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TASIGNA (NDA-022068)

(NILOTINIB HYDROCHLORIDE MONOHYDRATE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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02/08/2024 (SUPPL-41)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

Musculoskeletal and Connective Tissue Disorders: osteonecrosis

09/23/2021 (SUPPL-35)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.14 Effects on Growth and Development in Pediatric Patients

(Additions and/or revisions underlined)

Growth retardation has been reported in pediatric patients with Ph+ CML in chronic phase treated with Tasigna. In a pediatric trial with 58 patients with Ph+ CML in chronic phase with a median exposure of 56.7 months, growth deceleration (crossing at least two main height percentile lines from baseline) was observed in eight patients: five (9%) crossed two main percentile lines from baseline and three (5%) crossed three main percentile lines from baseline (percentile lines: 5th, 10th, 25th, 50th, 75th, 90th, and 95th). Growth deceleration was more pronounced in children who were less than age 12 at baseline. Adverse reactions associated with growth retardation were reported in 3 patients (5%). Monitor growth and development in pediatric patients receiving Tasigna treatment.

5.6 Hepatotoxicity

(Additions and/or revisions underlined)

Tasigna may result in hepatotoxicity as measured by elevations in bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase. Grade 3-4 elevations of bilirubin, AST, and ALT were reported at a higher frequency in pediatric than in adult patients. Monitor hepatic function tests monthly or as clinically indicated [see Warnings and Precautions (5.12)] and following dose adjustments. [see Dosage and Administration (2.6)].

6 Adverse Reactions

6.1 Clinical Trials Experience

(Extensive revisions; please refer to label)

8 Use in Specific Populations

8.4 Pediatric Use

(Additions and/or revisions underlined)

The safety and effectiveness of Tasigna have been established in pediatric patients greater than or equal to 1 year of age with newly diagnosed and resistant or intolerant Ph+ CML in chronic phase [see Clinical Studies (14.5)]. There are no data for pediatric patients under 2 years of age. Use of Tasigna in pediatric patients 1 year to less than 2 years of age with newly diagnosed or resistant or intolerant Ph+ CML in chronic phase is supported by efficacy in pediatric patients 2 to 6 years of age for these indications. The safety and effectiveness of Tasigna have been established in pediatric patients greater than or equal to 1 year of age with resistant or intolerant Ph+ CML in accelerated phase based on evidence of effectiveness from an adequate and well- controlled single-arm study in adults [see Clinical Studies (14.2)] with safety data from two pediatric studies as described in the next paragraph.

Use of Tasigna in pediatric patients 1 to less than 18 years of age is supported by evidence from two clinical trials [see Clinical Studies (14.5)]. The 25 patients with newly diagnosed Ph+ CML-CP were in the following age groups: 6 children (age 2 to less than 12 years) and 19 adolescents (age 12 to less than 18 years). The 44 patients with resistant or intolerant Ph+ CML-CP included 18 children (age 2 to less than 12 years) and 26 adolescents (age 12 to less than 18 years). All pediatric 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). No differences in efficacy or safety were observed between the different age subgroups in the two trials.

The frequency, type, and severity of adverse reactions observed were generally consistent with those observed in adults, with the exception of the laboratory abnormalities of hyperbilirubinemia (Grade 3/4: 16%) and transaminase elevation (AST Grade 3/4: 2.9%, ALT Grade 3/4: 10%), which were reported at a higher frequency in pediatric patients than in adults [see Adverse Reactions (6.1)]. For pediatric growth and development, growth retardation has been reported in pediatric patients with Ph+ CML-CP treated with Tasigna [see Warnings and Precautions (5.14), Adverse Reactions (6.1)].

The safety and effectiveness of Tasigna in pediatric patients below the age of 1 year with newly diagnosed, or resistant or intolerant Ph+ CML in chronic phase and accelerated phase, have not been established.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

(Additions and/or revisions underlined)

What is Tasigna?

Tasigna is a prescription medicine used to treat:

  • adults and children who have been newly diagnosed with a certain type of leukemia called Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase.

  • adults with chronic phase Ph+ CML or accelerated phase Ph+ CML who:

    • are no longer benefiting from other treatments, including imatinib (Gleevec), or

    • have taken other treatments, including imatinib (Gleevec), and cannot tolerate them.

