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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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.

Safety Profile

Safety in Newly Diagnosed Patients

More patients remained on therapy with TASIGNA throughout follow-up vs imatinib

Treatment discontinuation rates and proportion of patients on therapy with TASIGNA vs imatinib

 

Lower rates of gastrointestinal and myelosuppressive adverse events with TASIGNA vs imatinib

Common nonhematologic adverse events with TASIGNA vs imatinib

Nonhematologic AEs observed in 5% to 10% of patients were of mild to moderate severity, manageable, and generally did not require dose reduction.1 

TASIGNA® (nilotinib) capsules was associated with higher rates than imatinib of elevated lipase (9% vs 4%), hyperglycemia (7% vs <1%), increased ALT (4% vs 3%), and elevated total bilirubin (4% vs <1%); the rate of hypophosphatemia was lower with TASIGNA vs imatinib (8% vs 10%).1

 

 Rates of Grade 3/4 myelosuppression with TASIGNA vs imatinib

Low rate of pleural effusion with TASIGNA

TASIGNA has a low rate of pleural effusion (2%)1 


 

Additional Safety Information

SELECT CONSIDERATIONS WHEN CHOOSING A FRONTLINE THERAPY1

Grade 3/4 fluid retention—TASIGNA 3.9% vs imatinib 2.5%

  • Effusions (including pleural effusion, pericardial effusion, ascites) or pulmonary edema were observed in 2.2% of patients receiving TASIGNA 300 mg bid and in 2.1% of patients receiving imatinib
  • Effusions were severe (Grade 3/4) in 0.7% of patients receiving TASIGNA 300 mg bid and in no patients receiving imatinib
  • Similar events were also observed in postmarketing reports
  • 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) during TASIGNA treatment; evaluate etiology and treat patients accordingly

 

All-grade peripheral edema—TASIGNA 9% vs imatinib 20%

  • Unexpected, rapid weight gain should be carefully investigated, and if signs of severe fluid retention appear during treatment with TASIGNA, the etiology should be evaluated and patients treated accordingly 

 

QT prolongation

  • An increase in QTcF >60 msec from baseline was observed in 1 patient (0.4%) in the 300-mg bid treatment group. No patient had an absolute QTcF of >500 msec while on the study drug
  • 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
  • TASIGNA may need to be withheld and/or dose reduced for QT prolongation

 

Hepatic impairment

  • In a study of subjects with mild to severe hepatic impairment following a single-dose administration of 200 mg of TASIGNA, the mean AUC values were increased on average by 35%, 35%, and 56% in subjects with mild (Child-Pugh class A, score 5 to 6), moderate (Child-Pugh class B, score 7 to 9), and severe hepatic impairment (Child-Pugh class C, score 10 to 15), respectively, compared with a control group of subjects with normal hepatic function 
  • A lower starting dose is recommended in patients with hepatic impairment, and the QT interval should be monitored closely in these patients
  • TASIGNA may need to be withheld and/or dose reduced for hepatic impairment

 

Laboratory assessments

  • Complete blood counts should be performed every 2 weeks for the first 2 months and then monthly thereafter. Chemistry panels, including electrolytes, calcium, magnesium, liver enzymes, lipid profile, and glucose, should be checked prior to therapy and periodically

 

Concurrent medication with CYP3A4

  • Administration of TASIGNA with agents that are strong CYP3A4 inhibitors should be avoided. Concomitant use of TASIGNA with medicinal products and herbal preparations that are potent inducers of CYP3A4 is likely to reduce exposure to nilotinib to a clinically relevant extent. In patients receiving TASIGNA, concomitant use of alternative therapeutic agents with less potential for CYP3A4 induction should be selected

 

Safety in Imatinib-Resistant or -Intolerant Patients

ESTABLISHED TOLERABILITY AFTER FRONTLINE IMATINIB

All-grade nonhematologic AEs occurring in ≥10% of patients receiving second-line TASIGNA at 2 years1

Nonhematologic adverse events with second-line TASIGNA at 2 years

 

Grade 3/4 myelosuppression1

 Grade 3/4 myelosuppression with second-line TASIGNA

TASIGNA can cause Grade 3/4 thrombocytopenia, neutropenia, and anemia that is generally reversible and usually managed by dose interruption or reduction. Perform complete blood counts every 2 weeks for the first 2 months and then monthly or as clinically indicated.1


AE, adverse event; ENESTnd, Evaluating Nilotinib Efficacy and Safety in Clinical Trials in newly diagnosed patients; ECG, electrocardiogram; AUC, area under the curve.

References:

  1. Tasigna [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2019.
  2. Data on file. Study CAMN107A2303. Novartis Pharmaceuticals Corp; 2014.
  3. Hochhaus A, Saglio G, Hughes TP, et al. Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial. Leukemia. 2016;30(5):1044-1054. 

 

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.