Daunorubicin / cytarabine

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# Black Box Warning

# Overview
Daunorubicin / cytarabine is a liposomal combination of daunorubicin, an anthracycline topoisomerase inhibitor, and cytarabine, a nucleoside metabolic inhibitor that is FDA approved for the treatment of adults with newly-diagnosed therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC). There is a Black Box Warning for this drug as shown here.  Common adverse reactions include 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.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
- Daunorubicin / cytarabine is indicated for the treatment of adults with newly-diagnosed therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC).
- A full daunorubicin / cytarabine 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 daunorubicin / cytarabine, calculate the prior cumulative anthracycline exposure for the patient. Administer prophylactic anti-emetics before treatment with daunorubicin / cytarabine.
- For the first cycle of induction, the recommended dose of daunorubicin / cytarabine 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 daunorubicin / cytarabine. The recommended dose for the second induction cycle of daunorubicin / cytarabine 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 daunorubicin / cytarabine (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 daunorubicin / cytarabine consolidation until the absolute neutrophil count recovers to greater than 0.5 Gi/L and the platelet count recovers to greater 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 daunorubicin / cytarabine.
- If a planned dose of daunorubicin / cytarabine is missed, administer the dose as soon as possible and adjust the dosing schedule accordingly, maintaining the treatment interval.
- For hypersensitivity reactions of any grade/severity, interrupt daunorubicin / cytarabine infusion immediately and manage symptoms. Reduce the rate of infusion or discontinue treatment as outlined below.
- 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 daunorubicin / cytarabine.
- Moderate symptoms: Do not reinitiate infusion. For subsequent doses of daunorubicin / cytarabine, premedicate with antihistamines and/or corticosteroids prior to initiating infusion at same rate.
- Severe/life-threatening symptoms: Permanently discontinue daunorubicin / cytarabine treatment, treat according to the standard of care to manage symptoms, and monitor patient until symptoms resolve.
- Discontinue daunorubicin / cytarabine in patients who exhibit impaired cardiac function unless the benefit of continuing treatment outweighs the risk.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding daunorubicin / cytarabine Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.

### NonGuideline-Supported Use
There is limited information regarding daunorubicin / cytarabine Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Daunorubicin / cytarabine FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding daunorubicin / cytarabine Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.

### NonGuideline-Supported Use
There is limited information regarding daunorubicin / cytarabine Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.

# Contraindications
- The use of daunorubicin / cytarabine is contraindicated in patients with the following:
- History of serious hypersensitivity reaction to cytarabine, daunorubicin, or any component of the formulation.

# Warnings
- Due to substantial differences in the pharmacokinetic parameters, the dose and schedule recommendations for daunorubicin / cytarabine 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 daunorubicin / cytarabine.
- Serious or fatal hemorrhage events, including fatal central nervous system (CNS) hemorrhages, associated with prolonged severe thrombocytopenia, have occurred in patients treated with daunorubicin / cytarabine. In Study 1 (NCT01696084), the incidence of any grade hemorrhagic events during the entire treatment period was 74% of patients on the daunorubicin / cytarabine arm and 56% on the control arm. The most frequently reported hemorrhagic event was epistaxis (36% in daunorubicin / cytarabine arm and 18% in control arm). Grade 3 or greater events occurred in 12% of daunorubicin / cytarabine 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 daunorubicin / cytarabine arm and in 0.7% of patients on the control arm. Monitor blood counts regularly until recovery and administer platelet transfusion support as required.
- Daunorubicin / cytarabine 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 daunorubicininduced cardiac toxicity. Prior to administering daunorubicin / cytarabine, 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 daunorubicin / cytarabine and as clinically required. Discontinue daunorubicin / cytarabine in patients with impaired cardiac function unless the benefit of initiating or continuing treatment outweighs the risk. daunorubicin / cytarabine treatment is not recommended in patients with LVEF that is less than normal.
- Total cumulative doses of non-liposomal daunorubicin greater than 550 mg/m2 have been associated with an increased incidence of drug-induced congestive heart failure. The tolerable limit appears lower (400 mg/m2) in patients who received radiation therapy to the mediastinum.
- Calculate the lifetime cumulative anthracycline exposure prior to each cycle of daunorubicin / cytarabine. Daunorubicin / cytarabine treatment is not recommended in patients whose lifetime anthracycline exposure has reached the maximum cumulative limit. The exposure to daunorubicin following each cycle of daunorubicin / cytarabine is shown in Table 2.
- 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 daunorubicin / cytarabine and manage symptoms. If a severe or life-threatening hypersensitivity reaction occurs, discontinue daunorubicin / cytarabine permanently, treat symptoms according to the standard of care, and monitor until symptoms resolve.
- Reconstituted daunorubicin / cytarabine contains 5 mg/mL copper gluconate, of which 14% is elemental copper. There is no clinical experience with daunorubicin / cytarabine in patients with Wilsons disease or other copperrelated metabolic disorders. The maximum theoretical total exposure of copper under the recommended daunorubicin / cytarabine dosing regimen is 106 mg/m2. Consult with a hepatologist and nephrologist with expertise in managing acute copper toxicity in patients with Wilsons disease treated with daunorubicin / cytarabine. Monitor total serum copper, serum nonceruloplasmin bound copper, 24-hour urine copper levels and serial neuropsychological examinations in these patients. Use daunorubicin / cytarabine in patients with Wilsons disease only if the benefits outweigh the risks. Discontinue daunorubicin / cytarabine in patients with signs or symptoms of acute copper toxicity.
- Daunorubicin has been associated with severe local tissue necrosis at the site of drug extravasation. Administer daunorubicin / cytarabine by the intravenous route only. Do not administer by intramuscular or subcutaneous route.
- Based on its mechanism of action and findings from animal studies with daunorubicin and cytarabine, daunorubicin / cytarabine can cause embryo-fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of daunorubicin / cytarabine, 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 an mg/m2 basis. Patients should be advised to avoid becoming pregnant while taking daunorubicin / cytarabine. 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 daunorubicin / cytarabine.

