NILOTINIB ACCORD 200mg capsules medication leaflet

Nilotinib Accord 50 mg hard capsules

Nilotinib Accord 150 mg hard capsules

Nilotinib Accord 200 mg hard capsules

Nilotinib Accord 50 mg hard capsules

One hard capsule contains 50 mg nilotinib.

One hard capsule contains about 40 mg lactose (as monohydrate).

Nilotinib Accord 150 mg hard capsules

One hard capsule contains 150 mg nilotinib.

One hard capsule contains about 120 mg lactose (as monohydrate).

Nilotinib Accord 200 mg hard capsules

One hard capsule contains 200 mg nilotinib.

One hard capsule contains about 160 mg lactose (as monohydrate) and allura red AC.

For the full list of excipients, see section 6.1.

Hard capsule (capsule)

Nilotinib Accord 50 mg hard capsules

Hard gelatin capsule size “4” (approximately 14 mm in length) with red opaque cap and light yellowopaque body imprinted with black ink “SML” on the cap and “39” on the body containing off white togrey granular powder.

Nilotinib Accord 150 mg hard capsules

Hard gelatin capsule size “1” (approximately 19 mm in length) with red opaque cap and red opaquebody imprinted with black ink “SML” on the cap and “26” on the body containing off white to greygranular powder.

VAR/IB/INI-SPC Comaparison 2

Nilotinib Accord 200 mg hard capsules

Hard gelatin capsule size “0” (approximately 21 mm in length) with light yellow opaque cap and lightyellow opaque body imprinted with red ink “SML” on the cap and “27” on the body containing offwhite to grey granular powder.

Nilotinib Accord is indicated for the treatment of:

- adult and paediatric patients with newly diagnosed Philadelphia chromosome positive chronicmyelogenous leukaemia (CML) in the chronic phase,

- adult patients with chronic phase and accelerated phase Philadelphia chromosome positive CMLwith 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 resistanceor intolerance to prior therapy including imatinib.

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

Treatment should be continued as long as clinical benefit is observed or until unacceptable toxicityoccurs.

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

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 orintolerance to prior therapy.

Philadelphia chromosome positive CML paediatric patients

Dosing in paediatric patients is individualised and is based on body surface area (mg/m2). Therecommended dose of nilotinib is 230 mg/m2 twice daily, rounded to the nearest 50 mg dose (to amaximum single dose of 400 mg) (see table 1). Different strengths of nilotinib can be combined toattain the desired dose.

There is no experience with treatment of paediatric patients below 2 years of age. There are no data innewly diagnosed paediatric patients below 10 years of age and limited data in imatinib-resistant orintolerant paediatric patients below 6 years of age.

VAR/IB/INI-SPC Comaparison 3

Table 1 Paediatric dosing scheme of nilotinib 230 mg/m2 twice daily

Body surface area Dose in mg(BSA) (twice daily)

Up to 0.32 m2 50 mg0.33 - 0.54 m2 100 mg0.55 - 0.76 m2 150 mg0.77 - 0.97 m2 200 mg0.98 - 1.19 m2 250 mg1.20 - 1.41 m2 300 mg1.42 - 1.63 m2 350 mg≥1.64 = m2 400 mg

Adult Philadelphia chromosome positive CML patients in chronic phase who have been treated withnilotinib 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 aminimum of 3 years if a deep molecular response is sustained for a minimum of one year immediatelyprior to discontinuation of therapy. Discontinuation of nilotinib therapy should be initiated by aphysician 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 andcomplete blood count with differential monitored monthly for one year, then every 6 weeks for thesecond year, and every 12 weeks thereafter. Monitoring of BCR-ABL transcript levels must beperformed 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 shouldbe 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 consecutivemeasurements can return to the original monitoring schedule.

Patients who lose MMR must re-initiate treatment within 4 weeks of when loss of remission is knownto have occurred. Nilotinib therapy should be re-initiated at 300 mg twice daily or at a reduced doselevel 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 monitoredmonthly 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 asustained 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 ifa deep molecular response is sustained for a minimum of one year immediately prior to discontinuationof therapy. Discontinuation of nilotinib therapy should be initiated by a physician experienced in thetreatment of patients with CML (see sections 4.4 and 5.1).

Eligible patients who discontinue nilotinib therapy must have their BCR-ABL transcript levels andcomplete blood count with differential monitored monthly for one year, then every 6 weeks for thesecond year, and every 12 weeks thereafter. Monitoring of BCR-ABL transcript levels must be

VAR/IB/INI-SPC Comaparison 4performed 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-freephase (two consecutive measures separated by at least 4 weeks showing loss of MR4) or loss of majormolecular response (MMR=BCR-ABL/ABL ≤ 0.1%IS) must re-initiate treatment within 4 weeks ofwhen loss of remission is known to have occurred. Nilotinib therapy should be re-initiated at either300 mg or 400 mg twice daily. Patients who re-initiate nilotinib therapy should have their BCR-ABLtranscript levels monitored monthly until previous major molecular response or MR4 level isre-established and every 12 weeks thereafter (see section 4.4).

Dose adjustments or modifications

Nilotinib 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 ANC* <1.0 × 109/l 1. Treatment with nilotinib must bediagnosed chronic phase and/or platelet counts interrupted and blood count monitored.

CML at 300 mg twice 9 2. Treatment must be resumed withindaily and imatinib-resistant <50 × 10 /l 2 weeks at prior dose if ANCor intolerant CML in > 1.0 × 109/l and/or plateletschronic phase at 400 mg > 50 × 109/l.

twice daily 3. If blood counts remain low, a dosereduction to 400 mg once daily may berequired.

Adult patients with ANC* <0.5 × 109/l 1. Treatment with nilotinib must beimatinib-resistant or and/or platelet counts interrupted and blood count monitored.

intolerant CML in 9 2. Treatment must be resumed withinaccelerated phase at <10 × 10 /l 2 weeks at prior dose if ANC400 mg twice daily > 1.0 x 109/l and/or platelets> 20 × 109/l.3. If blood counts remain low, a dosereduction to 400 mg once daily maybe required.

Paediatric patients with ANC* <1.0 × 109/l 1. Treatment with nilotinib must benewly diagnosed CML in and/or platelet counts interrupted and blood count monitored.

chronic phase at 9 2. Treatment must be resumed within230 mg/m2 twice daily <50 × 10 /l 2 weeks at prior dose if ANCand > 1.5 × 109/l and/or platelets > 75 × 109/l.imatinib-resistant or 3. If blood counts remain low, a doseintolerant CML in reduction to 230 mg/m2 once daily maychronic phase at be required.230 mg/m2 twice daily 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 beinterrupted, and patients should be monitored and treated accordingly. If the prior dose was 300 mgtwice daily in adult newly diagnosed patients with CML in the chronic phase, or 400 mg twice daily inadult patients with imatinib-resistant or intolerant CML in chronic or accelerated phase, or 230 mg/m2twice daily in paediatric patients, dosing may be resumed at 400 mg once daily in adult patients and at230 mg/m2 once daily in paediatric patients once the toxicity has resolved. If the prior dose was400 mg once daily in adult patients or 230 mg/m2 once daily in paediatric patients, treatment should be

VAR/IB/INI-SPC Comaparison 5discontinued. If clinically appropriate, re-escalation of the dose to the starting dose of 300 mg twicedaily in adult newly diagnosed patients with CML in the chronic phase or to 400 mg twice daily inadult patients with imatinib-resistant or intolerant CML in chronic or accelerated phase or to230 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 bereduced to 400 mg once daily or interrupted. In paediatric patients, treatment must be interrupted untilthe event returns to Grade  1. Thereafter, if the prior dose was 230 mg/m2 twice daily, treatment canbe resumed at 230 mg/m2 once daily. If the prior dose was 230 mg/m2 once daily, treatment should bediscontinued. 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 transaminaseelevations 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, treatmentmust be interrupted until the levels return to Grade  1. Thereafter, if the prior dose was 230 mg/m2twice daily, treatment can be resumed at 230 mg/m2 once daily. If the prior dose was 230 mg/m2 oncedaily, 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.

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

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 notanticipated in patients with renal impairment.

Hepatic impairment has a modest effect on the pharmacokinetics of nilotinib. Dose adjustment is notconsidered necessary in patients with hepatic impairment. However, patients with hepatic impairmentshould be treated with caution (see section 4.4).

In clinical studies, patients with uncontrolled or significant cardiac disease (e.g., recent myocardialinfarction, congestive heart failure, unstable angina or clinically significant bradycardia) wereexcluded. 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 afterinitiating therapy and at least yearly during chronic therapy.

