Active ingredient: nilotinib Chemical name (CAS): 4-Methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5- (trifluoromethyl) phenyl]-3-[[4-(3-pyridinyl)-2- pyrimidinyl]amino]-benzamide, monohydrochloride, monohydrate Molecular formula: C28H22F3N7O.HCl.H2O CAS number: Free base - 641571-10-0 Molecular weight: 583.99 (as monohydrate) Structural formula:
H3C
N
H
N N
N
H3C
N
. HCl, H2O
N CF3
H
N
Each capsule contains 150 mg or 200 mg nilotinib base (as hydrochloride, monohydrate). Nilotinib is a white to slightly yellowish or slightly greenish yellowish powder. The solubility of nilotinib in aqueous solutions strongly decreases with increasing pH, and it is practically insoluble in buffer solutions of pH 4.5 and higher pH values. It is very soluble in dimethyl sulfoxide, sparingly soluble in ethanol and methanol, very slightly soluble in acetonitrile and n-octanol.
Capsule content: lactose, crospovidone, poloxamer, silica - colloidal anhydrous, magnesium stearate. Capsule: gelatin, titanium dioxide, iron oxide yellow, iron oxide red, Opacode S-1-277002 Black (150 mg printing ink), TekPrint SW-1102 Red Ink (200 mg printing ink).
Nilotinib inhibits BCR-ABL tyrosine kinase activity in the nanomolar range by binding to the ATP-binding site. It also inhibited 32/33 imatinib-resistant mutant forms of BCR-ABL tyrosine kinase that were tested. As a consequence, nilotinib inhibited the proliferation of cell lines carrying these enzymes. Orally- administered nilotinib, as a single agent, was also effective in reducing tumour burden and prolonging survival in a murine model of CML. Nilotinib had little or no effect against the majority of other protein kinases examined except for the platelet derived growth factor receptor (PDGFR and ), and stem cell factor receptor (KIT CSF-1R, DDR) kinases which it inhibited at concentrations within the range achieved following oral administration at therapeutic doses recommended for the treatment of CML.
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 serum concentration-time curve (AUC) of nilotinib are increased by 112% and 82%, respectively compared to fasting conditions when Tasigna is given with food. Administration of Tasigna 30 minutes or 2 hours after food increased bioavailability of nilotinib by 29% or 15%, respectively (see "DOSAGE AND ADMINISTRATION"). Nilotinib absorption (relative bioavailability) might be reduced by approximately 48% and 22% in patients with total gastrectomy and partial gastrectomy, respectively. 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.
The blood-to-serum ratio of nilotinib is 0.68. Serum protein binding is approximately 98% on the basis of in vitro experiments.
Main metabolic pathways identified in healthy subjects are oxidation and hydroxylation. Nilotinib is the main circulating component in the serum. Of the nilotinib metabolites, the pyrimidine-N-oxide metabolite (BEJ866) has been found to possess inhibitory activity against the Bcr-Abl kinase in transfected murine hematopoietic cells, albeit at concentrations much higher than those required by the parent drug, nilotinib. The mean serum exposure of BEJ866 is 1.0% of the exposure of nilotinib.
After a single dose of radiolabelled nilotinib in healthy subjects, greater than 90% of the dose was eliminated within 7 days mainly in faeces (93% of the dose). Parent drug accounted for 69% of the dose.
Steady-state nilotinib exposure was dose-dependent with less than dose-proportional increases in systemic exposure at dose levels higher than 400 mg given as once daily dosing. Daily serum exposure to nilotinib 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 serum exposure to nilotinib between the first dose and steady state was approximately 2-fold for daily dosing and 3.8-fold for twice-daily dosing. The apparent elimination half-life estimated from the multiple dose pharmacokinetics with daily dosing was approximately 17 hours. Inter-patient variability in nilotinib pharmacokinetics was moderate to high.
Age, body weight, or ethnic origin do not affect the pharmacokinetics of nilotinib, whereas there is an effect of gender, with exposure to nilotinib in female patients being approximately 20% greater than in male patients.
An open label, multicenter, randomised 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, or a maximum of two weeks of imatinib in emergent cases. 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 and 36 months of treatment (or discontinued earlier).The median time on treatment was approximately 36 months in all three treatment groups. The median actual dose intensity was 400 mg/day in the imatinib group, 594 mg/day in the nilotinib 300 mg twice daily group and 778 mg/day in the nilotinib 400 mg twice daily group. This study is on-going.
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 standardised baseline. The 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. 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, Table 1. In the nilotinib recommended dose of 300 mg twice daily, the rate 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 rate 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 rate of MMR at 3, 6, 9 and 12 months were 0.7%, 12.0%, 18.0% and 22.3%. The MMR rate at 12, 24 and 36 months is presented in Table 1.
Table 1 MMR rate
| TASIGNA 300 mg twice daily N=282 n (%) | TASIGNA 400 mg twice daily N=281 n (%) | Glivec 400 mg once daily N=283 n (%) | |
| Major Molecular Response at 12 months | 125(44.3) | 120(42.7) | 63(22.3) |
| 95% CI for response rate | [38.4, 50.3] | [36.8, 48.7] | [17.6, 27.6] |
| Major Molecular Response at 24 months | 174 (61.7) 1 | 166 (59.1) 1 | 106 (37.5) |
| 95% CI for response | [55.8,67.4] | [53.1,64.9] | [31.8,43.4] |
| Major Molecular Response at 36 months 2 | 165 (58.5) 1 | 161 (57.3) 1 | 109 (38.5) |
| 95% CI for response | [52.5,64.3] | [51.3,63.2] | [32.8,44.5] |
CMH test p-value for response rate (vs. Imatinib 400 mg) <0.0001
Only patients who were in MMR at a specific time point are included as responders for that time point. A total of 199 (35.2%) of all missing/unevaluable PCR assessments (n=17), atypical transcripts at baseline (n=7), or discontinuation prior to the 36-month time patients were not evaluable for MMR at 36 months (87 in the nilotinib 300 mg BID group and 112 in the imatinib group) due to point (n=175).
MMR rates by different time points (including patients who achieved MMR at or before those time points as responders) are presented in the cumulative incidence of MMR (Figure 1).
Figure 1 Cumulative Incidence of MMR
For all Sokal risk groups, the MMR rates at 12 months were higher in the two nilotinib groups than in the imatinib group. Based on the Kaplan-Meier analyses of time to first MMR among all patients are graphically displayed in Figure 1. The probability of achieving MMR at different time points were higher in both nilotinib groups compared to the imatinib group (HR=2.21 and stratified log-rank p<0.0001 between nilotinib 300 mg twice daily and imatinib, HR=1.92 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 2 and by different time-points are presented in Figure 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.
Table 2 Proportions of patients who had molecular response of <= 0.01% (4 log reduction and <= 0.0032% (4.5 log reduction) | ||||||
|---|---|---|---|---|---|---|
| TASIGNA 300 mg twice daily N=282 (%) | TASIGNA 400 mg twice daily N=281 (%) | Imatinib 400 mg once daily N=283 (%) | ||||
| <= 0.01% | <= 0.0032% | <= 0.01% | <= 0.0032% | <= 0.01% | <= 0.0032% | |
| At 12 months | 11.7 | 4.3 | 8.5 | 4.6 | 3.9 | 0.4 |
| At 24 months | 24.5 | 12.4 | 22.1 | 7.8 | 10.2 | 2.8 |
| At 36 months | 29.4 | 13.8 | 23.8 | 12.1 | 14.1 | 8.1 |
Figure 2 Cumulative incidence of molecular response of <= 0.01% (4-log reduction)
Figure 3 Cumulative incidence of molecular response of <= 0.0032% (4.5 log reduction)
Based on Kaplan-Meier estimates, the proportions of patients who achieved MMR and were maintaining response after 36 months were 95.0% (95% CI: 91.8% - 98.3%) in the nilotinib 300 mg twice daily group, 93.9% (95% CI: 90.3% - 97.4%) in the nilotinib 400 mg twice daily group and 88.4% (95% CI: 82.6% - 94.2%) in the imatinib 400 mg once daily group.
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, Table 3. 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.
| TASIGNA 300 mg twice daily N=282 n (%) | TASIGNA 400 mg twice daily N=281 n (%) | Imatinib 400 mg once daily N=283 n (%) | |
| By 12 months | |||
| Complete Cytogenetic Response | 226 (80.1) | 219 (77.9) | 184 (65.0) |
| 95% CI for response | [75.0,84.6] | [72.6,82.6] | [59.2,70.6] |
| CMH test p-value for response rate (vs. imatinib 400 mg) | <0.0001 | 0.0005 | |
| By 24 months | |||
| Complete Cytogenetic Response | 245 (86.9%) | 238 (84.7%) | 218 (77.0%) |
| 95% CI for response | [82.4, 90.6] | [79.9, 88.7] | [71.7, 81.8] |
| CMH test p-value for response rate (vs imatinib 400 mg) | 0.0018 | 0.0160 |
Based on Kaplan-Meier estimates, the proportions of patients who achieved CCyR and were maintaining response after 36 months were 99.1% (95% CI: 97.9% - 100%) in the nilotinib 300 mg twice daily group, 98.6% (95% CI: 97.1% - 100%) in the nilotinib 400 mg twice daily group and 97.5% (95% CI: 95.4% - 99.7%) in the imatinib 400 mg once daily group.
Progression to 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 36 months were 99.3%, 98.7% and 95.2%, respectively (HR=0.1599 and stratified log-rank p=0.0059 between nilotinib 300 mg BID and imatinib, HR=0.2457 and stratified log-rank p=0.0185 between nilotinib 400 mg BID and imatinib). Including clonal evolution as a criterion for progression, a total of 24 patients progressed to AP or BC on treatment by the cut-off date (2 in the nilotinib 300 mg twice daily group, 5 in the nilotinib 400 mg twice daily group and 17 in the imatinib 400 mg once daily group). The estimated rates of patients free from progression to AP or BC including clonal evolution at 36 months were 99.3%, 97.9% and 93.2%, respectively (HR=0.1106 and stratified log-rank p=0.0003 between nilotinib 300 mg BID and imatinib, HR = 0.2848 and stratified log-rank p=0.0085 between nilotinib 400 mg BID and imatinib). No new progression to AP/BC were reported since the 2-year analysis.
A total of 38 patients died during treatment or during the follow-up after discontinuation of treatment (13 in the nilotinib 300 mg twice daily group, 8 in the nilotinib 400 mg twice daily group and 17 in the imatinib 400 mg once daily group). Twenty-three (23) of these 38 deaths were related to CML (5 in the nilotinib 300 mg twice daily group, 4 in the nilotinib 400 mg twice daily group and 14 in the imatinib 400 mg once daily group). The estimated rates of patients alive at 36 months were 95.1%, 97.0% and 94.0%, respectively (HR=0.7537 and stratified log-rank p = 0.4413 between nilotinib 300 mg twice daily and imatinib, HR=0.4607 and stratified log-rank p = 0.0639 between nilotinib 400 mg twice daily and imatinib). Considering only CML-related deaths as events, the estimated rates of OS at 36 months were 98.1%, 98.5% and 95.2%, respectively (HR=0.3511 and stratified log-rank p = 0.0356 between nilotinib 300 mg twice daily and imatinib, HR=0.2784 and stratified log-rank p = 0.0159 between nilotinib 400 mg twice daily and imatinib).
An open label uncontrolled multicentre 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. The study is ongoing. Efficacy was based on 321 chronic phase (CP) patients and 137 accelerated phase (AP) patients enrolled. Median age was 58 years (range 21 - 85 years), with 31% of patients >= 65 years of age. There were 48% females and 52% males; 89% caucasian, 4% asian and 5% black patients. Tasigna was administered on a continuous basis (400 mg twice daily at least 2 hours after a meal and with no food for at least one hour after administration) unless there was evidence of inadequate response or disease progression where dose escalation to 600 mg twice daily was allowed.
Table 4 Duration of Exposure with Tasigna(r)
| Chronic Phase N = 321 | Accelerated Phase N = 137 | |
| Median duration of therapy in months (25th-75th percentiles) | 18.4 (6.4-28.0) | 8.7 (3.8-19.6) |
The patients' CML disease history is given in Table 5. Resistance to imatinib included failure to achieve a complete haematological response (by 3 months), cytogenetic response (by 6 months) or major cytogenetic response (by 12 months) or progression of disease after a previous cytogenetic or haematological response. Imatinib intolerance included patients who discontinued imatinib because of toxicity and who were not in major cytogenetic response at time of study entry. The majority of patients had a long history of CML that included extensive prior treatment with other antineoplastic agents including imatinib, hydroxyurea, interferon, and some who had even failed stem cell transplant (Table 5). The median highest prior imatinib dose had been 600 mg/day for both 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.
| Chronic Phase (n = 321) | Accelerated Phase (n = 137) | |
| Median time since diagnosis in months (range) | 58 (5-275) | 71 (2-298) |
| Imatinib Resistant Intolerant without MCyR | 226 (70%) 95 (30%) | 109 (80%) 27 (20%) |
| Median time of imatinib treatment in months (25th-75th percentiles) | 32 (17-49) | 28 (14-49) |
| Prior Hydroxyurea | 83% | 91% |
| Prior Interferon | 58% | 50% |
| Prior non-drug organ transplant | 7% | 8% |
MCyR = major cytogenetic response
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+ haematopoietic cells. Complete haematological response (CHR) in CP patients was evaluated as a secondary endpoint. For efficacy assessment, patients needed to have completed 6 months treatment or discontinued the study. The primary endpoint in the AP patients was overall confirmed haematological response (HR), defined in this trial as either a complete haematological response, no evidence of leukaemia or return to chronic phase. For efficacy assessment, patients needed to have completed 4 months treatment, discontinued the study or achieved a complete haematological response. Complete Haematologic Response (CHR) criteria: Chronic CML: White Blood Cell Count < 10 x 109 /L, no blasts or promyelocytes in peripheral blood, platelets < 450 x 109/L, < 5% myelocytes plus metamyelocytes in peripheral blood, basophils < 5% in bone marrow and peripheral blood, and no extramedullary involvement. Accelerated CML: Myeloblasts < 5% in bone marrow & 0 % in peripheral blood, Absolute Neutrophil Count >= 1.5 x 109/L, platelets >= 100 x 109/L, basophils < 5% in bone marrow and peripheral blood and no extramedullary involvement. The rates of response for the Chronic Phase (CP) and Accelerated Phase (AP) treatment arms are reported in Table 6.
| (Best Response Rate) | Chronic Phase | Accelerated Phase | ||
| Intolerant (n=95) | Resistant (n=226) | Total (n=321) | Total (n=137) | |
| Haematologic Response (%) | ||||
| Overall (95%CI) | - | - | - | 55 (47-64) |
| Complete | 90 (79-97) | 72 (64-79) | 76 1 (70-82) | 31 |
| NEL | - | - | - | 12 |
| Return to chronic phase | - | - | 12 | |
| Median time to HR (months) | - | - | 1.0 | 1.0 |
| Median duration of HR (months) | - | - | Not reached | 21.5 |
| Cytogenetic Response (%) | ||||
| Major (95%CI) | 66 (56-76) | 56 (49-63) | 59 (54-65) | 32 (24-41) |
| Complete | 51 | 41 | 44 | 21 |
| Partial | 16 | 15 | 15 | 11 |
| Median time to MCyR (months) | - | - | 2.8 | 2.8 |
| Median duration of MCyR (months) | - | - | Not reached | Not reached |
| Overall survival | ||||
| 24 month overall survival rate (%) (Kaplan-Meier estimate) | - | - | 87% | 70% |
NEL = no evidence of leukaemia/ marrow response; MCyR = major cytogenetic response; CHR = Complete Haematologic Response; HR = Haematologic Response
This result is for patients who had not achieved a complete haematological response at study entry (n = 207)
Tasigna was investigated separately in CML-CP and CML-AP patients with extensive previous treatment including a tyrosine kinase inhibitor in addition to imatinib. The majority (83% of CML-CP patients and 85% of CML-AP patients) were imatinib-resistant and the remainder imatinib-intolerant. In the 22 CML-CP patients, (32%) achieved a MCyR with Tasigna. In those without a CHR at baseline (n=16), (50%) achieved a CHR. In the 11 CML-AP patients, (36%) achieved a confirmed HR and one (9%) a MCyR.
Tasigna is indicated for the: treatment of adult patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukaemia (CML) in chronic phase. treatment of adults with chronic phase and accelerated phase Philadelphia chromosome positive chronic myeloid leukaemia (CML) resistant to or intolerant of prior therapy including imatinib.
Hypersensitivity to nilotinib or to any of the excipients.
Treatment with Tasigna is often associated with NCI CTC (National Cancer Institute Common Toxicity Criteria) Grade 3 or 4 thrombocytopenia, neutropenia and anaemia. 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 dose reduction (see "DOSAGE AND ADMINISTRATION").
In vitro
data suggest that nilotinib has the potential to prolong cardiac ventricular repolarisation (QT interval).
In the Phase III study in newly diagnosed Ph+ CML-CP patients the change from baseline in mean time-averaged QTcF interval at steady state observed in the nilotinib 300 mg twice daily group was 6 msec. At the recommended dose of 300 mg twice daily no patient had an absolute QTcF of >480 msec and no events of Torsade de Pointes were observed. In the Phase II study in imatinib-resistant and intolerant CML patients in chronic and accelerated phase, treated with nilotinib 400 mg twice daily, the change from baseline in mean time-averaged QTcF interval at steady state was 6 and 8 msec, respectively. QTcF of >500 msec was observed in 3 patients (<1% of patients in the Phase II study). 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. In addition, no clinically relevant arrhythmias were observed during the trial. In particular, no episodes of torsade de pointes (either transient or sustained) were observed. Clinically meaningful prolongation of the QT interval may occur when Tasigna is inappropriately taken with food, and/or strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT. Therefore, co-administration with food must be avoided (see "DOSAGE AND ADMINISTRATION") and concomitant use with strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT should be avoided (see "Interactions with Other Drugs"). The presence of hypokalaemia and hypomagnesaemia may place patients at risk of developing QT-prolongation (see "DOSAGE AND ADMINISTRATION"). 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 long QT syndrome, with uncontrolled or significant cardiac disease including recent myocardial infarction, congestive heart failure, unstable angina or clinically significant bradycardia. 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.
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 repolarisation 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.
It is recommended that the lipid profile should be assessed before initiating treatment with Tasigna and monitored during treatment, as clinically indicated (see "DOSAGE AND ADMINISTRATION"). If lipid lowering agents are needed, please refer to the INTERACTIONS WITH OTHER MEDICINES section before starting treatment since many cholesterol lowering drugs are also metabolized by the CYP3A4 pathway.
It is recommended that the glucose levels should be assessed before initiating treatment with Tasigna and monitored during treatment as clinically indicated (see "DOSAGE AND ADMINISTRATION"). If test results warrant therapy, physicians should follow their local standards of practice and treatment guidelines.
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.
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 AND ADMINISTRATION").
The use of Tasigna can cause electrolyte imbalances commonly (see "ADVERSE EFFECTS, Metabolism and Nutrition Disorders"). Electrolyte abnormalities must be corrected prior to initiating Tasigna and monitored periodically during therapy.
Clinical studies showed a risk of increased total bilirubin, ALT and AST levels associated with nilotinib (see "ADVERSE EFFECTS").
The bioavailability of nilotinib might be reduced in patients with total gastrectomy (see "PHARMACOLOGY"). More frequent follow-up of these patients should be considered.
Cases of tumour lysis syndrome have been reported in patients treated with Tasigna. For monitoring recommendations please refer to "DOSAGE AND ADMINISTRATION".
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. Pharmacokinetic parameters were subject to high inter-subject variability. 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. Patients with hepatic impairment might therefore have increased exposure to nilotinib and should be treated with caution (see monitoring recommendations in "DOSAGE AND ADMINISTRATION").
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.
The effect of nilotinib on male and female fertility is not known. In a fertility study in rats, no effects on sperm count/motility were noted in males and no effects on fertility were noted in males or females. The highest tested dose achieved an exposure (based on plasma AUC) of approximately 5 times that expected in humans at the recommended dose. Sexually active male or female patients taking Tasigna should use highly effective contraception.
There are no adequate data on the use of Tasigna in pregnant women. It should not be used during pregnancy. If the drug is used during pregnancy, the patient must be informed of the potential risk to the foetus. In animal studies, nilotinib induced embryofoeto toxicity at doses that also showed maternal toxicity. Increased postimplantation loss was observed in both the fertility study, which involved treatment of both males and females, and in the embryo toxicity study, which involved treatment of females. Embryo-lethality and foetal effects (mainly decreased foetal weights, and increased skeletal changes) in rats and increased resorption of foetuses and skeletal variations in rabbits were observed in the embryofoetal toxicity studies. Exposure to nilotinib in females at No-Observed-Adverse-Effect-Levels was generally less than or equal to that in humans at 400 mg/b.i.d. In a pre- and postnatal study, oral administration of nilotinib to female rats from day 6 of gestation to day 21 or 22 post partum 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). Adverse effects on the reproductive function of pups (lower mating and fertility indices) were also observed at the maternal dose of 60 mg/kg. The No- Observed-Adverse-Effect-Level in maternal animals and offspring was a maternal dose of 20 mg/kg (approximately 1.7 times the plasma AUC in patients at the recommended clinical dose). 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.
It is not known whether nilotinib is excreted in human milk. Studies in animals demonstrate that nilotinib is excreted into milk. Women taking Tasigna should therefore not breast-feed while taking Tasigna, as a risk to the infant cannot be excluded.
Safety and efficacy in children and adolescents below the age of 18 has not been established.
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.
Genotoxicity studies in bacterial and mammalian in vitro systems, with and without metabolic activation, and in a mammalian in vivo test did not reveal any evidence for a genotoxic potential of nilotinib.
In a 2 year carcinogenicity study, rats were administered oral doses of nilotinib up to 40 mg/kg/day. Exposures at the highest dose level were approximately 2 to 3 times the human steady state exposure (based on AUC) to nilotinib at the dose of 800 mg/day. The major target organ for drug-related lesions was the uterus (dilatation, vascular ectasia, hyperplasia endothelial cell, inflammation and/or epithelial hyperplasia). There was a dose-related increase in the severity of uterine squamous metaplasia and a non-statistically significant increase in the incidence of uterine squamous cell carcinoma at the highest dose. The clinical relevance of these findings is uncertain.
No studies on the effects of nilotinib on the ability to drive and operate machines have been performed. Patients experiencing dizziness, visual impairment or other undesirable 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 EFFECTS").
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 AND ADMINISTRATION"). Should treatment with any of these agents be required, it is recommended that therapy with Tasigna be interrupted if possible. If transient interruption of treatment with Tasigna is not possible, close monitoring of the individual for prolongation of the QT interval is indicated. 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.
Nilotinib is mainly metabolised in the liver, and is also a substrate for the multi-drug efflux pump, P-glycoprotein (Pgp). Therefore, absorption and subsequent elimination of systemically absorbed nilotinib may be influenced by drugs that affect CYP3A4 and/or Pgp. The bioavailability of nilotinib in healthy subjects was increased 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 AND ADMINISTRATION" and "PRECAUTIONS, QT Prolongation"). Alternative concomitant medications with no or minimal CYP3A4 inhibition should be considered. In a Phase I study of nilotinib given in combination with imatinib (a substrate of P-gp and CYP3A4), imatinib had a slight inhibitory effect on CYP3A4 and/or Pgp. When the two drugs were administered concomitantly, the AUC of nilotinib was increased by 18% to 40%.
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 serum 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. Drugs That May Have Their Systemic Concentrations Altered by Nilotinib Nilotinib is a competitive inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2D6 and UGT1A1 in vitro, with Ki value being lowest for CYP2C9 (Ki=0.13 microM). Caution should be exercised when co-administering Tasigna with drugs with a low therapeutic index which are substrates for the enzymes known to be inhibited by Tasigna (e.g. astemizole, terfenadine, cisapride, cyclosporine, fentanyl, pimozide, quinidine and ergot alkaloids). Some of these drugs also prolong the QT interval, hence ECG monitoring should also be done if alternative drugs cannot be used. A single-dose drug-drug interaction study in healthy subjects with warfarin 25 mg, a sensitive CYP2C9 substrate, and nilotinib 800 mg did not result in any changes in warfarin pharmacokinetics (Cmax, AUC0-[?]) or warfarin pharmacodynamics (prothrombin time [PT] and international normalised ratio [INR]). The single-dose drug-drug interaction study suggests that Tasigna can be used concurrently with warfarin (up to a dose of 25 mg) without increasing the anti-coagulant effect of warfarin. There are no steady-state pharmacokinetic or pharmacodynamic interaction data for co-administration of nilotinib and warfarin. Consequently, monitoring and control of warfarin pharmacodynamic markers (INR or PT) following initiation of nilotinib therapy (at least during the first 2 weeks) is recommended. Single-dose administration of nilotinib 600 mg with midazolam 4 mg (a CYP3A substrate) to healthy subjects increased midazolam exposure by 30%. There are no steady-state pharmacokinetic interaction data for co-administration of nilotinib and midazolam. Consequently, it is possible that greater exposure to midazolam might occur with steady - state co-administration of nilotinib and midazolam. Nilotinib is an inhibitor of P-glycoprotein in vitro at clinically relevant concentrations and may potentially influence the absorption/elimination and subsequent serum concentrations of concomitantly-administered drugs that are substrates for this multi-drug efflux pump. Concomitant administration of nilotinib with imatinib, increased the AUC of imatinib by 18% to 39%. Concomitant treatment with cholesterol lowering agents (e.g. statins), which are metabolized via the CYP3A4 pathway, should be administered with caution since systemic exposure may increase (see "PRECAUTIONS").
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").
The absorption and the bioavailability of nilotinib are increased if it is taken with food, resulting in higher serum concentration (see "DOSAGE AND ADMINISTRATION", and "Pharmacokinetics"). Tasigna must not be taken in conjunction with food and should be taken 2 hours after a meal. No food should be consumed for at least one hour after the dose is taken, except apple sauce for patients unable to swallow capsules (see "Dosage and Administration"). Grapefruit juice and other foods that are known to inhibit CYP3A4 should be avoided at any time. Solubility of nilotinib decreases with increasing pH and is practically insoluble in buffer solutions of pH 4.5 or higher. Hence, simultaneous treatment with nilotinib and antacids should be avoided. If antacid therapy is needed, the antacid dose should be administered at least 2 hours prior to or 2 hours after Tasigna dosing. Long-term suppression of gastric acid secretion by proton-pump inhibitors or H2-blockers may reduce nilotinib exposure and so concomitant use of H2-blockers and proton-pump inhibitors should be avoided.
Summary of the safety profile
The nilotinib safety profile is based on data from patients with newly diagnosed Ph+ CML- CP in a randomized, open label, active comparator-controlled phase-III trial and patients with resistant or intolerant Ph+ CML-CP and CML-AP which served as a basis for the listed indications (see Table 7 and "INDICATIONS").
In patients with newly diagnosed Ph+ CML-CP
The data reported below reflect exposure to Tasigna from a randomised phase III study in patients with newly diagnosed Ph+ CML-CP treated at the recommended dose of 300 mg twice daily (n=279). The median duration of treatment in new patients was 36.4 months (range 0.1 - 46.7 months). Non-haematologic adverse drug reactions (ADRs) reported with very common frequency (>=10%) were rash, pruritus, headache, nausea, fatigue, alopecia and myalgia. Most of these ADRs were mild to moderate in severity (Grade 1 or 2). Upper abdominal pain, constipation, diarrhoea, dry skin, muscle spasms, arthralgia, abdominal pain, peripheral oedema, vomiting, pain in extremity, dyspepsia and asthenia were observed less commonly ( <10% and >= 5%) and have been of mild to moderate severity, manageable and generally did not require dose reduction. Pleural and pericardial effusions, regardless of causality, occurred in 1% and <1% of patients, respectively, receiving TASIGNA 300 mg twice daily. Gastrointestinal haemorrhage, regardless of causality was reported in 2.5% of these patients. The change from baseline in mean time-averaged QTcF interval at steady state in the nilotinib recommended dose of 300 mg twice daily was 6 msec. In the nilotinib 400 mg twice daily group and the imatinib 400 mg once daily group the mean time-averaged QTcF interval at steady state was 6 msec and 3 msec respectively. No patient had an absolute QTcF of >500 msec while on study drug in any of the treatment groups and no events of Torsade de Pointes were observed. QTcF increase from baseline that exceeds 60 msec was observed in 4 patients while on study drug (one in the 300 mg twice daily treatment group and three in the 400 mg twice daily treatment group). No patients in any treatment group had a LVEF <45% during treatment. Also, there were no patients with 15% or greater decrease from baseline in LVEF. No sudden deaths have been reported in any treatment group. In the nilotinib 300 mg twice daily group, haematologic ADRs include myelosuppression: thrombocytopenia (18%), neutropenia (15%), and anaemia (7%). See Table 8 for Grade 3/4 laboratory abnormalities. Discontinuation due to adverse drug reactions was observed in 10% of patients.
In patients with resistant or intolerant Ph+ CML-CP and CML-AP
The data reported below reflect exposure to Tasigna in 458 patients with Ph+ CML-CP (n=321) and CML-AP (n=137) resistant to or intolerant to at least one prior therapy including imatinib in an open-label multicenter study treated at the recommended dose of 400 mg twice daily. Non-haematologic adverse drug reactions (ADRs) reported with very common frequency (>=10% in the combined CML-CP and CML-AP patient populations) were rash, pruritus, nausea, fatigue, headache, constipation, diarrhoea, vomiting and myalgia. Most of these ADRs were mild to moderate in severity. Alopecia, muscle spasms, decreased appetite, arthralgia, bone pain, abdominal pain, peripheral oedema and asthenia were observed less frequently (< 10% and >= 5%) and have been of mild to moderate severity (Grade 1 or 2). 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 was reported in 1% and <1% of patients, respectively. QTcF exceeding 500 msec was observed in this study in 4 patients (<1%). No episodes of Torsade de Pointes (transient or sustained) were observed. Haematologic ADRs include myelosuppression: thrombocytopenia (31%), neutropenia (17%), and anaemia (14%). See Table 8 for grade 3/4 laboratory abnormalities. Discontinuation due to adverse drug reactions was observed in 16% of CP and 10% of AP patients.
