TASIGNA® (nilotinib) Capsules by Novartis Pharmaceuticals Corporation


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Boxed WARNING

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 [see Warnings and Precautions (5.2)]. Obtain ECGs to monitor the QTc at baseline, seven days after initiation, and periodically thereafter, and following any dose adjustments [see Warnings and Precautions (5.2, 5.3, 5.7, 5.12)].

·        Sudden deaths have been reported in patients receiving Tasigna [see Warnings and Precautions (5.3)].  Do not administer Tasigna to patients with hypokalemia, hypomagnesemia, or long QT syndrome [see Contraindications (4), Warnings and Precautions (5.2)].

·        Avoid use of concomitant drugs known to prolong the QT interval and strong CYP3A4 inhibitors [see Drug Interactions (7.1, 7.2)].

·        Avoid food 2 hours before and 1 hour after taking the dose [see Dosage and Administration (2.1)].

 

 

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Indications & Usage

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.

 

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

Tasigna is indicated for the treatment of adult patients with chronic phase and accelerated phase Philadelphia chromosome positive chronic myelogenous leukemia (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 chronic phase Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) with resistance or intolerance to prior tyrosine-kinase inhibitor (TKI) therapy.

 

 

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Highlights of Dosage & Administration

HIGHLIGHTS OF DOSAGE AND ADMINISTRATION

 

·        Recommended Adult Dose: Newly diagnosed Ph+ CML-CP: 300 mg orally twice daily. Resistant or intolerant Ph+ CML-CP and CML-AP: 400 mg orally twice daily.

·        Recommended Pediatric Dose: Newly Diagnosed Ph+ CML-CP or Ph+ CML-CP resistant or intolerant to prior TKI therapy: 230 mg/m2 orally twice daily, rounded to the nearest 50 mg dose (to a maximum single dose of 400 mg). 

·        See Dosage and Administration for full dosing instructions and dose reduction instructions for toxicity. 

·        Reduce starting dose in patients with baseline hepatic impairment. 

·        Eligible newly diagnosed adult patients with Ph+ CML-CP who have received Tasigna for a minimum of 3 years and have achieved a sustained molecular response (MR4.5) and patients with Ph+ CML-CP resistant or intolerant to imatinib who have received Tasigna for at least 3 years and have achieved a sustained molecular response (MR4.5) may be considered for treatment discontinuation

 

DOSAGE FORMS AND STRENGTHS

 

Capsules: 50 mg, 150 mg, and 200 mg

 

 

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Contraindications

Tasigna is contraindicated in patients with hypokalemia, hypomagnesemia, or long QT syndrome.

 

 

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Highlights of Warnings & Precautions

HIGHLIGHTS OF WARNINGS AND PRECAUTIONS

 

·        Myelosuppression: Monitor complete blood count (CBC) during therapy and manage by treatment interruption or dose-reduction.

·        Cardiac and Arterial Vascular Occlusive Events: Evaluate cardiovascular status, monitor and manage cardiovascular risk factors during Tasigna therapy.

·        Pancreatitis and Elevated Serum Lipase: Monitor serum lipase; if elevations are accompanied by abdominal symptoms, interrupt doses and consider appropriate diagnostics to exclude pancreatitis.

·        Hepatotoxicity: Monitor hepatic function tests monthly or as clinically indicated.

·        Electrolyte Abnormalities: Tasigna can cause hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and hyponatremia. Correct electrolyte abnormalities prior to initiating Tasigna and monitor periodically during therapy. 

·        Tumor Lysis Syndrome: Maintain adequate hydration and correct uric acid levels prior to initiating therapy with Tasigna. 

·        Hemorrhage: Hemorrhage from any site may occur. Advise patients to report signs and symptoms of bleeding and medically manage as needed.  

·        Fluid Retention: Monitor patients for unexpected rapid weight gain, swelling, and shortness of breath. Manage medically. 

·        Effects on Growth and Development in Pediatric Patients: Growth retardation has been reported in pediatric patients treated with Tasigna. Monitor growth and development in pediatric patients. 

·        Embryo-Fetal Toxicity: Advise patients of potential risk to a fetus and to use effective contraception. 

·        Treatment Discontinuation: Patients must have typical BCR-ABL transcripts. An FDA-authorized test with a detection limit below MR4.5 must be used to determine eligibility for discontinuation. Patients must be frequently monitored by the FDA authorized test to detect possible loss of remission.

 

 

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Highlights of Adverse Reactions

HIGHLIGHTS OF ADVERSE REACTIONS

 

The most commonly reported non-hematologic adverse reactions (≥ 20%) in adult and pediatric patients were nausea, rash, headache, fatigue, pruritus, vomiting, diarrhea, cough, constipation, arthralgia, nasopharyngitis, pyrexia, and night sweats. Hematologic adverse drug reactions include myelosuppression: thrombocytopenia, neutropenia, and anemia.

 

To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

 

 

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Highlights of Drug Interactions

HIGHLIGHTS OF DRUG INTERACTIONS

 

·         Strong CYP3A Inhibitors: Avoid concomitant use with Tasigna, or reduce Tasigna dose if co-administration cannot be avoided.

·         Strong CYP3A Inducers: Avoid concomitant use with Tasigna. 

·         Proton Pump Inhibitors: Use short-acting antacids or H2 blockers as an alternative to proton pump inhibitors

 

 

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Highlights of Use in Specific Populations

HIGHLIGHTS OF USE IN SPECIFIC POPULATIONS

 

·         Lactation: Advise women not to breastfeed

 

 

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Information obtained from Tasigna® (nilotinib) Capsules full Prescribing Information.

 7/20    AM7-1233119

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INDICATIONS AND IMPORTANT SAFETY INFORMATION


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