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

The safety and efficacy of Nilotinib in paediatric patients with Philadelphia chromosome positive CMLin chronic phase from 2 to less than 18 years of age have been established (see sections 4.8, 5.1 and5.2). 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

VAR/IB/INI-SPC Comaparison 6diagnosed paediatric patients below 10 years of age and limited data in imatinib-resistant or intolerantpaediatric patients below 6 years of age.

Nilotinib Accord should be taken twice daily approximately 12 hours apart and must not be taken withfood. The hard capsules should be swallowed whole with water. No food should be consumed for2 hours before the dose is taken and no food should be consumed for at least one hour after the dose istaken.

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

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

Treatment with nilotinib is associated with (National Cancer Institute Common Toxicity Criteria grade3 and 4) thrombocytopenia, neutropenia and anaemia. Occurrence is more frequent in patients withimatinib-resistant or intolerant CML, in particular in patients with accelerated-phase CML. Completeblood 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 bywithholding nilotinib temporarily or dose reduction (see section 4.2).

Nilotinib has been shown to prolong cardiac ventricular repolarisation as measured by the QT intervalon 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 mgnilotinib twice daily, the change from baseline in mean time-averaged QTcF interval at steady statewas 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 acceleratedphase receiving 400 mg nilotinib twice daily, the change from baseline in mean time-averaged QTcFinterval at steady state was 5 and 8 msec, respectively. QTcF of > 500 msec was observed in < 1% ofthese 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 inpatients, the time-averaged mean placebo-subtracted QTcF change from baseline was7 msec (CI ± 4 msec). No subject had a QTcF >450 msec. Additionally, no clinically relevantarrhythmias were observed during the conduct of the trial. In particular, no episodes of torsade depointes (transient or sustained) were observed.

Significant prolongation of the QT interval may occur when nilotinib is inappropriately taken withstrong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong the QTinterval, and/or food (see section 4.5). The presence of hypokalaemia and hypomagnesaemia mayfurther enhance this effect. Prolongation of the QT interval may expose patients to the risk of fataloutcome.

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Nilotinib should be used with caution in patients who have or who are at significant risk of developingprolongation 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 recommendedprior to initiating nilotinib therapy and as clinically indicated. Hypokalaemia or hypomagnesaemiamust be corrected prior to nilotinib administration and should be monitored periodically duringtherapy.

Sudden death

Uncommon cases (0.1 to 1%) of sudden deaths have been reported in patients with imatinib-resistantor intolerant CML in chronic phase or accelerated phase with a past medical history of cardiac diseaseor significant cardiac risk factors. Co-morbidities in addition to the underlying malignancy were alsofrequently present as were concomitant medicinal products. Ventricular repolarisation abnormalitiesmay have been contributory factors. No cases of sudden death were reported in the Phase III study innewly diagnosed patients with CML in chronic phase.

Fluid retention and oedema

Severe forms of drug-related fluid retention such as pleural effusion, pulmonary oedema, andpericardial 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 gainshould be carefully investigated. If signs of severe fluid retention appear during treatment withnilotinib, the aetiology should be evaluated and patients treated accordingly (see section 4.2 forinstructions on managing non-haematological toxicities).

Cardiovascular events were reported in a randomised Phase III study in newly diagnosed CML patientsand observed in post-marketing reports. In this clinical study with a median on-therapy time of60.5 months, Grade 3-4 cardiovascular events included peripheral arterial occlusive disease (1.4% and1.1% at 300 mg and 400 mg nilotinib twice daily, respectively), ischaemic heart disease (2.2% and6.1% 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 advisedto seek immediate medical attention if they experience acute signs or symptoms of cardiovascularevents. The cardiovascular status of patients should be evaluated and cardiovascular risk factorsmonitored and actively managed during nilotinib therapy according to standard guidelines.

Appropriate therapy should be prescribed to manage cardiovascular risk factors (see section 4.2 forinstructions on managing non-haematological toxicities).

Reactivation of hepatitis B in patients who are chronic carriers of this virus has occurred after thesepatients received BCR-ABL tyrosine kinase inhibitors. Some cases resulted in acute hepatic failure orfulminant hepatitis leading to liver transplantation or a fatal outcome.

Patients should be tested for HBV infection before initiating treatment with nilotinib. Experts in liverdisease and in the treatment of hepatitis B should be consulted before treatment is initiated in patientswith positive hepatitis B serology (including those with active disease) and for patients who testpositive for HBV infection during treatment. Carriers of HBV who require treatment with nilotinibshould be closely monitored for signs and symptoms of active HBV infection throughout therapy andfor several months following termination of therapy (see section 4.8).

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

Eligibility for discontinuation of treatment

Eligible patients who are confirmed to express the typical BCR-ABL transcripts, e13a2/b2a2 ore14a2/b3a2, can be considered for treatment discontinuation. Patients must have typical BCR-ABLtranscripts to allow quantitation of BCR-ABL, evaluation of the depth of molecular response, anddetermination of a possible loss of molecular remission after discontinuation of treatment withnilotinib.

Monitoring of patients who have discontinued therapy

Frequent monitoring of BCR-ABL transcript levels in patients eligible for treatment discontinuationmust be performed with a quantitative diagnostic test validated to measure molecular response levelswith a sensitivity of at least MR4.5 (BCR-ABL/ABL ≤ 0.0032% IS). BCR-ABL transcript levels mustbe 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 receivednilotinib as first- or second-line therapy, or confirmed loss of MR4 (two consecutive measuresseparated by at least 4 weeks showing loss of MR4 (MR4=BCR-ABL/ABL ≤ 0.01%IS)) in CMLpatients who received nilotinib as second-line therapy will trigger treatment re-initiation within 4 weeksof when loss of remission is known to have occurred. Molecular relapse can occur during thetreatment-free phase, and long-term outcome data are not yet available. It is therefore crucial toperform frequent monitoring of BCR-ABL transcript levels and complete blood count with differentialin order to detect possible loss of remission (see section 4.2). For patients who fail to achieve MMRafter three months of treatment re-initiation, BCR-ABL kinase domain mutation testing should beperformed.

Laboratory tests and monitoring

Blood lipids

In a Phase III study in newly diagnosed CML patients, 1.1% of the patients treated with 400 mgnilotinib twice daily showed a Grade 3-4 elevation in total cholesterol; no Grade 3-4 elevations werehowever observed in the 300 mg twice daily dose group (see section 4.8). It is recommended that thelipid profiles be determined before initiating treatment with nilotinib, assessed at month 3 and 6 afterinitiating therapy and at least yearly during chronic therapy (see section 4.2). If a HMG-CoA reductaseinhibitor (a lipid-lowering agent) is required, please refer to section 4.5 before initiating treatmentsince 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 with400 mg nilotinib and 300 mg nilotinib twice daily, respectively, showed a Grade 3-4 elevation in bloodglucose. It is recommended that the glucose levels be assessed before initiating treatment with Nilotiniband 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.

The administration of nilotinib with agents that are strong CYP3A4 inhibitors (including, but notlimited to, ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir) should beavoided. Should treatment with any of these agents be required, it is recommended that nilotinibtherapy be interrupted if possible (see section 4.5). If transient interruption of treatment is not possible,

VAR/IB/INI-SPC Comaparison 9close monitoring of the individual for prolongation of the QT interval is indicated (see sections 4.2, 4.5and 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 exposureto nilotinib to a clinically relevant extent. Therefore, in patients receiving nilotinib, co-administrationof alternative therapeutic agents with less potential for CYP3A4 induction should be selected (seesection 4.5).

The bioavailability of nilotinib is increased by food. Nilotinib must not be taken in conjunction withfood (see sections 4.2 and 4.5) and should be taken 2 hours after a meal. No food should be consumedfor 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 bedispersed in one teaspoon of apple sauce and should be taken immediately. Not more than oneteaspoon of apple sauce and no food other than apple sauce must be used (see section 5.2).

Hepatic impairment has a modest effect on the pharmacokinetics of nilotinib. Single doseadministration of 200 mg of nilotinib resulted in increases in AUC of 35%, 35% and 19% in subjectswith mild, moderate and severe hepatic impairment, respectively, compared to a control group ofsubjects with normal hepatic function. The predicted steady-state Cmax of nilotinib showed anincrease of 29%, 18% and 22%, respectively. Clinical studies have excluded patients with alaninetransaminase (ALT) and/or aspartate transaminase (AST) >2.5 (or >5, if related to disease) times theupper 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 haveincreased 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 historyof pancreatitis. In case lipase elevations are accompanied by abdominal symptoms, nilotinib therapyshould 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.

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

Lactose (as monohydrate) (for 50 mg, 150 mg and 200 mg)

Nilotinib Accord hard capsules contain lactose. Patients with rare hereditary problems of galactoseintolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinalproduct.

