Tasigna®
(nilotinib) Capsules
QT PROLONGATION AND SUDDEN DEATHS
Tasigna prolongs the QT interval. Sudden deaths have been reported in patients receiving nilotinib. Tasigna should not be used in patients with hypokalemia, hypomagnesemia, or long QT syndrome (4). Hypokalemia or hypomagnesemia must be corrected prior to Tasigna administration and should be periodically monitored. Drugs known to prolong the QT interval and strong CYP3A4 inhibitors should be avoided. Patients should avoid food 2 hours before and 1 hour after taking dose. Use with caution in patients with hepatic impairment. ECGs should be obtained to monitor the QTc at baseline, seven days after initiation, and periodically thereafter, as well as following any dose adjustments. [See WARNINGS sections for details].
Tasigna (nilotinib) belongs to a pharmacologic class of drugs known as kinase inhibitors.
Nilotinib drug substance, a monohydrate mono-hydrochloride, is a white to slightly yellowish to slightly greenish yellow powder with the anhydrous molecular formula and weight, respectively, of C28H22F3N7O•HCl • H2O and 565.98. The solubility of Nilotinib in aqueous solutions decreases with increasing pH. Nilotinib is not optically active. The pKa1 was determined to be 2.1; pKa2 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, monohydrate. Its structure is shown below:
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Tasigna (nilotinib) capsules, for oral use, contain 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), and titanium dioxide.
Last updated on RxList: 11/16/2007
Tasigna (nilotinib) is indicated for the treatment of chronic phase and accelerated phase Philadelphia chromosome positive chronic myelogenous leukemia (CML) in adult patients resistant or intolerant to prior therapy that included imatinib. The effectiveness of Tasigna is based on hematologic and cytogenetic response rates [See CLINICAL STUDIES]. There are no controlled trials demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival.
The recommended dose of Tasigna (nilotinib) is 400 mg orally twice daily. [See CLINICAL PHARMACOLOGY]. Treatment should continue as long as the patient does not show evidence of progression or unacceptable toxicity.
Tasigna should be taken twice daily at approximately 12 hour intervals and should not be taken with food. The capsules should be swallowed whole with water. No 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. [See BOXED WARNING, WARNINGS AND PRECAUTIONS, CLINICAL PHARMACOLOGY AND CLINICAL STUDIES.
If a dose is missed, the patient should not take a make-up dose, but should resume taking the next prescribed daily dose.
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.
Table 1. Dose Adjustments for QT prolongation
| ECGs with a QTc > 480 msec |
|
Myelosuppression: Tasigna may need to be withheld and/or dose reduced for hematological toxicities (neutropenia, thrombocytopenia) that are not related to underlying leukemia (Table 2)
Table 2. Dose Adjustments for Neutropenia and Thrombocytopenia
| Chronic Phase or Accelerated Phase CML at 400 mg twice daily | ANC* < 1.0 x 109/L and/or platelet counts < 50 x 109/L |
|
| *ANC = absolute neutrophil count | ||
See Table 3 for dose adjustments for elevations of lipase, amylase, bilirubin, and/or hepatic transaminases. [See ADVERSE REACTIONS]
Table 3. Dose Adjustments for selected non-hematologic laboratory abnormalities
| Elevated serum lipase or amylase ≥ Grade 3 |
|
| Elevated bilirubin ≥ Grade 3 |
|
| Elevated hepatic transaminases ≥ Grade 3 |
|
Other non-hematologic toxicities: If other clinically significant moderate or severe non-hematologic toxicity develops, dosing should be withheld, and may be resumed at 400 mg once daily when the toxicity has resolved. If clinically appropriate, escalation of the dose back to 400 mg twice daily should be considered. [See WARNINGS and PRECAUTIONS and Use in Specific Populations].
Concomitant Strong CYP3A4 Inhibitors: The concomitant use of strong CYP3A4 inhibitors should be avoided (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 be interrupted. If patients must be co-administered a strong CYP3A4 inhibitor, based on pharmacokinetic studies, 400 mg once daily (a dose reduction to ½ of the original daily dose) is predicted to adjust the nilotinib AUC to the AUC observed without inhibitors. 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 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. [See BOXED WARNING, WARNINGS and PRECAUTIONS and DRUG INTERACTIONS].
Concomitant Strong CYP3A4 Inducers: The concomitant use of strong CYP3A4 inducers should be avoided (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital). Patients should also refrain from taking St. John's Wort. If patients must be co-administered a strong CYP3A4 inducer, the dose of Tasigna may need to be increased, depending on patient tolerability. If the strong inducer is discontinued the nilotinib dose should be reduced to the indicated dose. [See DRUG INTERACTIONS]
200 mg light yellow opaque hard gelatin capsules with a red axial imprint “NVR/TKI”.
Tasigna (nilotinib) capsules are light yellow opaque hard gelatin capsules, size 0 with the red axial imprint “NVR/TKI.” Tasigna capsules are supplied in blister packs.
