Tasigna

Nilotinib hydrochloride.

150 mg hard capsules: White to yellowish powder in red opaque hard gelatin capsules, size 1 with black axial imprint "NVR/BCR".
Each capsule contains 150 mg nilotinib base (as hydrochloride, monohydrate).
200 mg hard capsules: White to yellowish powder in light yellow opaque hard gelatin capsules, size 0 with red axial imprint "NVR/TKI".
Each capsule contains 200 mg nilotinib base (as hydrochloride, monohydrate).
Excipients/Inactive Ingredients: 150 mg hard capsules: Capsule content: Lactose monohydrate; Crospovidone; Poloxamer 188; Anhydrous colloidal silica/Colloidal silicon dioxide; Magnesium stearate.
Capsule shell: Gelatin; Titanium dioxide (E171); Iron oxide, red (E172), Iron oxide, yellow (E172).
Printing ink: Shellac; Iron oxide, black (E172); n-Butyl alcohol; Propylene glycol; Dehydrated ethanol; Isopropyl alcohol; Ammonium hydroxide.
200 mg hard capsules: Capsule content: Lactose monohydrate; Crospovidone; Poloxamer 188; Anhydrous colloidal silica/Colloidal silicon dioxide; Magnesium stearate.
Capsule shell: Gelatin; Titanium dioxide (E171); Iron oxide, yellow (E172).
Printing ink: Shellac; Dehydrated alcohol; Isopropyl alcohol; Butyl alcohol; Propylene glycol; Strong ammonia solution; Potassium hydroxide; Titanium dioxide; Industrial methylated spirit; Iron oxide, red (E172), Iron oxide, black (E172).

Pharmacotherapeutic Group: Antineoplastic agent - Protein-tyrosine kinase inhibitor.
Pharmacology: 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.
Pharmacodynamics: Tasigna has little or no effect against the majority of other protein kinases examined, including SRC, except for the platelet-derived growth factor (PDGF), KIT, colony stimulating factor 1 receptor (CSF1R), discoidin domain receptor (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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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 3 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 real-time quantitative polymerase chain reaction (RQ-PCR), which corresponds to a ≥3 log reduction of BCR-ABL transcript from standardized baseline.
The primary efficacy endpoint, 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), 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. (See 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 (hazard ratio/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 responses 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 and 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, 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 twice daily (b.i.d) and imatinib, HR=0.2457 and stratified log-rank p=0.0185 between nilotinib 400 mg b.i.d 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 evolution 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 b.i.d and imatinib, HR=0.2848 and stratified log-rank p=0.0085 between nilotinib 400 mg b.i.d 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).
Switch to Tasigna treatment in adult patients with Ph+ CML-CP who have not achieved a molecular response greater than or equal to a 4.5-log reduction with imatinib treatment: In an open-label, multicenter, randomized Phase III study, 207 adult patients with Ph+ CML-CP who received treatment with imatinib for at least 2 years, with no permanent imatinib dose adjustment within 6 months and no major toxicity within 3 months of study entry were enrolled in the study. Patients were randomized 1:1 either to receive Tasigna 400 mg twice daily (n=104) or to continue treatment with imatinib at the same dose (400 mg or 600 mg once daily) as administered prior to randomization (n=103). Randomization was stratified by duration of prior treatment with imatinib and duration of prior interferon use. The median time on treatment (from first day of treatment to last day of randomized treatment) at cut-off was 47.2 months in the Tasigna treatment arm, and 37.0 months and 26.7 months in the 400 mg and 600 mg dose cohorts of the imatinib arm, respectively.
The two treatment arms were well balanced with respect to demographic and baseline characteristics (including BCR-ABL transcript levels at study entry). Median age was 46 years in the Tasigna arm and 52 years in the imatinib arm, with 13.5% and 13.6% of patients aged ≥65 years in the Tasigna and imatinib treatment arms, respectively. There were more male (68.3% in the Tasigna treatment arm and 63.1% in the imatinib treatment arm) than female patients. More than 80% of all patients were Caucasians. Up to the cut-off date, the median actual dose intensity was 775.7 mg/day in the Tasigna treatment arm and 400 mg/day and 600 mg/day in the two dose cohorts of the imatinib treatment arm, respectively.
The primary endpoint of the study was the rate of confirmed best cumulative complete molecular response (CMR) within the first year of study therapy with Tasigna or imatinib. The rate of confirmed best cumulative CMR during the first 12 months was 12.5% in the Tasigna arm and 5.8% in the imatinib arm. The primary endpoint did not reach statistical significance at the early 12-month time point (p=0.1083), with an odds ratio (OR) of 2.096 in favor of Tasigna.
Longer-term follow-up of the primary outcome variable at 48-months was a secondary endpoint. Analyses conducted to assess the achievement of different levels of molecular response up to crossover in patients without the corresponding response at baseline showed that switching from imatinib to Tasigna was associated with a clinically meaningful increase in the numbers of patients attaining MMR, MR4.5, and CMR under their randomized treatment at Month 48 (see Table 5).

