Posology : מינונים

4.2     Posology and method of administration

Vyxeos liposomal treatment should be initiated and monitored under the supervision of a physician experienced in the use of chemotherapeutic medicinal products.

Vyxeos liposomal has a different posology than daunorubicin injection and cytarabine injection and it must not be interchanged with other daunorubicin and/or cytarabine containing products (see section 4.4).

Posology
Vyxeos liposomal dosing is based on the patient’s body surface area (BSA) according to the following schedule:

Table 1:        Dose and schedule for Vyxeos liposomal

Therapy                                      Dosing schedule

First induction          daunorubicin 44 mg/m2 and cytarabine 100 mg/m2 on days 1, 3, and 5 
Second induction           daunorubicin 44 mg/m2 and cytarabine 100 mg/m2 on days 1 and 3 
Consolidation              daunorubicin 29 mg/m2 and cytarabine 65 mg/m2 on days 1 and 3 

Recommended dosing schedule for induction of remission
The recommended dosing schedule of Vyxeos liposomal 44 mg/100 mg/m2, administered intravenously over 90 minutes:
•      on days 1, 3, and 5 as the first course of induction therapy.
•      on days 1 and 3 as subsequent course of induction therapy, if needed.

A subsequent course of induction may be administered in patients who do not show disease progression or unacceptable toxicity. The attainment of a normal-appearing bone marrow may require more than one induction course. Evaluation of the bone marrow following recovery from the previous course of induction therapy determines whether a further course of induction is required. Treatment should be continued as long as the patient continues to benefit or until disease progression up to maximum of 2 induction courses.

Recommended dosing schedule for consolidation
The first consolidation cycle should be administered 5 to 8 weeks after the start of the last induction.

The recommended dosing schedule of Vyxeos liposomal is 29 mg/65 mg/m2, administered intravenously over 90 minutes:
•      on days 1 and 3 as subsequent courses of consolidation therapy, if needed.

Consolidation therapy is recommended for patients achieving remission who have recovered to absolute neutrophil count (ANC) > 500/µL and the platelet count has recovered to greater than 50,000/µL in the absence of unacceptable toxicity. A subsequent course of consolidation may be administered in patients who do not show disease progression or unacceptable toxicity within the range of 5 to 8 weeks after the start of the first consolidation. Treatment should be continued as long as the patient continues to benefit or until disease progression, up to maximum of 2 consolidation courses.

Recommended dose adjustments during treatment
Patients should be monitored for haematologic response and toxicities.

Dosing should be delayed or permanently discontinued, if necessary, as described below.
Patients may be pre-medicated for nausea and vomiting. An anti-hyperuricemic therapy should be considered (e.g., allopurinol) prior to initiating Vyxeos liposomal.

Hypersensitivity

For mild hypersensitivity symptoms (e.g., mild flushing, rash, pruritus), the treatment should be stopped, and the patient should be supervised, including monitoring of vital signs. The treatment should be restarted slowly once the symptoms have resolved, by halving the rate of infusion and intravenous diphenhydramine (20-25 mg) and intravenous dexamethasone (10 mg) should be given.

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 4.4 and 4.8).


Missed dose
If a planned dose of Vyxeos liposomal is missed, the dose should be administered as soon as possible and the dosing schedule adjusted accordingly, maintaining the treatment interval.

Cardiotoxicity
Assessment of cardiac function prior to start of treatment is recommended, especially in patients with a high risk of cardiac toxicity. Vyxeos liposomal treatment should be discontinued in patients who develop signs or symptoms of cardiomyopathy, unless the benefits outweigh the risks (see section 4.4).

Special populations

Renal impairment
Dose adjustment is not required for patients with mild (creatinine clearance [CrCL] 60 mL/min to 89 mL/min by Cockcroft Gault equation [C-G]), moderate (CrCL 30 mL/min to 59 mL/min) or severe (CrCL<30 mL/min) renal impairment. There is no experience with Vyxeos liposomal in patients with end-stage renal disease managed with dialysis. (See section 5.2).

Hepatic impairment
Dose adjustment is not required for patients with a bilirubin level less than or equal to 50 µmol/L.
There is no experience with Vyxeos liposomal in patients with hepatic impairment resulting in a bilirubin level greater than 50 µmol/L. Vyxeos liposomal should only be used in patients with severe hepatic impairment if the benefits outweigh the risks (see section 4.4).

Elderly population
No dose adjustment is required in elderly patients (≥65 years) (see section 5.2).

Paediatric population
Outside its authorised indications Vyxeos liposomal has been studied in paediatric and young adult patients aged 1-21 years with relapsed AML. Due to the limited size of these trials, it is not possible to conclude that the benefits of the use outweigh the risks.

Currently available data are described in sections 5.1 and 5.2, but no recommendation on a posology can be made
Method of administration
Vyxeos liposomal is for intravenous use only. It must not be administered via an intramuscular, intrathecal, or subcutaneous route.

Vyxeos liposomal is administered by intravenous infusion over a period of 90 minutes. Care should be taken to ensure there is no extravasation to prevent the risk of tissue necrosis.

For instructions on reconstitution of the medicinal product before administration, see section 6.6.