Tasigna - Nilotinib capsule (Nilotinib)

• 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)]

  .

Tasigna is a kinase inhibitor 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. (
  1.1
       
  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 chronic phase (CP) and accelerated phase (AP) Ph+ CML resistant to or intolerant to prior therapy that included imatinib. (
  1.2
       
  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 greater than or equal to 1 year of age with Ph+ CML-CP and CML-AP resistant or intolerant to prior tyrosine-kinase inhibitor (TKI) therapy. (
  1.3
       
  Pediatric Patients With Resistant or Intolerant Ph+ CML-CP and CML-AP

  Tasigna is indicated for the treatment of pediatric patients greater than or equal to 1 year of age with chronic phase and accelerated phase Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) with resistance or intolerance to prior tyrosine-kinase inhibitor (TKI) therapy.
  )
  

• 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. (
  2.1
  Recommended Dosage

  Dose Tasigna twice daily at approximately 12-hour intervals on an empty stomach. No food should be consumed for at least 2 hours before the dose is taken and for at least 1 hour after the dose is taken. Advise patients to swallow the capsules whole with water

  [see Boxed Warning, Clinical Pharmacology (12.3)].

  For patients who are unable to swallow capsules, the contents of each capsule may be dispersed in 1 teaspoon of applesauce (puréed apple). The mixture should be taken immediately (within 15 minutes) and should not be stored for future use

  [see Clinical Pharmacology (12.3)]

  .

  Tasigna may be given in combination with hematopoietic growth factors, such as erythropoietin or G-CSF if clinically indicated. Tasigna may be given with hydroxyurea or anagrelide if clinically indicated.

  Dosage in Adult Patients with Newly Diagnosed Ph+ CML-CP

  The recommended dosage of Tasigna is 300 mg orally twice daily.

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

  The recommended dosage of Tasigna is 400 mg orally twice daily.

  Dosage in Pediatric Patients with Newly Diagnosed Ph+ CML-CP or Resistant or Intolerant Ph+ CML-CP and CML-AP

  The recommended dosage of Tasigna for pediatric patients is 230 mg/m²orally twice daily, rounded to the nearest 50 mg dose (to a maximum single dose of 400 mg) (see Table 1). If needed, attain the desired dose by combining different strengths of Tasigna capsules. Continue treatment as long as clinical benefit is observed or until unacceptable toxicity occurs.

  Table 1: Pediatric Dosing of Tasigna (230 mg/m²Twice Daily, Maximum Single Dose of 400 mg)

  Body surface area	Single dose	Total daily dose
  Up to 0.32 m2	50 mg	100 mg
  0.33 – 0.54 m2	100 mg	200 mg
  0.55 – 0.76 m2	150 mg	300 mg
  0.77 – 0.97 m2	200 mg	400 mg
  0.98 – 1.19 m2	250 mg	500 mg
  1.20 – 1.41 m2	300 mg	600 mg
  1.42 – 1.63 m2	350 mg	700 mg
  ≥ 1.64 m2	400 mg	800 mg
  )
  
• Recommended Pediatric Dose: Newly Diagnosed Ph+ CML-CP or Ph+ CML-CP and CML-AP 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). (
  2.1
  Recommended Dosage

  Dose Tasigna twice daily at approximately 12-hour intervals on an empty stomach. No food should be consumed for at least 2 hours before the dose is taken and for at least 1 hour after the dose is taken. Advise patients to swallow the capsules whole with water

  [see Boxed Warning, Clinical Pharmacology (12.3)].

  For patients who are unable to swallow capsules, the contents of each capsule may be dispersed in 1 teaspoon of applesauce (puréed apple). The mixture should be taken immediately (within 15 minutes) and should not be stored for future use

  [see Clinical Pharmacology (12.3)]

  .

  Tasigna may be given in combination with hematopoietic growth factors, such as erythropoietin or G-CSF if clinically indicated. Tasigna may be given with hydroxyurea or anagrelide if clinically indicated.

  Dosage in Adult Patients with Newly Diagnosed Ph+ CML-CP

  The recommended dosage of Tasigna is 300 mg orally twice daily.

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

  The recommended dosage of Tasigna is 400 mg orally twice daily.

  Dosage in Pediatric Patients with Newly Diagnosed Ph+ CML-CP or Resistant or Intolerant Ph+ CML-CP and CML-AP

  The recommended dosage of Tasigna for pediatric patients is 230 mg/m²orally twice daily, rounded to the nearest 50 mg dose (to a maximum single dose of 400 mg) (see Table 1). If needed, attain the desired dose by combining different strengths of Tasigna capsules. Continue treatment as long as clinical benefit is observed or until unacceptable toxicity occurs.