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Resistance or intolerant Ph+ CML: An open-label multicenter Phase II study was conducted to determine the efficacy of Tasigna (400 mg twice daily) in adult 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 6). 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 6.)

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Resistance to imatinib included failure to achieve a complete hematologic response (CHR) (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 (Table 7). 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 7.)

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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 in CP patients was evaluated as a secondary endpoint. The primary endpoint in the AP patients was overall confirmed hematologic response, 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 8.
The estimated 24-month overall survival rate in CML-AP patients was 70%. (See Table 8.)

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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.
Treatment discontinuation in newly diagnosed Ph+ CML-CP adult patients who have achieved a sustained deep molecular response: In an open-label, multicenter, single-arm study, 215 adult patients with Ph+ CML-CP treated with Tasigna in first-line for ≥2 years who achieved MR4.5 as measured with the MolecularMD MRDx BCR-ABL Test were enrolled to continue Tasigna treatment for an additional 52 weeks (Tasigna consolidation phase). Of the 215 patients, 190 patients (88.4%) entered the TFR phase after achieving a sustained deep molecular response during the consolidation phase, defined by the following criteria: The 4 last quarterly assessments (taken every 12 weeks) were at least MR4.0 (BCR-ABL/ABL ≤0.01% IS), and maintained for 1 year; The last assessment being MR4.5 (BCR-ABL/ABL ≤0.0032% IS); No more than two assessments falling between MR4.0 and MR4.5 (0.0032% IS <BCR-ABL/ABL ≤0.01% IS).
In the set of patients who entered the TFR phase, the median age was 55 years. The proportion of female patients was 49.5%, and 21.1% of the patients were ≥65 years of age. The median actual dose intensity during the 52-week Tasigna consolidation phase was 600.0 mg/day.
BCR-ABL levels were monitored every 4 weeks during the first 48 weeks of the TFR phase. Monitoring frequency was intensified to every 2 weeks upon the loss of MR4.0. Biweekly monitoring ended at one of the following time points: Loss of MMR requiring patient to re-initiate Tasigna treatment; When the BCR-ABL levels returned to a range between MR4.0 and MR4.5; When the BCR-ABL levels remained lower than MMR for 4 consecutive measurements (8 weeks from initial loss of MR4.0).
Any patient with loss of MMR during the TFR phase re-initiated Tasigna treatment at 300 mg twice daily or at a reduced dose level of 400 mg once daily if required from the perspective of tolerance, within 5 weeks after the collection date of the blood sample demonstrating loss of MMR. Patients who required re-initiation of Tasigna treatment were monitored for BCR-ABL levels every 4 weeks for the first 24 weeks and then every 12 weeks thereafter in patients who regained MMR.
The primary endpoint was the percentage of patients who were in MMR at 48 weeks after starting the TFR phase (considering any patient who required re-initiation of treatment as non-responder). Of the 190 patients who entered the TFR phase, 98 patients (51.6% [95% CI: 44.2, 58.9]) were in MMR in the TFR phase at 48 weeks.
Eighty-eight patients (46.3%) discontinued from the TFR phase due to loss of MMR, and 1 (0.5%), 1 (0.5%), and 3 patients (1.6%) due to death from unknown cause, physician decision, and subject decision, respectively. Among the 88 patients who discontinued the TFR phase due to loss of MMR, 86 patients restarted Tasigna treatment and 2 patients permanently discontinued from the study.
Of the 86 patients who restarted treatment due to loss of MMR in the TFR phase, 85 patients (98.8%) regained MMR, (one patient discontinued study permanently due to subject decision) and 76 patients (88.4%) regained MR4.5 by the time of the cut-off date.
The Kaplan-Meier (KM) estimated median time on Tasigna to regain MMR and MR4.5 was 7.9 weeks (95% CI: 5.1, 8.0) and 13.1 weeks (95% CI: 12.3, 15.7), respectively. The KM estimated MMR rate at 24 weeks of re-initiation was 98.8% (95% CI: 94.2, 99.9). The KM estimated MR4.5 rate at 24 weeks of re-initiation was 90.9% (95% CI: 83.2, 96.0).
Among the 190 patients in the TFR phase, 99 patients (52.1%) did not have a treatment-free survival (TFS) event on or before the 48 month cut-off date, and were censored at the date of their last assessment prior to cut-off. The KM estimate of median TFS has not yet been reached (Figure 4). (See Figure 4.)

