Posology : מינונים

4.2    Posology and method of administration

Therapy should be initiated by a physician experienced in the diagnosis and the treatment of patients with CML.

Posology
Treatment should be continued as long as clinical benefit is observed or until unacceptable toxicity 
TAS API SEP22 V14                                                                      EU SmPC 15JUN22 occurs.

If a dose is missed the patient should not take an additional dose, but take the usual prescribed next dose.

Posology for Philadelphia chromosome positive CML adult patients
The recommended dose of Tasigna is:
-     300 mg twice daily in newly diagnosed patients with CML in the chronic phase, -     400 mg twice daily in patients with chronic or accelerated phase CML with resistance or intolerance to prior therapy with imatinib.

For a dose of 300 mg twice daily, 150 mg capsules are available.
For a dose of 400 mg once daily (see dose adjustments below), 200 mg capsules are available.

Philadelphia chromosome positive CML patients in chronic phase who have been treated with nilotinib as first-line therapy and who achieved a sustained deep molecular response (MR4.5) Discontinuation of treatment may be considered in eligible Philadelphia chromosome positive (Ph+) CML patients in chronic phase who have been treated with nilotinib at 300 mg twice daily for a minimum of 3 years if a deep molecular response is sustained for a minimum of one year immediately prior to discontinuation of therapy. Discontinuation of nilotinib therapy should be initiated by a physician experienced in the treatment of patients with CML (see sections 4.4 and 5.1).

Eligible patients who discontinue nilotinib therapy must have their BCR-ABL transcript levels and complete blood count with differential monitored monthly for one year, then every 6 weeks for the second year, and every 12 weeks thereafter. Monitoring of BCR-ABL transcript levels must be performed with a quantitative diagnostic test validated to measure molecular response levels on the International Scale (IS) with a sensitivity of at least MR4.5 (BCR-ABL/ABL ≤0.0032% IS).

For patients who lose MR4 (MR4=BCR-ABL/ABL ≤0.01%IS) but not MMR (MMR=BCR- ABL/ABL ≤0.1%IS) during the treatment-free phase, BCR-ABL transcript levels should be monitored every 2 weeks until BCR-ABL levels return to a range between MR4 and MR4.5.
Patients who maintain BCR-ABL levels between MMR and MR4 for a minimum of 4 consecutive measurements can return to the original monitoring schedule.

Patients who lose MMR must re-initiate treatment within 4 weeks of when loss of remission is known to have occurred. Nilotinib therapy should be re-initiated at 300 mg twice daily or at a reduced dose level of 400 mg once daily if the patient had a dose reduction prior to discontinuation of therapy.
Patients who re-initiate nilotinib therapy should have their BCR-ABL transcript levels monitored monthly until MMR is re-established and every 12 weeks thereafter (see section 4.4).

Philadelphia chromosome positive CML patients in chronic phase who have achieved a sustained deep molecular response (MR 4.5) on nilotinib following prior imatinib therapy Discontinuation of treatment may be considered in eligible Philadelphia chromosome positive (Ph+) CML patients in chronic phase who have been treated with nilotinib for a minimum of 3 years if a deep molecular response is sustained for a minimum of one year immediately prior to discontinuation of therapy. Discontinuation of nilotinib therapy should be initiated by a physician experienced in the treatment of patients with CML (see sections 4.4 and 5.1).

Eligible patients who discontinue nilotinib therapy must have their BCR-ABL transcript levels and complete blood count with differential monitored monthly for one year, then every 6 weeks for the second year, and every 12 weeks thereafter. Monitoring of BCR-ABL transcript levels must be performed with a quantitative diagnostic test validated to measure molecular response levels on the International Scale (IS) with a sensitivity of at least MR4.5 (BCR-ABL/ABL ≤0.0032% IS).

TAS API SEP22 V14                                                                        EU SmPC 15JUN22 Patients with confirmed loss of MR4 (MR4= BCR-ABL/ABL ≤0.01%IS) during the treatment-free phase (two consecutive measures separated by at least 4 weeks showing loss of MR4) or loss of major molecular response (MMR=BCR-ABL/ABL ≤0.1%IS) must re-initiate treatment within 4 weeks of when loss of remission is known to have occurred. Nilotinib therapy should be re-initiated at either 300 mg or 400 mg twice daily. Patients who re-initiate nilotinib therapy should have their BCR-ABL transcript levels monitored monthly until previous major molecular response or MR4 level is re- established and every 12 weeks thereafter (see section 4.4).


Dose adjustments or modifications
Tasigna may need to be temporarily withheld and/or dose reduced for haematological toxicities (neutropenia, thrombocytopenia) that are not related to the underlying leukaemia (see Table 1).

