nilotinib

HOS-094790 · has-adverse-reaction-information · PDF-Seite 13

Summary of the safety profile The safety profile is based on pooled data from 3,422 patients treated with Tasigna in 13 clinical studies in the approved indications: adults and paediatric patients with newly diagnosed Philadelphia chromosome positive chronic myelogenous leukaemia (CML) in the chronic phase (5 clinical studies with 2,414 patients), adult patients with chronic phase and accelerated phase Philadelphia chromosome positive CML with resistance or intolerance to prior therapy including imatinib (6 clinical studies with 939 patients) and paediatric patients with chronic phase Philadelphia chromosome positive CML with resistance or intolerance to prior therapy including imatinib (2 clinical studies with 69 patients). These pooled data represents 9,039.34 patient-years of exposure. The safety profile of nilotinib is consistent across indications. The most common adverse reactions (incidence ≥15%) from the pooled safety data were: rash (26.4%), upper respiratory tract infection (including pharyngitis, nasopharyngitis, rhinitis) (24.8%) headache (21.9%), hyperbilirubinaemia (including blood bilirubin increased) (18.6%), arthralgia (15.8%), fatigue (15.4%), nausea (16.8%), pruritus (16.7%) and thrombocytopenia (16.4%). Tabulated list of adverse reactions Adverse reactions from clinical studies and post-marketing reports (Table 3) are listed by MedDRA system organ class and frequency category. Frequency categories are defined using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data). Table 3 Adverse drug reactions Infections and infestations Very common: Upper respiratory tract infection (including pharyngitis, nasopharyngitis, rhinitis) Common: Folliculitis, bronchitis, candidiasis (including oral candidiasis), pneumonia, gastroenteritis, urinary tract infection Uncommon: Herpes virus infection, anal abscess, candidiasis (candida infection), furuncle, sepsis, subcutaneous abscess, tinea pedis Rare: Hepatitis B reactivation Neoplasms benign, malignant and unspecified (including cysts and polyps) Uncommon: Skin papilloma Rare: Oral papilloma, paraproteinaemia Blood and lymphatic system disorders

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HOS-094786 · has-contraindication-information · PDF-Seite 6

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 6

HOS-094785 · has-indication-information · PDF-Seite 3

Tasigna is indicated for the treatment of: - adult and paediatric patients with newly diagnosed Philadelphia chromosome positive chronic myelogenous leukaemia (CML) in the chronic phase, - adult patients with chronic phase and accelerated phase Philadelphia chromosome positive CML with resistance or intolerance to prior therapy including imatinib. Efficacy data in patients with CML in blast crisis are not available, - paediatric patients with chronic phase Philadelphia chromosome positive CML with resistance or intolerance to prior therapy including imatinib.

HOS-094788 · has-interaction-information · PDF-Seite 10

Tasigna may be given in combination with haematopoietic growth factors such as erythropoietin or granulocyte colony-stimulating factor (G-CSF) if clinically indicated. It may be given with hydroxyurea or anagrelide if clinically indicated. Nilotinib is mainly metabolised in the liver with CYP3A4 expected to be the main contributor to the oxidative metabolism. Nilotinib is also a substrate for the multi-drug efflux pump, P-glycoprotein (P-gp). Therefore, absorption and subsequent elimination of systemically absorbed nilotinib may be influenced by substances that affect CYP3A4 and/or P-gp. Substances that may increase nilotinib serum concentrations Concomitant administration of nilotinib with imatinib (a substrate and moderator of P-gp and CYP3A4), had a slight inhibitory effect on CYP3A4 and/or P-gp. The AUC of imatinib was increased by 18% to 39%, and the AUC of nilotinib was increased by 18% to 40%. These changes are unlikely to be clinically important. 10 The exposure to nilotinib in healthy subjects was increased 3-fold when co-administered with the strong CYP3A4 inhibitor ketoconazole. Concomitant treatment with strong CYP3A4 inhibitors, including ketoconazole, itraconazole, voriconazole, ritonavir, clarithromycin, and telithromycin, should therefore be avoided (see section 4.4). Increased exposure to nilotinib might also be expected with moderate CYP3A4 inhibitors. Alternative concomitant medicinal products with no or minimal CYP3A4 inhibition should be considered. Substances that may decrease nilotinib serum concentrations Rifampicin, a potent CYP3A4 inducer, decreases nilotinib Cmax by 64% and reduces nilotinib AUC by 80%. Rifampicin and nilotinib should not be used concomitantly. The concomitant administration of other medicinal products that induce CYP3A4 (e.g. phenytoin, carbamazepine, phenobarbital and St. John’s Wort) is likewise likely to reduce exposure to nilotinib to a clinically relevant extent. In patients for whom CYP3A4 inducers are indicated, alternative agents with less enzyme induction potential should be selected. Nilotinib has pH dependent solubility, with lower solubility at higher pH. In healthy subjects receiving esomeprazole at 40 mg once daily for 5 days, gastric pH was markedly increased, but nilotinib absorption was only decreased modestly (27% decrease in Cmax and 34% decrease in AUC0-∞). Nilotinib may be used concurrently with esomeprazole or other proton pump i

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HOS-094789 · has-pregnancy-information · PDF-Seite 12

Women of childbearing potential/Contraception Women of childbearing potential have to use highly effective contraception during treatment with nilotinib and for up to two weeks after ending treatment. Pregnancy There are no or limited amount of data from the use of nilotinib in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Tasigna should not be used during pregnancy unless the clinical condition of the woman requires treatment with nilotinib. If it is used during pregnancy, the patient must be informed of the potential risk to the foetus. If a woman who is being treated with nilotinib is considering pregnancy, treatment discontinuation may be considered based on the eligibility criteria for discontinuing treatment as described in sections 4.2 and 4.4. There is a limited amount of data on pregnancies in patients while attempting treatment-free remission (TFR). If pregnancy is planned during the TFR phase, the patient must be informed of a potential need to re-initiate nilotinib treatment during pregnancy (see sections 4.2 and 4.4). Breast-feeding It is unknown whether nilotinib is excreted in human milk. Available toxicological data in animals have shown excretion of nilotinib in milk (see section 5.3). Since a risk to the newborns/infants cannot be excluded, women should not breast-feed during Tasigna treatment and for 2 weeks after the last dose. Fertility Animal studies did not show an effect on fertility in male and female rats (see section 5.3).

HOS-094787 · has-warning-information · PDF-Seite 7

Myelosuppression Treatment with nilotinib is associated with (National Cancer Institute Common Toxicity Criteria grade 3 and 4) thrombocytopenia, neutropenia and anaemia. Occurrence is more frequent in patients with imatinib-resistant or intolerant CML, in particular in patients with accelerated-phase CML. Complete blood counts should be performed every two weeks for the first 2 months and then monthly thereafter, or as clinically indicated. Myelosuppression was generally reversible and usually managed by withholding Tasigna temporarily or dose reduction (see section 4.2). QT prolongation Nilotinib has been shown to prolong cardiac ventricular repolarisation as measured by the QT interval on the surface ECG in a concentration-dependent manner in adult and paediatric patients. In the Phase III study in patients with newly diagnosed CML in chronic phase receiving 300 mg nilotinib twice daily, the change from baseline in mean time-averaged QTcF interval at steady state was 6 msec. No patient had a QTcF >480 msec. No episodes of torsade de pointes were observed. In the Phase II study in imatinib-resistant and intolerant CML patients in chronic and accelerated phase receiving 400 mg nilotinib twice daily, the change from baseline in mean time-averaged QTcF interval at steady state was 5 and 8 msec, respectively. QTcF of >500 msec was observed in <1% of these patients. No episodes of torsade de pointes were observed in clinical studies. In a healthy volunteer study with exposures that were comparable to the exposures observed in patients, the time-averaged mean placebo-subtracted QTcF change from baseline was 7 msec (CI ± 4 msec). No subject had a QTcF >450 msec. Additionally, no clinically relevant arrhythmias were observed during the conduct of the trial. In particular, no episodes of torsade de pointes (transient or sustained) were observed. Significant prolongation of the QT interval may occur when nilotinib is inappropriately taken with strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong the QT interval, and/or food (see section 4.5). The presence of hypokalaemia and hypomagnesaemia may further enhance this effect. Prolongation of the QT interval may expose patients to the risk of fatal outcome. Tasigna should be used with caution in patients who have or who are at significant risk of developing prolongation of QTc, such as those: - with congenital long QT prolongation - with uncontrolled or significant cardi

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