Vyxeos Drug Information

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.

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

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: • Calculate the Vyxeos dose based on daunorubicin and individual patient's body surface area (BSA). • Calculate the number of vials of Vyxeos based on the daunorubicin dose. • Remove the appropriate number of vials of Vyxeos 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. • 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: • Calculate the volume of reconstituted Vyxeos required using the following formula: • Gently invert each vial 5 times prior to withdrawing the reconstituted product for further dilution. • 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 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. • 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 •

For intravenous use only. • Do not mix Vyxeos with or administer as an infusion with other drugs. • 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 microns. • Flush the line after administration with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP.

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 VYXEOS was determined in a randomized trial for adults with newly diagnosed t‑AML or AML-MRC 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).

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.

The most common serious adverse reactions (incidence ≥ 5%) on the VYXEOS arm were dyspnea, myocardial toxicity, sepsis, pneumonia, febrile neutropenia, bacteremia and hemorrhage. 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.

Table 3: Common Adverse Reactions (≥ 10% Incidence in the VYXEOS arm) During the a Grouped terms: Hemorrhage: Anal hemorrhage, Blood blister, Blood urine present, Breast hematoma, Catheter site bruise, Catheter site hemorrhage, Central nervous system hemorrhage, Cerebral hematoma, Cerebral hemorrhage, Coagulopathy, Conjunctival hemorrhage, Contusion, Ecchymosis, Enterocolitis hemorrhagic, Epistaxis, Gastric hemorrhage, Gastrointestinal hemorrhage, Gingival bleeding, Hematemesis, Hematochezia, Hematoma, Hematuria, Hemoptysis, Hemorrhage, Hemorrhage intracranial, Hemorrhage subcutaneous, Hemorrhage urinary tract, Hemorrhoidal hemorrhage, Lip hematoma, Lip hemorrhage, Lower gastrointestinal hemorrhage, Melena, Mouth hemorrhage, Mucosal hemorrhage, Periorbital hematoma, Periorbital hemorrhage, Pharyngeal hematoma, Pharyngeal hemorrhage, Post procedural contusion, Post procedural hematoma, Post procedural hemorrhage, Pulmonary alveolar hemorrhage, Pulmonary hemorrhage, Purpura, Rectal hemorrhage, Retinal hemorrhage, Scleral hemorrhage, Scrotal hematoma, Skin ulcer hemorrhage, Small intestinal hemorrhage, Stomatitis hemorrhagic, Subdural hematoma, Subdural hemorrhage, Subgaleal hematoma, Tongue hemorrhage, Traumatic hematoma, Upper gastrointestinal hemorrhage, Urethral hemorrhage, Vaginal hemorrhage, Vessel puncture site hemorrhage, Vitreous hemorrhage; Rash: Dermatitis, Dermatitis acneiform, Dermatitis allergic, Dermatitis contact, Eczema, Erythema nodosum, Exfoliative rash, Psoriasis, Rash, Rash erythematous, Rash follicular, Rash generalized, Rash macular, Rash maculo-papular, Rash papular, Rash pruritic, Rash pustular, Skin exfoliation; Edema: Face edema, Fluid overload, Fluid retention, Generalized edema, Localized edema, Edema, Edema peripheral, Penile edema, Scrotal edema, Swelling, Swelling face; Diarrhea/Colitis: Cecitis, Colitis, Diarrhea, Enterocolitis, Ileitis, Neutropenic colitis, Enteritis, Enterocolitis; Mucositis: Anal erosion, Anorectal discomfort, Duodenitis, Gastric ulcer, Gastrointestinal inflammation, Gingival pain, Gingival swelling, Gingivitis, Glossodynia, Laryngeal inflammation, Lip ulceration, Mouth ulceration, Mucosal inflammation, Mucosal ulceration, Odynophagia, Edema mouth, Esophageal ulcer, Esophagitis, Oral mucosa erosion, Oral mucosal blistering, Oral mucosal erythema, Pharyngeal ulceration, Proctalgia, Proctitis, Rectal ulcer, Stomatitis, Tongue ulceration, Oropharyngeal pain, Oral pain, Oropharyngeal discomfort, Pharyngeal erythema; Musculoskeletal pain: Arthralgia, Back pain, Bone pain, Coccydynia, Limb discomfort, Musculoskeletal chest pain, Musculoskeletal pain, Myalgia, Neck pain, Pain in extremity, Pain in jaw; Abdominal pain: Abdominal pain, Abdominal distension, Abdominal pain upper, Abdominal discomfort, Abdominal pain lower, Abdominal tenderness; Cough: Cough, Productive Cough; Headache: Headache, Sinus Headache; Dyspnea: Acute respiratory distress syndrome, Acute respiratory failure, Bronchospasm, Dyspnea, Dyspnea exertional, Respiratory distress, Respiratory failure, Wheezing; Fatigue: Fatigue, Asthenia; Arrhythmia: Arrhythmia, Arrhythmia supraventricular, Atrial fibrillation, Atrial flutter, Atrial tachycardia, Atrioventricular block first degree, Atrioventricular block second degree, Bradycardia, Bundle branch block right, Extrasystoles, Heart rate increased, Nodal arrhythmia, Nodal rhythm, Sinus arrest, Sinus arrhythmia, Sinus bradycardia, Sinus tachycardia, Supraventricular tachycardia, Tachycardia, Ventricular extrasystoles, Ventricular tachycardia; Pneumonia (excluding fungal): Lung consolidation, Lung infection, Lung infiltration, Pneumonia, Pneumonia aspiration, Pneumonia bacterial, Pneumonia klebsiella, Pneumonia pseudomonas