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ICLUSIG is a brand name for Ponatinib, supplied as a tablet. The medicine, its uses, side effects and dosage are the same regardless of brand.
Used for: ICLUSIG (ponatinib tablets) is indicated for: • the treatment of adult patients with chronic phase (CP), accelerated phase (AP), or blast phase (BP) chronic myeloid leukemia (CML) or Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) for whom other tyrosine kinase inhibitor (TKI) therapy is not…
Verbatim from this product's HC label. Tap a section to expand.
1 Dosing Considerations ICLUSIG must only be prescribed and used in treatment initiated by a physician who is experienced in diagnosing patients with leukemia (in particular, CML or Ph+ ALL) and with treatments including antineoplastic therapy.
Before starting treatment with ICLUSIG, 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 optimized during treatment with ICLUSIG.
Monitoring for evidence of AOEs and VTEs should be performed and ICLUSIG should be interrupted or discontinued immediately in case of vascular occlusion (see Table 1). ICLUSIG® (ponatinib) – Product Monograph Page 6 of 55 Protected B / Protégé B Hematologic support such as platelet transfusion and hematopoietic growth factors can be used during treatment if clinically indicated.
Avoid co-administration of ICLUSIG with strong CYP3A inhibitors and strong CYP3A inducers. 4 Drug-Drug Interactions. Advise patients to take ICLUSIG exactly as prescribed and not to change their dose or to stop taking ICLUSIG unless they are told to do so by their healthcare provider.
6 Lactose Intolerance). 2 Recommended Dose and Dosage Adjustment CP-CML The recommended starting dosage of ICLUSIG is 45 mg orally once daily with a reduction to 15 mg orally once daily upon achievement of molecular response (≤1% BCR::ABL1IS).
Patients with loss of response can re-escalate the dose of ICLUSIG to a previously tolerated dosage of 30 mg or 45 mg orally once daily. Continue ICLUSIG until loss of response at the re-escalated dose or unacceptable toxicity. Consider discontinuing ICLUSIG if hematologic response has not occurred by 3 months.
AP-CML, BP-CML, and Ph+ ALL The recommended starting dosage is 45 mg of ICLUSIG once daily. Continue ICLUSIG until loss of response or unacceptable toxicity. Consider reducing the dose of ICLUSIG for patients with accelerated phase (AP) CML who have achieved a major cytogenetic response.
Consider discontinuing ICLUSIG if response has not occurred by 3 months. Health Canada has not authorized an indication for pediatric use. Dose Modifications for Adverse Reactions Recommendations for dose modifications of ICLUSIG for the management of adverse reactions are summarized in Table 1 and recommended dose reductions of ICLUSIG for adverse reactions are presented in Table 2.
2 Pharmacodynamics). Left ventricular ejection fraction (LVEF) should be evaluated in all patients prior to initiation of treatment with ICLUSIG, at three months after initiation of ICLUSIG, and whenever clinically indicated. ICLUSIG should be used with caution in patients with a history of congestive heart failure or conditions that could impair left ventricular function.
Patients receiving ICLUSIG should be monitored for signs and symptoms consistent with congestive heart failure, with treatment as clinically indicated, including interruption of ICLUSIG. 2 Recommended Dose and Dosage Adjustment). In PACE, 39 of 449 patients (9%) experienced heart failure or left ventricular dysfunction, including 28 patients (6%) with serious events and 4 patients (1%) with fatal events.
In OPTIC, 3 of 94 patients (3%) in the 45 mg cohort experienced heart failure (left ventricular dysfunction, heart failure, or ejection fraction decreased). Inform patients of the possibility of heart failure and abnormally slow or fast heart rates.
Advise patients to contact their healthcare provider if they experience symptoms such as shortness of breath, chest pain, palpitations, dizziness, or fainting. Hypertension Hypertension (including hypertensive crisis) occurred in ICLUSIG-treated patients.
Patients may require urgent clinical intervention. Hypertension may contribute to the risk of AOEs, including renal artery stenosis. During ICLUSIG treatment, blood pressure should be monitored and managed. Hypertension should be treated to normalize blood pressure.
ICLUSIG treatment should be temporarily interrupted, dose reduced or stopped if hypertension is not medically controlled. Monitoring for significant or unexplained hypertension is recommended as it may contribute to renal vascular disease.
