4.1. Therapeutic indications

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.

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 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.

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 Paediatric dosing scheme of nilotinib 230 mg/m2 twice daily

Body Surface Area (BSA)

Dose in mg

(twice daily)

Up to 0.32 m2

50 mg

0.33 – 0.54 m2

100 mg

0.55 – 0.76 m2

150 mg

0.77 – 0.97 m2

200 mg

0.98 – 1.19 m2

250 mg

1.20 – 1.41 m2

300 mg

1.42 – 1.63 m2

350 mg

≥1.64 m2

400 mg

Adult 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 adult 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).

Adult 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 adult 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

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

ANC* <1.0 x 109/l and/or platelet counts <50 x 109/l

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.

Adult patients with imatinib-resistant or intolerant CML in accelerated phase at 400 mg twice daily

ANC* <0.5 x 109/l and/or platelet counts <10 x 109/l

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.

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

ANC* <1.0 x 109/l and/or platelet counts <50 x 109/l

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.

*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).

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

Myelosuppression

Treatment with nilotinib is associated with (National Cancer Institute Common Toxicity Criteria grade 3 and 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 the QT interval, 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 drug-related 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 (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 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 (see section 4.2 for instructions on managing non-haematological toxicities).

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 section 4.8).

Special monitoring of adult Ph+ CML patients in chronic phase who have achieved a sustained deep molecular response

Eligibility for discontinuation of treatment

Eligible patients who are confirmed to express the typical BCR-ABL transcripts, e13a2/b2a2 or e14a2/b3a2, can be considered for treatment discontinuation. Patients must have typical BCR-ABL transcripts to allow quantitation of BCR-ABL, evaluation of the depth of molecular response, and determination of a possible loss of molecular remission after discontinuation of treatment with nilotinib.

Monitoring of patients who have discontinued therapy

Frequent monitoring of BCR-ABL transcript levels in patients eligible for treatment discontinuation must be performed with a quantitative diagnostic test validated to measure molecular response levels with a sensitivity of at least MR4.5 (BCR-ABL/ABL ≤0.0032% IS). BCR-ABL transcript levels must be assessed prior to and during treatment discontinuation (see sections 4.2 and 5.1).

Loss of major molecular response (MMR=BCR-ABL/ABL ≤0.1%IS) in CML patients who received nilotinib as first- or second-line therapy, or confirmed loss of MR4 (two consecutive measures separated by at least 4 weeks showing loss of MR4 (MR4=BCR-ABL/ABL ≤0.01%IS)) in CML patients who received nilotinib as second-line therapy will trigger treatment re-initiation within 4 weeks of when loss of remission is known to have occurred. Molecular relapse can occur during the treatment-free phase, and long-term outcome data are not yet available. It is therefore crucial to perform frequent monitoring of BCR-ABL transcript levels and complete blood count with differential in order to detect possible loss of remission (see section 4.2). For patients who fail to achieve MMR after three months of treatment re-initiation, BCR-ABL kinase domain mutation testing should be performed.

Laboratory tests and monitoring

Blood lipids

In a Phase III study in newly diagnosed CML patients, 1.1% of the patients treated with 400 mg nilotinib twice daily showed a Grade 3-4 elevation in total cholesterol; no Grade 3-4 elevations were however observed in the 300 mg twice daily dose group (see section 4.8). It is recommended that the lipid profiles be determined before initiating treatment with nilotinib, assessed at month 3 and 6 after initiating therapy and at least yearly during chronic therapy (see section 4.2). If a HMG-CoA reductase inhibitor (a lipid-lowering agent) is required, please refer to section 4.5 before initiating treatment since certain HMG-CoA reductase inhibitors are also metabolised by the CYP3A4 pathway.

Blood glucose

In a Phase III study in newly diagnosed CML patients, 6.9% and 7.2% of the patients treated with 400 mg nilotinib and 300 mg nilotinib twice daily, respectively, showed a Grade 3-4 elevation in blood glucose. It is recommended that the glucose levels be assessed before initiating treatment with Tasigna and monitored during treatment, as clinically indicated (see section 4.2). If test results warrant therapy, physicians should follow their local standards of practice and treatment guidelines.

