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Myelosuppression: Treatment with Tasigna is often associated with thrombocytopenia, neutropenia and anemia (NCI CTC Grade 3/4). The occurrence is more frequent in patients with imatinib-resistant or intolerant CML and in particular in patients with CML-AP. 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 reducing the dose (see Dosage & Administration).
QT Prolongation: In vitro data suggest that nilotinib has the potential to prolong cardiac ventricular repolarization (QT interval).
In the Phase III study in newly diagnosed Ph+ CML-CP patients the change from baseline in mean time-averaged QTcF interval at steady-state observed in the nilotinib 300 mg twice daily group was 6 msec. At the recommended dose of 300 mg twice daily no patient had an absolute QTcF of >480 msec and no events of Torsades de Pointes were observed.
In the Phase II study in imatinib-resistant or intolerant CML patients in chronic and accelerated phase, treated with nilotinib 400 mg twice daily, the change from baseline in mean time-averaged QTcF interval at steady-state was 5 msec and 8 msec, respectively. QTcF of >500 msec was observed in 4 patients (<1% of these patients).
In a healthy volunteer study with exposures that were comparable to the exposures observed in patients, the time-averaged mean placebo-subtracted QTcF change from baseline was 7 msec (CI ± 4 msec). No subject had a QTcF >450 msec. In addition, no clinically relevant arrhythmias were observed during the conduct of the trial. In particular, no episodes of Torsades de Pointes (either transient or sustained) were observed.
Clinically meaningful 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 interval; therefore, concomitant administration should be avoided (see Food-effects as follows and Interactions).
The presence of hypokalemia and hypomagnesemia may place patients at risk of developing QT prolongation (see Dosage & Administration).
Tasigna should be used with caution in patients who have or who are at significant risk of developing prolongation of QTc, such as those: with long QT syndrome; with uncontrolled or significant cardiac disease including recent myocardial infarction, congestive heart failure, unstable angina or clinically significant bradycardia.
Sudden death: In clinical trials, uncommon cases (0.1 to 1%) of sudden death have been reported in patients in imatinib-resistant or -intolerant CML patients in chronic and accelerated phase receiving Tasigna with a past medical history of cardiac disease or significant cardiac risk factors. Comorbidities in addition to the underlying malignancy were also frequently present as were concomitant medications. Ventricular repolarization abnormalities may have been contributory factors. Based on post-marketing exposure in patient-years, the estimated reporting rate for spontaneous reports of sudden death is 0.02% per patient-year. No cases of sudden deaths have been reported in the newly diagnosed Ph+ CML-CP Phase III study.
Cardiovascular events: Cardiovascular events were reported in a randomized, Phase III nilotinib trial in newly diagnosed CML patients and observed in the post-marketing reports. With a median time on therapy of 60.5 months in the clinical trial, Grade 3/4 cardiovascular events included peripheral arterial occlusive disease (1.4% and 1.1% at 300 mg and 400 mg twice a day respectively), ischemic heart disease (2.2% and 6.1% at 300 mg and 400 mg twice a day respectively) and ischemic cerebrovascular events (1.1% and 2.2% at 300 mg and 400 mg twice a day respectively). If acute signs or symptoms of cardiovascular events occur, advise patients to seek immediate medical attention. The cardiovascular status of patients should be evaluated and cardiovascular risk factors should be monitored and actively managed during Tasigna therapy according to standard guidelines (see Dosage & Administration).
Fluid retention: Severe forms of drug-related fluid retention such as pleural effusion, pulmonary edema, and pericardial effusion were uncommonly (0.1 to 1%) observed in a Phase III study of newly diagnosed CML patients. Similar events were observed in post-marketing reports. Unexpected, rapid weight gain should be carefully investigated. If signs of severe fluid retention appear during treatment with nilotinib, the etiology should be evaluated and patients treated accordingly (see Dosage & Administration).
Hepatitis B reactivation: Reactivation of hepatitis B can occur in patients who are chronic carriers of this virus after receiving a BCR-ABL tyrosine kinase inhibitor (TKI), such as nilotinib. Some cases involving drugs of the BCR-ABL TKI class resulted in acute hepatic failure or fulminant hepatitis leading to liver transplantation or a fatal outcome (see Adverse Reactions).
Patients should be tested for hepatitis B infection before initiating treatment with nilotinib. Patients currently on nilotinib should have baseline testing for hepatitis B infection in order to identify chronic carriers of the virus. Experts in liver disease and in the treatment of hepatitis B should be consulted before treatment is initiated in patients with positive hepatitis B serology (including those with active disease) and for patients who test positive for hepatitis B infection during treatment. Carriers of hepatitis B virus who require treatment with nilotinib should be closely monitored for signs and symptoms of active hepatitis B infection throughout therapy and for several months following termination of therapy.
