WARNINGS AND PRECAUTIONS
Treatment with Tasigna (nilotinib) can cause Grade 3/4 thrombocytopenia, neutropenia and anemia. Complete blood counts should be performed every two weeks for the first 2 months and then monthly thereafter, or as clinically indicated. Myelosuppression was generally reversible and usually managed by withholding Tasigna temporarily or dose reduction. [ See Dosage and Administration ( 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. Prolongation of the QT interval can result in a type of ventricular tachycardia called Torsade de pointes, which may result in syncope, seizure, and/or death.
Tasigna should not be used in patients who have hypokalemia, hypomagnesemia or long QT syndrome. Hypokalemia or hypomagnesemia must be corrected prior to initiating Tasigna and these electrolytes should be monitored periodically during therapy. Avoid drugs known to prolong the QT interval and strong CYP3A4 inhibitors. ECGs should be performed at baseline, seven days after initiation, periodically as clinically indicated and following dose adjustments. [ See Clinical Pharmacology (12.4) ] .
There were five sudden deaths reported in patients receiving nilotinib in an on-going study (n=867; 0.6%). A similar incidence was also reported in the expanded access program. The relative early occurrence of some of these deaths relative to the initiation of nilotinib suggests the possibility that ventricular repolarization abnormalities may have contributed to their occurrence.
4 Elevated Serum Lipase
The use of Tasigna can cause increases in serum lipase. Caution is recommended in patients with a previous history of pancreatitis. Serum lipase should be checked periodically.
The use of Tasigna may result in elevations in bilirubin, AST/ALT, and alkaline phosphatase. Hepatic function tests should be checked periodically.
6 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.
7 Drug Interactions
The administration of Tasigna with agents that are strong CYP3A4 inhibitors or prolong QT should be avoided. Should treatment with any of these agents be required, it is recommended that therapy with Tasigna be interrupted. If interruption of treatment with Tasigna is not possible, patients who require treatment with a drug that prolongs QT or strongly inhibits CYP3A4 should be closely monitored for prolongation of the QT interval. [ See Boxed Warning, Dos age and Administration (2), and Drug Interactions (7. 2 ) ] .
8 Food Effect s
The bioavailability of nilotinib is increased with food. Tasigna should not be taken with food. No food should be taken at least 2 hours before and at least one hour after the dose is taken. Grapefruit products and other foods that are known to inhibit CYP3A4 should be avoided. [ See Boxed Warning, Drug Interactions (7. 2 ) and Clinical Pharmacology (12.3) ].
9 Hepatic Impairment
Tasigna has not been investigated in patients with hepatic impairment. Clinical studies have excluded patients with ALT and/or AST >2.5 (or >5, if related to disease) times the upper limit of the normal range and/or total bilirubin >1.5 times the upper limit of the normal range. Metabolism of nilotinib is mainly hepatic. Caution is recommended in patients with hepatic impairment . These patients should be closely monitored for QT interval prolongation. [ See Boxed Warnin g , Dosage and Administration (2) and Use in Specific Populations (8.7) ].
Since the capsules contain lactose, Tasigna is not recommended for patients with rare hereditary problems of galactose intolerance, severe lactase deficiency or of glucose-galactose malabsorption.
1 1 Pregnancy
Pregnancy Category D
Tasigna can cause fetal harm when administered to a pregnant woman.
Nilotinib was studied for effects on embryo-fetal development in pregnant rats (GD 6-17) and rabbits (GD 7-20) given oral doses of 10, 30, 100 mg/kg/day, and 30, 100, 300 mg/kg/day, respectively. In rats, nilotinib at doses of 100 mg/kg/day (approximately 5.7 fold the AUC in patients at the recommended human dose) was associated with maternal toxicity (decreased gestation weight, gravid uterine weight, net weight gain, and food consumption). Nilotinib at doses ≥ 30 mg/kg/day resulted in embryo-fetal toxicity as shown by increased resorption and post-implantation loss, and at 100 mg/kg/day a decrease in viable fetuses. In rabbits, maternal toxicity at 300 mg/kg/day (approximately one-half the human exposure based on AUC) was associated with mortality, abortion, decreased gestation weights and decreased food consumption. Embryonic toxicity (increased resorption) and minor skeletal anomalies were observed at a dose of 300 mg/kg/day. Nilotinib is not considered teratogenic.
There are no adequate and well controlled studies with Tasigna in pregnant women. Women should be advised to avoid becoming pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
Monitoring Laboratory Tests
Complete blood counts should be performed every two weeks for the first two months and then monthly thereafter. Chemistry panels should be checked periodically. ECGs should be obtained at baseline, seven days after initiation and periodically thereafter, as well as following dose adjustments [ See Warnings and Precautions (5.2) ] . Laboratory monitoring for patients receiving Tasigna may need to be performed more or less frequently at the physician’s discretion.
USE IN SPECIFIC POPULATIONS
Pregnancy Category D [ See Warnings and Precautions (5. 1 1 ) ]
3 Nursing M others
It is not known whether nilotinib is excreted in human milk. One study in lactating rats demonstrates that nilotinib is excreted into milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from nilotinib, a decision should be made whether to discontinue nursing or to discontinue Tasigna taking into account the importance of the drug to the mother.
4 Pediatric Use
Safety and effectiveness of Tasigna in pediatric patients have not been established.
5 Geriatric Use
In the single clinical study of Tasigna, approximately 30% of patients were 65 or over. CML-CP: There was no difference in major cytogenetic response rate between patients aged <65 years and those > 65 years. CML-AP: The major hematologic response rate was 31% in patients < 65 years of age and 15% in patients > 65 years.
No major differences were observed for safety in patients ≥ 65 years of age as compared to patients < 65 years.
Cardiac D isorders
In the single clinical trial, patients with a history of uncontrolled or significant cardiovascular disease were excluded [ See Boxed Warning and Warnings and Precautions (5.2) ] .
7 Hepatic I mpairment
Tasigna has not been investigated in patients with hepatic impairment. Caution is recommended in patients with hepatic impairment [ See Boxed Warning, Dosage and Administration (2 ) and W arnings and Precautions (5. 9 ) ].
8 Renal I mpairment
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.