Drug Detail:Tasigna (Nilotinib [ nye-loe-ti-nib ])
Generic Name: NILOTINIB 200mg
Dosage Form: capsule
Drug Class: BCR-ABL tyrosine kinase inhibitors
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/m2 orally 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.
| 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 |
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.
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.
Dosage Modification for QT Interval Prolongation
See Table 2 for dose adjustments for QT interval prolongation [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.2)].
| Abbreviation: ECG, electrocardiogram. | |
| Degree of QTc Prolongation | Dosage Adjustment |
| ECGs with a QTc greater than 480 msec |
1. Withhold Tasigna, and perform an analysis of serum potassium and magnesium, and if below lower limit of normal, correct with supplements to within normal limits. Concomitant medication usage must be reviewed. 2. Resume within 2 weeks at prior dose if QTcF returns to less than 450 msec and to within 20 msec of baseline. 3. If QTcF is between 450 msec and 480 msec after 2 weeks, reduce the dose to 400 mg once daily in adults and 230 mg/m2 once daily in pediatric patients. 4. Discontinue Tasigna if, following dose-reduction to 400 mg once daily in adults and 230 mg/m2 once daily in pediatric patients, QTcF returns to greater than 480 msec. 5. An ECG should be repeated approximately 7 days after any dose adjustment. |
Dosage Modifications for Myelosuppression
Withhold or reduce Tasigna dosage for hematological toxicities (neutropenia, thrombocytopenia) that are not related to underlying leukemia (Table 3) [see Warnings and Precautions (5.1)].
| Abbreviations: ANC, absolute neutrophil count; Ph+ CML, Philadelphia chromosome positive chronic myeloid leukemia. | ||
| Diagnosis | Degree of Myelosuppression |
Dosage Adjustment |
Adult patients with:
|
ANC less than 1.0 x 109/L and/or platelet counts less than 50 x 109/L |
1. Stop Tasigna, and monitor blood counts. 2. Resume within 2 weeks at prior dose if ANC greater than 1.0 x 109/L and platelets greater than 50 x 109/L. 3. If blood counts remain low for greater than 2 weeks, reduce the dose to 400 mg once daily. |
Pediatric patients with:
|
ANC less than 1.0 x 109/L and/or platelet counts less than 50 x 109/L |
1. Stop Tasigna and monitor blood counts. 2. Resume within 2 weeks at prior dose if ANC greater than 1.5 x 109/L and/or platelets greater than 75 x 109/L. 3. If blood counts remain low for greater than 2 weeks, a dose reduction to 230 mg/m2 once daily may be required. 4. If event occurs after dose reduction, consider discontinuing treatment. |
Dosage Modifications for Selected Non-Hematologic Laboratory Abnormalities and Other Toxicities
See Table 4 for dosage adjustments for elevations of lipase, amylase, bilirubin, and/or hepatic transaminases [see Warnings and Precautions (5.5, 5.6) and Adverse Reactions (6.1)].
| Degree of Non-Hematologic Laboratory Abnormality | Dosage Adjustment |
| Elevated serum lipase or amylase greater than or equal to Grade 3 | Adult patients: 1. Withhold Tasigna, and monitor serum lipase or amylase. 2. Resume treatment at 400 mg once daily if serum lipase or amylase returns to less than or equal to Grade 1. |
| Pediatric patients: 1. Interrupt Tasigna until the event returns to less than or equal to Grade 1. 2. Resume treatment at 230 mg/m2 once daily if prior dose was 230 mg/m2 twice daily; discontinue treatment if prior dose was 230 mg/m2 once daily. |
|
| Elevated bilirubin greater than or equal to Grade 3 in adult patients and greater than or equal to Grade 2 in pediatric patients | Adult patients: 1. Withhold Tasigna, and monitor bilirubin. 2. Resume treatment at 400 mg once daily if bilirubin returns to less than or equal to Grade 1. |
| Pediatric patients: 1. Interrupt Tasigna until the event returns to less than or equal to Grade 1. 2. Resume treatment at 230 mg/m2 once daily if prior dose was 230 mg/m2 twice daily; discontinue treatment if prior dose was 230 mg/m2 once daily, and recovery to less than or equal to Grade 1 takes longer than 28 days. |
|
| Elevated hepatic transaminases greater than or equal to Grade 3 | Adult patients: 1. Withhold Tasigna, and monitor hepatic transaminases. 2. Resume treatment at 400 mg once daily if hepatic transaminases returns to less than or equal to Grade 1. |
| Pediatric patients: 1. Interrupt Tasigna until the event returns to less than or equal to Grade 1. 2. Resume treatment at 230 mg/m2 once daily if prior dose was 230 mg/m2 twice daily; discontinue treatment if prior dose was 230 mg/m2 once daily, and recovery to less than or equal to Grade 1 takes longer than 28 days. |
If clinically significant moderate or severe non-hematologic toxicity develops (including medically severe fluid retention), see Table 5 for dosage adjustments [see Adverse Reactions (6.1)].
| Abbreviations: CML-AP, chronic myeloid leukemia-accelerated phase; CML-CP, chronic myeloid leukemia-chronic phase; Ph+, Philadelphia chromosome positive. | |
| Degree of “Other Non-Hematologic Toxicity” | Dosage Adjustment |
| Other clinically moderate or severe non-hematologic toxicity | Adult patients: 1. Withhold Tasigna until toxicity has resolved. 2. Resume treatment at 400 mg once daily if previous dose was 300 mg twice daily in adult patients newly diagnosed with CML-CP or 400 mg twice daily in adult patients with resistant or intolerant CML-CP and CML-AP. 3. Discontinue treatment if the prior dose was 400 mg once daily in adult patients. 4. If clinically appropriate, consider re-escalation of the dose to 300 mg (newly diagnosed Ph+ CML-CP) or 400 mg (resistant or intolerant Ph+ CML-CP and CML-AP) twice daily. |
| Pediatric patients: 1. Interrupt Tasigna until toxicity has resolved. 2. Resume treatment at 230 mg/m2 once daily if previous dose was 230 mg/m2 twice daily; discontinue treatment if prior dose was 230 mg/m2 once daily. 3. If clinically appropriate, consider re-escalation of the dose to 230 mg/m2 twice daily. |
|
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)]:
| 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. |
Dosage Modification With Concomitant Strong CYP3A4 Inhibitors
Avoid the concomitant use of strong CYP3A4 inhibitors. Should treatment with any of these agents be required, interrupt therapy with Tasigna. If patients must be coadministered a strong CYP3A4 inhibitor, reduce dosage to 300 mg once daily in patients with resistant or intolerant Ph+ CML or to 200 mg once daily in patients with newly diagnosed Ph+ CML-CP. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inhibitors. If the strong inhibitor is discontinued, allow a washout period before adjusting Tasigna dose upward to the indicated dose. For patients who cannot avoid use of strong CYP3A4 inhibitors, monitor closely for prolongation of the QT interval [see Boxed Warning, Warnings and Precautions (5.2), Drug Interactions (7.1, 7.2), Clinical Pharmacology (12.3)].
