Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Incyte Biosciences Distribution B.V., Paasheuvelweg 25, 1105 BP Amsterdam, Netherlands
Iclusig is indicated in adult patients with:
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.
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.
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.
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.
Dose modifications for neutropenia (ANC* <1.0 × 109/L) and thrombocytopenia (platelet <50 × 109/L) that are unrelated to leukaemia are summarized in Table 1.
Table 1. Dose modifications for myelosuppression:
| ANC* <1,0 × 109/L or platelet <50 × 109/L | First occurrence: Iclusig should be withheld and resumed at the same dose after recovery to ANC ≥1.5 × 109/L and platelet ≥75 × 109/L |
| Recurrence at 45 mg: Iclusig should be withheld and resumed at 30 mg after recovery to ANC ≥1.5 × 109/L and platelet ≥75 × 109/L | |
| Recurrence at 30 mg: Iclusig should be withheld and resumed at 15 mg after recovery to ANC ≥1.5 × 109/L and platelet ≥75 × 109/L |
* ANC = absolute neutrophil count
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.
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
Dose interruption or discontinuation may be required as described in Table 3.
Table 3. Recommended dose modifications for hepatic toxicity:
| Elevation of liver transaminase >3 × ULN* | 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 |
| Persistent grade 2 (longer than 7 days) | Occurrence at 30 mg: Iclusig should be interrupted and resumed at 15 mg after recovery to ≤ Grade 1, or recovery to pretreatment grade |
| Grade 3 or higher | 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
Of the 449 patients in the clinical study of Iclusig, 155 (35%) were 5 years of age. Compared to patients <65 years, older patients are more likely to experience adverse reactions.
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 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.
The safety and efficacy of Iclusig in patients less than 18 years of age have not been established. No data are available.
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.
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.
Shelf life: 3 years.
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.
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.
No special requirements for disposal.
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