Tasigna Capsules (Nilotinib Capsules)
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Tasigna Capsules (Nilotinib Capsules)

Tasigna®
(nilotinib) Capsules

WARNING

QT PROLONGATION AND SUDDEN DEATHS

  • Tasigna prolongs the QT interval. Prior to Tasigna administration and periodically, monitor for hypokalemia or hypomagnesemia and correct deficiencies (see WARNINGS AND PRECAUTIONS). Obtain ECGs to monitor the QTc at baseline, seven days after initiation, and periodically thereafter, and follow any dose adjustments.
  • Sudden deaths have been reported in patients receiving nilotinib (see WARNINGS AND PRECAUTIONS). Do not administer Tasigna to patients with hypokalemia, hypomagnesemia, or long QT syndrome (see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS).
  • Avoid use of concomitant drugs known to prolong the QT interval and strong CYP3A4 inhibitors.
  • Patients should avoid food 2 hours before and 1 hour after taking dose (see WARNINGS AND PRECAUTIONS).

DRUG 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 C28H22F3N7O•HCl• H2O and 584. The solubility of nilotinib in aqueous solutions decreases with increasing pH. Nilotinib is notoptically 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:

Tasigna® (nilotinib) Structural Formula Illustration

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.

What are the possible side effects of nilotinib (Tasigna)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Stop using nilotinib and call your doctor at once if you have a serious side effect such as:

  • feeling like you might pass out, fast or pounding heartbeat, seizure (convulsions);
  • pale skin, weakness, feeling light-headed, rapid heart rate, trouble concentrating;
  • easy bruising, unusual bleeding (nose, mouth, vagina, or rectum), purple or red pinpoint spots under your skin;
  • fever, chills, body...

Read All Potential Side Effects and See Pictures of Tasigna Capsules »

What are the precautions when taking nilotinib capsules (Tasigna Capsules)?

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 product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: liver disease, pancreatitis.

Nilotinib may cause a condition that affects the heart rhythm (QT prolongation). QT prolongation can infrequently result in serious (rarely fatal) fast/irregular heartbeat and other symptoms (such as severe dizziness, fainting) that require immediate medical attention. The risk of QT prolongation may be increased if you have certain medical conditions or are taking...

Read All Potential Precautions of Tasigna Capsules »

Last reviewed on RxList: 1/9/2013
This monograph has been modified to include the generic and brand name in many instances.

INDICATIONS

Newly Diagnosed Ph+ CML-CP

Tasigna (nilotinib) is indicated for the treatment of adult patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase. The effectiveness of Tasigna is based on major molecular response and cytogenetic response rates [see Clinical Studies]. The study is ongoing and further data will be required to determine long-term outcome.

Resistant or Intolerant Ph+ CML-CP and CML-AP

Tasigna is indicated for the treatment of chronic phase and accelerated phase Philadelphia chromosome positive chronic myelogenous leukemia (Ph+ 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].

DOSAGE AND ADMINISTRATION

Recommended Dosing

Tasigna should be taken twice daily at approximately 12 hour intervals and must 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].

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 [see CLINICAL PHARMACOLOGY].

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.

Newly Diagnosed Ph+ CML-CP

The recommended dose of Tasigna is 300 mg orally twice daily [see CLINICAL PHARMACOLOGY].

Resistant or Intolerant Ph+ CML-CP and CML-AP

The recommended dose of Tasigna (nilotinib) is 400 mg orally twice daily [see CLINICAL PHARMACOLOGY].

Dose Adjustments or Modifications

QT interval prolongation

Table 1: Dose Adjustments for QT Prolongation

ECGs with a QTc > 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 <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.
  4. If, following dose-reduction to 400 mg once daily, QTcF returns to > 480 msec, Tasigna should be discontinued.
  5. An ECG should be repeated approximately 7 days after any dose adjustment.

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

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* < 1.0 x 109/L and/or platelet counts < 50 x 109/L
  1. Stop Tasigna, and monitor blood counts
  2. Resume within 2 weeks at prior dose if ANC > 1.0 x 109/L and platelets > 50 x 109/L
  3. If blood counts remain low for >2 weeks, reduce the dose to 400 mg once daily
*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
  1. Withhold Tasigna, and monitor serum lipase or amylase
  2. Resume treatment at 400 mg once daily if serum lipase or amylase returns to
Elevated bilirubin ≥ Grade 3
  1. Withhold Tasigna, and monitor bilirubin
  2. Resume treatment at 400 mg once daily if bilirubin returns to
Elevated hepatic transaminases ≥ Grade 3
  1. Withhold Tasigna, and monitor hepatic transaminases
  2. Resume treatment at 400 mg once daily if hepatic transaminases returns to

Other Non-hematologic Toxicities

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 CMLAP) 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 [see WARNINGS AND PRECAUTIONS, Use In Specific Populations].

Hepatic Impairment

If possible, consider alternative therapies. If Tasigna must be administered to patients with hepatic impairment, consider the following dose reduction:

Table 4: Dose Adjustments for Hepatic Impairment (At Baseline)

Newly diagnosed Ph+ CML in chronic phase at 300 mg twice daily Mild, Moderate or Severe* An initial dosing regimen of 200 mg twice daily followed by dose escalation to 300 mg twice daily based on tolerability
Resistant or intolerant Ph+ CML in chronic phase or accelerated phase at 400 mg twice daily Mild or Moderate* An initial dosing regimen of 300 mg twice daily followed by dose escalation to 400 mg twice daily based on tolerability
Severe* A starting dose of 200 mg twice daily followed by a sequential dose escalation to 300 mg twice daily and then to 400 mg twice daily based on tolerability
* Mild = mild hepatic impairment (Child-Pugh Class A); Moderate = moderate hepatic impairment (Child-Pugh Class B); Severe = severe hepatic impairment (Child-Pugh Class C) [see WARNINGS AND PRECAUTIONS, Use in Specific Populations].

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 be interrupted. If patients must be coadministered 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 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, DRUG INTERACTIONS].

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 when co-administered with such agents is unlikely to compensate for the loss of exposure [see DRUG INTERACTIONS].

HOW SUPPLIED

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”.

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 capsules are supplied in blister packs.

150 mg

Carton of 4 blister packs of (4x28) ..............................NDC 0078-0592-87
Blisters of 28 capsules .................................................NDC 0078-0592-51

200 mg

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].

Manufactured by: Novartis Pharma Stein AG, Stein, Switzerland. Distributed by: Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936. December 2012/October 2011

Last reviewed on RxList: 1/9/2013
This monograph has been modified to include the generic and brand name in many instances.

SIDE EFFECTS

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, WARNINGS AND PRECAUTIONS].

Myelosuppression [see WARNINGS AND PRECAUTIONS]

QT prolongation [see BOXED WARNING, WARNINGS AND PRECAUTIONS]

Sudden deaths [see BOXED WARNING, WARNINGS AND PRECAUTIONS]

Elevated serum lipase [see WARNINGS AND PRECAUTIONS]

Hepatotoxicity [see WARNINGS AND PRECAUTIONS]

Electrolyte abnormalities [see BOXED WARNING, WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

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 Patients with Newly Diagnosed Ph+ CML-CP

The data below reflect exposure to Tasigna from a randomized trial in patients with newly diagnosed Ph+ CML in chronic phase treated at the recommended dose of 300 mg twice daily (n=279). The median time on treatment in the nilotinib 300 mg twice daily group was 36.4 months (range 0.1 – 46.7 months). The median actual dose intensity was 594 mg/day in the nilotinib 300 mg twice daily group. The most common ( > 10%) non-hematologic adverse drug reactions were rash, pruritus, headache, nausea, fatigue and myalgia. Upper abdominal pain, alopecia, constipation, diarrhea, dry skin, muscle spasms, arthralgia, abdominal pain, peripheral edema, vomiting, pain in extremity, dyspepsia, and asthenia were observed less commonly ( ≤ 10% and > 5%) and have been of mild to moderate severity, manageable and generally did not require dose reduction. Pleural and pericardial effusions, occurred in 1% and < 1% of patients, respectively. Gastrointestinal hemorrhage was reported in 2.5% of patients.

Increase in QTcF > 60 msec from baseline was observed in 1 patient (0.4%) in the 300 mg twice daily treatment group. No patient had an absolute QTcF of > 500 msec while on study drug.

The most common hematologic adverse drug reactions (all grades) were myelosuppression including: thrombocytopenia (18%), neutropenia (15%) and anemia (7%). See Table 7 for Grade 3/4 laboratory abnormalities.

Discontinuation due to adverse reactions, regardless of relationship to study drug, was observed in 10% of patients.

In Patients with Resistant or Intolerant Ph+ CML-CP and CML-AP

In the single open-label multicenter clinical trial, a total of 458 patients with Ph+ CML-CP and CML-AP resistant to or intolerant to at least one prior therapy including imatinib were treated (CML-CP=321; CMLAP= 137) at the recommended dose of 400 mg twice daily.

The median duration of exposure in days for CML-CP and CML-AP patients is 561 (range 1-1096) and 264 (range 2-1160), respectively. The median dose intensity for patients with CML-CP and CML-AP is 789 mg/day (range 151–1110) and 780 mg/day (range 150-1149), respectively 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 20 (range 1-345), and the median duration in days of dose interruptions for the CML-AP patients was 23 (range 1–234).

In patients with CML-CP, the most commonly reported non-hematologic adverse drug reactions ( ≥ 10%) were rash, pruritus, nausea, fatigue, headache, constipation, diarrhea, vomiting and myalgia. The common serious drug-related adverse reactions ( ≥ 1% and < 10%) were thrombocytopenia, neutropenia and anemia.

In patients with CML-AP, the most commonly reported non-hematologic adverse drug reactions ( ≥ 10%) were rash, pruritus and fatigue. The common serious adverse drug reactions ( ≥ 1% and < 10%) were thrombocytopenia, neutropenia, febrile neutropenia, pneumonia, leukopenia, intracranial hemorrhage, elevated lipase and pyrexia.

Sudden deaths and QT prolongation were reported. The maximum mean QTcF change from baseline at steadystate was 10 msec. Increase in QTcF > 60 msec from baseline was observed in 4.1% of the patients and QTcF of > 500 msec was observed in 4 patients ( < 1%) [see BOXED WARNING, WARNINGS AND PRECAUTIONS, CLINICAL PHARMACOLOGY].

Discontinuation due to adverse drug reactions was observed in 16% of CML-CP and 10% of CML-AP patients.

Most Frequently Reported Adverse Reactions

Tables 5 and 6 show the percentage of patients experiencing non-hematologic adverse reactions (excluding laboratory abnormalities) regardless of relationship to study drug. Adverse reactions reported in greater than 10% of patients who received at least one dose of Tasigna are listed.

Table 5: Most Frequently Reported Non-hematologic Adverse Reactions (Regardless of Relationship to Study Drug) in Patients with Newly Diagnosed Ph+ CML-CP ( ≥ 10% in Tasigna 300 mg twice daily or Imatinib 400 mg once daily groups) 36-Month Analysisa

    Patients with Newly Diagnosed Ph+ CML-CP
TASIGNA 300 mg twice daily Imatinib 400 mg once daily TASIGNA 300 mg twice daily Imatinib 400 mg once daily
N=279 N=280 N=279 N=280
Body System and Preferred Term All Grades (%) CTC Gradesb 3/ 4 (%)
Skin and subcutaneous tissue disorders Rash 38 18 < 1 2
  Pruritus 21 7 < 1 0
  Alopecia 13 6 0 0
  Dry skin 10 6 0 0
Gastrointestinal disorders Nausea 21 40 1 1
  Constipation 18 7 < 1 0
  Diarrhea 16 44 < 1 3
  Vomiting 14 25 0 < 1
  Abdominal pain upper 17 13 1 < 1
  Abdominal pain 15 11 1 < 1
  Dyspepsia 8 11 0 0
Nervous system disorders Headache 30 20 3 < 1
  Dizziness 10 10 0 < 1
General disorders and administration site conditions Fatigue 22 17 1 1
  Pyrexia 13 12 < 1 0
  Asthenia 13 10 < 1 0
  Peripheral edema 9 20 < 1 0
  Face edema < 1 13 0 < 1
Musculoskeletal and connective tissue disorders Myalgia 18 18 < 1 < 1
  Arthralgia 18 14 < 1 < 1
  Muscle spasms 12 33 0 1
  Pain in extremity 11 14 < 1 < 1
  Back pain 15 14 < 1 1
Respiratory, thoracic and mediastinal disorders Cough 15 11 0 0
  Oropharyngeal pain 10 6 0 0
Infections and infestations Nasopharyngitis 24 19 0 0
  Upper respiratory tract infection 15 11 < 1 0
  Influenza 11 8 0 0
Eye disorders Eyelid edema 1 18 0 < 1
  Periorbital edema < 1 15 0 0
Psychiatric disorders Insomnia 10 9 0 0
a Excluding laboratory abnormalities
b NCI Common Terminology Criteria for Adverse Events, Version 3.0

Table 6: Most Frequently Reported Non-hematologic Adverse Reactions in Patients with Resistant or Intolerant Ph+ CML Receiving Tasigna 400 mg Twice Daily (Regardless of Relationship to Study Drug) ( ≥ 10% in any Group) 24-Month Analysisa

Body System and Preferred Term   CML-CP
N=321
CML-AP
N=137
All Grades (%) CTC Gradesb 3 / 4 (%) All Grades (%) CTC Gradesb 3 / 4 (%)
Skin and subcutaneous tissue disorders Rash 36 2 29 0
  Pruritus 32 < 1 20 0
  Night sweat 12 < 1 27 0
  Alopecia 11 0 12 0
Gastrointestinal disorders Nausea 37 1 22 <1
  Constipation 26 < 1 19 0
  Diarrhea 28 3 24 2
  Vomiting 29 < 1 13 0
  Abdominal pain 15 2 16 3
  Abdominal pain upper 14 < 1 12 <1
  Dyspepsia 10 < 1 4 0
Nervous system disorders Headache 35 2 20 1
General disorders and administration site conditions Fatigue 32 3 23 < 1
  Pyrexia 22 < 1 28 2
  Asthenia 16 0 14 1
  Peripheral edema 15 < 1 12 0
  Myalgia 19 2 16 < 1
Musculoskeletal and connective tissue disorders Arthralgia 26 2 16 0
  Muscle spasms 13 < 1 15 0
  Bone pain 14 < 1 15 2
  Pain in extremity 20 2 18 1
  Back pain 17 2 15 < 1
  Musculoskeletal pain 11 < 1 12 1
Respiratory, thoracic and mediastinal disorders Cough 27 < 1 18 0
  Dyspnea 15 2 9 2
  Oropharyngeal pain 11 0 7 0
Infections and infestations Nasopharyngitis 24 < 1 15 0
  Upper respiratory tract infection 12 0 10 0
Metabolism and nutrition disorders Decreased appetitec 15 < 1 17 < 1
Psychiatric disorders Insomnia 12 1 7 0
Vascular disorders Hypertension 10 2 11 < 1
a Excluding laboratory abnormalities
b NCI Common Terminology Criteria for Adverse Events, Version 3.0
c Also includes preferred term anorexia

Laboratory Abnormalities

Table 7 shows the percentage of patients experiencing treatment-emergent Grade 3/4 laboratory abnormalities in patients who received at least one dose of Tasigna.

Table 7: Percent Incidence of Clinically Relevant Grade 3/4* Laboratory Abnormalities

  Patient Population
Newly Diagnosed Ph+ CML-CP Resistant or Intolerant Ph+
TASIGNA 300 mg twice daily N=279 (%) Imatinib 400 mg once daily
N=280 (%)
CML-CP CML-AP
TASIGNA 400 mg twice daily
N=321 (%)
TASIGNA 400 mg twice daily
N=137 (%)
Hematologic Parameters
Thrombocytopenia 10 9 301 423
Neutropenia 12 21 312 424
Anemia 4 6 11 27
Biochemistry Parameters
Elevated lipase 8 4 18 18
Hyperglycemia 6 0 12 6
Hypophosphatemia 6 9 17 15
Elevated bilirubin (total) 4 < 1 7 9
Elevated SGPT (ALT) 4 3 4 4
Hyperkalemia 2 1 6 4
Hyponatremia 1 < 1 7 7
Hypokalemia < 1 2 2 9
Elevated SGOT (AST) 1 1 3 2
Decreased albumin 0 < 1 4 3
Hypocalcemia < 1 < 1 2 5
Elevated alkaline phosphatase 0 < 1 < 1 1
Elevated creatinine 0 < 1 < 1 < 1
*NCI Common Terminology Criteria for Adverse Events, version 3.0
1CML-CP: Thrombocytopenia: 12% were grade 3, 18% were grade 4
2CML-CP: Neutropenia: 16% were grade 3, 15% were grade 4
3CML-AP: Thrombocytopenia: 11% were grade 3, 32% were grade 4
4CML-AP: Neutropenia: 16% were grade 3, 26% were grade 4

Additional Data from Clinical Trials

The following adverse drug reactions were reported in patients in the Tasigna clinical studies at the recommended doses. These adverse drug reactions are ranked under a heading of frequency, the most frequent first using the following convention: common ( ≥ 1% and < 10%), uncommon ( ≥ 0.1% and < 1%), and unknown frequency (single events). For laboratory abnormalities, very common events ( ≥ 10%), which were not included in Tables 5 and 6, 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: Common: folliculitis, upper respiratory tract infection (including pharyngitis, nasopharyngitis, rhinitis). Uncommon: pneumonia, bronchitis, urinary tract infection, candidiasis (including oral candidiasis), gastroenteritis. Unknown frequency: sepsis, subcutaneous abscess, anal abscess, furuncle, tinea pedis.

Neoplasms Benign, Malignant and Unspecified: Common: Skin papilloma. Unknown frequency: oral papilloma, paraproteinemia.

Blood and Lymphatic System Disorders: Common: febrile neutropenia, pancytopenia, lymphopenia. Unknown frequency: thrombocythemia, leukocytosis, eosinophilia.

Immune System Disorders: Unknown frequency: hypersensitivity.

Endocrine Disorders: Uncommon: hyperthyroidism, hypothyroidism. Unknown frequency: hyperparathyroidism secondary, thyroiditis.

Metabolism and Nutrition Disorders: Very Common: hypophosphatemia. Common: electrolyte imbalance (including hypomagnesemia, hyperkalemia, hypokalemia, hyponatremia, hypocalcemia, hypercalcemia, hyperphosphatemia), diabetes mellitus, hyperglycemia, hypercholesterolemia, hyperlipidemia. Uncommon: gout, dehydration, increased appetite. Unknown frequency: hyperuricemia, hypoglycemia, dyslipidemia.

Psychiatric Disorders: Common: depression, insomnia, anxiety. Unknown frequency: disorientation, confusional state, amnesia, dysphoria.

Nervous System Disorders: Common: dizziness, peripheral neuropathy, hypoesthesia, paresthesia. Uncommon: intracranial hemorrhage, migraine, loss of consciousness (including syncope), tremor, disturbance in attention, hyperesthesia. Unknown frequency: brain edema, optic neuritis, lethargy, dysesthesia, restless legs syndrome.

Eye Disorders: Common: eye hemorrhage, periorbital edema, eye pruritus, conjunctivitis, dry eye (including xerophthalmia). Uncommon: vision impairment, vision blurred, visual acuity reduced, photopsia, hyperemia (scleral, conjunctival, ocular), eye irritation, conjunctival hemorrhage. Unknown frequency: papilloedema, diplopia, photophobia, eye swelling, blepharitis, eye pain, chorioretinopathy, conjunctivitis allergic, ocular surface disease.

Ear and Labyrinth Disorders: Common: vertigo. Unknown frequency: hearing impaired, ear pain, tinnitus.

Cardiac Disorders: Common: angina pectoris, arrhythmia (including atrioventricular block, cardiac flutter, extrasystoles, atrial fibrillation, tachycardia, bradycardia), palpitations, electrocardiogram QT prolonged. Uncommon: cardiac failure, pericardial effusion, coronary artery disease, cyanosis, cardiac murmur. Unknown frequency: myocardial infarction, ventricular dysfunction, pericarditis, ejection fraction decrease.

Vascular Disorders: Common: hypertension, flushing. Uncommon: hypertensive crisis, peripheral arterial occlusive disease, hematoma. Unknown frequency: shock hemorrhagic, hypotension, thrombosis, arteriosclerosis.

Respiratory, Thoracic and Mediastinal Disorders: Common: dyspnea, dyspnea exertional, epistaxis, cough, dysphonia. Uncommon: pulmonary edema, pleural effusion, interstitial lung disease, pleuritic pain, pleurisy, pharyngolaryngeal pain, throat irritation. Unknown frequency: pulmonary hypertension, wheezing, oropharyngeal pain.

Gastrointestinal Disorders: Common: pancreatitis, abdominal discomfort, abdominal distension, dyspepsia, dysgeusia, flatulence. Uncommon: gastrointestinal hemorrhage, melena, mouth ulceration, gastroesophageal reflux, stomatitis, esophageal pain, dry mouth, sensitivity of teeth. Unknown frequency: gastrointestinal ulcer perforation, retroperitoneal hemorrhage, hematemesis, gastric ulcer, esophagitis ulcerative, subileus, gastritis, enterocolitis, hemorrhoids, hiatus hernia, rectal hemorrhage, gingivitis.

Hepatobiliary Disorders: Very Common: hyperbilirubnemia. Common: hepatic function abnormal. Uncommon: hepatotoxicity, toxic hepatitis, jaundice. Unknown frequency: cholestasis, hepatomegaly.

Skin and Subcutaneous Tissue Disorders: Common: night sweats, eczema, urticaria, erythema, hyperhidrosis, contusion, acne, dermatitis (including allergic, exfoliative and acneiform), dry skin. Uncommon: exfoliative rash, drug eruption, pain of skin, ecchymosis, swelling of face. Unknown frequency: psoriasis, erythema multiforme, erythema nodosum, skin ulcer, palmar-plantar erythrodysesthesia syndrome, petechiae, photosensitivity, blister, dermal cyst, sebaceous hyperplasia, skin atrophy, skin discoloration, skin exfoliation, skin hyperpigmentation, skin hypertrophy, hyperkeratosis.

Musculoskeletal and Connective Tissue Disorders: Common: bone pain, musculoskeletal chest pain, musculoskeletal pain, back pain, neck pain, flank pain. Uncommon: musculoskeletal stiffness, muscular weakness, joint swelling. Unknown frequency: arthritis.

Renal and Urinary Disorders: Common: pollakiuria. Uncommon: dysuria, micturition urgency, nocturia. Unknown frequency: renal failure, hematuria, urinary incontinence, chromaturia.

Reproductive System and Breast Disorders: Uncommon: breast pain, gynecomastia, erectile dysfunction. Unknown frequency: breast induration, me orrhagia, nipple swelling.

General Disorders and Administration Site Conditions: Common: pyrexia, chest pain (including non-cardiac chest pain), pain, chest discomfort, malaise. Uncommon: face edema, gravitational edema, influenza-like illness, chills, feeling body temperature change (including feeling hot, feeling cold). Unknown frequency: localized edema.

Investigations: Very Common: alanine aminotransferase increased, aspartate aminotransferase increased, lipase increased. Common: hemoglobin decreased, blood amylase increased, gamma-glutamyltransferase increased, blood creatinine phosphokinase increased, blood alkaline phosphatase increased, weight decreased, weight increased. Uncommon: blood lactate dehydrogenase increased, blood urea increased, globulins decreased.

Unknown frequency: troponin increased, blood bilirubin unconjugated increased, blood insulin increased, blood insulin decreased, insulin C-peptide decreased, lipoprotein increased (including very low density and high density), blood parathyroid hormone increased.

Read the Tasigna Capsules (nilotinib capsules) Side Effects Center for a complete guide to possible side effects »

DRUG INTERACTIONS

Effects of Nilotinib on Drug Metabolizing Enzymes and Drug Transport Systems

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 vitro 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 with midazolam (a CYP3A4 substrate) to healthy subjects increased midazolam exposure by 30%. Single-dose administration of Tasigna to healthy subjects did not change the pharmacokinetics and pharmacodynamics of warfarin (a CYP2C9 substrate). The ability of Tasigna to induce metabolism has not been determined in vivo. Exercise caution when co-administering Tasigna with substrates for these enzymes that have a narrow therapeutic index.

Nilotinib inhibits human P-glycoprotein (P-gp). If Tasigna is administered with drugs that are substrates of Pgp, increased concentrations of the substrate drug are likely, and caution should be exercised.

Drugs that Inhibit or Induce Cytochrome P450 3A4 Enzymes

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 with agents that are strong CYP3A4 inhibitors should be avoided [see BOXED WARNING, DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS]. Concomitant use of Tasigna 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, concomitant use of alternative therapeutic agents with less potential for CYP3A4 induction should be selected.

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.

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%.

Drugs that Affect Gastric pH

Nilotinib has pH-dependent solubility, with decreased solubility at higher pH. Drugs such as proton pump inhibitors that inhibit gastric acid secretion to elevate the gastric pH may decrease the solubility of nilotinib and reduce its bioavailability. In healthy subjects, co-administration of a single 400 mg dose of Tasigna with multiple doses of esomeprazole (a proton pump inhibitor) at 40 mg daily decreased the nilotinib AUC by 34%. Increasing the dose of Tasigna when co-administered with such agents is not likely to compensate for the loss of exposure. Since proton pump inhibitors affect pH of the upper GI tract for an extended period, separation of doses may not eliminate the interaction. The concomitant use of proton pump inhibitors with Tasigna should be used with caution. If an H2 blocker or an antacid is necessary, the doses between the H2 blocker and Tasigna or the doses between the antacid and Tasigna should be separated by at least several hours. However, no clinical study has been conducted to evaluate the effect of H2 blockers or antacids on nilotinib pharmacokinetics.

Drugs that Inhibit Drug Transport Systems

Nilotinib is a substrate of the efflux transporter P-glycoprotein (P-gp, ABCB1). If Tasigna is administered with drugs that inhibit P-gp, increased concentrations of nilotinib are likely, and caution should be exercised.

Drugs that May Prolong the QT Interval

The administration of Tasigna with agents that may prolong the QT interval such as anti-arrhythmic medicines should be avoided [see BOXED WARNING, DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS].

Last reviewed on RxList: 1/9/2013
This monograph has been modified to include the generic and brand name in many instances.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Myelosuppression

Treatment with Tasigna can cause Grade 3/4 thrombocytopenia, neutropenia and anemia. Perform complete blood counts 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].

QT Prolongation

Tasigna has been shown to prolong cardiac ventricular repolarization as measured by the QT interval on the surface ECG in a concentration-dependent manner [see ADVERSE REACTIONS, CLINICAL PHARMACOLOGY]. 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 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.

Significant prolongation of the QT interval may occur when Tasigna is inappropriately taken with food and/or strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT. Therefore, coadministration 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

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.

Elevated Serum Lipase

The use of Tasigna can cause increases in serum lipase. Caution is recommended in patients with a previous history of pancreatitis. If lipase elevations are accompanied by abdominal symptoms, interrupt dosing and consider appropriate diagnostics to exclude pancreatitis. Test serum lipase levels monthly or as clinically indicated.

Hepatotoxicity

The use of Tasigna may result in elevations in bilirubin, AST/ALT, and alkaline phosphatase. Hepatic function tests should be checked monthly or as clinically indicated.

Electrolyte Abnormalities

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.

Drug Interactions

The administration of Tasigna with agents that are strong CYP3A4 inhibitors or anti-arrhythmic drugs (including, but not limited to amiodarone, disopyramide, procainamide, quinidine and sotalol) and other drugs that may prolong QT interval (including, but not limited to chloroquine, clarithromycin, haloperidol, methadone, moxifloxacin and pimozide) 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, DRUG INTERACTIONS].

Food Effects

The bioavailability of nilotinib is increased with food. Tasigna must not be taken with food. No food should be taken for at least 2 hours before and for 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].

Hepatic Impairment

Nilotinib exposure is increased in patients with impaired hepatic function. A lower starting dose is recommended for patients with mild to severe hepatic impairment (at baseline) and QT interval should be monitored closely [see DOSAGE AND ADMINISTRATION and Use in Specific Populations].

Tumor Lysis Syndrome

Cases of tumor lysis syndrome have been reported in Tasigna 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.

Total Gastrectomy

The exposure of nilotinib is reduced in patients with total gastrectomy. More frequent follow-up of these patients should be considered. Dose increase or alternative therapy may be considered in patients with total gastrectomy [see CLINICAL PHARMACOLOGY].

Lactose

Since the capsules contain lactose, Tasigna is not recommended for patients with rare hereditary problems of galactose intolerance, severe lactase deficiency with a severe degree of intolerance to lactose-containing products or of glucose-galactose malabsorption.

Monitoring Laboratory Tests

Complete blood counts should be performed every two weeks for the first two months and then monthly thereafter. Chemistry panels, including the lipid profile, should be checked periodically. ECGs should be obtained at baseline, seven days after initiation and periodically thereafter, as well as following dose adjustments. Laboratory monitoring for patients receiving Tasigna may need to be performed more or less frequently at the physician's discretion.

Use in Pregnancy

There are no adequate and well controlled studies of Tasigna in pregnant women. However, Tasigna may cause fetal harm when administered to a pregnant woman. Nilotinib caused embryo-fetal toxicities in animals at maternal exposures that were lower than the expected human exposure at the recommended doses of 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. Women of child-bearing potential should avoid becoming pregnant while taking Tasigna [see Use in Specific Populations].

Patient Counseling Information

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.

Taking Tasigna

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 anytime during Tasigna treatment [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS and Medication Guide].

If a dose is missed, the patient should not take a make-up dose, but should resume taking the next prescribed daily dose.

Should patients be unable to swallow capsules, the contents of each capsule may be dispersed in one teaspoon of applesauce and the mixture swallowed immediately (within 15 minutes).

Drug Interactions

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].

Pregnancy

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 highly effective contraceptives if taking Tasigna. Sexually active female patients taking Tasigna should use adequate contraception [see WARNINGS AND PRECAUTIONS and Use in Specific Populations].

Compliance

Patients should be advised of the following:

  • Continue taking Tasigna every day for as long as their doctor tells them.
  • This is a long-term treatment.
  • Do not change dose or stop taking Tasigna without first consulting their doctor.
  • If a dose is missed, take the next dose as scheduled. Do not take a double dose to make up for the forgotten capsules.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

A 2-year carcinogenicity study was conducted orally in rats at nilotinib doses of 5, 15 and 40 mg/kg/day. Exposures in animals at the highest dose tested were approximately 2-3 fold the human exposure (based on AUC) at the nilotinib dose of 400 mg twice daily. The study was negative for carcinogenic findings.

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 dose of 400 mg twice daily) or 300 mg/kg in rabbits (approximately one-half the AUC in patients at the dose of 400 mg twice daily). 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 dose of 400 mg twice daily) 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.

Use In Specific Populations

Pregnancy

Pregnancy Category D [see WARNINGS AND PRECAUTIONS].

Based on its mechanism of action and findings in animals, Tasigna may cause fetal harm when administered to a pregnant woman. There are no adequate and well controlled studies with Tasigna in pregnant women. Women should be advised to avoid becoming pregnant while on Tasigna. 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/m² (approximately 0.7 times the clinical dose of 400 mg twice daily based on body surface area). At doses up to 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.

Nursing Mothers

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 Tasigna, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

The safety and effectiveness of Tasigna in pediatric patients 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 < 65 years and those ≥ 65 years.
  • Patients with resistant or intolerant CML-CP: There was no difference in major cytogenetic response rate between patients aged < 65 years and those ≥ 65 years.
  • Patients with resistant or intolerant CML-AP: The hematologic response rate was 44% in patients < 65 years of age and 29% in patients ≥ 65 years.

No major differences for safety were observed in patients ≥ 65 years of age as compared to patients < 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].

Hepatic Impairment

Nilotinib exposure is increased in patients with impaired hepatic function. In a study of subjects with mild to severe hepatic impairment following a single dose administration of 200 mg of Tasigna, the mean AUC values were increased on average of 35%, 35% and 56% in subjects with mild (Child-Pugh class A, score 5-6), moderate (Child-Pugh class B, score 7-9) and severe hepatic impairment (Child-Pugh class C, score 10-15), respectively, compared to a control group of subjects with normal hepatic function. Table 8 summarizes the Child-Pugh Liver Function Classification applied in this study. A lower starting dose is recommended in patients with hepatic impairment and the QT interval should be monitored closely in these patients [see DOSAGE AND ADMINISTRATION].

Table 8: Child-Pugh Liver Function Classification

Assessment Degree of Abnormality Score
Encephalopathy Grade None 1
1 or 2 2
3 or 4 3
Ascites Absent 1
Slight 2
Moderate 3
Total Bilirubin (mg/dL) < 2 1
2 - 3 2
> 3 3
Serum Albumin (g/dL) > 3.5 1
2.8 - 3.5 2
< 2.8 3
Prothrombin Time (seconds prolonged) < 4 1
4 - 6 2
> 6 3

Renal Impairment

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 reviewed on RxList: 1/9/2013
This monograph has been modified to include the generic and brand name in many instances.

OVERDOSE

Overdose with nilotinib has been reported, where an unspecified number of Tasigna capsules were ingested in combination with alcohol and other drugs. Events included neutropenia, vomiting, and drowsiness. In the event of overdose, the patient should be observed and appropriate supportive treatment given.

CONTRAINDICATIONS

Do not use in patients with hypokalemia, hypomagnesemia, or long QT syndrome [see BOXED WARNING].

Last reviewed on RxList: 1/9/2013
This monograph has been modified to include the generic and brand name in many instances.

CLINICAL PHARMACOLOGY

Mechanism of Action

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 patients with Ph+ CML. 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), c-KIT (210 nM), CSF-1R (125-250 nM) and DDR1 (3.7 nM).

Pharmacokinetics

Absorption and Distribution

The absolute bioavailability of nilotinib has not been determined. As compared to an oral drink solution (pH of 1.2 to 1.3), relative bioavailability of nilotinib capsule is approximately 50%. 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 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 in vitro 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 [see WARNINGS AND PRECAUTIONS].

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.

QT/QTc Prolongation

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 ADVERSE REACTIONS].

Pharmacogenomics

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].

Clinical Studies

Newly Diagnosed Ph+ CML-CP

An open label, multicenter, randomized trial was conducted to determine the efficacy of Tasigna 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). Subsequent analyses were done when patients completed 24 and 36 months of treatment (or discontinued earlier). The median time on treatment was approximately 36 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.

Two patients in the nilotinib arm progressed to either accelerated phase or blast crisis (both within the first 6 months of treatment) while 17 patients on the imatinib arm progressed to either accelerated phase or blast crisis (8 patients within first 6 months, 4 within 6-12 months, 4 within 12-18 months and 1 within 18-24 months). Between the 24 and 36 month analyses, there were no new progressions to AP/BC in either treatment arm.

Table 9: Efficacy (MMR and CCyR) of TASIGNA Compared to Imatinib in Newly Diagnosed Ph+ CMLCP

  TASIGNA 300 mg twice daily
N = 282
Imatinib 400 mg once daily
N = 283
MMR at 12 months (95% CI) 44% (38.4, 50.3) 22% (17.6, 27.6)
  P-Valuea < 0.0001
CCyRb by 12 months (95% CI) 80% (75.0, 84.6) 65% (59.2, 70.6)
MMR at 24 months (95% CI) 62% (55.8,67.4) 38% (31.8,43.4)
CCyRb by 24 months (95% CI) 87% (82.4,90.6) 77% (71.7, 81.8)
a CMH test stratified by Sokal risk group
b CCyR: 0% Ph+ metaphases. Cytogenetic responses were based on the percentage of Ph-positive metaphases among ≥ 20 metaphase cells in each bone marrow sample.

Patients with Resistant or Intolerant Ph+ CML-CP and CML-AP

A single arm, open label, multicenter study was conducted to evaluate the efficacy and safety of Tasigna (400 mg twice daily) 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, 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 intolerant. The median time of prior imatinib treatment was approximately 32 (CML-CP) and 28 (CML-AP) months. Prior 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 patientswith 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 CMLAP patients are reported in Table 10.

Median durations of response had not been reached at the time of data analysis.

Table 10: Efficacy of Tasigna in Resistant or Intolerant Ph+ CML-CP and CML-AP

Cytogenetic Response Rate (Unconfirmed) (%)a Chronic Phase
(n = 321)
Major (95% CI) 51% (46% - 57%)
Complete (95% CI) 37% (32% - 42%)
Partial (95% CI) 15% (11% - 19%)
  Accelerated Phase
(n = 137)
Hematologic Response Rate (Confirmed) (95% CI)b 39% (31% - 48%)
Complete Hematologic Response Rate (95% CI) 30% (22% - 38%)
No Evidence of Leukemia (95% CI) 9% (5% -16%)
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.

Patients with Chronic Phase

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%.

Patients with Accelerated Phase

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.

Last reviewed on RxList: 1/9/2013
This monograph has been modified to include the generic and brand name in many instances.

PATIENT INFORMATION

Medication Guide

TASIGNA®
(ta-sig-na)
(nilotinib) Capsules

Read this Medication Guide before you start taking Tasigna® and each time you get a refill. There may be new information. This information 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 heartbeat, which may lead to sudden death.

Your doctor should check the electrical activity of your heart with a test called an electrocardiogram (ECG):

  • before starting Tasigna
  • 7 days after starting Tasigna
  • with any dose changes
  • regularly during Tasigna treatment

You may lower your chances for having QTc prolongation with Tasigna if you:

  • Take Tasigna:
    • on an empty stomach. Do not take Tasigna with food.
    • at least 2 hours after eating any food, and
    • wait at least 1 hour before eating any food
  • Avoid grapefruit, grapefruit juice, and any supplement containing grapefruit extract while taking Tasigna. Food and grapefruit products increase the amount of Tasigna in your body.
  • Avoid taking other medicines or supplements with Tasigna that can also cause QTc prolongation.
  • Tasigna can interact with many medicines and supplements and increase your chance for serious and life-threatening side effects.
  • Do not take any other medicine while taking Tasigna unless your doctor tells you it is okay to do so.
  • If you cannot swallow Tasigna capsules whole, you may open the Tasigna capsule and sprinkle the contents of each capsule in 1 teaspoon of applesauce (puréed apple). Swallow the mixture right away (within 15 minutes). For more information, see “How should I take Tasigna?”

Call your doctor right away if you feel lightheaded, faint or have an irregular heartbeat while taking Tasigna. These can be symptoms of QTc prolongation.

What is Tasigna?

Tasigna is a prescription medicine used to treat a type of leukemia called Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in adults who:

  • are newly diagnosed, or
  • are no longer benefiting from previous other treatments, including treatment with imatinib (Gleevec®), or
  • have taken other treatments, including imatinib (Gleevec®), and cannot tolerate them

It is not known if Tasigna is safe or effective in children.

Who should not take Tasigna?

Do not take if you have:

  • low levels of potassium or magnesium in your blood
  • long QTc syndrome

What should I tell my doctor before starting Tasigna?

Tasigna may not be right for you. Before taking Tasigna, tell your doctor about all of your medical conditions, including if you have:

  • heart problems
  • irregular heartbeat
  • QTc prolongation or a family history of it
  • liver problems
  • had pancreatitis
  • low blood levels of potassium or magnesium in your blood
  • a severe problem with lactose (milk sugar) or other sugars. The Tasigna capsules contain lactose. Most patients who have mild or moderate lactose intolerance can take Tasigna.
  • had a surgical procedure involving the removal of the entire stomach (total gastrectomy)
  • are pregnant or plan to become pregnant. Tasigna may harm your unborn baby. If you are able to become pregnant, you should use effective birth control during treatment with Tasigna. Talk to your doctor about the best birth control methods to prevent pregnancy while you are taking Tasigna.
  • are breastfeeding or plan to breastfeed. It is not known if Tasigna passes into your breast milk. You and your doctor should decide if you will take Tasigna or breastfeed. You should not do both.

Tell your doctor about all the medicines you take, including prescription and non prescription medicines, vitamins and herbal supplements.

Tasigna can interact with many medicines and supplements and increase your chance for serious and life-threatening side effects. See “What is the most important information I should know about Tasigna?”

Know the medicines you take. Keep a list of them and show it to your doctor and pharmacist when you get a new medicine.

How should I take Tasigna?

  • Take Tasigna exactly as your doctor tells you to take it. Do not change your dose or stop taking Tasigna unless your doctor tells you.
  • Tasigna is a long-term treatment.
  • Your doctor will tell you how many Tasigna capsules to take and when to take them.
    • Do not take Tasigna with food. Take Tasigna at least 2 hours after you eat and at least 1 hour before you eat.
  • Swallow Tasigna capsules whole with water. If you cannot swallow Tasigna capsules whole, tell your doctor
  • If you cannot swallow Tasigna capsules whole:
    • Open the Tasigna capsules and sprinkle the contents in 1 teaspoon of applesauce (puréed apple).
      • Do not use more than 1 teaspoon of applesauce.
      • Only use applesauce. Do not sprinkle Tasigna onto other foods.
    • Swallow the mixture right away (within 15 minutes).
  • Do not drink grapefruit juice, eat grapefruit, or take supplements containing grapefruit extract at any time during treatment. See “What is the most important information I should know about Tasigna?”
  • If you miss a dose, just take your next dose as scheduled. Do not make up for a missed dose.
  • If you take too much Tasigna, call your doctor or poison control center right away. Symptoms may include vomiting and drowsiness. During treatment with Tasigna your doctor will do tests to check for side effects and to see how well Tasigna is working for you. The tests will check your:
    • heart
    • blood cells (white blood cells, red blood cells, and platelets). Your blood cells should be checked every two weeks for the first two months and then monthly.
    • electrolytes (potassium, magnesium)
    • pancreas and liver function
    • bone marrow samples
  • Your doctor may change your dose. Your doctor may have you stop Tasigna for some time or lower your dose if you have side effects with it.

What are the possible side effects of Tasigna?

Tasigna may cause serious side effects including:

  • See “What is the most important information I should know about Tasigna?”
  • Low blood counts. Low blood counts are common with Tasigna. Your doctor will check your blood counts regularly during treatment with Tasigna. Symptoms of low blood counts include:
    • unexplained bleeding or bruising
    • blood in urine or stool
    • unexplained weakness
  • Liver damage. Symptoms include yellow skin and eyes.
  • Pancreas inflammation (pancreatitis). Symptoms include sudden stomach area pain with nausea and vomiting.
  • Bleeding in the brain. Symptoms include sudden headache, changes in your eyesight, not being aware of what is going on around you and becoming unconscious.
  • Tumor Lysis Syndrome (TLS). TLS is caused by a fast breakdown of cancer cells.
  • TLS can cause you to have:
    • kidney failure and the need for dialysis treatment
    • an abnormal heart beat

Your doctor may do blood tests to check you for TLS.

The most common side effects of Tasigna include:

  • low blood count
  • rash
  • nausea
  • fever
  • headache
  • itching
  • tiredness
  • stomach (abdominal) pain
  • diarrhea
  • constipation
  • muscle and joint pain
  • back pain
  • muscle spasms
  • weakness
  • hair loss
  • runny or stuffy nose, sneezing, sore throat
  • cough

Tell your doctor if you have any side effect that bothers you or does not go away.

These are not all of the possible side effects of Tasigna. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Tasigna?

  • Store Tasigna at room temperature, 59° to 86°F (15° to 30°C).
  • Safely throw away medicine that is out of date or no longer needed.
  • Keep Tasigna and all medicines out of the reach of children.

General information about Tasigna

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Tasigna for a condition for which it was not prescribed. Do not give Tasigna to other people, even if they have the same problem you have. It may harm them.

This Medication Guide summarizes the most important information about Tasigna. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Tasigna that is written for healthcare professionals.

For more information, go to www.us.tasigna.com or call 1-866-411-8274.

What are the ingredients in Tasigna?

Active ingredient: nilotinib

Inactive ingredients: colloidal silicon dioxide, crospovidone, lactose monohydrate, magnesium stearate and poloxamer 188.

The capsule shell contains gelatin, titanium dioxide (E171), iron oxide yellow (E172) and iron oxide black or iron oxide red for stamping of the imprint (E172).

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Last reviewed on RxList: 1/9/2013
This monograph has been modified to include the generic and brand name in many instances.

>

PATIENT INFORMATION

Medication Guide

TASIGNA®
(ta-sig-na)
(nilotinib) Capsules

Read this Medication Guide before you start taking Tasigna® and each time you get a refill. There may be new information. This information 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 heartbeat, which may lead to sudden death.

Your doctor should check the electrical activity of your heart with a test called an electrocardiogram (ECG):

  • before starting Tasigna
  • 7 days after starting Tasigna
  • with any dose changes
  • regularly during Tasigna treatment

You may lower your chances for having QTc prolongation with Tasigna if you:

  • Take Tasigna:
    • on an empty stomach. Do not take Tasigna with food.
    • at least 2 hours after eating any food, and
    • wait at least 1 hour before eating any food
  • Avoid grapefruit, grapefruit juice, and any supplement containing grapefruit extract while taking Tasigna. Food and grapefruit products increase the amount of Tasigna in your body.
  • Avoid taking other medicines or supplements with Tasigna that can also cause QTc prolongation.
  • Tasigna can interact with many medicines and supplements and increase your chance for serious and life-threatening side effects.
  • Do not take any other medicine while taking Tasigna unless your doctor tells you it is okay to do so.
  • If you cannot swallow Tasigna capsules whole, you may open the Tasigna capsule and sprinkle the contents of each capsule in 1 teaspoon of applesauce (puréed apple). Swallow the mixture right away (within 15 minutes). For more information, see “How should I take Tasigna?”

Call your doctor right away if you feel lightheaded, faint or have an irregular heartbeat while taking Tasigna. These can be symptoms of QTc prolongation.

What is Tasigna?

Tasigna is a prescription medicine used to treat a type of leukemia called Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in adults who:

  • are newly diagnosed, or
  • are no longer benefiting from previous other treatments, including treatment with imatinib (Gleevec®), or
  • have taken other treatments, including imatinib (Gleevec®), and cannot tolerate them

It is not known if Tasigna is safe or effective in children.

Who should not take Tasigna?

Do not take if you have:

  • low levels of potassium or magnesium in your blood
  • long QTc syndrome

What should I tell my doctor before starting Tasigna?