  • children with chronic phase Ph+ CML or accelerated phase Ph+ CML who:

    • are no longer benefiting from treatment with a tyrosine-kinase inhibitor medicine, or

    • have taken a tyrosine-kinase inhibitor medicine and cannot tolerate it.

It is not known if Tasigna is safe and effective in children younger than 1 year of age with newly diagnosed, resistant, or intolerant Ph+ CML in chronic phase.

The long-term effects of treating children with Tasigna for a long period of time are not known.

09/23/2021 (SUPPL-36)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.14 Effects on Growth and Development in Pediatric Patients

(Additions and/or revisions underlined)

Growth retardation has been reported in pediatric patients with Ph+ CML in chronic phase treated with Tasigna. In a pediatric trial with 58 patients with Ph+ CML in chronic phase with a median exposure of 56.7 months, growth deceleration (crossing at least two main height percentile lines from baseline) was observed in eight patients: five (9%) crossed two main percentile lines from baseline and three (5%) crossed three main percentile lines from baseline (percentile lines: 5th, 10th, 25th, 50th, 75th, 90th, and 95th). Growth deceleration was more pronounced in children who were less than age 12 at baseline. Adverse reactions associated with growth retardation were reported in 3 patients (5%). Monitor growth and development in pediatric patients receiving Tasigna treatment.

5.6 Hepatotoxicity

(Additions and/or revisions underlined)

Tasigna may result in hepatotoxicity as measured by elevations in bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase. Grade 3-4 elevations of bilirubin, AST, and ALT were reported at a higher frequency in pediatric than in adult patients. Monitor hepatic function tests monthly or as clinically indicated [see Warnings and Precautions (5.12)] and following dose adjustments. [see Dosage and Administration (2.6)].

6 Adverse Reactions

6.1 Clinical Trials Experience

(Extensive revisions; please refer to label)

8 Use in Specific Populations

8.4 Pediatric Use

(Additions and/or revisions underlined)

The safety and effectiveness of Tasigna have been established in pediatric patients greater than or equal to 1 year of age with newly diagnosed and resistant or intolerant Ph+ CML in chronic phase [see Clinical Studies (14.5)]. There are no data for pediatric patients under 2 years of age. Use of Tasigna in pediatric patients 1 year to less than 2 years of age with newly diagnosed or resistant or intolerant Ph+ CML in chronic phase is supported by efficacy in pediatric patients 2 to 6 years of age for these indications. The safety and effectiveness of Tasigna have been established in pediatric patients greater than or equal to 1 year of age with resistant or intolerant Ph+ CML in accelerated phase based on evidence of effectiveness from an adequate and well- controlled single-arm study in adults [see Clinical Studies (14.2)] with safety data from two pediatric studies as described in the next paragraph.

Use of Tasigna in pediatric patients 1 to less than 18 years of age is supported by evidence from two clinical trials [see Clinical Studies (14.5)]. The 25 patients with newly diagnosed Ph+ CML-CP were in the following age groups: 6 children (age 2 to less than 12 years) and 19 adolescents (age 12 to less than 18 years). The 44 patients with resistant or intolerant Ph+ CML-CP included 18 children (age 2 to less than 12 years) and 26 adolescents (age 12 to less than 18 years). All pediatric 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). No differences in efficacy or safety were observed between the different age subgroups in the two trials.

The frequency, type, and severity of adverse reactions observed were generally consistent with those observed in adults, with the exception of the laboratory abnormalities of hyperbilirubinemia (Grade 3/4: 16%) and transaminase elevation (AST Grade 3/4: 2.9%, ALT Grade 3/4: 10%), which were reported at a higher frequency in pediatric patients than in adults [see Adverse Reactions (6.1)]. For pediatric growth and development, growth retardation has been reported in pediatric patients with Ph+ CML-CP treated with Tasigna [see Warnings and Precautions (5.14), Adverse Reactions (6.1)].

The safety and effectiveness of Tasigna in pediatric patients below the age of 1 year with newly diagnosed, or resistant or intolerant Ph+ CML in chronic phase and accelerated phase, have not been established.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

(Additions and/or revisions underlined)

What is Tasigna?

Tasigna is a prescription medicine used to treat:

  • adults and children who have been newly diagnosed with a certain type of leukemia called Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase.

