Tasigna^® 150 mg hard capsules

One hard capsule contains 150 mg nilotinib (as hydrochloride monohydrate).

Excipient(s) with known effect:

Once hard capsule contains 117.08 mg lactose (as monohydrate).

For the full list of excipients, see section 6.1.

Hard capsule

White to yellowish powder in red opaque hard gelatin capsules, size 1 with black axial imprint “NVR/BCR”.

Tasigna is indicated for the treatment of adult patients with newly diagnosed Philadelphia chromosome positive chronic myelogenous leukaemia (CML) in the chronic phase.

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

Posology

The recommended dose of Tasigna is 300 mg twice daily. Treatment should be continued as long as the patient continues to benefit.

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

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

Dose adjustments or modifications

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

Table 1 Dose adjustments for neutropenia and thrombocytopenia

*ANC = absolute neutrophil count

If clinically significant moderate or severe non-haematological toxicity develops, dosing should be interrupted, and may be resumed at 400 mg once daily once the toxicity has resolved. If clinically appropriate, re-escalation of the dose to 300 mg twice daily should be considered.

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

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

Elderly patients

Approximately 12% of subjects in the clinical study 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.

Patients with 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.

Patients with 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).

Patients with 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).

Paediatric population

The safety and efficacy of Tasigna in children from birth to less than 18 years have not yet been established (see section 5.1). Therefore, its use in paediatric patients is not recommended due to a lack of data on safety and efficacy.

Method of administration

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

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

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

Myelosuppression

Treatment with Tasigna is associated with (National Cancer Institute Common Toxicity Criteria grade 3-4) thrombocytopenia, neutropenia and anaemia. 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

Tasigna has been shown to prolong cardiac ventricular repolarisation as measured by the QT interval on the surface ECG in a concentration-dependent manner.

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 a healthy volunteer study with exposures that were comparable to the exposures observed in patients, the time-averaged mean placebo-subtracted QTcF change from baseline was 7 msec (CI ± 4 msec). No subject had a QTcF >450 msec. Additionally, no clinically relevant arrhythmias were observed during the conduct of the trial. In particular, no episodes of torsade de pointes (transient or sustained) were observed.

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

Tasigna should be used with caution in patients who have or who are at significant risk of developing prolongation of QTc, such as those:

- with congenital long QT prolongation

- with uncontrolled or significant cardiac disease including recent myocardial infarction, congestive heart failure, unstable angina or clinically significant bradycardia.

- taking anti-arrhythmic medicinal products or other substances that lead to QT prolongation.

Close monitoring for an effect on the QTc interval is advisable and a baseline ECG is recommended prior to initiating therapy with Tasigna 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.

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 therapy with Tasigna 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 Tasigna 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 Tasigna, 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 should 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 C_max 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, Tasigna 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 therapy with Tasigna (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.

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.

Substances that may increase nilotinib serum concentrations

Nilotinib is mainly metabolised in the liver and is also a substrate for the multi-drug efflux pump, P-glycoprotein (P-gp). Therefore, absorption and subsequent elimination of systemically absorbed nilotinib may be influenced by substances that affect CYP3A4 and/or P-gp. 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 C_max 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 C_max and 34% decrease in AUC0-∞). Nilotinib may be used concurrently with esomeprazole or other proton pump inhibitors as needed.

In a healthy subjects study, no significant change in nilotinib pharmacokinetics was observed when a single 400 mg dose of Tasigna 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 Tasigna 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

Nilotinib is a relatively strong inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2D6 and UGT1A1 in vitro, 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 addition, single-dose administration of Tasigna with orally administered midazolam to healthy subjects increased midazolam exposure by 30%. It cannot be excluded that the effect of nilotinib is greater at steady state. Caution should be exercised when co-administering Tasigna with substrates of these enzymes that have a narrow therapeutic index [e.g. astemizole, terfenadine, cisapride, pimozide, quinidine, bepridil or ergot alkaloids (ergotamine, dihydroergotamine)].

