July 24, 2016
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"The U.S. Food and Drug Administration today approved a new use of Gleevec (imatinib) to treat children newly diagnosed with Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL).

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Tasigna Capsules


Mechanism Of Action

Nilotinib is an inhibitor of the BCR-ABL kinase. Nilotinib binds to and stabilizes the inactive conformation of the kinase domain of ABL protein. In vitro, nilotinib inhibited BCR-ABL mediated proliferation of murine leukemic cell lines and human cell lines derived from patients with Ph+ CML. Under the conditions of the assays, nilotinib was able to overcome imatinib resistance resulting from BCR-ABL kinase mutations, in 32 out of 33 mutations tested. In vivo, nilotinib reduced the tumor size in a murine BCR-ABL xenograft model. Nilotinib inhibited the autophosphorylation of the following kinases at IC50 values as indicated: BCR-ABL (20 to 60 nM), PDGFR (69 nM), c-KIT (210 nM), CSF-1R (125 to 250 nM), and DDR1 (3.7 nM).


Absorption and Distribution

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%. Peak concentrations of nilotinib are reached 3 hours after oral administration.

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 following 400 mg twice-daily dosing at steady state was 35% higher than with 800 mg once-daily dosing. Steady state exposure (AUC) of nilotinib with 400 mg twice-daily dosing was 13% higher than with 300 mg twice-daily dosing. The average steady state nilotinib trough and peak concentrations did not change over 12 months. There was no relevant increase in exposure to nilotinib when the dose was increased from 400 mg twice-daily to 600 mg twice-daily.

The bioavailability of nilotinib was increased when given with a meal. Compared to the fasted state, the systemic exposure (AUC) increased by 82% when the dose was given 30 minutes after a high fat meal.

Single dose administration of two 200 mg nilotinib capsules each dispersed in 1 teaspoon of applesauce and administered within 15 minutes was shown to be bioequivalent to a single dose administration of two 200 mg intact capsules. The blood-to-serum ratio of nilotinib is 0.68. Serum protein binding is approximately 98% on the basis of in vitro experiments.

Median steady-state trough concentration of nilotinib was decreased by 53% in patients with total gastrectomy compared to patients who had not undergone surgeries [see WARNINGS AND PRECAUTIONS].

Pharmacokinetics, Metabolism and Excretion

The apparent elimination half-life estimated from the multiple dose pharmacokinetic studies with daily dosing was approximately 17 hours. Inter-patient variability in nilotinib AUC was 32% to 64%. Steady state conditions were 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.

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.

After a single dose of radiolabeled nilotinib in healthy subjects, more than 90% of the administered dose was eliminated within 7 days: mainly in feces (93% of the dose). Parent drug accounted for 69% of the dose.

Age, body weight, gender, or ethnic origin did not significantly affect the pharmacokinetics of nilotinib.

Drug-Drug Interactions

In a Phase 1 trial of nilotinib 400 mg twice-daily in combination with imatinib 400 mg daily or 400 mg twice-daily, the AUC increased 30% to 50% for nilotinib and approximately 20% for imatinib.


Tasigna can increase bilirubin levels. A pharmacogenetic analysis of 97 patients evaluated the polymorphisms of UGT1A1 and its potential association with hyperbilirubinemia during Tasigna treatment. In this study, the (TA)7/(TA)7 genotype was associated with a statistically significant increase in the risk of hyperbilirubinemia relative to the (TA)6/(TA)6 and (TA)6/(TA)7 genotypes. However, the largest increases in bilirubin were observed in the (TA)7/(TA)7 genotype (UGT1A1*28) patients [see WARNINGS AND PRECAUTIONS].

QT/QTc Prolongation

In a placebo-controlled study in healthy volunteers designed to assess the effects of Tasigna on the QT interval, administration of Tasigna was associated with concentration-dependent QT prolongation; the maximum mean placebo-adjusted QTcF change from baseline was 18 msec (1-sided 95% Upper CI: 26 msec). A positive control was not included in the QT study of healthy volunteers. Peak plasma concentrations in the QT study were 26% lower than those observed in patients enrolled in the single-arm study [see BOXED WARNING, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS].

Clinical Studies

Newly Diagnosed Ph+ CML-CP

An open-label, multicenter, randomized trial was conducted to determine the efficacy of Tasigna versus imatinib tablets in adult patients with cytogenetically confirmed newly diagnosed Ph+ CML-CP. Patients were within 6 months of diagnosis and were previously untreated for CML-CP, except for hydroxyurea and/or anagrelide. 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.

Median age was 46 years in the imatinib group and 47 years in both nilotinib groups, with 12%, 13%, and 10% of patients ≥ 65 years of age in imatinib 400 mg once-daily, 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 (56%, 56%, and 62% in imatinib 400 mg once-daily, nilotinib 300 mg twice-daily and nilotinib 400 mg twice-daily treatment groups, respectively). More than 60% of all patients were Caucasian, and 25% were Asian.

The primary data analysis was performed when all 846 patients completed 12 months of treatment (or discontinued earlier). Subsequent analyses were done when patients completed 24, 36, 48, and 60 months of treatment (or discontinued earlier). The median time on treatment was approximately 61 months in all three treatment groups.

The primary efficacy endpoint was major molecular response (MMR) at 12 months after the start of study medication. MMR was defined as ≤ 0.1% BCR-ABL/ABL % by international scale measured by RQ-PCR, which corresponds to a ≥ 3 log reduction of BCR-ABL transcript from standardized baseline. Efficacy endpoints are summarized in Table 9.

Two patients in the nilotinib arm progressed to either accelerated phase or blast crisis (both within the first 6 months of treatment) while 12 patients on the imatinib arm progressed to either accelerated phase or blast crisis (7 patients within first 6 months, 2 patients within 6 to 12 months, 2 patients within 12 to 18 months and 1 patient within 18 to 24 months).

Table 9: Efficacy (MMR and CCyR) of TASIGNA Compared to Imatinib in Newly Diagnosed Ph+ CML-CP

  TASIGNA 300 mg twice-daily
Imatinib 400 mg once-daily
MMR at 12 months (95% CI) 44% (38.4, 50.3) 22% (17.6, 27.6)
  P-Valuea < 0.0001
CCyRb by 12 months (95% CI) 80% (75.0, 84.6) 65% (59.2, 70.6)
MMR at 24 months (95% CI) 62% (55.8, 67.4) 38% (31.8, 43.4)
CCyRb by 24 months (95% CI) 87% (82.4, 90.6) 77% (71.7, 81.8)
aCMH test stratified by Sokal risk group
bCCyR: 0% Ph+ metaphases. Cytogenetic responses were based on the percentage of Ph-positive metaphases among ≥ 20 metaphase cells in each bone marrow sample.

By the 60 months, MMR was achieved by 77% of patients on Tasigna and 60% of patients on imatinib. Median overall survival was not reached in either arm. At the time of the 60-month final analysis, the estimated survival rate was 93.7% for patients on Tasigna and 91.7% for patients on imatinib.

Patients With Resistant Or Intolerant Ph+ CML-CP And CML-AP

A single-arm, open-label, multicenter study was conducted to evaluate the efficacy and safety of Tasigna (400 mg twice-daily) in patients with imatinib-resistant or -intolerant CML with separate cohorts for chronic and accelerated phase disease. The definition of imatinib resistance included failure to achieve a complete hematologic response (by 3 months), cytogenetic response (by 6 months) or major cytogenetic response (by 12 months) or progression of disease after a previous cytogenetic or hematologic response. Imatinib intolerance was defined as discontinuation of treatment due to toxicity and lack of a major cytogenetic response at time of study entry. At the time of data cut-off, 321 patients with CML-CP and 137 patients with CML-AP with a minimum follow-up of 24 months were enrolled. In this study, about 50% of CML-CP and CML-AP patients were males, over 90% (CML-CP) and 80% (CML-AP) were Caucasian, and approximately 30% were age 65 years or older.

Overall, 73% of patients were imatinib resistant while 27% were imatinib intolerant. The median time of prior imatinib treatment was approximately 32 (CML-CP) and 28 (CML-AP) months. Prior therapy included hydroxyurea in 85% of patients, interferon in 56% and stem cell or bone marrow transplant in 8%. The median highest prior imatinib dose was 600 mg/day for patients with CML-CP and CML-AP, 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.

Median duration of nilotinib treatment was 18.4 months in patients with CML-CP and 8.7 months in patients with CML-AP.

The efficacy endpoint in CML-CP was unconfirmed major cytogenetic response (MCyR) which included complete and partial cytogenetic responses.

The efficacy endpoint in CML-AP was confirmed hematologic response (HR), defined as either a complete hematologic response (CHR) or no evidence of leukemia (NEL). The rates of response for CML-CP and CML-AP patients are reported in Table 10.

Median durations of response had not been reached at the time of data analysis.

Table 10: Efficacy of Tasigna in Resistant or Intolerant Ph+ CML-CP and CML-AP

Cytogenetic Response Rate (Unconfirmed) (%)a
  Chronic Phase
Major (95% CI) 51% (46%-57%)
Complete (95% CI) 37% (32%-42%)
Partial (95% CI) 15% (11%-19%)
  Accelerated Phase
Hematologic Response Rate (Confirmed) (95% CI)b 39% (31%-48%)
Complete Hematologic Response Rate (95% CI) 30% (22%-38%)
No Evidence of Leukemia (95% CI) 9% (5%-16%)
aCytogenetic response criteria: Complete (0% Ph + metaphases) or partial (1% to 35%). Cytogenetic responses were based on the percentage of Ph-positive metaphases among ≥ 20 metaphase cells in each bone marrow sample.
bHematologic response=CHR + NEL (all responses confirmed after 4 weeks).

CHR (CML-CP): WBC < 10 x 109L, platelets < 450,000/mm³, no blasts or promyelocytes in peripheral blood, < 5% myelocytes + metamyelocytes in bone marrow, < 20% basophils in peripheral blood, and no extramedullary involvement.
CHR (CML-AP): neutrophils > 1.5 x 109L, platelets > 100 x 109L, no myeloblasts in peripheral blood, myeloblasts < 5% in bone marrow, and no extramedullary involvement.
NEL: same criteria as for CHR but neutrophils > 1.0 x 109L and platelets > 20 x 109L without transfusions or bleeding.

Patients with Chronic Phase

The MCyR rate in 321 CML-CP patients was 51%. The median time to MCyR among responders was 2.8 months (range 1 to 28 months). The median duration of MCyR cannot be estimated. The median duration of exposure on this single arm-trial was 18.4 months. Among the CML-CP patients who achieved MCyR, 62% of them had MCyR lasting more than 18 months. The CCyR rate was 37%.

Patients with Accelerated Phase

The overall confirmed hematologic response rate in 137 patients with CML-AP was 39%. The median time to first hematologic response among responders was 1 month (range 1 to 14 months). Among the CML-AP patients who achieved HR, 44% of them had a response lasting for more than 18 months.

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.

Last reviewed on RxList: 11/30/2015
This monograph has been modified to include the generic and brand name in many instances.

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