Blisters of 28 capsules.....................................................NDC 0078-xxxx-xx
Each blister pack contains 2 blister cards of 14 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, 200 mg, should be stored at 25° C (77° F); excursions permitted between 15°-30° C (59° -86° F) [see USP Controlled Room Temperature].
Novartis Pharmaceuticals Corporation., East Hanover, New Jersey
07936. Rev: October 2007
Manufactured by: Novartis Pharma Stein AG., Stein, Switzerland. FDA revision
date: 10/29/2007
Last updated on RxList: 11/16/2007
The following serious adverse reactions can occur with Tasigna and are discussed in greater detail in other sections of the package insert. [See BOXED WARNING and WARNINGS and PRECAUTIONS].
QT prolongation and Sudden Deaths. [See BOXED WARNING, WARNINGS and PRECAUTIONS]
Myelosuppression. [See WARNINGS and PRECAUTIONS]
Elevated serum lipase. [See WARNINGS and PRECAUTIONS]
Hepatotoxicity. [See WARNINGS and PRECAUTIONS]
Electrolyte abnormalities. [See BOXED WARNING and WARNINGS and PRECAUTIONS]
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
In the single open-label multicenter clinical trial, a total of 438 patients were treated (CML-CP=318; CML-AP=120).
The median duration of exposure in days for CML-CP and CML-AP patients is 245 (range 1-502) and 138 (range 2-503), respectively. The median dose intensity of 797 mg/day (range 145 - 1149) was similar for both the chronic and accelerated phase patients and corresponded to the planned 400 mg twice daily dosing.
The median cumulative duration in days of dose interruptions for the CML-CP patients was 18 (range 1-185), and the median duration in days of dose interruptions for the CML-AP patients was 22 (range 1 - 163).
In CML-CP patients, the most commonly reported drug-related adverse reactions ( > 10%) were rash, pruritis, nausea, fatigue, headache, constipation, diarrhea and vomiting. The common serious drug-related adverse reactions were thrombocytopenia and neutropenia.
In CML-AP patients, the most commonly reported drug-related adverse reactions ( > 10%) were rash, pruritus and constipation. The common serious drug-related adverse reactions were thrombocytopenia, neutropenia, pneumonia, febrile neutropenia, leukopenia, intracranial hemorrhage, elevated lipase and pyrexia.
Sudden deaths and QT prolongation were reported. [See BOXED WARNING and WARNINGS and PRECAUTIONS]
Discontinuation for drug related adverse reactions was observed in 11% of CML-CP and 8% of CML-AP patients.
Table 4 shows the percentage of patients experiencing treatment-emergent adverse reactions (excluding laboratory abnormalities) regardless of relationship to study drug. Adverse reactions reported in at least 10% of patients who received at least one dose of Tasigna are listed.
Table 4. Treatment-emergent Adverse Reactions Reported in ≥ 10% of Patients in the Clinical Studya
| CML-CP n=318 |
CML-AP n=120 |
||||
| Body System and preferred term | All Grades (%) | CTC Gradesb 3 / 4(%) | All Grades (%) | CTC Gradesb 3 / 4 (%) | |
| Skin and subcutaneous tissue disorders: | Rash | 33 | 2 | 28 | 0 |
| Pruritus | 29 | 1 | 20 | 0 | |
| Gastrointestinal disorders: | Nausea | 31 | 1 | 18 | < 1 |
| Diarrhea | 22 | 3 | 19 | 2 | |
| Constipation | 21 | < 1 | 18 | 0 | |
| Vomiting | 21 | < 1 | 10 | 0 | |
| Abdominal pain | 11 | 1 | 13 | 3 | |
| Nervous system disorders | Headache | 31 | 3 | 21 | 2 |
| General disorders and administration site conditions | Fatigue | 28 | 1 | 16 | < 1 |
| Pyrexia | 14 | 1 | 24 | 2 | |
| Asthenia | 14 | 0 | 12 | 2 | |
| Edema, peripheral | 11 | 0 | 11 | 0 | |
| Musculoskeletal and connective tissue disorders | Arthralgia | 18 | 2 | 16 | 0 |
| Myalgia | 14 | 2 | 14 | < 1 | |
| Pain in extremity | 13 | 1 | 16 | 2 | |
| Bone pain | 11 | < 1 | 13 | < 1 | |
| Muscle spasms | 11 | < 1 | 14 | 0 | |
| Back pain | 10 | < 1 | 12 | < 1 | |
| Respiratory, thoracic and mediastinal disorders | Cough | 17 | < 1 | 13 | 0 |
| Dyspnea | 11 | 1 | 8 | 3 | |
| Infections and infestations | Nasopharyngitis | 16 | < 1 | 11 | 0 |
| a Excluding laboratory abnormalities
b NCI Common Terminology Criteria for Adverse Events, Version 3.0 |
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Table 5 shows the percentage of patients experiencing treatment-emergent Grade 3/4 laboratory abnormalities in patients who received at least one dose of Tasigna.
