Tasigna 50mg and 200 mg hard capsules
Novartis Pharmaceuticals UK Ltd
contact details
Active ingredient
nilotinib hydrochloride monohydrate
Legal Category
POM: Prescription only medicine
Tasigna® 50 mg hard capsules - *not currently marketed in the UK
Tasigna® 200 mg hard capsules
Tasigna 50 mg hard capsules
One hard capsule contains 50 mg nilotinib (as hydrochloride monohydrate).
Excipient with known effect
One hard capsule contains 39.03 mg lactose monohydrate.
Tasigna 200 mg hard capsules
One hard capsule contains 200 mg nilotinib (as hydrochloride monohydrate).
Excipient with known effect
One hard capsule contains 156.11 mg lactose monohydrate.
For the full list of excipients, see section 6.1.
Hard capsule.
Tasigna 50 mg hard capsules
White to yellowish powder in hard gelatin capsule with red opaque cap and light yellow opaque body, size 4 with black radial imprint “NVR/ABL” on cap.
Tasigna 200 mg hard capsules
White to yellowish powder in light yellow opaque hard gelatin capsules, size 0 with red axial imprint “NVR/TKI”.
Tasigna is indicated for the treatment of:
- adult and paediatric patients with newly diagnosed Philadelphia chromosome positive chronic myelogenous leukaemia (CML) in the chronic phase,
- adult patients with chronic phase and accelerated phase Philadelphia chromosome positive CML with resistance or intolerance to prior therapy including imatinib. Efficacy data in patients with CML in blast crisis are not available,
- paediatric patients with chronic phase Philadelphia chromosome positive CML with resistance or intolerance to prior therapy including imatinib.
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 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 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.
For a dose of 300 mg twice daily, 150 mg hard capsules are available.
Posology for Philadelphia chromosome positive CML paediatric patients
Dosing in paediatric patients is individualised and is based on body surface area (mg/m2). The recommended dose of nilotinib is 230 mg/m2 twice daily, rounded to the nearest 50 mg dose (to a maximum single dose of 400 mg) (see Table 1). Different strengths of Tasigna hard capsules can be combined to attain the desired dose.
There is no experience with treatment of paediatric patients below 2 years of age. There are no data in newly diagnosed paediatric patients below 10 years of age and limited data in imatinib-resistant or intolerant paediatric patients below 6 years of age.
Table 1 Dosing scheme of nilotinib 230 mg/m2 twice daily
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Body Surface Area (BSA)
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Dose in mg
(twice daily)
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Up to 0.32 m2
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50 mg
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0.33 – 0.54 m2
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100 mg
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0.55 – 0.76 m2
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150 mg
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0.77 – 0.97 m2
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200 mg
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0.98 – 1.19 m2
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250 mg
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1.20 – 1.41 m2
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300 mg
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1.42 – 1.63 m2
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350 mg
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≥1.64 m2
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400 mg
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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).
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 2).
Table 2 Dose adjustments for neutropenia and thrombocytopenia
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Adult patients with newly diagnosed chronic phase CML at 300 mg twice daily
and
imatinib-resistant or intolerant CML in chronic phase at 400 mg twice daily
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ANC* <1.0 x 109/l and/or platelet counts <50 x 109/l
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1. Treatment with nilotinib must be interrupted and blood count monitored.
2. Treatment must be resumed within 2 weeks at prior dose if ANC >1.0 x 109/l and/or platelets >50 x 109/l.
3. If blood counts remain low, a dose reduction to 400 mg once daily may be required.
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Adult patients with imatinib-resistant or intolerant CML in accelerated phase at 400 mg twice daily
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ANC* <0.5 x 109/l and/or platelet counts <10 x 109/l
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1. Treatment with nilotinib must be interrupted and blood count monitored.
