Tasigna Information
Tasigna (Nilotinib) Dosage And Administration
Tasigna (Nilotinib) should be taken twice daily at approximately 12 hour intervals and must not be taken with food. The capsules should be swallowed whole with waterNo food should be consumed for at least 2 hours before the dose is taken and no food should be consumed for at least one hour after the dose is taken .
For patients who are unable to swallow capsules, the contents of each capsule may be dispersed in one teaspoon of applesauce (puréed apple). The mixture should be taken immediately (within 15 minutes) and should not be stored for future use .
Tasigna (Nilotinib) may be given in combination with hematopoietic growth factors such as erythropoietin or G-CSF if clinically indicated. Tasigna (Nilotinib) may be given with hydroxyurea or anagrelide if clinically indicated.
The recommended dose of Tasigna (Nilotinib) is 300 mg orally twice daily .
The recommended dose of Tasigna (Nilotinib) is 400 mg orally twice daily .
QT interval prolongation:
Myelosuppression
Tasigna (Nilotinib) may need to be withheld and/or dose reduced for hematological toxicities (neutropenia, thrombocytopenia) that are not related to underlying leukemia (Table 2).
*ANC = absolute neutrophil count
See Table 3 for dose adjustments for elevations of lipase, amylase, bilirubin, and/or hepatic transaminases
If other clinically significant moderate or severe non-hematologic toxicity develops, withhold dosing, and resume at 400 mg once daily when the toxicity has resolved. If clinically appropriate, escalation of the dose back to 300 mg (newly diagnosed Ph+ CML-CP) or 400 mg (resistant or intolerant Ph+ CML-CP and CML-AP) twice daily should be considered. For Grade 3 to 4 lipase elevations, dosing should be withheld, and may be resumed at 400 mg once daily. Test serum lipase levels monthly or as clinically indicated. For Grade 3 to 4 bilirubin or hepatic transaminase elevations, dosing should be withheld, and may be resumed at 400 mg once daily. Test bilirubin and hepatic transaminases levels monthly or as clinically indicated
Hepatic Impairment
If possible, consider alternative therapies. If Tasigna (Nilotinib) must be administered to patients with hepatic impairment, consider the following dose reduction:
* Mild = mild hepatic impairment (Child-Pugh Class A); Moderate = moderate hepatic impairment (Child-Pugh Class B); Severe = severe hepatic impairment (Child-Pugh Class C).
Concomitant Strong CYP3A4 Inhibitors
Avoid the concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole). Grapefruit products may also increase serum concentrations of nilotinib and should be avoided. Should treatment with any of these agents be required, it is recommended that therapy with Tasigna (Nilotinib) be interrupted. If patients must be co-administered a strong CYP3A4 inhibitor, based on pharmacokinetic studies, consider a dose reduction 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, a washout period should be allowed before the Tasigna (Nilotinib) dose is adjusted upward to the indicated dose. Close monitoring for prolongation of the QT interval is indicated for patients who cannot avoid strong CYP3A4 inhibitors .
Concomitant Strong CYP3A4 Inducers
Avoid the concomitant use of strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital). Patients should also refrain from taking St. John’s Wort. Based on the nonlinear pharmacokinetic profile of nilotinib, increasing the dose of Tasigna (Nilotinib) when co-administered with such agents is unlikely to compensate for the loss of exposure
Tasigna (Nilotinib) dosage Forms And Strengths
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”.