In the event of significant worsening, labile or treatment-resistant hypertension, interrupt treatment and consider evaluating for renal artery stenosis. In PACE, hypertension was observed in 32% (142/449) of patients (12% grade 3 or greater); hypertensive crisis was observed in two patients (<1%).
, Hypertension and Monitoring and Laboratory Tests). • Do not use in patients who are not adequately hydrated and with uncorrected high uric acid levels (see 7 WARNINGS AND PRECAUTIONS, Tumour Lysis Syndrome). 3 SERIOUS WARNINGS AND PRECAUTIONS BOX Serious Warnings and Precautions ICLUSIG should only be prescribed and monitored by a physician who is experienced in the use of antineoplastic therapy and in the treatment of CML or Ph+ ALL.
• AOEs, including fatalities, occurred in ICLUSIG-treated patients. AOEs included fatal myocardial infarction, fatal cerebral infarction, fatal mesenteric artery occlusion, disseminated intravascular coagulation, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, sometimes resulting in amputation, and the need for urgent revascularization procedures.
Patients with and without cardiovascular risk factors, including patients 50 years or ICLUSIG® (ponatinib) – Product Monograph Page 5 of 55 Protected B / Protégé B younger, experienced these events. Monitor for evidence of AOEs. Interrupt or discontinue ICLUSIG immediately in case of an AOE.
2 Recommended Dose and Dosage Adjustment, 7 WARNINGS AND PRECAUTIONS, Arterial Occlusive Events). • Venous thromboembolic events (VTEs) occurred in ICLUSIG-treated patients. Cases of pulmonary embolism have been reported, some of which were fatal.
Monitor for evidence of VTEs. 2 Recommended Dose and Dosage Adjustment, 7 WARNINGS AND PRECAUTIONS, Venous Thromboembolic Events). • Heart failure (some fatal), including left ventricular dysfunction and ejection fraction decrease, occurred in ICLUSIG-treated patients.
Monitor for signs or symptoms consistent with heart failure and treat as clinically indicated. 2 Recommended Dose and Dosage Adjustment, 7 WARNINGS AND PRECAUTIONS, Heart Failure and Left Ventricular Dysfunction). • Hemorrhage events (some fatal), including intracranial hemorrhage, hemorrhagic gastritis, and hemorrhagic cerebral infarction occurred in ICLUSIG-treated patients.
• ICLUSIG is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.
• Do not use in patients with unmanaged cardiovascular risk factors, including uncontrolled hypertension. Hypertension may contribute to the risk of arterial occlusive events (AOEs). Blood pressure should be monitored and managed to avoid hypertension (see also 7 WARNINGS AND PRECAUTIONS, Hypertension and Monitoring and Laboratory Tests).
• Do not use in patients who are not adequately hydrated and with uncorrected high uric acid levels (see 7 WARNINGS AND PRECAUTIONS, Tumour Lysis Syndrome).
Not medical advice. Always read the patient information leaflet and follow your prescriber or pharmacist.
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For a dose of 30 mg or 15 mg once daily, 15 mg tablets are available. Table 1. Recommended ICLUSIG Dose Modifications for Adverse Reactions Adverse Reaction Severity ICLUSIG Dose Modification AOE: cardiovascular or cerebrovascular Grade 1 Interrupt ICLUSIG until resolved, then resume at same dose.
Grade 2 Interrupt ICLUSIG until ≤ Grade 1, then resume at next lower dose. Discontinue ICLUSIG if recurrence. Grade 3 or Grade 4 Discontinue ICLUSIG. AOE: peripheral vascular and other or Grade 1 Interrupt ICLUSIG until resolved, then resume at same dose.
Grade 2 Interrupt ICLUSIG until ≤ Grade 1, then resume at same dose. ICLUSIG® (ponatinib) – Product Monograph Page 7 of 55 Protected B / Protégé B Adverse Reaction Severity ICLUSIG Dose Modification VTE If recurrence, interrupt ICLUSIG until ≤ Grade 1, then resume at next lower dose.
Grade 3 Interrupt ICLUSIG until ≤ Grade 1, then resume at next lower dose. Discontinue ICLUSIG if recurrence. Grade 4 Discontinue ICLUSIG. Heart Failure Grade 2 or 3 Interrupt ICLUSIG until ≤ Grade 1, then resume at next lower dose. Discontinue ICLUSIG if recurrence.
