormal white blood 
cells. Iclusig blocks this signal, thereby stopping the production of these cells. 
 
 
2. What you need to know before you take Iclusig 
 
Do not take Iclusig 
 if you are allergic to ponatinib or any of the other ingredients of this medicine (listed in section 

6). 
 
Warnings and precautions  
 
Talk to your doctor or pharmacist before taking Iclusig if you have: 
 a liver or pancreas disorder or reduced kidney function. Your doctor may want to take additional 

precautions. 



39 

 a history of alcohol abuse 
 had a prior heart attack or stroke 
 a history of blood clots in your blood vessels 
 a history of renal artery stenosis (narrowing of the blood vessels to one or both kidneys) 
 heart problems, including heart failure, irregular heartbeats, and QT prolongation 
 high blood pressure 
 or have had an aneurysm (enlargement and weakening of a blood vessel wall) or a tear in a 

blood vessel wall 
 a history of bleeding issues 
 ever had or might now have a hepatitis B infection. This is because Iclusig could cause hepatitis 

B to become active again, which can be fatal in some cases. Patients will be carefully checked 
by their doctor for signs of this infection before treatment is started. 

 
Your doctor will perform: 
 evaluations of your heart function and the condition of your arteries and veins 
 a complete blood count 

This will be repeated every 2 weeks for the first 3 months after starting the therapy. Afterwards 
it is performed monthly or as indicated by the doctor. 

 checks of the serum protein known as lipase 
A serum protein called lipase will be checked every 2 weeks for the first 2 months, then 
periodically. A break in treatment or a decrease in dose may be required when lipase is 
increased. 

 liver tests 
Liver function tests will be performed periodically, as indicated by your doctor. 
 

A brain condition called posterior reversible encephalopathy syndrome (PRES) has been reported in 
patients treated with ponatinib. Symptoms may include sudden onset of severe headache, confusion, 
seizures, and vision changes. Tell your doctor straight away if you experience any of these symptoms 
during your treatment with ponatinib, because it could be serious. 
 
Children and adolescents 
 
Do not give this medicine to children under 18 years because no data are available in children. 
 
Other medicines and Iclusig 
 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. 
The following medicines can affect or be affected by Iclusig: 
 ketoconazole, itraconazole, voriconazole: medicines to treat fungal infections. 
 indinavir, nelfinavir, ritonavir, saquinavir: medicines to treat HIV infection. 
 clarithromycin, telithromycin, troleandomycin: medicines to treat bacterial infections. 
 nefazodone: a medicine to treat depression. 
 St. John’s wort: a herbal product used to treat depression.  
 carbamazepine: a medicine to treat epilepsy, euphoric/depressive stages and certain pain 

conditions. 
 phenobarbital, phenytoin: medicines to treat epilepsy. 
 rifabutin, rifampicin: medicines to treat tuberculosis or certain other infections. 
 digoxin: a medicine to treat heart weakness. 
 dabigatran: a medicine to prevent the formation of blood clots. 
 colchicine: a medicine to treat gout attacks. 
 pravastatin, rosuvastatin: medicines to lower elevated cholesterol levels. 
 methotrexate: a medicine to treat severe joint inflammation (rheumatoid arthritis), cancer and 

the skin disease psoriasis. 
 sulfasalazine: a medicine to treat severe bowel and rheumatic joint inflammation. 
 
Iclusig with food and drink 
Avoid grapefruit products such as grapefruit juice. 



40 

 
Pregnancy and breast-feeding 
 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor or pharmacist for advice before taking this medicine.  
 
 Contraceptive advice for men and women 

Women of childbearing age being treated with Iclusig should avoid becoming pregnant. Men 
receiving treatment with Iclusig are advised not to father a child during treatment. Effective 
contraception must be used during treatment. 
Only use Iclusig during pregnancy if your doctor tells you it is absolutely necessary, as 
potential risks exist for the unborn child. 
 

 Breast-feeding 
Stop breast-feeding during treatment with Iclusig. It is not known if Iclusig passes into breast 
milk. 
 

Driving and using machines 
 
You should take special care when driving and using machines as patients taking Iclusig may 
experience visual disturbance, dizziness, sleepiness, and tiredness. 
 
Iclusig contains lactose 
 
If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor 
before taking this medicine. 
 
 
3. How to take Iclusig 
 
Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor 
or pharmacist if you are not sure.  
 
Iclusig therapy should be prescribed by a doctor experienced in leukaemia treatment. 
 
Iclusig is available as: 
 a 45 mg film-coated tablet for the recommended dose.  
 a 15 mg film-coated tablet and a 30 mg film-coated tablet to allow for dose adjustments. 
 
The recommended starting dose is one 45 mg film-coated tablet once daily. 
 