# Adverse Reactions

## Clinical 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 daunorubicin / cytarabine was determined in a randomized trial for adults with newly-diagnosed t-AML or AML-MRC which included 153 patients treated with daunorubicin / cytarabine 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/m2 daunorubicin (or equivalent). On study, the median number of cycles administered was 2 (range, 14 cycles) on the daunorubicin / cytarabine arm and 1 (range, 14 cycles) on the control arm. The median cumulative daunorubicin dose was 189 mg/m2 (range, 44337 mg/m2) on the daunorubicin / cytarabine arm and 186 mg/m2 (range, 44532 mg/m2) on the control arm.
- Nine patients each on the daunorubicin / cytarabine 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 daunorubicin / cytarabine arm included infection, CNS hemorrhage, and respiratory failure. Overall, all-cause day-30 mortality was 6% in the daunorubicin / cytarabine arm and 11% in the control arm. During the first 60 days of the study, 14% (21/153) of patients died in the daunorubicin / cytarabine arm vs. 21% (32/151) of patients in the 7+3 treatment group.
- The most common serious adverse reactions (incidence  5%) on the daunorubicin / cytarabine arm were dyspnea, myocardial toxicity, sepsis, pneumonia, febrile neutropenia, bacteremia and hemorrhage. Adverse reactions led to discontinuation of daunorubicin / cytarabine in 18% (28/153) of patients, and 13% (20/151) in the control arm. The adverse reactions leading to discontinuation on the daunorubicin / cytarabine 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 daunorubicin / cytarabine 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.
- During the consolidation phase (both consolidation cycles pooled) the two most common adverse reactions on the daunorubicin / cytarabine arm are the same as those during induction, hemorrhagic events and febrile neutropenia. These occurred at lower rates in the pooled consolidation phase (43% and 29%, respectively), compared to the induction phase. All of the common adverse reactions ( 10% incidence in the daunorubicin / cytarabine arm) seen in the pooled consolidation phase were also seen in the induction phase. These occurred at lower incidence in the consolidation phase, with the exception of chills, dizziness and pyrexia, where the incidences were relatively similar across the induction and consolidation cycles.
- Other notable adverse drug reactions that occurred in less than 10% of patients treated with daunorubicin / cytarabine during induction or consolidation included:
- Ear and labyrinth disorders: Deafness, Deafness unilateral
- Eye Disorders: Eye Conjunctivitis, Dry eye, Eye edema, Eye swelling, Eye irritation, Eye pain, Ocular discomfort, Ocular hyperemia, Periorbital edema, Scleral hyperemia
- Gastrointestinal disorders: Dyspepsia
- Psychiatric disorders: Hallucinations
- Respiratory, thoracic and mediastinal disorders: Pneumonitis
- All patients developed severe neutropenia, thrombocytopenia, and anemia. See Table 4 for the incidences of Grade 3 thrombocytopenia and Grade 4 neutropenia that were prolonged in the absence of active leukemia.
- Grade 3-4 chemistry abnormalities occurring in greater than 5% of daunorubicin / cytarabine treated patients in Study 1 are presented in Table 5.

