VYXEOS LIPOSOMAL Powder for concentrate for solution for infusion Ref.[51372] Active ingredients: Cytarabine Cytarabine and Daunorubicin Daunorubicin

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:

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.

There is no specific experience in the management of overdose in patients. If overdose occurs, exacerbation of adverse reactions associated with Vyxeos liposomal are expected and supportive treatment (incuding anti-infectives, blood and platelet transfusions, colony-stimulating factors, and intensive care as needed) should be provided until the patient recovers. Observe the patient carefully over time for signs of cardiotoxicity and provide appropriate supportive therapy as clinically indicated.

Unopened vials: 36 months.

Stability of reconstituted suspension in the vial

Chemical and physical in-use stability has been demonstrated for 4 hours at 2°C to 8°C when kept in an upright position.

From a microbiological point of view, unless the method of opening/reconstitution/dilution precludes the risk of microbial contamination, the product should be used immediately.

If not used immediately, in-use storage times and conditions are the responsibility of the user.

Stability of diluted infusion solution

Chemical and physical in-use stability has been demonstrated for 4 hours at 2°C to 8°C.

From a microbiological point of view, unless the method of opening/reconstitution/dilution precludes the risk of microbial contamination, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user.

The maximum combined storage time for reconstituted product in the vial and reconstituted product diluted into an infusion bag is up to 4 hours at 2°C to 8°C.

Store in a refrigerator (2°C-8°C).

Keep the vial in the original carton in order to protect from light. Store in an upright position.

For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3.

50 mL vial (type 1 glass) with a stopper (chlorobutyl rubber), and an overseal (aluminium) containing 44 mg daunorubicin and 100 mg cytarabine.

Each pack contains either 1 vial, 2 vials or 5 vials. Not all pack sizes may be marketed.

Vyxeos liposomal is a cytotoxic medicinal product. Applicable special handling and disposal procedures should be followed. The product is intended for single use only. Any unused product should be disposed of in accordance with local requirements for cytotoxic agents.

Preparation instructions

• Determine the dose and number of vials of Vyxeos liposomal based on the individual patient’s BSA as outlined in section 4.2.
• Remove the appropriate number of vials of Vyxeos liposomal from the refrigerator and equilibrate to the room temperature (15°C to 30°C) for 30 minutes.
• Then, reconstitute each vial with 19 mL of sterile water for injections using a 20 mL syringe, and immediately thereafter start a 5-minute timer.
• Carefully swirl the contents of the vial for 5 minutes while gently inverting the vial every 30 seconds.
• Do not heat, vortex, or shake vigorously.
• After reconstitution, let it rest for 15 minutes.
• The reconstituted product should be an opaque, purple, homogeneous dispersion, essentially free from visual particulates.
• If the reconstituted product is not diluted into an infusion bag immediately, store in a refrigerator (2ºC to 8ºC) for up to 4 hours.
• Following the storage of reconstituted product in the vial for up to 4 hours at 2°C to 8°C in an upright position, the reconstituted product must immediately be diluted into an infusion solution and run for the 90-minute infusion time.
  • Reconstituted product in the vial and reconstituted product which has been diluted into an infusion solution are stable for a maximum combined storage time of up to 4 hours when stored at 2°C to 8°C, The 4-hour stability period for the reconstituted product in the vial does not allow for an additional 4-hour stability period after the appropriate dose from the reconstituted vial is diluted into the infusion solution.
  • The 4-hour stability period when reconstituted product diluted into the infusion bag is stored at 2°C to 8°C does not include the time required for reconstitution or the 90-minute infusion time.
  • The diluted infusion solution must be immediately infused for the 90-minute infusion time following the up to 4-hour stability period.
• Calculate the volume of reconstituted Vyxeos liposomal required using the following formula: [volume required (mL) = dose of daunorubicin (mg/m²) x patient’s BSA (m²)/2.2 (mg/mL)]. The concentration of the reconstituted solution is 44 mg/20 mL (2.2 mg/mL) daunorubicin and 100 mg/20 mL (5 mg/mL) cytarabine.
• Gently invert each vial 5 times prior to withdrawing the concentrate for dilution.
• Aseptically withdraw the calculated volume of reconstituted Vyxeos liposomal from the vial(s) with a sterile syringe and transfer it to an infusion bag containing 500 mL of sodium chloride 9 mg/mL (0.9%) solution for injection, or 5% glucose. There may be residual product remaining in the vial. Discard unused portion.
• Gently invert the bag to mix the solution. The dilution of the reconstituted product results in a deep purple, translucent, homogeneous dispersion.
• If the diluted infusion solution is not used immediately, store in a refrigerator (2°C to 8°C) for up to 4 hours.
• Gently invert the bag to mix the solution after refrigeration.

Administration instructions

• Do not mix Vyxeos liposomal with, or administer as an infusion with, other medicinal products.
• Administer Vyxeos liposomal by constant intravenous infusion over 90 minutes via an infusion pump through a central venous catheter or a peripherally inserted central catheter. An in-line membrane filter may be used for the intravenous infusion of Vyxeos liposomal, provided the minimum pore diameter of the filter is greater than or equal to 15 µm.
• Flush the line after administration with sodium chloride 9 mg/mL (0.9%) solution for injection.

This medicinal product could have potential risk for the environment due to the cytotoxic and antimitotic activities, which could induce possible reproductive effects. All materials used for dilution and administration should be disposed of according to local procedures applicable to the discarding of antineoplastic agents. Any unused medicinal product or waste material should be disposed of in accordance with local requirements for cytotoxic agents.