Table 5. Incidence of Clinically Relevant Grade 3/4 Laboratory Abnormalities
| CML-CP N=318 |
CML-AP N=120 |
|
| Grades 3/4 * | Grades 3/4 * | |
| Hematologic Parameters | ||
| -Thrombocytopenia | 28%1 | 37%2 |
| -Neutropenia2 | 28% | 37%3 |
| -Anemia | 8% | 23% |
| BiochemistryParameters | ||
| -Elevated lipase | 15% | 17% |
| -Hyperglycemia | 11% | 4% |
| -Hypophosphatemia | 10% | 10% |
| -Elevated Bilirubin (total) | 9% | 10% |
| -Elevated SGPT (ALT) | 4% | 2% |
| -Hyperkalemia | 4% | 3% |
| -Hyponatremia | 3% | 3% |
| -Hypokalemia | 1% | 5% |
| -Elevated SGOT (AST) | 1% | 1% |
| -Decreased albumin | 1% | 1% |
| -Hypocalcemia | 1% | 4% |
| -Elevated alkaline phosphatase | 1% | 3% |
| -Elevated creatinine | < 1% | 0% |
| *NCI Common Terminology Criteria for Adverse
Events, version 3.0 1CML-CP: Thrombocytopenia: 11% were grade 3, 17% were grade 4 2CML-AP: Thrombocytopenia: 7% were grade 3, 30% were grade 4 3CML-AP: Neutropenia: 12% were grade 3, 25% were grade 4 |
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The following drug related adverse reactions are ranked under a heading of frequency, the most frequent first using the following convention: common (1% -10%), and uncommon (0.1%-1%) adverse reactions single events are captured as unknown frequency. For laboratory abnormalities, very common events ( ≥ 1/10) not included in Table 4 are also reported. These adverse reactions are included based on clinical relevance, and ranked in order of decreasing seriousness within each category.
Infections and Infestations: Uncommon: pneumonia, urinary tract infection, gastroenteritis, pharyngitis. Unknown frequency: sepsis, bronchitis, herpes simplex, candidiasis.
Blood and Lymphatic System Disorders: Common: febrile neutropenia, pancytopenia. Unknown frequency: thrombocytosis, leukocytosis.
Endocrine Disorders: Uncommon: hyperthyroidism. Unknown frequency: hypothyroidism, thyroiditis.
Metabolism and Nutrition Disorders: Common: hypomagnesemia, hyperkalemia, hyperglycemia, anorexia. Uncommon: hypokalemia, hyponatremia, hypocalcemia, hypophosphatemia, dehydration, decreased appetite, increased appetite. Unknown frequency: diabetes mellitus, hypercalcemia, hyperphosphatemia.
Psychiatric Disorders: Common: Insomnia. Uncommon: depression, anxiety. Unknown frequency: disorientation, confusional state.
Nervous System Disorders: Common: dizziness, paresthesia Uncommon: intracranial hemorrhage, migraine, tremor, hypoesthesia, hyperesthesia. Unknown frequency: brain edema, loss of consciousness, optic neuritis, peripheral neuropathy.
Eye Disorders: Uncommon: eye hemorrhage, visual acuity reduced, periorbital edema, conjunctivitis, eye irritation, dry-eye. Unknown frequency: papilloedema, diplopia, vision blurred, photophobia, eye swelling, blepharitis, eye pain.
Ear and Labyrinth Disorders: Common: vertigo. Unknown frequency: hearing impaired, ear pain.
Cardiac Disorders: Common: palpitations, electrocardiogram QT prolonged. Uncommon: cardiac failure, angina pectoris, atrial fibrillation, pericardial effusion, coronary artery disease, cardiomegaly, cardiac murmur, bradycardia. Unknown frequency: myocardial infarction, ventricular dysfunction, pericarditis, cardiac flutter, extrasysoles,
Vascular Disorders: Common: hypertension, flushing. Uncommon: hypertensive crisis, hematoma. Unknown frequency: shock hemorrhagic, hypotension, thrombosis.
Respiratory, Thoracic and Mediastinal Disorders: Common: dyspnea, dyspnea exertional, cough, dysphonia. Uncommon: pulmonary edema, pleural effusion, interstitial lung disease, pleuritic pain, pleurisy, epistaxis, pharyngolaryngeal pain, throat irritation. Unknown frequency: pulmonary hypertension.
Gastrointestinal Disorders: Common: abdominal discomfort, dyspepsia, flatulence. Uncommon: pancreatitis, gastrointestinal hemorrhage, melena, abdominal distension, mouth ulceration, gastroesophageal reflux, stomatitis, dry mouth Unknown frequency: gastrointestinal ulcer perforation, retroperitoneal hemorrhage, hematemesis, gastric ulcer, esophagitis ulcerative, subileus.
Hepatobiliary Disorders: Uncommon: hepatitis Unknown frequency: hepatotoxicity, hepatomegaly, jaundice.
Skin and Subcutaneous Tissue Disorders: Common: night sweats, eczema, urticaria, alopecia, erythema, hyperhidrosis, dry skin. Uncommon: exfoliative rash, ecchymosis, swelling face, Unknown frequency: erythema nodosum, skin ulcer, petechiae, photosensitivity.