## Postmarketing Experience
There is limited information regarding Daunorubicin / cytarabine Postmarketing Experience in the drug label.

# Drug Interactions
- Cardiotoxic Agents
- Hepatotoxic Agents
- Concomitant use of cardiotoxic agents may increase the risk of cardiotoxicity. Assess cardiac function more frequently when daunorubicin / cytarabine is coadministered with cardiotoxic agents.
- Concomitant use with hepatotoxic agents may impair liver function and increase the toxicity of daunorubicin / cytarabine. Monitor hepatic function more frequently when daunorubicin / cytarabine is coadministered with hepatotoxic agents.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA):
- Based on anecdotal data of cytarabine in pregnant women and results of studies of daunorubicin and cytarabine in animals, daunorubicin / cytarabine can cause embryo-fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of daunorubicin / cytarabine, 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 mg/m2 basis. Patients should be advised to avoid becoming pregnant while taking daunorubicin / cytarabine. 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.
Human
- 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
- 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 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 mg/m2 basis).
Pregnancy Category (AUS): 
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Daunorubicin / cytarabine in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Daunorubicin / cytarabine during labor and delivery.

### Nursing Mothers
- 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 daunorubicin / cytarabine and for at least 2 weeks after the last dose.

### Pediatric Use
- Safety and effectiveness of daunorubicin / cytarabine in pediatric patients have not been established.

### Geriatic Use
- Of the 375 patients who received daunorubicin / cytarabine (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%).

### Gender
There is no FDA guidance on the use of Daunorubicin / cytarabine with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Daunorubicin / cytarabine with respect to specific racial populations.

### 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)) or moderate (CLCR 30 mL/min to 59 mL/min) renal impairment. Daunorubicin / cytarabine has not been studied in patients with severe renal impairment (CLCR 15 mL/min to 29 mL/min) or end-stage renal disease.

### Hepatic Impairment
- Dosage adjustment is not required for patients with a bilirubin level less than or equal to 3 mg/dL. Daunorubicin / cytarabine has not been studied in patients with bilirubin level greater than 3 mg/dL.

### Females of Reproductive Potential and Males
- Daunorubicin / cytarabine can cause fetal harm when administered to a pregnant woman. Verify the pregnancy status of females of reproductive potential prior to initiating daunorubicin / cytarabine.
Females
- Advise females of reproductive potential to use effective contraception during treatment with daunorubicin / cytarabine and for at least 6 months after the last dose.
Males
- Advise males with female partners of reproductive potential to use effective contraception during treatment with daunorubicin / cytarabine and for at least 6 months after the last dose.
- Based on findings of daunorubicin and cytarabine in animals, male fertility may be compromised by treatment with daunorubicin / cytarabine.

### Immunocompromised Patients
There is no FDA guidance one the use of Daunorubicin / cytarabine in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- Daunorubicin / cytarabine is a cytotoxic drug. Follow applicable special handling and disposal procedures. Daunorubicin / cytarabine is supplied as a single-dose vial and does not contain any preservatives. Do not save any unused portions for later administration.
- Preparation Instructions:
- Calculate the daunorubicin / cytarabine dose based on daunorubicin and individual patients BSA.
- Calculate the number of vials of daunorubicin / cytarabine based on the daunorubicin dose.
- Remove the appropriate number of vials of daunorubicin / cytarabine from the refrigerator and equilibrate to the room temperature for 30 minutes.
- Then, reconstitute each vial with 19 mL of Sterile Water for Injection using a sterile syringe and immediately thereafter start a 5-minute timer.
- Carefully swirl the contents of the vial for 5 minutes while gently inverting the vial every 30 seconds.
- Do not heat, vortex, or shake vigorously.
- After reconstitution, let rest for 15 minutes.
- 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.
- Gently invert each vial 5 times prior to withdrawing the reconstituted product for further dilution. If the reconstituted product is not diluted into an infusion bag immediately, store in refrigerator at 2oC to 8oC for up to 4 hours.
- Calculate the volume of reconstituted daunorubicin / cytarabine required using the following formula: 
- 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.
- 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.
- If the diluted infusion solution is not used immediately, store in refrigerator at 2oC to 8oC for up to 4 hours.
- 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.
- For intravenous use only.
- Do not mix daunorubicin / cytarabine with or administer as an infusion with other drugs.
- Administer daunorubicin / cytarabine by constant intravenous infusion over 90 minutes via an infusion pump through a central venous catheter or a peripherally inserted central catheter. Do not use an in-line filter.
- Flush the line after administration with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP.