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Potassium (for50 mg, 150 mg and 200 mg)

This medicine contains potassium, less than 1 mmol (39 mg) per capsule, i.e. essentially ‘potassium-free’.

Sodium (for 200 mg)

This medicine contains less than 1 mmol sodium (23 mg) per capsule, that is to say essentially ˋ sodiumfree´.

Allura red AC (for 200 mg)

This medicine contains allura red AC, which may cause allergic reactions.

Laboratory abnormalities of mild to moderate transient elevations of aminotransferases and totalbilirubin have been observed in children at a higher frequency than in adults, indicating a higher risk ofhepatotoxicity in the paediatric population (see section 4.8). Liver function (bilirubin and hepatictransaminases levels) should be monitored monthly or as clinically indicated. Elevations of bilirubinand hepatic transaminases should be managed by withholding nilotinib temporarily, dose reductionand/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). Closemonitoring of growth in paediatric patients under nilotinib treatment is recommended.

Nilotinib may be given in combination with haematopoietic growth factors such as erythropoietin orgranulocyte colony-stimulating factor (G-CSF) if clinically indicated. It may be given withhydroxyurea or anagrelide if clinically indicated.

Nilotinib is mainly metabolised in the liver with CYP3A4 expected to be the main contributor to theoxidative 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 beinfluenced 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 increasedby 18% to 39%, and the AUC of nilotinib was increased by 18% to 40%. These changes are unlikely tobe clinically important.

The exposure to nilotinib in healthy subjects was increased 3-fold when co-administered with thestrong 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 expectedwith 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 AUCby 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

VAR/IB/INI-SPC Comaparison 11a clinically relevant extent. In patients for whom CYP3A4 inducers are indicated, alternative agentswith less enzyme induction potential should be selected.

Nilotinib has pH dependent solubility, with lower solubility at higher pH. In healthy subjects receivingesomeprazole at 40 mg once daily for 5 days, gastric pH was markedly increased, but nilotinibabsorption 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 whena 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 administeredapproximately 10 hours before and approximately 2 hours after the dose of nilotinib.

In the same study as above, administration of an antacid (aluminium hydroxide/magnesiumhydroxide/simethicone) 2 hours before or after a single 400 mg dose of nilotinib also did not alternilotinib pharmacokinetics. Therefore, if necessary, an antacid may be administered approximately2 hours before or approximately 2 hours after the dose of nilotinib.

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 pharmacokineticparameters or warfarin pharmacodynamics measured as prothrombin time (PT) and internationalnormalised ratio (INR). There are no steady-state data. This study suggests that a clinically meaningfuldrug-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) followinginitiation 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 systemicexposure (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 othermedicinal products primarily metabolised by CYP3A4 (e.g. certain HMG-CoA reductase inhibitors)may be increased when co-administered with nilotinib. Appropriate monitoring and dose adjustmentmay be necessary for medicinal products that are CYP3A4 substrates and have a narrow therapeuticindex (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 increasethe 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 QTinterval, including those patients taking anti-arrhythmic medicinal products such as amiodarone,disopyramide, procainamide, quinidine and sotalol or other medicinal products that may lead to QTprolongation such as chloroquine, halofantrine, clarithromycin, haloperidol, methadone andmoxifloxacin (see section 4.4).

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

VAR/IB/INI-SPC Comaparison 12

Interaction studies have only been performed in adults.

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

There are no or limited amount of data from the use of nilotinib in pregnant women. Studies in animalshave shown reproductive toxicity (see section 5.3). Nilotinib should not be used during pregnancyunless the clinical condition of the woman requires treatment with nilotinib. If it is used duringpregnancy, 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 discontinuationmay be considered based on the eligibility criteria for discontinuing treatment as described in sections4.2 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 apotential need to re-initiate nilotinib treatment during pregnancy (see sections 4.2 and 4.4).

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

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

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

The safety profile is based on pooled data from 3 422 patients treated with nilotinib in 13 clinicalstudies in the approved indications: adults and paediatric patients with newly diagnosed Philadelphiachromosome positive chronic myelogenous leukaemia (CML) in the chronic phase (5 clinical studieswith 2 414 patients), adult patients with chronic phase and accelerated phase Philadelphia chromosomepositive CML with resistance or intolerance to prior therapy including imatinib (6 clinical studies with939 patients) and paediatric patients with chronic phase Philadelphia chromosome positive CML withresistance or intolerance to prior therapy including imatinib (2 clinical studies with 69 patients). Thesepooled data represents 9 039.34 patient-years of exposure. The safety profile of nilotinib is consistentacross 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%)

VAR/IB/INI-SPC Comaparison 13headache (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%).

Adverse reactions from clinical studies and post-marketing reports (table 3) are listed by MedDRAsystem organ class and frequency category. Frequency categories are defined using the followingconvention: 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 theavailable data).

Table 3 Adverse drug reactions

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

Very common: Anaemia, thrombocytopenia

Common: Leukopenia, leukocytosis, neutropenia, thrombocythaemia

Uncommon: Eosinophilia, febrile neutropenia, lymphopenia, pancytopenia

Uncommon: Hypersensitivity

Very common: Growth retardation

Common: Hypothyroidism

Uncommon: Hyperthyroidism

Rare: Hyperparathyroidism secondary, thyroiditis

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

Uncommon: Dehydration, increased appetite, dyslipidaemia, hypoglycaemia

Rare: Appetite disorder, tumour lysis syndrome

Common: Depression, insomnia, anxiety

Uncommon: Amnesia, confusional state, disorientation

Rare: Dysphoria

VAR/IB/INI-SPC Comaparison 14

Very common: Headache

Common: Dizziness, hypoaesthesia, paraesthesia, migraine

Uncommon: Cerebrovascular accident, intracranial/cerebral haemorrhage, ischaemicstroke, transient ischaemic attack, cerebral infarction, loss ofconsciousness (including syncope), tremor, disturbance in attention,hyperaesthesia, dysaesthesia, lethargy, peripheral neuropathy, restlesslegs syndrome, facial paralysis

Rare: Basilar artery stenosis, brain oedema, optic neuritis

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 surfacedisease, periorbital oedema, photophobia

Rare: Chorioretinopathy, papilloedema

Ear and labyrinth disorders

Common: Vertigo, ear pain, tinnitus

Uncommon: Hearing impaired (hypoacusis)

Common: Angina pectoris, arrhythmia (including atroventricular block, cardiacflutter, ventricular extrasystoles, tachycardia, atrial fibrillation,bradycardia), palpitations, electrocardiogram QT prolonged, coronaryartery disease

Uncommon: Myocardial infarction, cardiac murmur, pericardial effusion, cardiacfailure, diastolic dysfunction, left bundle branch block, pericarditis

Rare: Cyanosis, ejection fraction decreased

Not known: Ventricular dysfunction

Common: Hypertension, flushing, peripheral arterial occlusive disease

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

Rare: Shock haemorrhagic

Very common: Cough

Common: Dyspnoea, dyspnoea exertional, epistaxis, oropharyngeal pain

Uncommon: Pulmonary oedema, pleural effusion, interstitial lung disease, pleuriticpain, pleurisy, throat irritation, dysphonia, pulmonary hypertension,wheezing

Rare: Pharyngolaryngeal pain

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, oesophagealpain, 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

Very common: Hyperbilirubinaemia (including blood bilirubin increased)

Common: Hepatic function abnormal

Uncommon: Hepatotoxicity, toxic hepatitis, jaundice, cholestasis, hepatomegaly

VAR/IB/INI-SPC Comaparison 15

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, skinhyperpigmentation, skin hypertrophy, skin ulcer

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

Very common Myalgia, arthralgia, back pain, pain in extremity

Common: Musculoskeletal chest pain, musculoskeletal pain, neck pain, muscularweakness, muscle spasms, bone pain

Uncommon: Musculoskeletal stiffness, joint swelling, arthritis, flank pain

Common: Pollakiuria, dysuria

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

Common: Erectile dysfunction, menorrhagia

Uncommon: Breast pain, gynaecomastia, nipple swelling

Rare: Breast induration

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

Very common: Alanine aminotransferase increased, lipase increased

Common: Haemoglobin decreased, blood amylase increased, aspartateaminotransferase increased, blood alkaline phosphatase increased, gamma-glutamyltransferase increased, blood creatinine phosphokinase increased,weight decreased, weight increased, elevated creatinine, total cholesterolincreased

Uncommon: Blood lactate dehydrogenase increased, blood urea increased, bloodbilirubin 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.