Musculoskeletal and Connective Tissue Disorders: Common: musculoskeletal chest pain, musculoskeletal pain. Uncommon: muscular weakness. Unknown frequency: Arthritis, joint swelling.
Renal and Urinary Disorders: Uncommon: dysuria, micturition urgency, nocturia, pollakiuria. Unknown frequency: renal failure, hematuria, urinary incontinence.
Reproductive System and Breast Disorders: Uncommon: breast pain, gynecomastia, erectile dysfunction.
General Disorders and Administration Site Conditions: Common: pyrexia. Uncommon: chest pain, face edema, gravitational edema, influenza-like illness, chills, malaise.
Investigations: Very common: lipase increased. Common: blood amylase increased, alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin increased, blood alkaline phosphatase increased, gamma-glutamyltransferase increased, blood creatinine phosphokinase increased, blood glucose increased, weight decreased, weight increased. Uncommon: blood lactate dehydrogenase increased, blood glucose decreased, blood creatinine increased, blood urea increased. Unknown frequency: troponin increased, blood potassium decreased, blood bilirubin unconjugated increased.
Nilotinib is a competitive inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2D6 and UGT1A1 in vitro, potentially increasing the concentrations of drugs eliminated by these enzymes. In addition, single-dose administration of Tasigna with midazolam (a CYP3A4 substrate) to healthy subjects increased midazolam exposure by 30%. Caution should be exercised when co-administering Tasigna with substrates for these enzymes that have a narrow therapeutic index. Since warfarin is metabolized by CYP2C9 and CYP3A4 it should be avoided if possible.
In vitro studies also suggest that nilotinib may induce CYP2B6, CYP2C8 and CYP2C9, and thereby has the potential to decrease the concentrations of drugs which are eliminated by these enzymes.
Nilotinib inhibits human P-glycoprotein. If Tasigna is administered with drugs that are substrates of Pgp, 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.
Ketoconazole: In healthy subjects receiving ketoconazole, a CYP3A4 inhibitor, at 400 mg once daily for 6 days, systemic exposure (AUC) to nilotinib was increased approximately 3-fold. [See BOX WARNING and WARNINGS and PRECAUTIONS]
Rifampicin: In healthy subjects receiving the CYP3A4 inducer, rifampicin, at 600 mg daily for 12 days, systemic exposure (AUC) to nilotinib was decreased approximately 80%.
Nilotinib is a substrate of the efflux transporter P-glycoprotein (Pgp, ABCB1). If Tasigna is administered with drugs that inhibit Pgp, increased concentrations of nilotinib are likely, and caution should be exercised.
Last updated on RxList: 12/13/2007
Treatment with Tasigna (nilotinib) can cause Grade 3/4 thrombocytopenia, neutropenia and anemia. Complete blood counts should be performed every two weeks for the first 2 months and then monthly thereafter, or as clinically indicated. Myelosuppression was generally reversible and usually managed by withholding Tasigna temporarily or dose reduction. [See DOSAGE AND ADMINISTRATION]
Tasigna 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.
Tasigna should not be used in patients who have hypokalemia, hypomagnesemia or long QT syndrome. Hypokalemia or hypomagnesemia must be corrected prior to initiating Tasigna and these electrolytes should be monitored periodically during therapy. Avoid drugs known to prolong the QT interval and strong CYP3A4 inhibitors. ECGs should be performed at baseline, seven days after initiation, periodically as clinically indicated and following dose adjustments. [See CLINICAL PHARMACOLOGY]
There were five sudden deaths reported in patients receiving nilotinib in an on-going study (n=867; 0.6%). A similar incidence was also reported in the expanded access program. 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 use of Tasigna can cause increases in serum lipase. Caution is recommended in patients with a previous history of pancreatitis. Serum lipase should be checked periodically.
The use of Tasigna may result in elevations in bilirubin, AST/ALT, and alkaline phosphatase. Hepatic function tests should be checked periodically.
The use of Tasigna can cause hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and hyponatremia. Electrolyte abnormalities must be corrected prior to initiating Tasigna and these electrolytes should be monitored periodically during therapy.
The administration of Tasigna with agents that are strong CYP3A4-inhibitors or prolong QT should be avoided. Should treatment with any of these agents be required, it is recommended that therapy with Tasigna be interrupted. If interruption of treatment with Tasigna is not possible, patients who require treatment with a drug that prolongs QT or strongly inhibits CYP3A4 should be closely monitored for prolongation of the QT interval. [See BOXED WARNING, DOSAGE AND ADMINISTRATION, and DRUG INTERACTIONS]
The bioavailability of nilotinib is increased with food. Tasigna should 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. [See BOXED WARNING, DRUG INTERACTIONS and CLINICAL PHARMACOLOGY].
