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.

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 and cardiovascular risk factors should be actively managed. Cardiovascular status should continue to be monitored and therapy 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.

Dose adjustments or modifications

Dose modifications should be considered for the management of treatment toxicity. 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

Non-haematological adverse reactions

If a severe non-haematological adverse reaction occurs, treatment should be withheld. After the event is resolved or attenuated in severity, Iclusig may be resumed at the same dose or at a reduced dose according to initial grade of the adverse reaction.

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

For patients whose adverse reactions are resolved, escalation of the dose back to 45 mg once daily should be considered, if clinically appropriate.

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

Iclusig has not been studied in patients with hepatic impairment. As hepatic elimination is a major route of excretion for Iclusig, the presence of moderate to severe hepatic impairment may result in increased plasma concentrations. Caution is recommended when administering Iclusig to patients with varying degrees of hepatic impairment (see section 4.4).

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.

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, 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.

Iclusig should not be used in patients with a history of myocardial infarction or stroke, unless the potential benefit of treatment outweighs the potential risk (see sections 4.2 and 4.8).

Before starting treatment with ponatinib, the cardiovascular status of the patient should be assessed and cardiovascular risk factors should be actively managed. Cardiovascular status should continue to be monitored and therapy optimised during treatment with ponatinib.

Monitoring for evidence of thromboembolism and vascular occlusion should be performed and 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 may contribute to risk of arterial thrombotic events. During Iclusig treatment, blood pressure elevations should be monitored and managed and hypertension should be treated to normal. Iclusig treatment should be temporarily interrupted if hypertension is not medically controlled (see section 4.2).

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.

Liver function abnormality

Iclusig may result in elevation in ALT, AST, bilirubin, and alkaline phosphatase. Liver function tests should be performed periodically, as clinically indicated.

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).

Elevated gastric pH

Caution should be exercised with concurrent use of Iclusig and medicinal products that elevate the gastric pH (such as proton pump inhibitors, H2 blockers, or antacids) as these may decrease the solubility of ponatinib and subsequently reduce its bioavailability.

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

Caution is recommended when administering Iclusig to patients with varying degrees of hepatic impairment (see section 4.2).

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 with concurrent use of Iclusig and moderate or strong CYP3A inhibitors such as atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, voriconazole, and grapefruit juice.

Substances that may decrease ponatinib serum concentrations

CYP3A inducers

The effect of CYP3A inducers on ponatinib pharmacokinetics has not been studied. Based on the role of CYP3A in the metabolism of ponatinib, it is anticipated that strong inducers will decrease ponatinib systemic exposures; however, the magnitude of decrease is unknown. Caution should be exercised with concurrent use of Iclusig and strong CYP3A inducers such as carbamazepine, phenobarbital, phenytoin, rifabutin, rifampicin, and St. John's Wort.

Elevated gastric pH

The aqueous solubility of ponatinib is pH dependent, with higher pH resulting in lower solubility. Medicinal products that elevate the gastric pH (such as proton pump inhibitors, H2 blockers, or antacids) may decrease the solubility of ponatinib and subsequently reduce its bioavailability. However, no clinical studies have been conducted.

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.

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 i