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  • Tasigna
    / Novartis


    Active Ingredient
    Nilotinib (HCl monohydrate) 150 mg, 200 mg

    Status in Israel
    RX

    Presentation and Status in Health Basket

    Presentation Basket Yarpa Pharmasoft

    Capsules

    112 X 150 mg

    partial basket chart 3416 20707

    Capsules

    40 X 200 mg

    partial basket chart 37071 20743

    Capsules

    120 X 200 mg

    partial basket chart 37070 20742

    Related information


    Dosage

    Therapy should be initiated by a physician experienced in the diagnosis and the treatment of patients with CML.
    Treatment should be continued as long as clinical benefit is observed or until unacceptable toxicity 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, 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.
    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=BCRABL/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.
    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.
    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).
    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 reestablished and every 12 weeks thereafter.
    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 at doctor’s leaflet).
    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.
    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.
    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 imatinibresistant 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.
    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.
    Increases in total serum cholesterol levels have been reported with nilotinib therapy.
    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. Blood glucose levels should be assessed prior to initiating nilotinib therapy and monitored during treatment.
    Paediatric population: The safety and efficacy of Tasigna in children from birth to less than 18 years have not yet been established. Therefore, its use in paediatric patients is not recommended due to a lack of data on safety and efficacy.
    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.


    Indications

    Tasigna 150mg and 200mg are indicated for the treatment of adult patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukaemia (CML) in the chronic phase.
    Tasigna 200mg only is indicated also for the treatment of Philadelphia chromosome positive chronic myeloid leukaemia (Ph+CML) in chronic phase or accelerated phase in patients resistant to or experiencing significant toxicity during treatment with imatinib.


    Contra-Indications

    Hypersensitivity to the active substance or to any of the excipients.


    Special Precautions

    Myelosuppression: Treatment with nilotinib is associated with (National Cancer Institute Common Toxicity Criteria grade 3-4) thrombocytopenia, neutropenia and anaemia. Occurrence is more frequent in patients with imatinib-resistant or intolerant CML, in particular in patients with accelerated-phase CML. Complete blood counts should be performed every two weeks for the first 2 months and then monthly thereafter, or as clinically indicated. Myelosuppression was generally reversible and usually managed by withholding Tasigna temporarily or dose reduction.
    QT prolongation: Nilotinib has been shown to prolong cardiac ventricular repolarisation as measured by the QT interval on the surface ECG in a concentration-dependent manner in adult.
    Significant prolongation of the QT interval may occur when nilotinib is inappropriately taken with strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT, and/or food. The presence of hypokalaemia and hypomagnesaemia may further enhance this effect. Prolongation of the QT interval may expose patients to the risk of fatal outcome.
    Tasigna should be used with caution in patients who have or who are at significant risk of developing prolongation of QTc, such as those:
    – with congenital long QT prolongation
    – with uncontrolled or significant cardiac disease including recent myocardial infarction, congestive heart failure, unstable angina or clinically significant bradycardia.
    – taking anti-arrhythmic medicinal products or other substances that lead to QT prolongation.
    Close monitoring for an effect on the QTc interval is advisable and a baseline ECG is recommended prior to initiating nilotinib therapy and as clinically indicated. Hypokalemia or hypomagnesemia must be corrected prior to TASIGNA administration and potassium and magnesium blood levels should be monitored periodically during therapy, particularly in patients at risk for these electrolyte abnormalities.
    Sudden death: Uncommon cases (0.1 to 1%) of sudden deaths have been reported in patients with imatinib-resistant or intolerant CML in chronic phase or accelerated phase with a past medical history of cardiac disease or significant cardiac risk factors. Co-morbidities in addition to the underlying malignancy were also frequently present as were concomitant medicinal products. Ventricular repolarisation abnormalities may have been contributory factors. No cases of sudden death were reported in the Phase III study in newly diagnosed patients with CML in chronic phase.
    Fluid retention and oedema: Severe forms of fluid retention such as pleural effusion, pulmonary oedema, and pericardial effusion were uncommonly (0.1 to 1%) observed in a Phase III study of newly diagnosed CML patients.
    Similar events were observed in post-marketing reports. Unexpected, rapid weight gain should be carefully investigated. If signs of severe fluid retention appear during treatment with nilotinib, the aetiology should be evaluated and patients treated accordingly.
    Cardiovascular events: Cardiovascular events were reported in a randomised Phase III study in newly diagnosed CML patients and observed in post-marketing reports. In this clinical study with a median on-therapy time of 60.5 months, Grade 3-4 cardiovascular events included peripheral arterial occlusive disease (1.4% and 1.1% at 300 mg and 400 mg nilotinib twice daily, respectively), ischaemic heart disease (2.2% and 6.1% at 300 mg and 400 mg nilotinib twice daily, respectively) and ischaemic cerebrovascular events (1.1% and 2.2% at 300 mg and 400 mg nilotinib twice daily, respectively). Patients should be advised to seek immediate medical attention if they experience acute signs or symptoms of cardiovascular events. The cardiovascular status of patients should be evaluated and cardiovascular risk factors monitored and actively managed during nilotinib therapy according to standard guidelines.
    Appropriate therapy should be prescribed to manage cardiovascular risk factors.
    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 nilotinib. 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 nilotinib should be closely monitored for signs and symptoms of active HBV infection throughout therapy and for several months following termination of therapy.
    See prescribing information for full details.


    Side Effects

    Most common: Headache, Nausea, Upper abdominal pain, Rash, Pruritus,  Alopecia, Myalgia, Fatigue.
    See prescribing information for full details.


    Drug interactions

    Tasigna may be given in combination with haematopoietic growth factors such as erythropoietin or granulocyte colony-stimulating factor (G-CSF) if clinically indicated. It may be given with hydroxyurea or anagrelide if clinically indicated.
    Nilotinib is mainly metabolised in the liver and is also a substrate for the multi-drug efflux pump, P-glycoprotein (P-gp). Therefore, absorption and subsequent elimination of systemically absorbed nilotinib may be influenced by substances that affect CYP3A4 and/or P-gp.
    See prescribing information for full details.


    Pregnancy and Lactation

    Pregnancy: There are no or limited amount of data from the use of nilotinib in pregnant women. Studies in animals have shown reproductive toxicity. Tasigna should not be used during pregnancy unless the clinical condition of the woman requires treatment with nilotinib. If it is used during pregnancy, the patient must be informed of the potential risk to the foetus.
    If a woman who is being treated with nilotinib is considering pregnancy, treatment discontinuation may be considered based on the eligibility criteria for discontinuing treatment as described in
    sections at ths doctor’s leaflet. There is a limited amount of data on pregnancies in patients while attempting treatment-free remission (TFR). If pregnancy is planned during the TFR phase, the patient must be informed of a potential need to re-initiate nilotinib treatment during pregnancy.
    Breast-feeding: It is unknown whether nilotinib is excreted in human milk. Available toxicological data in animals have shown excretion of nilotinib in milk. A risk to the newborns/infants cannot be excluded. Tasigna should not be used during breast-feeding.


    Overdose

    Isolated reports of intentional overdose with nilotinib were reported, where an unspecified number of Tasigna capsules were ingested in combination with alcohol and other medicinal products. Events included neutropenia, vomiting and drowsiness. No ECG changes or hepatotoxicity were reported.
    Outcomes were reported as recovered.
    In the event of overdose, the patient should be observed and appropriate supportive treatment given.


    Manufacturer
    Novartis Pharma Stein AG Switzerland
    Licence holder
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