Tasigna has not been investigated in patients with hepatic impairment. Clinical studies have excluded patients with ALT and/ or AST > 2.5 (or > 5, if related to disease) times the upper limit of the normal range and/or total bilirubin > 1.5 times the upper limit of the normal range. Metabolism of nilotinib is mainly hepatic. Caution is recommended in patients with hepatic impairment. These patients should be closely monitored for QT interval prolongation. [See BOXED WARNING, DOSAGE AND ADMINISTRATION and Use in Specific Populations].
Since the capsules contain lactose, Tasigna is not recommended for patients with rare hereditary problems of galactose intolerance, severe lactase deficiency or of glucose-galactose malabsorption.
See Medication Guide
A Medication Guide is required for distribution with Tasigna. Encourage patients to read the Tasigna Medication Guide. The complete text of the Medication Guide is reprinted at the end of this document.
Tasigna doses should be taken twice daily approximately 12 hours apart and should not be taken with food. The capsules should be swallowed whole with water.
Patients should be advised to take Tasigna on an empty stomach. Tasigna should be taken at least 2 hours after a meal. No food should be consumed for at least one hour after the dose is taken. Patients should not consume grapefruit products and other foods that are known to inhibit CYP3A4 at all times during Tasigna treatment. [See DOSAGE AND ADMINISTRATION].
Tasigna, and certain other medicines, including over the counter medications or herbal supplements (such as St. John's Wort) can interact with each other. [See WARNINGS and PRECAUTIONS and DRUG INTERACTIONS].
Patients should be advised that the use of Tasigna during pregnancy may cause harm to the fetus and should not be taken during pregnancy, unless necessary. Women of childbearing potential should use effective contraceptives if taking Tasigna. Sexually active female patients taking Tasigna should use adequate contraception. [See WARNINGS and PRECAUTIONS and Use in Specific Populations].
Patients should be advised of the following
Tasigna can cause fetal harm when administered to a pregnant woman.
Nilotinib was studied for effects on embryo-fetal development in pregnant rats (GD 6-17) and rabbits (GD 7-20) given oral doses of 10, 30, 100 mg/kg/day, and 30, 100, 300 mg/kg/day, respectively. In rats, nilotinib at doses of 100 mg/kg/day (approximately 5.7 fold the AUC in patients at the recommended human dose) was associated with maternal toxicity (decreased gestation weight, gravid uterine weight, net weight gain, and food consumption). Nilotinib at doses ≥ 30 mg/kg/day 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.
There are no adequate and well-controlled studies with Tasigna in pregnant women. Women should be advised to avoid becoming pregnant. 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.
Complete blood counts should be performed every two weeks for the first two months and then monthly thereafter. Chemistry panels should be checked periodically. ECGs should be obtained at baseline, seven days after initiation and periodically thereafter, as well as following dose adjustments. [See WARNINGS and PRECAUTIONS]. Laboratory monitoring for patients receiving Tasigna may need to be performed more or less frequently at the physician's discretion.
Carcinogenicity studies have not been performed.
Nilotinib was not mutagenic in a bacterial mutagenesis (Ames) assay, was not clastogenic in a chromosome aberration assay in human lymphocytes, did not induce DNA damage (comet assay) in L5178Y mouse lymphoma cells, nor was it clastogenic in an in vivo rat bone marrow micronucleus assay with two oral treatments at doses up to 2000 mg/kg/dose.
There were no effects on male or female rat and female rabbit mating or fertility at doses up to 180 mg/kg in rats (approximately 4-7 fold for males and females, respectively, the AUC in patients at the recommended human dose) or 300 mg/kg in rabbits (approximately one-half the AUC in patients at the recommended human dose). The effect of Tasigna on human fertility is unknown. In a study where male and female rats were treated with nilotinib at oral doses of 20-180 mg/kg/day (approximately 1-6.6 fold the AUC in patients at the recommended human dose) during the pre-mating and mating periods and then mated, and dosing of pregnant rats continued through gestation day 6, nilotinib increased post-implantation loss and early resorption, and decreased the number of viable fetuses and litter size at all doses tested.
Pregnancy Category D. [See WARNINGS and PRECAUTIONS]
It is not known whether nilotinib is excreted in human milk. One study in lactating rats demonstrates that nilotinib is excreted into milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from nilotinib, a decision should be made whether to discontinue nursing or to discontinue Tasigna taking into account the importance of the drug to the mother.
Safety and effectiveness of Tasigna in pediatric patients have not been established.
In the single clinical study of Tasigna, approximately 30% of patients were 65 or over. CML-CP: There was no difference in major cytogenetic response rate between patients aged < 65 years and those > 65 years. CML-AP: The major hematologic response rate was 31% in patients < 65 years of age and 15% in patients > 65 years.
No major differences were observed for safety in patients ≥ 65 years of age as compared to patients < 65 years.
In the single clinical trial, patients with a history of uncontrolled or significant cardiovascular disease were excluded. [See BOXED WARNING and WARNINGS and PRECAUTIONS].
Tasigna has not been investigated in patients with hepatic impairment. Caution is recommended in patients with hepatic impairment. [See BOXED WARNING, DOSAGE AND ADMINISTRATION and WARNINGS and PRECAUTIONS].