  Table 1: Pediatric Dosing of Tasigna (230 mg/m²Twice Daily, Maximum Single Dose of 400 mg)

  Body surface area	Single dose	Total daily dose
  Up to 0.32 m2	50 mg	100 mg
  0.33 – 0.54 m2	100 mg	200 mg
  0.55 – 0.76 m2	150 mg	300 mg
  0.77 – 0.97 m2	200 mg	400 mg
  0.98 – 1.19 m2	250 mg	500 mg
  1.20 – 1.41 m2	300 mg	600 mg
  1.42 – 1.63 m2	350 mg	700 mg
  ≥ 1.64 m2	400 mg	800 mg
  )
  
• See Dosage and Administration for full dosing instructions and dose-reduction instructions for toxicity. (
  2.1
  Recommended Dosage

  Dose Tasigna twice daily at approximately 12-hour intervals on an empty stomach. No food should be consumed for at least 2 hours before the dose is taken and for at least 1 hour after the dose is taken. Advise patients to swallow the capsules whole with water

  [see Boxed Warning, Clinical Pharmacology (12.3)].

  For patients who are unable to swallow capsules, the contents of each capsule may be dispersed in 1 teaspoon of applesauce (puréed apple). The mixture should be taken immediately (within 15 minutes) and should not be stored for future use

  [see Clinical Pharmacology (12.3)]

  .

  Tasigna may be given in combination with hematopoietic growth factors, such as erythropoietin or G-CSF if clinically indicated. Tasigna may be given with hydroxyurea or anagrelide if clinically indicated.

  Dosage in Adult Patients with Newly Diagnosed Ph+ CML-CP

  The recommended dosage of Tasigna is 300 mg orally twice daily.

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

  The recommended dosage of Tasigna is 400 mg orally twice daily.

  Dosage in Pediatric Patients with Newly Diagnosed Ph+ CML-CP or Resistant or Intolerant Ph+ CML-CP and CML-AP

  The recommended dosage of Tasigna for pediatric patients is 230 mg/m²orally twice daily, rounded to the nearest 50 mg dose (to a maximum single dose of 400 mg) (see Table 1). If needed, attain the desired dose by combining different strengths of Tasigna capsules. Continue treatment as long as clinical benefit is observed or until unacceptable toxicity occurs.

  Table 1: Pediatric Dosing of Tasigna (230 mg/m²Twice Daily, Maximum Single Dose of 400 mg)

  Body surface area	Single dose	Total daily dose
  Up to 0.32 m2	50 mg	100 mg
  0.33 – 0.54 m2	100 mg	200 mg
  0.55 – 0.76 m2	150 mg	300 mg
  0.77 – 0.97 m2	200 mg	400 mg
  0.98 – 1.19 m2	250 mg	500 mg
  1.20 – 1.41 m2	300 mg	600 mg
  1.42 – 1.63 m2	350 mg	700 mg
  ≥ 1.64 m2	400 mg	800 mg
  )
• Reduce starting dose in patients with baseline hepatic impairment. (
  2.7
  Dosage Modification for Hepatic Impairment

  If possible, consider alternative therapies. If Tasigna must be administered to patients with hepatic impairment, consider the following dose reduction

  [see Use in Specific Populations (8.7)]

  :

  Table 6: Dose Adjustments for Adult Patients With Hepatic Impairment

  Diagnosis	Degree of hepatic impairment	Dosage adjustment
  Newly diagnosed Ph+ CML in chronic phase	Mild (Child-Pugh A), Moderate (Child-Pugh B), or Severe (Child-Pugh C)	Reduce dosage to 200 mg twice daily. Increase dosage to 300 mg twice daily based on tolerability.
  Resistant or intolerant Ph+ CML in chronic phase or accelerated phase	Mild or Moderate	Reduce dosage to 300 mg twice daily. Increase dosage to 400 mg twice daily based on tolerability.
  	Severe	Reduce dosage to 200 mg twice daily. Increase dosage to 300 mg twice daily and then to 400 mg twice daily based on tolerability.
  )
  
• 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. (
  2.2
  Discontinuation of Treatment After a Sustained Molecular Response (MR4.5) on Tasigna

  Patient Selection

  Eligibility for Discontinuation of Treatment

  Ph+ CML-CP patients with typical BCR-ABL transcripts, who have been taking Tasigna for a minimum of 3 years and have achieved a sustained molecular response (MR4.5, corresponding to = BCR-ABL/ABL ≤ 0.0032% IS), may be eligible for treatment discontinuation

  [see Clinical Studies (14.3, 14.4)]

  . Information on FDA authorized tests for the detection and quantitation of BCR-ABL transcripts to determine eligibility for treatment discontinuation is available at http://www.fda.gov/CompanionDiagnostics.

