Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use

Other daunorubicin and/or cytarabine-containing products
Vyxeos liposomal must not be substituted or interchanged with other daunorubicin and/or cytarabine containing products. Due to substantial differences in the pharmacokinetic parameters, the dose and schedule recommendations for Vyxeos liposomal are different from those for daunorubicin hydrochloride injection, cytarabine injection, daunorubicin citrate liposome injection, and cytarabine liposome injection. The medicinal product name and dose should be verified prior to administration to avoid dosing errors.

Severe myelosuppression
Severe myelosuppression (including fatal infections and haemorrhagic events) has been reported in patients after administration of a therapeutic dose of Vyxeos liposomal. Serious or fatal haemorrhagic events, including fatal central nervous system (CNS) haemorrhages, associated with severe thrombocytopenia, have occurred in patients treated with Vyxeos liposomal. Baseline assessment of blood counts should be obtained, and patients should be carefully monitored during treatment with Vyxeos liposomal for possible clinical complications due to myelosuppression. Due to the long plasma half-life of Vyxeos liposomal, time to recovery of ANC and platelets may be prolonged and require additional monitoring.

Prophylactic anti-infectives (including anti-bacterial, anti-virals, anti-fungals) may be administered during the period of profound neutropenia until ANC returns to 500/μL or greater. If myelosuppressive complications occur, appropriate supportive measures should be used, e.g., anti-infectives, colony- stimulating factors, transfusions. Blood counts should be regularly monitored until recovery (see section 4.8).

Cardiotoxicity
Cardiotoxicity is a known risk of anthracycline treatment. Prior therapy with anthracyclines (including patients who have previously received the recommended maximum cumulative doses of doxorubicin or daunorubicin hydrochloride), pre-existing cardiac disease (including impaired cardiac function), previous radiotherapy of the mediastinum, or concomitant use of cardiotoxic products may increase the risk of daunorubicin-induced cardiac toxicity.

In two single arm studies of 65 anthracycline pre-treated children with relapsed or refractory AML treated with a single induction cycle (Cycle 1) of Vyxeos liposomal, cardiac disorders (including sinus tachycardia, QT prolongation and ejection fraction decreased) were observed. Several other long- term studies of treatment with anthracycline/ anthracenedione in children suggest that congestive cardiomyopathies with a latency of many years may occur (see section 4.8) 

Total cumulative doses of non-liposomal daunorubicin greater than 550 mg/m2 have been associated with an increased incidence of treatment-induced congestive heart failure. This limit appears lower (400 mg/m2) in patients who received radiation therapy to the mediastinum. The relationship between cumulative Vyxeos liposomal dose and the risk of cardiac toxicity has not been determined. Total cumulative exposure of daunorubicin has been described in the table below.

Table 2:         Cumulative exposure of daunorubicin per course of Vyxeos liposomal 
Therapy                  Daunorubicin         Number of doses        Daunorubicin per per dose             per course               course
First induction                44 mg/m2                  3                  132 mg/m2 Second induction                44 mg/m2                  2                   88 mg/m2 Each consolidation                 29 mg/m2                  2                   58 mg/m2 
A baseline cardiac evaluation with an electrocardiogram (ECG) and a multi-gated radionuclide angiography (MUGA) scan or an echocardiography (ECHO) is recommended, especially in patients with risk factors for increased cardiac toxicity. Cardiac function should be closely monitored.

Treatment with Vyxeos liposomal should be discontinued in patients with impaired cardiac function unless the benefit of initiating or continuing treatment outweighs the risk (see sections 4.5 and 4.8).

Pregnancy warning/women of childbearing potential
Patients should be advised to avoid becoming pregnant while receiving Vyxeos liposomal. Male patients and women of childbearing potential must use an effective method of contraception during treatment and for 6 months following the last dose of Vyxeos liposomal (see section 4.6).

Hypersensitivity reactions
Serious hypersensitivity reactions, including anaphylactic reactions, have been reported with daunorubicin and cytarabine.

For moderate hypersensitivity symptoms (e.g., moderate rash, flushing, mild dyspnoea, chest discomfort) the treatment should be stopped. Intravenous diphenhydramine (20-25 mg or equivalent) and intravenous dexamethasone (10 mg) should be given. The infusion should not be restarted. When the patient is retreated, Vyxeos liposomal should be given at the same dose and rate and with premedication.

For severe/life-threatening hypersensitivity symptoms (e.g., hypotension requiring vasopressor therapy, angioedema, respiratory distress requiring bronchodilation therapy, generalised urticaria), the treatment should be stopped. Intravenous diphenhydramine (20-25 mg) and dexamethasone (10 mg) should be given, and an epinephrine (adrenaline) or bronchodilators should be added if indicated. Do not reinitiate infusion, and do not retreat. Treatment with Vyxeos liposomal should be permanently discontinued. Patients should be monitored until symptoms resolve (see sections 4.2 and 4.8).

Tissue necrosis
Daunorubicin has been associated with local tissue necrosis at the site of medicinal product extravasation. In clinical studies with Vyxeos liposomal, one event of extravasation occurred, but no necrosis was observed. Care should be taken to ensure that there is no extravasation of medicinal product when Vyxeos liposomal is administered. Vyxeos liposomal should be administered intravenously only. Do not administer via an intramuscular, intrathecal, or subcutaneous route (see section 4.2).

Evaluation of hepatic and renal function
Hepatic impairment may increase the risk of toxicity associated with daunorubicin and cytarabine.
Evaluation of hepatic function using conventional clinical laboratory tests is recommended prior to administration of Vyxeos liposomal and periodically during treatment. There is no experience with Vyxeos liposomal in patients with baseline serum bilirubin greater than 50 µmol/L, or end-stage renal disease managed with dialysis. Vyxeos liposomal should only be used in patients with severe hepatic impairment if the benefits outweigh the risks (see section 4.2).

Laboratory tests
Vyxeos liposomal may induce hyperuricemia secondary to rapid lysis of leukaemic cells. Blood uric acid levels should be monitored and appropriate therapy initiated in the event that hyperuricemia develops.

History of Wilson’s disease or other copper-related disorder
Each vial contains 100 mg of copper gluconate, which corresponds to 14 mg of elemental copper.
Vyxeos liposomal should only be used in patients with a history of Wilson’s disease or other copper- related disorder if the benefits outweigh the risks (see section 6.1). Discontinue Vyxeos liposomal in patients with signs or symptoms of acute copper toxicity.

Immunosuppressant effects/Increased susceptibility to infections
Administration of live or live-attenuated vaccines in patients that are immunocompromised by chemotherapeutic agents may result in serious or fatal infections. Vaccination with a live vaccine should be avoided in patients receiving Vyxeos liposomal. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.

Gastrointestinal mucositis and diarrhoea
It should be taken into consideration that the absorption of oral accompanying medicinal products may be considerably influenced by gastrointestinal mucositis and/or diarrhoea frequently occurring in association with intensive chemotherapy.

Effects on Driving

4.7   Effects on ability to drive and use machines

Vyxeos liposomal has minor influence on the ability to drive and use machines. Fatigue and dizziness have been reported with the use of Vyxeos liposomal. Therefore, caution is recommended when driving or operating machines.