  • adults with chronic phase Ph+ CML or accelerated phase Ph+ CML who:

    • are no longer benefiting from other treatments, including imatinib (Gleevec), or

    • have taken other treatments, including imatinib (Gleevec), and cannot tolerate them.

  • children with chronic phase Ph+ CML or accelerated phase Ph+ CML who:

    • are no longer benefiting from treatment with a tyrosine-kinase inhibitor medicine, or

    • have taken a tyrosine-kinase inhibitor medicine and cannot tolerate it.

It is not known if Tasigna is safe and effective in children younger than 1 year of age with newly diagnosed, resistant, or intolerant Ph+ CML in chronic phase.

The long-term effects of treating children with Tasigna for a long period of time are not known.

12/08/2020 (SUPPL-33)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Following Table 10, additions and/or revisions underlined:

Additional Data from Clinical Trials

Nervous System Disorders: Common: peripheral neuropathy, hypoesthesia, paresthesia. Uncommon: intracranial hemorrhage, ischemic stroke, transient ischemic attack, cerebral infarction, migraine, loss of consciousness (including syncope), tremor, disturbance in attention, hyperesthesia, facial paralysis. Unknown frequency: basilar artery stenosis, brain edema, optic neuritis, lethargy, dysesthesia, restless legs syndrome.

6.2 Postmarketing Experience

Newly added information:

Nervous System Disorders: facial paralysis

8 Use in Specific Populations

8.4 Pediatric Use

Newly added information to the end of the subsection:

The safety and effectiveness of Tasigna in pediatric patients below the age of 1 year with newly diagnosed, or resistant or intolerant Ph+ CML in chronic phase, has not been established.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Embryo-Fetal Toxicity

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy. [see Warnings and Precautions (5.15), Use in Specific Populations (8.1)].

Advise females of reproductive potential to use effective contraception during treatment and for at least 14 days after receiving the last dose of Tasigna [see Use in Specific Populations ( 8.3)].

09/25/2019 (SUPPL-31)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.14 Effects on Growth and Development in Pediatric Patients

(additions and/or revisions are underlined)

Growth retardation has been reported in pediatric patients with Ph+ CML in chronic phase treated with Tasigna. In a pediatric trial with 58 patients with Ph+ CML in chronic phase after a median follow-up of 33 months, 12% (n = 7) of patients experienced a decrease of two main height percentile lines (percentile lines: 5th, 10th, 25th, 50th, 75th, 90th, and 95th). Adverse reactions associated with growth retardation were reported in 3 patients (5%). Monitor growth and development in pediatric patients receiving Tasigna treatment.

6 Adverse Reactions

(additions and/or revisions are underlined)

The following clinically significant adverse reactions can occur with Tasigna and are discussed in greater detail in other sections of labeling:

  • Myelosuppression

  • QT Prolongation

  • Sudden Deaths

  • Cardiac and Arterial Vascular Occlusive Events

  • Pancreatitis and Elevated Serum Lipase

  • Hepatotoxicity

  • Electrolyte Abnormalities

  • Hemorrhage

  • Fluid Retention

6.1 Clinical Trials Experience

(additions and/or revisions are underlined)

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

In the single-arm, open-label multicenter clinical trial, a total of 458 patients with Ph+ CML-CP and CML-AP resistant to or intolerant to at least one prior therapy including imatinib were treated (CML-CP=321; CML- AP=137) at the recommended dose of 400 mg twice daily.

In Pediatric Patients with Newly Diagnosed Ph+ CML-CP or Resistant or Intolerant Ph+ CML-CP

The data below reflect exposure to Tasigna from two studies in pediatric patients from 2 to less than 18 years of age with either newly diagnosed Ph+ CML-CP or imatinib/dasatinib resistant or intolerant Ph+ CML-CP treated at the recommended dose of 230 mg/m^2 twice daily (n = 69). The median time on treatment with Tasigna was 13.8 months (range: 0.7 to 30.9 months). The median actual dose intensity was 435.5 mg/m^2/day (range: 149 to 517 mg/m^2/day), and the median relative dose intensity was 94.7% (range: 32 to 112%). Forty patients (58.0%) had relative dose intensity superior to 90%.

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.