Interactions with other medicinal products

The administration of Tasigna with agents that are strong CYP3A4 inhibitors (including, but not limited to, ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir) should be avoided. Should treatment with any of these agents be required, it is recommended that nilotinib therapy be interrupted if possible (see section 4.5). If transient interruption of treatment is not possible, close monitoring of the individual for prolongation of the QT interval is indicated (see sections 4.2, 4.5 and 5.2).

Concomitant use of nilotinib with medicinal products that are potent inducers of CYP3A4 (e.g., phenytoin, rifampicin, carbamazepine, phenobarbital and St. John's Wort) is likely to reduce exposure to nilotinib to a clinically relevant extent. Therefore, in patients receiving nilotinib, co-administration of alternative therapeutic agents with less potential for CYP3A4 induction should be selected (see section 4.5).

Food effect

The bioavailability of nilotinib is increased by food. Tasigna must not be taken in conjunction with food (see sections 4.2 and 4.5) and should be taken 2 hours after a meal. No food should be consumed for at least one hour after the dose is taken. Grapefruit juice and other foods that are known to inhibit CYP3A4 should be avoided. For patients who are unable to swallow hard capsules, the content of each hard capsule may be dispersed in one teaspoon of apple sauce and should be taken immediately. Not more than one teaspoon of apple sauce and no food other than apple sauce must be used (see section 5.2).

Hepatic impairment

Hepatic impairment has a modest effect on the pharmacokinetics of nilotinib. Single dose administration of 200 mg of nilotinib resulted in increases in AUC of 35%, 35% and 19% in subjects with mild, moderate and severe hepatic impairment, respectively, compared to a control group of subjects with normal hepatic function. The predicted steady-state Cmax of nilotinib showed an increase of 29%, 18% and 22%, respectively. Clinical studies have excluded patients with alanine transaminase (ALT) and/or aspartate transaminase (AST) >2.5 (or >5, if related to disease) times the upper limit of the normal range and/or total bilirubin >1.5 times the upper limit of the normal range. Metabolism of nilotinib is mainly hepatic. Patients with hepatic impairment might therefore have increased exposure to nilotinib and should be treated with caution (see section 4.2).

Serum lipase

Elevation in serum lipase has been observed. Caution is recommended in patients with previous history of pancreatitis. In case lipase elevations are accompanied by abdominal symptoms, nilotinib therapy should be interrupted and appropriate diagnostic measures considered to exclude pancreatitis.

Total gastrectomy

The bioavailability of nilotinib might be reduced in patients with total gastrectomy (see section 5.2). More frequent follow-up of these patients should be considered.

Tumour lysis syndrome

Due to possible occurrence of tumour lysis syndrome (TLS) correction of clinically significant dehydration and treatment of high uric acid levels are recommended prior to initiating nilotinib therapy (see section 4.8).

Lactose

Tasigna hard capsules contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Paediatric population

Laboratory abnormalities of mild to moderate transient elevations of aminotransferases and total bilirubin have been observed in children at a higher frequency than in adults, indicating a higher risk of hepatotoxicity in the paediatric population (see section 4.8). Liver function (bilirubin and hepatic transaminases levels) should be monitored monthly or as clinically indicated. Elevations of bilirubin and hepatic transaminases should be managed by withholding nilotinib temporarily, dose reduction and/or discontinuation of nilotinib (see section 4.2). In a study in the CML paediatric population, growth retardation has been documented in patients treated with nilotinib (see section 4.8). Close monitoring of growth in paediatric patients under nilotinib treatment is recommended.

4.5. Interaction with other medicinal products and other forms of interaction

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 with CYP3A4 expected to be the main contributor to the oxidative metabolism. Nilotinib 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.

Substances that may increase nilotinib serum concentrations

Concomitant administration of nilotinib with imatinib (a substrate and moderator of P-gp and CYP3A4), had a slight inhibitory effect on CYP3A4 and/or P-gp. The AUC of imatinib was increased by 18% to 39%, and the AUC of nilotinib was increased by 18% to 40%. These changes are unlikely to be clinically important.

