Tasigna Prescribing Information
- 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)].
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 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 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), 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), 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)].
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.”
Pregnancy
Risk Summary
Based on findings from animal studies and the mechanism of action, Tasigna can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. 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 (see Data). 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% to 4% and 15% to 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 ≥ 30 mg/kg/day. At ≥ 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.
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 AUC0-24h or AUC0-INF values. No rat metabolites of nilotinib were detected that were unique to milk.
Females and Males of Reproductive Potential
Based on animal studies, Tasigna can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].
Pregnancy Testing
Females of reproductive potential should have a pregnancy test prior to starting treatment with Tasigna.
Contraception
Females
Advise females of reproductive potential to use effective contraception during treatment with Tasigna and for 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 [see Nonclinical Toxicology (13.1)].
Pediatric Use
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.
Geriatric Use
In the clinical trials of Tasigna (patients with newly diagnosed Ph+ CML-CP and resistant or intolerant Ph+ CML-CP and CML-AP), approximately 12% and 30% of patients were 65 years or over, respectively.
- Patients with newly diagnosed Ph+ CML-CP: There was no difference in major molecular response between patients aged less than 65 years and those greater than or equal to 65 years.
- Patients with resistant or intolerant CML-CP: There was no difference in major cytogenetic response rate between patients aged less than 65 years and those greater than or equal to 65 years.
- Patients with resistant or intolerant CML-AP: The hematologic response rate was 44% in patients less than 65 years of age and 29% in patients greater than or equal to 65 years.
No major differences for safety were observed in patients greater than or equal to 65 years of age as compared to patients less than 65 years.
Cardiac Disorders
In the clinical trials, patients with a history of uncontrolled or significant cardiovascular disease, including recent myocardial infarction, congestive heart failure, unstable angina or clinically significant bradycardia, were excluded. Caution should be exercised in patients with relevant cardiac disorders [see Boxed Warning, Warnings and Precautions (5.2)].
Hepatic Impairment
Reduce the Tasigna dosage in patients with hepatic impairment and monitor the QT interval closely in these patients [see Dosage and Administration (2.7), Clinical Pharmacology (12.3)].
Tasigna is contraindicated in patients with hypokalemia, hypomagnesemia, or long QT syndrome [see Boxed Warning].