Clinical studies have not been performed in patients with impaired renal function. Clinical 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.
Last updated on RxList: 11/16/2007
No cases of overdose have been reported. In the event of overdose, the patient should be observed and appropriate supportive treatment given.
Do not use in patients with hypokalemia, hypomagnesemia, or long QT syndrome. [See BOXED WARNING]
Last updated on RxList: 11/16/2007
Nilotinib is an inhibitor of the Bcr-Abl kinase. Nilotinib binds to and stabilizes the inactive conformation of the kinase domain of Abl protein. In vitro, nilotinib inhibited Bcr-Abl mediated proliferation of murine leukemic cell lines and human cell lines derived from Ph+ CML patients. Under the conditions of the assays, nilotinib was able to overcome imatinib resistance resulting from Bcr-Abl kinase mutations, in 32 out of 33 mutations tested. In vivo, nilotinib reduced the tumor size in a murine Bcr-Abl xenograft model. Nilotinib inhibited the autophosphorylation of the following kinases at IC50 values as indicated: Bcr-Abl (20-60 nM), PDGFR (69 nM) and c-Kit (210 nM).
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 dosing. Daily serum exposure to nilotinib of 400 mg twice daily dosing at steady state was 35% higher than with 800 mg once daily dosing. There was no relevant increase in exposure to nilotinib when the dose was increased with 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.
The blood-to-serum ratio of nilotinib is 0.68. Serum protein binding is approximately 98% on the basis of in vitro experiments.
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.
In a placebo controlled study in healthy volunteers designed to assess the effects of Tasigna on the QT interval, administration of Tasigna was associated with concentration-dependent QT prolongation; the maximum mean placebo-adjusted QTcF change from baseline was 18 msec (1-sided 95% Upper CI: 26 msec). A positive control was not included in the QT study of healthy volunteers. Peak plasma concentrations in the QT study were 26% lower than those observed in patients enrolled in the single-arm study. [See BOXED WARNING, WARNINGS and PRECAUTIONS and CLINICAL STUDIES].
Tasigna can increase bilirubin levels. A pharmacogenetic analysis of 97 patients evaluated the polymorphisms of UGT1A1 and its potential association with hyperbilirubinemia during Tasigna treatment. In this study, the (TA)7/(TA)7 genotype was associated with a statistically significant increase in the risk of hyperbilirubinemia relative to the (TA)6/(TA)6 and (TA)6/(TA)7 genotypes. However, the largest increases in bilirubin were observed in the (TA)7/(TA)7 genotype (UGT1A1*28) patients. [See WARNINGS and PRECAUTIONS].
A single open label multicenter study was conducted to evaluate the efficacy and safety of Tasigna in patients with imatinib-resistant or -intolerant CML with separate cohorts for chronic and accelerated phase disease. The 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 response. Imatinib intolerance was defined as discontinuation of treatment due to toxicity and lack of a major cytogenetic response at time of study entry. At the time of data cut-off, 280 CML-CP patients with a minimum follow-up of 6 months and 105 CML-AP patients with a minimum follow-up of 4 months were enrolled. Of these, 232 CML-CP and all CML-AP patients were evaluable for efficacy. In this study, about 50% of CML-CP and CML-AP patients were males, over 80% were Caucasian, and approximately 30% were age 65 years or older.
Overall, 73% of patients were imatinib resistant while 27% were imatinib-intolerant. The median time of prior imatinib treatment was approximately 31 months. Prior therapy included hydroxyurea in 85% of patients, interferon in 62% and stem cell or bone marrow transplant in 8%. The median highest prior imatinib dose was 600 mg/day for CML-CP patients and 800 mg/day for CML-AP patients, and the highest prior imatinib dose was ≥ 600 mg/day in 77% of all patients with 44% of patients receiving imatinib doses ≥ 800 mg/day.
Median duration of nilotinib treatment was 8.7 months in CML-CP patients and 5.6 months in CML-AP patients.
The efficacy endpoint in chronic phase CML was unconfirmed major cytogenetic response (MCyR) which included complete and partial cytogenetic responses.
The efficacy endpoint in accelerated phase CML 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 6.