### Monitoring
- Evidence of chemotherapeutic response is indicative of efficacy.
- Blood counts: Prior to each consolidation cycle.
- Cardiac function, ECG: Prior to initiating induction and as clinically indicated. Assess more frequently when coadministered with another cardiotoxic agent.
- Cardiac function, echocardiography (ECHO) or multi-gated radionucleotide angiography (MUGA): Prior to initiating induction, before each consolidation cycle, and as clinically indicated. Assess more frequently when coadministered with another cardiotoxic agent.
- Copper levels in patients with Wilson disease or other copper-related metabolic disorders.
- Hypersensitivity reactions.
- Liver function studies: Prior to initiating induction and before each consolidation cycle. Assess more frequently when coadministered with another hepatotoxic agent.
- Neuropsychological examinations in patients with Wilson disease or other copper-related metabolic disorders: Serially during treatment.
- Pregnancy: Prior to initiating treatment.
- Renal function studies: Prior to initiating induction and before each consolidation cycle.

# IV Compatibility
There is limited information regarding the compatibility of Daunorubicin / cytarabine and IV administrations.

# Overdosage
There is limited information regarding Daunorubicin / cytarabine overdosage.  If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

# Pharmacology

## Mechanism of Action
- Daunorubicin / cytarabine (daunorubicin and cytarabine) liposome for injection is a liposomal formulation of daunorubicin and cytarabine at a fixed 1:5 molar ratio. The 1:5 molar ratio of daunorubicin:cytarabine has been shown to have synergistic effects at killing leukemia cells in vitro and in murine models. Daunorubicin has antimitotic and cytotoxic activity, which is achieved 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 is a cell cycle phase-specific antineoplastic agent, affecting cells only during the S-phase of cell division. Cytarabine acts primarily through inhibition of DNA polymerase. Based on animal data, the liposomes enter and persist in the bone marrow, where they are taken up intact by bone marrow cells. In leukemia bearing mice, the liposomes are taken up by leukemia cells to a greater extent than by normal bone marrow cells. After cellular internalization, liposomes undergo degradation releasing cytarabine and daunorubicin within the intracellular environment.

## Structure

## Pharmacodynamics
- At the therapeutic exposures with the recommended dosing regimen, no large mean changes in the QTc interval (i.e., > 20 msecs) were observed. An exposure-QTc analysis suggested no concentration-dependent QTc interval prolongation.