Growth Retardation in Pediatric Population

In a multicenter, open-label, single-arm study of 58 pediatric patients with newly diagnosed or resistant Ph+ CML-CP treated with Tasigna, with a median exposure of 33 months in each cohort, adverse reactions associated with growth and deceleration of growth in regard to height were reported in 3 patients (5%). The adverse reactions include growth retardation in 2 adolescent patients and growth hormone deficiency with body height below normal in the remaining patient (age category: child). Of the 58 pediatric patients, 12% (n = 7) experienced a decrease of two main height percentiles compared with baseline (percentile lines: 5th, 10th, 25th, 50th, 75th, 90th, and 95th). Close monitoring of growth in pediatric patients under Tasigna treatment is recommended.

8 Use in Specific Populations

8.4 Pediatric Use

(additions and/or revisions are underlined)

The safety and effectiveness of Tasigna have been established in pediatric patients greater than or equal to 1 year of age with newly diagnosed and resistant or intolerant Ph+ CML in chronic phase. There are no data for pediatric patients under 2 years of age. Use of Tasigna in pediatric patients 1 to less than 2 years of age is supported by efficacy in pediatric patients 2 to 6 years of age.

Use of Tasigna in pediatric patients 1 to less than 18 years of age is supported by evidence from two clinical trials. The 25 patients with newly diagnosed Ph+ CML-CP were in the following age groups: 6 children (age 2 to less than 12 years) and 19 adolescents (age 12 to less than 18 years). The 44 patients with resistant or intolerant Ph+ CML-CP included 18 children (age 2 to less than 12 years) and 26 adolescents (age 12 to less than 18 years). All pediatric patients received Tasigna treatment at a dose of 230 mg/m^2 twice daily, rounded to the nearest 50 mg dose (to a maximum single dose of 400 mg). No differences in efficacy or safety were observed between the different age subgroups in the two trials.

The frequency, type, and severity of adverse reactions observed were generally consistent with those observed in adults, with the exception of the laboratory abnormalities of hyperbilirubinemia (Grade 3/4: 13%) and transaminase elevation (AST Grade 3/4: 1%, ALT Grade 3/4: 9%), which were reported at a higher frequency in pediatric patients than in adults. For pediatric growth and development, growth retardation has been reported in pediatric patients with Ph+ CML-CP treated with Tasigna.

The long-term effects of prolonged treatment with Tasigna in pediatric patients are unknown.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

(additions and/or revisions are underlined)

What are the possible side effects of Tasigna? Tasigna may cause serious side effects, including:

  • Abnormal growth or development in children. Effects on growth and development have happened in children with chronic phase Ph+ CML during treatment with Tasigna. Some children and adolescents may have slower than normal growth during treatment with Tasigna.

PATIENT COUNSELING INFORMATION

(additions and/or revisions are underlined)

...

Effects on Growth and Development in Pediatric Patients

Inform pediatric patients and their caregivers of the possibility of developing growth abnormalities. Growth retardation has been reported in pediatric patients treated with Tasigna. Therefore, monitor growth and development in pediatric patients.

08/21/2018 (SUPPL-29)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

(Newly Added Subsection)

The following adverse reactions have been identified during post approval use of Tasigna. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and Lymphatic System Disorders: thrombotic microangiopathy

03/22/2018 (SUPPL-27)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.14 Effects on Growth and Development in Pediatric Patients

(new subsection added)

Adverse reactions associated with growth and development can occur in pediatric patients receiving BCR-ABL tyrosine kinase inhibitors. The long-term effect of prolonged treatment with BCR-ABL tyrosine kinase inhibitors on growth and development in pediatric patients are unknown. Therefore, monitor growth and development in pediatric patients receiving BCR-ABL tyrosine kinase inhibitor treatment.

5.6 Hepatotoxicity

(additions underlined)

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 than in adult patients. Monitor hepatic function tests monthly or as clinically indicated.

6 Adverse Reactions

6.1 Clinical Trials Experience

(additions underlined)

In Pediatric Patients with Newly Diagnosed Ph+ CML-CP or Resistant or Intolerant Ph+ CML-CP

The data below reflect exposure to Tasigna from two studies in pediatric patients from 2 to less than 18 years of age with either newly diagnosed Ph+ CML-CP or imatinib/dasatinib resistant or intolerant Ph+ CML-CP treated at the recommended dose of 230 mg/m2 twice daily (n=69). The median time on treatment with Tasigna was 13.8 months (range: 0.7 to 30.9 months). The median actual dose intensity was 435.5 mg/m2/day (range: 149 to 517 mg/m2/day), and the median relative dose intensity was 94.7% (range: 32 to 112%). Forty patients (58.0%) had relative dose intensity superior to 90%.