Sudden death

Uncommon cases (0.1 to 1%) of sudden deaths have been reported in nilotinib clinical studies and/orcompassionate use programs in patients with imatinib -resistant or intolerant CML in chronic phaseor accelerated phase with a past medical history of cardiac disease or significant cardiac risk factors(see section 4.4).

VAR/IB/INI-SPC Comaparison 16

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

The safety of nilotinib in paediatric patients (from 2 to <18 years of age) with Philadelphiachromosome positive CML in chronic phase (n=58) has been investigated in one main study over aperiod of 60 months (see section 5.1). In paediatric patients, the frequency, type and severity ofadverse reactions observed have been generally consistent with those observed in adults, with theexception of hyperbilirubinaemia/blood bilirubin increase (Grade 3/4: 10.3%) and transaminaseelevation (AST Grade 3/4: 1.7%, ALT Grade 3/4: 12.1%) which were reported at a higher frequencythan in adult patients. Bilirubin and hepatic transaminase levels should be monitored duringtreatment (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 innewly 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 werereported in 3 patients (5.2%). Close monitoring of growth in paediatric patients under nilotinibtreatment is recommended (see section 4.4).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Isolated reports of intentional overdose with nilotinib were reported, where an unspecified number ofnilotinib hard capsules were ingested in combination with alcohol and other medicinal products. Eventsincluded 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.

Pharmacotherapeutic group: Antineoplastic agents, BCR-ABL tyrosine kinase inhibitors, ATCcode: L01EA03.

Nilotinib is a potent inhibitor of the ABL tyrosine kinase activity of the BCR-ABL oncoprotein bothin cell lines and in primary Philadelphia-chromosome positive leukaemia cells. The substance bindswith high affinity to the ATP-binding site in such a manner that it is a potent inhibitor of wild-type

BCR-ABL and maintains activity against 32/33 imatinib-resistant mutant forms of BCR-ABL. As a

VAR/IB/INI-SPC Comaparison 17consequence of this biochemical activity, nilotinib selectively inhibits the proliferation and inducesapoptosis in cell lines and in primary Philadelphia-chromosome positive leukaemia cells from CMLpatients. In murine models of CML, as a single agent nilotinib reduces tumour burden and prolongssurvival following oral administration.

Nilotinib has little or no effect against the majority of other protein kinases examined, including Src,except for the PDGF, KIT and Ephrin receptor kinases, which it inhibits at concentrations within therange achieved following oral administration at therapeutic doses recommended for the treatment of

CML (see table 4).

Table 4 Kinase profile of nilotinib (phosphorylation IC50 nM)

BCR-ABL PDGFR KIT20 69 210

Clinical studies in newly diagnosed CML in chronic phase

An open-label, multicentre, randomised Phase III study was conducted to determine the efficacy ofnilotinib versus imatinib in 846 adult patients with cytogenetically confirmed newly diagnosed

Philadelphia chromosome positive CML in the chronic phase. Patients were within six months ofdiagnosis and were previously untreated, with the exception of hydroxyurea and/or anagrelide.

Patients were randomised 1:1:1 to receive either nilotinib 300 mg twice daily (n=282), nilotinib 400 mgtwice daily (n=281) or imatinib 400 mg once daily (n=283). Randomisation was stratified by Sokal riskscore at the time of diagnosis.

Baseline characteristics were well balanced between the three treatment arms. Median age was 47 yearsin both nilotinib arms and 46 years in the imatinib arm, with 12.8%, 10.0% and 12.4% of patients were≥ 65 years of age in the nilotinib 300 mg twice daily, nilotinib 400 mg twice daily and imatinib 400 mgonce daily treatment arms, respectively. There were slightly more male than female patients (56.0%,62.3% and 55.8%, in the nilotinib 300 mg twice daily, 400 mg twice daily and imatinib 400 mg oncedaily arm, respectively). More than 60% of all patients were Caucasian and 25% of all patients were

Asian.

The primary data analysis time point was when all 846 patients completed 12 months of treatment (ordiscontinued earlier). Subsequent analyses reflect when patients completed 24, 36, 48, 60 and 72months of treatment (or discontinued earlier). The median time on treatment was approximately 70months in the nilotinib treatment groups and 64 months in the imatinib group. The median actual doseintensity was 593 mg/day for nilotinib 300 mg twice daily, 772 mg/day for nilotinib 400 mg twicedaily and 400 mg/day for imatinib 400 mg once daily. This study is ongoing.

The primary efficacy endpoint was major molecular response (MMR) at 12 months. MMR wasdefined as ≤0.1% BCR-ABL/ABL% by international scale (IS) measured by RQ-PCR, whichcorresponds to a ≥3 log reduction of BCR-ABL transcript from standardised baseline. The MMR rateat 12 months was statistically significantly higher for nilotinib 300 mg twice daily compared toimatinib 400 mg once daily (44.3% versus 22.3%, p<0.0001). The rate of MMR at 12 months, wasalso statistically significantly higher for nilotinib 400 mg twice daily compared to imatinib 400 mgonce daily (42.7% versus 22.3%, p<0.0001).

The rates of MMR at 3, 6, 9 and 12 months were 8.9%, 33.0%, 43.3% and 44.3% for nilotinib 300 mgtwice daily, 5.0%, 29.5%, 38.1% and 42.7% for nilotinib 400 mg twice daily and 0.7%, 12.0%, 18.0%and 22.3% for imatinib 400 mg once daily.

The MMR rate at 12, 24, 36, 48, 60 and 72 months is presented in table 5.

VAR/IB/INI-SPC Comaparison 18

Table 5 MMR rate

Nilotinib Nilotinib Imatinib300 mg twice daily 400 mg twice daily 400 mg once dailyn=282 n=281 n=283(%) (%) (%)

MMRat 12 months

Response (95% CI) 44.31 (38.4; 50.3) 42.71 (36.8; 48.7) 22.3 (17.6; 27.6)

MMR at 24 months

Response (95% CI) 61.71 (55.8; 67.4) 59.11 (53.1; 64.9) 37.5 (31.8; 43.4)

MMR at 36 months2

Response (95% CI) 58.51 (52.5; 64.3) 57.31 (51.3; 63.2) 38.5 (32.8; 44.5)

MMR at 48 months3

Response (95% CI) 59.91 (54.0; 65.7) 55.2 (49.1; 61.1) 43.8 (38.0; 49.8)

MMR at 60 months4

Response (95% CI) 62.8 (56.8; 68.4) 61.2 (55.2; 66.9) 49.1 (43.2; 55.1)

MMR at 72 months5

Response (95% CI) 52.5 (46.5; 58.4) 57.7 (51.6; 63.5) 41.7 (35.9; 47.7)1 Cochran-Mantel-Haenszel (CMH) test p-value for response rate (vs. imatinib 400 mg) < 0.00012 Only patients who were in MMR at a specific time point are included as responders for that timepoint. A total of 199 (35.2%) of all patients were not evaluable for MMR at 36 months (87 in thenilotinib 300 mg twice daily group and 112 in the imatinib group) due to missing/unevaluable PCRassessments (n=17), atypical transcripts at baseline (n=7), or discontinuation prior to the 36-monthtime point (n=175).3 Only patients who were in MMR at a specific time point are included as responders for that timepoint. A total of 305 (36.1%) of all patients were not evaluable for MMR at 48 months (98 in thenilotinib 300 mg BID group, 88 in the nilotinib 400 mg BID group and 119 in the imatinib group)due to missing/unevaluable PCR assessments (n=18), atypical transcripts at baseline (n=8), ordiscontinuation prior to the 48-month time point (n=279).4 Only patients who were in MMR at a specific time point are included as responders for that timepoint. A total of 322 (38.1%) of all patients were not evaluable for MMR at 60 months (99 in thenilotinib 300 mg twice daily group, 93 in the nilotinib 400 mg twice daily group and 130 in theimatinib group) due to missing/unevaluable PCR assessments (n=9), atypical transcripts at baseline(n=8) or discontinuation prior to the 60-month time point (n=305).5 Only patients who were in MMR at a specific time point are included as responders for that timepoint. A total of 395 (46.7%) of all patients were not evaluable for MMR at 72 months (130 in thenilotinib 300 mg twice daily group, 110 in the nilotinib 400 mg twice daily group and 155 in theimatinib group) due to missing/unevaluable PCR assessments (n=25), atypical transcripts at baseline(n=8) or discontinuation prior to the 72-month time point (n=362).

MMR rates by different time points (including patients who achieved MMR at or before those timepoints as responders) are presented in the cumulative incidence of MMR (see Figure 1).

VAR/IB/INI-SPC Comaparison 19

Figure 1 Cumulative incidence of MMR

For all Sokal risk groups, the MMR rates at all time points remained consistently higher in the twonilotinib groups than in the imatinib group.