Most Frequently Reported Adverse Drug Reactions
Non-haematologic ADRs (excluding laboratory abnormalities) that were reported in at least 5% of the patients in any of the Tasigna clinical studies are shown in Table 7. These are ranked under heading of frequency, the most frequent first. Within each frequency grouping adverse drug reactions are presented in order of decreasing seriousness. In addition the corresponding frequency category for each adverse drug reaction is based on the following (CIOMS III) convention: very common (>=1/10) or common (>=1/100, <1/10). The frequency is based on the highest for any Tasigna group in the two studies, using one decimal precision for percentages.
Comparison of Common Non-Laboratory Adverse Reactions in Clinical Trials
Table 7 Most Frequently Reported Non-haematologic Adverse Drug Reactions (>=5% in any TASIGNA Group)
Newly Diagnosed Ph+ CML-CP Resistant or Intolerant Ph+ CML-CP and CML-AP
36 months analysis 24 months analysis
300 mg twice daily
TASIGNA
400 mg twice daily
IMATINIB
400 mg once daily
TASIGNA
300 mg twice daily
TASIGNA
400 mg twice daily
IMATINIB
400 mg once daily
TASIGNA
400 mg twice daily
| System Organ Class Frequency | ALL GRADES (%) | GRADE 3 or 4 (%) | ALL GRADES (%) | GRADE 3/4 (%) | CML-CP GRADE 3/4 (%) | CML-AP GRADE 3/4 (%) | ||||||
| Adverse Reaction | N=279 % | N=277 % | N=280 % | N=279 % | N=277 % | N=280 % | N=458 % | N=458 % | N=321 % | N=137 % | ||
| Metabolism and nutrition | Common | Decreased | 4 | 4 | 3 | 0 | 0 | 0 | 8 | <1 | <1 | 0 |
| disorders | appetite 1 | |||||||||||
| Nervous system disorders | Very | Headache | 15 | 22 | 9 | 1 | 1 | <1 | 15 | 1 | 2 | <1 |
| common | ||||||||||||
| Gastrointestinal disorders | Very | Nausea | 14 | 21 | 34 | <1 | 1 | 0 | 20 | <1 | <1 | <1 |
| common | ||||||||||||
| Very | Constipation | 10 | 7 | 3 | 0 | <1 | 0 | 12 | <1 | <1 | 0 | |
| common | ||||||||||||
| Very | Diarrhoea | 9 | 7 | 30 | <1 | 0 | 2 | 11 | 2 | 2 | <1 | |
| common | ||||||||||||
| Very common | Vomiting | 6 | 9 | 18 | 0 | 1 | 0 | 10 | <1 | <1 | 0 | |
| Common | Abdominal pain upper | 10 | 8 | 8 | 1 | 0 | <1 | 5 | <1 | <1 | 0 | |
| Common | Abdominal pain | 6 | 5 | 4 | 0 | <1 | 0 | 6 | <1 | <1 | <1 | |
| Common | Dyspepsia | 5 | 6 | 5 | 0 | <1 | 0 | 3 | 0 | 0 | 0 | |
| Skin and subcutaneous tissue disorders | Very common | Rash | 33 | 37 | 14 | <1 | 3 | 2 | 28 | 1 | 2 | 0 |
| Very common | Pruritus | 18 | 14 | 5 | <1 | <1 | 0 | 24 | <1 | <1 | 0 | |
| Very common | Alopecia | 10 | 14 | 5 | 0 | 0 | 0 | 9 | 0 | 0 | 0 | |
| Common | Dry Skin | 9 | 10 | 5 | 0 | 0 | 0 | 5 | 0 | 0 | 0 | |
| Common | Erythema | 2 | 6 | 3 | 0 | 0 | 0 | 5 | <1 | <1 | 0 | |
| Musculoskeletal and connective tissue disorders | Very common | Myalgia | 10 | 11 | 12 | <1 | <1 | <1 | 10 | <1 | <1 | <1 |
| Common | Arthralgia | 7 | 9 | 8 | <1 | 0 | <1 | 7 | <1 | 1 | 0 | |
| Common | Muscle spasms | 9 | 8 | 29 | 0 | <1 | 1 | 8 | <1 | <1 | 0 | |
| Common | Bone pain | 4 | 5 | 3 | 0 | <1 | <1 | 6 | <1 | <1 | 0 | |
| Common | Pain in extremity | 5 | 3 | 7 | <1 | <1 | <1 | 5 | <1 | <1 | <1 | |
| General disorders and administration site conditions | Very common | Fatigue | 11 | 9 | 10 | 0 | <1 | <1 | 17 | 1 | 1 | <1 |
| Common | Asthenia | 9 | 5 | 8 | <1 | <1 | 0 | 6 | 0 | 0 | 0 |
| Common | Oedema peripheral | 5 | 6 | 17 | <1 | 0 | 0 | 6 | 0 | 0 | 0 |
| 1 Also includes preferred term anorexia Percentages are rounded to integer for presentation in this table. However, percentages with one decimal precision are used to identify terms with a frequency of at least 5% and to classify terms according to frequency categories. | |||||||||||
Additional Data from Clinical Trials
The following adverse drug reactions were reported in patients in the Tasigna clinical studies at the recommended doses at the following frequency (very common is >= 1/10; common is >= 1/100 and < 1/10; uncommon is >1/1,000 and <1/100; single events are captured as Unknown in frequency). For laboratory abnormalities, very common events (>=1/10) not included in Table 7 are also reported. These adverse reactions are included based on clinical relevance and ranked in order of decreasing seriousness within each category.