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.

7 Drug Interactions

7.1 Effect of Other Drugs on Tasigna

(subsection revised, additions underlined)

Strong CYP3A Inhibitors

Concomitant use with a strong CYP3A inhibitor increased nilotinib concentrations compared to Tasigna alone [see Clinical Pharmacology (12.3)], which may increase the risk of Tasigna toxicities. Avoid concomitant use of strong CYP3A inhibitors with Tasigna. If patients must be coadministered a strong CYP3A4 inhibitor, reduce Tasigna dose [see Dosage and Administration (2.8)].

Strong CYP3A Inducers

Concomitant use with a strong CYP3A inducer decreased nilotinib concentrations compared to Tasigna alone [see Clinical Pharmacology (12.3)], which may reduce Tasigna efficacy. Avoid concomitant use of strong CYP3A inducers with Tasigna.

Proton Pump Inhibitors (PPIs)

Concomitant use with a PPI decreased nilotinib concentrations compared to Tasigna alone [see Clinical Pharmacology (12.3)], which may reduce Tasigna efficacy. Avoid concomitant use of PPI with Tasigna. As an alternative to PPIs, use H2 blockers approximately 10 hours before or approximately 2 hours after the dose of Tasigna, or use antacids approximately 2 hours before or approximately 2 hours after the dose of Tasigna.

7.2 Drugs that Prolong the QT Interval

(additions underlined)

Avoid coadministration of Tasigna with agents that may prolong the QT interval such as anti-arrhythmic drugs

8 Use in Specific Populations

8.4 Pediatric Use

(subsection revised, additions underlined)

The safety and effectiveness of Tasigna have been established in pediatric patients greater than or equal to 1 year of age with newly diagnosed and resistant or intolerant Ph+ CML in chronic phase. There are no data for pediatric patients under 2 years of age. Use of Tasigna in pediatric patients 1 to less than 2 years of age is supported by efficacy in pediatric patients 2 to 6 years of age.

Use of Tasigna in pediatric patients 1 to less than 18 years of age is supported by evidence from two clinical trials. The 25 patients with newly diagnosed Ph+ CML-CP were in the following age groups: 6 children (age 2 to less than 12 years) and 19 adolescents (age 12 to less than 18 years). The 44 patients with resistant or intolerant Ph+ CML-CP included 18 children (age 2 to less than 12 years) and 26 adolescents (age 12 to less than 18 years). All pediatric 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). No differences in efficacy or safety were observed between the different age subgroups in the two trials.

The frequency, type, and severity of adverse reactions observed were generally consistent with those observed in adults, with the exception of the laboratory abnormalities of hyperbilirubinemia (Grade 3/4: 13%) and

transaminase elevation (AST Grade 3/4: 1%, ALT Grade 3/4: 9%), which were reported at a higher frequency in pediatric patients than in adults.

The long-term effects of prolonged treatment with Tasigna in pediatric patients are unknown.

8.7 Hepatic Impairment

(subsection revised, additions underlined)

Reduce the Tasigna dosage in patients with hepatic impairment and monitor the QT interval closely in these patients.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Medication Guide

(additions and revisions, please refer to label)


PATIENT COUNSELING INFORMATION

(additions underlined)

Hepatotoxicity

Advise patients that Tasigna can increase the risk of hepatotoxicity and that patients with previous history of liver diseases may be at risk. Advise patients to seek immediate medical attention if any symptoms suggestive of hepatotoxicity occur, such as stomach pain, yellow skin and eyes, and dark-colored urine.

Effects on Growth and Development in Pediatric Patients

Inform pediatric patients and their caregivers of the possibility of developing growth abnormalities. Therefore, monitor growth and development in pediatric patients.