Table 6. Efficacy of Tasigna in CML
| Cytogenetic Response Rate | Chronic Phase |
| (Unconfirmed) (%)a | n=232 |
| Major (95%CI) | 40% (33,46) |
| Complete (95% CI) | 28% (22,34) |
| Partial (95% CI) | 12% (8,16) |
| Accelerated Phase | |
| n=105 | |
| Hematologic Response Rate (95%CI)b | 26% (18,35) |
| Complete Hematologic Response Rate (95% CI) | 18% (11,27) |
| No evidence of Leukemia (95%CI) | 8% (3,15) |
| a Cytogenetic response criteria:
Complete (0% Ph + metaphases) or partial (1-35%). Cytogenetic responses
were based on the percentage of Ph-positive metaphases among ≥ 20 metaphase
cells in each bone marrow sample. b Hematologic response = CHR + NEL (all responses confirmed after 4 weeks). CHR (CML-CP): WBC < 10 x 109 /L, platelets < 450,000/mm3, no blasts or promyelocytes in peripheral blood, < 5% myelocytes + metamyelocytes in bone marrow, < 20% basophils in peripheral blood, and no extramedullary involvement. CHR (CML-AP): neutrophils ≥ 1.5 x 109 /L, platelets ≥ 100 x 109 /L, no myeloblasts in peripheral blood, myeloblasts < 5% in bone marrow, and no extramedullary involvement. NEL: same criteria as for CHR but neutrophils ≥ 1.0 x 109 /L and platelets ≥ 20 x 109 /L without transfusions or bleeding. |
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The median duration of response has not been reached for CML-CP and CML-AP. Based on current follow-up, 59% of CML-CP patients with a major cytogenetic response had a duration of response of at least 6 months. Based on current follow-up, 63% of CML-AP patients with a confirmed hematologic response had a duration of response of at least 6 months.
After imatinib failure, 24 different BCR-ABL mutations were noted in 19% of chronic phase and 25% of accelerated phase CML patients who were evaluated for mutations. Patients harbouring a variety of BCR-ABL mutations associated with imatinib resistance, except T315I, responded to Tasigna.
In this study of imatinib-resistant or intolerant CML patients, the maximum mean QTcF change from baseline at steady state was 10 msec. Increase in QTcF > 60 msec from baseline was observed in 2.1% of the patients and QTcF of > 500 msec was observed in 3 patients ( < 1%). No episodes of torsade de pointes were observed in clinical studies. [See BOXED WARNING, WARNINGS and PRECAUTIONS and CLINICAL PHARMACOLOGY]
Last updated on RxList: 11/16/2007
Medication Guide
TASIGNA® (ta-sig-na)
(nilotinib) Capsules
Read the Medication Guide that comes with Tasigna®before you start using it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your doctor about your medical condition or treatment.
What is the most important information I should know about Tasigna?
TASIGNA can cause a possible life-threatening heart problem called QTc prolongation.QTc prolongation causes an irregular heart beat, which may lead to sudden death.
Your doctor should check your heart with a test called an "ECG":
You may lower your chances for having QTc prolongation with Tasigna if you:
Food and grapefruit products increase blood levels of Tasigna in your body.
Call your doctor right away if you faint or have an irregular heartbeat while taking Tasigna.These can be symptoms of QTc prolongation.
What is Tasigna?
Tasigna is used to treat a type of leukemia called Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in adult patients who:
Tasigna has not been studied in children.
What should I tell my doctor before starting Tasigna?
Tell your doctor about all of your health problems, including if you:
Tell your doctor if you are pregnant or planning to become pregnant. Tasigna can harm a fetus (unborn baby).
Tell your doctor if you are breastfeeding. Women should not breastfeed while taking Tasigna.
How should I take Tasigna?
What are the possible side effects of Tasigna?
Possible Serious side effects include:
Call your doctor right away if you have any of the above problems or symptoms while taking Tasigna.
The most common side effects of Tasigna include:
How should I store Tasigna?
General information about Tasigna
What are the ingredients in Tasigna?
This Medication Guide has been approved by the U.S. Food and
Drug Administration.
Last updated on RxList: 11/16/2007
IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.
NILOTINIB - ORAL
(nye-LOE-ti-nib)
COMMON BRAND NAME(S): Tasigna
WARNING: This drug can infrequently cause serious (possibly fatal) irregular heartbeats (QT prolongation). Nilotinib should not be used in people with low blood levels of certain minerals (potassium, magnesium) or a certain heart problem (long QT syndrome). To lower your risk, your doctor will order certain blood tests (potassium/magnesium levels, liver function tests) before and during treatment with nilotinib. You should have a heart test (EKG) before starting nilotinib. The EKG should be repeated 7 days after your first dose, when your dose is changed, and periodically while you are taking nilotinib.
To decrease the risk of this effect, do not eat for 2 hours before or 1 hour after taking your dose. Other drugs/foods may increase the risk of an irregular heartbeat. Therefore, before taking this drug, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist. See also How to Use and Drug Interactions sections.
USES: Nilotinib is used to treat a certain type of blood cancer (chronic myelogenous leukemia-CML). It works by slowing or stopping the growth of cancer cells.
HOW TO USE: Read the Medication Guide provided by your pharmacist before you start using nilotinib and each time you get a refill. If you have any questions, consult your doctor or pharmacist.
Avoid eating grapefruit or drinking grapefruit juice while being treated with this medication unless your doctor instructs you otherwise. Grapefruit can increase the amount of certain medications in your bloodstream. Consult your doctor or pharmacist for more details.
Take this medication by mouth on an empty stomach, usually twice daily about 12 hours apart or as directed by your doctor. Swallow the capsule whole with water. Do not open, break, or chew the capsules. Do not eat any food for at least 2 hours before or for 1 hour after taking your dose. Taking this medication with food can increase the amount of drug in your body and increase the risk of serious side effects.
