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FDA Alerts

Pharmacist's Applications to Practice

HOPA, through the Publications Committee, will review new drug updates and provide analysis and research on the application of these new drugs or indications.

The letters “PAP” after drugs listed below indicates that they include this additional analysis.  


August 3, 2017

https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209401s000lbl.pdf

On August 3, 2017, the U.S. Food and Drug Administration granted regular approval to a liposome-encapsulated combination of daunorubicin and cytarabine (VYXEOS™, Jazz Pharmaceuticals, Inc.) for the treatment of adults with newly-diagnosed therapy-related AML (t-AML) or AML with myelodysplasia-related changes (AML-MRC), two types of AML having a poor prognosis.

This is the first FDA-approved treatment specifically for patients with t-AML or AML-MRC.

Approval was based on data from Study CLTR0310-301 (NCT01696084), a randomized (1:1), multicenter, open-label, active-controlled trial comparing Vyxeos to a standard combination of daunorubicin and cytarabine (7+3) in 309 patients 60-75 years of age with newly-diagnosed t-AML or AML-MRC. Vyxeos demonstrated an estimated median overall survival of 9.6 months compared with 5.9 months for the 7+3 control (hazard ratio 0.69; 95% CI: 0.52, 0.90; p=0.005).

The most common adverse reactions occurring in greater than 25% of patients treated with Vyxeos were hemorrhage events, febrile neutropenia, rash, edema, nausea, mucositis, diarrhea, constipation, musculoskeletal pain, fatigue, abdominal pain, dyspnea, headache, cough, decreased appetite, arrhythmia, pneumonia, bacteremia, chills, sleep disorders and vomiting.

Each Vyxeos vial contains 44 mg daunorubicin and 100 mg cytarabine encapsulated together in liposomes. The volume of reconstituted Vyxeos required for each dose is calculated based on the daunorubicin dose (mg/m2) using body surface area. Since Vyxeos is a fixed-dose combination, and dosing based on the daunorubicin component, the corresponding cytarabine dose is included and does not need to be calculated.

For the first induction cycle, the recommended dose of Vyxeos is (daunorubicin 44 mg/m2 and cytarabine 100 mg/m2) liposome via intravenous infusion over 90 minutes on days 1, 3, and 5. If needed, the same dose is administered on days 1 and 3 of second induction. The recommended dose for each cycle of consolidation therapy is (daunorubicin 29 mg/m2 and cytarabine 65 mg/m2) liposome via intravenous infusion over 90 minutes on days 1 and 3.

The prescribing information includes a boxed warning not to substitute Vyxeos with other daunorubin- or cytarabine-containing products. Full prescribing information is available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209401s000lbl.pdf.

FDA previously granted Breakthrough Therapy and Orphan Drug designations to the combination product for this indication, as well as priority review. FDA approval took place two months ahead of the goal date. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics, available at:
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf

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).

 

Pharmacist’s Applications to Practice

Daunorubicin and Cytarabine for Treatment of Adults with Newly Diagnosed Therapy-Related Acute Myeloid Leukemia or Acute Myeloid Leukemia with Myelodysplasia-Related Changes

Author: Jeff Engle, PharmD MS
PGY-2 Hematology/Oncology Pharmacy Resident
University of Minnesota Medical Center
Fairview, MN

What is the potential role for liposomal daunorubicin and cytarabine in the management of acute myeloid leukemia (AML)?

  • Liposome-encapsulated daunorubicin with cytarabine is the first medication approved by the U.S. Food and Drug Administration (FDA) specifically for therapy-related AML (t-AML) or AML with myelodysplasia-related changes (AML-MRC).
  • Approval was granted based on Study CLTR0310-301, a phase 3 multicenter randomized open-label study (N = 309) of patients aged 60–75 with newly diagnosed t-AML or AML-MRC who received liposomal daunorubicin with cytarabine (daunorubicin 44 mg/m2 and cytarabine 100 mg/m2 on days 1, 3, and 5) or 7+3 (daunorubicin 60 mg/m2 and cytarabine 100 mg/m2) as induction chemotherapy.1
    • A second induction course was allowed, and consolidation cycles also included the liposomal formulation at a lower dose as compared to the second induction course.
    • A statistically significant improvement in complete response rate (38% vs. 26%, p = .036) and overall survival (9.6 months vs 5.9 months; hazard ratio [HR] .69, p = .005) was demonstrated with liposome-encapsulated daunorubicin with cytarabine.
    • Adverse effects were similar between the treatment arms with some exceptions. Grade 3 or higher hemorrhagic events associated with severe thrombocytopenia were reported in 12% of patients receiving liposome-encapsulated daunorubicin with cytarabine and in 8% of patients receiving conventional therapy. Grade 3 thrombocytopenia (28% vs. 12%) and grade 4 neutropenia (17% vs. 3%) were higher in patients treated with the liposomal formulation.1
  • National Comprehensive Cancer Network (NCCN) Guidelines for AML treatment stratify treatment recommendations for patients 60 years and older with newly diagnosed AML according to whether the patient is a candidate for intensive remission induction chemotherapy. For those patients with newly diagnosed t-AML or AML-MRC without an FLT3 mutation, NCCN Category 2A recommendations include participation in a clinical trial, cytarabine with an anthracycline, or lower-intensity chemotherapy with azacitidine or decitabine.2
  • The FDA approval trial used 7+3 as a comparator, but according to guidelines, these patients would also be eligible for lower-intensity therapy with azacitidine or decitabine. Azacitidine has been compared to conventional therapy in trials.3,4 These studies compared azacitidine to conventional care, which included best supportive care, low-dose cytarabine, or intensive chemotherapy. These studies showed potential benefit for azacitidine in older patients and those with poor-risk cytogenetics compared with conventional therapy, although the sample sizes were small, which limits any firm conclusions.
    • Rates of hematologic adverse events were similar for standard 7+3 and azacitidine.4
  • Liposome-encapsulated daunorubicin and cytarabine should be considered in older adults (ages 60–75) with t-AML or AML-MRC who are candidates for intensive remission induction chemotherapy with cytarabine and an anthracycline.

What role can the pharmacist play in the management of patients on liposomal daunorubicin and cytarabine?

  • Adverse effects and monitoring parameters do not vary substantially from those for agents traditionally used in this patient population. Because the rates of bleeding are reportedly higher than what is observed with 7+3, providers should be educated to monitor platelets closely, and patients should be educated on signs and symptoms of hemorrhagic events.1
  • Pharmacists can ensure appropriate cardiac function by recommending multiple-gated acquisition (MUGA) scans or echocardiograms prior to treatment initiation and consolidation therapy.
  • Pharmacists will play a critical role in ensuring accurate dosing of liposomal daunorubicin with cytarabine, depending on the course of therapy. Providers should be educated on dosing on the basis of the daunorubicin component of the medication.1
  • Pharmacists can provide recommendations if cardiac impairment is detected; liposomal daunorubicin with cytarabine is not recommended in patients with less than normal cardiac function.1
  • Serious hypersensitivity reactions have occurred with liposomal daunorubicin and cytarabine, and precautions are listed in the package insert. The incidence of hypersensitivity reactions has not been reported in phase 2 and 3 trials, and premedications are not recommended prior to the first dose. If a reaction occurs, the pharmacist can recommend appropriate infusion-rate adjustments and addition of antihistamines and corticosteroids as premedications according to the package insert.
  • Daunorubicin is a vesicant and has been associated with severe tissue necrosis if the drug extravasates. Daunorubicin should be administered only intravenously, and patients should be monitored closely for drug extravasation.

Clinical Pearls

  • Do not interchange the liposome-encapsulated formulation with other daunorubicin- or cytarabine-containing products.
  • In animal models, liposome-encapsulated daunorubicin and cytarabine were taken up to a greater extent by leukemic cells than by normal bone marrow cells and, upon internalization, released cytarabine and daunorubicin intracellularly.5,6
  • A reconstituted vial of liposome-encapsulated daunorubicin and cytarabine contains 5 mg/ml copper gluconate (14% elemental copper), so caution should be used in patients with copper-related metabolic disorders such as Wilson disease.1
  • The prepared product for administration should be a deep purple color and may alter the color of a patient’s urine, sweat, and tears.1

References

  1. Vyxeos [package insert]. Palo Alto, CA. Jazz Pharmaceuticals, 2017.
  2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Acute Myeloid Leukemia: Version 3.2017. https://www.nccn.org/professionals/physician_gls/pdf/aml.pdf. Accessed September 19, 2017.
  3. Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al; International Vidaza High-Risk MDS Survival Study. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol. 2009;10(3):223-232.
  4. Dombret H, Seymour JF, Butrym A, et al. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood. 2015;126(3):291-299.
  5. Lim WS, Tardi PG, Dos Santos N, et al. Leukemia-selective uptake and cytotoxicity of CPX-351, a synergistic fixed-ratio cytarabine:daunorubicin formulation, in bone marrow xenografts. Leuk Res. 2010;34(9):1214-1223.
  6. Lancet JE, Cortes JE, Hogge DE, et al. Phase 2 trial of CPX-351, a fixed 5:1 molar ratio of cytarabine/daunorubicin, vs cytarabine/daunorubicin in older adults with untreated AML. Blood. 2014;123(21):3239-3246.
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