Infections and Infestations
Common:folliculitis, upper respiratory tract infection (including pharyngitis, nasopharyngitis, rhinitis) Uncommon:pneumonia, bronchitis, urinary tract infection, herpes virus infection, candidiasis (including oral candidiasis), gastroenteritis Unknown frequency: sepsis, subcutaneous abscess, anal abscess, furuncle, tinea pedis
Neoplasms Benign, Malignant and Unspecified
Common:skin papilloma Unknown frequency: oral papilloma, paraproteinemia
Blood and Lymphatic System Disorders
Very Common:neutropenia, thrombocytopenia Common:eosinophilia, febrile neutropenia, pancytopenia, lymphopenia, anaemia Uncommon:haemoglobin decreased Unknown frequency: thrombocythaemia, leukocytosis
Immune System Disorders
Unknown frequency: hypersensitivity
Endocrine Disorders
Uncommon:hyperthyroidism, hypothyroidism Unknown frequency: hyperparathyroidism secondary, thyroiditis, blood parathyroid hormone increased
Metabolism and Nutrition Disorders
Very Common:hypophosphataemia (including blood phosphorus decreased) Common:electrolyte imbalance (including hyperkalaemia, hypokalaemia, hyponatraemia, hypocalcaemia, hypercalcaemia, hyperphosphataemia, hypomagnesaemia), hyperglycaemia, diabetes mellitus, hypercholesterolaemia, hyperlipidaemia, hypertriglyceridemia Uncommon:gout, dehydration, increased appetite, dyslipidemia, blood glucose decreased Unknown frequency: hyperuricemia, hypoglycaemia
Psychiatric Disorders
Common:depression, insomnia, anxiety Unknown frequency: disorientation, confusional state, amnesia, dysphoria
Nervous System Disorders
Common:dizziness, peripheral neuropathy, hypoaesthesia, paraesthesia Uncommon:intracranial haemorrhage, migraine, loss of consciousness (including syncope), tremor, disturbance in attention, hyperaesthesia Unknown frequency: brain oedema, optic neuritis, lethargy, dysaesthesia, restless legs syndrome
Eye Disorders
Common:eye haemorrhage, periorbital oedema, eye pruritus, conjunctivitis, dry eye (including xerophthalmia) Uncommon:vision impairment, vision blurred, visual acuity reduced, eyelid oedema, photopsia, hyperaemia (scleral, conjunctival, ocular), eye irritation, conjunctival haemorrhage Unknown frequency: papilloedema, diplopia, photophobia, eye swelling, blepharitis, eye pain, chorioretinopathy, conjunctivitis allergic, ocular surface disease
Ear and Labyrinth Disorders
Common:vertigo Unknown frequency: hearing impaired, ear pain, tinnitus
Cardiac Disorders
Common:angina pectoris, arrhythmia (including atrioventricular block, cardiac flutter, extrasystoles, atrial fibrillation, tachycardia, bradycardia), palpitations, electrocardiogram QT prolonged Uncommon:cardiac failure, pericardial effusion, coronary artery disease, cardiomegaly, cyanosis, cardiac murmur Unknown frequency: myocardial infarction, ventricular dysfunction, pericarditis, ejection fraction decrease, blood pressure increased, troponin increased
Vascular Disorders
Common:hypertension, flushing Uncommon:hypertensive crisis, peripheral arterial occlusion disease, haematoma, arteriosclerosis Unknown frequency: 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 Unknown frequency: pulmonary hypertension, wheezing, oropharyngeal pain
Gastrointestinal Disorders
Common:pancreatitis, abdominal discomfort, abdominal distension, dyspepsia, dysgeusia, flatulence Uncommon:gastrointestinal haemorrhage, melaena, mouth ulceration, gastroesophageal reflux, stomatitis, oesophageal pain, dry mouth, gastritis, sensitivity of teeth Unknown frequency: gastrointestinal ulcer perforation, retroperitoneal haemorrhage, haematemesis, gastric ulcer, oesophagitis ulcerative, subileus, enterocolitis, haemorrhoids, hiatus hernia, rectal haemorrhage, gingivitis
Hepatobiliary Disorders
Very Common:hyperbilirubinemia (including blood bilirubin increased) Common:hepatic function abnormal Uncommon:hepatotoxicity, toxic hepatitis, jaundice, blood creatinine increased Unknown frequency: cholestasis, hepatomegaly
Skin and Subcutaneous Tissue Disorders
Common:night sweats, eczema, urticaria, erythema, hyperhidrosis, contusion, acne, dermatitis (including allergic, exfoliative and acneiform), dry skin, Uncommon:exfoliative rash, drug eruption, pain of skin, ecchymosis, swelling face Unknown frequency: psoriasis, erythema multiforme, erythema nodosum, skin ulcer, palmar-plantar erthrodysaesthesia syndrome, petechiae, photosensitivity, blister, dermal cyst, sebaceous hyperplasia, skin atrophy, skin discolouration, skin exfoliation, skin hyperpigmentation, skin hypertrophy, hyperkeratosis
Musculoskeletal and Connective Tissue Disorders
Common:musculoskeletal chest pain, musculoskeletal pain, back pain, neck pain, flank pain, blood creatine kinase (CK) increased Uncommon:musculoskeletal stiffness, muscular weakness, joint swelling Unknown frequency: arthritis
Renal and Urinary Disorders
Common:pollakiuria Uncommon:dysuria, micturition urgency, nocturia, Unknown frequency: renal failure, haematuria, urinary incontinence, chromaturia
Reproductive System and Breast Disorders
Uncommon:breast pain, gynaecomastia, erectile dysfunction. Unknown frequency: breast induration, menorrhagia, nipple swelling
General Disorders and Administration Site Conditions
Very common:fatigue Common:pyrexia, chest pain (including non-cardiac chest pain), pain, chest discomfort, malaise, asthenia, peripheral oedema Uncommon:face oedema, gravitational oedema, influenza-like illness, chills, feeling body temperature change (including feeling hot, feeling cold) Unknown frequency: localised oedema
Investigations
Very Common:alanine aminotransferase (ALT) increased, aspartate aminotransferase (AST) increased, lipase increased Common:haemoglobin decreased, blood amylase increased, gamma-glutamyltransferase increased, blood creatinine phosphokinase increased, blood alkaline phosphatase increased, blood insulin increased, weight decreased, weight increased, lipoprotein increased (including very low density and high density) Uncommon:blood lactate dehydrogenase increased, blood urea increased, globulins decreased Unknown frequency: troponin increased, blood bilirubin unconjugated increased, blood insulin decreased, insulin C-peptide decreased, blood parathyroid hormone increased