The dosage is based on your medical condition, response to treatment, and certain other drugs you may be taking. Your doctor will order blood tests to adjust the dose.
Do not increase your dose or take this medication more often than prescribed. Your condition will not improve any faster, and the risk of serious side effects may be increased.
Since this drug can be absorbed through the skin and lungs, women who are pregnant or who may become pregnant should not handle this medication or breathe the dust from the contents of the capsules.
Tell your doctor immediately if you have severe/persistent diarrhea or vomiting. These conditions can lower the levels of potassium and magnesium in your blood, increasing your risk of a certain serious side effect on the heart (QT prolongation). Your doctor may need to order blood tests or adjust your dose. Seek immediate medical attention if you have signs of low blood minerals such as muscle weakness/cramping. (See also Warning section.)
Many people using this medication have serious side effects. However, your doctor has prescribed this drug because he or she has judged that the benefit to you is greater than the risk of side effects. Careful monitoring by your doctor may decrease your risk.
Tell your doctor immediately if any of these very serious side effects occur: easy bleeding/bruising, bloody/black stool, signs of infection (e.g., fever, chills, persistent sore throat), fast/pounding/irregular heartbeat, severe dizziness, fainting, shortness of breath.
Tell your doctor immediately if any of these rare but very serious side effects occur: confusion, severe abdominal/stomach pain, persistent nausea/vomiting, seizures, unusual tiredness, bloody/pink urine, dark urine, vision changes, yellowing skin/eyes.
A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any of the following symptoms of a serious allergic reaction: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.
This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.
Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.
PRECAUTIONS: Before taking nilotinib, tell your doctor or pharmacist if you are allergic to it; or to lactose/galactose; or if you have any other allergies.
This medication should not be used if you have a certain medical condition. Before using this medicine, consult your doctor or pharmacist if you have: certain heart problem (QT prolongation in the EKG).
Before using this medication, tell your doctor or pharmacist your medical history, especially of: heart disease (e.g., heart failure, slow/irregular heartbeat), family history of certain heart problem (QT prolongation in the EKG, sudden cardiac death), liver disease, low levels of potassium or magnesium in the blood, pancreatitis.
Before having surgery, tell your doctor or dentist that you are taking this medication.
Do not have immunizations/vaccinations without the consent of your doctor, and avoid contact with people who have recently received oral polio vaccine or flu vaccine inhaled through the nose. Wash your hands well to prevent the spread of infections.
To lower your risk of getting cut, bruised, or injured, use caution with sharp objects like razors and nail cutters, and avoid activities such as contact sports.
This medication is not recommended for use during pregnancy. It may harm an unborn baby. Therefore, it is important to prevent pregnancy while taking this medication. Consult your doctor for more details and to discuss using at least 2 reliable forms of birth control (e.g., condoms, birth control pills) while taking this medication. If you become pregnant or think you may be pregnant, tell your doctor immediately.
It is not known whether this drug passes into breast milk. Because of the possible risk to the infant, breast-feeding while using this drug is not recommended. Consult your doctor before breast-feeding.
Many other drugs interact with nilotinib. Some examples are certain HIV medications, antibiotics, antifungals, and medications to treat seizures. Drug interactions may increase serious side effects or cause your medications to stop working properly. Your doctor or pharmacist should check for interactions and may need to adjust your treatment. Therefore, before using nilotinib, tell your doctor and pharmacist of all prescription and nonprescription/herbal products you may use.
Nilotinib and many other medications may affect the heart rhythm (QT prolongation in the EKG). These drugs include amiodarone, dofetilide, pimozide, procainamide, quinidine, sotalol, and erythromycin, among others. This is not a complete list. QT prolongation can infrequently result in serious (sometimes fatal) fast/irregular heartbeat and other symptoms (e.g., severe dizziness, fainting) that require immediate medical attention. Ask your doctor or pharmacist for more details and for instructions on how you may reduce your risk of this effect.
Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: warfarin, certain "water pills" (potassium-wasting diuretics such as hydrochlorothiazide, furosemide).
Check the labels on all your nonprescription/herbal medications. They may contain medications that can interact with nilotinib (e.g., the acid blocker cimetidine, herbal products to lower cholesterol, St. John's wort). Ask your pharmacist about using those products safely.
This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.
OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center.
NOTES: Do not share this medication with others.
Laboratory and/or medical tests (e.g., complete blood count, EKG, electrolyte levels, liver function, lipase levels) should be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.
MISSED DOSE: If you miss a dose, take it as soon as you remember, but do not take if it is less than 2 hours before or 1 hour after a meal. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.
STORAGE: Store at room temperature at 77 degrees F (25 degrees C) away from light and moisture. Brief storage between 59-86 degrees F (15-30 degrees C) is permitted. Do not store in the bathroom. Keep all medicines away from children and pets.
Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.
MEDICAL ALERT: Your condition can cause complications in a medical emergency. For information about enrolling in MedicAlert, call 1-800-854-1166 (USA) or 1-800-668-1507 (Canada).
Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.
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