In a retrospective analysis, 91% (234/258) of patients on nilotinib 300 mg twice daily achieved

BCR-ABL levels ≤ 10% at 3 months of treatment compared to 67% (176/264) of patients on imatinib400 mg once daily. Patients with BCR-ABL levels ≤10% at 3 months of treatment show a greateroverall survival at 72 months compared to those who did not achieve this molecular response level(94.5% vs. 77.1% respectively [p=0.0005]).

Based on the Kaplan-Meier analysis of time to first MMR the probability of achieving MMR atdifferent time points was higher for both nilotinib at 300 mg and 400 mg twice daily compared toimatinib 400 mg once daily (HR=2.17 and stratified log-rank p< 0.0001 between nilotinib 300 mgtwice daily and imatinib 400 mg once daily, HR=1.88 and stratified log-rank p< 0.0001 betweennilotinib 400 mg twice daily and imatinib 400 mg once daily).

The proportion of patients who had a molecular response of ≤0.01% and ≤0.0032% by IS at differenttime points are presented in table 6 and the proportion of patients who had a molecular response of≤0.01% and ≤0.0032% by IS by different time points are presented in figures 2 and 3. Molecularresponses of ≤0.01% and ≤0.0032% by IS correspond to a ≥4 log reduction and ≥4.5 log reduction,respectively, of BCR-ABL transcripts from a standardised baseline.

Table 6 Proportions of patients who had molecular response of ≤ 0.01% (4 log reduction)and ≤ 0.0032% (4.5 log reduction)

Nilotinib Nilotinib Imatinib300 mg twice daily 400 mg twice daily 400 mg once dailyn=282 n=281 n=283(%) (%) (%)≤ 0.01% ≤ 0.0032% ≤ 0.01% ≤ 0.0032% ≤ 0.01% ≤ 0.0032%

At 12 months 11.7 4.3 8.5 4.6 3.9 0.4

At 24 months 24.5 12.4 22.1 7.8 10.2 2.8

At 36 months 29.4 13.8 23.8 12.1 14.1 8.1

At 48 months 33.0 16.3 29.9 17.1 19.8 10.2

At 60 months 47.9 32.3 43.4 29.5 31.1 19.8

VAR/IB/INI-SPC Comaparison 20

At 72 months 44.3 31.2 45.2 28.8 27.2 18.0

Figure 2 Cumulative incidence of molecular response of ≤ 0.01% (4-log reduction)

Figure 3 Cumulative incidence of molecular response of ≤ 0.0032% (4.5 log reduction)

Based on Kaplan-Meier estimates of the duration of first MMR, the proportions of patients who weremaintaining response for 72 months among patients who achieved MMR were 92.5%(95% CI: 88.6-96.4%) in the nilotinib 300 mg twice daily group, 92.2% (95% CI: 88.5-95.9%) in thenilotinib 400 mg twice daily group and 88.0% (95% CI: 83.0-93.1%) in the imatinib 400 mg oncedaily group.

Complete cytogenetic response (CCyR) was defined as 0% Ph+ metaphases in the bone marrow basedon a minimum of 20 metaphases evaluated. Best CCyR rate by 12 months (including patients who

VAR/IB/INI-SPC Comaparison 21achieved CCyR at or before the 12 month time point as responders) was statistically higher for bothnilotinib 300 mg and 400 mg twice daily compared to imatinib 400 mg once daily, see table 7.

CCyR rate by 24 months (includes patients who achieved CCyR at or before the 24 month time pointas responders) was statistically higher for both the nilotinib 300 mg twice daily and 400 mg twice dailygroups compared to the imatinib 400 mg once daily group.

Table 7 Best CCyR rate

Nilotinib Nilotinib Imatinib300 mg twice 400 mg twice 400 mg once dailydaily daily n=283n=282 n=281 (%)(%) (%)

By 12 months

Response (95% CI) 80.1 (75.0; 84.6) 77.9 (72.6; 82.6) 65.0 (59.2; 70.6)

No response 19.9 22.1 35.0

CMH test p-value for response rate < 0.0001 0.0005(versus imatinib 400 mg once daily)

By 24 months

Response (95% CI) 86.9 (82.4; 90.6) 84.7 (79.9; 88.7) 77.0 (71.7; 81.8)

No response 13.1 15.3 23.0

CMH test p-value for response rate 0.0018 0.0160(versus imatinib 400 mg once daily)

Based on Kaplan-Meier estimates, the proportions of patients who were maintaining response for72 months among patients who achieved CCyR were 99.1% (95% CI: 97.9-100%) in the nilotinib300 mg twice daily group, 98.7% (95% CI: 97.1-100%) in the nilotinib 400 mg twice daily group and97.0% (95% CI: 94.7-99.4%) in the imatinib 400 mg once daily group.

Progression to accelerated phase (AP) or blast crisis (BC) on treatment is defined as the time from thedate of randomisation to the first documented disease progression to accelerated phase or blast crisis or

CML-related death. Progression to accelerated phase or blast crisis on treatment was observed in atotal of 17 patients: 2 patients on nilotinib 300 mg twice daily, 3 patients on nilotinib 400 mg twicedaily and 12 patients on imatinib 400 mg once daily. The estimated rates of patients free fromprogression to accelerated phase or blast crisis at 72 months were 99.3%, 98.7% and 95.2%,respectively (HR=0.1599 and stratified log-rank p=0.0059 between nilotinib 300 mg twice daily andimatinib once daily, HR=0.2457 and stratified log-rank p=0.0185 between nilotinib 400 mg twice dailyand imatinib once daily). No new events of progression to AP/BC were reported on-treatment since the2-year analysis.

Including clonal evolution as a criterion for progression, a total of 25 patients progressed to acceleratedphase or blast crisis on treatment by the cut-off date (3 in the nilotinib 300 mg twice daily group, 5 inthe nilotinib 400 mg twice daily group and 17 in the imatinib 400 mg once daily group). The estimatedrates of patients free from progression to accelerated phase or blast crisis including clonal evolution at72 months were 98.7%, 97.9% and 93.2%, respectively (HR=0.1626 and stratified log-rank p=0.0009between nilotinib 300 mg twice daily and imatinib once daily, HR=0.2848 and stratified log-rankp=0.0085 between nilotinib 400 mg twice daily and imatinib once daily).

A total of 55 patients died during treatment or during the follow-up after discontinuation of treatment(21 in the nilotinib 300 mg twice daily group, 11 in the nilotinib 400 mg twice daily group and 23 inthe imatinib 400 mg once daily group). Twenty-six (26) of these 55 deaths were related to CML (6 inthe nilotinib 300 mg twice daily group, 4 in the nilotinib 400 mg twice daily group and 16 in theimatinib 400 mg once daily group). The estimated rates of patients alive at 72 months were 91.6%,95.8% and 91.4%, respectively (HR=0.8934 and stratified log-rank p=0.7085 between nilotinib 300 mgtwice daily and imatinib, HR=0.4632 and stratified log-rank p=0.0314 between nilotinib 400 mg twicedaily and imatinib). Considering only CML-related deaths as events, the estimated rates of overall

VAR/IB/INI-SPC Comaparison 22survival at 72 months were 97.7%, 98.5% and 93.9%, respectively (HR=0.3694 and stratified log-rankp=0.0302 between nilotinib 300 mg twice daily and imatinib, HR=0.2433 and stratified log-rankp=0.0061 between nilotinib 400 mg twice daily and imatinib).

Clinical studies in imatinib-resistant or intolerant CML in chronic phase and accelerated phase

An open-label, uncontrolled, multicentre Phase II study was conducted to determine the efficacy ofnilotinib in adult patients with imatinib resistant or intolerant CML with separate treatment arms forchronic and accelerated phase disease. Efficacy was based on 321 CP patients and 137 AP patientsenrolled. Median duration of treatment was 561 days for CP patients and 264 days for AP patients (seetable 8). Nilotinib was administered on a continuous basis (twice daily 2 hours after a meal and with nofood for at least one hour after administration) unless there was evidence of inadequate response ordisease progression. The dose was 400 mg twice daily and dose escalation to 600 mg twice daily wasallowed.

Table 8 Duration of exposure with nilotinib

Chronic phase Accelerated phasen=321 n=137

Median duration of therapy in days 561 264(25th-75th percentiles) (196-852) (115-595)

Resistance to imatinib included failure to achieve a complete haematological response (by 3 months),cytogenetic response (by 6 months) or major cytogenetic response (by 12 months) or progression ofdisease after a previous cytogenetic or haematological response. Imatinib intolerance includedpatients who discontinued imatinib because of toxicity and were not in major cytogenetic responseat time of study entry.