  Patients with typical BCR-ABL transcripts (e13a2/b2a2 or e14a2/b3a2), who achieve the sustained MR4.5 criteria, are eligible for discontinuation of Tasigna. Patients must continue to be monitored for possible loss of molecular remission after treatment discontinuation. Use the same FDA-authorized test to consistently monitor molecular response levels while on and off treatment.

  Consider discontinuation in patients with newly diagnosed Ph+ CML-CP who have:

  • been treated with Tasigna for at least 3 years
  • maintained a molecular response of at least MR4.0 (corresponding to = BCR-ABL/ABL ≤ 0.01% IS) for one year prior to discontinuation of therapy
  • achieved an MR4.5 for the last assessment taken immediately prior to discontinuation of therapy
  • been confirmed to express the typical BCR-ABL transcripts (e13a2/b2a2 or e14a2/b3a2)
  • no history of accelerated phase or blast crisis
  • no history of prior attempts of treatment-free remission discontinuation that resulted in relapse.

  Consider discontinuation in patients with Ph+ CML-CP that are resistant or intolerant to imatinib who have achieved a sustained molecular response (MR4.5) on Tasigna who have:

  • been treated with Tasigna for a minimum of 3 years
  • been treated with imatinib only prior to treatment with Tasigna
  • achieved a molecular response of MR4.5 (corresponding to = BCR-ABL/ABL ≤ 0.0032% IS)
  • sustained an MR4.5 for a minimum of one year immediately prior to discontinuation of therapy
  • been confirmed to express the typical BCR-ABL transcripts (e13a2/b2a2 or e14a2/b3a2)
  • no history of accelerated phase or blast crisis
  • no history of prior attempts of treatment-free remission discontinuation that resulted in relapse.

  Monitor BCR-ABL transcript levels and complete blood count (CBC) with differential in patients who have discontinued Tasigna therapy monthly for one year, then every 6 weeks for the second year, and every 12 weeks thereafter

  [see Warnings and Precautions (5.16)].

  Upon the loss of MR4.0 (corresponding to = BCR-ABL/ABL ≤ 0.01% IS) during the treatment-free phase, monitor BCR-ABL transcript levels every 2 weeks until BCR-ABL levels remain lower than major molecular response [(MMR), corresponding to MR3.0 or = BCR-ABL/ABL ≤ 0.1% IS] for 4 consecutive measurements. The patient can then proceed to the original monitoring schedule.
  ,
  2.3
  Reinitiation of Treatment in Patients Who Lose Molecular Response After Discontinuation of Therapy With Tasigna

  • Newly diagnosed patients who lose MMR must reinitiate treatment within 4 weeks at the dose level prior to discontinuation of therapy
    [see Warnings and Precautions (5.16)]
    . Patients who reinitiate Tasigna therapy should have their BCR-ABL transcript levels monitored monthly until major molecular response is re-established and every 12 weeks thereafter.
  • Patients resistant or intolerant to prior treatment that included imatinib with confirmed loss of MR4.0 (2 consecutive measures separated by at least 4 weeks showing loss of MR4.0) or loss of MMR must reinitiate treatment within 4 weeks at the dose level prior to discontinuation of therapy
    [see Warnings and Precautions (5.16)]
    . Patients who reinitiate Tasigna therapy should have their BCR-ABL transcript levels monitored monthly until previous major molecular response or MR4.0 is re-established and every 12 weeks thereafter.
  ,
  5.16
  Monitoring of BCR-ABL Transcript Levels

  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 ≤ 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

  [see Clinical Studies (14.3,14.4), Dosage and Administration (2.2)]

  .

  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 ≤ 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 ≤ 0.01% IS).

  For patients who fail to achieve MMR after three months of treatment reinitiation, 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 reinitiate 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.
  )
  

Capsules:

• 50 mg red opaque cap and light-yellow opaque body hard gelatin capsules with black radial imprint “NVR/ABL.”
• 150 mg red opaque hard gelatin capsules with black axial imprint “NVR/BCR.”
• 200 mg light-yellow opaque hard gelatin capsules with a red axial imprint “NVR/TKI.”

• Lactation:
  Advise women not to breastfeed. (
  8.2
       
  Lactation

  Risk Summary

  There are no data on 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 breastfed child, advise women not to breastfeed during treatment with Tasigna and for 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 AUC_0-24hor AUC_0-INFvalues. No rat metabolites of nilotinib were detected that were unique to milk.
  )