VYXEOS is indicated for the treatment of newly diagnosed therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC) in adults and pediatric patients 1 year and older. VYXEOS is a liposomal combination of daunorubicin, an anthracycline topoisomerase inhibitor, and cytarabine, a nucleoside metabolic inhibitor, that is indicated for the treatment of newly diagnosed therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC) in adults and pediatric patients 1 year and older.
( 1 )
Contraindications
The use of VYXEOS is contraindicated in patients with the following:
History of serious hypersensitivity reaction to cytarabine, daunorubicin, or any component of the formulation [see Warnings and Precautions ( 5.4 )] .
History of serious hypersensitivity to daunorubicin, cytarabine or any component of the formulation. ( 4 )
Warnings and precautions
Hemorrhage: Serious or fatal hemorrhagic events with associated prolonged thrombocytopenia have occurred with VYXEOS. Monitor blood counts regularly until recovery. ( 5.2 )
Cardiotoxicity: 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. ( 2.2 , 5.3 )
Hypersensitivity: If severe or life-threatening hypersensitivity reaction occurs, discontinue VYXEOS, treat according to standard of care, and monitor until signs and symptoms resolve. ( 2.2 , 5.4 )
Tissue Necrosis: Daunorubicin has been associated with local tissue necrosis at the site of drug extravasation. Confirm intravenous access before administration. ( 5.6 )
Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. ( 5.7 , 8.1 , 8.3 )
5.1Do Not Interchange With Other Daunorubicin And/Or Cytarabine-Containing Products Due
to substantial differences in the pharmacokinetic parameters, the dose and schedule recommendations for VYXEOS are different from those for 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. Do not substitute other preparations of daunorubicin or cytarabine for VYXEOS.
or fatal hemorrhage events, including fatal central nervous system (CNS) hemorrhages, associated with prolonged severe thrombocytopenia, have occurred in patients treated with VYXEOS. In Study 1 (NCT01696084), the incidence of any grade hemorrhagic events during the entire treatment period was 74% of patients on the VYXEOS arm and 56% on the control arm. The most frequently reported hemorrhagic event was epistaxis (36% in VYXEOS arm and 18% in control arm).
Grade 3 or greater events occurred in 12% of VYXEOS treated patients and 8% of patients treated with 7+3. Fatal treatment-emergent CNS hemorrhage not in the setting of progressive disease occurred in 2% of patients on the VYXEOS arm and in 0.7% of patients on the control arm. Monitor blood counts regularly until recovery and administer platelet transfusion support as required [see Adverse Reactions ( 6.1 )].
5.3Cardiotoxicity
VYXEOS contains the anthracycline daunorubicin, which has a known risk of cardiotoxicity. Prior therapy with anthracyclines, pre-existing cardiac disease, previous radiotherapy to the mediastinum, or concomitant use of cardiotoxic drugs may increase the risk of daunorubicin-induced cardiac toxicity. Prior to administering VYXEOS, obtain an electrocardiogram (ECG) and assess cardiac function by multi-gated radionuclide angiography (MUGA) scan or echocardiography (ECHO).
Repeat MUGA or ECHO determinations of left ventricular ejection fraction (LVEF) prior to consolidation with VYXEOS and as clinically required. Discontinue VYXEOS in patients with impaired cardiac function unless the benefit of initiating or continuing treatment outweighs the risk. VYXEOS treatment is not recommended in patients with LVEF that is less than normal. Total cumulative doses of non-liposomal daunorubicin greater than 550 mg/m 2 have been associated with an increased incidence of drug-induced congestive heart failure.
The tolerable limit appears lower (400 mg/m 2 ) in patients who received radiation therapy to the mediastinum. Calculate the lifetime cumulative anthracycline exposure prior to each cycle of VYXEOS. VYXEOS treatment is not recommended in patients whose lifetime anthracycline exposure has reached the maximum cumulative limit. The exposure to daunorubicin following each cycle of VYXEOS is shown in Table 2. Table 2: Cumulative Exposure of Daunorubicin per Cycle of VYXEOS Therapy Daunorubicin per Dose Number of Doses per Cycle Daunorubicin per Cycle First Induction Cycle 44 mg/m 2 3 132 mg/m 2 Second Induction Cycle 44 mg/m 2 2 88 mg/m 2 Each Consolidation Cycle 29 mg/m 2 2 58 mg/m 2
5.4Hypersensitivity Reactions Serious
or fatal hypersensitivity reactions, including anaphylactic reactions, have been reported with daunorubicin and cytarabine. Monitor patients for hypersensitivity reactions. If a mild or moderate hypersensitivity reaction occurs, interrupt or slow the rate of infusion with VYXEOS and manage symptoms. If a severe or life-threatening hypersensitivity reaction occurs, discontinue VYXEOS permanently, treat symptoms according to the standard of care, and monitor until symptoms resolve [see Dosage and Administration ( 2.2 )] .
5.5Copper Overload Reconstituted
VYXEOS contains 5 mg/mL copper gluconate, of which 14% is elemental copper. There is no clinical experience with VYXEOS in patients with Wilson’s disease or other copper-related metabolic disorders. The maximum theoretical total exposure of copper under the recommended VYXEOS dosing regimen is 106 mg/m 2 [see Dosage and Administration ( 2.1 )] . Consult with a hepatologist and nephrologist with expertise in managing acute copper toxicity in patients with Wilson’s disease treated with VYXEOS.
Monitor total serum copper, serum non-ceruloplasmin bound copper, 24-hour urine copper levels and serial neuropsychological examinations in these patients. 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.
5.6Tissue Necrosis
Daunorubicin has been associated with severe local tissue necrosis at the site of drug extravasation. Administer VYXEOS by the intravenous route only. Confirm patency of the intravenous access before administration. Do not administer by the intramuscular or subcutaneous route.
5.7Embryo-Fetal Toxicity Based
on its mechanism of action and findings from animal studies with daunorubicin and cytarabine, VYXEOS can cause embryo-fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of VYXEOS, daunorubicin, or cytarabine in pregnant women. Daunorubicin and cytarabine are reproductive and developmental toxicants in multiple species (mice, rats, and/or dogs), starting at a dose that was approximately 0.02 times the exposure in patients at the recommended human dose on a mg/m 2 basis.
Patients should be advised to avoid becoming pregnant while taking VYXEOS. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, apprise the patient of the potential risk to a fetus. Advise females and males of reproductive potential to use effective contraception during treatment and for 6 months following the last dose of VYXEOS [see Use in Specific Populations ( 8.1 ) and ( 8.3 )] .
Interactions
Monitor cardiac function more frequently when coadministered with cardiotoxic agents. ( 7.1 )
Monitor hepatic function more frequently when coadministered with hepatotoxic agents. ( 7.2 )
7.1Cardiotoxic Agents
Concomitant use of cardiotoxic agents may increase the risk of cardiotoxicity. Assess cardiac function more frequently when VYXEOS is coadministered with cardiotoxic agents [see Warnings and Precautions ( 5.3 )].
7.2Hepatotoxic Agents
Concomitant use with hepatotoxic agents may impair liver function and increase the toxicity of VYXEOS. Monitor hepatic function more frequently when VYXEOS is coadministered with hepatotoxic agents.
Pregnancy and breastfeeding
8.1Pregnancy Risk Summary Based
on anecdotal data of cytarabine in pregnant women and results of studies of daunorubicin and cytarabine in animals, VYXEOS can cause embryo-fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of VYXEOS, daunorubicin, or cytarabine in pregnant women. Daunorubicin and cytarabine are reproductive and developmental toxicants in multiple species (mice, rats, and/or dogs), starting at a dose that was approximately 0.02 times the exposure in patients at the recommended human dose on a mg/m 2 basis [see Animal Data] .
Patients should be advised to avoid becoming pregnant while taking VYXEOS. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential harm to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications.
In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2 to 4% and 15 to 20%, respectively. Data Human Data Cytarabine can cause fetal harm if a pregnant woman is exposed to the drug. Four anecdotal cases of major limb malformations have been reported in infants after their mothers received intravenous cytarabine, alone or in combination with other agents, during the first trimester.
Animal Data A liposomal formulation of daunorubicin was administered to rats on gestation days 6 through 15 at 0.3, 1.0, or 2.0 mg/kg/day (about 0.04, 0.14, or 0.27 the recommended human dose on a mg/m 2 basis) and produced severe maternal toxicity and embryolethality at 2.0 mg/kg/day and was embryotoxic and caused fetal malformations (anophthalmia, microphthalmia, incomplete ossification) at 0.3 mg/kg/day. Embryotoxicity was characterized by increased embryo-fetal deaths, reduced numbers of litters, and reduced litter sizes.
Cytarabine was teratogenic in mice (cleft palate, phocomelia, deformed appendages, skeletal abnormalities) when doses ≥ 2 mg/kg/day were administered intraperitoneal (IP) during the period of organogenesis (about 0.06 times the recommended human dose on a mg/m 2 basis), and in rats (deformed appendages) when 20 mg/kg was administered as a single IP dose on day 12 of gestation (about 1.2 times the recommended human dose on a mg/m 2 basis).
Single IP doses of 50 mg/kg in rats (about 3 times the recommended human dose on a mg/m 2 basis) on day 14 of gestation reduced prenatal and postnatal brain size and permanent impairment of learning ability. Cytarabine was embryotoxic in mice when administered during the period of organogenesis. Embryotoxicity was characterized by decreased fetal weight at 0.5 mg/kg/day (about 0.02 times the recommended human dose on a mg/m 2 basis), and increased early and late resorptions and decreased live litter sizes at 8 mg/kg/day (about 0.24 times the recommended human dose on a mg/m 2 basis).
Adverse reactions
The following adverse reactions are discussed in greater detail in other sections of the labeling:
Hemorrhage [see Warnings and Precautions ( 5.2 )]
Cardiotoxicity [see Warnings and Precautions ( 5.3 )]
Hypersensitivity Reactions [see Warnings and Precautions ( 5.4 )]
Copper Overload [see Warnings and Precautions ( 5.5 )]
Tissue Necrosis [see Warnings and Precautions ( 5.6 )] The most common adverse reactions (incidence ≥ 25%) are hemorrhagic 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. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Jazz Pharmaceuticals, Inc. at 1-800-520-5568 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of VYXEOS was determined in a randomized trial for adults with newly diagnosed t‑AML or AML-MRC [see Clinical Studies ( 14 )] which included 153 patients treated with VYXEOS and 151 patients treated with a standard combination of cytarabine and daunorubicin (7+3).
At study entry, patients were required to have a LVEF of at least 50% and a prior lifetime cumulative anthracycline exposure less than 368 mg/m 2 daunorubicin (or equivalent). On study, the median number of cycles administered was 2 (range, 1–4 cycles) on the VYXEOS arm and 1 (range, 1–4 cycles) on the control arm. The median cumulative daunorubicin dose was 189 mg/m 2 (range, 44–337 mg/m 2 ) on the VYXEOS arm and 186 mg/m 2 (range, 44–532 mg/m 2 ) on the control arm.
Nine patients each on the VYXEOS arm (6%) and the control arm (6%) had a fatal adverse reaction on treatment or within 30 days of therapy that was not in the setting of progressive disease. Fatal adverse reactions on the VYXEOS arm included infection, CNS hemorrhage, and respiratory failure. Overall, all-cause day-30 mortality was 6% in the VYXEOS arm and 11% in the control arm. During the first 60 days of the study, 14% (21/153) of patients died in the VYXEOS arm vs. 21% (32/151) of patients in the 7+3 treatment group.
The most common serious adverse reactions (incidence ≥ 5%) on the VYXEOS arm were dyspnea, myocardial toxicity, sepsis, pneumonia, febrile neutropenia, bacteremia and hemorrhage. Adverse reactions led to discontinuation of VYXEOS in 18% (28/153) of patients, and 13% (20/151) in the control arm. The adverse reactions leading to discontinuation on the VYXEOS arm included prolonged cytopenias, infection, cardiotoxicity, respiratory failure, hemorrhage (GI and CNS), renal insufficiency, colitis, and generalized medical deterioration.
The most common adverse reactions (incidence ≥ 25%) in patients on the VYXEOS arm were hemorrhagic 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. The incidences of common adverse drug reactions during the induction phase in Study 1 are presented in Table 3.
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