Overall, 73% of patients were imatinib-resistant, while 27% were imatinib-intolerant. The majority ofpatients had a long history of CML that included extensive prior treatment with other antineoplasticagents, including imatinib, hydroxyurea, interferon, and some had even failed organ transplant(table 9). The median highest prior imatinib dose had been 600 mg/day. The highest prior imatinibdose was  600 mg/day in 74% of all patients, with 40% of patients receiving imatinib doses 800 mg/day.

Table 9 CML disease history characteristics

Chronic phase Accelerated phase(n=321) (n=137)*

Median time since diagnosis in months 58 71(range) (5-275) (2-298)

Imatinib

Resistant 226 (70%) 109 (80%)

Intolerant without MCyR 95 (30%) 27 (20%)

Median time of imatinib treatment in 975 857days (519-1,488) (424-1,497)(25th-75th percentiles)

Prior hydroxyurea 83% 91%

Prior interferon 58% 50%

Prior bone marrow transplant 7% 8%

* Missing information on imatinib-resistant/intolerant status for one patient.

The primary endpoint in the CP patients was major cytogenetic response (MCyR), defined aselimination (CCyR, complete cytogenetic response) or significant reduction to <35% Ph+ metaphases(partial cytogenetic response) of Ph+ haematopoietic cells. Complete haematological response (CHR)in CP patients was evaluated as a secondary endpoint. The primary endpoint in the AP patients wasoverall confirmed haematological response (HR), defined as either a complete haematologicalresponse, no evidence of leukaemia or return to chronic phase.

VAR/IB/INI-SPC Comaparison 23

Chronic phase

The MCyR rate in 321 CP patients was 51%. Most responders achieved their MCyR rapidlywithin 3 months (median 2.8 months) of starting nilotinib treatment and these were sustained.

The median time to achieve CCyR was just past 3 months (median 3.4 months). Of the patientswho achieved MCyR, 77% (95% CI: 70% - 84%) were maintaining response at 24 months.

Median duration of MCyR has not been reached. Of the patients who achieved CCyR, 85%(95% CI: 78% - 93%) were maintaining response at 24 months. Median duration of CCyR has notbeen reached. Patients with a CHR at baseline achieved a MCyR faster (1.9 versus 2.8 months).

Of CP patients without a baseline CHR, 70% achieved a CHR, median time to CHR was 1 monthand median duration of CHR was 32.8 months. The estimated 24 month overall survival rate in

CML-CP patients was 87%.

Accelerated phase

The overall confirmed HR rate in 137 AP patients was 50%. Most responders achieved a HR earlywith nilotinib treatment (median 1.0 months) and these have been durable (median duration ofconfirmed HR was 24.2 months). Of the patients who achieved HR, 53% (95% CI: 39% - 67%)were maintaining response at 24 months. MCyR rate was 30% with a median time to response of2.8 months. Of the patients who achieved MCyR, 63% (95% CI: 45% - 80%) were maintainingresponse at 24 months. Median duration of MCyR was 32.7 months. The estimated 24 monthoverall survival rate in CML-AP patients was 70%.

The rates of response for the two treatment arms are reported in table 10.

Table 10 Response in CML(Best response rate) Chronic phase Accelerated phase

Intolerant Resistant Total Intoleran Resistant Total*(n=95) (n=226) (n=321) t (n=109) (n=137)(n=27)

Haematological

Response (%)

Overall (95% CI) - - - 48 (29-68) 51 (42-61) 50 (42-59)

Complete 87 (74-94) 65 (56-72) 701 (63-76) 37 28 30

NEL - - - 7 10 9

Return to CP - - - 4 13 11

Cytogenetic

Response (%)

Major (95% CI) 57 (46-67) 49 (42-56) 5 1 (46-57) 33 (17-54) 29 (21-39) 30 (22-38)

Complete 41 35 37 22 19 2016 14 15 11 10 10

Partial

NEL = no evidence of leukaemia/marrow response1 114 CP patients had a CHR at baseline and were therefore not assessable for complete haematologicalresponse

* Missing information on imatinib-resistant/intolerant status for one patient.

Efficacy data in patients with CML-BC are not yet available. Separate treatment arms were alsoincluded in the Phase II study to investigate nilotinib in a group of CP and AP patients who had beenextensively pre-treated with multiple therapies including a tyrosine kinase inhibitor agent in addition toimatinib. Of these patients 30/36 (83%) were treatment resistant not intolerant. In 22 CP patientsevaluated for efficacy nilotinib induced a 32% MCyR rate and a 50% CHR rate. In 11 AP patients,evaluated for efficacy, treatment induced a 36% overall HR rate.

After imatinib failure, 24 different BCR-ABL mutations were noted in 42% of chronic phase and 54%of accelerated phase CML patients who were evaluated for mutations. Nilotinib demonstrated efficacy

VAR/IB/INI-SPC Comaparison 24in patients harboring a variety of BCR-ABL mutations associated with imatinib resistance, except

T315I.

Treatment discontinuation in adult Ph+ CML patients in chronic phase who have been treated withnilotinib as first-line therapy and who have achieved a sustained deep molecular response

In an open-label, single-arm study, 215 adult patients with Ph+ CML in chronic phase treated withnilotinib in first-line for ≥ 2 years who achieved MR4.5 as measured with the MolecularMD MRDx

BCR-ABL test were enrolled to continue nilotinib treatment for additional 52 weeks (nilotinibconsolidation phase). 190 of 215 patients (88.4%) entered the TFR phase after achieving a sustaineddeep molecular response during the consolidation phase, defined by the following criteria:

- the 4 last quarterly assessments (taken every 12 weeks) were at least MR4.0 (BCR-ABL/ABL≤ 0.01% IS), and maintained for one year

- the last assessment being MR4.5 (BCR-ABL/ABL ≤ 0.0032% IS)

- no more than two assessments falling between MR4.0 and MR4.5 (0.0032% IS< BCR-ABL/ABL ≤ 0.01% IS).

The primary endpoint was the percentage of patients in MMR at 48 weeks after starting the TFR phase(considering any patient who required re-initiation of treatment as non-responder).

Table 11 Treatment-free remission after nilotinib first-line treatment

Patients entered TFR phase 190weeks after starting TFR phase 48 weeks 264 weekspatients remaining in MMR or 98 (51.6%, [95% CI: 44.2, 79[2] (41.6%, 95% CI: 34.5,better 58.9]) 48.9)

Patients discontinued TFR phase 93 [1] 109due to loss of MMR 88 (46.3%) 94 (49.5%)due to other reasons 5 15

Patients restarted treatment after loss of 86 91

MMRregaining MMR 85 (98.8%) 90 (98.9%)regaining MR4.5 76 (88.4%) 84 (92,3%)[1] One patient did not lose MMR by week 48 but discontinued TFR phase.

[2] For 2 patients, PCR assessment was not available at week 264 therefore their response was notconsidered for the week 264 data cut-off analysis.

The time by which 50% of all retreated patients regained MMR and MR4.5 was 7 and 12.9 weeks,respectively. The cumulative rate of MMR regained at 24 weeks after treatment re-initiation was97.8% (89/91 patients) and MR4.5 regained at 48 weeks was 91.2% (83/91 patients).

The Kaplan-Meier estimate of median treatment-free survival (TFS) was 120.1 weeks (95% CI: 36.9,not estimable [NE]) (Figure 4); 91 of 190 patients (47.9%) did not have a TFS event.

VAR/IB/INI-SPC Comaparison 25

Figure 4 Kaplan-Meier estimate of treatment-free survival after start of TFR (full analysisset)

Treatment discontinuation in adult CML patients in chronic phase who have achieved a sustaineddeep molecular response on nilotinib treatment following prior imatinib therapy

In an open-label, single-arm study, 163 adult patients with Ph+ CML in chronic phase taking tyrosinekinase inhibitors (TKIs) for ≥ 3 years (imatinib as initial TKI therapy for more than 4 weeks withoutdocumented MR4.5 on imatinib at the time of switch to nilotinib, then switched to nilotinib for at leasttwo years), and who achieved MR4.5 on nilotinib treatment as measured with the MolecularMD

MRDx BCR-ABL test were enrolled to continue nilotinib treatment for additional 52 weeks (nilotinibconsolidation phase). 126 of 163 patients (77.3%) entered the TFR phase after achieving a sustaineddeep molecular response during the consolidation phase, defined by the following criterion:

- The 4 last quarterly assessments (taken every 12 weeks) showed no confirmed loss of MR4.5(BCR-ABL/ABL ≤0.0032% IS) during one year.

The primary endpoint was the proportion of patients without confirmed loss of MR4.0or loss of MMR within 48 weeks following treatment discontinuation.