Your doctor may reduce your dose or tell you to temporarily stop taking Iclusig if: 
 an appropriate response to the treatment is reached  
 the number of white blood cells called neutrophils is reduced. 
 the number of blood platelets is reduced. 
 a severe side effect occurs, not affecting the blood 

- pancreas inflammation. 
- increased levels of the serum proteins lipase or amylase. 

 you develop heart or blood vessel problems. 
 you have a liver disorder. 
 
Iclusig use may be resumed at the same, or a reduced dose, after the event is resolved or controlled. 
Your doctor may evaluate your response to the treatment at regular intervals. 
 



41 

Method of use 
 
Swallow the tablets whole, with a glass of water. The tablets can be taken with or without food. Do not 
crush or dissolve the tablets. 
 
Do not swallow the desiccant canister contained in the bottle. 
 
Duration of use 
 
Make sure you take Iclusig daily for as long as it is prescribed. This is a long-term treatment.  
 
If you take more Iclusig than you should 
 
Talk to your doctor immediately if this occurs.  
 
If you forget to take Iclusig 
 
Do not take a double dose to make up for a forgotten dose. Take your next dose at your regular time.  
 
If you stop taking Iclusig 
 
Do not stop taking Iclusig without your doctor’s permission. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Patients aged 65 and over are more likely to be affected by side effects.  
 
Seek medical attention immediately if you experience any of the following serious side effects. 
 
If abnormal results from blood tests are received, a doctor should be contacted immediately. 
 
Serious side effects (common: may affect up to 1 in 10 people): 
 lung infection (may cause breathing difficulty) 
 pancreas inflammation. Inform your doctor immediately if pancreas inflammation occurs. 

Symptoms are severe pain in the stomach and back. 
 fever, often with other signs of infection due to decreased number of white blood cells  
 heart attack (symptoms include: sudden feeling of increased heart rate, chest pain, 

breathlessness) 
 changes in blood levels:  

- decreased number of red blood cells (symptoms include: weakness, dizziness, fatigue) 
- decreased number of blood platelets (symptoms include: increased tendency to bleed or 

bruise) 
- decreased number of white blood cells called neutrophilis (symptoms include: increase 

tendency of infection) 
- increased level of the serum protein known as lipase 

 a heart rhythm disorder, abnormal pulse 
 heart failure (symptoms include: weakness, fatigue, swollen legs) 
 uncomfortable pressure, fullness, squeezing or pain in the centre of the chest (Angina pectoris) 

and chest pain not in connection with the heart 
 high blood pressure 
 narrowing of the arteries in the brain 
 problems of the blood vessels in the heart muscle 



42 

 blood infection 
 swollen, or red area of skin that feels hot and tender (cellulitis) 
 dehydration 
 breathing difficulties 
 fluid in the thorax (may cause breathing difficulty) 
 diarrhoea 
 blood clot in a deep vein, sudden vein obstruction, blood clot in a blood vessel of the lung 

(symptoms include: hot flush, flushing, redness of the face, breathing difficulty) 
 stroke (symptoms include: difficulty to speak or move, sleepiness, migraine, abnormal 

sensations) 
 blood circulation problems (symptoms include: pain in the legs or arms, coldness of the 

extremities of the limbs) 
 blood clot in the main arteries carrying blood to the head or neck (carotid artery) 
 constipation 
 sodium decrease in the blood 
 increased tendency to bleed or bruise 
 
Other possible side effects that may occur with the following frequencies are: 
 
Very common side effects (may affect more than 1 in 10 people): 
 upper airway infection (may cause breathing difficulty) 
 decreased appetite  
 insomnia 
 headache, dizziness 
 cough 
 diarrhoea, vomiting, nausea  
 increased blood levels of several liver enzymes called: 

- alanine aminotransferase 
- aspartate aminotransferase 

 rash, dry skin, itching 
 pain in bones, joints, pain in muscles, back, arms or legs, muscle spasms 
 fatigue, accumulation of fluid in arms and/or legs, fever, pain 
 
Common side effects (may affect up to 1 in 10 people): 
 inflammation of hair follicles, swollen, red area of skin or underneath skin that feels hot and 

tender 
 decreased activity of thyroid gland  
 fluid retention 
 low calcium, phosphate or potassium levels in the blood 
 increased blood sugar or uric acid levels in the blood, high blood fat values of triglycerides 
 weight loss 
 mini stroke 
 nerve disorder in the arms and/or legs (often causes numbness and pain in the hands and feet) 
 lethargy, migraine 
 increased or reduced sense of touch or sensation, abnormal sensation such as prickling, tingling 

and itchiness 
 blurred vision, dry eye, infection in the eye, visual disturbance 
 tissue swelling in eyelid or around the eyes, caused by excess fluid 
 palpitation 
 pain in one or both legs when walking or exercising, which disappears after some minutes of 

rest 
 hot flush, flushing 
 nosebleed, difficulty producing voice sounds, hypertension in the lungs 
 increased blood levels of liver and pancreatic enzymes: 