aeruginosa, Pneumonia viral; Sleep disorders: Abnormal dreams, Insomnia, Nightmare, Sleep apnea syndrome, Sleep disorder; Bacteremia (excluding sepsis): Bacillus test positive, Bacteremia, Bacteroides bacteremia, Corynebacterium test positive, Enterobacter bacteremia, Enterococcal bacteremia, Enterococcus test positive, Escherichia bacteremia, Klebsiella bacteremia, Pseudomonal bacteremia, Pseudomonas test positive, Staphylococcal bacteremia, Staphylococcus test positive, Stomatococcus test positive, Streptococcal bacteremia, Streptococcus test positive, Escherichia test positive, Klebsiella test positive; Vomiting: Retching, Vomiting; Hypotension: Hypotension, Orthostatic hypotension; Non-conduction cardiotoxicity: Acute coronary syndrome, Acute endocarditis, Acute myocardial infarction, Angina pectoris, Aortic valve incompetence, Cardiac arrest, Cardiac failure, Cardiac failure congestive, Cardiac murmur, Cardiogenic shock, Cardiomegaly, Cardiomyopathy, Cardiotoxicity, Cytotoxic cardiomyopathy, Diastolic dysfunction, Dilatation atrial, Dilatation ventricular, Ejection fraction decreased, Endocarditis, Left ventricular dysfunction, Mitral valve incompetence, Myocardial infarction, Pericardial effusion, Pericarditis, Restrictive cardiomyopathy, Right ventricular hypertrophy; Dizziness: Dizziness, Dizziness postural, Dizziness exertional; Fungal infection: Aspergillosis, Bronchopulmonary aspergillosis, Candida test positive, Candidiasis, Fungemia, Fungal infection, Fungal skin infection, Intertrigo candida, Lower respiratory tract infection fungal, Oral candidiasis, Pneumonia fungal, Pulmonary mycosis, Sinusitis fungal, Skin candida, Tinea cruris, Tinea infection, Vulvovaginal mycotic infection, Wound infection fungal, Zygomycosis, Mycotic aneurysm; Hypertension: Blood pressure increased, Hypertension; Hypoxia: Hypoxia, Oxygen saturation decreased; Upper respiratory infection (excluding fungal): Acute sinusitis, Chronic sinusitis, Increased upper airway secretion, Nasal congestion, Pharyngitis, Rhinitis, Rhinorrhea, Sinus congestion, Sinusitis, Sinusitis bacterial, Upper respiratory tract congestion, Upper respiratory tract infection, Upper-airway cough syndrome, Viral upper respiratory tract infection; Chest pain: Chest discomfort, Chest pain, Non-cardiac chest pain, Pleuritic pain; Catheter/device/injection site reaction: Catheter site discharge, Catheter site erosion, Catheter site erythema, Catheter site inflammation, Catheter site edema, Catheter site pain, Catheter site pruritus, Catheter site rash, Infusion site edema, Infusion site pain, Infusion site vesicles, Catheter site related reaction; Delirium: Cognitive disorder, Confusional state, Delirium; Pruritis: Anal pruritis, Ear pruritis, Pruritis, Pruritis generalized; Sepsis (excluding fungal): Enterobacter sepsis, Escherichia sepsis, Klebsiella sepsis, Neutropenic sepsis, Sepsis, Septic shock, Staphylococcal sepsis, Streptococcal sepsis, Urosepsis, Viral sepsis; Renal insufficiency: Acute prerenal failure, Azotemia, Oliguria, Renal failure, Renal failure acute, Renal failure chronic; Transfusion reactions: Allergic transfusion reaction, Febrile non-hemolytic transfusion reaction, Transfusion reaction; Visual impairment (except bleeding): Photophobia, Photopsia, Photosensitivity reaction, Retinal tear, Scintillating scotoma, Uveitis, Vision blurred, Visual acuity reduced, Visual impairment, Vitreous detachment, Vitreous floaters b Adverse reactions were graded using NCI CTCAE version 3.0. During the consolidation phase (both consolidation cycles pooled) the two most common adverse reactions on the VYXEOS 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 VYXEOS 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 VYXEOS 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 Laboratory Abnormalities 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. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: Infusion-related reactions

Cardiotoxic Agents

Concomitant use of cardiotoxic agents may increase the risk of cardiotoxicity. Assess cardiac function more frequently when VYXEOS is coadministered with cardiotoxic agents.

Hepatotoxic 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 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.

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 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. 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.

Pediatric Use Newly Diagnosed t-AML or AML-MRC 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 exposures of total daunorubicin and cytarabine observed in pediatric patients were within the values observed in adults given the same dose based on body surface area. No new safety signals were observed in pediatric patients in these two single-arm trials.

No differences in safety were observed by age. Newly Diagnosed de novo AML The safety and effectiveness of VYXEOS in pediatric patients with de novo AML were assessed but not established in an open-label, randomized study (NCT04293562) comparing VYXEOS plus gemtuzumab ozogamicin to standard chemotherapy plus gemtuzumab ozogamicin. The VYXEOS arm included 324 pediatric patients less than 17 years old.

No new safety signals were identified in the pediatric patients treated with VYXEOS and gemtuzumab ozogamicin in this trial.

• 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.