Iclusig 15 mg film-coated tablets

Iclusig 45 mg film-coated tablets

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

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

Excipients with known effect

Each 15 mg film-coated tablet contains 40 mg of lactose monohydrate.

Each 45 mg film-coated tablet contains 120 mg of lactose monohydrate

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

15 mg tablet: white, biconvex, round film-coated tablet that is approximately 6 mm in diameter, with “A5” debossed on one side.

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

Iclusig is indicated in adult patients with

• chronic phase, accelerated phase, or blast phase chronic myeloid leukaemia (CML) who 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 Assessment of cardiovascular status prior to start of therapy and 4.4 Situations where an alternative treatment may be considered.

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.

Consider discontinuing ponatinib if a complete haematologic response has not occurred by 3 months (90 days).

The risk of vascular occlusive events is likely to be dose-related. There is insufficient data available to make formal recommendations on dose reduction (in the absence of an adverse event) in patients with chronic phase (CP) CML who have achieved Major Cytogenetic Response. If a dose reduction is considered, the following factors should be to taken into account in the individual benefit-risk 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 film-coated tablets are available.

Myelosuppression

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

Table 1 Dose modifications for myelosuppression

Vascular occlusion

In a patient suspected of developing an arterial or venous occlusive event, 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 thrombotic 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

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 severe hepatic impairment (see section 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

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.

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

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. The frequency of these events is greater in patients with accelerated phase CML (AP-CML) or blast 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).

Vascular occlusion

Arterial and venous thrombosis and occlusions, including fatal myocardial infarction, stroke, retinal vascular occlusions associated in some cases with permanent visual impairment or vision loss, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, 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. Vascular occlusion adverse events were more frequent with increasing age and in patients with prior history of ischaemia, hypertension, diabetes, or hyperlipidaemia.

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

In the phase 2 trial, arterial and venous occlusive adverse reactions have occurred in 23% 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 9.6%, 7.3%, and 6.9% of Iclusig-treated patients, respectively. Venous occlusive reactions (treatment-emergent frequencies) occurred in 5.0% of patients.

In the phase 2 trial, serious arterial and venous occlusive adverse reactions occurred in 18% of patients (treatment-emergent frequencies). Serious arterial cardiovascular, cerebrovascular, and peripheral vascular occlusive adverse reactions (treatment-emergent frequencies) occurred in 6.7%, 5.6%, and 5.1% of Iclusig treated patients, respectively. Serious venous occlusive reactions (treatment-emergent frequencies) occurred in 4.5% of patients (see section 4.8).

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 thromboembolism and vascular 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 vascular occlusion. A benefit -risk consideration should guide a decision to restart Iclusig therapy (see sections 4.2 and 4.8).

Hypertension

Hypertension may contribute to risk of arterial thrombotic events. 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).

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.

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. Monitor patients for signs or symptoms consistent with heart failure and treat as clinically indicated, including interruption of Iclusig. Consider discontinuation of ponatinib 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 eva luated 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. 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

Serious bleeding events and haemorrhage, including fatalities, occurred in Iclusig-treated patients. The incidence of serious bleeding events was higher in patients with AP-CML, BP-CML and Ph+ ALL. Cerebral haemorrhage and gastrointestinal haemorrhage were the most commonly reported serious bleeding events. Most haemorrhagic events, but not all, occurred in patients with grade 3/4 thrombocytopenia. Interrupt Iclusig for serious or severe haemorrhage and eva luate.

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 severe hepatic impairment (see section 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.

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 AUC_0-∞ and C_max 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, 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 AUC_0-∞ and C_max 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.

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

The effect of Iclusig on male and female fertility is unknown.

Iclusig has a 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.

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. At the time of reporting, all ongoing patients had a minimum follow-up of 27 months. The median duration of treatment with Iclusig was 866 days in CP-CML patients, 590 days in AP-CML patients, and 86 days in BP-CML/Ph+ ALL patients. The median dose intensity was 36 mg or, 80% of the expected 45 mg dose.

The most common serious adverse reactions >1% (treatment-emergent frequencies) were pneumonia (6.5%), pancreatitis ( 5.6%), pyrexia (4.2%), abdominal pain (4.0%), myocardial infarction (3.6%), atrial fibrillation (3.3%), anaemia, (3.3%), platelet count decreased (3.1%), febrile neutropenia (2.9%), cardiac failure (2.0%), lipase increased (1.8%), dyspnea (1.6%), diarrhoea (1.6%), neutrophil count decreased (1.3%), pancytopenia (1.3%), and pericardial effusion (1.3%).

Serious arterial cardiovascular, cerebrovascular, and peripheral vascular occlusive adverse reactions (treatment-emergent frequencies) occurred in 6.7%, 5.6%, and 5.1% of Iclusig treated patients, respectively. Serious venous occlusive reactions (treatment-emergent frequencies) occurred in 4.5% of patients.

Overall, the most common adverse reactions (≥20%) were platelet count decreased, rash, dry skin, and abdominal pain.

Arterial cardiovascular, cerebrovascular, and peripheral vascular occlusive adverse reactions (treatment-emergent frequencies) occurred in 9.6%, 7.3%, and 6.9% of Iclusig-treated patients, respectively. Venous occlusive reactions (treatment-emergent frequencies) occurred in 5.0% of patients. Overall arterial and venous occlusive adverse reactions have occurred in 23% of Iclusig-treated patients from the phase 2 trial, with serious adverse reactions occurring in 18% of patients. Some patients experienced more than one type of event.

The rates of treatment-related adverse events resulting in discontinuation were 14% in CP-CML, 7% in AP-CML and 4% in BP-CML/Ph+ ALL.

Tabulated list of adverse reactions

Adverse reactions reported in all CML and Ph+ ALL patients are presented in Table 3. Frequency categories are very common ( ≥ 1/10), common ( ≥ 1/100 to < 1/10) and uncommon ( ≥ 1/1000 to < 1/100), rare ( ≥ 1/10,000 to < 1/1000), very rare ( < 1/10,000), and not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 3 Adverse reactions observed in CML and Ph+ ALL patients – frequency reported by incidence of treatment emergent events

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