TASIGNA

Nilotinib, also known as AMN107, is a tyrosine kinase inhibitor under investigation as a possible treatment for chronic myelogenous leukemia (CML).

I clinical trial in 2006 showed that this drug was relatively safe and offered significant therapeutic benefits in cases of CML which were found to be resistant to treatment with imatinib (Gleevec), another tyrosine kinase inhibitor used as a first-line treatment for CML.

For the potential treatment of various leukemias, including chronic myeloid leukemia (CML).

Nilotinib is a transduction inhibitor that targets BCR-ABL, c-kit and PDGF, for the potential treatment of various leukemias, including chronic myeloid leukemia (CML).

Tyrosine-protein kinase

ABL1 Inhibitor Mast/stem cell growth factor receptor Kit Inhibitor Platelet-derived growth factor receptor Inhibitor + 2 more targets.

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Overdose with nilotinib has been reported, where an unspecified number of nilotinib capsules were ingested in combination with alcohol and other drugs.

Events included neutropenia, vomiting, and drowsiness.

In the event of overdose, observe the patient and provide appropriate supportive treatment.

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

Newly diagnosed

Ph+ CML-CP: 300 mg orally twice daily.

Resistant or intolerant

Ph+ CML-CP and CML-AP: 400 mg orally twice daily.

Newly Diagnosed Ph+ CML-CP or Ph+ CML-CP resistant or intolerant to prior TKI therapy: 230 mg/m 2 orally twice daily, rounded to the nearest 50 mg dose (to a maximum single dose of 400 mg).

See Dosage and

Administration for full dosing instructions and dose-reduction instructions for toxicity.

Reduce starting dose in patients with baseline hepatic impairment.

Eligible newly diagnosed adult patients with

Ph+ CML-CP who have received nilotinib capsules 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 nilotinib capsules for at least 3 years and have achieved a sustained molecular response (MR4.5) may be considered for treatment discontinuation. 2.1 Recommended Dosage Dose nilotinib capsules 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.

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.

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

Nilotinib capsules may be given with hydroxyurea or anagrelide if clinically indicated.

Dosage in Adult Patients with Newly Diagnosed Ph+ CML-CP The recommended dosage of nilotinib capsules are 300 mg orally twice daily.

Dosage in Adult Patients with Resistant or Intolerant Ph+ CML-CP and CML-AP The recommended dosage of nilotinib capsules are 400 mg orally twice daily.

Dosage in Pediatric Patients with Newly Diagnosed Ph+ CML-CP or Resistant or Intolerant Ph+ CML-CP The recommended dosage of nilotinib capsules 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) .

If needed, attain the desired dose by combining different strengths of nilotinib capsules.

Continue treatment as long as clinical benefit is observed or until unacceptable toxicity occurs.

Table 1: Pediatric Dosing of Nilotinib capsules (230 mg/m 2 Twice Daily, Maximum Single Dose of 400 mg) Body surface area Single dose Total daily dose Up to 0.32 m 2 50 mg 100 mg 0.33 – 0.54 m 2 100 mg 200 mg 0.55 – 0.76 m 2 150 mg 300 mg 0.77 – 0.97 m 2 200 mg 400 mg 0.98 – 1.19 m 2 250 mg 500 mg 1.20 – 1.41 m 2 300 mg 600 mg 1.42 – 1.63 m 2 350 mg 700 mg ≥ 1.64 m 2 400 mg 800 mg Additional pediatric use information is approved for Novartis Pharmaceuticals Corporation’s TASIGNA (nilotinib) capsules.

However, due to Novartis Pharmaceuticals Corporation’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 2.2 Discontinuation of Treatment After a Sustained Molecular Response (MR4.5) on Nilotinib Capsules Patient Selection Eligibility for Discontinuation of Treatment Ph+ CML-CP patients with typical BCR-ABL transcripts, who have been taking nilotinib capsules 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.

Information on

FDA authorized tests for the detection and quantitation of BCR-ABL transcripts to determine eligibility for treatment discontinuation is available at Patients with typical BCR-ABL transcripts (e13a2/b2a2 or e14a2/b3a2), who achieve the sustained MR4.5 criteria, are eligible for discontinuation of nilotinib capsules.

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 nilotinib capsules 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 nilotinib capsules who have: been treated with nilotinib capsules for a minimum of 3 years been treated with imatinib only prior to treatment with nilotinib capsules 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.

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

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 Nilotinib Capsules Newly diagnosed patients who lose MMR must reinitiate treatment within 4 weeks at the dose level prior to discontinuation of therapy.

Patients who reinitiate nilotinib capsules 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.

Patients who reinitiate nilotinib capsules 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. 2.4 Dosage Modification for QT Interval Prolongation See Table for dose adjustments for QT interval prolongation.

Table 2: Dosage Adjustments for Adult and Pediatric Patients With QT Prolongation Degree of QTc prolongation Dosage adjustment ECGs with a QTc greater than 480 msec 1.

Withhold nilotinib capsules, 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/m 2 once daily in pediatric patients. 4.

Discontinue nilotinib capsules if, following dose-reduction to 400 mg once daily in adults and 230 mg/m 2 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.