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Treatment discontinuation in Ph+ CML-CP adult patients who have achieved a sustained deep molecular response on Tasigna following prior imatinib therapy: In an open-label, multicenter, single-arm study, 163 adult patients with Ph+ CML-CP taking TKIs for ≥3 years (imatinib as initial TKI therapy for more than 4 weeks without documented MR4.5 on imatinib at the time of switch to Tasigna, then switched to Tasigna for at least two years), and who achieved MR4.5 on Tasigna treatment as measured with the MolecularMD MRDx BCR-ABL Test were enrolled to continue Tasigna treatment for an additional 52 weeks (Tasigna consolidation phase). Of the 163 patients, 126 patients (77.3%) entered the TFR phase after achieving a sustained deep molecular response during the consolidation phase, defined by the following criterion: The 4 last quarterly assessments (taken every 12 weeks) showed no confirmed loss of MR4.5 (BCR-ABL/ABL ≤0.0032% IS) during 1 year.
The median age of the patients who entered the TFR phase was 56 years. The proportion of female patients was 55.6%, and 27.8% of the patients were ≥65 years of age. The median actual dose intensity during the 52-week Tasigna consolidation phase was 771.8 mg/day with 52.4% and 29.4% of patients receiving a daily Tasigna dose of 800 mg and 600 mg just before entry into the TFR phase, respectively.
Patients who entered the TFR phase but experienced two consecutive measurements of BCR-ABL/ABL >0.01% IS were considered having a confirmed loss of MR4.0, triggering re-initiation of Tasigna treatment. Patients with loss of MMR in the TFR phase immediately restarted Tasigna treatment without confirmation. All patients who restarted Tasigna therapy had BCR-ABL transcript levels monitored every 4 weeks for the first 24 weeks, then once every 12 weeks.
The primary endpoint was defined as the proportion of patients without confirmed loss of MR4.0 or loss of MMR within 48 weeks following discontinuation of Tasigna therapy. Of the 126 patients who entered the TFR phase, 73 patients (57.9%, [95% CI: 48.8, 66.7]) had no loss of MMR, no confirmed loss of MR4.0, and no re-initiation of Tasigna therapy within 48 weeks after the start of the TFR phase.
Among the 53 patients who discontinued from the TFR phase due to confirmed loss of MR4.0 or loss of MMR, 51 patients restarted Tasigna therapy and 2 patients permanently discontinued from the study. Of the 51 patients who restarted Tasigna treatment due to confirmed loss of MR4.0 or loss of MMR in the TFR phase, 48 patients (94.1%) regained MR4.0 and 3 patients (5.9%) did not regain MR4.0. Forty-seven patients (92.2%) regained MR4.5 and 4 patients (7.8%) did not regain MR4.5 by the time of the cut-off date.
The Kaplan-Meier (KM) estimated median time on Tasigna to regain MR4.0 and MR4.5 was 12.0 weeks (95% CI: 8.3, 12.7) and 13.1 weeks (95% CI: 12.4, 16.1), respectively. The KM estimated rate of MR4.0 at 48 weeks of re-initiation was 100.0%. (95% CI: not estimated). The KM estimated rate of MR4.5 at 48 weeks of re-initiation was 94.8% (95% CI: 85.1, 99.0).
Among the 126 patients in the TFR phase, 74 patients (58.7%) did not have a treatment-free survival (TFS) event on or before the 48-month cut-off date, and were censored at the date of their last assessment prior to cut-off. The other 52 patients had a TFS event (18 patients had confirmed loss of MR4.0, and 34 patients lost MMR). The median TFS has not yet been reached (Figure 5). (See Figure 5.)

