TASIGNA (nilotinib) Warnings/ Precautions1Myelosuppression QT prolongation Sudden death Fluid retention and oedema Cardiovascular events Hepatitis B reactivation Special monitoring of adult Ph+ CML-CP patients with sustained DMR Blood lipids Blood glucose Interactions with other medicinal products Food effect Hepatic impairment Serum lipase Total gastrectomy Tumor lysis syndrome Lactose Contraindications
Treatment with TASIGNA is associated with (National Cancer Institute Common Toxicity Criteria grade 3-4) thrombocytopenia, neutropenia and anaemia. 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.
TASIGNA has been shown to prolong cardiac ventricular repolarisation as measured by the QT interval on the surface ECG in a concentration-dependent manner.
In the Phase Ill study in patients with newly diagnosed CML in chronic phase receiving 300 mg TASIGNA twice daily, the change from baseline in mean time-averaged OTcF interval at steady state was 6 msec. No patient had an OTcF >480 msec. No episodes of torsade de pointes were observed.
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. Additionally, no clinically relevant arrhythmias were observed during the conduct of the trial. In particular, no episodes of torsade de pointes (transient or sustained) were observed.
TASIGNA should be used with caution in patients who have or who are at significant risk of developing prolongation of OTc, such as those:
- with congenital long QT prolongation
- with uncontrolled or significant cardiac disease including recent myocardial infarction, congestive heart failure, unstable angina or clinically significant bradycardia
- taking anti-arrhythmic medicinal products or other substances that lead to QT prolongation
Close monitoring for an effect on the QTc interval is advisable and a baseline ECG is recommended prior to initiating therapy with TASIGNA and as clinically indicated. Hypokalaemia or hypomagnesaemia must be corrected prior to TASIGNA administration and should be monitored periodically during therapy.
Uncommon cases (0.1 to 1%) of sudden deaths have been reported in patients with imatinib-resistant or intolerant CML in chronic phase or accelerated phase 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 medicinal products. Ventricular repolarization abnormalities may have been contributory factors.
No cases of sudden death were reported in the Phase Ill study in newly diagnosed patients with CML in chronic phase.
Fluid retention and oedema
Severe forms of fluid retention such as pleural effusion, pulmonary oedema, and pericardial effusion were uncommonly (0.1 to 1%) observed in a Phase Ill 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, the aetiology should be evaluated and patients treated accordingly.
Cardiovascular events were reported in a randomised Phase Ill study in newly diagnosed CML patients and observed in postmarketing reports. In this clinical study with a median on-therapy time of 60.5 months, Grade 3-4 cases of cardiovascular events included peripheral arterial occlusive disease (1.4% and 1.1% at 300 mg and 400 mg TASIGNA twice daily, respectively), ischaemic heart disease (2.2% and 6.1% at 300 mg and 400 mg TASIGNA twice daily, respectively) and ischaemic cerebrovascular events (1.1% and 2.2% at 300 mg and 400 mg TASIGNA twice daily, respectively).
Patients should be advised to seek immediate medical attention if they experience acute signs or symptoms of cardiovascular events.
The cardiovascular status of patients should be evaluated and cardiovascular risk factors monitored and actively managed during TASIGNA therapy according to standard guidelines. Appropriate therapy should be prescribed to manage cardiovascular risk factors.
Hepatitis B reactivation
Reactivation of hepatitis B in patients who are chronic carriers of this virus has occurred after these patients received BCR-ABL tyrosine kinase inhibitors. Some cases resulted in acute hepatic failure or fulminant hepatitis leading to liver transplantation or a fatal outcome.
Patients should be tested for HBV infection before initiating treatment with TASIGNA. 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 HBV infection during treatment. Carriers of HBV who require treatment with TASIGNA should be closely monitored for signs and symptoms of active HBV infection throughout therapy and for several months following termination of therapy.
Special monitoring of adult Ph+ CML-CP 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, evaluation of the depth of molecular response, and determination of a possible loss of molecular remission after discontinuation of treatment with TASIGNA.
Monitoring of patients who have discontinued therapy
Frequent 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/ABL ≤0.0032% IS). BCR-ABL transcript levels must be assessed prior to and during treatment discontinuation (see sections 4.2 and 5.1).
Loss of major molecular response (MMR=BCR-ABL/ABL ≤0.1%IS) or confirmed loss of MR4 (two consecutive measures separated by at least 4 weeks showing loss of MR4 (MR4=BCR-ABL/ABL ≤0.01%IS)) will trigger treatment re-initiation within 4 weeks of when loss of remission is known to have occurred. Molecular relapse can occur during the treatment-free phase, and long-term outcome data are not yet available. It is therefore crucial to perform frequent monitoring of BCR-ABL transcript levels and complete blood count with differential in order to detect possible loss of remission (see section 4.2). For patients who fail to achieve MMR after three months of treatment re-initiation, BCR-ABL kinase domain mutation testing should be performed.
In a Phase Ill study in newly diagnosed CML patients, 1.1% of the patients treated with 400 mg TASIGNA twice daily showed a Grade 3-4 elevation in total cholesterol; no Grade 3-4 elevations were however observed in the 300 mg twice daily dose group.
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. If a HMG-CoA reductase inhibitor (a lipid-lowering agent) is required, please refer to section 4.5 of the prescribing information before initiating treatment since certain HMG-CoA reductase inhibitors are also metabolised by the CYP3A4 pathway.
In a Phase III study in newly diagnosed CML patients, 6.9% and 7.2% of the patients treated with 400 mg nilotinib and 300 mg nilotinib twice daily, respectively, showed a Grade 3-4 elevation in blood glucose.
It is recommended that the glucose levels be assessed before initiating treatment with TASIGNA and monitored during treatment, as clinically indicated. If test results warrant therapy, physicians should follow their local standards of practice and treatment guidelines.
Interactions with other medicinal products
The administration of TASIGNA with agents that are strong CYP3A4 inhibitors (including, but not limited to, ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir) should be avoided. Should treatment with any of these agents be required, it is recommended that therapy with TASIGNA be interrupted if possible. If transient interruption of treatment is not possible, close monitoring of the individual for prolongation of the QT interval is indicated.
Concomitant use of TASIGNA with medicinal products that are potent inducers of CYP3A4 (e.g. phenytoin, rifampicin, carbamazepine, phenobarbital and St. John’s Wort) is likely to reduce exposure to nilotinib to a clinically relevant extent. Therefore, in patients receiving TASIGNA, co-administration of alternative therapeutic agents with less potential for CYP3A4 induction should be selected.
The bioavailability of nilotinib is increased by food. TASIGNA must not be taken in conjunction with food 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. For patients who are unable to swallow hard capsules, the content of each hard capsule may be dispersed in one teaspoon of apple sauce and should be taken immediately. Not more than one teaspoon of apple sauce and no food other than apple sauce must be used.
Hepatic impairment has a modest effect on the pharmacokinetics of TASIGNA. Clinical studies have excluded patients with alanine transaminase (ALT) and/or aspartate transaminase (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 TASIGNA is mainly hepatic. Patients with hepatic impairment might therefore have increased exposure to TASIGNA and should be treated with caution.
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, TASIGNA should be interrupted and appropriate diagnostic measures considered to exclude pancreatitis.
The bioavailability of nilotinib might be reduced in patients with total gastrectomy. More frequent follow-up of these patients should be considered.
Tumor lysis syndrome
Due to possible occurrence of tumor lysis syndrome (TLS) correction of clinically significant dehydration and treatment of high uric acid levels are recommended prior to initiating therapy with TASIGNA.
TASIGNA hard capsules contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Hypersensitivity to TASIGNA or to any of the excipients.
DMR, deep molecular response; ECG, electrocardiogram; QTcF, QT interval; TFR, treatment-free remission.
Please see Important Safety Information and full Prescribing Information for TASIGNA.
- TASIGNA® (nilotinib) Summary of Product Characteristics. Basel, Switzerland: Novartis Pharma AG; May 2017.