Special monitoring of Ph+ CML-CP adult patients who have achieved a sustained deep molecular response: Eligibility for discontinuation of treatment: Eligible patients who are confirmed to express the typical BCR-ABL transcripts, e13a2/b2a2 or e14a2/b3a2, can be considered for treatment discontinuation. Patients must have typical BCR-ABL transcripts to allow quantitation of BCR-ABL levels, evaluation of the depth of molecular response, and determination of a possible loss of molecular remission after Tasigna treatment discontinuation.
Monitoring of patients who have discontinued therapy: Monitoring of BCR-ABL transcript levels in patients eligible for treatment discontinuation must be performed with a quantitative diagnostic test validated to measure molecular response levels with a sensitivity of at least MR4.5. BCR-ABL transcript levels must be assessed prior to and during treatment discontinuation (see Dosage & Administration and Pharmacology: Pharmacodynamics: Clinical Studies under Actions).
Loss of MMR or confirmed loss of MR4.0 (two consecutive measures separated by at least 4 weeks showing loss of MR4.0) will trigger treatment re-initiation within 4 weeks of when loss of remission is known to have occurred. Frequent monitoring of BCR-ABL transcript levels and complete blood count with differential is required to detect possible loss of remission (see Dosage & Administration and Pharmacology: Pharmacodynamics: Clinical Studies under Actions). For patients who fail to achieve MMR after three months of treatment re-initiation, BCR-ABL kinase domain mutation testing should be performed.
Laboratory tests and monitoring: Blood lipids: In a Phase III study in newly diagnosed CML patients, 1.1% of the patients treated with 400 mg nilotinib twice a day had a Grade 3/4 elevation in total cholesterol; however, there were no Grade 3/4 elevations in the 300 mg twice a day dose group (see Adverse Reactions). It is recommended that the lipid profiles be determined before initiating treatment with Tasigna, assessed at month 3 and 6 after initiating therapy, and at least yearly during chronic therapy (see Dosage & Administration). If a hydroxymethylglutaryl-CoA (HMG CoA) reductase inhibitor (a lipid lowering agent) is needed, refer to INTERACTIONS, before starting treatment since certain HMG CoA reductase inhibitors are metabolized by the CYP3A4 pathway.
Blood glucose: In a Phase III study in newly diagnosed CML patients, 6.9% of the patients treated with 400 mg nilotinib twice a day had a Grade 3/4 elevation in blood glucose; and 7.2% of the patients treated with 300 mg nilotinib twice a day had a Grade 3/4 elevation in blood glucose. It is recommended that the glucose levels should be assessed before initiating treatment with Tasigna and monitored during treatment as clinically indicated (see Dosage & Administration). If test results warrant therapy, physicians should follow their local standards of practice and treatment guidelines.
Interactions: The administration of Tasigna with agents that are strong CYP3A4 inhibitors and drugs that may prolong the QT interval such as anti-arrhythmic medicines should be avoided (see Dosage & Administration and Interactions). Should treatment with any of these agents be required, it is recommended that therapy with Tasigna be interrupted if possible (see Interactions). If transient interruption of treatment with Tasigna is not possible, close monitoring of the individual for prolongation of the QT interval is indicated (see Dosage & Administration, Interactions and Pharmacology under Actions).
Concomitant use of Tasigna with medicinal products 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 (see Interactions).
Food-effects: The bioavailability of nilotinib is increased by food. Tasigna must not be taken in conjunction with food (see Dosage & Administration and Interactions) and should be taken 2 hours after a meal. No food should be consumed for at least one hour after the dose is taken.
Grapefruit juice and other foods that are known to inhibit CYP3A4 should be avoided at any time.
Hepatic impairment: Hepatic impairment has a modest effect on the pharmacokinetics of nilotinib. Single dose administration of nilotinib resulted in increases in AUC of 35%, 35% and 19% in subjects with mild, moderate and severe hepatic impairment respectively, compared to a control group of subjects with normal hepatic function. The predicted steady-state Cmax of nilotinib showed an increase of 29%, 18% and 22% respectively. Clinical studies have excluded patients with alanine transaminase (ALT) and/or aspartate aminotransferase (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 (see Monitoring recommendations and dose adjustments under Dosage & Administration).
Serum lipase: Elevation in serum lipase has been observed. Caution is recommended in patients with previous history of pancreatitis. In case lipase elevations are accompanied by abdominal symptoms, doses should be interrupted and appropriate diagnostics should be considered in order to exclude pancreatitis (see Dosage & Administration).
Total gastrectomy: The bioavailability of nilotinib might be reduced in patients with total gastrectomy (see Pharmacology under Actions). More frequent follow-up of these patients should be considered.
Tumor lysis syndrome: Cases of TLS have been reported in patients treated with Tasigna. For monitoring recommendations refer to Dosage & Administration.
Lactose: 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.