Grade 4 Discontinue ICLUSIG. Hepatic Toxicity AST or ALT greater than 3 times ULN Interrupt ICLUSIG until ≤ Grade 1, then resume at next lower dose. AST or ALT at least 3 times ULN concurrent with bilirubin greater than 2 times ULN and alkaline phosphatase less than 2 times ULN Discontinue ICLUSIG.
0 times ULN and asymptomatic Consider interrupting ICLUSIG until resolution then resume at same dose. 5 times ULN) then resume at next lower dose. 0 times ULN and symptomatic Interrupt ICLUSIG until complete resolution of symptoms and after recovery of lipase elevation ≤ Grade 1, then resume at next lower dose.
5 × 109/L and platelets at least 75 × 109/L, then resume at same dose. If recurrence, interrupt ICLUSIG until resolution, then resume at next lower dose. ICLUSIG® (ponatinib) – Product Monograph Page 8 of 55 Protected B / Protégé B Adverse Reaction Severity ICLUSIG Dose Modification Other Non-hematologic Adverse Reactions Grade 2 Interrupt ICLUSIG until ≤ Grade 1, then resume at same dose.
If recurrence, interrupt ICLUSIG until ≤ Grade 1, then resume at next lower dose. Grade 3 or 4 Interrupt ICLUSIG until ≤ Grade 1, then resume at next lower dose. Discontinue ICLUSIG if recurrence. 0. ANC = absolute neutrophil count; AOE = arterial occlusive event; ULN = upper limit of normal; VTE = venous thromboembolic event Table 2.
Recommended Dose Reductions for ICLUSIG for Adverse Reactions Dose Reduction Dosage for Patients with CP-CML Dosage for Patients with AP-CML, BP-CML, and Ph+ ALL First 30 mg orally once daily 30 mg orally once daily Second 15 mg orally once daily 15 mg orally once daily Subsequent Reduction Permanently discontinue ICLUSIG in patients […]
Eight patients (2%) experienced treatment- emergent symptomatic hypertension as a serious adverse reaction. In the 45 mg cohort of OPTIC, 32% (30/94) patients experienced a hypertension event. Two patients (2%) in the 45 mg cohort experienced hypertension as a serious adverse reaction, including hypertensive crisis.
Serious cases of artery dissection have been reported in patients using Vascular Endothelial Growth Factor Receptors (VEGFR) TKIs, including ICLUSIG, with or without hypertension. ICLUSIG® (ponatinib) – Product Monograph Page 13 of 55 Protected B / Protégé B Inform patients of the possibility of new or worsening of existing hypertension.
Advise patients to contact their healthcare provider for elevated blood pressure or if symptoms of hypertension occur including confusion, headache, dizziness, chest pain, or shortness of breath. Cardiac Arrhythmias In PACE, arrhythmia adverse events occurred in 20% (89/449; 7% [33/449] grade 3 or greater) of ICLUSIG-treated patients.
Atrial fibrillation was the most common arrhythmia and occurred in 8% (34/449) of patients, approximately half of which were grade 3 or 4. Other grade 3 or 4 arrhythmia events included syncope (9 patients; 2%), tachycardia and bradycardia (2 patients each; <1%), and electrocardiogram QT prolonged, atrial flutter, supraventricular tachycardia, ventricular tachycardia, atrial tachycardia, atrioventricular block complete, cardio-respiratory arrest, loss of consciousness, and sinus node dysfunction (1 patient each; <1%).
Symptomatic bradyarrhythmias that led to a requirement for pacemaker implantation occurred in 1% (3/449) of ICLUSIG-treated patients. The cardiac rhythms (1 case each) identified were complete heart block, sick sinus syndrome, and atrial fibrillation with bradycardia and pauses.
In the 45 mg cohort of OPTIC, 16% (15/94) of patients experienced cardiac arrhythmias (6% grade 3-4); the most common were atrial fibrillation and tachycardia (2% each). Advise patients to report signs and symptoms suggestive of slow heart rate (fainting, dizziness) or rapid heart rate (chest pain, palpitations, dizziness).
Interrupt ICLUSIG and evaluate. Fluid Retention In PACE, fluid retention adverse events occurred in 32% (4% grade 3 or greater) of patients treated with ICLUSIG. These events included peripheral edema, pericardial effusion, and pleural effusion.