| Newly diagnosed Ph+ CML-CP | Resistant or intolerant Ph+ | ||||
| TASIGNA 300mg twice daily N=279 | TASIGNA 400mg twice daily N=277 | IMATINIB 400mg once daily N=280 | CML-CP N=321 % | CML-AP N=137 % | |
| Haematological Parameters | |||||
| Myelosuppression | |||||
| - Neutropenia | 12% | 11% | 21% | 31% | 42% |
| - Thrombocytopenia | 10% | 12% | 9% | 30% | 42% |
| - Anaemia | 4% | 5% | 6% | 11% | 27% |
| Biochemistry Parameters | |||||
| - Elevated creatinine | 0% | 0% | <1% | 1% | <1%% |
| - Elevated lipase | 8% | 8% | 4% | 18% | 18% |
| - Elevated AST | 1% | 3% | 1% | 3% | 2% |
| - Elevated ALT | 4% | 9% | 3% | 4% | 4% |
| - Hypophosphatemia | 6% | 8% | 9% | 17% | 15% |
| - Elevated Bilirubin (total) | 4% | 8% | <1% | 7% | 9% |
| - Elevated glucose | 7% | 6% | <1% | 12% | 6% |
| - Elevated Cholesterol (total) | 0% | 1% | 0% | * | * |
Comparison of Severe Laboratory Abnormalities in Clinical Trials Table 8 Grade 3/4 Laboratory Abnormalities
Percentages with one decimal precision are used and rounded to integer for presentation in this table.
* parameter not collected
Adverse drug reactions from spontaneous reports and literature cases (frequency not known)
The following adverse reactions have been derived from post marketing experience with Tasigna via spontaneous case reports, literature cases, expanded access programs, and clinical studies other than the global registration trials. Because 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 unknown:cases of tumour lysis syndrome have been reported in patients treated with Tasigna.
Therapy should be initiated by a physician experienced in the treatment of patients with CML and should continue as long as the patient continues to benefit. Tasigna should be taken twice daily taken approximately 12 hours apart, and must not be taken with food. No food should be consumed for at least 2 hours before and 1 hour after the dose is taken (see "PRECAUTIONS" and "Pharmacokinetics"). The capsules should be swallowed whole with water. 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 "Pharmacokinetics"). Tasigna may be given in combination with haematopoietic growth factors such as erythropoietin or G-CSF if clinically indicated. Tasigna may be given with hydroxyurea or anagrelide if clinically indicated.
The recommended dose of Tasigna is 300 mg twice daily (see "Pharmacokinetics").
The recommended dose of Tasigna is 400 mg twice daily (see "Pharmacokinetics").
A baseline ECG is recommended prior to initiating therapy with Tasigna and should be repeated after 7 days and as clinically indicated. Hypokalaemia or hypomagnesaemia 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 serum cholesterol levels have been reported with Tasigna therapy (see "PRECAUTIONS"). Lipid profiles should be assessed prior to initiating Tasigna therapy and as clinically indicated during treatment. 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 as clinically indicated during treatment. Due to possible occurrence of Tumour Lysis Syndrome (TLS) correction of clinically significant dehydration and treatment of high uric acid levels are recommended prior to initiating therapy with Tasigna (see "ADVERSE EFFECTS"). Tasigna may need to be temporarily withheld and/or dose reduced for haematological toxicities (neutropenia, thrombocytopenia) that are not related to underlying leukaemia (Table 9).
| Newly diagnosed CML in chronic phase at 300 mg twice daily Resistant or intolerant CML in chronic Phase CML at 400 mg twice daily | ANC * < 1.0 x 10 9 /L and/or platelet counts < 50 x 10 9 /L | Stop Tasigna, and monitor blood counts Resume within 2 weeks at prior dose if ANC > 1.0 x 10 9 /L and/or platelets > 50 x 10 9 /L If blood counts remain low, a dose reduction to 400 mg once daily may be required |
| Resistant or intolerant CML in accelerated Phase at 400 mg twice daily | ANC * < 0.5 x 10 9 /L and/or platelet counts < 10 x 10 9 /L | Stop Tasigna, and monitor blood counts Resume within 2 weeks at prior dose if ANC > 1.0 x 10 9 /L and/or platelets > 20 x 10 9 /L If blood counts remain low, a dose reduction to 400 mg once daily may be required |
*ANC = absolute neutrophil count
If clinically significant moderate or severe non-haematological toxicity develops, dosing should be interrupted, and may be resumed at 400 mg once daily once the toxicity has resolved. If clinically appropriate, re-escalation of the dose to 300 mg (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 or 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 EFFECTS"). Elevated bilirubin and hepatic transaminases: For Grade 3 or 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 EFFECTS"). If a dose is missed the patient should not take an additional dose, but take the usual prescribed next dose.
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. In the event of overdose, the patient should be observed and appropriate supportive treatment given.
Tasigna 150 mg: white to yellowish powder in red opaque hard gelatin capsules, size 1 with black axial imprint "NVR/BCR" Tasigna 200 mg: white to slightly yellowish powder in light yellow opaque hard gelatin capsules, size 0 with red axial imprint "NVR/TKI" Tasigna is available in 28's (weekly), 40's, 42's and 112's and 120's (monthly) packs. The weekly pack contains 2 calendar cards (daytime and night time) of 14 capsules or a carton of 28 capsules. The monthly pack consists of 4 packs of 28 capsules or 3 packs of 40 capsules.
Storage:
Store below 30degC.
Novartis Pharmaceuticals Australia Pty Ltd ABN 18 004 244 160 54 Waterloo Road North Ryde NSW 2113
Prescription Only Medicine (Schedule 4)
17 January 2008
21 October 2013
= Registered Trademark
(tas211013i.doc) based on CDS of 31.07.13