12/22/2017 (SUPPL-26)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.12 Hemorrhage

(Additions and/or revisions are underlined)

Serious hemorrhagic events, including fatal events, have occurred in patients with CML treated with Tasigna. In a randomized trial in patients with newly diagnosed Ph+ CML in chronic phase comparing Tasigna and imatinib, Grade 3 or 4 hemorrhage occurred in 1.1% of patients in the Tasigna 300 mg twice daily arm, in 1.8% patients in the Tasigna 400 mg twice daily arm, and 0.4% of patients in the imatinib arm. GI hemorrhage occurred in 2.9% and 5.1% of patients in the Tasigna 300 mg twice daily and 400 mg twice daily arms and in 1.4% of patients in the imatinib arm, respectively. Grade 3 or 4 events occurred in 0.7% and 1.4% of patients in the Tasigna 300 mg twice daily and 400 mg twice daily arms, respectively, and in no patients in the imatinib arm. Monitor for signs and symptoms of bleeding and medically manage as needed.

5.17 Embryo-Fetal Toxicity

(Additions and/or revisions are underlined)

Based on findings from animal studies and its mechanism of action, Tasigna can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of nilotinib to pregnant rats and rabbits during organogenesis caused adverse developmental outcomes including embryo-fetal lethality/fetal effects (small renal papilla, fetal edema, and skeletal variations) in rats and increased resorptions of fetuses and fetal skeletal variations in rabbits at maternal AUCs approximately 2 and 0.5 times, respectively, the AUC in patients receiving the recommended dose. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for at least 14 days after the last dose.

5.18 Monitoring of BCR-ABL Transcript Levels

(Newly added subsection)

Monitoring of BCR-ABL Transcript Levels in Patients Who Discontinued Tasigna

Monitor BCR-ABL transcript levels in patients eligible for treatment discontinuation using an FDA authorized test validated to measure molecular response levels with a sensitivity of at least MR4.5 (BCR-ABL/ABL less than or equal to 0.0032% IS). In patients who discontinue Tasigna therapy, assess BCR-ABL transcript levels monthly for one year, then every 6 weeks for the second year, and every 12 weeks thereafter during treatment discontinuation.

Newly diagnosed patients must reinitiate Tasigna therapy within 4 weeks of a loss of Major Molecular Response (MMR, corresponding to MR3.0 or = BCR-ABL/ABL less than or equal to 0.1%IS).

Patients resistant or intolerant to prior treatment which included imatinib must reinitiate Tasigna therapy within 4 weeks of a loss of MMR or confirmed loss of MR4.0 (two consecutive measures separated by at least 4 weeks showing loss of MR4.0, corresponding to = BCR-ABL/ABL less than or equal to 0.01%IS).

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

Monitoring of BCR-ABL Transcript Levels in Patients who have Reinitiated Therapy after Loss of Molecular Response

Monitor CBC and BCR-ABL transcripts in patients who re-initiate treatment with Tasigna due to loss of molecular response quantitation every 4 weeks until a major molecular response is re-established, then every 12 weeks.

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions are underlined)

Treatment discontinuation in Ph+ CML-CP patients who have achieved a sustained molecular response (MR 4.5)

In eligible patients who discontinued Tasigna therapy after attaining a sustained molecular response (MR4.5), musculoskeletal symptoms (e.g. myalgia, pain in extremity, arthralgia, bone pain, spinal pain, or musculoskeletal pain), were reported more frequently than before treatment discontinuation in the first year, as noted in Table 8. The rate of new musculoskeletal symptoms generally decreased in the second year after treatment discontinuation. In the newly diagnosed population in whom musculoskeletal symptoms occurred at any time during the TFR phase, 23/53 (43.4%) had not resolved by the TFR end date or data cut-off date. In the population previously treated with imatinib in whom musculoskeletal events occurred at any time during the TFR phase, 32/57 (56.1%) had not resolved by the data cut-off date.

The rate of musculoskeletal symptoms decreased in patients who entered the nilotinib treatment re-initiation (NTRI) phase, at 11/88 (12.5%) in the newly diagnosed population and 14/56 (25%) in the population previously treated with imatinib. Other adverse reactions observed in the Tasigna re-treatment phase were similar to those observed Tasigna use in patients with newly diagnosed Ph+ CML-CP and resistant or intolerant Ph+ CML-CP and CML-AP.

7 Drug Interactions

7.2 Drugs that Inhibit or Induce Cytochrome P450 3A4 Enzymes

(Additions and/or revisions are underlined)

Nilotinib undergoes metabolism by CYP3A4, and concomitant administration of strong inhibitors or inducers of CYP3A4 can increase or decrease nilotinib concentrations significantly. Avoid the administration of Tasigna with agents that are strong CYP3A4 inhibitors. 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. Therefore, in patients receiving Tasigna, select alternative therapeutic agents with less potential for CYP3A4 induction for concomitant use.

