Important Safety Information, including Boxed WARNING:

TASIGNA prolongs the QT interval. Prior to TASIGNA administration and periodically, monitor for hypokalemia or hypomagnesemia and correct deficiencies. Obtain ECGs to monitor the QTc at baseline,...+

See More

INDICATIONS for TASIGNA® (nilotinib) Capsules

Adult and Pediatric Patients With Newly Diagnosed Ph+ CML-CP

TASIGNA is indicated for the treatment of adult and pediatric patients greater than or equal to 1 year of age with newly diagnosed Philadelphia chromosome–positive chronic myeloid leukemia (Ph+ CML) in chronic phase (CP).

Adult Patients With Resistant or Intolerant Ph+ CML-CP and CML-AP

TASIGNA is indicated for the treatment of adult patients with CP and accelerated phase (AP) Ph+ CML resistant or intolerant to prior therapy that included imatinib.

Pediatric Patients With Resistant or Intolerant Ph+ CML-CP

TASIGNA is indicated for the treatment of pediatric patients greater than or equal to 1 year of age with Ph+ CML-CP with resistance or intolerance to prior tyrosine kinase inhibitor (TKI) therapy.

Other Uses

Treatment-Free Remission

TASIGNA IS THE ONLY TKI WITH TFR DATA IN ITS LABEL1

TFR is the ability for eligible patients who achieved sustained MR4.5 to maintain MMR (frontline) or MR4 (second line) after discontinuing TASIGNA® (nilotinib) capsules. These patients no longer take oral therapy but continue to be actively managed through frequently scheduled monitoring to identify possible loss of molecular response.1

 

ENESTfreedom: the first clinical trial specifically designed to study TFR in frontline TASIGNA1,2

Entry criteria

To enter the study, adult patients with Ph+ CML-CP had to have:

  • At least 2 years on frontline TASIGNA
  • Typical BCR-ABL1 transcripts (e13a2/b2a2 or e14a2/b3a2)
  • MR4.5 at screening

 

Phase 1: Consolidation phase

215 patients entered a 52-week consolidation phase, where they had to maintain a deep response (assessed every 12 weeks) per the following criteria:

  • Assessments had to be MR4 or deeper
  • No more than 2 assessments could fall between MR4 and MR4.5
  • The last assessment had to be MR4.5 

 

Phase 2: TFR phase

TFR eligibility with frontline TASIGNA

190/215 patients completed the consolidation phase to enter the TFR phase, where they discontinued TASIGNA (with frequently scheduled monitoring).1  

 

ENESTfreedom TFR results through 96 weeks1

49%

Patients who achieved TFR for 96 weeks after discontinuing TASIGNA with frequently scheduled monitoring (n=93/190; 95% CI, 41.6%-56.3%)

46% of patients lost MMR and promptly reinitiated TASIGNA (n=88/190)   

 

Rapid response upon prompt TASIGNA reinitiation1

98%

Patients who regained MMR at 24 weeks after TASIGNA reinitiation (n=86/88)

86% of all patients regained MR4.5 at 24 weeks after TASIGNA reinitiation (n=76/88)

Patients who required reinitiation of TASIGNA were monitored for BCR-ABL1 levels every 4 weeks for the first 24 weeks, and then every 12 weeks thereafter in patients who regained MMR. 

ENESTfreedom (Evaluating Nilotinib Efficacy and Safety in clinical Trials-freedom) is an open-label, multicenter, single-arm, Phase 2 trial of 215 adult patients with Ph+ CML-CP treated with frontline TASIGNA for ≥ 2 years. Patients who had achieved MR4.5 (measured with the MolecularMD MRDx® BCR-ABL test) were enrolled in a 52-week consolidation phase and could enter the TFR phase after achieving a sustained molecular response. Efficacy results were based on the number of patients who remained in the TFR phase with MMR at 96 weeks. Patients with a loss of MMR during the TFR phase reinitiated TASIGNA within 5 weeks at 300 mg bid or at a reduced dose of 400 mg qd if required from the perspective of tolerance.