2. Treatment must be resumed within 2 weeks at prior dose if ANC >1.0 x 109/l and/or platelets >20 x 109/l.
3. If blood counts remain low, a dose reduction to 400 mg once daily may be required.
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Paediatric patients with newly-diagnosed CML in chronic phase at 230 mg/m2 twice daily
and
imatinib-resistant or intolerant CML in chronic phase at 230 mg/m2 twice daily
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ANC* <1.0 x 109/l and/or platelet counts <50 x 109/l
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1. Treatment with nilotinib must be interrupted and blood count monitored.
2. Treatment must be resumed within 2 weeks at prior dose if ANC >1.5 x 109/l and/or platelets >75 x 109/l.
3. If blood counts remain low, a dose reduction to 230 mg/m2 once daily may be required.
4. If event occurs after dose reduction, consider discontinuing treatment.
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*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, or 230 mg/m2 twice daily in paediatric patients, dosing may be resumed at 400 mg once daily in adult patients and at 230 mg/m2 once daily in paediatric patients once the toxicity has resolved. If the prior dose was 400 mg once daily in adult patients or 230 mg/m2 once daily in paediatric 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 or to 230 mg/m2 twice daily in paediatric patients 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. In paediatric patients, treatment must be interrupted until the event returns to Grade ≤1. Thereafter, if the prior dose was 230 mg/m2 twice daily, treatment can be resumed at 230 mg/m2 once daily. If the prior dose was 230 mg/m2 once daily, treatment should be discontinued. 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. For Grade ≥2 bilirubin elevations or Grade ≥3 hepatic transaminase elevations in paediatric patients, treatment must be interrupted until the levels return to Grade ≤1. Thereafter, if the prior dose was 230 mg/m2 twice daily, treatment can be resumed at 230 mg/m2 once daily. If the prior dose was 230 mg/m2 once daily, and recovery to Grade ≤1 takes longer than 28 days, treatment should be discontinued. Bilirubin and hepatic transaminases levels should be tested monthly or as clinically indicated.
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
The safety and efficacy of Tasigna in paediatric patients with Philadelphia chromosome positive CML in chronic phase from 2 to less than 18 years of age have been established (see sections 4.8, 5.1 and 5.2). There is no experience in paediatric patients below 2 years of age or in paediatric patients with Philadelphia chromosome positive CML in accelerated phase or blast crisis. There are no data in newly diagnosed paediatric patients below 10 years of age and limited data in imatinib-resistant or intolerant paediatric patients below 6 years of age.
Method of administration
Tasigna should be taken twice daily approximately 12 hours apart and must not be taken with food. The hard 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 hard capsules, the content of each hard 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).
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
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 (see section 4.2).
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 and paediatric patients.
In the Phase III study in patients with newly diagnosed CML in chronic phase receiving 300 mg nilotinib twice daily, the change from baseline in mean time-averaged QTcF interval at steady state was 6 msec. No patient had a QTcF >480 msec. No episodes of torsade de pointes were observed.
In the Phase II study in imatinib-resistant and intolerant CML patients in chronic and accelerated phase receiving 400 mg nilotinib twice daily, the change from baseline in mean time-averaged QTcF interval at steady state was 5 and 8 msec, respectively. QTcF of >500 msec was observed in <1% of these patients. No episodes of torsade de pointes were observed in clinical studies.
In a healthy volunteer study with exposures that were comparable to the exposures observed in patients, the time-averaged mean placebo-subtracted QTcF change from baseline was 7 msec (CI ± 4 msec). No subject had a QTcF >450 msec. Additionally, no clinically relevant arrhythmias were observed during the conduct of the trial. In particular, no episodes of torsade de pointes (transient or sustained) were observed.
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 (see section 4.5). 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. Hypokalaemia or hypomagnesaemia must be corrected prior to Tasigna administration and should be monitored periodically during therapy.
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 eva luated and patients treated accordingly (see section 4.2 for instructions on managing non-haematological toxicities).
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 eva luated 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 (see section 4.2 for instructions on managing non-haematological toxicities).
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