8 Use in Specific Populations

8.1 Pregnancy

(Pregnancy and Lactation Labeling Rule (PLLR) conversion; Additions and/or revisions are underlined)

Risk Summary

Based on findings from animal studies and the mechanism of action, Tasigna can cause fetal harm when administered to a pregnant woman.

There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies, administration of nilotinib to pregnant rats and rabbits during organogenesis caused adverse developmental outcomes including embryo-fetal lethality, fetal effects, and fetal variations in rats and rabbits at maternal exposures (AUC) approximately 2 and 0.5 times, respectively, the exposures in patients at the recommended dose. Advise pregnant women of the potential risk to a fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies are 2-4% and 15-20%, respectively.

Data

Animal Data

In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses of nilotinib up to 100 mg/kg/day and 300 mg/kg/day, respectively, during the period of organogenesis.

In rats, oral administration of nilotinib produced embryo-lethality/fetal effects at doses greater than or equal to 30 mg/kg/day. At greater than or equal to 30 mg/kg/day skeletal variations of incomplete ossification of the frontals and misshapen sternebra were noted, and there was an increased incidence of small renal papilla and fetal edema. At 100 mg/kg/day, nilotinib was associated with maternal toxicity (decreased gestation weight, gravid uterine weight, net weight gain, and food consumption) and resulted in a single incidence of cleft palate and two incidences of pale skin were noted in the fetuses. A single incidence of dilated ureters was noted in a fetus also displaying small renal papilla at 100 mg/kg/day. Additional variations of forepaw and hindpaw phalanx unossified, fused sternebra, bipartite sternebra ossification, and incomplete ossification of the cervical vertebra were noted at 100 mg/kg/day.

In rabbits, oral administration of nilotinib resulted in the early sacrifice of two females, maternal toxicity and increased resorption of fetuses at 300 mg/kg/day. Fetal skeletal variations (incomplete ossification of the hyoid, bent hyoid, supernumerary short detached ribs and the presence of additional ossification sites near the nasals, frontals and in the sternebral column) were also increased at this dose in the presence of maternal toxicity.

Slight maternal toxicity was evident at 100 mg/kg/day but there were no reproductive or embryo-fetal effects at this dose.

At 30 mg/kg/day in rats and 300 mg/kg/day in rabbits, the maternal systemic exposure (AUC) were 72700 ng*hr/mL and 17100 ng*hr/mL respectively, representing approximately 2 and 0.5 times the exposure in humans at the highest recommended dose 400 mg twice daily.

When pregnant rats were dosed with nilotinib during organogenesis and through lactation, the adverse effects included a longer gestational period, lower pup body weights until weaning and decreased fertility indices in the pups when they reached maturity, all at a maternal dose of 60 mg/kg (i.e., 360 mg/m2, approximately 0.7 times the clinical dose of 400 mg twice daily based on body surface area). At doses up to 20 mg/kg (i.e., 120 mg/m2, approximately 0.25 times the clinical dose of 400 mg twice daily based on body surface area) no adverse effects were seen in the maternal animals or the pups.

8.2 Lactation

(Pregnancy and Lactation Labeling Rule (PLLR) conversion; Additions and/or revisions are underlined)

Risk Summary

No data are available regarding the presence of nilotinib or its metabolites in human milk or its effects on a breastfed child or on milk production. However, nilotinib is present in the milk of lactating rats. Because of the potential for serious adverse reactions in a nursing child, advise lactating women not to breastfeed during treatment with Tasigna and for at least 14 days after the last dose.

Animal Data

After a single 20 mg/kg of [14C] nilotinib dose to lactating rats, the transfer of parent drug and its metabolites into milk was observed. The overall milk-to-plasma exposure ratio of total radioactivity was approximately 2, based on the AUC0-24h or AUC0-infinity values. No rat metabolites of nilotinib were detected that were unique to milk.

8.3 Females and Males of Reproductive Potential

(Pregnancy and Lactation Labeling Rule (PLLR) conversion; Additions and/or revisions are underlined)

Pregnancy

Based on animal studies, Tasigna can cause fetal harm when administered to a pregnant woman. Females of reproductive potential should have a pregnancy test prior to starting treatment with Tasigna.

