Posology : מינונים

4.2      Posology and method of administration

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.

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.

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 and 30 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
First occurrence:
• Iclusig should be withheld and resumed at the initial 45 mg dose after recovery to ANC ≥ 1.5 x 109/L and platelet
≥ 75 x 109/L
Second occurrence:
ANC* < 1.0 x 109/L
• Iclusig should be withheld and resumed at 30 mg after or recovery to platelet < 50 x 109/L
ANC ≥ 1.5 x 109/L and platelet ≥ 75 x 109/L
Third occurrence:
• Iclusig should be withheld and resumed at 15 mg after recovery to
ANC ≥ 1.5 x 109/L and platelet ≥ 75 x 109/L
*ANC = absolute neutrophil count

Arterial occlusion and venous thromboembolism
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.

Pancreatitis
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            Iclusig should be continued at the same dose lipase/amylase
Occurrence at 45 mg:
• Iclusig should be withheld and resumed at 30 mg after recovery to ≤ Grade 1 (< 1.5 x IULN)
Grade 3 or 4 asymptomatic
Recurrence at 30 mg: elevation of lipase/amylase
• Iclusig should be withheld and resumed at 15 mg after
(> 2.0 x IULN*) only recovery to ≤ Grade 1 (< 1.5 x IULN)
Recurrence at 15 mg:
• Iclusig discontinuation should be considered
Occurrence at 45 mg:
Grade 3 pancreatitis
• Iclusig should be withheld and resumed at 30 mg after
recovery to < Grade 2
Recurrence at 30 mg:
• Iclusig should be withheld and resumed at 15 mg after recovery to < Grade 2
Recurrence at 15 mg:
• Iclusig discontinuation should be considered
Grade 4 pancreatitis                  Iclusig should be discontinued
*IULN = institution upper limit of normal

Hepatic toxicity
Dose interruption or discontinuation may be required as described in Table 3.

Table 3       Recommended dose modifications for hepatic toxicity
Elevation of liver transaminase         Occurrence at 45 mg:
> 3 × ULN*                                • Iclusig should be interrupted and hepatic function should be monitored
Persistent grade 2 (longer                • clusig should be resumed at 30 mg after recovery to than 7 days)                                 ≤ Grade 1 (< 3 × ULN), or recovery to pre-treatment grade
Grade 3 or higher                       Occurrence at 30 mg:
• Iclusig should be interrupted and resumed at 15 mg after recovery to ≤ Grade 1, or recovery to pre- treatment grade
Occurrence at 15 mg:
• Iclusig should be discontinued
Elevation of AST or ALT ≥ 3 × ULN       Iclusig should be discontinued concurrent with an elevation of bilirubin > 2 × ULN and alkaline phosphatase < 2 × ULN
*ULN = Upper Limit of Normal for the lab

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 hepatic impairment (see sections 4.4 and 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
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.