 

ENESTop: the first clinical trial specifically designed to study TFR in second-line TASIGNA1,3

Entry criteria

To enter the study, adult patients with Ph+ CML-CP had to have:

  • At least 3 years of TKI therapy (imatinib for >4 weeks frontline and TASIGNA for 2 years second line)
  • Typical BCR-ABL1 transcripts (e13a2/b2a2 or e14a2/b3a2)
  • No documented MR4.5 at time of switch to TASIGNA
  • MR4.5 at screening

  

Phase 1: Consolidation phase

163 patients entered a 52-week consolidation phase, where they had to maintain a deep response (assessed every 12 weeks) per the following criteria:

  • The last 4 quarterly assessments had to be MR4.5

 

Phase 2: TFR phase 

TFR eligibility with second-line TASIGNA

126/163 patients completed the consolidation phase to enter the TFR phase, where they discontinued TASIGNA (with frequently scheduled monitoring).1  

 

ENESTop TFR results through 96 weeks1

53%

Patients who achieved TFR for 96 weeks after discontinuing TASIGNA with frequently scheduled monitoring (n=67/126; 95% CI, 44.1%-62.1%)

44% of patients lost MMR/MR4 and promptly reinitiated TASIGNA (n=56/126)

 

Rapid response upon prompt TASIGNA reinitiation1

93%

Patients who regained MMR at 24 weeks after TASIGNA reinitiation (n=52/56)

91% of all patients regained MR4.5 by 48 weeks after TASIGNA reinitiation (n=51/56)

Patients who required reinitiation of TASIGNA were monitored for BCR-ABL1 levels every 4 weeks for the first 24 weeks, and then every 12 weeks thereafter.

 

ENESTop (Evaluating Nilotinib Efficacy and Safety in clinical Trials-stop) is an open-label, multicenter, single-arm, Phase 2 trial of 163 adult patients with Ph+ CML-CP treated with TKI therapy for ≥3 years (imatinib for >4 weeks frontline and TASIGNA for ≥2 years second line) who had no documented MR4.5 on imatinib at the time of switch to TASIGNA, and achieved MR4.5 (measured with the MolecularMD MRDx® BCR-ABL test) with TASIGNA. Patients were enrolled in a 52-week consolidation phase, and could enter the TFR phase after achieving a sustained molecular response. Efficacy results were based on the number of patients who remained in the TFR phase with MMR or MR4 at 96 weeks. Patients with 2 consecutive measurements of BCR-ABL1/ABL1 >0.01% IS or loss of MMR during the TFR phase reinitiated TASIGNA.

 

No patients in ENESTfreedom or ENESTop progressed to AP/BC at 144 weeks4,5

 

Ongoing management is key to TFR: how to actively manage patients in TFR with TASIGNA1

Monitor patients in TFR by BCR-ABL1 level

Ongoing management informs when to increase testing frequency, and when to reinitiate TASIGNA should a patient lose molecular response.

  TFR Monitoring Schedule

 

TFR Monitoring Schedule

 

Advise patients of potential low-grade musculoskeletal symptoms

  • Musculoskeletal symptoms (eg, myalgia, pain in extremity, arthralgia, bone pain, spinal pain, or musculoskeletal pain) may occur more frequently than before TFR 
  • During TFR, musculoskeletal symptoms were reported more frequently during the first year than the second year (all grades: 48% in the first year vs 15% in the second year; Grade 3/4: 3% in the first year vs 1% in the second year)
  • The rate of new musculoskeletal symptoms generally decreased in the second year after treatment discontinuation. 

 


Pediatric Indications

TASIGNA for pediatric patients with newly diagnosed Ph+ CML-CP or resistant or intolerant Ph+ CML-CP1

The safety and efficacy of TASIGNA in pediatric patients with Ph+ CML-CP have been investigated in two studies: Study CAMN107A2120 (NCT01077544), an open-label, single-arm, multi-center study that evaluated the pharmacokinetics, safety, and preliminary efficacy of TASIGNA in pediatric patients with Ph+ CML resistant or intolerant to imatinib or dasatinib (n=11), and Study CAMN107A2203 (NCT01844765), an open-label, single-arm, multi-center study evaluating the efficacy and safety of TASIGNA in pediatric patients with Ph+ CML-CP resistant or intolerant to imatinib or dasatinib (n=33) and newly diagnosed Ph+ CML-CP (n=25). In both studies, patients received TASIGNA treatment at a dose of 230 mg/m2 twice daily, rounded to the nearest 50 mg dose (to a maximum single dose of 400 mg). Data was pooled from a total of 69 pediatric patients (from 2 to less than 18 years of age) with either newly diagnosed Ph+ CML-CP (n=25; 6 children from 2 to less than 12 years and 19 adolescents from 12 to less than 18 years) or imatinib/dasatinib resistant or intolerant Ph+ CML-CP (n=44; 18 children from 2 to less than 12 years and 26 adolescents from 12 to less than 18 years).  

The median time on treatment with TASIGNA was 13.8 months (range: 0.7 to 30.9 months). 