Contraception

Females

Based on animal studies, Tasigna can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with Tasigna and for at least 14 days after the last dose.

Infertility

The risk of infertility in females or males of reproductive potential has not been studied in humans. In studies in rats and rabbits, the fertility in males and females was not affected.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Hemorrhage

Advise patients that serious hemorrhagic events, including fatal events, have occurred in patients with CML treated with Tasigna.  Advise patients to seek immediate medical attention if symptoms suggestive of hemorrhage occur, such as uncontrolled bleeding, changes in eyesight, unconsciousness, or sudden headache or sudden confusion in surroundings.

Treatment Free Remission (TFR)

Advise patients that frequent monitoring is required to detect possible loss of remission if TFR is attempted. Advise patients that musculoskeletal symptoms such as muscle pain, pain in extremity, joint pain, bone pain, or spinal pain, may occur more frequently than before treatment discontinuation .

Embryo-Fetal Toxicity

Advise females to inform their healthcare provider if they are pregnant or become pregnant. Inform female patients of the risk to a fetus and potential loss of the pregnancy.

Advise females of reproductive potential to use effective contraception during treatment and for at least 14 days after receiving the last dose of Tasigna.

Lactation

Advise lactating women not to breastfeed during treatment with Tasigna and for at least 14 days after the last dose.

Medication Guide TASIGNA (ta-sig-na) (nilotinib) capsules

(Extensive changes; please refer to labeling)

02/21/2017 (SUPPL-24)

Approved Drug Label (PDF)

4 Contraindications

(Additions and/or revisions are underlined)

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

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

A Medication Guide is required for distribution with Tasigna. The complete text of the Medication Guide is reprinted at the end of this document.

Myelosuppression

Advise patients that treatment with Tasigna can cause serious thrombocytopenia, neutropenia, and anemia. Advise patients to seek immediate medical attention if symptoms suggestive of low blood counts occur, such as fever, chills or other signs of infection, unexplained bleeding or bruising, or unexplained weakness or shortness of breath.

QT Prolongation

Advise patients that Tasigna can cause possibly life-threatening, abnormal heart beat. Advise patients to seek immediate medical attention if symptoms of abnormal heart beat occur, such as feeling lightheaded, faint or experiencing an irregular heartbeat.

Cardiac and Arterial Vascular Occlusive Events

…Advise patients to seek immediate medical attention if any symptoms suggestive of a cardiovascular event occur, such as chest or leg pain, numbness or weakness, or problems walking or speaking occur suddenly.

Pancreatitis and Elevated Serum Lipase

Advise patients that Tasigna can increase the risk of pancreatitis and that patients with a previous history of pancreatitis may be at greater risk. Advise patients to seek immediate medical attention if symptoms suggestive of pancreatitis occur, such as sudden stomach area pain with accompanying nausea and vomiting.

Tumor Lysis Syndrome

Advise patients that Tasigna can cause tumor lysis syndrome and to seek immediate medical attention if any symptoms suggestive of tumor lysis syndrome occur such as an abnormal heartbeat or less urine production.

Fluid Retention

Advise patients that Tasigna can cause fluid retention and to seek immediate medical attention if any symptoms suggestive of fluid retention such as shortness of breath, rapid weight gain, or swelling occur.

Drug Interactions

Advise patients that Tasigna and certain other medicines…

Nursing Mothers

It is not known whether nilotinib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Tasigna, decide whether to advise discontinuing nursing or discontinuing the drug, taking into account the importance of the drug to the mother.

Medication Guide

(Additions and/or revisions are underlined)

What is Tasigna?

It is not known if Tasigna is safe and effective in children.

 

General information about the safe and effective use of Tasigna.

…Do not give Tasigna to other people, even if they have the same symptoms that you have…

 

For more information, go to www.Tasigna.com or call 1-866-411-8274.

09/27/2016 (SUPPL-23)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Additional Data from Clinical Trials (addition underlined)

Infections and Infestations: Common: folliculitis. Uncommon: pneumonia, bronchitis, urinary tract infection, candidiasis (including oral candidiasis). Unknown frequency: hepatitis B virus reactivation, sepsis, subcutaneous abscess, anal abscess, furuncle, tinea pedis.