Vyxeos

Recommended Dosage

A full VYXEOS course consists of 1-2 cycles of Induction and up to 2 cycles of Consolidation at the dose and schedule listed in Table 1. Prior to initiating each cycle of VYXEOS, calculate the prior cumulative anthracycline exposure for the patient [see Warnings and Precautions ]. Administer prophylactic anti-emetics before treatment with VYXEOS.

a Only for patients failing to achieve a response with the first induction cycle.

For the first cycle of induction, the recommended dose of VYXEOS is (daunorubicin 44 mg/m2 and cytarabine 100 mg/m2) liposome administered via intravenous infusion over 90 minutes on days 1, 3, and 5. Prior to initiating induction, assess cardiac function and obtain liver and renal function studies. For patients who do not achieve remission with the first induction cycle, a second induction cycle may be administered 2 to 5 weeks after the first if there was no unacceptable toxicity with VYXEOS. The recommended dose for the second induction cycle of VYXEOS is (daunorubicin 44 mg/m2 and cytarabine 100 mg/m2) liposome administered via intravenous infusion over 90 minutes on days 1 and 3.

Administer the first consolidation cycle 5 to 8 weeks after the start of the last induction. The recommended dose for each cycle of consolidation therapy is VYXEOS (daunorubicin 29 mg/m2 and cytarabine 65 mg/m2) liposome administered via intravenous infusion over 90 minutes on days 1 and 3.

Assess cardiac function, complete blood counts, liver and renal function before each consolidation cycle. Do not start VYXEOS consolidation until the absolute neutrophil count recovers to greater than 0.5 Gi/L and the platelet count recovers to greater than 50 Gi/L in the absence of unacceptable toxicity. Administer the second consolidation cycle 5 to 8 weeks after the start of the first consolidation cycle in patients who do not show disease progression or unacceptable toxicity to VYXEOS.

Dosage Modification

Missed Doses of VYXEOS

If a planned dose of VYXEOS is missed, administer the dose as soon as possible and adjust the dosing schedule accordingly, maintaining the treatment interval.

Hypersensitivity Reactions

For hypersensitivity reactions of any grade/severity, interrupt VYXEOS infusion immediately and manage symptoms. Reduce the rate of infusion or discontinue treatment as outlined below [see Warnings and Precautions ].

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Mild symptoms: Once symptoms resolve, reinitiate infusion at half the prior rate of infusion. Consider premedication with antihistamines and/or corticosteroids for subsequent doses of VYXEOS.

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Moderate symptoms: Do not reinitiate infusion. For subsequent doses of VYXEOS, premedicate with antihistamines and/or corticosteroids prior to initiating infusion at same rate.

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Severe/life-threatening symptoms: Permanently discontinue VYXEOS treatment, treat according to the standard of care to manage symptoms, and monitor patient until symptoms resolve.

Cardiotoxicity

Discontinue VYXEOS in patients who exhibit impaired cardiac function unless the benefit of continuing treatment outweighs the risk [see Warnings and Precautions ].

Preparation and Handling Instructions

VYXEOS is a hazardous drug. Follow applicable special handling and disposal procedures.1 VYXEOS is supplied as a single-dose vial and does not contain any preservatives. Do not save any unused portions for later administration.

Reconstitute and further dilute VYXEOS prior to intravenous infusion.

Reconstitution:

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Calculate the VYXEOS dose based on daunorubicin and individual patient's BSA.

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Calculate the number of vials of VYXEOS based on the daunorubicin dose.

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Remove the appropriate number of vials of VYXEOS from the refrigerator and equilibrate to the room temperature for 30 minutes.

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Then, reconstitute each vial with 19 mL of Sterile Water for Injection using a sterile syringe and immediately thereafter start a 5-minute timer.

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Carefully swirl the contents of the vial for 5 minutes while gently inverting the vial every 30 seconds.

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Do not heat, vortex, or shake vigorously.

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After reconstitution, let rest for 15 minutes.

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The reconstituted product should be an opaque, purple, homogeneous dispersion, essentially free from visible particulates. After reconstitution (but before final dilution), each mL will contain 2.2 mg of daunorubicin and 5 mg of cytarabine.

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Use the reconstituted solution immediately. If needed, store the reconstituted solution in the vial refrigerated at 2ºC to 8ºC (36°F to 46°F) for up to 4 hours. Note that the reconstituted product in the vial and the reconstituted product which has been diluted into an infusion solution are stable for a total of 4 hours (not 4 hours each) when stored at 2°C to 8°C.

Dilution:

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Calculate the volume of reconstituted VYXEOS required using the following formula:
[volume required (mL) = dose of daunorubicin (mg/m2) X patient's BSA (m2) ÷ 2.2 (mg/mL)]

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Gently invert each vial 5 times prior to withdrawing the reconstituted product for further dilution.

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Aseptically withdraw the calculated volume of the reconstituted product from the vial(s) with a sterile syringe and transfer it to an infusion bag containing 500 mL of 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. There may be residual product remaining in the vial. Discard unused portion.

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Gently invert the bag to mix the solution. The dilution of the reconstituted product results in a deep purple, translucent, homogeneous dispersion, free from visible particulates.

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If the diluted infusion solution is not used immediately, store in a refrigerator at 2ºC to 8ºC (36°F to 46°F) for up to 4 hours. If the reconstituted solution in the vial was stored for 4 hours, the diluted infusion solution must be used immediately and cannot be stored for an additional 4 hours.

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Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Only solutions without visible particles should be used.

Administration Instructions

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For intravenous use only.

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Do not mix VYXEOS with or administer as an infusion with other drugs.

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Administer VYXEOS by constant intravenous infusion over 90 minutes via an infusion pump through a central venous catheter or a peripherally inserted central catheter. An in-line membrane filter may be used for the intravenous infusion of Vyxeos, provided the minimum pore diameter of the filter is greater than or equal to 15 µm.

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Flush the line after administration with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP.

Pregnancy

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/m2 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/m2 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 IP during the period of organogenesis (about 0.06 times the recommended human dose on a mg/m2 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/m2 basis). Single IP doses of 50 mg/kg in rats (about 3 times the recommended human dose on a mg/m2 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/m2 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/m2 basis).

Lactation

Risk Summary

There are no data on the presence of daunorubicin, cytarabine, or their metabolites in human milk, their effects on the breastfed infant, or their effects on milk production. Because of the potential for serious adverse reactions in breastfed infants, advise lactating women not to breastfeed during treatment with VYXEOS and for 2 weeks after the last dose.

Females and Males of Reproductive Potential

VYXEOS can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations ].

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to initiating VYXEOS.

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment with VYXEOS and for 6 months after the last dose.

Males

Advise males with female partners of reproductive potential to use effective contraception during treatment with VYXEOS and for 6 months after the last dose [see Nonclinical Toxicology ].

Inferrtility

Based on findings of daunorubicin and cytarabine in animals, male fertility may be compromised by treatment with VYXEOS [see Nonclinical Toxicology ].

Pediatric Use

The safety and effectiveness of VYXEOS have been established in pediatric patients 1 year and older with newly diagnosed t AML or AML-MRC. The use of VYXEOS for this indication is supported by evidence of effectiveness from an adequate and well-controlled study in adults with data on safety from two single-arm trials, which included patients in the following age groups: 7 patients 1 year to less than 2 years old, 33 patients 2 years to less than 12 years old, 13 patients 12 years old to less than 17 years old. [see Clinical Pharmacology ]. No new safety signals were observed in pediatric patients in these two single-arm trials. No differences in safety were observed by age. The safety and effectiveness of VYXEOS in pediatric patients less than 1 year of age with newly-diagnosed t-AML or AML-MRC have not been established.

Geriatric Use

Of the 375 patients who received VYXEOS (daunorubicin 44 mg/m2 and cytarabine 100 mg/m2) liposome in clinical studies, 57% were 65 years and over. No overall differences in safety were observed between these patients and younger patients, with the exception of bleeding events, which occurred more frequently in patients 65 years and older compared to younger patients (77% vs. 59%).

Renal Impairment

Dosage adjustment is not required for patients with mild (creatinine clearance [CLCR] 60 mL/min to 89 mL/min by Cockcroft Gault equation [C-G]), moderate (CLCR 30 mL/min to 59 mL/min) or severe (CLCR 15 mL/min to 29 mL/min) renal impairment. VYXEOS has not been studied in patients with end-stage renal disease on hemodialysis [see Clinical Pharmacology ].

Hepatic Impairment

Dosage adjustment is not required for patients with a bilirubin level less than or equal to 3 mg/dL. VYXEOS has not been studied in patients with bilirubin level greater than 3 mg/dL [see Clinical Pharmacology ].