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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, C_max 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 nilotininb 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.
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 (see Use in Pregnancy & Lactation), phototoxicity and carcinogenicity (rat and mice) studies.
Safety pharmacology and repeated dose toxicity: Nilotinib did not have effects on central nervous system (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.
Carcinogenicity and mutagenicity: 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 2 to 3 times 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 (NOEL) 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).
Juvenile animal studies: 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 NOEL 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.
Phototoxicity: 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.

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.

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 granulocyte colony-stimulating factor (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 adult patients with newly diagnosed Ph+ CML- Chronic Phase (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 clinical benefit is observed or until unacceptable toxicity occurs.
Dosage in newly diagnosed Ph+ CML-CP adult patients who have achieved a sustained deep molecular response (MR4.5): Discontinuation of treatment may be considered in eligible Ph+ CML-CP patients who have been treated with Tasigna at 300 mg twice daily for a minimum of 3 years if a deep molecular response is sustained for a minimum of one year immediately prior to discontinuation of therapy. Discontinuation of Tasigna should be initiated by a physician experienced in the treatment of patients with CML (see Precautions and Pharmacology: Pharmacodynamics: Clinical Studies under Actions).
Patients who are eligible to discontinue Tasigna therapy must have their BCR-ABL transcript levels and complete blood count with differential monitored monthly for one year, then every 6 weeks for the second year, and every 12 weeks thereafter. Monitoring of BCR-ABL transcript levels must be performed with a quantitative diagnostic test validated to measure molecular response levels on the International Scale (IS) with a sensitivity of at least molecular response 4.5 (MR4.5).
For patients who lose MR4.0 but not major molecular response (MMR) during the treatment-free phase, BCR-ABL transcript levels should be monitored every 2 weeks until BCR-ABL levels return to a range between MR4.0 and MR4.5. Patients who maintain BCR-ABL levels between MMR and MR4.0 for a minimum of 4 consecutive measurements can return to the original monitoring schedule.
Patients who lose MMR must re-initiate treatment within 4 weeks of when loss of remission is known to have occurred. Tasigna therapy should be re-initiated at 300 mg twice daily or at a reduced dose level of 400 mg once daily if the patient had a dose reduction prior to discontinuation of therapy. Patients who re-initiate Tasigna therapy should have their BCR-ABL transcript levels monitored monthly until MMR is re-established (see Precautions and Pharmacology: Pharmacodynamics: Clinical Studies under Actions).
Dosage in adult patients with Ph+ CML-CP and CML- Accelerated Phase (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 clinical benefit is observed or until unacceptable toxicity occurs.
Dosage in Ph+ CML-CP adult patients who have achieved a sustained deep molecular response (MR4.5) on Tasigna following prior imatinib therapy: Discontinuation of treatment may be considered in eligible Ph+ CML-CP patients who have been treated with Tasigna for a minimum of 3 years if a deep molecular response is sustained for a minimum of one year immediately prior to discontinuation of therapy. Discontinuation of Tasigna should be initiated by a physician experienced in the treatment of patients with CML (see Precautions and Pharmacology: Pharmacodynamics: Clinical Studies under Actions).
Patients who are eligible to discontinue Tasigna therapy must have their BCR-ABL transcript levels and complete blood count with differential monitored monthly for one year, then every 6 weeks for the second year, and every 12 weeks thereafter. Monitoring of BCR-ABL transcript levels must be performed with a quantitative diagnostic test validated to measure molecular response levels on the International Scale (IS) with a sensitivity of at least MR4.5.
Patients with confirmed loss of MR4.0 (two consecutive measures separated by at least 4 weeks showing loss of MR4.0) or loss of MMR must re-initiate treatment within 4 weeks of when loss of remission is known to have occurred. Tasigna therapy should be re-initiated at either 300 mg or 400 mg twice daily. Patients who re-initiate Tasigna therapy should have their BCR-ABL transcript levels monitored monthly until previous MMR or MR4.0 is re-established (see Precautions and Pharmacology: Pharmacodynamics: Clinical Studies under Actions).
Monitoring recommendations and dose adjustments: A baseline electrocardiogram (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 9).

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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: Asymptomatic serum lipase elevations were observed. Few of these elevations were associated with clinical symptoms such as abdominal pain or a diagnosis of pancreatitis. Overall, this finding was clinically manageable in the majority of patients without requirement for dose reduction or interruption. For Grade 3 to 4 lipase elevations, doses in adult patients 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: In clinical studies, the majority of bilirubin and hepatic transaminase laboratory abnormalities in patients were of low grade toxicity which did not require dose interruption or reduction. For Grade 3 to 4 bilirubin or hepatic transaminase elevations in adult patients, 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: 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: Tasigna has not been investigated in patients with 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).
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 or above): 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.
Method of 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.

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 is contraindicated in patients with known hypersensitivity to nilotinib or to any of the excipients.

QT Prolongation and Sudden Deaths: Tasigna prolongs the QT interval. Sudden deaths have been reported in patients receiving nilotinib. Tasigna should not be used in patients with hypokalemia, hypomagnesemia, or long QT syndrome. Hypokalemia or hypomagnesemia must be corrected prior to Tasigna administration and should be periodically monitored. Drugs known to prolong the QT interval and strong CYP3A4 inhibitors should be avoided. Patients should avoid food 2 hours before and 1 hour after taking dose. Use with caution in patients with hepatic impairment. ECGs should be obtained to monitor the QTc at baseline, seven days after initiation, and periodically thereafter, as well as following any dose adjustments.

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: In vitro data suggest that nilotinib has the potential to prolong cardiac ventricular repolarization (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 Torsades de Pointes were observed.
In the Phase II study in imatinib-resistant or 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 5 msec and 8 msec, respectively. QTcF of >500 msec was observed in 4 patients (<1% of these patients).
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 conduct of the trial. In particular, no episodes of Torsades 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 interval; therefore, concomitant administration should be avoided (see Food-effects as follows and Interactions).
The presence of hypokalemia and hypomagnesemia may place patients at risk of developing QT prolongation (see Dosage & 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.
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).
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).
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.
Special monitoring of Ph+ CML-CP adult patients who have achieved a sustained deep molecular response: Eligibility for discontinuation of treatment: Eligible patients who are confirmed to express the typical BCR-ABL transcripts, e13a2/b2a2 or e14a2/b3a2, can be considered for treatment discontinuation. Patients must have typical BCR-ABL transcripts to allow quantitation of BCR-ABL levels, evaluation of the depth of molecular response, and determination of a possible loss of molecular remission after Tasigna treatment discontinuation.
Monitoring of patients who have discontinued therapy: Monitoring of BCR-ABL transcript levels in patients eligible for treatment discontinuation must be performed with a quantitative diagnostic test validated to measure molecular response levels with a sensitivity of at least MR4.5. BCR-ABL transcript levels must be assessed prior to and during treatment discontinuation (see Dosage & Administration and Pharmacology: Pharmacodynamics: Clinical Studies under Actions).
Loss of MMR or confirmed loss of MR4.0 (two consecutive measures separated by at least 4 weeks showing loss of MR4.0) will trigger treatment re-initiation within 4 weeks of when loss of remission is known to have occurred. Frequent monitoring of BCR-ABL transcript levels and complete blood count with differential is required to detect possible loss of remission (see Dosage & Administration and Pharmacology: Pharmacodynamics: Clinical Studies under Actions). For patients who fail to achieve MMR after three months of treatment re-initiation, BCR-ABL kinase domain mutation testing should be performed.
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 Adverse 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 hydroxymethylglutaryl-CoA (HMG CoA) reductase inhibitor (a lipid lowering agent) is needed, 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 Dosage & Administration, Interactions and Pharmacology under Actions).
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 C_max of nilotinib showed an increase of 29%, 18% and 22% respectively. Clinical studies have excluded patients with alanine transaminase (ALT) and/or aspartate aminotransferase (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 and dose adjustments 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 TLS have been reported in patients treated with Tasigna. For monitoring recommendations 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.

Pregnancy: Risk Summary: Tasigna can cause fetal harm when administered to a pregnant woman. There are no adequate data on the use of Tasigna in pregnant women. Reproductive studies in rats and rabbits have demonstrated that nilotinib induced embryo-toxicity and/or feto-toxicity (following prenatal exposure to nilotinib) at exposures equal to the one achieved in humans at the maximum recommended human dose of 400 mg twice daily. Tasigna should not be used during pregnancy unless necessary. If it is used during pregnancy or if the patient becomes pregnant while taking Tasigna, the patient must be informed of the potential risk to the fetus.
If a woman who is being treated with Tasigna is considering pregnancy, treatment discontinuation may be considered based on the eligibility criteria for discontinuing treatment. There is a limited amount of data on pregnancies in patients while attempting TFR. If pregnancy is planned during the TFR phase, the patient must be informed of a potential need to re-initiate Tasigna treatment during pregnancy (see Dosage & Administration and Precautions).
Animal Data: Nilotinib did not induce teratogenicity, but did show embryo- and feto-toxicity 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 embryo-toxicity 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 (NOAEL) 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 NOAEL in maternal animals and offspring was a maternal dose of 20 mg/kg.
Lactation: Risk Summary: It is not known whether nilotinib is excreted in human milk. Studies in animals demonstrate that nilotinib is excreted into breast milk. Lactating women should not breast-feed while taking Tasigna and for 2 weeks after the last dose, as a risk to the infant cannot be excluded.
Females and males of reproductive potential: Contraception: Females: Females of reproductive potential must be advised to use effective method of contraception (methods that result in less than 1% pregnancy rates) while receiving Tasigna and for up to 2 weeks after ending treatment with Tasigna.
Infertility: 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.

Summary of the safety profile: The nilotinib safety profile described as follows is based on data from adult patients with newly diagnosed Ph+ CML-CP in a randomized, open label, active comparator-controlled Phase III trial and adult patients with resistant or intolerant Ph+ CML-CP and CML-AP which served as a basis for the listed indications (see Table 10 and Indications/Uses). Safety information from two Tasigna treatment discontinuation studies in adult patients and from a Phase III study in adult patients with Ph+ CML in chronic phase with suboptimal response to imatinib is also provided.
In adult patients with newly diagnosed Ph+ CML-CP: The data reported as follows reflect exposure to Tasigna from a randomized Phase III study in adult patients with newly diagnosed Ph+ CML in chronic phase treated at the recommended dose of 300 mg twice daily (n=279). The median time on treatment was 60.5 months (range 0.1 to 70.8 months).
Non-hematologic adverse drug reactions (ADRs) reported with very common frequency (≥10%) were rash, pruritus, headache, nausea, fatigue, alopecia, myalgia, and upper abdominal pain. Most of these ADRs were mild to moderate in severity (Grade 1 or 2). Constipation, diarrhoea, dry skin, muscle spasms, arthralgia, abdominal pain, peripheral oedema, vomiting 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 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 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 change from baseline in 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 Tasigna treatment groups and no events of Torsades de Pointes were observed. QTcF increase from baseline that exceeds 60 msec was observed in 5 patients while on Tasigna (one in the 300 mg twice daily treatment group and four in the 400 mg twice daily treatment group).
No patients in any treatment group had a left ventricular ejection fraction (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 (8%). Biochemistry ADRs 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%). See Table 12 for Grade 3/4 laboratory abnormalities.
Discontinuation due to adverse drug reactions was observed in 10% of patients.
In adult patients with resistant or intolerant Ph+ CML-CP and CML-AP: The data reported as follows reflect exposure to Tasigna in 458 adult 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 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 central nervous system (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 Torsades de Pointes (transient or sustained) were observed.
Haematologic ADRs include myelosuppression: thrombocytopenia (31%), neutropenia (17%), and anaemia (14%). See Table 12 for Grade 3/4 laboratory abnormalities.
Discontinuation due to adverse drug reactions was observed in 16% of CP and 10% of AP patients.
In adult patients with Ph+ CML-CP who have not achieved a molecular response greater than or equal to a 4.5-log reduction with imatinib treatment: The data reported as follows were generated in a randomized, open-label, Phase III study where adult male and female patients diagnosed with Ph+ CML-CP and after two years of imatinib therapy were exposed to Tasigna 400 mg twice daily versus imatinib 400 mg or 600 mg once daily for 48 months. Patients randomized to the imatinib arm received the same dose of imatinib as prior to randomization. The median duration of exposure was 47.2 months in the Tasigna arm and 37.0 months and 26.7 months in the 400 mg and 600 mg dose cohorts of the imatinib arm, respectively.
The adverse drug reactions reported by at least 20% of the patients in the Tasigna group and more frequently compared to the imatinib group were headache, rash, and pruritus. A greater proportion of patients in the Tasigna group reported adverse events (AEs) leading to discontinuation and AEs requiring dose adjustment/interruption compared to those in the imatinib group. Increases in bilirubin and transaminases were commonly reported following Tasigna treatment.
Up to the 48-month cut-off date, three on-treatment deaths have been observed (two in the Tasigna arm and one in the imatinib arm). Three patients died more than 28 days after study drug discontinuation (one in the Tasigna arm and two in the imatinib arm).
QTc intervals >450 ms were observed in 4 patients receiving Tasigna therapy on Day 8. No patient had a QTc interval >480 ms. Increases in QTc interval from baseline of >30 ms were reported for 8 patients (7.9%). No patient experienced QTc prolongation >60 ms in the Tasigna group.
Most frequently reported adverse drug reactions: Non-haematologic ADRs (excluding laboratory abnormalities) that were reported in at least 5% of the adult patients in any of the Tasigna clinical studies that serve as a basis for the listed indications are shown in Table 10. 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 to <1/10). The frequency is based on the highest for any Tasigna group in the two studies, using one decimal precision for percentages. (See Table 10.)