In patients with resistant or intolerant CML, the major molecular response (MMR; BCR-ABL/ABL ≤0.1% IS) rate was 40.9% (18/44, 95% CI: 26.3%, 56.8%) at 12 cycles (28 days per cycle). In patients with newly diagnosed CML, the MMR rate was 60.0% (15/25, 95% CI: 38.7%, 78.9%) at 12 cycles. In patients with resistant or intolerant CML, the cumulative MMR rate was 47.7% (21/44) by cycle 12. In patients with newly diagnosed CML, the cumulative MMR rate was 64.0% (16/25) by cycle 12.  

Among the 21 patients with resistant or intolerant CML who were in MMR at any time on treatment, the median time to first MMR was 2.8 months (range: 0.0 to 11.3). For the 17 patients with newly diagnosed CML who achieved MMR, the median time to first MMR was 5.6 months (range: 2.7 to 16.6). 

Among patients with resistant or intolerant CML, 4.5% of patients achieved BCR-ABL/ABL ≤0.0032% IS (MR4.5) by the cut-off date. Among patients with newly diagnosed CML, the percentage of patients who achieved MR4.5 was 28.0%. 

None of the 21 patients with resistant or intolerant CML who were in MMR on treatment had confirmed loss of MMR, with a median follow-up of 11.3 months. Among the 17 patients with newly diagnosed CML who achieved MMR, one patient had confirmed loss of MMR 3 months after achieving this response; in these patients, the median follow-up was 11.1 months. One patient with resistant or intolerant CML progressed to AP/BC after about 10 months on treatment. 

In pediatric patients with Ph+ CML-CP, the most common (greater than 20%) non-hematologic adverse drug reactions were headache, rash, hyperbilirubinemia, alanine aminotransferase increased, pyrexia, nausea, upper respiratory tract infection, aspartate aminotransferase increased, and vomiting. The most common (greater than 5%) Grade 3/4 non-hematologic adverse drug reactions were alanine aminotransferase increased and hyperbilirubinemia.

Laboratory abnormalities of hyperbilirubinemia (Grade 3/4: 13%) and transaminase elevation (AST Grade 3/4: 1%, ALT Grade 3/4: 9%), were reported at a higher frequency than in adult patients.

The most common hematological adverse drug reactions (greater than or equal to 30% of patients, of all grades) were decreases in total white blood cells (54%), platelet count (44%), absolute neutrophils (41%), absolute lymphocytes (32%), and hemoglobin (30%).

Discontinuation due to adverse reactions occurred in 9 patients (13%). The adverse reactions leading to discontinuation were hyperbilirubinemia (6%) and rash (4%).

Increase in QTcF greater than 30 msec from baseline was observed in 17 patients (25%). No patient had an absolute QTcF of greater than 500 msec or QTcF increase of greater than 60 msec from baseline.


TFR, treatment-free remission; MR, molecular response; MMR, major molecular response; IS, International Scale; FDA, Food and Drug Administration; CCyR, complete cytogenetic response; ENEST, Evaluating Nilotinib Efficacy and Safety in Clinical Trials.   

References:

  1. Tasigna [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2019.
  2. Hochhaus A, Masszi T, Giles FJ, et al. Treatment-free remission following frontline nilotinib in patients with chronic myeloid leukemia in chronic phase: results from the ENESTfreedom study. Leukemia. 2017;31(7):1525-1531.  
  3. Mahon F-X, Boquimpani C, Kim D-W, et al. Treatment-free remission after second-line nilotinib treatment in patients with chronic myeloid leukemia in chronic phase: results from a single-group, phase 2, open-label study. Ann Intern Med. 2018;168(7):461-470.
  4. Radich JP, Masszi T, G’omez Casares MT, et al. ENESTfreedom 144-week update: long-term treatment-free remission (TFR) following frontline nilotinib in patients with chronic myeloid leukemia in chronic phase (CML-CP). Clin Lymphoma Myeloma Leuk. 2018;18(suppl 1):S226. 
  5. Hughes TP, Boquimpani C, Takahashi N, et al. ENESTop 144-week update: long-term treatment-free remission (TFR) in patients with chronic myeloid leukemia in chronic phase (CML-CP) after stopping second-line nilotinib. Clin Lymphoma Myeloma Leuk. 2018;18(suppl 1):S222.

INDICATIONS for TASIGNA® (nilotinib) Capsules

Adult and Pediatric Patients With Newly Diagnosed Ph+ CML-CP

TASIGNA is indicated for the treatment of adult and pediatric patients greater than or equal to 1 year of age with newly diagnosed Philadelphia chromosome–positive chronic myeloid leukemia (Ph+ CML) in chronic phase (CP).

Adult Patients With Resistant or Intolerant Ph+ CML-CP and CML-AP

TASIGNA is indicated for the treatment of adult patients with CP and accelerated phase (AP) Ph+ CML resistant or intolerant to prior therapy that included imatinib.

Pediatric Patients With Resistant or Intolerant Ph+ CML-CP

TASIGNA is indicated for the treatment of pediatric patients greater than or equal to 1 year of age with Ph+ CML-CP with resistance or intolerance to prior tyrosine kinase inhibitor (TKI) therapy.

IMPORTANT SAFETY INFORMATION for TASIGNA® (nilotinib) Capsules

WARNING: QT PROLONGATION AND SUDDEN DEATHS
  • TASIGNA prolongs the QT interval. Prior to TASIGNA administration and periodically, monitor for hypokalemia or hypomagnesemia and correct deficiencies. Obtain ECGs to monitor the QTc at baseline, 7 days after initiation, and periodically thereafter, and following any dose adjustments
  • Sudden deaths have been reported in patients receiving TASIGNA. Do not administer TASIGNA to patients with hypokalemia, hypomagnesemia, or long QT syndrome
  • Avoid use of concomitant drugs known to prolong the QT interval and strong CYP3A4 inhibitors
  • Avoid food 2 hours before and 1 hour after taking the dose

 

CONTRAINDICATIONS

Do not use in patients with hypokalemia, hypomagnesemia, or long QT syndrome.

WARNINGS AND PRECAUTIONS

Myelosuppression

Treatment with TASIGNA can cause Grade 3/4 thrombocytopenia, neutropenia, and anemia. Perform complete blood counts every 2 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.

QT Prolongation

TASIGNA prolongs the QT interval. ECGs should be performed at baseline, 7 days after initiation, periodically as clinically indicated, and following dose adjustments. Correct hypokalemia or hypomagnesemia prior to administration and monitor periodically.

Significant 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 and concomitant use with strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT should be avoided. The presence of hypokalemia and hypomagnesemia may further enhance this effect.

Sudden Deaths

Sudden deaths have been reported in patients with Ph+ CML treated with TASIGNA. The relatively early occurrence of some of these deaths relative to the initiation of TASIGNA suggests the possibility that ventricular repolarization abnormalities may have contributed to their occurrence.

Cardiac and Arterial Vascular Occlusive Events

Cardiovascular events, including arterial vascular occlusive events, were reported in a randomized, clinical trial in patients with newly diagnosed Ph+ CML and observed in the postmarketing reports of patients receiving TASIGNA therapy. Cases of cardiovascular events included ischemic heart disease-related events, peripheral arterial occlusive disease, and ischemic cerebrovascular events.

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.

Pancreatitis and Elevated Serum Lipase

TASIGNA can cause increases in serum lipase. Patients with a previous history of pancreatitis may be at greater risk of elevated serum lipase. If lipase elevations are accompanied by abdominal symptoms, interrupt dosing and consider appropriate diagnostics to exclude pancreatitis. Test serum lipase levels monthly or as clinically indicated.

Hepatotoxicity

TASIGNA may result in hepatotoxicity as measured by elevations in bilirubin, AST/ALT, and alkaline phosphatase. Grade 3/4 elevations of bilirubin, AST, and ALT were reported at a higher frequency in pediatric patients than in adults. Monitor hepatic function tests monthly or as clinically indicated.

Electrolyte Abnormalities

The use of TASIGNA can cause hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and hyponatremia. Correct electrolyte abnormalities prior to initiating TASIGNA and monitor these electrolytes periodically during therapy.

Tumor Lysis Syndrome

Tumor lysis syndrome cases have been reported in patients taking TASIGNA who have resistant or intolerant Ph+ CML. Malignant disease progression, high white blood cell counts, and/or dehydration were present in most of these cases. Maintain adequate hydration and correct uric acid levels prior to initiating therapy with TASIGNA.

Hemorrhage

Serious hemorrhage, including fatal events, from any site, including the GI tract, was reported in patients with Ph+ CML receiving TASIGNA. Monitor patients for signs and symptoms of bleeding and medically manage as needed.

Total Gastrectomy

Since the exposure of TASIGNA is reduced in patients with total gastrectomy, perform more frequent monitoring of these patients. Consider dose increase or alternative therapy in patients with total gastrectomy.

Lactose

Since the capsules contain lactose, TASIGNA is not recommended for patients with rare hereditary problems of galactose intolerance, severe lactase deficiency with a severe degree of intolerance to lactose-containing products, or of glucose-galactose malabsorption.

Monitoring Laboratory Tests

Complete blood counts should be performed every 2 weeks for the first 2 months and then monthly thereafter. Perform chemistry panels, including electrolytes, calcium, magnesium, liver enzymes, lipid profile, and glucose prior to therapy and periodically. ECGs should be obtained at baseline, 7 days after initiation, and periodically thereafter, as well as following dose adjustments.

Monitor lipid profiles and glucose periodically during the first year of TASIGNA therapy and at least yearly during chronic therapy. Assess glucose levels before initiating treatment with TASIGNA and monitor during treatment as clinically indicated. If test results warrant therapy, physicians should follow their local standards of practice and treatment guidelines.

Fluid Retention

Grade 3/4 fluid retention including pleural effusion, pericardial effusion, ascites, and pulmonary edema have been reported in patients with Ph+ CML receiving TASIGNA. Monitor patients for signs of severe fluid retention (eg, unexpected rapid weight gain or swelling) and for symptoms of respiratory or cardiac compromise (eg, shortness of breath); evaluate etiology and treat patients accordingly.

Effects on Growth and Development in Pediatric Patients

Growth retardation has been reported in pediatric patients with Ph+ CML in chronic phase treated with TASIGNA. Monitor growth and development in pediatric patients receiving TASIGNA treatment.

Embryo-Fetal Toxicity

TASIGNA can cause fetal harm. Advise females to inform their doctor if they are pregnant or become pregnant. Inform female patients of the risk to the fetus and potential for loss of the pregnancy. Advise females of reproductive potential to use effective contraception during treatment and for 14 days after receiving the last dose of TASIGNA. Advise lactating women not to breastfeed during treatment with TASIGNA and for at least 14 days after the last dose.

Monitoring of BCR-ABL Transcript Levels

Monitor BCR-ABL transcript levels in patients eligible for treatment discontinuation using an FDA-authorized test validated to measure molecular response (MR) levels with a sensitivity of at least MR4.5. In patients who discontinue TASIGNA therapy, assess BCR-ABL transcript levels monthly for 1 year, then every 6 weeks for the second year, and every 12 weeks thereafter during treatment discontinuation.

Following a loss of MMR (first line/second line) or confirmed loss of MR4 (2 consecutive measures separated by at least 4 weeks showing loss of MR4 in second line), patients should reinitiate TASIGNA within 4 weeks of when the loss of remission is known to have occurred.

Monitor CBC and BCR-ABL transcripts in patients who reinitiate treatment with TASIGNA due to loss of MR quantitation every 4 weeks until MMR is reestablished and then every 12 weeks.

For patients who fail to achieve MMR after 3 months of treatment reinitiating, BCR-ABL kinase domain mutation testing should be performed.

ADVERSE REACTIONS

The most commonly reported nonhematologic adverse reactions (≥20%) in adult and pediatric patients receiving TASIGNA were nausea, rash, headache, fatigue, pruritus, vomiting, diarrhea, cough, constipation, arthralgia, nasopharyngitis, pyrexia, and night sweats.

Hematologic adverse drug reactions (all grades) include myelosuppression: thrombocytopenia, neutropenia, and anemia.

Musculoskeletal symptoms (eg, myalgia, pain in extremity, arthralgia, bone pain, spinal pain, or musculoskeletal pain) have been reported in eligible patients who discontinued TASIGNA therapy after attaining a sustained MR4.5. The rate of new musculoskeletal symptoms (all grades) generally decreased from the first year (34%-48%) to the second year (9%-15%) after treatment discontinuation.

DOSE ADJUSTMENTS OR MODIFICATIONS

TASIGNA may need to be temporarily withheld and/or dose reduced for QT prolongation, hepatic impairment, hematologic toxicities that are not related to underlying leukemia, clinically significant moderate or severe nonhematologic toxicities, laboratory abnormalities (lipase, bilirubin, or hepatic transaminase elevations) or concomitant use of strong CYP3A4 inhibitors.

DRUG INTERACTIONS

Avoid concomitant use of strong CYP3A4 inhibitors with TASIGNA, or reduce TASIGNA dose if co-administration cannot be avoided. Avoid concomitant use of strong CYP3A4 inducers with TASIGNA. Use short-acting antacids or H2 blockers as an alternative to proton pump inhibitors.

Please see full Prescribing Information, including Boxed WARNING, by clicking the link at the top of this page.