Daunorubicin & Cytarabine Liposome (Vyxeos™)

What is daunorubicin and cytarabine liposome? Daunorubicin and cytarabine liposome is the first dual-drug liposomal encapsulation product approved by the FDA. How does this drug work? Daunorubicin inhibits DNA and RNA synthesis by forming complexes with DNA, inhibiting topoisomerase II activity, inhibiting DNA polymerase activity, affecting regulation of gene expression, and producing DNA-damaging free radicals. Cytarabine decreases DNA synthesis by inhibiting DNA polymerase. The fixed 1:5 molar ratio of daunorubicin:cytarabine was shown to be the most synergistic ratio for killing leukemia cells in vitro and in murine models. What is it approved for? Daunorubicin and cytarabine liposome is approved for the treatment of adults with newly diagnosed therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC). Daunorubicin and cytarabine liposome was approved based on results from an open-label, multicenter, randomized, phase III trial. Patients with newly diagnosed t-AML or AML-MRC between the ages of 60 and 75 years old were eligible for inclusion. A total of 309 patients were randomized to daunorubicin and cytarabine liposome or cytarabine and daunorubicin (7+3 or 5+2) induction and consolidation. The complete remission rate was higher with daunorubicin and cytarabine liposome (38% vs. 26%, p=0.036). Median event-free survival (2.5 vs. 1.3 months, p=0.021) and overall survival (9.6 vs. 5.9 months, p=0.005) were significantly better in patients who received daunorubicin and cytarabine liposome (J Clin Oncol 2016;34:15_suppl.7000). How do you administer this drug? Induction with daunorubicin 44 mg/m2 and cytarabine 100 mg/m2 liposome is given intravenously over 90 minutes on days 1, 3, and 5. If second induction is needed, the same dose is given on days 1 and 3. Daunorubicin 29 mg/m2 and cytarabine 65 m/m2 liposome is given on days 1 and 3 for up to 2 cycles of consolidation. Are there any premedications needed for daunorubicin and cytarabine liposome? Prophylactic antiemetics, such as ondansetron and dexamethasone, should be administered prior to daunorubicin and cytarabine liposome since this medication has a moderate emetic risk. What are side effects associated with daunorubicin and cytarabine liposome (≥ 10%)? Side effects more commonly observed with daunorubicin and cytarabine liposome included (≥ 5% over control arm): Hematologic: hemorrhage, prolonged thrombocytopenia, prolonged neutropenia Infections: fungal, upper respiratory, catheter/device/injection site Other: rash, pruritus, cough, headache, visual impairment What are some other side effects? Patients may develop cardiotoxicity, hypersensitivity reactions, and tissue necrosis. Before administering daunorubicin and cytarabine liposome, the patient's cumulative anthracycline exposure should be calculated and assessed for appropriateness. Since daunorubicin and cytarabine liposome contains copper gluconate, copper overload may also occur. Are there any important drug interactions? Monitor cardiac and hepatic function at baseline and when used with other cardiotoxic and hepatotoxic agents, respectively. How do I adjust the dose in the setting of renal or hepatic insufficiency? Dose adjustments are not required for renal or hepatic insufficiency. Daunorubicin and cytarabine liposome is metabolized in the liver and excreted renally, but has not been studied in patients with severe renal impairment/end-stage renal disease or bilirubin levels greater than 3 mg/dL. Practical tips: If patients develop a hypersensitivity reaction, premedicate patients with an antihistamine and/or corticosteroid prior to subsequent doses. Do not interchange daunorubicin and cytarabine liposome with other daunorubicin and/or cytarabine products. Daunorubicin and cytarabine liposome has unique preparation instructions that pharmacy staff should be trained on. The total preparation time takes close to an hour with key steps including equilibration to room temperature, reconstitution followed by swirling vial contents, and aseptically transferring the medication to an infusion bag. What should my patients know? Patients should be educated on the administration schedule of daunorubicin and cytarabine liposome, as well as side effects, and contact their health care provider if they develop a hypersensitivity reaction, uncontrolled nausea or vomiting, or fever or chills. Side effects that patients should be educated on include low blood counts, increased risk of infection, hypersensitivity reactions, and cardiotoxicity. What else should I know? Daunorubicin and cytarabine liposome should only be used in patients with t-AML or AML-MRC. Patients who received daunorubicin and cytarabine liposome had more prolonged thrombocytopenia and neutropenia leading to increased infections and hemorrhage. Daunorubicin and cytarabine liposome has unique preparation instructions and should not be interchanged with other daunorubicin and/or cytarabine products. What useful links are available? https://vyxeos.com/ https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm569950.htm Any ongoing clinical trials related to daunorubicin and cytarabine liposome? Multiple clinical trials with daunorubicin and cytarabine liposome are ongoing including trials in adult patients with newly diagnosed, relapsed/refractory AML, and myelodysplastic syndromes as well as exploration of use in the pediatric population. More can be found at https://clinicaltrials.gov. MALLORY L. CRAIN, PHARMD, is PGY2 Oncology Resident, Department of Pharmacy at Barnes-Jewish Hospital, St. Louis, Mo. RAMASWAMY GOVINDAN, MD, Professor of Medicine; Anheuser Busch Chair in Medical Oncology; and Director, Section of Medical Oncology, Division of Oncology, Washington University School of Medicine, serves as the Pharmacy Forum column physician advisor.Mallory L. Crain, PharmD: Mallory L. Crain, PharmDRamaswamy Govindan, MD: Ramaswamy Govindan, MD