The exposure to nilotinib in healthy subjects was increased 3-fold when co-administered with the strong CYP3A4 inhibitor ketoconazole. Concomitant treatment with strong CYP3A4 inhibitors, including ketoconazole, itraconazole, voriconazole, ritonavir, clarithromycin, and telithromycin, should therefore be avoided (see section 4.4). Increased exposure to nilotinib might also be expected with moderate CYP3A4 inhibitors. Alternative concomitant medicinal products with no or minimal CYP3A4 inhibition should be considered.

Substances that may decrease nilotinib serum concentrations

Rifampicin, a potent CYP3A4 inducer, decreases nilotinib Cmax by 64% and reduces nilotinib AUC by 80%. Rifampicin and nilotinib should not be used concomitantly.

The concomitant administration of other medicinal products that induce CYP3A4 (e.g. phenytoin, carbamazepine, phenobarbital and St. John's Wort) is likewise likely to reduce exposure to nilotinib to a clinically relevant extent. In patients for whom CYP3A4 inducers are indicated, alternative agents with less enzyme induction potential should be selected.

Nilotinib has pH dependent solubility, with lower solubility at higher pH. In healthy subjects receiving esomeprazole at 40 mg once daily for 5 days, gastric pH was markedly increased, but nilotinib absorption was only decreased modestly (27% decrease in Cmax and 34% decrease in AUC0-∞). Nilotinib may be used concurrently with esomeprazole or other proton pump inhibitors as needed.

In a study in healthy subjects, no significant change in nilotinib pharmacokinetics was observed when a single 400 mg dose of nilotinib was administered 10 hours after and 2 hours before famotidine. Therefore, when the concurrent use of a H2 blocker is necessary, it may be administered approximately 10 hours before and approximately 2 hours after the dose of Tasigna.

In the same study as above, administration of an antacid (aluminium hydroxide/magnesium hydroxide/simethicone) 2 hours before or after a single 400 mg dose of nilotinib also did not alter nilotinib pharmacokinetics. Therefore, if necessary, an antacid may be administered approximately 2 hours before or approximately 2 hours after the dose of Tasigna.

Substances that may have their systemic concentration altered by nilotinib

In vitro, nilotinib is a relatively strong inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2D6 and UGT1A1, with Ki value being lowest for CYP2C9 (Ki=0.13 microM).

A single-dose drug-drug interaction study in healthy volunteers with 25 mg warfarin, a sensitive CYP2C9 substrate, and 800 mg nilotinib did not result in any changes in warfarin pharmacokinetic parameters or warfarin pharmacodynamics measured as prothrombin time (PT) and international normalised ratio (INR). There are no steady-state data. This study suggests that a clinically meaningful drug-drug interaction between nilotinib and warfarin is less likely up to a dose of 25 mg of warfarin. Due to lack of steady-state data, control of warfarin pharmacodynamic markers (INR or PT) following initiation of nilotinib therapy (at least during the first 2 weeks) is recommended.

In CML patients, nilotinib administered at 400 mg twice daily for 12 days increased the systemic exposure (AUC and Cmax) of oral midazolam (a substrate of CYP3A4) 2.6-fold and 2.0-fold, respectively. Nilotinib is a moderate CYP3A4 inhibitor. As a result, the systemic exposure of other medicinal products primarily metabolised by CYP3A4 (e.g. certain HMG-CoA reductase inhibitors) may be increased when co-administered with nilotinib. Appropriate monitoring and dose adjustment may be necessary for medicinal products that are CYP3A4 substrates and have a narrow therapeutic index (including but not limited to alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, sirolimus and tacrolimus) when co-administered with nilotinib.

The combination of nilotinib with those statins that are mainly eliminated by CYP3A4, may increase the potential for statin-induced myopathy, including rhabdomyolysis.

Anti-arrhythmic medicinal products and other substances that may prolong the QT interval

Nilotinib should be used with caution in patients who have or may develop prolongation of the QT interval, including those patients taking anti-arrhythmic medicinal products such as amiodarone, disopyramide, procainamide, quinidine and sotalol or other medicinal products that may lead to QT prolongation such as chloroquine, halofantrine, clarithromycin, haloperidol, methadone and moxifloxacin (see section 4.4).

