Special Warning : אזהרת שימוש

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, anemia 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 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, retinalarterial 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 withhistory 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 in25% 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).

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 patient 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 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.



Effects on Driving

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.