Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use

Myelosuppression

Treatment with nilotinib is associated with (National Cancer Institute Common Toxicity Criteria grade 3 and 4) thrombocytopenia, neutropenia and anaemia. Occurrence is more frequent in patients with imatinib-resistant or intolerant CML, in particular in patients with accelerated-phase CML.
Complete blood counts should be performed every two weeks for the first 2 months and then monthly TAS API SEP22 V14                                                                         EU SmPC 15JUN22 thereafter, or as clinically indicated. Myelosuppression was generally reversible and usually managed by withholding Tasigna temporarily or dose reduction (see section 4.2).

QT prolongation

Nilotinib has been shown to prolong cardiac ventricular repolarisation as measured by the QT interval on the surface ECG in a concentration-dependent manner in adult patients.

In the Phase III study in patients with newly diagnosed CML in chronic phase receiving 300 mg nilotinib twice daily, the change from baseline in mean time-averaged QTcF interval at steady state was 6 msec. No patient had a QTcF >480 msec. No episodes of torsade de pointes were observed.

In the Phase II study in imatinib-resistant and intolerant CML patients in chronic and accelerated phase receiving 400 mg nilotinib twice daily, the change from baseline in mean time-averaged QTcF interval at steady state was 5 and 8 msec, respectively. QTcF of >500 msec was observed in <1% of these patients. No episodes of torsade de pointes were observed in clinical studies.

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.

Significant prolongation of the QT interval may occur when nilotinib is inappropriately taken with strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong the QT interval, and/or food (see section 4.5). The presence of hypokalaemia and hypomagnesaemia may further enhance this effect. Prolongation of the QT interval may expose patients to the risk of fatal outcome.

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 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 nilotinib therapy and as clinically indicated. Hypokalaemia or hypomagnesaemia must be corrected prior to Tasigna administration and potassium and magnesium blood levels should be monitored periodically during therapy, particularly in patients at risk for these electrolyte abnormalities.

Sudden death

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. Co-morbidities in addition to the underlying malignancy were also frequently present as were concomitant medicinal products. Ventricular repolarisation abnormalities may have been contributory factors. No cases of sudden death were reported in the Phase III study in newly diagnosed patients with CML in chronic phase.

Fluid retention and oedema

Severe forms of drug-related fluid retention such as pleural effusion, pulmonary oedema, and pericardial effusion were uncommonly (0.1 to 1%) observed in a Phase III study of newly diagnosed TAS API SEP22 V14                                                                        EU SmPC 15JUN22 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 aetiology should be evaluated and patients treated accordingly (see section 4.2 for instructions on managing non-haematological toxicities).


Cardiovascular events
Cardiovascular events were reported in a randomised Phase III study in newly diagnosed CML patients and observed in post-marketing reports. In this clinical study with a median on-therapy time of 60.5 months, Grade 3-4 cardiovascular events included peripheral arterial occlusive disease (1.4% and 1.1% at 300 mg and 400 mg nilotinib twice daily, respectively), ischaemic heart disease (2.2% and 6.1% at 300 mg and 400 mg nilotinib twice daily, respectively) and ischaemic cerebrovascular events (1.1% and 2.2% at 300 mg and 400 mg nilotinib 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 nilotinib therapy according to standard guidelines.
Appropriate therapy should be prescribed to manage cardiovascular risk factors (see section 4.2 for instructions on managing non-haematological toxicities).

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 nilotinib. 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 nilotinib should be closely monitored for signs and symptoms of active HBV infection throughout therapy and for several months following termination of therapy (see section 4.8).

Special monitoring of adult Ph+ CML patients in chronic phase 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 nilotinib.

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) in CML patients who received nilotinib as first-or second-line therapy, 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)) in CML patients who received nilotinib as second-line therapy 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 TAS API SEP22 V14                                                                        EU SmPC 15JUN22 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.

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 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 (see section 4.8). It is recommended that the lipid profiles be determined before initiating treatment with nilotinib, assessed at month 3 and 6 after initiating therapy and at least yearly during chronic therapy (see section 4.2). If a HMG-CoA reductase inhibitor (a lipid-lowering agent) is required, please refer to section 4.5 before initiating treatment since certain HMG-CoA reductase inhibitors are also metabolised by the CYP3A4 pathway.

Blood glucose
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 (see section 4.2). 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 nilotinib therapy be interrupted if possible (see section 4.5). If transient interruption of treatment is not possible, close monitoring of the individual for prolongation of the QT interval is indicated (see sections 4.2, 4.5 and 5.2).

Concomitant use of nilotinib 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 nilotinib, co-administration of alternative therapeutic agents with less potential for CYP3A4 induction should be selected (see section 4.5).

Food effect

The bioavailability of nilotinib is increased by food. Tasigna must not be taken in conjunction with food (see sections 4.2 and 4.5) 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 capsules, the content of each 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 (see section 5.2).

Hepatic impairment

Hepatic impairment has a modest effect on the pharmacokinetics of nilotinib. Single dose administration of 200 mg 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 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 
TAS API SEP22 V14                                                                          EU SmPC 15JUN22 nilotinib is mainly hepatic. Patients with hepatic impairment might therefore have increased exposure to nilotinib and should be treated with caution (see section 4.2).

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, nilotinib therapy should be interrupted and appropriate diagnostic measures considered to exclude pancreatitis.

Total gastrectomy

The bioavailability of nilotinib might be reduced in patients with total gastrectomy (see section 5.2).
More frequent follow-up of these patients should be considered.
Tumour lysis syndrome

Due to possible occurrence of tumour lysis syndrome (TLS) correction of clinically significant dehydration and treatment of high uric acid levels are recommended prior to initiating nilotinib therapy (see section 4.8).

Lactose

Tasigna 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.

Effects on Driving

4.7    Effects on ability to drive and use machines

Tasigna has no or negligible influence on the ability to drive and use machines. However, it is recommended that patients experiencing dizziness, fatigue, visual impairment or other undesirable effects with a potential impact on the ability to drive or use machines safely should refrain from these activities as long as the undesirable effects persist (see section 4.8).