Avopef

1 INDICATIONS AND USAGE AVOPEF is a topoisomerase inhibitor indicated, in combination with other chemotherapy and/or immunotherapy, for the treatment of adult patients with: Refractory testicular cancer ( 1.1 ) Small cell lung cancer ( 1.2 ) 1.1 Refractory Testicular Cancer AVOPEF, in combination with chemotherapy, is indicated for the treatment of refractory testicular cancer in adult patients. 1.2 Small Cell Lung Cancer AVOPEF, in combination with chemotherapy and immunotherapy, is indicated for the first-line treatment of small cell lung cancer (SCLC) in adult patients.

2 DOSAGE AND ADMINISTRATION Refractory Testicular Cancer : 50 mg/m 2 to 100 mg/m 2 administered intravenously daily on Days 1 to 5, or 100 mg/m 2 administered intravenously daily on Days 1, 3 and 5. ( 2.2 ) Small Cell Lung Cancer : 35 mg/m 2 administered intravenously daily on days 1 to 4, or 50 mg/m 2 administered intravenously daily on days 1 to 5. ( 2.3 ) