Tasigna

Tasigna

nilotinib

Nhà sản xuất:

Novartis Pharma

Nhà phân phối:

Phytopharma
Thông tin kê toa chi tiết tiếng Anh
Contents
Nilotinib.
Description
150 mg Hard Capsules: Each capsule contains 150 mg nilotinib base (as hydrochloride, monohydrate).
200 mg Hard Capsules: Each capsule contains 200 mg nilotinib base (as hydrochloride, monohydrate).
Excipients/Inactive Ingredients: 150 mg Hard Capsules: Capsule content: Lactose monohydrate; crospovidone; poloxamer 188; silica colloidal, anhydrous/colloidal silicon dioxide; magnesium stearate.
Capsule shell: Gelatin; titanium dioxide (E 171); iron oxide, red (E 172), iron oxide, yellow (E 172).
Printing ink: Iron oxide, black (E 172).
200 mg Hard Capsules: Capsule content: Lactose monohydrate; Crospovidone; Poloxamer 188; Silica colloidal, anhydrous/Colloidal silicon dioxide; Magnesium stearate.
Capsule shell: Gelatin; Titanium dioxide (E 171); Iron oxide, yellow (E 172).
Printing ink: Iron oxide, red (E 172), Iron oxide, black (E172).
Action
Pharmacotherapeutic Group: Antineoplastic agents - Protein-tyrosine kinase inhibitor. ATC Code: L01XE08.
Pharmacology: Pharmacodynamics: Tasigna has little or no effect against the majority of other protein kinases examined, including SRC, except for the PDGF, KIT, CSF-1R, DDR 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 1).


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Mechanism of Action: Tasigna is a potent and selective inhibitor of the ABL tyrosine kinase activity of the BCR-ABL oncoprotein both in cell lines and in primary Philadelphia-chromosome positive leukemia cells. The drug binds strongly within 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 BCR-ABL dependent cell lines and in primary Philadelphia-chromosome positive leukemia cells derived from CML patients. In murine models of CML, as a single agent nilotinib reduces tumor burden and prolongs survival following oral administration.
Clinical Studies: Newly diagnosed Ph+ CML-CP: An open label, multicenter, randomized Phase III study was conducted to determine the efficacy of Tasigna versus imatinib in adult patients with cytogenetically confirmed newly diagnosed Ph+ CML-CP. Patients were within six months of diagnosis and were previously untreated for CML-CP, except for hydroxyurea and/or anagrelide. In addition, patients were stratified according to Sokal risk score at time of diagnosis.
Efficacy was based on a total of 846 patients (283 patients in the imatinib 400 mg once daily group, 282 patients in the nilotinib 300 mg twice daily group, 281 patients in the nilotinib 400 mg twice daily group).
Baseline characteristics were well balanced between the three groups. Median age was 46 years in the imatinib group and 47 years in both nilotinib groups, with 12.4%, 12.8% and 10.0% were ≥65 years of age in imatinib, nilotinib 300 mg twice daily and nilotinib 400 mg twice daily treatment groups, respectively. There were slightly more male than female patients in all groups (55.8%, 56.0% and 62.3% in imatinib, nilotinib 300 mg twice daily and nilotinib 400 mg twice daily, respectively). More than 60% of all patients were Caucasian, and 25% 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, 36, 48 and 60 months of treatment (or discontinued earlier). The median time on treatment was approximately 60 months in all three treatment groups. The median actual dose intensity was 400 mg/day in the imatinib group, 593 mg/day in the nilotinib 300 mg twice daily group and 773 mg/day in the nilotinib 400 mg twice daily group. This study is on-going.
Major molecular response (MMR): The primary efficacy variable was MMR at 12 months after the start of study medication. MMR was defined as ≤0.1% BCR-ABL/ABL % by international scale measured by RQ-PCR, which corresponds to a ≥3 log reduction of BCR-ABL transcript from standardized baseline.
The primary efficacy endpoint, Major Molecular Response (MMR) rate at 12 months was statistically significantly superior in the nilotinib 300 mg twice daily group compared to the imatinib 400 mg once daily group (44.3% vs. 22.3%, p<0.0001). The rate of MMR at 12 months, was also statistically significantly higher in the nilotinib 400 mg twice daily group compared to the imatinib 400 mg once daily group (42.7% vs. 22.3%, p<0.0001). (See Table 2.)
At the nilotinib recommended dose of 300 mg twice daily, the rates of MMR at 3, 6, 9 and 12 months were 8.9%, 33.0%, 43.3% and 44.3%. In the nilotinib 400 mg twice daily group, the rates of MMR at 3, 6, 9 and 12 months were 5.0%, 29.5%, 38.1% and 42.7%. In the imatinib 400 mg once daily group, the rates of MMR at 3, 6, 9 and 12 months were 0.7%, 12.0%, 18.0% and 22.3%.
The MMR rates at 12, 24, 36, 48 and 60 months are presented in Table 2.


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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.)


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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.
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 imatinib 400 mg once daily. Patients with BCR-ABL levels ≤10% at 3 months of treatment show a greater overall survival at 60 months compared to those who did not achieve this molecular response level (97% vs. 82% respectively [p=0.0116]).
Based on the Kaplan-Meier analyses of time to first MMR among all patients the probability of achieving MMR at different time points were higher in both nilotinib groups compared to the imatinib group (HR=2.20 and stratified log-rank p<0.0001 between nilotinib 300 mg twice daily and imatinib, HR=1.90 and stratified log-rank p<0.0001 between nilotinib 400 mg twice daily and imatinib).
The proportions of patients who had a molecular response of ≤0.01% and ≤0.0032% by International Scale (IS) at different time-points is presented in Table 3 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 corresponds to a ≥4 log reduction and ≥4.5 log reduction, respectively, of BCR-ABL transcripts from a standardized baseline. (See Table 3, Figures 2 and 3.)


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Duration of MMR: Based on Kaplan-Meier estimates of the duration of first MMR, the proportions of patients who were maintaining response after 60 months among patients who achieved MMR were 93.4% (95% CI: 89.9% to 96.9%) in the nilotinib 300 mg twice daily group, 92.0% (95% CI: 88.2% to 95.8%) in the nilotinib 400 mg twice daily group and 89.1% (95% CI: 84.2% to 94.0%) in the imatinib 400 mg once daily group.
Complete Cytogenetic response (CCyR): CCyR was defined as 0% Ph+ metaphases in the bone marrow based on a minimum of 20 metaphases evaluated. CCyR rate by 12 months (includes patients who achieved CCyR at or before the 12 month time point as responders) was statistically higher for both the nilotinib 300 mg twice daily and 400 mg twice daily groups compared to imatinib 400 mg once daily group. (See Table 4.)
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 imatinib 400 mg once daily group. (See Table 4.)


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Duration of CCyR: Based on Kaplan-Meier estimates, the proportions of patients who were maintaining response after 60 months among patients who achieved CCyR were 99.1% (95% CI: 97.9% to 100%) in the nilotinib 300 mg twice daily group, 98.7% (95% CI: 97.1% to 100%) in the nilotinib 400 mg twice daily group and 97.0% (95% CI: 94.7% to 99.4%) in the imatinib 400 mg once daily group.
Progression to AP/BC on treatment: Progression to AP/BC on treatment is defined as the time from the date of randomization to the first documented disease progression to AP/BC or CML-related death. Overall by the cut-off date, 17 patients progressed to AP or BC on treatment (2 in the nilotinib 300 mg twice daily group, 3 in the nilotinib 400 mg twice daily group and 12 in the imatinib 400 mg once daily group). The estimated rates of patients free from progression to AP or BC at 60 months were 99.3%, 98.7% and 95.2%, respectively (HR=0.1599 and stratified log-rank p=0.0059 between nilotinib 300 mg BID and imatinib, HR=0.2457 and stratified log-rank p=0.0185 between nilotinib 400 mg BID and imatinib). No new events of progression to AP/BC were reported on-treatment since the 2-year analysis.
Including clonal evolution as a criterion for progression, a total of 25 patients progressed to AP or BC on treatment by the cut-off date (3 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 AP or BC including clonal at 60 months were 98.7%, 97.9% and 93.2%, respectively (HR=0.1626 and stratified log-rank p=0.0009 between nilotinib 300 mg BID and imatinib, HR=0.2848 and stratified log-rank p=0.0085 between nilotinib 400 mg BID and imatinib).
Overall survival (OS): A total of 50 patients died during treatment or during the follow-up after discontinuation of treatment (18 in the nilotinib 300 mg twice daily group, 10 in the nilotinib 400 mg twice daily group and 22 in the imatinib 400 mg once daily group). Twenty-six (26) of these 50 deaths were related to CML (6 in the nilotinib 300 mg twice daily group, 4 in the nilotinib 400 mg twice daily group and 16 in the imatinib 400 mg once daily group). The estimated rates of patients alive at 60 months were 93.7%, 96.2% and 91.7%, respectively (HR=0.8026 and stratified log-rank p=0.4881 between nilotinib 300 mg twice daily and imatinib, HR=0.4395 and stratified log-rank p=0.0266 between nilotinib 400 mg twice daily and imatinib). Considering only CML-related deaths as events, the estimated rates of OS at 60 months were 97.7%, 98.5% and 93.8%, respectively (HR=0.3673 and stratified log-rank p=0.0292 between nilotinib 300 mg twice daily and imatinib, HR=0.2411 and stratified log-rank p=0.0057 between nilotinib 400 mg twice daily and imatinib).
Resistant or intolerant Ph+ CML: An open-label multicenter Phase II study was conducted to determine the efficacy of Tasigna (400 mg twice daily) in patients with imatinib resistant or intolerant CML with separate treatment arms for chronic and accelerated phase disease. Efficacy was based on 321 CP patients and 137 AP patients enrolled. Median duration of treatment was 561 days and 264 days, respectively (see Table 5). Tasigna was administered on a continuous basis, (twice daily 2 hours after a meal and no additional food for at least one hour) unless there was evidence of inadequate response or disease progression. Dose escalation to 600 mg twice daily was allowed. (See Table 5.)


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Resistance to imatinib included failure to achieve a complete hematologic response (by 3 months), cytogenetic response (by 6 months) or major cytogenetic response (by 12 months) or progression of disease after a previous cytogenetic or hematologic response. Imatinib intolerance included patients who discontinued imatinib because of toxicity and were not in major cytogenetic response at time of study entry.
Overall, 73% of patients were imatinib-resistant while 27% were imatinib-intolerant. The majority of patients had a long history of CML that included extensive prior treatment with other antineoplastic agents such as imatinib, hydroxyurea, interferon, and some that had even failed stem cell transplant (see Table 6). The median highest prior imatinib dose had been 600 mg/day for CP and AP patients, and the highest prior imatinib dose was ≥600 mg/day in 74% of all patients with 40% of patients receiving imatinib doses ≥800 mg/day. (See Table 6.)


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The primary endpoint in the CP patients was major cytogenetic response (MCyR), defined as elimination (CCyR, complete cytogenetic response) or significant reduction to <35% Ph+ metaphases (partial cytogenetic response) of Ph+ hematopoietic cells. Complete hematologic response (CHR) in CP patients was evaluated as a secondary endpoint. The primary endpoint in the AP patients was overall confirmed hematologic response (HR), defined as either a complete hematologic response, no evidence of leukemia or return to chronic phase.
Chronic Phase: The MCyR rate in 321 CP patients was 59%. Most responders achieved their MCyR rapidly within 3 months (median 2.8 months) of starting Tasigna treatment and these were sustained. The CCyR rate was 44%. The median time to achieve CCyR was just past 3 months (median 3.3 months). Of the patients who achieved MCyR, 77% (95% CI: 71% to 84%) were maintaining response at 24 months. Median duration of MCyR has not been reached. Of the patients who achieved CCyR, 84% (95% CI: 77% to 91%) were maintaining response at 24 months. Median duration of CCyR has not been reached. Patients with a CHR at baseline achieved a MCyR faster (1.4 vs. 2.8 months). Of CP patients without a baseline CHR, 76% achieved a CHR, median time to CHR was 1 month and median duration of CHR has not been reached.
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 55%. Most responders achieved a HR early with Tasigna treatment (median 1.0 months) and these have been durable (median duration of confirmed HR was 21.5 months). Of the patients who achieved HR, 49% (95% CI: 35% to 62%) were maintaining response at 24 months. MCyR rate was 32% with a median time to response of 2.8 months. Of the patients who achieved MCyR, 66% (95% CI: 50% to 82%) were maintaining response at 24 months. Median duration of MCyR has not been reached. The rates of response for the two treatment arms are reported in Table 7.
The estimated 24-month overall survival rate in CML-AP patients was 70%. (See Table 7.)


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Separate treatment arms were also included in the Phase II study to study Tasigna in a group of CP and AP patients who had been extensively pre-treated with multiple therapies including a tyrosine kinase inhibitor agent in addition to imatinib. Of these patients 30/36 (83%) were treatment-resistant. In 22 CP patients evaluated for efficacy, Tasigna 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. Tasigna demonstrated efficacy in patients harboring a variety of BCR-ABL mutations associated with imatinib resistance, except T315I.
Pharmacokinetics: 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, Cmax and area under the 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 DOSAGE & ADMINISTRATION, PRECAUTIONS and INTERACTIONS). Nilotinib absorption (relative bioavailability) may be reduced by approximately 48% and 22% in patients with total gastrectomy and partial gastrectomy, respectively.
Distribution: Blood-to-plasma ratio of nilotinib is 0.68. Plasma protein binding is approximately 98% on the basis of in vitro experiments.
Biotransformation/Metabolism: 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, greater than 90% of the dose was eliminated within 7 days mainly in feces. Parent drug accounted for 69% of the dose.
The apparent elimination half-life estimated from the multiple dose PK with daily dosing was approximately 17 hours. Inter-patient variability in nilotinib PK was moderate to high (%CV: 33% to 43%).
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 systemic exposure to nilotinib of 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 with 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.
Steady state conditions were essentially achieved by day 8. An increase in systemic exposure to nilotinib between the first dose and steady state was approximately 2-fold for the 400 mg once daily dosing and 3.8-fold for the 400 mg twice-daily dosing.
Bioavailability/bioequivalence studies: Single-dose administration of 400 mg of nilotinib, using 2 capsules of 200 mg whereby the content of each capsule was dispersed in one teaspoon of applesauce, was shown to be bioequivalent with a single dose administration of 2 intact capsules of 200 mg.
Toxicology: Non-Clinical Safety Data: Nilotinib has been evaluated in safety pharmacology, repeated dose toxicity, genotoxicity, reproductive toxicity, phototoxicity and carcinogenicity (rat and mice) studies.
Nilotinib did not have effects on CNS or respiratory functions. In vitro cardiac safety studies demonstrated a preclinical signal for QT prolongation. No effects were seen in ECG measurements in dogs or monkeys treated up to 39 weeks or in a special telemetry study in dogs.
Repeated dose toxicity studies in dogs up to 4 weeks duration and in cynomolgus monkeys 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, the histological alterations only showed partial reversibility. Exposures at the lowest dose levels where 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 up to 26 weeks. Mainly reversible increases in cholesterol levels were seen in rats, dogs and monkeys.
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.
In the 2-year rat carcinogenicity study, 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 were representing approximately 2x to 3x human daily steady state exposure (based on AUC) to nilotinib at the dose of 800 mg/day. The major target organ for non-neoplastic lesions was the uterus (dilatation, vascular ectasia, hyperplasia endothelial cell, inflammation and/or epithelial hyperplasia).
In the 26-week Tg.rasH2 mouse carcinogenicity study, in which nilotinib was administered at 30, 100 and 300 mg/kg/day, skin papillomas/carcinomas were detected at 300 mg/kg, representing approximately 30 to 40 times (based on AUC) the human exposure at the maximum approved dose of 800 mg/day (administered as 400 mg twice daily). The No-Observed-Effect-Level for the skin neoplastic lesions was 100 mg/kg/day, representing approximately 10 to 20 times the human exposure at the maximum approved dose of 800 mg/day (administered as 400 mg twice daily). The major target organs for non-neoplastic lesions were the skin (epidermal hyperplasia), the growing teeth (degeneration/atrophy of the enamel organ of upper incisors and inflammation of the gingiva/odontogenic epithelium of incisors) and the thymus (increased incidence and/or severity of decreased lymphocytes).
Nilotinib did not induce teratogenicity, but did show embryo- and fetotoxicity at doses which also showed maternal toxicity. Increased post implantation loss was observed in both the fertility study, with treatment of both males and females, and in the embryotoxicity study with the treatment of females. Embryo-lethality and fetal effects (mainly decreased fetal weights, visceral and skeletal variations) in rats and increased resorption of fetuses and skeletal variations in rabbits were present in the embryo toxicity studies. 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 pre- and postnatal study, the oral administration of nilotinib to female rats from day 6 of gestation to day 21 or 22 postpartum resulted in maternal effects (reduced food consumption and lower body weight gains) and longer gestation period at 60 mg/kg. The maternal dose of 60 mg/kg was associated with decreased pup body weight and changes in some physical development parameters (the mean day for pinna unfolding, tooth eruption and eye opening was earlier). The No-Observed-Adverse-Effect-Level in maternal animals and offspring was a maternal dose of 20 mg/kg.
In a juvenile development study, nilotinib was administered via oral gavage to juvenile rats from the first week postpartum through young adult (day 70 postpartum) at doses of 2, 6 and 20 mg/kg/day. Effects were limited to the dose of 20 mg/kg/day and consisted of reductions in body weight parameters and food consumption with recovery after dosing ceased. The No-Observed-Effect-level in juvenile rats was considered to be 6 mg/kg/day. Overall, the toxicity profile in juvenile rats was comparable to that observed in adult rats.
Nilotinib was shown to absorb light in the UV-B and UV-A range, and to be distributed into the skin showing a phototoxic potential in vitro. However, no phototoxicity has been observed in vivo. Therefore the risk that nilotinib causes photosensitization in patients is considered very low.
Indications/Uses
Tasigna hard capsules are indicated for the: treatment of adult patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase; treatment of chronic phase and accelerated phase Philadelphia chromosome positive chronic myelogenous leukemia (Ph+ CML) in adult patients resistant to or intolerant to at least one prior therapy including imatinib.
Dosage/Direction for Use
Tasigna is available in two dosage strengths (150 mg and 200 mg).
Treatment with Tasigna should be initiated by a physician experienced in the treatment of patients with CML.
Tasigna may be given in combination with hematopoietic growth factors such as erythropoietin or G-CSF if clinically indicated. Tasigna may be given with hydroxyurea or anagrelide if clinically indicated.
Monitoring of response to Tasigna therapy in Ph+ CML patients should be performed both routinely and when therapy is modified, to identify suboptimal response, loss of response to therapy, poor patient compliance, or possible drug-drug interaction. Results of monitoring should guide appropriate CML management.
General target population: Dosage in newly diagnosed Ph+ CML-CP: The recommended dose of Tasigna is 300 mg twice daily (see PHARMACOLOGY: PHARMACODYNAMICS: CLINICAL STUDIES under ACTIONS). Treatment should be continued as long as the patient continues to benefit.
Dosage in Ph+ CML-CP and CML-AP resistant to or intolerant to at least one prior therapy including imatinib: The recommended dose of Tasigna is 400 mg twice daily (see PHARMACOLOGY: PHARMACODYNAMICS: CLINICAL STUDIES under ACTIONS). Treatment should be continued as long as the patient continues to benefit.
Monitoring recommendations and dose adjustments: A baseline ECG is recommended prior to initiating therapy with Tasigna and should be repeated after 7 days and as clinically indicated. Hypokalemia or hypomagnesemia must be corrected prior to Tasigna administration and potassium and magnesium blood levels should be monitored periodically during therapy, particularly in patients at risk for these electrolyte abnormalities (see PRECAUTIONS).
Increases in total serum cholesterol levels have been reported with Tasigna therapy (see PRECAUTIONS). Lipid profiles should be determined prior to initiating Tasigna therapy, assessed at month 3 and 6 after initiating therapy, and at least yearly during chronic therapy.
Increases in blood glucose levels have been reported with Tasigna therapy (see PRECAUTIONS). Blood glucose levels should be assessed prior to initiating Tasigna therapy and monitored during treatment.
Due to possible occurrence of Tumor Lysis Syndrome (TLS), correction of clinically significant dehydration and treatment of high uric acid levels are recommended prior to initiating therapy with Tasigna (see ADVERSE REACTIONS).
Tasigna may need to be temporarily withheld and/or dose reduced for hematological toxicities (neutropenia, thrombocytopenia) that are not related to underlying leukemia (see Table 8).


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If clinically significant moderate or severe non-hematologic 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 (newly diagnosed Ph+ CML-CP) or 400 mg (resistant or intolerant Ph+ CML-CP and CML-AP) twice daily should be attempted.
Elevated serum lipase: For Grade 3 to 4 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 PRECAUTIONS and ADVERSE REACTIONS).
Elevated bilirubin and hepatic transaminases: For Grade 3 to 4 bilirubin or 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 (see ADVERSE REACTIONS).
Special populations: Pediatric patients (below 18 years): Safety and efficacy in children and adolescents below the age of 18 has not been established.
Geriatric patients (≥65 years of age): Approximately 12% and 30% of subjects in the clinical studies (newly diagnosed Ph+ CML-CP and resistant or intolerant Ph+ CML-CP and CML-AP) were 65 years of age or older. No major differences were observed for safety and efficacy in patients ≥65 years of age as compared to adults 18 to 65 years of age.
Renal impairment: Clinical studies have not been performed in patients with impaired renal function. Clinical studies have excluded patients with serum creatinine concentration >1.5 times the upper limit of the normal range.
Since nilotinib and its metabolites are not renally excreted, a decrease in total body clearance is not anticipated in patients with renal impairment.
Hepatic impairment: Hepatic impairment has a modest effect on the pharmacokinetics of nilotinib. Dose adjustment is not considered necessary in hepatically impaired patients. Patients with hepatic impairment should be treated with caution (see PRECAUTIONS).
Cardiac disorders: In clinical studies, patients with uncontrolled or significant cardiac disease including 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 PRECAUTIONS).
Administration: Tasigna should be taken twice daily, at approximately 12 hour intervals, and must not be taken with food. The capsules should be swallowed whole with water. No food should be consumed for at least two hours before the dose is taken and no additional food should be consumed for at least one hour after the dose is taken (see PRECAUTIONS and INTERACTIONS).
For patients who are unable to swallow capsules, the content of each capsule may be dispersed in one teaspoon of applesauce (pureed apple) and should be taken immediately. Not more than one teaspoon of applesauce and no food other than applesauce must be used (see PHARMACOLOGY under ACTIONS).
If a dose is missed the patient should not take an additional dose, but take the usual prescribed next dose.
Overdosage
Isolated reports of intentional overdose with nilotinib were reported, where an unspecified number of Tasigna capsules were ingested in combination with alcohol and other drugs. Events included neutropenia, vomiting and drowsiness. No ECG changes or hepatotoxicity were reported. Outcomes were reported as recovered.
Treatment: In the event of overdose, the patient should be observed and appropriate supportive treatment given.
Contraindications
Tasigna is contraindicated in patients with known hypersensitivity to nilotinib or to any of the excipients.
Special Precautions
Myelosuppression: Treatment with Tasigna is often associated with thrombocytopenia, neutropenia and anemia (NCI CTC Grade 3/4). The occurrence is more frequent in patients with imatinib-resistant or intolerant CML and in particular in patients with CML-AP. 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 reducing the dose (see DOSAGE & ADMINISTRATION).
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 INTERACTIONS). 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: In clinical trials, uncommon cases (0.1 to 1%) of sudden death have been reported in patients in imatinib-resistant or -intolerant CML patients in chronic and accelerated phase receiving Tasigna with a past medical history of cardiac disease or significant cardiac risk factors. Comorbidities in addition to the underlying malignancy were also frequently present as were concomitant medications. Ventricular repolarization abnormalities may have been contributory factors. Based on post-marketing exposure in patient-years, the estimated reporting rate for spontaneous reports of sudden death is 0.02% per patient-year. No cases of sudden deaths have been reported in the newly diagnosed Ph+ CML-CP Phase III study.
Cardiovascular events: Cardiovascular events were reported in a randomized, Phase III nilotinib trial in newly diagnosed CML patients and observed in the post-marketing reports. With a median time on therapy of 60.5 months in the clinical trial, Grade 3/4 cardiovascular events included peripheral arterial occlusive disease (1.4% and 1.1% at 300 mg and 400 mg twice a day respectively), ischemic heart disease (2.2% and 6.1% at 300 mg and 400 mg twice a day respectively) and ischemic cerebrovascular events (1.1% and 2.2% at 300 mg and 400 mg twice a day respectively). If acute signs or symptoms of cardiovascular events occur, advise patients to seek immediate medical attention. The cardiovascular status of patients should be evaluated and cardiovascular risk factors should be monitored and actively managed during Tasigna therapy according to standard guidelines (see DOSAGE & ADMINISTRATION and discussion on non-haematological toxicities under ADVERSE REACTIONS).
Fluid retention: Severe forms of drug-related fluid retention such as pleural effusion, pulmonary edema, and pericardial effusion were uncommonly (0.1 to 1%) observed in a Phase III study of newly diagnosed CML patients. Similar events were observed in post-marketing reports. Unexpected, rapid weight gain should be carefully investigated. If signs of severe fluid retention appear during treatment with nilotinib, the etiology should be evaluated and patients treated accordingly (see DOSAGE & ADMINISTRATION and discussion on dose adjustments for adverse drug reactions, and non-haematological adverse drug reactions under ADVERSE REACTIONS).
Hepatitis B reactivation: Reactivation of hepatitis B can occur in patients who are chronic carriers of this virus after receiving a BCR-ABL tyrosine kinase inhibitor (TKI), such as nilotinib. Some cases involving drugs of the BCR-ABL TKI class resulted in acute hepatic failure or fulminant hepatitis leading to liver transplantation or a fatal outcome (see ADVERSE REACTIONS).
Patients should be tested for hepatitis B infection before initiating treatment with nilotinib. Patients currently on nilotinib should have baseline testing for hepatitis B infection in order to identify chronic carriers of the virus. Experts in liver disease and in the treatment of hepatitis B should be consulted before treatment is initiated in patients with positive hepatitis B serology (including those with active disease) and for patients who test positive for hepatitis B infection during treatment. Carriers of hepatitis B virus who require treatment with nilotinib should be closely monitored for signs and symptoms of active hepatitis B infection throughout therapy and for several months following termination of therapy.
Laboratory tests and monitoring: Blood lipids: In a Phase III study in newly diagnosed CML patients, 1.1% of the patients treated with 400 mg nilotinib twice a day had a Grade 3/4 elevation in total cholesterol; however, there were no Grade 3/4 elevations in the 300 mg twice a day dose group (see Investigations under ADVERSE DRUG REACTIONS). It is recommended that the lipid profiles be determined before initiating treatment with Tasigna, assessed at month 3 and 6 after initiating therapy, and at least yearly during chronic therapy (see DOSAGE & ADMINISTRATION). If a HMG-CoA reductase inhibitor (a lipid lowering agent) is needed, please refer to INTERACTIONS, before starting treatment since certain HMG-CoA reductase inhibitors are metabolized by the CYP3A4 pathway.
Blood glucose: In a Phase III study in newly diagnosed CML patients, 6.9% of the patients treated with 400 mg nilotinib twice a day had a Grade 3/4 elevation in blood glucose; and 7.2% of the patients treated with 300 mg nilotinib twice a day had a Grade 3/4 elevation in blood glucose. It is recommended that the glucose levels should be assessed before initiating treatment with Tasigna and monitored during treatment as clinically indicated (see DOSAGE & ADMINISTRATION). If test results warrant therapy, physicians should follow their local standards of practice and treatment guidelines.
Interactions: The administration of Tasigna with agents that are strong CYP3A4 inhibitors and drugs that may prolong the QT interval such as anti-arrhythmic medicines should be avoided (see DOSAGE & ADMINISTRATION and INTERACTIONS). Should treatment with any of these agents be required, it is recommended that therapy with Tasigna be interrupted if possible (see INTERACTIONS). If transient interruption of treatment with Tasigna is not possible, close monitoring of the individual for prolongation of the QT interval is indicated (see PHARMACOLOGY under ACTIONS, DOSAGE & ADMINISTRATION, AND INTERACTIONS).
Concomitant use of Tasigna with medicinal products that are potent inducers of CYP3A4 is likely to reduce exposure to nilotinib to a clinically relevant extent. Therefore, in patients receiving Tasigna, concomitant use of alternative therapeutic agents with less potential for CYP3A4 induction should be selected (see INTERACTIONS).
Food Effects: The bioavailability of nilotinib is increased by food. Tasigna must not be taken in conjunction with food (see DOSAGE & ADMINISTRATION and INTERACTIONS) 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 at any time.
Hepatic Impairment: Hepatic impairment has a modest effect on the pharmacokinetics of nilotinib. Single dose administration of nilotinib resulted in increases in AUC of 35%, 35% and 19% in subjects with mild, moderate and severe hepatic impairment respectively, compared to a control group of subjects with normal hepatic function. The predicted steady-state Cmax of nilotinib showed an increase of 29%, 18% and 22% respectively. Clinical studies have excluded patients with ALT and/ or 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. Caution is recommended in patients with hepatic impairment (see monitoring recommendations under DOSAGE & ADMINISTRATION).
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, doses should be interrupted and appropriate diagnostics should be considered in order to exclude pancreatitis (see DOSAGE & ADMINISTRATION).
Total gastrectomy: The bioavailability of nilotinib might be reduced in patients with total gastrectomy (see PHARMACOLOGY under ACTIONS). More frequent follow-up of these patients should be considered.
Tumor lysis syndrome: Cases of tumor lysis syndrome have been reported in patients treated with Tasigna. For monitoring recommendations, please refer to DOSAGE & ADMINISTRATION.
Lactose: Since the capsules contain lactose, Tasigna is not recommended for patients with rare hereditary problems of galactose intolerance, severe lactase deficiency or of glucose-galactose malabsorption.
Effects on Ability to Drive and Use Machines: No studies on the effects of nilitinib on the ability to drive and operate machines have been performed. Patients experiencing dizziness, visual impairment or other undersirable effects with a potential impact on the ability to safely drive or use machines should refrain from these activities as long as these undesirable effects persist (see ADVERSE REACTIONS)
Use In Pregnancy & Lactation
Women of childbearing potential: Women of childbearing potential must be advised to use highly effective method of contraception while receiving Tasigna and for up to 2 weeks after ending treatment.
Use in Pregnancy: There are no adequate data on the use of Tasigna in pregnant women. Studies in animals showed no teratogenicity, but embryo- and fetotoxicity was seen at doses which also showed maternal toxicity (see PHARMACOLOGY: TOXICOLOGY: NON-CLINICAL SAFETY DATA under ACTIONS). Tasigna should not be used during pregnancy unless necessary. If it is used during pregnancy, the patient must be informed of the potential risk to the fetus.
Use in Breast-feeding: It is not known whether nilotinib is excreted in human milk. Studies in animals demonstrate that nilotinib is excreted into breast milk. Women taking Tasigna should not breast-feed while taking Tasigna, as a risk to the infant cannot be excluded.
Fertility: The effect of nilotinib on male and female fertility is not known. In animal studies, no effects on sperm count/motility, and on fertility were noted in male and female rats up to the highest tested dose of approximately 5-fold greater than the recommended dosage for humans. (see PHARMACOLOGY: TOXICOLOGY: NON-CLINICAL SAFETY DATA under ACTIONS).
Adverse Reactions
150 mg Hard Capsules: Summary of the safety profile: The data described as follows 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 60.5 months (range 0.1-70.8 months).
The most frequent (≥10%) non-haematological adverse reactions were rash, pruritus, headache, nausea, fatigue, alopecia, myalgia and upper abdominal pain. Most of these adverse reactions were mild to moderate in severity. Constipation, dry skin, asthenia, muscle spasms, diarrhoea, arthralgia, abdominal pain, vomiting and peripheral oedema were observed less commonly (<10% and ≥5%), were of mild to moderate severity, manageable and generally did not require dose reduction.
Treatment-emergent haematological toxicities include myelosuppression: thrombocytopenia (18%), neutropenia (15%) and anaemia (8%). Biochemical adverse drug reactions include alanine aminotransferase increased (24%), hyperbilirubinaemia (16%), aspartate aminotransferase increased (12%), lipase increased (11%), blood bilirubin increased (10%), hyperglycaemia (4%), hypercholesterolaemia (3%) and hypertriglyceridaemia (<1%). Pleural and pericardial effusions, regardless of causality, occurred in 2% and <1% of patients, respectively, receiving Tasigna 300 mg twice daily. Gastrointestinal haemorrhage, regardless of causality, was reported in 3% 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%.
Discontinuation due to adverse drug reactions was observed in 10% of patients.
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 9. These are ranked under heading of frequency, with the most frequent appearing first, using one decimal precision for percentages and the following convention: very common (≥1/10) or common (≥1/100 to <1/10). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. (See Table 9.)


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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 9 are also reported. These adverse reactions are included based on clinical relevance and ranked in order of decreasing seriousness within each category using the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), not known (cannot be estimated from the available data).
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, hepatitis B reactivation.
Neoplasms benign, malignant and unspecified (including cysts and polyps): Common: skin papilloma.
Not known: oral papilloma, paraproteinaemia.
Blood and lymphatic system disorders: Common: leukopenia, eosinophilia, lymphopenia.
Uncommon: pancytopenia.
Not known: febrile neutropenia.
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, hypertriglyceridaemia, hyperglycaemia, decreased appetite, hypocalcaemia, hypokalaemia.
Uncommon: hyperkalaemia, dyslipidaemia, gout.
Not known: hyperuricaemia, hypoglycaemia, appetite disorder.
Psychiatric disorders: Common: insomnia, depression, anxiety.
Not known: amnesia, dysphoria.
Nervous system disorders: Common: dizziness, hypoaesthesia, peripheral neuropathy.
Uncommon: ischaemic stroke, cerebral infarction, migraine, paraesthesia.
Not known: cerebrovascular accident, basilar artery stenosis, syncope, 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: angina pectoris, arrhythmia (including atrioventricular block, tachycardia, atrial fibrillation, ventricular extrasystoles, bradycardia), electrocardiogram QT prolonged, palpitations, myocardial infarction.
Uncommon: cardiac failure, cyanosis.
Not known: 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: intermittent claudication, peripheral arterial occlusive disease, arteriosclerosis.
Not known: haematoma, peripheral artery stenosis.
Respiratory, thoracic and mediastinal disorders: Common: dyspnoea, cough.
Uncommon: pleural effusion.
Not known: dyspnoea exertional, pleurisy, epistaxis, oropharyngeal pain.
Gastrointestinal disorders: Common: abdominal distension, abdominal discomfort, dysgeusia, flatulence.
Uncommon: pancreatitis, gastritis, sensitivity of teeth.
Not known: oesophageal ulcer, gastric ulcer, oesophageal pain, stomatitis, dry mouth, 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, eczema.
Uncommon: drug eruption, skin pain.
Not known: erythema multiforme, 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, muscular weakness.
Uncommon: musculoskeletal pain, flank pain.
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 of 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, lipoprotein cholesterol (including low density and high density) increased, total cholesterol increased, blood triglycerides increased.
Common: haemoglobin decreased, blood amylase increased, blood alkaline phosphatase increased, gamma-glutamyltransferase increased, weight increased, blood insulin increased, globulins decreased.
Not known: blood parathyroid hormone increased, 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 10.


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Treatment discontinuation in Ph+ CML-CP patients who have achieved a sustained deep molecular response: After discontinuation of TASIGNA therapy within the framework of attempting treatment-free remission (TFR), patients may experience musculoskeletal symptoms more frequently than before treatment discontinuation, e.g., myalgia, pain in extremity, arthralgia, bone pain, spinal pain, or musculoskeletal pain.
Postmarketing experience: The following adverse reactions have been derived from post-marketing experience with Tasigna via spontaneous case reports, literature cases, expanded access programmes, and clinical studies other than the global registration trials. Since these reactions are reported voluntarily 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.
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.
200 mg Hard Capsules: Summary of the safety profile: The data described as follows reflect exposure to Tasigna in a total of 717 patients from a randomised Phase III study in patients with newly diagnosed Ph+ 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=321) and accelerated phase (n=137) treated at the recommended dose of 400 mg twice daily.
In patients with newly diagnosed CML in chronic phase: The median duration of exposure was 60.5 months (range 0.1-70.8 months).
The most frequent (≥10%) non-haematological adverse reactions were rash, pruritus, headache, nausea, fatigue, alopecia, myalgia and upper abdominal pain. Most of these adverse reactions were mild to moderate in severity. Constipation, dry skin, asthenia, muscle spasms, diarrhoea, arthralgia, abdominal pain, vomiting and peripheral oedema were observed less commonly (<10% and ≥5%) were of mild to moderate severity, manageable and generally did not require dose reduction.
Treatment-emergent haematological toxicities include myelosuppression: thrombocytopenia (18%), neutropenia (15%) and anaemia (8%). Biochemical adverse drug reactions include alanine aminotransferase increased (24%), hyperbilirubinaemia (16%), aspartate aminotransferase increased (12%), lipase increased (11%), blood bilirubin increased (10%), hyperglycaemia (4%), hypercholesterolaemia (3%) and hypertriglyceridaemia (<1%). Pleural and pericardial effusions, regardless of causality, occurred in 2% and <1% of patients, respectively, receiving Tasigna 300 mg twice daily. Gastrointestinal haemorrhage, regardless of causality, was reported in 3% 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%.
Discontinuation due to adverse drug reactions was observed in 10% of patients.
In patients with imatinib-resistant or intolerant CML in chronic phase and accelerated phase: The data described as follows 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 most frequent (≥10%) non-haematological drug-related adverse events were rash, pruritus, nausea, fatigue, headache, vomiting, myalgia, constipation and diarrhoea. Most of these adverse events were mild to moderate in severity. Alopecia, muscle spasms, decreased appetite, arthralgia, abdominal pain, bone pain, peripheral oedema, asthenia, upper abdominal pain, dry skin, erythema and pain in extremity were observed less commonly (<10% and ≥5%) and have been of mild to moderate severity (Grade 1 or 2). Discontinuation due to adverse drug reactions was observed in 16% of chronic phase and 10% of accelerated phase 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 11. These are ranked under heading of frequency; with the most frequent appearing first, using one decimal precision for percentages and the following convention: very common (≥1/10) or common (≥1/100 to <1/10). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. (See Table 11.)


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The following adverse reactions were reported in patients in the Tasigna clinical studies at a frequency of less than 5%. For laboratory abnormalities, very common events (≥1/10) not included in Table 11 are also reported. These adverse reactions are included based on clinical relevance and ranked in order of decreasing seriousness within each category using the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), not known (cannot be estimated from the available data).
Infections and infestations: Common: folliculitis, upper respiratory tract infection (including pharyngitis, nasopharyngitis, rhinitis).
Uncommon: pneumonia, urinary tract infection, gastroenteritis, bronchitis, herpes virus infection, candidiasis (including oral candidiasis).
Not known: sepsis, subcutaneous abscess, anal abscess, furuncle, tinea pedis, hepatitis B reactivation.
Neoplasms benign, malignant and unspecified (including cysts and polyps): Common: skin papilloma.
Not known: oral papilloma, paraproteinaemia.
Blood and lymphatic system disorders: Common: leukopenia, eosinophilia, febrile neutropenia, pancytopenia, lymphopenia.
Uncommon: thrombocythaemia, leukocytosis.
Immune system disorders: Not known: hypersensitivity.
Endocrine disorders: Uncommon: hyperthyroidism, hypothyroidism.
Not known: hyperparathyroidism secondary, thyroiditis.
Metabolism and nutrition disorders: Very common: hypophosphataemia (including blood phosphorus decreased).
Common: electrolyte imbalance (including hypomagnesaemia, hyperkalaemia, hypokalaemia, hyponatraemia, hypocalcaemia, hypercalcaemia, hyperphosphataemia), diabetes mellitus, hyperglycaemia, hypercholesterolaemia, hyperlipidaemia, hypertriglyceridaemia.
Uncommon: dehydration, increased appetite, gout, dyslipidaemia.
Not known: hyperuricaemia, hypoglycaemia.
Psychiatric disorders: Common: depression, insomnia, anxiety.
Not known: disorientation, confusional state, amnesia, dysphoria.
Nervous system disorders: Common: dizziness, peripheral neuropathy, hypoaesthesia, paraesthesia.
Uncommon: intracranial haemorrhage, ischaemic stroke, transient ischaemic attack, cerebral infarction, migraine, loss of consciousness (including syncope), tremor, disturbance in attention, hyperaesthesia.
Not known: cerebrovascular accident, brain oedema, optic neuritis, lethargy, dysaesthesia, restless legs syndrome.
Eye disorders: Common: eye haemorrhage, periorbital oedema, eye pruritus, conjunctivitis, dry eye (including xerophthalmia).
Uncommon: visual impairment, vision blurred, conjunctival haemorrhage, visual acuity reduced, eyelid oedema, photopsia, hyperaemia (scleral, conjunctival, ocular), eye irritation.
Not known: papilloedema, chorioretinopathy, diplopia, photophobia, eye swelling, blepharitis, eye pain, conjunctivitis allergic, ocular surface disease.
Ear and labyrinth disorders: Common: vertigo.
Not known: hearing impaired, ear pain, tinnitus.
Cardiac disorders: Common: angina pectoris, arrhythmia (including atroventricular block, cardiac flutter, extrasystoles, tachycardia, atrial fibrillation, bradycardia), palpitations, electrocardiogram QT prolonged.
Uncommon: cardiac failure, myocardial infarction, coronary artery disease, cardiac murmur, pericardial effusion, cyanosis.
Not known: ventricular dysfunction, pericarditis, ejection fraction decreased.
Vascular disorders: Common: hypertension, flushing, peripheral artery stenosis.
Uncommon: hypertensive crisis, peripheral arterial occlusive disease, intermittent claudication, arterial stenosis limb, haematoma, arteriosclerosis.
Not known: shock haemorrhagic, hypotension, thrombosis.
Respiratory, thoracic and mediastinal disorders: Common: dyspnoea, dyspnoea exertional, epistaxis, cough, dysphonia.
Uncommon: pulmonary oedema, pleural effusion, interstitial lung disease, pleuritic pain, pleurisy, pharyngolaryngeal pain, throat irritation.
Not known: pulmonary hypertension, wheezing, oropharyngeal pain.
Gastrointestinal disorders: Common: pancreatitis, abdominal discomfort, abdominal distension, dysgeusia, flatulence.
Uncommon: gastrointestinal haemorrhage, melaena, mouth ulceration, gastroesophageal reflux, stomatitis, oesophageal pain, dry mouth, gastritis, sensitivity of teeth.
Not known: gastrointestinal ulcer perforation, retroperitoneal haemorrhage, haematemesis, gastric ulcer, oesophagitis ulcerative, subileus, enterocolitis, haemorrhoids, hiatus hernia, rectal haemorrhage, gingivitis.
Hepatobiliary disorders: Very common: hyperbilirubinaemia (including blood bilirubin increased).
Common: hepatic function abnormal.
Uncommon: hepatotoxicity, toxic hepatitis, jaundice.
Not known: cholestasis, hepatomegaly.
Skin and subcutaneous tissue disorders: Common: night sweats, eczema, urticaria, hyperhidrosis, contusion, acne, dermatitis (including allergic, exfoliative and acneiform).
Uncommon: exfoliative rash, drug eruption, skin pain, ecchymosis, swelling face.
Not known: erythema multiforme, erythema nodosum, skin ulcer, palmar-plantar erythrodysaesthesia syndrome, petechiae, photosensitivity, blister, dermal cysts, sebaceous hyperplasia, skin atrophy, skin discolouration, skin exfoliation, skin hyperpigmentation, skin hypertrophy, hyperkeratosis, psoriasis.
Musculoskeletal and connective tissue disorders: Common: musculoskeletal chest pain, musculoskeletal pain, back pain, flank pain, neck pain, muscular weakness.
Uncommon: musculoskeletal stiffness, joint swelling.
Not known: arthritis.
Renal and urinary disorders: Common: pollakiuria.
Uncommon: dysuria, micturition urgency, nocturia.
Not known: renal failure, haematuria, urinary incontinence, chromaturia.
Reproductive system and breast disorders: Uncommon: breast pain, gynaecomastia, erectile dysfunction.
Not known: breast induration, menorrhagia, nipple swelling.
General disorders and administration site conditions: Common: chest pain (including non-cardiac chest pain), pain, pyrexia, chest discomfort, malaise.
Uncommon: face oedema, gravitational oedema, influenza-like illness, chills, feeling of body temperature change (including feeling hot, feeling cold).
Not known: localised oedema.
Investigations: Very common: alanine aminotransferase increased, aspartate aminotransferase increased, lipase increased, lipoprotein cholesterol (including low density and high density) increased, total cholesterol increased, blood triglycerides increased.
Common: haemoglobin decreased, blood amylase increased, blood alkaline phosphatase increased, gamma-glutamyltransferase increased, blood creatinine phosphokinase increased, weight decreased, weight increased, blood insulin increased, globulins decreased.
Uncommon: blood lactate dehydrogenase increased, blood glucose decreased, blood urea increased.
Not known: troponin increased, blood bilirubin unconjugated increased, blood insulin decreased, insulin C-peptide decreased, blood parathyroid hormone increased.
Clinically relevant or severe abnormalities of routine haematological or biochemistry laboratory values are presented in Table 12.


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Treatment discontinuation in Ph+ CML-CP patients who have achieved a sustained deep molecular response: After discontinuation of TASIGNA therapy within the framework of attempting treatment-free remission (TFR), patients may experience musculoskeletal symptoms more frequently than before treatment discontinuation, e.g., myalgia, pain in extremity, arthralgia, bone pain, spinal pain, or musculoskeletal pain.
Sudden death: Uncommon cases (0.1 to 1%) of sudden deaths have been reported in Tasigna clinical trials and/or compassionate use programs in patients with imatinib-resistant or intolerant CML in chronic phase or accelerated phase with a past medical history of cardiac disease or significant cardiac risk factors (see PRECAUTIONS).
Postmarketing experience: The following adverse reactions have been derived from post-marketing experience with Tasigna via spontaneous case reports, literature cases, expanded access programmes, and clinical studies other than the global registration trials. Since these reactions are reported voluntarily 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.
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.
Drug Interactions
Nilotinib is mainly metabolized 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 drugs that affect CYP3A4 and/or P-gp.
Drugs that may increase nilotinib serum concentrations: In a Phase I study of nilotinib given in combination with imatinib (a substrate of P-gp and CYP3A4), both drugs had a slight inhibitory effect on CYP3A4 and/or P-gp. When the two drugs were administered concomitantly, the AUC of imatinib was increased by 18% to 39%, and the AUC of nilotinib was increased by 18% to 40%.
The bioavailability of nilotinib in healthy subjects was increased by 3-fold when co-administered with the strong CYP3A4 inhibitor ketoconazole. Concurrent treatment with strong CYP3A4 inhibitors should therefore be avoided (including but not limited to ketoconazole, itraconazole, voriconazole, ritonavir, clarithromycin, and telithromycin) (see DOSAGE & ADMINISTRATION and discussion on QT prolongation under PRECAUTIONS). Alternative concomitant medications with no or minimal CYP3A4 inhibition should be considered.
Drugs that may decrease nilotinib serum concentrations: In healthy subjects receiving the CYP3A4 inducer, rifampicin, at 600 mg daily for 12 days, systemic exposure (AUC) to nilotinib was decreased approximately 80%.
Inducers of CYP3A4 activity could increase the metabolism of nilotinib and thereby decrease plasma concentrations of nilotinib. The concomitant administration of medications that induce CYP3A4 (e.g. phenytoin, rifampicin, carbamazepine, phenobarbital, and St. John's Wort) may reduce exposure to nilotinib. In patients for whom CYP3A4 inducers are indicated, alternative agents with less enzyme induction potential should be considered.
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-∞). Tasigna 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 an 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 mentioned previously, administration of an antacid (aluminum 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.
Drugs that may have their systemic concentration altered by nilotinib: In vitro nilotinib is identified as a competitive inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2D6 and UGT1A1, with Ki value being lowest for CYP2C9 (Ki=0.13 microM).
In CML patients, nilotinib administered at 400 mg twice daily for 12 days increased the systemic exposure of oral midazolam (a substrate of CYP3A4) 2.6-fold. Nilotinib is a moderate CYP3A4 inhibitor. As a result, the systemic exposure of other drugs primarily metabolized by CYP3A4 (e.g. certain HMG-CoA reductase inhibitors) may be increased when co-administered with nilotinib. Appropriate monitoring and dose adjustment may be necessary for drugs that are CYP3A4 substrates and have a narrow therapeutic index (including but not limited to alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, sirolimus and tacrolimus) when co-administered with nilotinib.
In healthy subjects, nilotinib at clinically relevant concentrations was not found to alter the pharmacokinetics or pharmacodynamics of warfarin, a sensitive CYP2C9 substrate. Tasigna can be used concurrently with warfarin without increasing the anticoagulant effect.
Anti-arrhythmic medicines and other drugs that may prolong the QT interval: Concomitant use of anti-arrhythmic medicines (including, but not limited to amiodarone, disopyramide, procainamide, quinidine and sotalol) and other drugs that may prolong the QT interval (including, but not limited to chloroquine, halofantrine, clarithromycin, haloperidol, methadone, moxifloxacin, bepridil and pimozide) should be avoided (see PRECAUTIONS).
Food interactions: The absorption and the bioavailability of nilotinib are increased if it is taken with food, resulting in higher serum concentration (see PHARMACOLOGY under ACTIONS, DOSAGE & ADMINISTRATION, AND PRECAUTIONS).
Grapefruit juice and other foods that are known to inhibit CYP3A4 should be avoided at any time.
Caution For Usage
Instructions for Use, Handling and Disposal: Not applicable.
Incompatibilities: Not applicable.
Storage
Do not store above 30°C. Protect from moisture.
Keep drug in original package.
Shelf-Life: 36 months from the manufacturing date.
ATC Classification
L01XE08 - nilotinib ; Belongs to the class of protein kinase inhibitors, other antineoplastic agents. Used in the treatment of cancer.
Presentation/Packing
Cap 150 mg (white to yellowish powder in red opaque hard gelatin capsule, size 1 with black axial imprint "NVR/BCR") x 7 x 4's. 200 mg (white to yellowish powder in light yellow opaque hard gelatin capsule, size 0 with red axial imprint "NVR/TKI") x 7 x 4's.
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