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,...+

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Efficacy—Second Line

Signs of Intolerance

SWITCH TO TASIGNA FOR PATIENTS WITH INTOLERANCE TO IMATINIB

How to identify patients who are INTOLERANT to imatinib1

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Side effects with imatinib can impact your patients

Prevalence of common adverse events for imatinib intolerance

Minimal nonhematologic cross-intolerance was observed with TASIGNA after frontline imatinib2

In a post hoc analysis, among 75 patients intolerant to imatinib, zero patients required a dose reduction or discontinuation of TASIGNA® (nilotinib) capsules due to the same Grade 3/4 nonhematologic adverse events2


Signs of Resistance

SWITCH TO TASIGNA FOR PATIENTS WITH RESISTANCE TO IMATINIB

How to identify patients who are RESISTANT to imatinib1,4,5

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Patients on frontline imatinib may fail to meet key milestones at 3, 6, and 12 months

Measuring EMR is the most accurate method to assess long-term prognosis and allows for earlier switch6

Failure to achieve EMR with frontline imatinibFailure to achieve MMR with frontline imatinib        

*A post hoc analysis of patients receiving imatinib 400 mg qd (n=264) in ENESTnd with typical b2a2 and/or b3a2 BCR-ABL1 transcripts and evaluable RQ-PCR samples at 3 months. Data were grouped based on BCR-ABL1 transcript levels at 3 months: 1%, >1% to 10%, and >10%. At 3 months, 19 patients in the imatinib arm had unevaluable BCR-ABL1 transcript levels (atypical transcripts at baseline, missing RQ-PCR samples, or discontinued therapy) and were excluded from the analysis.7


MCyR and MMR

FAST AND SUSTAINED RESPONSES FOR PATIENTS WHO SWITCHED TO TASIGNA

Study A2101: Year 1 MCyR rate8

Year 1 MCyR TASIGNA

Median time to MCyR1:

1.4 months in responders with CHR at baseline

2.8 months in responders without CHR at baseline

 

Study A2101: Year 2 MCyR and MMR rates1

Year 2 MCyR and MMR TASIGNA

STUDY DESIGN: A single-arm, open-label, multicenter study in 321 patients with imatinib-resistant or -intolerant Ph+ CML-CP and 137 patients with Ph+ CML-AP. Patients received TASIGNA 400 mg bid for a minimum follow-up of 24 months (median duration 18.4 months). The definition of imatinib resistance included failure to achieve CHR by 3 months, cytogenetic response by 6 months, or MCyR 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 MCyR at time of study entry. The efficacy end point in CML-CP was unconfirmed MCyR, which included complete (CCyR, 37% [95% CI, 32%-42%]) and partial (PCyR, 15% [95% CI, 11%-19%]) cytogenetic responses. The efficacy end point in CML-AP was confirmed hematologic response, defined as either a CHR or NEL. Cytogenetic responses were based on the percentage of Ph+ metaphases among ≥20 metaphase cells in each bone marrow sample (CCyR, 0% Ph+ metaphases; PCyR, 1%-35% Ph+ metaphases).8

 


Estimated Overall Survival

OVERALL SURVIVAL FOR PATIENTS IN CHRONIC PHASE WHO SWITCHED TO TASIGNA

Survival rates among imatinib-resistant or -intolerant patients in chronic phase treated for a median of 32 months before switching to TASIGNA1,9

95%87%

 


EMR, early molecular response; MMR, major molecular response; ENESTnd, Evaluating Nilotinib Efficacy and Safety in Clinical Trials in newly diagnosed patients; RQ-PCR, real-time quantitative polymerase chain reaction; MCyR, major cytogenetic response; CHR, complete hematologic response; CCyR, complete cytogenetic response; PCyR, partial cytogenetic response; NEL, no evidence of leukemia.

References: 

  1. Kantarjian HM, Giles FJ, Bhalla KN, et al. Nilotinib is effective in patients with chronic myeloid leukemia in chronic phase after imatinib resistance or intolerance: 24-month follow-up results. Blood. 2011;117(4):1141-1145. 
  2. Cortes JE, Hochhaus A, le Coutre PD, et al. Minimal cross-intolerance with nilotinib in patients with chronic myeloid leukemia in chronic or accelerated phase who are intolerant to imatinib. Blood. 2011;117(21):5600-5606. 
  3. O’Brien SG, Guilhot F, Larson RA, et al; the IRIS Investigators. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003;384(11):994-1004. 
  4. Baccarani M, Deininger MW, Rosti G, et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood. 2013;122(6):872-884. 
  5. Hochhaus A, Saussele S, Rosti G, et al; the ESMO Guidelines Committee. Chronic myeloid leukemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017;28(suppl 4):iv41-iv51. 
  6. Marin D, Ibrahim AR, Lucas C, et al. Assessment of BCR-ABL1 transcript levels at 3 months is the only requirement for predicting outcome for patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors. J Clin Oncol. 2012;30(3):232-238.
  7. Hughes TP, Saglio G, Kantarjian HM, et al. Early molecular response predicts outcomes in patients with chronic myeloid leukemia in chronic phase treated with frontline nilotinib or imatinib. Blood. 2014;123(9):1353-1360.
  8. Tasigna [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2018. 
  9. Data on file. Study CAMN107A2101. Novartis Pharmaceuticals Corp; 2009.

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

Adverse reactions associated with growth and development can occur in pediatric patients receiving BCR-ABL tyrosine kinase inhibitors (TKIs). The long-term effects of prolonged treatment with BCR-ABL TKIs on growth and development in pediatric patients are unknown. Monitor growth and development in pediatric patients receiving BCR-ABL TKI 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.