Tasigna (Nilotinib) contraindications
Do not use in patients with hypokalemia, hypomagnesemia, or long QT syndrome
Tasigna (Nilotinib) warnings And Precautions
Tasigna (Nilotinib) has been shown to prolong cardiac ventricular repolarization as measured by the QT interval on the surface ECG in a concentration-dependent manner Prolongation of the QT interval can result in a type of ventricular tachycardia called torsade de pointes, which may result in syncope, seizure, and/or death. ECGs should be performed at baseline, seven days after initiation, periodically as clinically indicated and following dose adjustments
Tasigna (Nilotinib) should not be used in patients who have hypokalemia, hypomagnesemia or long QT syndrome. Hypokalemia or hypomagnesemia must be corrected prior to initiating Tasigna (Nilotinib) and these electrolytes should be monitored periodically during therapy
Significant prolongation of the QT interval may occur when Tasigna (Nilotinib) is inappropriately taken with food and/or strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT. Therefore, co-administration with food must be avoided and concomitant use with strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT should be avoided . The presence of hypokalemia and hypomagnesemia may further enhance this effect .
Sudden deaths have been reported in patients with CML treated with nilotinib in clinical studies (n= 5,661; 0.3%). The relative early occurrence of some of these deaths relative to the initiation of nilotinib suggests the possibility that ventricular repolarization abnormalities may have contributed to their occurrence.
The bioavailability of nilotinib is increased with food. Tasigna (Nilotinib) must not be taken with food. No food should be taken at least 2 hours before and at least one hour after the dose is taken. Grapefruit products and other foods that are known to inhibit CYP3A4 should be avoided .
Cases of tumor lysis syndrome have been reported in Tasigna (Nilotinib) treated patients with resistant or intolerant CML. Malignant disease progression, high WBC counts and/or dehydration were present in the majority of these cases. Due to potential for tumor lysis syndrome, maintain adequate hydration and correct uric acid levels prior to initiating therapy with Tasigna (Nilotinib) .
Tasigna (Nilotinib) adverse Reactions
The following serious adverse reactions can occur with Tasigna (Nilotinib) and are discussed in greater detail in other sections of the package insert
Myelosuppression
QT prolongation
Sudden deaths
Elevated serum lipase
Hepatotoxicity
Electrolyte abnormalities
Tasigna (Nilotinib) drug Interactions
Nilotinib is a competitive inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2D6 and UGT1A1 , potentially increasing the concentrations of drugs eliminated by these enzymes. studies also suggest that nilotinib may induce CYP2B6, CYP2C8 and CYP2C9, and decrease the concentrations of drugs which are eliminated by these enzymes.
Single-dose administration of Tasigna (Nilotinib) with midazolam (a CYP3A4 substrate) to healthy subjects increased midazolam exposure by 30%. Single-dose administration of Tasigna (Nilotinib) to healthy subjects did not change the pharmacokinetics and pharmacodynamics of warfarin (a CYP2C9 substrate). The ability of Tasigna (Nilotinib) to induce metabolism has not been determined Exercise caution when co-administering Tasigna (Nilotinib) with substrates for these enzymes that have a narrow therapeutic index.
Nilotinib inhibits human P-glycoprotein (P-gp). If Tasigna (Nilotinib) is administered with drugs that are substrates of P-gp, increased concentrations of the substrate drug are likely, and caution should be exercised.
Nilotinib undergoes metabolism by CYP3A4, and concomitant administration of strong inhibitors or inducers of CYP3A4 can increase or decrease nilotinib concentrations significantly. The administration of Tasigna (Nilotinib) with agents that are strong CYP3A4 inhibitors should be avoided . Concomitant use of Tasigna (Nilotinib) 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 (Nilotinib) , concomitant use of alternative therapeutic agents with less potential for CYP3A4 induction should be selected.