ECG, electrocardiogram. 2.5 Dosage Modifications for Myelosuppression Withhold or reduce nilotinib capsules dosage for hematological toxicities (neutropenia, thrombocytopenia) that are not related to underlying leukemia (Table 3) .

Table 3: Dosage Adjustments for Neutropenia and Thrombocytopenia Diagnosis Degree of myelosuppression Dosage adjustment Adult patients with: Newly diagnosed Ph+ CML in chronic phase at 300 mg twice daily Resistant or intolerant Ph+ CML in chronic phase or accelerated phase at 400 mg twice daily ANC less than 1.0 x 10 9 /L and/or platelet counts less than 50 x 10 9 /L Stop nilotinib capsules, and monitor blood counts.

Resume within 2 weeks at prior dose if ANC greater than 1.0 x 10 9 /L and platelets greater than 50 x 10 9 /L. If blood counts remain low for greater than 2 weeks, reduce the dose to 400 mg once daily.

Pediatric patients with

Newly diagnosed Ph+ CML in chronic phase at 230 mg/m 2 twice daily Resistant or intolerant Ph+ CML in chronic phase at 230 mg/m 2 twice daily ANC less than 1.0 x 10 9 /L and/or platelet counts less than 50 x 10 9 /L Stop nilotinib capsules and monitor blood counts.

Resume within 2 weeks at prior dose if ANC greater than 1.5 x 10 9 /L and/or platelets greater than 75 x 10 9 /L. If blood counts remain low for greater than 2 weeks, a dose reduction to 230 mg/m 2 once daily may be required.

If event occurs after dose reduction, consider discontinuing treatment.

ANC, absolute neutrophil count; Ph+ CML, Philadelphia chromosome positive chronic myeloid leukemia. 2.6 Dosage Modifications for Selected Non-Hematologic Laboratory Abnormalities and Other Toxicities See Table for dosage adjustments for elevations of lipase, amylase, bilirubin, and/or hepatic transaminases.

Table 4: Dosage Adjustments for Selected Non-Hematologic Laboratory Abnormalities Degree of non-hematologic laboratory abnormality Dosage adjustment Elevated serum lipase or amylase greater than or equal to Grade 3 Adult patients: 1.

Withhold nilotinib capsules, 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

Interrupt nilotinib capsules until the event returns to less than or equal to Grade 1.

Resume treatment at 230 mg/m 2 once daily if prior dose was 230 mg/m 2 twice daily; discontinue treatment if prior dose was 230 mg/m 2 once daily.

Elevated bilirubin greater than or equal to Grade in adult patients and greater than or equal to Grade in pediatric patients Adult patients: 1.

Withhold nilotinib capsules, 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 nilotinib capsules until the event returns to less than or equal to Grade 1. 2.

Resume treatment at 230 mg/m 2 once daily if prior dose was 230 mg/m 2 twice daily; discontinue treatment if prior dose was 230 mg/m 2 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 nilotinib capsules, and monitor hepatic transaminases. 2.

Resume treatment at 400 mg once daily if hepatic transaminases returns to less than or equal to Grade 1.

Interrupt nilotinib capsules until the event.

Nilotinib 50 mg capsules are light yellow opaque colour body and red opaque colour cap imprinted with “MN5” with black ink.

Nilotinib 150 mg capsules are red opaque colour body and red opaque colour cap imprinted with“MN4” with black ink.

Nilotinib 200 mg capsules are light yellow opaque colour body and light yellow opaque colour cap imprinted with “MN3” with black ink.

Nilotinib 50 mg capsules are supplied in bottles and nilotinib 150 mg and 200 mg capsules are supplied in blister packs. 50 mg Bottle of 120 capsules.NDC 72205-237-92 150 mg Carton of 4 blister packs of (4x28) .NDC 72205-238-64 Blisters of 28 capsules.NDC 72205-238-63 200 mg Carton of 4 blister packs of (4x28) .NDC 72205-239-64 Blisters of 28 capsules.NDC 72205-239-63 Nilotinib capsules should be stored at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) .

Based on findings from animal studies and the mechanism of action, nilotinib 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 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% to 4% and 15% to 20%, respectively.

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 nghr/mL and 17100 nghr/mL, respectively, representing approximately 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/m 2, 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/m 2, 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.

The safety and effectiveness of nilotinib 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 nilotinib 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 to 6 years of age for these indications.

Use of nilotinib in pediatric patients 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 to less than 12 years) and 19 adolescents (age to less than 18 years).

The 44 patients with resistant or intolerant Ph+ CML-CP included 18 children (age to less than 12 years) and 26 adolescents (age to less than 18 years).

All pediatric patients received nilotinib 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: 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.

For pediatric growth and development, growth retardation has been reported in pediatric patients with Ph+ CML-CP treated with nilotinib.

The safety and effectiveness of nilotinib 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.

Additional pediatric use information is approved for Novartis Pharmaceuticals Corporation’s TASIGNA (nilotinib) capsules.

However, due to Novartis Pharmaceuticals Corporation’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

In the clinical trials of nilotinib (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.