## Pharmacokinetics
- The pharmacokinetics of daunorubicin and cytarabine administered as daunorubicin / cytarabine were investigated in adult patients who received a dose of daunorubicin 44 mg/m2 and cytarabine 100 mg/m2 administered as a 90-minute intravenous infusion on days 1, 3, and 5. The pharmacokinetics of each drug was based on total plasma concentrations (i.e., encapsulated plus unencapsulated drug).
- Following the dose administered on day 5, the mean (% coefficient of variation ) maximum plasma concentration (Cmax) for daunorubicin was 26.0 (32.7%) mcg/mL and cytarabine was 62.2 (33.7%) mcg/mL. The mean (%CV) area under the curve (AUC) during one dosing interval for daunorubicin was 637 (38.4%) mcgh/mL and cytarabine was 1900 (44.3%) mcgh/mL.
- The accumulation ratio was 1.3 for daunorubicin and 1.4 for cytarabine. There was no evidence of time-dependent kinetics or major departures from dose proportionality over the range of 1.3 mg/3 mg per m2 to 59 mg/134 mg per m2 (0.03 to 1.3 times the approved recommended dosage).
- The volume of distribution (%CV) for daunorubicin is 6.6 L (36.8%) and cytarabine is 7.1 L (49.2%). Plasma protein binding was not evaluated.
- Daunorubicin / cytarabine exhibits a prolonged half-life (%CV) of 31.5 h (28.5%) for daunorubicin and 40.4 h (24.2%) for cytarabine with greater than 99% of the daunorubicin and cytarabine in the plasma remaining encapsulated within the liposomes. The clearance (%CV) is 0.16 L/h (53.3%) for daunorubicin and 0.13 L/h (60.2%) for cytarabine.
Metabolism
- Subsequent to release from daunorubicin / cytarabine liposomes, daunorubicin is catalyzed by aldoketo reductase and carbonyl reductase enzymes to the active metabolite daunorubicinol. Cytarabine is metabolized by cytidine deaminase to the inactive metabolite 1--D-arabinofuranosyluracil (AraU).
Excretion
- Urinary excretion of daunorubicin and daunorubicinol accounts for 9% of the administered dose of daunorubicin, and urinary excretion of cytarabine and AraU accounts for 71% of the administered dose of cytarabine.
- Age, sex, race, body weight, body mass index, and white blood cell count do not have a clinically important effect on the exposure of total daunorubicin or cytarabine after adjusting dose by body surface area.
Patients with Renal Impairment
- The pharmacokinetics of total daunorubicin and cytarabine were not clinically significantly altered in patients with mild or moderate renal impairment (CLCR 30 mL/min to 89 mL/min, as estimated by C-G). The potential effects of severe renal impairment (CLCR 15 mL/min to 29 mL/min, C-G) and end-stage renal disease on the pharmacokinetics of daunorubicin and cytarabine administered as daunorubicin / cytarabine are unknown.
Patients with Hepatic Impairment
- The pharmacokinetics of total cytarabine and daunorubicin were not altered in patients with bilirubin less than and equal to 3 mg/dL. The pharmacokinetics in patients with bilirubin greater than 3 mg/dL is unknown.

## Nonclinical Toxicology
- Carcinogenicity, mutagenicity, and impairment of fertility studies with (daunorubicin and cytarabine) liposome for injection have not been conducted.
- Carcinogenicity and mutagenicity studies have been conducted with daunorubicin. Published literature reported data that suggest daunorubicin (5 mg/kg) could be tumorigenic in rats at 0.68 times the recommended human dose on an mg/m2 basis. A high incidence of mammary tumors was observed about 120 days after a single intravenous dose of 12.5 mg/kg daunorubicin in rats (about 1.7 times the recommended human dose on an mg/m22 basis). A carcinogenic evaluation of daunorubicin by the IARC Working Group classified daunorubicin as a possible human carcinogen based on sufficient evidence in animals and inadequate data in humans. Daunorubicin was mutagenic in in vitro tests (Ames assay, V79 hamster cell assay), and clastogenic in in vitro (CCRF-CEM human lymphoblasts) and in in vivo (SCE assay in mouse bone marrow) tests.
- Daunorubicin intravenous doses of 0.25 mg/kg/day (about 0.12 times the recommended human dose on a mg/m2 basis) in male dogs caused testicular atrophy and total aplasia of spermatocytes in the seminiferous tubules.
- Cytarabine was mutagenic in in vitro tests and was clastogenic in vitro (chromosome aberrations and SCE in human leukocytes) and in vivo (chromosome aberrations and SCE assay in rodent bone marrow, mouse micronucleus assay). Cytarabine caused the transformation of hamster embryo cells and rat H43 cells in vitro.
- No studies assessing the impact of cytarabine on fertility are available in the literature. Cytarabine was clastogenic to meiotic cells; a dose-dependent increase in sperm-head abnormalities and chromosomal aberrations occurred in mice given IP cytarabine.

# Clinical Studies
- Study 1 (NCT01696084) was a randomized, multicenter, open-label, active-controlled study which compared daunorubicin / cytarabine to a standard combination of cytarabine and daunorubicin (7+3) in patients 60 to 75 years of age with newly diagnosed t-AML or AML-MRC. The patients were randomized (1:1) and stratified by age and AML subtype to receive daunorubicin / cytarabine or 7+3 for induction and consolidation. Daunorubicin / cytarabine (daunorubicin 44 mg/m2 and cytarabine 100 mg/m2) liposome was given intravenously on days 1, 3, and 5 for the first induction and on days 1 and 3 for the second induction if needed. For consolidation, the daunorubicin / cytarabine dose was (daunorubicin 29 mg/m2 and cytarabine 65 mg/m2) liposome on days 1 and 3. In the 7+3 arm, first induction consisted of cytarabine 100 mg/m2/day on days 1 through 7 by continuous infusion and daunorubicin 60 mg/m2/day on days 1, 2, and 3; for second induction and consolidation cycles, cytarabine 100 mg/m2/day was given on days 1 through 5 and daunorubicin 60 mg/m2/day on days 1 and 2. Patients could receive up to 2 cycles of induction and 2 cycles of consolidation in each arm. A second induction was highly recommended for patients who did not achieve a response and was mandatory for patients achieving greater than 50% reduction in percent blasts. Post remission therapy with hematopoietic stem cell transplantation (HSCT) was permitted either in place of or after consolidation chemotherapy.
- There were 153 patients randomized to daunorubicin / cytarabine and 156 patients randomized to the 7+3 control arm. The randomized patients had a median age of 68 (range, 60-75 years), 61% were male, and 88% had an ECOG performance status of 01. Twenty percent had t-AML, 54% had AML with an antecedent hematological disorder, and 25% had de novo AML with myelodysplasia-related cytogenetic abnormalities. Thirty-four percent had been treated previously with a hypomethylating agent for MDS. Fifty-four percent of patients with cytogenetics data had an adverse karyotype. The demographic and baseline disease characteristics were generally balanced between the study arms. FLT3 mutation was identified in 15% (43/279) of patients tested, and NPM1 mutation was identified in 9% (25/283) patients tested.
- All patients on the daunorubicin / cytarabine arm and 97% of those on the control arm received at least 1 cycle of induction, and 32% on the daunorubicin / cytarabine arm and 21% on the control arm received at least 1 cycle of consolidation. The rate of HSCT in first CR was 20% in the daunorubicin / cytarabine arm and 12% in the control arm; the overall rate of HSCT (induction failure, first CR, or as salvage after relapse) was 34% (52/153) in the daunorubicin / cytarabine arm and 25% (39/156) on the control arm.
- Efficacy was established on the basis of overall survival from the date of randomization to death from any cause. Daunorubicin / cytarabine demonstrated superiority in overall survival compared with the 7+3 control (Figure 1). The efficacy results are shown in Table 6.

# How Supplied
- Daunorubicin / cytarabine liposome for injection is supplied as a sterile, preservative-free, purple, lyophilized cake, in a single-dose vial. Each daunorubicin / cytarabine vial (NDC 68727-745-01) contains 44 mg daunorubicin and 100 mg cytarabine.
- NDC 68727-745-02: Carton containing 2 vials of daunorubicin / cytarabine
- NDC 68727-745-05: Carton containing 5 vials of daunorubicin / cytarabine

## Storage
- Store unreconstituted daunorubicin / cytarabine vials in a refrigerator at 2C to 8C (36F to 46F) in an upright position. The vial should be stored in its original carton to protect from light.
- Daunorubicin / cytarabine is a cytotoxic drug. Follow applicable special handling and disposal procedures.

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
- Inform patients of the risk of fatal bleeding. Advise patients of the need for periodic monitoring of blood counts and of the importance of keeping scheduled appointments for blood work and necessary transfusions. Advise patients to contact a healthcare provider for new onset fever or symptoms of infection or if they notice signs of bruising or bleeding.
- Advise patients to contact their healthcare provider if they develop symptoms of heart failure.
- Inform patients of the risk of hypersensitivity reactions, including anaphylaxis. Describe the symptoms of hypersensitivity reactions, including anaphylaxis, and instruct the patient to seek medical attention immediately if they experience such symptoms.
- Daunorubicin / cytarabine can cause fetal harm when administered during pregnancy. Advise females of reproductive potential to use effective contraception during treatment and for 6 months following the last dose of daunorubicin / cytarabine and to inform their healthcare provider of a known or suspected pregnancy before and during treatment with daunorubicin / cytarabine.
- Advise patients not to breastfeed during treatment with daunorubicin / cytarabine and for at least 2 weeks after the last dose.
- Advise males of reproductive potential that daunorubicin / cytarabine may cause temporary or permanent infertility.
- Advise patients to speak with their physicians about any other medication they are currently taking.

# Precautions with Alcohol
Alcohol-Daunorubicin / cytarabine interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.

# Brand Names
- Vyxeos

# Look-Alike Drug Names
There is limited information regarding Daunorubicin / cytarabine Look-Alike Drug Names in the drug label.

# Drug Shortage Status
Drug Shortage

# Price