Table 12 Treatment-free remission after nilotinib treatment following prior imatinib therapy

Patients entered TFR phase 126weeks after starting TFR phase 48 weeks 264 weekspatients remaining in MMR, no 73 (57.9%, [95% CI: 48.8, 54 (42.9% [54/126, 95%confirmed loss of MR4.0, and no 66.7]) CI: 34.1, 52.0])re-initiation of nilotinib

Patients discontinued TFR Phase 53 74 [1]due to confirmed loss of MR4.0 or 53 (42.1%) 61 (82.4%)loss of MMRdue to other reasons 0 13

Patients restarted treatment after loss of 51 59

MMR or confirmed loss of MR4.0regaining MR4.0 48 (94.1%) 56 (94.9%)regaining MR4.5 47 (92.2%) 54 (91.5%)[1] two patients had MMR (PCR assessment) at 264 weeks but were discontinued later and had nofurther PCR assessment.

VAR/IB/INI-SPC Comaparison 26

The Kaplan-Meier estimated median time on nilotinib to regain MR4.0 and MR4.5 was 11.1 weeks(95% CI:8.1, 12.1) and 13.1 weeks (95% CI:12.0, 15.9), respectively. The cumulative rate of MR4 and

MR4.5 regained by 48 weeks after treatment re-initiation was 94.9% (56/59 patients) and 91.5%(54/59 patients), respectively.

The median TFS Kaplan-Meier estimate is 224 weeks (95% CI: 39.9, NE) (Figure 5); 63 of126 patients (50.0%) did not have a TFS event.

Figure 5 Kaplan-Meier estimate of treatment-free survival after start of TFR (full analysisset)

In the main paediatric study conducted with nilotinib, a total of 58 patients from 2 to < 18 years ofage (25 patients newly diagnosed Ph+ CML in chronic phase and 33 patients imatinib/dasatinib-resistant or imatinib-intolerant Ph+ CML in chronic phase) received nilotinib treatment at a dose of230 mg/m2 twice daily, rounded to the nearest 50 mg dose (to a maximum single dose of 400 mg).

Key study data are summarised in table 13.

Table 13 Summary data for the main paediatric study conducted with nilotinib

Newly diagnosed Ph+ resistant or intolerant Ph+

CML-CP CML-CP(n=25) (n=33)

Median time on treatment in 51.9 (1.4 - 61.2) 60.5 (0.7 - 63.5)month, (range)

Median (range) actual dose 377.0 (149 - 468) 436.9 (196 - 493)intensity (mg/m2/day)

Relative dose intensity (%)compared to the planned doseof 230 mg/m2 twice daily

Median (range) 82.0 (32-102) 95.0 (43-107)

Number of patients with 12 (48.0%) 19 (57.6%)>90%

MMR (BCR-ABL/ABL 60%, (38.7, 78.9) 48.5%, (30.8, 66.5)≤ 0.1%) IS at 12 cycles, (95%

CI)

MMR by cycle 12, (95% CI) 64.0%, (42.5, 82.0) 57.6%, (39.2, 74.5)

VAR/IB/INI-SPC Comaparison 27

MMR by cycle 66, (95% CI) 76.0%, (54.9, 90.6) 60.6%, (42.1, 77.1)

Median time to MMR in month 5.56 (5.52, 10.84) 2.79 (0.03, 5.75)(95% CI)

No. of patients (%) achieved 14 (56.0%) 9 (27.3%)

MR4.0 (BCR-ABL/ABL≤ 0.01% IS) by cycle 66

No. of patients (%) achieved 11 (44.0%) 4 (12.1%)

MR4.5 (BCR-ABL/ABL≤ 0.0032% IS) by cycle 66

Confirmed loss of MMR 3 out of 19 None out of 20among patients who achieved

MMR

Emergent mutation while on None Nonetreatment

Disease progression while on 1 patient temporarily matched 1 patient progressed to AP/BCtreatment the technical definition for after 10.1 months on treatmentprogression to AP/BC *

Overall survival

No. of events 0 0

Death on treatment 3 (12%) 1 (3%)

Death during survival Not estimable Not estimablefollow up

* one patient temporarily matched the technical definition for progression to AP/BC (due to increasedbasophil cell count), one month after the start of nilotinib (with temporary treatment interruption of13 days during first cycle). The patient remained in the study, went back to CP and was in CHR and

CCyR by 6 cycles of nilotinib treatment.

Peak concentrations of nilotinib are reached 3 hours after oral administration. Nilotinib absorptionfollowing oral administration was approximately 30%. The absolute bioavailability of nilotinib has notbeen determined. As compared to an oral drink solution (pH of 1.2 to 1.3), relative bioavailability ofnilotinib capsule is approximately 50%. In healthy volunteers, Cmax and area under the serumconcentration-time curve (AUC) of nilotinib are increased by 112% and 82%, respectively, comparedto fasting conditions when nilotinib is given with food. Administration of nilotinib 30 minutes or2 hours after food increased bioavailability of nilotinib by 29% or 15%, respectively (see sections 4.2,4.4 and 4.5).

Nilotinib absorption (relative bioavailability) might be reduced by approximately 48% and 22% inpatients with total gastrectomy and partial gastrectomy, respectively.

The blood-to-plasma ratio of nilotinib is 0.71. Plasma protein binding is approximately 98% on thebasis of in vitro experiments.

Main metabolic pathways identified in healthy subjects are oxidation and hydroxylation. Nilotinib isthe main circulating component in the serum. None of the metabolites contribute significantly to thepharmacological activity of nilotinib. Nilotinib is primarily metabolised by CYP3A4, with possibleminor contribution from CYP2C8.

VAR/IB/INI-SPC Comaparison 28

After a single dose of radiolabelled nilotinib in healthy subjects, more than 90% of the dose waseliminated within 7 days, mainly in faeces (94% of the dose). Unchanged nilotinib accounted for 69%of the dose.

The apparent elimination half-life estimated from the multiple-dose pharmacokinetics with dailydosing was approximately 17 hours. Inter-patient variability in nilotinib pharmacokinetics wasmoderate to high.

Steady-state nilotinib exposure was dose-dependent, with less than dose-proportional increases insystemic exposure at dose levels higher than 400 mg given as once-daily dosing. Daily systemicexposure to nilotinib with 400 mg twice-daily dosing at steady state was 35% higher than with 800 mgonce-daily dosing. Systemic exposure (AUC) of nilotinib at steady state at a dose level of 400 mgtwice daily was approximately 13.4% higher than at a dose level of 300 mg twice daily. The averagenilotinib trough and peak concentrations over 12 months were approximately 15.7% and 14.8% higherfollowing 400 mg twice-daily dosing compared to 300 mg twice daily. There was no relevant increasein exposure to nilotinib when the dose was increased from 400 mg twice daily to 600 mg twice daily.

Steady-state conditions were essentially achieved by day 8. An increase in serum exposure to nilotinibbetween the first dose and steady state was approximately 2-fold for daily dosing and 3.8-fold fortwice-daily dosing.

Bioavailability/bioequivalence studies

Single-dose administration of 400 mg nilotinib, using 2 hard capsules of 200 mg whereby the content ofeach hard capsule was dispersed in one teaspoon of apple sauce, was shown to be bioequivalent with asingle-dose administration of 2 intact hard capsules of 200 mg.

Following administration of nilotinib in paediatric patients at 230 mg/m2 twice daily, rounded to thenearest 50 mg dose (to a maximum single dose of 400 mg), steady-state exposure and clearance ofnilotinib were found to be similar (within 2-fold) to adult patients treated with 400 mg twice daily. Thepharmacokinetic exposure of nilotinib following a single or multiple doses appeared to be comparablebetween paediatric patients from 2 years to < 10 years and from ≥ 10 years to < 18 years.

Nilotinib has been evaluated in safety pharmacology, repeated-dose toxicity, genotoxicity,reproductive toxicity, phototoxicity and carcinogenicity (rats and mice) studies.

Safety pharmacology studies

Nilotinib did not have effects on CNS or respiratory functions. In vitro cardiac safety studiesdemonstrated a preclinical signal for QT prolongation, based upon block of hERG currents andprolongation of the action potential duration in isolated rabbit hearts by nilotinib. No effects wereseen in ECG measurements in dogs or monkeys treated for up to 39 weeks or in a special telemetrystudy in dogs.

Repeated-dose toxicity studies

Repeated-dose toxicity studies in dogs of up to 4 weeks’ duration and in cynomolgus monkeys of upto 9 months’ duration revealed the liver as the primary target organ of toxicity of nilotinib.