Of the 94 patients in the 45 mg cohort in OPTIC, 5% patients experienced fluid retention adverse events. The most frequent fluid retention events were peripheral edema and pleural effusion. Patients should be monitored for fluid retention.
Interrupt, reduce or discontinue ICLUSIG as clinically indicated. Inform patients of the possibility of developing fluid retention and to contact their healthcare provider for symptoms such as leg swelling, abdominal swelling, weight gain, or shortness of breath.
Driving and Operating Machinery The effect of ICLUSIG on the ability to drive or operate machinery was not specifically measured; however, in clinical studies with ICLUSIG, visual impairment, blurred vision, dizziness, mental status changes, and confusion were reported.
Patients should be advised not to drive or operate machinery if they experience any of these symptoms while taking ICLUSIG. Gastrointestinal Gastrointestinal Perforation and Impaired Wound Healing Serious gastrointestinal perforation (fistula) was reported in a patient 38 days following cholecystectomy.
ICLUSIG may impair wound healing based on the mechanism of action. Temporary interruption of ICLUSIG therapy should be considered in patients prior to undergoing major surgical procedures. Clinical judgment of adequate wound healing should guide the decision to resume ICLUSIG treatment after surgery.
Advise patients […]
Most hemorrhagic events, but not all, occurred in patients with grade 3 or 4 thrombocytopenia. 2 Recommended Dose and Dosage Adjustment, 7 WARNINGS AND PRECAUTIONS, Hemorrhage). • Hepatotoxicity (including fatal acute hepatic failure) has been reported.
Monitor hepatic function prior to and during treatment. 2 Recommended Dose and Dosage Adjustment). • Myelosuppression (thrombocytopenia, neutropenia, and anemia) has been reported in ICLUSIG- treated patients. 2 Recommended Dose and Dosage Adjustment, 7 WARNINGS AND PRECAUTIONS, Myelosuppression).
• Pancreatitis and elevations in serum lipase or amylase have been reported. 2 Recommended Dose and Dosage Adjustment, 7 WARNINGS AND PRECAUTIONS, Pancreatitis and Serum Lipase). 1 Dosing Considerations ICLUSIG must only be prescribed and used in treatment initiated by a physician who is experienced in diagnosing patients with leukemia (in particular, CML or Ph+ ALL) and with treatments including antineoplastic therapy.
Before starting treatment with ICLUSIG, 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 optimized during treatment with ICLUSIG.
Monitoring for evidence of AOEs and VTEs should be performed and ICLUSIG should be interrupted or discontinued immediately in case of vascular occlusion (see Table 1). ICLUSIG® (ponatinib) – Product Monograph Page 6 of 55 Protected B / Protégé B Hematologic support such as platelet transfusion and hematopoietic growth factors can be used during treatment if clinically indicated.
Avoid co-administration of ICLUSIG with strong CYP3A inhibitors and strong CYP3A inducers. 4 Drug-Drug Interactions. Advise patients to take ICLUSIG exactly as prescribed and not to change their dose or to stop taking ICLUSIG unless they are told to do so by their healthcare provider.
6 Lactose Intolerance). 2 Recommended Dose and Dosage Adjustment CP-CML The recommended starting dosage of ICLUSIG is 45 mg orally once daily with a reduction to 15 mg orally once daily upon achievement of molecular response (≤1% BCR::ABL1IS).
Patients with loss of response can re-escalate the dose of ICLUSIG to a previously tolerated dosage of 30 mg or 45 mg orally once daily. Continue ICLUSIG until loss of response at the re-escalated dose or unacceptable toxicity. Consider discontinuing ICLUSIG if hematologic response has not occurred by 3 months.
AP-CML, BP-CML, and Ph+ ALL The recommended starting dosage is 45 mg of ICLUSIG once daily. Continue ICLUSIG until loss of response or unacceptable toxicity. Consider reducing the dose of ICLUSIG for patients with accelerated phase (AP) CML who have achieved a major cytogenetic response.
Consider discontinuing ICLUSIG if response has not occurred by 3 months. Health Canada has not authorized an indication for pediatric use. Dose Modifications for Adverse Reactions Recommendations for dose modifications of ICLUSIG for the management of adverse reactions are summarized in Table 1 and recommended dose reductions of ICLUSIG for adverse reactions are presented in Table 2.
For a dose of 30 mg or 15 mg once daily, 15 mg tablets are available. Table 1. Recommended ICLUSIG Dose Modifications for […]