Food interactions

The absorption and bioavailability of nilotinib are increased if it is taken with food, resulting in a higher serum concentration (see sections 4.2, 4.4 and 5.2). Grapefruit juice and other foods that are known to inhibit CYP3A4 should be avoided.

Paediatric population

Interaction studies have only been performed in adults.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential/Contraception

Women of childbearing potential have to use highly effective contraception during treatment with nilotinib and for up to two weeks after ending treatment.

Pregnancy

There are no or limited amount of data from the use of nilotinib in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). 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 4.2 and 4.4. 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 (see sections 4.2 and 4.4).

Breast-feeding

It is unknown whether nilotinib is excreted in human milk. Available toxicological data in animals have shown excretion of nilotinib in milk (see section 5.3). Since a risk to the newborns/infants cannot be excluded, women should not breast-feed during Tasigna treatment and for 2 weeks after the last dose.

Fertility

Animal studies did not show an effect on fertility in male and female rats (see section 5.3).

4.7. Effects on ability to drive and use machines

Tasigna has no or negligible influence on the ability to drive and use machines. However, it is recommended that patients experiencing dizziness, fatigue, visual impairment or other undesirable effects with a potential impact on the ability to drive or use machines safely should refrain from these activities as long as the undesirable effects persist (see section 4.8).

4.8. Undesirable effects

Summary of the safety profile

The safety profile is based on pooled data from 3,422 patients treated with Tasigna in 13 clinical studies in the approved indications: adults and paediatric patients with newly diagnosed Philadelphia chromosome positive chronic myelogenous leukaemia (CML) in the chronic phase (5 clinical studies with 2,414 patients), adult patients with chronic phase and accelerated phase Philadelphia chromosome positive CML with resistance or intolerance to prior therapy including imatinib (6 clinical studies with 939 patients) and paediatric patients with chronic phase Philadelphia chromosome positive CML with resistance or intolerance to prior therapy including imatinib (2 clinical studies with 69 patients). These pooled data represents 9,039.34 patient-years of exposure.

The safety profile of nilotinib is consistent across indications.

The most common adverse reactions (incidence ≥15%) from the pooled safety data were: rash (26.4%), upper respiratory tract infection (including pharyngitis, nasopharyngitis, rhinitis) (24.8%) headache (21.9%), hyperbilirubinaemia (including blood bilirubin increased) (18.6%), arthralgia (15.8%), fatigue (15.4%), nausea (16.8%), pruritus (16.7%) and thrombocytopenia (16.4%).

Tabulated list of adverse reactions

Adverse reactions from clinical studies and post-marketing reports (Table 3) are listed by MedDRA system organ class and frequency category. Frequency categories are defined using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).

Table 3 Adverse drug reactions

Infections and infestations

Very common:

Upper respiratory tract infection (including pharyngitis, nasopharyngitis, rhinitis)

Common:

Folliculitis, bronchitis, candidiasis (including oral candidiasis), pneumonia, gastroenteritis, urinary tract infection

Uncommon:

Herpes virus infection, anal abscess, candidiasis (candida infection), furuncle, sepsis, subcutaneous abscess, tinea pedis

Rare:

Hepatitis B reactivation

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Uncommon:

Skin papilloma

Rare:

Oral papilloma, paraproteinaemia

Blood and lymphatic system disorders

Very common:

Anaemia, thrombocytopenia

Common:

Leukopenia, leukocytosis, neutropenia, thrombocythaemia

Uncommon:

Eosinophilia, febrile neutropenia, lymphopenia, pancytopenia

Immune system disorders

Uncommon:

Hypersensitivity

Endocrine disorders

Very common:

Growth retardation

Common:

Hypothyroidism

Uncommon:

Hyperthyroidism

Rare:

Hyperparathyroidism secondary, thyroiditis

Metabolism and nutrition disorders

Common:

Electrolyte imbalance (including hypomagnesaemia, hyperkalaemia, hypokalaemia, hyponatraemia, hypocalcaemia, hypercalcaemia, hyperphosphataemia), diabetes mellitus, hyperglycaemia, hypercholesterolaemia, hyperlipidaemia, hypertriglyceridaemia, decreased appetite, gout, hyperuricaemia, hypophosphataemia (including blood phosphorus decreased)

Uncommon:

Dehydration, increased appetite, dyslipidaemia, hypoglycaemia

Rare:

Appetite disorder, tumour lysis syndrome

Psychiatric disorders

Common:

Depression, insomnia, anxiety

Uncommon:

Amnesia, confusional state, disorientation

Rare:

Dysphoria

Nervous system disorders

Very common:

Headache

Common:

Dizziness, hypoaesthesia, paraesthesia, migraine

Uncommon:

Cerebrovascular accident, intracranial/cerebral haemorrhage, ischaemic stroke, transient ischaemic attack, cerebral infarction, loss of consciousness (including syncope), tremor, disturbance in attention, hyperaesthesia, dysaesthesia, lethargy, peripheral neuropathy, restless legs syndrome, facial paralysis

Rare:

Basilar artery stenosis, brain oedema, optic neuritis

Eye disorders

Common:

Conjunctivitis, dry eye (including xerophthalmia), eye irritation, hyperaemia (scleral, conjunctival, ocular), vision blurred

Uncommon:

Visual impairment, conjunctival haemorrhage, visual acuity reduced, eyelid oedema, blepharitis, photopsia, conjunctivitis allergic, diplopia, eye haemorrhage, eye pain, eye pruritus, eye swelling, ocular surface disease, periorbital oedema, photophobia

Rare:

Chorioretinopathy, papilloedema

Ear and labyrinth disorders

Common:

Vertigo, ear pain, tinnitus

Uncommon:

Hearing impaired (hypoacusis)

Cardiac disorders

Common:

Angina pectoris, arrhythmia (including atroventricular block, cardiac flutter, ventricular extrasystoles, tachycardia, atrial fibrillation, bradycardia), palpitations, electrocardiogram QT prolonged, coronary artery disease

Uncommon:

Myocardial infarction, cardiac murmur, pericardial effusion, cardiac failure, diastolic dysfunction, left bundle branch block, pericarditis

Rare:

Cyanosis, ejection fraction decreased

Not known:

Ventricular dysfunction

Vascular disorders

Common:

Hypertension, flushing, peripheral arterial occlusive disease

Uncommon:

Hypertensive crisis, intermittent claudication, peripheral artery stenosis, haematoma, arteriosclerosis, hypotension, thrombosis

Rare:

Shock haemorrhagic

Respiratory, thoracic and mediastinal disorders

Very common:

Cough

Common:

Dyspnoea, dyspnoea exertional, epistaxis, oropharyngeal pain

Uncommon:

Pulmonary oedema, pleural effusion, interstitial lung disease, pleuritic pain, pleurisy, throat irritation, dysphonia, pulmonary hypertension, wheezing

Rare:

Pharyngolaryngeal pain

Gastrointestinal disorders

Very common:

Nausea, upper abdominal pain, constipation, diarrhoea, vomiting

Common:

Pancreatitis, abdominal discomfort, abdominal distension, flatulence, abdominal pain, dyspepsia, gastritis, gastroesophageal reflux, haemorrhoids, stomatitis

Uncommon:

Gastrointestinal haemorrhage, melaena, mouth ulceration, oesophageal pain, dry mouth, sensitivity of teeth (hyperaesthesia teeth), dysgeusia, enterocolitis, gastric ulcer, gingivitis, hiatus hernia, rectal haemorrhage

Rare:

Gastrointestinal ulcer perforation, haematemesis, oesophageal ulcer, oesophagitis ulcerative, retroperitoneal haemorrhage, subileus

Hepatobiliary disorders

Very common:

Hyperbilirubinaemia (including blood bilirubin increased)

Common:

Hepatic function abnormal

Uncommon:

Hepatotoxicity, toxic hepatitis, jaundice, cholestasis, hepatomegaly

Skin and subcutaneous tissue disorders

Very common:

Rash, pruritus, alopecia

Common:

Night sweats, eczema, urticaria, hyperhidrosis, contusion, acne, dermatitis (including allergic, exfoliative and acneiform), dry skin, erythema

Uncommon:

Exfoliative rash, drug eruption, skin pain, ecchymosis, swelling face, blister, dermal cysts, erythema nodosum, hyperkeratosis, petechiae, photosensitivity, psoriasis, skin discolouration, skin exfoliation, skin hyperpigmentation, skin hypertrophy, skin ulcer

Rare:

Erythema multiforme, palmar-plantar erythrodysaesthesia syndrome, sebaceous hyperplasia, skin atrophy

Musculoskeletal and connective tissue disorders

Very common

Myalgia, arthralgia, back pain, pain in extremity

Common:

Musculoskeletal chest pain, musculoskeletal pain, neck pain, muscular weakness, muscle spasms, bone pain

Uncommon:

Musculoskeletal stiffness, joint swelling, arthritis, flank pain

Renal and urinary disorders

Common:

Pollakiuria, dysuria

Uncommon:

Micturition urgency, nocturia, chromaturia, haematuria, renal failure, urinary incontinence

Reproductive system and breast disorders

Common:

Erectile dysfunction, menorrhagia

Uncommon:

Breast pain, gynaecomastia, nipple swelling

Rare:

Breast induration

General disorders and administration site conditions

Very common

Fatigue, pyrexia

Common:

Chest pain (including non-cardiac chest pain), pain, chest discomfort, malaise, asthenia and oedema peripheral, chills, influenza-like illness

Uncommon:

Face oedema, gravitational oedema, feeling body temperature change (including feeling hot, feeling cold), localised oedema

Rare:

Sudden death

Investigations

Very common:

Alanine aminotransferase increased, lipase increased

Common:

Haemoglobin decreased, blood amylase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, gamma-glutamyltransferase increased, blood creatinine phosphokinase increased, weight decreased, weight increased, elevated creatinine, total cholesterol increased

Uncommon:

Blood lactate dehydrogenase increased, blood urea increased, blood bilirubin unconjugated increased, blood parathyroid hormone increased, blood triglycerides increased, globulins decreased, lipoprotein cholesterol (including low density and high density) increased, troponin increased

Rare:

Blood glucose decreased, blood insulin decreased, blood insulin increased, insulin C-peptide decreased

Note: Not all adverse drug reactions were observed in paediatric studies.

Description of selected adverse reactions

Sudden death

Uncommon cases (0.1 to 1%) of sudden deaths have been reported in Tasigna clinical studies and/or compassionate use programs 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 (see section 4.4).

Hepatitis B reactivation

Hepatitis B reactivation has been reported in association with BCR-ABL TKIs. Some cases resulted in acute hepatic failure or fulminant hepatitis leading to liver transplantation or a fatal outcome (see section 4.4).

Paediatric population

The safety of nilotinib in paediatric patients (from 2 to <18 years of age) with Philadelphia chromosome positive CML in chronic phase (n=58) has been investigated in one main study over a period of 60 months (see section 5.1). In paediatric patients, the frequency, type and severity of adverse reactions observed have been generally consistent with those observed in adults, with the exception of hyperbilirubinaemia/blood bilirubin increase (Grade 3/4: 10.3%) and transaminase elevation (AST Grade 3/4: 1.7%, ALT Grade 3/4: 12.1%) which were reported at a higher frequency than in adult patients. Bilirubin and hepatic transaminase levels should be monitored during treatment (see sections 4.2 and 4.4).

Growth retardation in paediatric population

In a study conducted in the CML paediatric population, with a median exposure of 51.9 months in newly diagnosed patients and 59.9 months in imatinib/dasatinib-resistant or imatinib-intolerant Ph+ CML-CP patients, growth deceleration (crossing at least two main percentile lines from baseline) was observed in eight patients: five (8.6%) crossed two main percentile lines from baseline and three (5.2%) crossed three main percentile lines from baseline. Growth retardation related events were reported in 3 patients (5.2%). Close monitoring of growth in paediatric patients under nilotinib treatment is recommended (see section 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Isolated reports of intentional overdose with nilotinib were reported, where an unspecified number of Tasigna hard 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.