Rifampicin:
Tasigna (Nilotinib) use In Specific Populations
Pregnancy Category D
Based on its mechanism of action and findings in animals, Tasigna (Nilotinib) may cause fetal harm when administered to a pregnant womanThere are no adequate and well controlled studies with Tasigna (Nilotinib) in pregnant women. Women should be advised to avoid becoming pregnant while on Tasigna (Nilotinib) . If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
Nilotinib was studied for effects on embryo-fetal development in pregnant rats and rabbits given oral doses of 10, 30, 100 mg/kg/day, and 30, 100, 300 mg/kg/day, respectively, during organogenesis. In rats, nilotinib at doses of 100 mg/kg/day (approximately 5.7 times the AUC in patients at the dose of 400 mg twice daily) was associated with maternal toxicity (decreased gestation weight, gravid uterine weight, net weight gain, and food consumption). Nilotinib at doses ≥30 mg/kg/day (approximately 2 times the AUC in patients at the dose of 400 mg twice daily) resulted in embryo-fetal toxicity as shown by increased resorption and post-implantation loss, and at 100 mg/kg/day, a decrease in viable fetuses. In rabbits, maternal toxicity at 300 mg/kg/day (approximately one-half the human exposure based on AUC) was associated with mortality, abortion, decreased gestation weights and decreased food consumption. Embryonic toxicity (increased resorption) and minor skeletal anomalies were observed at a dose of 300 mg/kg/day. Nilotinib is not considered teratogenic.
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 360 mg/m (approximately 0.7 times the clinical dose of 400 mg twice daily based on body surface area)At doses up to 120 mg/m (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.
In the clinical trials of Tasigna (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.
No major differences for safety were observed in patients ≥65 years of age as compared to patients
Clinical studies have not been performed in patients with impaired renal functionClinical studies have excluded patients with serum creatinine concentration >1.5 times the upper limit of the normal range.
Since nilotinib and its metabolites are not renally excreted, a decrease in total body clearance is not anticipated in patients with renal impairment.
Tasigna (Nilotinib) overdosage
Overdose with nilotinib has been reported, where an unspecified number of Tasigna (Nilotinib) capsules were ingested in combination with alcohol and other drugsEvents included neutropenia, vomiting, and drowsinessIn the event of overdose, the patient should be observed and appropriate supportive treatment given.
Tasigna (Nilotinib) description
Tasigna (Nilotinib) belongs to a pharmacologic class of drugs known as kinase inhibitors.
Nilotinib drug substance, a monohydrate monohydrochloride, is a white to slightly yellowish to slightly greenish yellow powder with the anhydrous molecular formula and weight, respectively, of CHFNO•HCl • HO and 584. The solubility of nilotinib in aqueous solutions decreases with increasing pH. Nilotinib is not optically active. The pK1 was determined to be 2.1; pK2 was estimated to be 5.4.
The chemical name of nilotinib is 4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide, monohydrochloride, monohydrateIts structure is shown below:
Tasigna (Nilotinib) capsules, for oral use, contain 150 mg or 200 mg nilotinib base, anhydrous (as hydrochloride, monohydrate) with the following inactive ingredients: colloidal silicon dioxide, crospovidone, lactose monohydrate, magnesium stearate and polyoxamer 188. The capsules contain gelatin, iron oxide (red), iron oxide (yellow), iron oxide (black) and titanium dioxide.
Tasigna (Nilotinib) clinical Pharmacology
Peak concentrations of nilotinib are reached 3 hours after oral administration.
Steady-state nilotinib exposure was dose-dependent with less than dose-proportional increases in systemic exposure at dose levels higher than 400 mg given as once daily dosingDaily serum exposure to nilotinib following 400 mg twice daily dosing at steady state was 35% higher than with 800 mg once daily dosing. Steady state exposure (AUC) of nilotinib with 400 mg twice daily dosing was 13% higher than with 300 mg twice daily dosing. The average steady state nilotinib trough and peak concentrations did not change over 12 months. There was no relevant increase in exposure to nilotinib when the dose was increased from 400 mg twice daily to 600 mg twice daily.
The bioavailability of nilotinib was increased when given with a meal. Compared to the fasted state, the systemic exposure (AUC) increased by 82% when the dose was given 30 minutes after a high fat meal.
Single dose administration of two 200 mg nilotinib capsules each dispersed in one teaspoon of applesauce and administered within 15 minutes was shown to be bioequivalent to a single dose administration of two 200 mg intact capsules. The blood-to-serum ratio of nilotinib is 0.68. Serum protein binding is approximately 98% on the basis of experiments.
