Tasigna^® 200 mg hard capsules

One hard capsule contains 200 mg nilotinib (as hydrochloride monohydrate).

Excipient

Lactose monohydrate: 156.11 mg per capsule.

For a full list of excipients, see section 6.1.

Hard capsule

White to yellowish powder in light yellow opaque hard gelatin capsules, size 0 with red axial imprint “NVR/TKI”.

Tasigna is indicated for the treatment of adult patients with:

- newly diagnosed Philadelphia chromosome positive chronic myelogenous leukaemia (CML) in the chronic phase,

- chronic phase and accelerated phase Philadelphia chromosome positive CML with resistance or intolerance to prior therapy including imatinib. Efficacy data in patients with CML in blast crisis are not available.

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

Posology

The recommended dose of Tasigna:

- 300 mg twice daily in newly diagnosed patients with CML in the chronic phase,

- 400 mg twice daily in patients with chronic or accelerated phase CML with resistance or intolerance to prior therapy.

Treatment should be continued as long as the patient continues to benefit.

For a dose of 300 mg twice daily, 150 mg capsules are available.

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 the starting dose of 300 mg twice daily in newly diagnosed patients with CML in the chronic phase or to 400 mg twice daily in patients with imatinib-resistant or intolerant CML in chronic phase and accelerated phase 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.

Paediatric population

The safety and efficacy of Tasigna in paediatric patients 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.

Elderly patients

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

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).

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).

Method of administration

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

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

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

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.

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

Myelosuppression

Treatment with Tasigna is associated with (National Cancer Institute Common Toxicity Criteria grade 3-4) thrombocytopenia, neutropenia and anaemia. Occurrence is more frequent in patients with imatinib-resistant or intolerant CML, in particular in patients with accelerated-phase CML. Complete blood counts should be performed every two weeks for the first 2 months and then monthly thereafter, or as clinically indicated. Myelosuppression was generally reversible and usually managed by withholding Tasigna temporarily or dose reduction (see section 4.2).

QT prolongation

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 the Phase II study in imatinib-resistant and intolerant CML patients in chronic and accelerated phase receiving 400 mg nilotinib twice daily, the change from baseline in mean time-averaged QTcF interval at steady state was 5 and 8 msec, respectively. QTcF of>500 msec was observed in <1% of these patients. No episodes of torsade de pointes were observed in clinical studies.

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

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

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

- with congenital long QT prolongation

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

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

Close monitoring for an effect on the QTc interval is advisable and a baseline ECG is recommended prior to initiating 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 capsules, the content of each 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.

Lactose

Tasigna 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.

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 sections 4.2 and 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.

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 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 effective contraception during treatment with Tasigna.

Pregnancy

There are no adequate 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).

No studies on the effects of nilotinib on the ability to drive and use machines have been performed. 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).

The data described below reflect exposure to Tasigna in a total of 717 patients from a randomised Phase III study in newly diagnosed patients with CML in chronic phase treated at the recommended dose of 300 mg twice daily (n=279) and from an open-label multicentre Phase II study in patients with imatinib-resistant or intolerant CML in chronic phase (n=318) and accelerated phase (n=120) treated at the recommended dose of 400 mg twice daily.

Newly diagnosed CML in chronic phase

At data cut-off in the Phase III study, 64% of the patients had a duration of exposure of more than 12 months and 16.5% of patients had a duration of exposure of more than 18 months; the median duration of exposure was 14 months.

The most frequent 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 and peripheral oedema were observed less commonly and have been of mild to moderate severity. Discontinuation for adverse events regardless of causality was observed in 6.8% of patients.

Treatment-emergent haematological toxicities include myelosuppression: thrombocytopenia (17%), neutropenia (14%) and anaemia (6%). Pleural and pericardial effusions occurred in <1% of patients receiving Tasigna. Gastrointestinal haemorrhage was reported in <1% of patients.

The change from baseline in mean time-averaged QTcF interval at steady state was 6 msec. No patient had a QTcF>480 msec. QTcF increase from baseline exceeding 60 msec was observed <1% of patients. No sudden deaths or episodes of torsade de pointes (transient or sustained) have been 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%.

Imatinib-resistant or intolerant CML in chronic phase and accelerated phase

The data described below reflect exposure to Tasigna in 458 patients in an open-label multicentre Phase II study in patients with imatinib-resistant or intolerant CML in chronic phase (n=321) and accelerated phase (n=137) treated at the recommended dose of 400 mg twice daily. The median duration of exposure in days was 561 (1-1,096) for the CML-CP patients and 264 (2-1,160) for the CML-AP patients.

The most frequent non-haematological drug-related adverse events were rash, pruritus, nausea, fatigue, headache, abdominal pain, constipation and diarrhoea. Most of these adverse events were mild to moderate in severity. Vomiting, myalgia, alopecia, muscle spasms, anorexia, arthralgia, bone pain, peripheral oedema and asthenia were observed commonly and have been of mild to moderate severity (Grade 1 or 2). Discontinuation for drug-related adverse reactions was observed in 16% of CP and 10% of AP patients.

Treatment-emergent haematological toxicities include myelosuppression: thrombocytopenia (31%), neutropenia (17%) and anaemia (14%). Pleural and pericardial effusions as well as complications of fluid retention occurred in <1% of patients receiving Tasigna. Cardiac failure was observed in <1% of patients. Gastrointestinal and CNS haemorrhage were reported in 1% and <1% of patients, respectively.

QTcF exceeding 500 msec was observed in <1% of patients. No episodes of torsade de pointes (transient or sustained) were observed.

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 in Tasigna clinical studies 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, undesirable effects are presented in order of decreasing seriousness.

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

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