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Vyxeos
Sponsor
Device/Product name
Vyxeos
Active Ingredient
Daunorubicin (as hydrochloride) and cytarabine
Date of decision
Published
Submission type
New chemical entity, New fixed dose combination
ATC codes
L01XY01
Decision
Approved
What was the decision based on
The decision was based on quality (chemistry and manufacturing), nonclinical (pharmacology and toxicology) and clinical (pharmacology, safety and efficacy) information submitted by the sponsor. The benefit-risk profile of Vyxeos was considered favourable for the therapeutic use approved.
What steps were involved in the decision process
Registration timeline
The following table summarises the key steps and dates for this application.
| Description | Date |
|---|---|
| Submission dossier accepted and first round evaluation commenced | 1 June 2021 |
| First round evaluation completed | 15 November 2021 |
| Sponsor provides responses on questions raised in first round evaluation | 4 February 2022 |
| Second round evaluation completed | 10 February 2022 |
| Delegate's overall benefit-risk assessment | 5 April 2022 |
| Sponsor's pre-Advisory Committee response | Not applicable |
| Advisory Committee meeting | Not applicable |
| Registration decision (Outcome) | 27 May 2022 |
| Completion of administrative activities and registration on ARTG | 3 June 2022 |
| Number of working days from submission dossier acceptance to registration decision* | 181 |
*Statutory timeframe for standard applications is 255 working days
Date of entry onto ARTG
Original publication date
Black triangle scheme
Yes. This product will remain in the scheme for 5 years, starting on the date the product is first supplied in Australia
Dose forms
Powder for injection
Strength
44 mg of daunorubicin (2.2 mg/1 mL); 100 mg of cytarabine (5 mg/1 mL)
Other ingredients
Distearoylphosphatidylcholine, distearoylphosphatidylglycerol, cholesterol, copper gluconate, trolamine and sucrose
Containers
Vial
Pack sizes
1 and 2
Routes of administration
Intravenous infusion
Dosage
Vyxeos must be initiated and monitored under the supervision of physicians experienced in the use of chemotherapeutic medicinal products.
Vyxeos dosing is based on the patient’s body surface area (BSA). Dosage should be administered as a first induction, second induction and consolidation dose.
Recommended dosing schedule for induction of remission
The recommended dosing schedule of Vyxeos 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.
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 is 29 mg/65 mg/m2, administered intravenously over 90 minutes:
- on Days 1 and 3 as subsequent courses of consolidation therapy, if needed.
For further information refer to the Product Information.
Pregnancy category
D
Drugs which have caused, are suspected to have caused or may be expected to cause, an increased incidence of human fetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects. Accompanying texts should be consulted for further details.
The use of any medicine during pregnancy requires careful consideration of both risks and benefits by the treating health professional. This must not be used as the sole basis of decision making in the use of medicines during pregnancy. The TGA does not provide advice on the use of medicines in pregnancy for specific cases. More information is available from obstetric drug information services in your State or Territory.
Drugs which have caused, are suspected to have caused or may be expected to cause, an increased incidence of human fetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects. Accompanying texts should be consulted for further details.
The use of any medicine during pregnancy requires careful consideration of both risks and benefits by the treating health professional. This must not be used as the sole basis of decision making in the use of medicines during pregnancy. The TGA does not provide advice on the use of medicines in pregnancy for specific cases. More information is available from obstetric drug information services in your State or Territory.
What was approved
Vyxeos (daunorubicin and cytarabine) was approved for the following therapeutic use:
Vyxeos is indicated for the treatment of adults with newly diagnosed, therapy-related acute myeloid leukaemia (t-AML) or AML with myelodysplasia-related changes (AMLMRC).
What is this medicine and how does it work
Vyxeos is a liposomal formulation of a fixed combination of daunorubicin and cytarabine in a 1:5 molar ratio. The 1:5 molar ratio has been shown in vitro and in vivo to maximise synergistic antitumour activity in acute myeloid leukaemia (AML).
Daunorubicin has antimitotic and cytotoxic activity, which is achieved by forming complexes with deoxyribonucleic acid (DNA), inhibiting topoisomerase II activity, inhibiting DNA polymerase activity, affecting regulation of gene expression, and producing DNA-damaging free radicals.
Cytarabine is a cell cycle phase-specific antineoplastic agent, affecting cells only during the S phase of cell division. Intracellularly, cytarabine is converted into cytarabine-5-triphosphate (ara-CTP), which is the active metabolite. The mechanism of action is not completely understood, but it appears that ara-CTP acts primarily through inhibition of DNA synthesis. Incorporation into DNA and ribonucleic acid (RNA) may also contribute to cytarabine cytotoxicity. Cytarabine is cytotoxic to proliferating mammalian cells in culture.
Based on data in animals, Vyxeos liposomes accumulate and persist at a higher concentration in the bone marrow, where they are preferentially taken up intact by leukaemia cells. In leukaemia-bearing mice, the liposomes are taken up by leukaemia cells to a greater extent than by normal bone marrow cells. After internalisation, Vyxeos liposomes undergo degradation, releasing daunorubicin and cytarabine within the intracellular environment.
Daunorubicin has antimitotic and cytotoxic activity, which is achieved by forming complexes with deoxyribonucleic acid (DNA), inhibiting topoisomerase II activity, inhibiting DNA polymerase activity, affecting regulation of gene expression, and producing DNA-damaging free radicals.
Cytarabine is a cell cycle phase-specific antineoplastic agent, affecting cells only during the S phase of cell division. Intracellularly, cytarabine is converted into cytarabine-5-triphosphate (ara-CTP), which is the active metabolite. The mechanism of action is not completely understood, but it appears that ara-CTP acts primarily through inhibition of DNA synthesis. Incorporation into DNA and ribonucleic acid (RNA) may also contribute to cytarabine cytotoxicity. Cytarabine is cytotoxic to proliferating mammalian cells in culture.
Based on data in animals, Vyxeos liposomes accumulate and persist at a higher concentration in the bone marrow, where they are preferentially taken up intact by leukaemia cells. In leukaemia-bearing mice, the liposomes are taken up by leukaemia cells to a greater extent than by normal bone marrow cells. After internalisation, Vyxeos liposomes undergo degradation, releasing daunorubicin and cytarabine within the intracellular environment.
What post-market commitments will the sponsor undertake
- Vyxeos (daunorubicin and cytarabine) is to be included in the Black Triangle Scheme. The Product Information (PI) and Consumer Medicine Information (CMI) for Vyxeos must include the black triangle symbol and mandatory accompanying text for five years, which starts from the date that the sponsor notifies the TGA of supply of the product.
- For all injectable products the Product Information must be included with the product as a package insert.