Median steady-state trough concentration of nilotinib was decreased by 53% in patients with total gastrectomy compared to patients who had not undergone surgeries .
Pharmacokinetics, Metabolism and Excretion
The apparent elimination half-life estimated from the multiple dose pharmacokinetic studies with daily dosing was approximately 17 hours. Inter-patient variability in nilotinib AUC was 32% to 64%. Steady state conditions were achieved by Day 8. An increase in serum exposure to nilotinib between the first dose and steady state was approximately 2-fold for daily dosing and 3.8-fold for twice-daily dosing.
Main metabolic pathways identified in healthy subjects are oxidation and hydroxylation. Nilotinib is the main circulating component in the serum. None of the metabolites contribute significantly to the pharmacological activity of nilotinib.
After a single dose of radiolabeled nilotinib in healthy subjects, more than 90% of the administered dose was eliminated within 7 days: mainly in feces (93% of the dose)Parent drug accounted for 69% of the dose.
Age, body weight, gender, or ethnic origin did not significantly affect the pharmacokinetics of nilotinib.
Drug-Drug Interactions
In a Phase 1 trial of nilotinib 400 mg twice daily in combination with imatinib 400 mg daily or 400 mg twice daily, the AUC increased 30%-50% for nilotinib and approximately 20% for imatinib.
Tasigna (Nilotinib) clinical Studies
An open label, multicenter, randomized trial was conducted to determine the efficacy of Tasigna (Nilotinib) versus imatinib tablets in adult patients with cytogenetically confirmed newly diagnosed Ph+ CML-CP. Patients were within six months of diagnosis and were previously untreated for CML-CP, except for hydroxyurea and/or anagrelide. Efficacy was based on a total of 846 patients: 283 patients in the imatinib 400 mg once daily group, 282 patients in the nilotinib 300 mg twice daily group, 281 patients in the nilotinib 400 mg twice daily group.
Median age was 46 years in the imatinib group and 47 years in both nilotinib groups, with 12%, 13% and 10% of patients ≥65 years of age in imatinib 400 mg once daily, nilotinib 300 mg twice daily and nilotinib 400 mg twice daily treatment groups, respectively. There were slightly more male than female patients in all groups (56%, 56% and 62% in imatinib 400 mg once daily, nilotinib 300 mg twice daily and nilotinib 400 mg twice daily treatment groups, respectively). More than 60% of all patients were Caucasian, and 25% were Asian.
The primary data analysis was performed when all 846 patients completed 12 months of treatment (or discontinued earlier). A second data analysis was performed when all 846 patients completed 24 months of treatment (or discontinued earlier). The median time on treatment at the time of the second analysis was 25 months in all three treatment groups. This study is on-going and further data will be required to determine long-term outcome.
The primary efficacy endpoint was major molecular response (MMR) at 12 months after the start of study medication. MMR was defined as ≤0.1% BCR-ABL/ABL % by international scale measured by RQ-PCR, which corresponds to a ≥3 log reduction of BCR-ABL transcript from standardized baseline. Efficacy endpoints are summarized in Table 9 below.
After 24 months of minimum follow-up, two patients on the nilotinib arm progressed to either accelerated phase or blast crisis while 17 patients on the imatinib arm progressed to either accelerated phase or blast crisis.