Alterations included increased alanine aminotransferase and alkaline phosphatase activity andhistopathology findings (mainly sinusoidal cell or Kupffer cell hyperplasia/hypertrophy, bile duct

VAR/IB/INI-SPC Comaparison 29hyperplasia and periportal fibrosis). In general the changes in clinical chemistry were fully reversibleafter a four-week recovery period and the histological alterations showed partial reversibility.

Exposures at the lowest dose levels at which the liver effects were seen were lower than the exposurein humans at a dose of 800 mg/day. Only minor liver alterations were seen in mice or rats treated forup to 26 weeks. Mainly reversible increases in cholesterol levels were seen in rats, dogs andmonkeys.

Genotoxicity studies

Genotoxicity studies in bacterial in vitro systems and in mammalian in vitro and in vivo systems withand without metabolic activation did not reveal any evidence for a mutagenic potential of nilotinib.

Carcinogenicity studies

In the 2-year rat carcinogenicity study, the major target organ for non-neoplastic lesions was theuterus (dilatation, vascular ectasia, endothelial cell hyperplasia, inflammation and/or epithelialhyperplasia). There was no evidence of carcinogenicity upon administration of nilotinib at 5, 15 and40 mg/kg/day. Exposures (in terms of AUC) at the highest dose level represented approximately 2x to3x human daily steady-state exposure (based on AUC) to nilotinib at the dose of 800 mg/day.

In the 26-week Tg.rasH2 mouse carcinogenicity study, in which nilotinib was administered at 30, 100and 300 mg/kg/day, skin papillomas/carcinomas were detected at 300 mg/kg, representingapproximately 30 to 40 times (based on AUC) the human exposure at the maximum approved dose of800 mg/day (administered as 400 mg twice daily). The No-Observed-Effect-Level for the skinneoplastic lesions was 100 mg/kg/day, representing approximately 10 to 20 times the human exposureat the maximum approved dose of 800 mg/day (administered as 400 mg twice daily). The major targetorgans for non-neoplastic lesions were the skin (epidermal hyperplasia), the growing teeth(degeneration/atrophy of the enamel organ of upper incisors and inflammation of thegingiva/odontogenic epithelium of incisors) and the thymus (increased incidence and/or severity ofdecreased lymphocytes).

Reproductive toxicity and fertility studies

Nilotinib did not induce teratogenicity, but did show embryo- and foetotoxicity at doses that alsoshowed maternal toxicity. Increased post-implantation loss was observed in both the fertility study,which involved treatment of both males and females, and the embryotoxicity study, which involvedtreatment of females. Embryo-lethality and foetal effects (mainly decreased foetal weights, prematurefusion of the facial bones (fused maxilla/zygomatic) visceral and skeletal variations) in rats andincreased resorption of foetuses and skeletal variations in rabbits were present in the embryotoxicitystudies. In a pre- and postnatal development study in rats, maternal exposure to nilotinib causedreduced pup body weight with associated changes in physical development parameters as well asreduced mating and fertility indices in the offspring. Exposure to nilotinib in females at

No-Observed-Adverse-Effect-Levels was generally less or equal to that in humans at 800 mg/day.

No effects on sperm count/motility or on fertility were noted in male and female rats up to the highesttested dose, approximately 5 times the recommended dosage for humans.

In a juvenile development study, nilotinib was administered via oral gavage to juvenile rats from thefirst week post partum through young adult (day 70 post partum) at doses of 2, 6 and 20 mg/kg/day.

Besides standard study parameters, evaluations of developmental landmarks, CNS effects, mating andfertility were performed. Based on a reduction in body weight in both genders and a delayed preputialseparation in males (which may be associated with the reduction in weight), the No-Observed-Effect-

Level in juvenile rats was considered to be 6 mg/kg/day. The juvenile animals did not exert increasedsensitivity to nilotinib relative to adults. In addition, the toxicity profile in juvenile rats wascomparable to that observed in adult rats.

VAR/IB/INI-SPC Comaparison 30

Phototoxicity studies

Nilotinib was shown to absorb light in the UV-B and UV-A range, is distributed into the skin andshowed a phototoxic potential in vitro, but no effects have been observed in vivo. Therefore the riskthat nilotinib causes photosensitisation in patients is considered very low.

Lactose monohydrate

Crospovidone

Polysorbate 80

Magnesium aluminometasilicate

Colloidal anhydrous silica

Magnesium stearate

Nilotinib Accord 50 mg and 150 mg hard capsules

Gelatin

Titanium dioxide (E171)

Iron oxide red (E172)

Iron oxide yellow (E172)

Nilotinib Accord 200 mg hard capsules

Gelatin

Titanium dioxide (E171)

Iron oxide yellow (E172)

Nilotinib Accord 50 mg and 150 mg hard capsules

Shellac

Black iron oxide (E172)

Potassium hydroxide

Nilotinib Accord 200 mg hard capsules

Shellac

Sodium hydroxide

Titanium dioxide (E171)

Povidone

Allura red AC

Not applicable.

VAR/IB/INI-SPC Comaparison 31

3 years

This medicinal product does not require any special storage conditions.

Nilotinib Accord is available in the following pack sizes:

Nilotinib Accord 50 mg hard capsules

PVC/PVDC/Alu blisters or PVC/PVDC/Alu perforated unit dose blisters.

* Unit packs containing 40 hard capsules (5 blisters, each containing 8 hard capsules) orperforated unit dose blisters of 40 × 1 hard capsules (5 blisters, each containing 8 hardcapsules).

* Multipacks containing 120 (3 packs of 40) hard capsules or 120 × 1 (3 packs of 40 × 1) hardcapsules

Nilotinib Accord 150 mg and 200 mg hard capsules

PVC/PVDC/Alu blisters or PVC/PVDC/Alu perforated unit dose blisters

* Unit packs containing 28 hard capsules (4 blisters, each containing 7 hard capsules or 2 blisters,each containing 14 hard capsules or 7 daily blisters, each containing 4 hard capsules) or 40 hardcapsules (5 blisters, each containing 8 hard capsules) or perforated unit dose blisters of28 × 1 hard capsules (4 blisters, each containing 7 hard capsules or 2 blisters, each containing14 hard capsules or 7 daily blisters, each containing 4 hard capsules) or 40 × 1 hard capsules(5 blisters, each containing 8 hard capsules).

* Multipacks containing 112 (4 packs of 28) hard capsules, 120 (3 packs of 40) hard capsules or392 (14 packs of 28) hard capsule or perforated unit dose blisters of 112 × 1 (4 packs of 28 × 1)hard capsules, 120 × 1 (3 packs of 40 × 1) hard capsules or 392 × 1 (14 packs of 28 × 1) hardcapsule.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Accord Healthcare S.L.U.

World Trade Center, Moll de Barcelona, s/n

Edifici Est, 6a Planta08039 Barcelona

Spain

50 mg capsule, hard

EU/1/24/1845/001 40 capsules

EU/1/24/1845/002 40 x 1 capsules (unit dose)

EU/1/24/1845/003 120 (3 x 40) capsules (multipack)

EU/1/24/1845/004 120 (3 x 40 x 1) capsules (unit dose) (multipack)

VAR/IB/INI-SPC Comaparison 32150 mg capsule, hard

EU/1/24/1845/005 28 capsules

EU/1/24/1845/006 28 x 1 capsules (unit dose)

EU/1/24/1845/007 40 capsules

EU/1/24/1845/008 40 x 1 capsules (unit dose)

EU/1/24/1845/009 112 (4 x 28) capsules (multipack)

EU/1/24/1845/010 120 (3 x 40) capsules (multipack)

EU/1/24/1845/011 392 (14 x 28) capsules (multipack)

EU/1/24/1845/012 112 (4 x 28 x 1) capsules (unit dose) (multipack)

EU/1/24/1845/013 120 (3 x 40 x 1) capsules (unit dose) (multipack)

EU/1/24/1845/014 392 (14 x 28 x 1) capsules (unit dose) (multipack)200 mg capsule, hard

EU/1/24/1845/015 28 capsules

EU/1/24/1845/016 28 x 1 capsules (unit dose)

EU/1/24/1845/017 40 capsules

EU/1/24/1845/018 40 x 1 capsules (unit dose)

EU/1/24/1845/019 112 (4 x 28) capsules (multipack)

EU/1/24/1845/020 120 (3 x 40) capsules (multipack)

EU/1/24/1845/021 392 (14 x 28) capsules (multipack)

EU/1/24/1845/022 112 (4 x 28 x 1) capsules (unit dose) (multipack)

EU/1/24/1845/023 120 (3 x 40 x 1) capsules (unit dose) (multipack)

EU/1/24/1845/024 392 (14 x 28 x 1) capsules (unit dose) (multipack)

Date of first authorisation: 22 August 2024

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu

VAR/IB/INI-SPC Comaparison 33