Clinical Pharmacology Corner: FDA Approves VYXEOS (Daunorubicin and Cytarabine)

FDA Approves VYXEOS® (Daunorubicin and Cytarabine) for the Treatment of Adults with Newly-Diagnosed Therapy-Related Acute Myeloid Leukemia (t-AML) or AML with Myelodysplasia-Related Changes (AML-MRC)

On August 3, 2017, the U.S Food and Drug Administration (FDA) approved VYXEOS (daunorubicin and cytarabine) liposome for injection for the treatment of adult patients with newly-diagnosed therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC). The approved recommended dosage of VYXEOS is 44 mg/100 mg per m² (daunorubicin/cytarabine) administered as a 90-minute intravenous infusion or more on days 1, 3, and 5 for the first induction cycle and on days 1 and 3 for subsequent induction cycle(s) if needed. Prior to initiation induction, assess cardiac function and obtain liver and renal function studies. A dose of 29 mg/65 mg per m² on days 1 and 3 via intravenous infusion over 90 minutes or more is recommended for consolidation cycle(s).

Do not interchange with other daunorubicin and/or cytarabine-containing products. VYXEOS has different dosage recommendations than daunorubicin hydrochloride injection, cytarabine injection, daunorubicin citrate liposome injection, and cytarabine liposome injection. Verify drug name and dose prior to preparation and administration to avoid dosing errors.

Serious or fatal hemorrhagic events with associated prolonged thrombocytopenia have occurred with VYXEOS; monitor blood counts regularly until recovery. VYXEOS treatment is not recommended in patients with cardiac function that is less than normal. Discontinue VYXEOS in patients with impaired cardiac function unless the benefit of continuing treatment outweighs the risk. If a mild or moderate hypersensitivity reaction occurs, interrupt or slow the rate of VYXEOS infusion, and manage symptoms (see linked prescribing information below regarding premedication for subsequent dosing). If severe or life-threatening hypersensitivity reaction occurs, discontinue VYXEOS, treat according to standard of care, and monitor until signs and symptoms resolve. Use VYXEOS in patients with Wilson’s disease only if the benefits outweigh the risks. Discontinue VYXEOS in patients with signs or symptoms of acute copper toxicity. Daunorubicin has been associated with local tissue necrosis at the site of drug extravasation; administer VYXEOS intravenously only with care.

Mechanism of Action (MOA), General Pharmacokinetics (PK), and Pharmacodynamics (PD)

• MOA: VYXEOS is a liposomal formulation of daunorubicin and cytarabine in a 1:5 molar ratio. Daunorubicin has antimitotic and cytotoxic activity, and cytarabine is a cell cycle phase-specific antineoplastic agent.
• Pharmacokinetics: Following the recommended approved dose, the mean (% coefficient of variation, CV) maximal concentration (Cmax) for daunorubicin was 26.0 (32.7%) mcg/mL and cytarabine was 62.2 (33.6%) mcg/mL. During one dosing interval, the mean (%CV) area under the curve (AUC) for daunorubicin was 637 (38.3%) mcg∙h/mL and cytarabine was 1900 (44.4%) mcg∙h/mL. 
• Accumulation: The accumulation ratio was 1.3 for daunorubicin and 1.4 for cytarabine. 
• Dose Proportionality: There was no evidence of time-dependent kinetics or major departures from dose proportionality over the range of 1.3 mg/3 mg per m² to 59 mg/134 mg per m² (0.03 to 1.3 times the approved recommended dosage).
• Distribution: The volume of distribution (%CV) for daunorubicin is 6.6 L (37%) and cytarabine is 7.1 L (49%). Plasma protein binding was not evaluated.
• Elimination: VYXEOS exhibits a half-life (%CV) of 31.5 h (29%) for daunorubicin and 40.4 h (24%) for cytarabine with greater than 99% of the daunorubicin and cytarabine in the plasma remaining encapsulated within the liposomes.
• Metabolism: Subsequent to release from VYXEOS liposomes, daunorubicin is catalyzed by aldoketo reductase and carbonyl reductase enzymes to the active metabolite daunorubicinol. Cytarabine is metabolized by cytidine deaminase to the inactive metabolite 1-β-D-arabinofuranosyluracil (AraU). 
• Excretion: Urinary excretion of daunorubicin and daunorubicinol accounts for 9% of the administered dose of daunorubicin, and urinary excretion of cytarabine and AraU accounts for 70% of the administered dose of cytarabine.

Drug Interactions 

Cardiotoxic agents: Concomitant use may increase the risk of cardiotoxicity. Monitor cardiac function more frequently when VYXEOS is used concomitantly with cardiotoxic agents.

Hepatotoxic agents: Concomitant use may impair liver function and increase the toxicity of VYXEOS. Monitor hepatic function more frequently when VYXEOS is used concomitantly with hepatotoxic agents.

Use in Specific Populations

Age, sex, race, mild or moderate renal impairment (CLcr 30-89 mL/min), bilirubin ≤ 3 mg/dL, body weight, body mass index, and white blood cell count do not have a clinically significant effect on the pharmacokinetics of total daunorubicin or cytarabine after adjusting dose by body surface area. The pharmacokinetics in patients with severe renal impairment (CLcr 15-29 mL/min), end-stage renal disease, or bilirubin > 3 mg/dL are unknown.

Efficacy and Safety

Efficacy of VYXEOS was demonstrated in a randomized, multicenter, open-label, active-controlled trial which compared the recommended dosage of VYXEOS to a standard combination of cytarabine and daunorubicin (7+3) in patients 60 years to 75 years of age with newly diagnosed t-AML or AML-MRC. Additional information regarding efficacy trial(s) can be found in the full prescribing information linked below.

The most common adverse reactions (incidence ≥ 25%) were hemorrhagic events, febrile neutropenia, edema, nausea, mucositis, diarrhea, constipation, musculoskeletal pain, fatigue, abdominal pain, dyspnea, headache, cough, decreased appetite, arrhythmia, pneumonia, bacteremia, chills, sleep disorders, and vomiting.

Full prescribing information is available at https://go.usa.gov/xREkz.

Visit Drugs@FDA at http://go.usa.gov/cMsjT for prescribing and patient information, approval letters, reviews and other information for FDA-approved drug products, which are often available shortly following approval.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

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This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.

FDA/Center for Drug Evaluation and Research (CDER)
Office of Translational Sciences
Office of Clinical Pharmacology
Email: ocp@fda.hhs.gov