a
b
A single arm, open label, multicenter study was conducted to evaluate the efficacy and safety of Tasigna (Nilotinib) (400 mg twice daily) in patients with imatinib-resistant or -intolerant CML with separate cohorts for chronic and accelerated phase diseaseThe definition of imatinib resistance included failure to achieve a complete hematologic response (by 3 months), cytogenetic response (by 6 months) or major cytogenetic response (by 12 months) or progression of disease after a previous cytogenetic or hematologic responseImatinib intolerance was defined as discontinuation of treatment due to toxicity and lack of a major cytogenetic response at time of study entryAt the time of data cut-off, 321 patients with CML-CP and 137 patients with CML-AP with a minimum follow-up of 24 months were enrolled. In this study, about 50% of CML-CP and CML-AP patients were males, over 90% (CML-CP) and 80% (CML-AP) were Caucasian, and approximately 30% were age 65 years or older
Overall, 73% of patients were imatinib resistant while 27% were imatinib intolerantThe median time of prior imatinib treatment was approximately 32 (CML-CP) and 28 (CML-AP) monthsPrior therapy included hydroxyurea in 85% of patients, interferon in 56% and stem cell or bone marrow transplant in 8%The median highest prior imatinib dose was 600 mg/day for patients with CML-CP and CML-AP, and the highest prior imatinib dose was ≥600 mg/day in 74% of all patients with 40% of patients receiving imatinib doses ≥800 mg/day
Median duration of nilotinib treatment was 18.4 months in patients with CML-CP and 8.7 months in patients with CML-AP
The efficacy endpoint in CML-CP was unconfirmed major cytogenetic response (MCyR) which included complete and partial cytogenetic responses
The efficacy endpoint in CML-AP was confirmed hematologic response (HR), defined as either a complete hematologic response (CHR) or no evidence of leukemia (NEL)The rates of response for CML-CP and CML-AP patients are reported in Table 10.
Median durations of response had not been reached at the time of data analysis.
a
b
CHR (CML-CP): WBC
CHR (CML-AP): neutrophils 1.5 x 10/L, platelets 100 x 10 /L, no myeloblasts in peripheral blood, myeloblasts
NEL: same criteria as for CHR but neutrophils 1.0 x 10/L and platelets 20 x 10/L without transfusions or bleeding.
The MCyR rate in 321 CML-CP patients was 51%. The median time to MCyR among responders was 2.8 months (range 1 to 28 months). The median duration of MCyR cannot be estimated. The median duration of exposure on this single arm trial was 18.4 months. Among the CML-CP patients who achieved MCyR, 62% of them had MCyR lasting more than 18 months. The CCyR rate was 37%.
The overall confirmed hematologic response rate in 137 patients with CML-AP was 39%. The median time to first hematologic response among responders was 1.0 month (range 1 to 14 months). Among the CML-AP patients who achieved HR, 44% of them had a response lasting for more than 18 months.
After imatinib failure, 24 different BCR-ABL mutations were noted in 42% of chronic phase and 54% of accelerated phase CML patients who were evaluated for mutations.
Tasigna (Nilotinib) how Supplied/storage And Handling
Tasigna (Nilotinib) 150 mg capsules are red opaque hard gelatin capsules, size 1 with black axial imprint “NVR/BCR”. Tasigna (Nilotinib) 200 mg capsules are light yellow opaque hard gelatin capsules, size 0 with the red axial imprint “NVR/TKI.” Tasigna (Nilotinib) capsules are supplied in blister packs.
Carton of 4 blister packs of (4x28) ………………………….…….NDC 0078-0592-87
Blisters of 28 capsules……………………………………….…….NDC 0078-0592-51
Carton of 4 blister packs of (4x28) ………………………….…….NDC 0078-0526-87
Blisters of 28 capsules……………………………………….…….NDC 0078-0526-51
Each blister pack contains one folded blister card of 28 capsules each, for dosing two in the morning and two in the evening at 12 hour intervals over a 7 day period.
Tasigna (Nilotinib) capsules should be stored at 25°C (77°F); excursions permitted between 15°-30°C (59°-86°F) [see USP Controlled Room Temperature].
Tasigna (Nilotinib) patient Counseling Information
See Medication Guide
A Medication Guide is required for distribution with Tasigna (Nilotinib) . Encourage patients to read the Tasigna (Nilotinib) Medication Guide. The complete text of the Medication Guide is reprinted at the end of this document.
Tasigna (Nilotinib)
Tasigna (Nilotinib)
Tasigna (Nilotinib)