- amylase 
- alkaline phosphatase 
- gamma-glutamyltransferase 



43 

 heartburn caused by reflux of stomach juices, inflammation in the mouth, abdominal swelling or 
discomfort or indigestion, dry mouth 

 stomach bleeding (symptoms include: stomach pain, vomiting blood) 
 increased blood level of bilirubin - the yellow breakdown substance of the blood pigment 

(symptoms include: dark amber urine) 
 pain in skeletal system or neck  
 skin rash, peeling of the skin, abnormal thickening of the skin, redness, bruising, skin pain, 

changes in skin colour, hair loss  
 tissue swelling in face caused by excess fluid 
 night sweats, increased sweating 
 inability to develop or maintain an erection 
 chills, flu-like illness 
 
Uncommon side effects (may affect up to 1 in 100 people): 
 metabolic disorders caused by the break-down products of dying cancer cells 
 bleeding in the brain 
 obstruction of the blood vessels in the eye 
 heart problems, left sided chest pain, dysfunction of the left heart chamber 
 narrowing of the blood vessels, poor blood circulation, sudden increase in blood pressure 
 renal artery stenosis (narrowing of the blood vessels to one or both kidneys) 
 circulatory problems in the spleen 
 liver damage, jaundice (symptoms include: yellowing of the skin and eyes) 
 headache, confusion, seizures, and loss of vision, which may be symptoms of a brain condition 

known as posterior reversible encephalopathy syndrome (PRES). 
 
Not known (frequency cannot be estimated from the available data): 
 recurrence (reactivation) of Hepatitis B infection when you have had hepatitis B in the past (a 

liver infection). 
 troubling skin rashes involving blisters or peeling and spread across the body, and involving 

tiredness. Inform your doctor immediately if you experience these symptoms.     
 an enlargement and weakening of a blood vessel wall or a tear in a blood vessel wall 

(aneurysms and artery dissections). 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not 
listed in this leaflet. You can also report side effects directly via the national reporting system listed in 
Appendix V. By reporting side effects, you can help provide more information on the safety of this 
medicine. 
 
 
5. How to store Iclusig 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the bottle label and carton after EXP. 
The expiry date refers to the last day of that month. 
 
Store in the original container in order to protect from light.  
 
The bottle contains one sealed plastic canister containing a molecular sieve desiccant. Keep the 
canister in the bottle. Do not swallow the desiccant canister. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


44 

6. Contents of the pack and other information 
 
What Iclusig contains 
 
 The active substance is ponatinib. 

Each 15 mg film-coated tablet contains 15 mg ponatinib (as ponatinib hydrochloride). 
Each 30 mg film-coated tablet contains 30 mg ponatinib (as ponatinib hydrochloride). 
Each 45 mg film-coated tablet contains 45 mg ponatinib (as ponatinib hydrochloride). 

 The other ingredients are lactose monohydrate, microcrystalline cellulose, sodium starch 
glycolate, silica (colloidal anhydrous), magnesium stearate, talc, macrogol 4000, polyvinyl 
alcohol, titanium dioxide (E171). See section 2 “Iclusig contains lactose”. 

 
What Iclusig looks like and contents of the pack 
 
Iclusig film-coated tablets are white, round and rounded on the upper and lower side. 
Iclusig 15 mg film-coated tablets are approximately 6 mm in diameter with "A5" on one side. 
Iclusig 30 mg film-coated tablets are approximately 8 mm in diameter with "C7" on one side. 
Iclusig 45 mg film-coated tablets are approximately 9 mm in diameter with "AP4" on one side. 
 
Iclusig is available in plastic bottles, each containing one canister of a molecular sieve desiccant. 
Bottles are packed within a cardboard box. 
Bottles of Iclusig 15 mg contain either 30, 60 or 180 film-coated tablets. 
Bottles of Iclusig 30 mg contain 30 film-coated tablets. 
Bottles of Iclusig 45 mg contain either 30 or 90 film-coated tablets.  
 
Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder 
 
Incyte Biosciences Distribution B.V. 
Paasheuvelweg 25 
1105 BP Amsterdam 
Netherlands 
 
Manufacturer 
 
Haupt Pharma Amareg GmbH 
Donaustaufer Str. 378 
93055 Regensburg 
Germany 
 
Incyte Biosciences Distribution B.V. 
Paasheuvelweg 25 
1105 BP Amsterdam 
Netherlands 
 
Tjoapack Netherlands B.V. 
Nieuwe Donk 9 
4879 AC Etten-Leur 
Netherlands 
 
This leaflet was last revised in {MM/YYYY}. 
 
Detailed information on this medicine is available on the European Medicines Agency website: 
http://www.ema.europa.eu.  

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

	SUMMARY OF PRODUCT CHARACTERISTICS
	A.	MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE
	B.	CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C.	OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION 
	D.	CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET