nilotinib
Dosage Form: capsule
FULL PRESCRIBING INFORMATION
- Tasigna prolongs the QT interval. Prior to Tasigna administration and periodically, monitor for hypokalemia or hypomagnesemia and correct deficiencies (5.2). Obtain ECGs to monitor the QTc at baseline, seven days after initiation, and periodically thereafter, and follow any dose adjustments (5.2, 5.3, 5.6, 5.12).
- Sudden deaths have been reported in patients receiving nilotinib (5.3). Do not administer Tasigna to patients with hypokalemia, hypomagnesemia, or long QT syndrome (4, 5.2).
- Avoid use of concomitant drugs known to prolong the QT interval and strong CYP3A4 inhibitors (5.7).
- Patients should avoid food 2 hours before and 1 hour after taking dose (5.8).
INDICATIONS AND USAGE
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 (14.1)]. 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 (14.2)].
Tasigna 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 (5.8), Clinical Pharmacology (12.3)].
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 (12.3)].
Tasigna may be given in combination with hematopoietic growth factors such as erythropoietin or G-CSF if clinically indicated. Tasigna may be given with hydroxyurea or anagrelide if clinically indicated.
Newly Diagnosed Ph+ CML-CP
The recommended dose of Tasigna is 300 mg orally twice daily [see Clinical Pharmacology (12.3)].
Resistant or Intolerant Ph+ CML-CP and CML-AP
The recommended dose of Tasigna (nilotinib) is 400 mg orally twice daily [see Clinical Pharmacology (12.3)].
Dose Adjustments or Modifications
QT interval 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).
| 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 (6.1)].
| 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 ≤Grade 1 |
| Elevated bilirubin ≥Grade 3 | 1. Withhold Tasigna, and monitor bilirubin 2. Resume treatment at 400 mg once daily if bilirubin returns to ≤Grade 1 |
| 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 ≤Grade 1 |
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 CML-AP) twice daily should be considered. For Grade 3 to 4 lipase elevations, dosing should be withheld, and may be resumed at 400 mg once daily. Test serum lipase levels monthly or as clinically indicated. For Grade 3 to 4 bilirubin or hepatic transaminase elevations, dosing should be withheld, and may be resumed at 400 mg once daily. Test bilirubin and hepatic transaminases levels monthly or as clinically indicated [see Warnings and Precautions (5.4, 5.5), Use in Specific Populations (8.7)].
Hepatic Impairment
If possible, consider alternative therapies. If Tasigna must be administered to patients with hepatic impairment, consider the following dose reduction:
| 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 (5.9), Use in Specific Populations (8.7)].
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 co-administered a strong CYP3A4 inhibitor, based on pharmacokinetic studies, consider a dose reduction to 300 mg once daily in patients with resistant or intolerant Ph+ CML or to 200 mg once daily in patients with newly diagnosed Ph+ CML-CP. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inhibitors. If the strong inhibitor is discontinued, a washout period should be allowed before the Tasigna 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 (5.2, 5.7), Drug Interactions (7.2)].
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 (7.2)].
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”.
CONTRAINDICATIONS
Do not use in patients with hypokalemia, hypomagnesemia, or long QT syndrome [see Boxed Warning].
WARNINGS AND 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 (2.2)].
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 (6.1), Clinical Pharmacology (12.4)]. 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 [see Warnings and Precautions (5.12)].
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 [see Warnings and Precautions (5.12)].
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, co-administration with food must be avoided and concomitant use with strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT should be avoided [see Warnings and Precautions (5.7, 5.8)]. The presence of hypokalemia and hypomagnesemia may further enhance this effect [see Warnings and Precautions (5.6, 5.12)].
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 [see Warnings and Precautions (5.12)].
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 [see Warnings and Precautions (5.12)].
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 (2.2), Drug Interactions (7.2)].
Food Effects
The bioavailability of nilotinib is increased with food. Tasigna must not be taken with food. No food should be taken at least 2 hours before and at least one hour after the dose is taken. Grapefruit products and other foods that are known to inhibit CYP3A4 should be avoided [see Boxed Warning, Drug Interactions (7.2) and Clinical Pharmacology (12.3)].
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 (2.2) and Use in Specific Populations (8.7)].
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 12.3)].
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 [see Warnings and Precautions (5.2)]. 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 (8.1)].
ADVERSE REACTIONS
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 (5)].
Myelosuppression [see Warnings and Precautions (5.1)]
QT prolongation [see Boxed Warning, Warnings and Precautions (5.2)]
Sudden deaths [see Boxed Warning, Warnings and Precautions (5.3)]
Elevated serum lipase [see Warnings and Precautions (5.4)]
Hepatotoxicity [see Warnings and Precautions (5.5)]
Electrolyte abnormalities [see Boxed Warning, Warnings and Precautions (5.6)]
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.
Newly diagnosed Ph+ CML-CP
The data below reflect exposure to Tasigna from a randomized trial in newly diagnosed patients with 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 25 months (range 0.1 – 35.4 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 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% of patients. 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 (17%), neutropenia (15%) and anemia (7%). See Table 7 for Grade 3/4 laboratory abnormalities.
Discontinuation due to adverse events regardless of causality was observed in 9% of patients.
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; CML-AP=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 steady-state 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 (5.2, 5.3), Clinical Pharmacology (12.4)].
Discontinuation due to drug-related adverse 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 drug 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.
| 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 | 37 | 18 | <1 | 2 |
| Pruritus | 20 | 7 | <1 | 0 | |
| Alopecia | 11 | 6 | 0 | 0 | |
| Periorbital edema | <1 | 15 | 0 | 0 | |
| Gastrointestinal disorders | Nausea | 20 | 39 | 1 | 1 |
| Constipation | 17 | 6 | 0 | 0 | |
| Diarrhea | 14 | 40 | <1 | 2 | |
| Vomiting | 11 | 24 | 0 | <1 | |
| Abdominal pain upper | 15 | 11 | <1 | <1 | |
| Abdominal pain | 14 | 10 | 1 | 0 | |
| Nervous system disorders | Headache | 30 | 18 | 3 | <1 |
| General disorders and administration site conditions | Fatigue | 21 | 16 | 1 | 1 |
| Pyrexia | 11 | 12 | <1 | 0 | |
| Asthenia | 11 | 10 | <1 | 0 | |
| Edema, peripheral | 8 | 18 | 0 | 0 | |
| Face edema | <1 | 11 | 0 | <1 | |
| Musculoskeletal and connective tissue disorders | Myalgia | 14 | 18 | <1 | 0 |
| Arthralgia | 17 | 13 | <1 | <1 | |
| Muscle spasms | 11 | 31 | 0 | <1 | |
| Pain in extremity | 11 | 13 | <1 | <1 | |
| Back pain | 14 | 11 | <1 | 1 | |
| Respiratory, thoracic and mediastinal disorders | Cough | 14 | 9 | 0 | 0 |
| Infections and infestations | Nasopharyngitis | 22 | 17 | 0 | 0 |
| Upper respiratory tract infection | 14 | 10 | <1 | 0 | |
| Eye disorders | Eyelid edema | 1 | 16 | 0 | <1 |
a Excluding laboratory abnormalities
b NCI Common Terminology Criteria for Adverse Events, Version 3.0
| Body System and Preferred Term | CML-CP | CML-AP | |||
| N=321 | 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 | |
| Edema, peripheral | 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 | Anorexia | 12 | <1 | 15 | <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
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.
| Patient Population | ||||
| Newly Diagnosed Ph+ CML-CP | Resistant or Intolerant Ph+ | |||
| CML-CP | CML-AP | |||
| Tasigna 300 mg twice daily N=279 (%) | Imatinib 400 mg once daily N=280 (%) | 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 | 5 | 11 | 27 |
| Biochemistry Parameters | ||||
| Elevated lipase | 7 | 3 | 18 | 18 |
| Hyperglycemia | 6 | 0 | 12 | 6 |
| Hypophosphatemia | 5 | 8 | 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 | 0 | 4 | 3 |
| Hypocalcemia | <1 | 0 | 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 adverse drug reactions listed under “Investigations”, 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. Uncommon: upper respiratory tract infection (including nasopharyngitis, pharyngitis, rhinitis), 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.
Blood and Lymphatic System Disorders: Common: febrile neutropenia, pancytopenia, lymphopenia. Unknown frequency: thrombocythaemia, leukocytosis, eosinophilia.
Immune System Disorders: Unknown frequency: hypersensitivity.
Endocrine Disorders: Uncommon: hyperthyroidism, hypothyroidism. Unknown frequency: hyperparathyroidism secondary, thyroiditis.
Metabolism and Nutrition Disorders: Common: electrolyte imbalance (including hypomagnesemia, hyperkalemia, hypokalemia, hyponatremia, hypocalcemia, hypophosphatemia, hypercalcemia, hyperphosphatemia), diabetes mellitus, hyperglycemia, hypercholesterolemia, hyperlipidemia, decreased appetite. Uncommon: dehydration, increased appetite. Unknown frequency: hyperuricemia, gout, 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. Uncommon: vision impairment, vision blurred, visual acuity reduced, photopsia, hyperemia (scleral, conjunctival, ocular), eye irritation. Unknown frequency: papilloedema, diplopia, photophobia, eye swelling, blepharitis, eye pain, chorioretinopathy, conjunctival hemorrhage, 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.
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.
Gastrointestinal Disorders: Common: pancreatitis, abdominal discomfort, abdominal distension, dyspepsia, dysgeusia, flatulence. Uncommon: gastrointestinal hemorrhage, melena, mouth ulceration, gastroesophageal reflux, stomatitis, esophageal pain, dry mouth. Unknown frequency: gastrointestinal ulcer perforation, retroperitoneal hemorrhage, hematemesis, gastric ulcer, esophagitis ulcerative, subileus, gastritis, enterocolitis, hemorrhoids, hiatus hernia, rectal hemorrhage, gingivitis.
Hepatobiliary Disorders: Common: hepatic function abnormal. Uncommon: hepatotoxicity, hepatitis, jaundice. Unknown frequency: cholestasis, hepatomegaly.
Skin and Subcutaneous Tissue Disorders: Common: night sweats, eczema, urticaria, erythema, hyperhidrosis, contusion, acne, dermatitis (including allergic and acneiform), dry skin. Uncommon: exfoliative rash, drug eruption, pain of skin, ecchymosis, swelling of face. Unknown frequency: 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.
Musculoskeletal and Connective Tissue Disorders: Common: bone pain, musculoskeletal chest pain, musculoskeletal 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, menorrhagia, nipple swelling.
General Disorders and Administration Site Conditions: Common: pyrexia, chest pain (including non-cardiac chest pain), pain (including neck pain and back 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: 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. Unknown frequency: troponin increased, blood bilirubin unconjugated increased, blood insulin increased, lipoprotein increased (including very low density and high density), blood parathyroid hormone increased.
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 subs
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