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

Nilotinib should be used with caution in patients who have or may develop prolongation of QT, 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).

Other interactions that may affect serum concentrations

The absorption of Tasigna is 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.

Women of childbearing potential

Women of childbearing potential have to use highly effective contraception during treatment with Tasigna.

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.

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). A risk to the newborns/infants cannot be excluded. Tasigna should not be used during breast-feeding.

Fertility

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

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).

Summary of the safety profile

The data described below reflect exposure to Tasigna in 279 patients from a randomised Phase III study in patients with newly diagnosed Ph+ CML in chronic phase treated with 300 mg of nilotinib twice daily. The median duration of exposure was 36.4 months (range 0.1-46.7 months).

The most frequent (≥10%) non-haematological adverse reactions were rash, pruritus, headache, nausea, fatigue, and myalgia. Most of these adverse reactions were mild to moderate in severity. Upper abdominal pain, alopecia, constipation, diarrhoea, asthenia, dry skin, muscle spasms, arthralgia, vomiting, abdominal pain, peripheral oedema, dyspepsia and pain in extremity were observed less commonly (<10% and ≥5%), were of mild to moderate severity, manageable and generally did not require dose reduction. Discontinuation due to adverse drug reactions was observed in 10% of patients.

Treatment-emergent haematological toxicities include myelosuppression: thrombocytopenia (18%), neutropenia (15%) and anaemia (7%). Pleural and pericardial effusions, regardless of causality, occurred in 1% and <1% of patients, respectively, receiving Tasigna 300 mg twice daily. Gastrointestinal haemorrhage, regardless of causality, was reported in 2.5% of these patients.

The change from baseline in mean time-averaged QTcF interval at steady state was 6 msec. No patient had an absolute QTcF >500 msec while on the study medicinal product. QTcF increase from baseline exceeding 60 msec was observed in <1% of patients while on the study medicinal product. No sudden deaths or episodes of torsade de pointes (transient or sustained) were observed. No decrease from baseline in mean left ventricular ejection fraction (LVEF) was observed at any time during treatment. No patient had a LVEF of <45% during treatment nor an absolute reduction in LVEF of more than 15%.

Most frequently reported adverse reactions in Tasigna clinical studies

Non-haematological adverse reactions (excluding laboratory abnormalities) that are reported in at least 5% of the patients treated with 300 mg of nilotinib twice daily in the randomised Phase III study are shown in Table 2. These are ranked under heading of frequency 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). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 2 Non-haematological adverse reactions (≥5% of all patients)

The following adverse reactions were reported in the Tasigna Phase III study at a frequency of less than 5%. For laboratory abnormalities, very common events (≥1/10) not included in Table 2 are also reported. These adverse reactions are included based on clinical relevance and ranked in order of decreasing seriousness within each category.

Infections and infestations:

Common: folliculitis, upper respiratory tract infection (including pharyngitis, nasopharyngitis, rhinitis).

Not known: herpes virus infection, oral candidiasis, subcutaneous abscess, anal abscess, tinea pedis.

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

Common: skin papilloma.

Not known: oral papilloma, paraproteinaemia.

Blood and lymphatic system disorders:

Common: lymphopenia.

Uncommon: pancytopenia.

Not known: febrile neutropenia, eosinophilia.

Immune system disorders:

Not known: hypersensitivity.

Endocrine disorders:

Not known: hyperparathyroidism secondary.

Metabolism and nutrition disorders:

Very common: hypophosphataemia (including blood phosphorus decreased).

Common: diabetes mellitus, hypercholesterolaemia, hyperlipidaemia, hyperglycaemia, decreased appetite.

Uncommon: hyperkalaemia, hypocalcaemia, hypokalaemia, gout.

Not known: hyperuricaemia, hypoglycaemia, dyslipidaemia, appetite disorder.

Psychiatric disorders:

Common: insomnia, anxiety.

Not known: depressed mood, amnesia, dysphoria.

Nervous system disorders:

Common: dizziness, hypoaesthesia, peripheral neuropathy.

Uncommon: paraesthesia.

Not known: syncope, migraine, tremor, lethargy, dysaesthesia, restless legs syndrome, hyperaesthesia.

Eye disorders:

Common: eye pruritus, conjunctivitis, dry eye (including xerophthalmia).

Uncommon: eyelid oedema, photopsia, conjunctival haemorrhage, hyperaemia (scleral, conjunctival, ocular).

Not known: periorbital oedema, blepharitis, eye pain, chorioretinopathy, conjunctivitis allergic, ocular surface disease, vision blurred.

Ear and labyrinth disorders:

Common: vertigo.

Cardiac disorders*:

Common: arrhythmia (including tachycardia, atrial fibrillation, ventricular extrasystoles, sinus bradycardia), electrocardiogram QT prolonged, palpitations.

Uncommon: angina pectoris, cyanosis.

Not known: cardiac failure, ejection fraction decrease, pericardial effusion, pericarditis, diastolic dysfunction, left bundle branch block.

*reported in 300 mg twice daily and/or 400 mg twice daily treatment arm of phase III study

Vascular disorders:

Common: hypertension, flushing.

Uncommon: peripheral arterial occlusive disease.

Not known: haematoma, arteriosclerosis.

Respiratory, thoracic and mediastinal disorders:

Common: dyspnoea, cough.

Not known: pleural effusion, dyspnoea exertional, pleurisy, epistaxis, oropharyngeal pain.

Gastrointestinal disorders:

Common: abdominal distension, abdominal discomfort, dysgeusia, flatulence.

Uncommon: pancreatitis, sensitivity of teeth.

Not known: oesophageal ulcer, gastric ulcer, oesophageal pain, stomatitis, dry mouth, gastritis, enterocolitis, haemorrhoids, hiatus hernia, rectal haemorrhage, gingivitis.

Hepatobiliary disorders:

Very common: hyperbilirubinaemia (including blood bilirubin increased).

Common: hepatic function abnormal.

Uncommon: jaundice.

Not known: toxic hepatitis.

Skin and subcutaneous tissue disorders:

Common: erythema, hyperhidrosis, contusion, acne, dermatitis (including allergic, exfoliative and acneiform), night sweats.

Uncommon: drug eruption, skin pain.

Not known: erythema multiforme, eczema, urticaria, blister, dermal cyst, sebaceous hyperplasia, swelling face, skin atrophy, skin hypertrophy, skin exfoliation, skin hyperpigmentation, skin discolouration, hyperkeratosis, psoriasis.

Musculoskeletal and connective tissue disorders:

Common: bone pain, back pain.

Uncommon: musculoskeletal pain, flank pain, muscular weakness.

Renal and urinary disorders:

Not known: dysuria, pollakiuria, chromaturia.

Reproductive system and breast disorders:

Uncommon: erectile dysfunction.

Not known: gynaecomastia, breast induration, menorrhagia, nipple swelling.

General disorders and administration site conditions:

Common: pyrexia, chest pain (including non-cardiac chest pain), chest discomfort.

Uncommon: pain, chills, feeling body temperature change (including feeling hot, feeling cold), malaise.

Not known: face oedema, localised oedema.

Investigations:

Very common: alanine aminotransferase increased, aspartate aminotransferase increased, lipase increased.

Common: haemoglobin decreased, platelet count decreased, blood amylase increased, blood alkaline phosphatase increased, gamma-glutamyltransferase increased, weight increased.

Uncommon: neutrophil count decreased, globulins decreased, blood insulin increased.

Not known: lipoprotein increased (including very low density and high density), blood parathyroid hormone increased, blood potassium increased, white blood cell count decreased, blood insulin decreased, insulin C-peptide decreased, weight decreased.

Clinically relevant or severe abnormalities of routine haematological or biochemistry laboratory values are presented in Table 3.

Table 3 Grade 3-4 laboratory abnormalities

Postmarketing experience

The following adverse reactions have been derived from spontaneous case reports, literature cases, expanded access programmes, and clinical studies other than the global registration trials. Since these reactions are reported from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to nilotinib exposure.

Frequency rare: Cases of tumour lysis syndrome have been reported in patients treated with Tasigna.

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.

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors, ATC code: L01XE08

Nilotinib is a potent inhibitor of the ABL tyrosine kinase activity of the BCR-ABL oncoprotein both in cell lines and in primary Philadelphia-chromosome positive leukaemia cells. The substance binds with 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 consequence of this biochemical activity, nilotinib selectively inhibits the proliferation and induces apoptosis in cell lines and in primary Philadelphia-chromosome positive leukaemia cells from CML patients. In murine models of CML, as a single agent nilotinib reduces tumour burden and prolongs survival 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 the range 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)

Clinical studies in newly diagnosed CML in chronic phase

An open-label, multicentre, randomised Phase III study was conducted to determine the efficacy of Nilotinib versus imatinib in 846 adult patients with cytogenetically confirmed newly diagnosed Philadelphia chromosome positive CML in the chronic phase. Patients were within six months of diagnosis 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 mg twice daily (n=281) or imatinib 400 mg once daily (n=283). Randomisation was stratified by Sokal risk score at the time of diagnosis.

Baseline characteristics were well balanced between the three treatment arms. Median age was 47 years in 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 mg once 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 once daily 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 (or discontinued earlier). Subsequent analyses reflect when patients completed 24 and 36 months of treatment (or discontinued earlier). The median time on treatment was approximately 36 months in all three treatment groups. The median actual dose intensity was 594 mg/day for nilotinib 300 mg twice daily, 778 mg/day for nilotinib 400 mg twice daily 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 was defined as ≤0.1% BCR-ABL/ABL% by international scale (IS) measured by RQ-PCR, which corresponds to a ≥3 log reduction of BCR-ABL transcript from standardised baseline. The MMR rate at 12 months was statistically significantly higher for nilotinib 300 mg twice daily compared to imatinib 400 mg once daily (44.3% versus 22.3%, p<0.0001). The rate of MMR at 12 months, was also statistically significantly higher for nilotinib 400 mg twice daily compared to imatinib 400 mg once 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 mg twice 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 and 36 months is presented in Table 5.

Table 5 MMR rate

¹ Cochran-Mantel-Haenszel (CMH) test p-value for response rate (vs. imatinib 400 mg) <0.0001

² Only patients who were in MMR at a specific time point are included as responders for that time point. A total of 199 (35.2%) of all patients were not evaluable for MMR at 36 months (87 in the nilotinib 300 mg twice daily group and 112 in the imatinib group) due to missing/unevaluable PCR assessments (n=17), atypical transcripts at baseline (n=7), or discontinuation prior to the 36-month time point (n=175).

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

Figure 1 Cumulative incidence of MMR

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

Based on the Kaplan-Meier analysis of time to first MMR the probability of achieving MMR at different time points was higher for both nilotinib at 300 mg and 400 mg twice daily compared to imatinib 400 mg once daily (HR=2.21 and stratified log-rank p<0.0001 between nilotinib 300 mg twice daily and imatinib 400 mg once daily, HR=1.92 and stratified log-rank p<0.0001 between nilotinib 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 different time 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. Molecular response 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)

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, the proportions of patients who achieved MMR and were maintaining response after 36 months were 95.0% (95% CI: 91.8-98.3%) in the nilotinib 300 mg twice daily group, 93.9% (95% CI: 90.3-97.4%) in the nilotinib 400 mg twice daily group and 88.4% (95% CI: 82.6-94.2%) in the imatinib 400 mg once daily group.

Complete cytogenetic response (CCyR) was defined as 0% Ph+ metaphases in the bone marrow based on a minimum of 20 metaphases evaluated. Best CCyR rate by 12 months (including patients who achieved CCyR at or before the 12 month time point as responders) was statistically higher for both nilotinib 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 point as responders) was statistically higher for both the nilotinib 300 mg twice daily and 400 mg twice daily groups compared to the imatinib 400 mg once daily group.

Table 7 Best complete cytogenetic response (CCyR) rate

Based on Kaplan-Meier estimates, the proportions of patients who achieved CCyR and were maintaining response after 36 months were 99.1% (95% CI: 97.9-100%) in the nilotinib 300 mg twice daily group, 98.6% (95% CI: 97.1-100%) in the nilotinib 400 mg twice daily group and 97.5% (95% CI: 95.4-99.7%) 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 the date 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 a total of 17 patients: 2 patients on nilotinib 300 mg twice daily, 3 patients on nilotinib 400 mg twice daily and 12 patients on imatinib 400 mg once daily. The estimated rates of patients free from progression to accelerated phase or blast crisis at 36 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 and imatinib once daily, HR=0.2457 and stratified log-rank p=0.0185 between nilotinib 400 mg twice daily and imatinib once daily).

Including clonal evolution as a criterion for progression, a total of 24 patients progressed to accelerated phase or blast crisis on treatment by the cut-off date (2 in the nilotinib 300 mg twice daily group, 5 in the nilotinib 400 mg twice daily group and 17 in the imatinib 400 mg once daily group). The estimated rates of patients free from progression to accelerated phase or blast crisis including clonal evolution at 36 months were 99.3%, 97.9% and 93.2%, respectively (HR=0.1106 and stratified log-rank p=0.0003 between nilotinib 300 mg twice daily and imatinib once daily, HR=0.2848 and stratified log-rank p=0.0085 between nilotinib 400 mg twice daily and imatinib once daily).

No new progressions to AP/BC were reported since the 2-year analysis.

A total of 38 patients died during treatment or during the follow-up after discontinuation of treatment. (13 in the nilotinib 300 mg twice daily group, 8 in the nilotinib 400 mg twice daily group and 17 in the imatinib 400 mg once daily group). Twenty-three (23) of these 38 deaths were related to CML (5 in the nilotinib 300 mg twice daily group, 4 in the nilotinib 400 mg twice daily group and 14 in the imatinib 400 mg once daily group). The estimated rates of patients alive at 36 months were 95.1%, 97.0% and 94.0%, respectively (HR=0.7537 and stratified log-rank p=0.4413 between nilotinib 300 mg twice daily and imatinib, HR=0.4607 and stratified log-rank p=0.0639 between nilotinib 400 mg twice daily and imatinib). Considering only CML-related deaths as events, the estimated rates of overall survival at 36 months were 98.1%, 98.5% and 95.2%, respectively (HR=0.3511 and stratified log-rank p=0.0356 between nilotinib 300 mg twice daily and imatinib, HR=0.2784 and stratified log-rank p=0.0159 between nilotinib 400 mg twice daily and imatinib).

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with Tasigna in paediatric patients from birth to less than 18 years in the treatment of Philadelphia chromosome positive chronic myeloid leukaemia (see section 4.2 for information on paediatric use).

Absorption

Peak concentrations of nilotinib are reached 3 hours after oral administration. Nilotinib absorption following oral administration was approximately 30%. The absolute bioavailability of nilotinib has not been determined. As compared to an oral drink solution (pH of 1.2 to 1.3), relative bioavailability of nilotinib capsule is approximately 50%. In healthy volunteers, C_max and area under the serum concentration-time curve (AUC) of nilotinib are increased by 112% and 82%, respectively, compared to fasting conditions when Tasigna is given with food. Administration of Tasigna 30 minutes or 2 hours after food increased bioavailability of nilotinib by 29% or 15%, respectively (see sections 4.2, 4.4 and 4.5).