Tasigna may not be right for you. Before taking Tasigna, tell your doctor about all of your medical conditions, including if you have:

  • heart problems
  • irregular heartbeat
  • QTc prolongation or a family history of it
  • liver problems
  • had pancreatitis
  • low blood levels of potassium or magnesium in your blood
  • a severe problem with lactose (milk sugar) or other sugars. The Tasigna capsules contain lactose. Most patients who have mild or moderate lactose intolerance can take Tasigna.
  • had a surgical procedure involving the removal of the entire stomach (total gastrectomy)
  • are pregnant or plan to become pregnant. Tasigna may harm your unborn baby. If you are able to become pregnant, you should use effective birth control during treatment with Tasigna. Talk to your doctor about the best birth control methods to prevent pregnancy while you are taking Tasigna.
  • are breastfeeding or plan to breastfeed. It is not known if Tasigna passes into your breast milk. You and your doctor should decide if you will take Tasigna or breastfeed. You should not do both.

Tell your doctor about all the medicines you take, including prescription and non prescription medicines, vitamins and herbal supplements.

Tasigna can interact with many medicines and supplements and increase your chance for serious and life-threatening side effects. See “What is the most important information I should know about Tasigna?”

Know the medicines you take. Keep a list of them and show it to your doctor and pharmacist when you get a new medicine.

How should I take Tasigna?

  • Take Tasigna exactly as your doctor tells you to take it. Do not change your dose or stop taking Tasigna unless your doctor tells you.
  • Tasigna is a long-term treatment.
  • Your doctor will tell you how many Tasigna capsules to take and when to take them.
    • Do not take Tasigna with food. Take Tasigna at least 2 hours after you eat and at least 1 hour before you eat.
  • Swallow Tasigna capsules whole with water. If you cannot swallow Tasigna capsules whole, tell your doctor
  • If you cannot swallow Tasigna capsules whole:
    • Open the Tasigna capsules and sprinkle the contents in 1 teaspoon of applesauce (puréed apple).
      • Do not use more than 1 teaspoon of applesauce.
      • Only use applesauce. Do not sprinkle Tasigna onto other foods.
    • Swallow the mixture right away (within 15 minutes).
  • Do not drink grapefruit juice, eat grapefruit, or take supplements containing grapefruit extract at any time during treatment. See “What is the most important information I should know about Tasigna?”
  • If you miss a dose, just take your next dose as scheduled. Do not make up for a missed dose.
  • If you take too much Tasigna, call your doctor or poison control center right away. Symptoms may include vomiting and drowsiness. During treatment with Tasigna your doctor will do tests to check for side effects and to see how well Tasigna is working for you. The tests will check your:
    • heart
    • blood cells (white blood cells, red blood cells, and platelets). Your blood cells should be checked every two weeks for the first two months and then monthly.
    • electrolytes (potassium, magnesium)
    • pancreas and liver function
    • bone marrow samples
  • Your doctor may change your dose. Your doctor may have you stop Tasigna for some time or lower your dose if you have side effects with it.

What are the possible side effects of Tasigna?

Tasigna may cause serious side effects including:

  • See “What is the most important information I should know about Tasigna?”
  • Low blood counts. Low blood counts are common with Tasigna. Your doctor will check your blood counts regularly during treatment with Tasigna. Symptoms of low blood counts include:
    • unexplained bleeding or bruising
    • blood in urine or stool
    • unexplained weakness
  • Liver damage. Symptoms include yellow skin and eyes.
  • Pancreas inflammation (pancreatitis). Symptoms include sudden stomach area pain with nausea and vomiting.
  • Bleeding in the brain. Symptoms include sudden headache, changes in your eyesight, not being aware of what is going on around you and becoming unconscious.
  • Tumor Lysis Syndrome (TLS). TLS is caused by a fast breakdown of cancer cells.
  • TLS can cause you to have:
    • kidney failure and the need for dialysis treatment
    • an abnormal heart beat

Your doctor may do blood tests to check you for TLS.

The most common side effects of Tasigna include:

  • low blood count
  • rash
  • nausea
  • fever
  • headache
  • itching
  • tiredness
  • stomach (abdominal) pain
  • diarrhea
  • constipation
  • muscle and joint pain
  • back pain
  • muscle spasms
  • weakness
  • hair loss
  • runny or stuffy nose, sneezing, sore throat
  • cough

Tell your doctor if you have any side effect that bothers you or does not go away.

These are not all of the possible side effects of Tasigna. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Tasigna?

  • Store Tasigna at room temperature, 59° to 86°F (15° to 30°C).
  • Safely throw away medicine that is out of date or no longer needed.
  • Keep Tasigna and all medicines out of the reach of children.

General information about Tasigna

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Tasigna for a condition for which it was not prescribed. Do not give Tasigna to other people, even if they have the same problem you have. It may harm them.

This Medication Guide summarizes the most important information about Tasigna. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Tasigna that is written for healthcare professionals.

For more information, go to www.us.tasigna.com or call 1-866-411-8274.

What are the ingredients in Tasigna?

Active ingredient: nilotinib

Inactive ingredients: colloidal silicon dioxide, crospovidone, lactose monohydrate, magnesium stearate and poloxamer 188.

The capsule shell contains gelatin, titanium dioxide (E171), iron oxide yellow (E172) and iron oxide black or iron oxide red for stamping of the imprint (E172).

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Last reviewed on RxList: 1/9/2013
This monograph has been modified to include the generic and brand name in many instances.

Disclaimer

Tasigna Capsules Consumer

IMPORTANT: HOW TO USE THIS INFORMATION: This is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate for you. This information is not individual medical advice and does not substitute for the advice of your health care professional. Always ask your health care professional for complete information about this product and your specific health needs.

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. If unable to swallow the capsules, the capsules may be opened and the contents sprinkled in 1 teaspoon of applesauce. This mixture should be swallowed right away (within 15 minutes). Use only 1 teaspoon of applesauce. Do not sprinkle the contents onto other types of food.

Drink plenty of fluids during treatment with this medication, unless otherwise directed by your doctor.

If you are taking antacids or acid blockers (such as cimetidine), take nilotinib 2 to 3 hours before or after these medicines.

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.

Disclaimer

Tasigna Capsules Consumer (continued)

SIDE EFFECTS: See also Warning section.

Nausea, vomiting, headache, tiredness, constipation, and diarrhea may occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

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).

Seek immediate medical attention if any of these rare but serious side effects occur: 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, toe/joint pain, painful urination, change in the amount of urine, 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.

In the US -

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

Read the Tasigna Capsules (nilotinib capsules) Side Effects Center for a complete guide to possible side effects »

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 product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: liver disease, pancreatitis.

Nilotinib may cause a condition that affects the heart rhythm (QT prolongation). QT prolongation can infrequently result in serious (rarely fatal) fast/irregular heartbeat and other symptoms (such as severe dizziness, fainting) that require immediate medical attention. The risk of QT prolongation may be increased if you have certain medical conditions or are taking other drugs that may affect the heart rhythm (see also Drug Interactions section). Before using nilotinib, tell your doctor or pharmacist if you have any of the following conditions: certain heart problems (heart failure, slow heartbeat, QT prolongation in the EKG), family history of certain heart problems (QT prolongation in the EKG, sudden cardiac death).

Low levels of potassium or magnesium in the blood may also increase your risk of QT prolongation. This risk may increase if you use certain drugs (such as diuretics/"water pills") or if you have conditions such as severe sweating, diarrhea, or vomiting. Talk to your doctor about using nilotinib safely.

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.

Disclaimer

Tasigna Capsules Consumer (continued)

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with them first.

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.

Many drugs besides nilotinib may affect the heart rhythm (QT prolongation), including amiodarone, dofetilide, pimozide, procainamide, quinidine, sotalol, macrolide antibiotics (such as erythromycin), among others. Therefore, before using nilotinib, report all medications you are currently using to your doctor or pharmacist.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: warfarin.

Check the labels on all your nonprescription/herbal medications. They may contain medications that can interact with nilotinib (e.g., the acid blocker cimetidine, proton pump inhibitors (such as omeprazole), 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, uric acid level) 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 December 2011. Copyright(c) 2011 First Databank, Inc.

