VYXEOS
Clinical safety rating: caution
Comprehensive clinical and safety monograph for VYXEOS (VYXEOS).
Daunorubicin and cytarabine are both antineoplastic agents. Daunorubicin intercalates with DNA, inhibits topoisomerase II, and generates free radicals leading to DNA damage and cell death. Cytarabine is a nucleoside analog that inhibits DNA polymerase by competing with cytidine triphosphate, incorporating into DNA and RNA, and causing chain termination.
| Metabolism | Daunorubicin is metabolized via aldo-keto reductases to daunorubicinol, which is active. Cytarabine is primarily metabolized by cytidine deaminase to inactive uracil arabinoside (ara-U). |
| Excretion | Primarily hepatobiliary excretion; 70-80% of dose recovered in feces as metabolites, less than 10% in urine as unchanged liposomal daunorubicin and cytarabine. |
| Half-life | Daunorubicin: terminal half-life approximately 56 h; cytarabine: terminal half-life approximately 31 h. The prolonged half-lives reflect sustained release from liposomes, allowing continuous exposure. |
| Protein binding | Daunorubicin: approximately 60-70% bound to albumin and tissue proteins; cytarabine: approximately 15% bound to albumin. |
| Volume of Distribution | Daunorubicin: Vd approximately 0.5-1 L/kg, indicating extensive tissue distribution; cytarabine: Vd approximately 0.3-0.5 L/kg, distributed mainly in total body water. |
| Bioavailability | Not applicable (IV only); oral bioavailability not established for liposomal formulation. |
| Onset of Action | IV infusion: antileukemic effect begins within days, with cytoreduction noted as early as 24-48 hours post-infusion. |
| Duration of Action | The liposomal formulation extends duration of cytotoxic concentrations; daunorubicin and cytarabine remain detectable in plasma for >7 days. Clinical effect persists through the treatment cycle. |
| Molecular Weight | 527.5 |
Each unit contains 44 mg daunorubicin and 100 mg cytarabine. Adults: 1 unit/m² IV over 90 minutes on days 1, 3, and 5 for induction; up to 2 cycles. For consolidation: 1 unit/m² IV over 90 minutes on days 1 and 3; up to 2 cycles.
| Dosage form | POWDER |
| Renal impairment | Contraindicated in severe renal impairment (CrCl < 30 mL/min). For CrCl 30-60 mL/min: reduce dose by 25%. Monitor renal function. |
| Liver impairment | Contraindicated in severe hepatic impairment (Child-Pugh C). For Child-Pugh B: reduce dose by 50%. For Child-Pugh A: no adjustment needed. |
| Pediatric use | Safety and efficacy not established. No standard pediatric dosing. Use only in clinical trials. |
| Geriatric use | No specific dose adjustment based on age alone. Monitor renal and hepatic function; consider dose reduction in frail elderly patients due to increased toxicity risk. |
| 1st trimester | Avoid use due to teratogenicity, based on animal studies and its mechanism of action (topoisomerase II inhibition, DNA intercalation). |
| 2nd trimester | Avoid use due to potential fetal harm. May cause fetal myelosuppression, growth retardation, and malformations. |
| 3rd trimester | Avoid use. Risk of neonatal myelosuppression, anemia, and infection. |
Clinical note
Comprehensive clinical and safety monograph for VYXEOS (VYXEOS).
| Placental transfer | Both daunorubicin and cytarabine cross the placenta. Cytarabine shows significant transfer; daunorubicin is detectable in fetal tissues. |
| Breastfeeding | Not recommended. Daunorubicin and cytarabine are present in human milk. Potential for serious adverse reactions in nursing infants, including immunosuppression, myelosuppression, and carcinogenesis. Discontinue breastfeeding or discontinue drug. |
■ FDA Black Box Warning
WARNING: DAUNORUBICIN IS A CARDIOTOXIC AGENT. DAUNORUBICIN CAN CAUSE MYELOSUPPRESSION AND SEVERE BLEEDING. VYXEOS IS A LIPOSOMAL FORMULATION; DO NOT SUBSTITUTE FOR OTHER DAUNORUBICIN OR CYTARABINE PRODUCTS.
| Serious Effects |
Hypersensitivity to daunorubicin, cytarabine, or any liposomal componentHistory of severe myelosuppression (unless benefit outweighs risk)Severe hepatic impairment
| Precautions | Cardiotoxicity: Left ventricular dysfunction, especially with cumulative doses; monitor cardiac function., Myelosuppression: Severe, can lead to fatal infections or bleeding., Hemorrhage: Fatal hemorrhages reported., Tumor lysis syndrome: Risk due to rapid lysis., Hepatotoxicity: Elevations in bilirubin and transaminases., Embryo-fetal toxicity: Can cause fetal harm; advise effective contraception. |
| Food/Dietary | No specific food interactions reported. Avoid grapefruit and grapefruit juice due to potential CYP3A4 interaction with other components, although data are limited. Maintain adequate hydration to prevent tumor lysis syndrome. |
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| Lactation Rating | L5 (Contraindicated) |
| Teratogenic Risk | VYXEOS (daunorubicin and cytarabine liposome) is contraindicated in pregnancy. It is embryotoxic and fetotoxic in animals. First trimester: high risk of major malformations (neural tube, cardiac). Second/third trimester: risk of fetal growth restriction, preterm birth, and neonatal myelosuppression. Use effective contraception. |
| Fetal Monitoring | Monitor complete blood counts (CBC) with differential, hepatic function, renal function, cardiac function (echocardiogram or MUGA), and fetal growth (ultrasound). Monitor for signs of infection, bleeding, and cardiac toxicity. |
| Fertility Effects | Both daunorubicin and cytarabine can cause gonadal toxicity, leading to infertility. In females: may cause ovarian failure, premature menopause. In males: may cause azoospermia or oligospermia. Effect may be irreversible. |
| Clinical Pearls | VYXEOS is a liposomal encapsulation of daunorubicin and cytarabine in a fixed 1:5 molar ratio. It is indicated for adults with newly diagnosed therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC). Do not substitute with other daunorubicin/cytarabine products due to different pharmacokinetics. Monitor for cardiotoxicity (echocardiogram prior to each cycle), myelosuppression, and hepatotoxicity. Premedicate for infusion reactions. Administer as a 90-minute IV infusion on days 1, 3, and 5; no dose adjustment for mild-moderate renal or hepatic impairment but avoid in severe impairment. |
| Patient Advice | VYXEOS is a combination chemotherapy used for certain types of acute myeloid leukemia. · It is given as an intravenous infusion over 90 minutes on days 1, 3, and 5 of each treatment cycle. · Common side effects include fever, infection, nausea, vomiting, diarrhea, constipation, mouth sores, fatigue, and bleeding or bruising. · You will have regular blood tests to monitor blood counts, heart function, and liver function. · Report any signs of infection (fever, chills), bleeding (unusual bruising, black stools), shortness of breath, or chest pain immediately. · Avoid pregnancy and breastfeeding while on this medication. · Do not take any other medications, including over-the-counter drugs or supplements, without consulting your doctor. |