Table 1      Dose adjustments for neutropenia and thrombocytopenia

Adult patients with     ANC* <1.0 x 109/l and/or platelet    1. Treatment with nilotinib must be interrupted newly diagnosed         counts <50 x 109/l                      and blood count monitored.
chronic phase CML                                            2. Treatment must be resumed within 2 weeks at 300 mg twice                                                 at prior dose if ANC >1.0 x 109/l and/or daily                                                           platelets >50 x 109/l.
and                                                          3. If blood counts remain low, a dose reduction imatinib-resistant or                                           to 400 mg once daily may be required.
intolerant CML in chronic phase at
400 mg twice daily
Adult patients with     ANC* <0.5 x 109/l and/or platelet    1. Treatment with nilotinib must be interrupted imatinib-resistant or   counts <10 x 109/l                      and blood count monitored.
intolerant CML in                                            2. Treatment must be resumed within 2 weeks accelerated phase at                                            at prior dose if ANC >1.0 x 109/l and/or 400 mg twice daily                                              platelets >20 x 109/l.
3. If blood counts remain low, a dose reduction to 400 mg once daily may be required.
*ANC = absolute neutrophil count

If clinically significant moderate or severe non-haematological toxicity develops, dosing should be interrupted, and patients should be monitored and treated accordingly. If the prior dose was 300 mg twice daily in adult newly diagnosed patients with CML in the chronic phase, or 400 mg twice daily in adult patients with imatinib-resistant or intolerant CML in chronic or accelerated phase, dosing may be resumed at 400 mg once daily in adult patients once the toxicity has resolved. If the prior dose was 400 mg once daily in adult patients, treatment should be discontinued. If clinically appropriate, re- escalation of the dose to the starting dose of 300 mg twice daily in adult newly diagnosed patients with CML in the chronic phase or to 400 mg twice daily in adult patients with imatinib-resistant or intolerant CML in chronic or accelerated phase should be considered.

Elevated serum lipase: For Grade 3-4 serum lipase elevations, doses in adult patients should be reduced to 400 mg once daily or interrupted. Serum lipase levels should be tested monthly or as clinically indicated (see section 4.4).

Elevated bilirubin and hepatic transaminases: For Grade 3-4 bilirubin and hepatic transaminase elevations in adult patients, doses should be reduced to 400 mg once daily or interrupted. Bilirubin and hepatic transaminases levels should be tested monthly or as clinically indicated.



TAS API SEP22 V14                                                                      EU SmPC 15JUN22 Special populations

Elderly
Approximately 12% of subjects in the Phase III study in patients with newly diagnosed CML in chronic phase and approximately 30% of subjects in the Phase II study in patients with imatinib- resistant or intolerant CML in chronic phase and accelerated phase were 65 years of age or over. No major differences were observed for safety and efficacy in patients ≥65 years of age as compared to adults aged 18 to 65 years.

Renal impairment
Clinical studies have not been performed in patients with impaired renal function.
Since nilotinib and its metabolites are not renally excreted, a decrease in total body clearance is not anticipated in patients with renal impairment.

Hepatic impairment
Hepatic impairment has a modest effect on the pharmacokinetics of nilotinib. Dose adjustment is not considered necessary in patients with hepatic impairment. However, patients with hepatic impairment should be treated with caution (see section 4.4).

Cardiac disorders
In clinical studies, patients with uncontrolled or significant cardiac disease (e.g., recent myocardial infarction, congestive heart failure, unstable angina or clinically significant bradycardia) were excluded. Caution should be exercised in patients with relevant cardiac disorders (see section 4.4).

Increases in total serum cholesterol levels have been reported with nilotinib therapy (see section 4.4).
Lipid profiles should be determined prior to initiating nilotinib therapy, assessed at month 3 and 6 after initiating therapy and at least yearly during chronic therapy.

Increases in blood glucose levels have been reported with nilotinib therapy (see section 4.4). Blood glucose levels should be assessed prior to initiating nilotinib therapy and monitored during treatment.

Paediatric population
Tasigna is not indicated for paediatric patients

Method of administration
Tasigna should be taken twice daily approximately 12 hours apart and must not be taken with food.
The capsules should be swallowed whole with water. No food should be consumed for 2 hours before the dose is taken and no food should be consumed for at least one hour after the dose is taken.

For patients who are unable to swallow capsules, the content of each capsule may be dispersed in one teaspoon of apple sauce (puréed apple) and should be taken immediately. Not more than one teaspoon of apple sauce and no food other than apple sauce must be used (see sections 4.4 and 5.2).