Tasigna Capsules Patient Information Including Side Effects

Brand Names: Tasigna

Generic Name: nilotinib (Pronunciation: nye LOE ti nib)

What is nilotinib (Tasigna Capsules)?

Nilotinib interferes with the growth of some cancer cells.

Nilotinib is used to treat a type of blood cancer called Philadelphia chromosome positive chronic myeloid leukemia (CML).

Nilotinib may also be used for other purposes not listed in this medication guide.

What are the possible side effects of nilotinib (Tasigna Capsules)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Stop using nilotinib and call your doctor at once if you have a serious side effect such as:

  • feeling like you might pass out, fast or pounding heartbeat, seizure (convulsions);
  • pale skin, weakness, feeling light-headed, rapid heart rate, trouble concentrating;
  • easy bruising, unusual bleeding (nose, mouth, vagina, or rectum), purple or red pinpoint spots under your skin;
  • fever, chills, body aches, flu symptoms, sores in your mouth and throat;
  • feeling short of breath, even with mild exertion;
  • swelling, rapid weight gain;
  • redness or crusting around your hair follicles;
  • sudden headache, confusion, or problems with vision;
  • nausea, upper stomach pain, itching, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes);
  • severe pain in your upper stomach spreading to your back; or
  • cough with yellow or green mucus, stabbing chest pain, wheezing, feeling short of breath.

Less serious side effects may be more likely to occur, such as:

  • mild skin rash or itching;
  • diarrhea, constipation;
  • headache, neck or back pain;
  • weight changes;
  • tired feeling; or
  • cold symptoms such as stuffy nose, sneezing, sore throat.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Read the Tasigna Capsules (nilotinib capsules) Side Effects Center for a complete guide to possible side effects »

What is the most important information I should know about nilotinib (Tasigna Capsules)?

You should not use nilotinib if you are allergic to it, or if you have low blood levels of potassium or magnesium, or a history of "Long QT syndrome."

You should not breast-feed while you are taking nilotinib.

Before using nilotinib, tell your doctor if you have heart disease or a heart rhythm disorder, liver disease, a personal history of pancreatitis, a family history of "Long QT syndrome," or if your stomach has been surgically removed (total gastrectomy).

You will need regular medical tests to be sure this medication is not causing harmful effects. Your cancer treatments may be delayed based on the results of these tests. Visit your doctor regularly.

Call your doctor at once if you have a serious side effect such as feeling light-headed with a fast or pounding heartbeat, pale skin, easy bruising or bleeding, fever, flu symptoms, cough with stabbing chest pain, mouth sores, feeling light-headed or short of breath, swelling, sudden headache or vision problems, upper stomach pain, dark urine, or jaundice (yellowing of the skin or eyes).

Side Effects Centers

Tasigna Capsules Patient Information including How Should I Take

What should I discuss with my healthcare provider before taking nilotinib (Tasigna Capsules)?

You should not use nilotinib if you are allergic to it, or if you have:

  • low blood levels of potassium or magnesium; or
  • a history of "Long QT syndrome."

If you have any of these other conditions, you may need dose adjustment or special tests:

  • heart disease or heart rhythm disorder;
  • liver disease;
  • a personal history of pancreatitis;
  • a family history of "Long QT syndrome"; or
  • if your stomach has been surgically removed (total gastrectomy).

FDA pregnancy category D. Do not use nilotinib if you are pregnant. It could harm the unborn baby. Use effective birth control, and tell your doctor if you become pregnant during treatment.

It is not known whether nilotinib passes into breast milk or if it could harm a nursing baby. You should not breast-feed while you are taking nilotinib.

Nilotinib capsules may contain lactose. Talk to your doctor before using this medication if you have galactose intolerance, or severe problems with lactose (milk sugar).

How should I take nilotinib (Tasigna Capsules)?

Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.

Nilotinib is usually taken every 12 hours. Follow your doctor's instructions.

Take nilotinib on an empty stomach, at least 1 hour before or 2 hours after eating. Do not take nilotinib with food.

Take this medicine with a full glass of water.

Do not break or open a nilotinib capsule. Swallow the pill whole.

You may open the nilotinib capsule and sprinkle the medicine into a spoonful of applesauce to make swallowing easier. Swallow right away without chewing. Do not save the mixture for later use. Discard the empty capsule.

To be sure this medication is helping your condition and not causing harmful effects, your blood and bone marrow will need to be tested often. Your heart function will also need to be checked using an electrocardiograph or ECG (sometimes called an EKG). This machine measures electrical activity of the heart. Your cancer treatments may be delayed based on the results of these tests. Visit your doctor regularly.

Do not stop using nilotinib or change your dose without talking to your doctor. If you stop taking the medication too soon, your condition may get worse.

Store nilotinib at room temperature away from moisture and heat.

Side Effects Centers

Tasigna Capsules Patient Information including If I Miss a Dose

What happens if I miss a dose (Tasigna Capsules)?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose (Tasigna Capsules)?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose may cause drowsiness or vomiting.

What should I avoid while taking nilotinib (Tasigna Capsules)?

Do not take with food. Food can increase your blood levels of nilotinib and may increase your risk of harmful side effects.

Grapefruit and grapefruit juice may interact with nilotinib and lead to potentially dangerous effects. Discuss the use of grapefruit products with your doctor.

What other drugs will affect nilotinib (Tasigna Capsules)?

Many drugs can interact with nilotinib. Below is just a partial list. Tell your doctor if you are using:

  • arsenic trioxide (Trisenox);
  • conivaptan (Vaprisol);
  • droperidol (Inapsine);
  • imatinib (Gleevec);
  • isoniazid (for treating tuberculosis);
  • midazolam (Versed);
  • pimozide (Orap);
  • St. John's wort;
  • a blood thinner such as warfarin (Coumadin, Jantoven);
  • an antibiotic such as clarithromycin (Biaxin), erythromycin (E.E.S., EryPed, Ery-Tab, Erythrocin, Pediazole), moxifloxacin (Avelox), telithromycin (Ketek), and others;
  • antifungal medication such as itraconazole (Sporanox), ketoconazole (Nizoral), miconazole (Oravig), or voriconazole (Vfend);
  • an antidepressant such as amitriptylline (Elavil, Vanatrip, Limbitrol), clomipramine (Anafranil), desipramine (Norpramin), or nefazodone;
  • anti-malaria medications such as chloroquine (Arelan), halofantrine (Halfan), or mefloquine (Lariam);
  • heart or blood pressure medication such as amiodarone (Cordarone, Pacerone), diltiazem (Cartia, Cardizem), dofetilide (Tikosyn), disopyramide (Norpace), dronedarone (Multaq), felodipine (Plendil), ibutilide (Corvert), nicardipine (Cardene), procainamide (Procan, Pronestyl), propafenone (Rythmol), quinidine (Quin-G), or sotalol (Betapace);
  • HIV/AIDS medicine such as delavirdine (Rescriptor), fosamprenavir (Lexiva), indinavir (Crixivan), ritonavir (Kaletra, Norvir), and others;
  • medicines used to prevent organ transplant rejection, such as cyclosporine (Gengraf, Neoral, Sandimmune), sirolimus (Rapamune), or tacrolimus (Prograf);
  • medicine to prevent or treat nausea and vomiting such as dolasetron (Anzemet), droperidol (Inapsine), or ondansetron (Zofran);
  • medicines to treat psychiatric disorders, such as chlorpromazine (Thorazine), clozapine (FazaClo, Clozaril), haloperidol (Haldol), pimozide (Orap), thioridazine (Mellaril), or ziprasidone (Geodon);
  • migraine headache medicine such as sumatriptan (Imitrex, Treximet) or zolmitriptan (Zomig);
  • narcotic medication such as methadone (Methadose, Diskets, Dolophine); or
  • stomach acid reducers such as dexlansoprazole (Dexilant), esomeprazole (Nexium), lansoprazole (Prevacid), omeprazole (Prilosec), pantoprazole (Protonix), or rabeprazole (Aciphex).

Where can I get more information?

Your pharmacist can provide more information about nilotinib.


Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.

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