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Additional data from clinical trials: The following adverse drug reactions were reported in adult patients in the Tasigna clinical studies which serve as a basis for the listed indications at the recommended doses at a frequency of less than 5% (common is ≥1/100 to <1/10; uncommon is ≥1/1,000 to <1/100; single events are captured as frequency not known) (Table 11). For laboratory abnormalities, very common events (≥1/10) not included in Table 10 are also reported. These adverse drug reactions are included based on clinical relevance and ranked in decreasing order of seriousness within each category, obtained from two clinical studies: Newly diagnosed Ph+ CML-CP 60 months' analysis and Resistant or intolerant Ph+ CML-CP and CML-AP 24 months' analysis. (See Tables 11a and 11b.)

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Laboratory abnormalities: Clinically relevant or severe abnormalities of routine haematologic or biochemistry laboratory values in adult patients are presented in Table 12. (See Table 12.)

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Treatment discontinuation in adult 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.
In a Phase II clinical study with newly diagnosed patients with Ph+ CML-CP (N=190), musculoskeletal symptoms within a year of Tasigna discontinuation were reported in 24.7% vs. 16.3% within the previous year on Tasigna treatment.
In a Phase II clinical study with patients with Ph+ CML-CP on Tasigna and previously treated with imatinib (N=126), musculoskeletal symptoms within a year of discontinuation were reported in 42.1% vs. 14.3% within the previous year on Tasigna treatment.
Adverse drug reactions from spontaneous reports and literature cases (frequency not known): The following adverse drug 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 not known: Tumour lysis syndrome, facial paralysis.

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 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 C_max and 34% decrease in AUC_0-∞). 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 as previously mentioned, 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.
Antiarrhythmic 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 Dosage & Administration, Precautions and Pharmacology under Actions).
Grapefruit juice and other foods that are known to inhibit CYP3A4 should be avoided at any time.

Incompatibilities: Not applicable.

Targeted Cancer Therapy

L01EA03 - nilotinib ; Belongs to the class of BCR-ABL tyrosine kinase inhibitors. Used in the treatment of cancer.

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