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

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

Distribution

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

Biotransformation

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

Elimination

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

Linearity/non-linearity

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

Characteristics in patients

Steady-state conditions were essentially achieved by day 8. An increase in serum exposure to nilotinib between the first dose and steady state was approximately 2-fold for daily dosing and 3.8-fold for twice-daily dosing. The apparent elimination half-life estimated from the multiple-dose pharmacokinetics with daily dosing was approximately 17 hours. Inter-patient variability in nilotinib pharmacokinetics was moderate to high.

Nilotinib has been evaluated in safety pharmacology, repeated dose toxicity, genotoxicity, reproductive toxicity, phototoxicity studies and a rat carcinogenicity study.

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

Repeated-dose toxicity studies in dogs of up to 4 weeks' duration and in cynomolgus monkeys of up to 9 months' duration revealed the liver as the primary target organ of toxicity of nilotinib. Alterations included increased alanine aminotransferase and alkaline phosphatase activity and histopathology findings (mainly sinusoidal cell or Kupffer cell hyperplasia/hypertrophy, bile duct hyperplasia and periportal fibrosis). In general the changes in clinical chemistry were fully reversible after 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 exposure in humans at a dose of 800 mg/day. Only minor liver alterations were seen in mice or rats treated for up to 26 weeks. Mainly reversible increases in cholesterol levels were seen in rats, dogs and monkeys.

In the 2-year rat carcinogenicity study, the major target organ for non-neoplastic lesions was the uterus (dilatation, vascular ectasia, endothelial cell hyperplasia, inflammation and/or epithelial hyperplasia). There was no evidence of carcinogenicity upon administration of nilotinib at 5, 15 and 40 mg/kg/day. Exposures (in terms of AUC) at the highest dose level represented approximately 2x to 3x human daily steady-state exposure (based on AUC) to nilotinib at the dose of 800 mg/day.

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

Nilotinib did not induce teratogenicity, but did show embryo- and foetotoxicity at doses that also showed 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 involved treatment of females. Embryo-lethality and foetal effects (mainly decreased foetal weights, premature fusion of the facial bones (fused maxilla/zygomatic) visceral and skeletal variations) in rats and increased resorption of foetuses and skeletal variations in rabbits were present in the embryotoxicity studies. In a pre- and postnatal development study in rats, maternal exposure to nilotinib caused reduced pup body weight with associated changes in physical development parameters as well as reduced 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.

In a juvenile development study, nilotinib was administered via oral gavage to juvenile rats from the first 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 and fertility were performed. Based on a reduction in body weight in both genders and a delayed preputial separation 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 increased sensitivity to nilotinib relative to adults. In addition, the toxicity profile in juvenile rats was comparable to that observed in adult rats.

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

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

Hard capsule content

Lactose monohydrate

Crospovidone

Poloxamer 188

Silica, colloidal anhydrous

Magnesium stearate

Hard capsule shell

Gelatin

Titanium dioxide (E171)

Red iron oxide (E172)

Yellow iron oxide (E172)

Printing ink

Shellac

Black iron oxide (E172)

Not applicable.

3 years.

Do not store above 30°C.

Store in the original package in order to protect from moisture.

PVC/PVDC/Al blisters.

Tasigna is available in the following pack sizes:

• Unit packs containing 28 hard capsules (7 daily blisters, each containing 4 hard capsules) or 40 hard capsules (5 blisters, each containing 8 hard capsules).

• Multipacks containing 112 (4 packs of 28) hard capsules or 120 (3 packs of 40) hard capsules.

Not all pack sizes may be marketed.

No special requirements for disposal.

Novartis Europharm Limited

Wimblehurst Road

Horsham

West Sussex, RH12 5AB

United Kingdom

EU/1/07/422/005-006

EU/1/07/422/009-010

Date of first authorisation: 19 November 2007

Date of latest renewal: 19 November 2012

17 January 2013

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu

POM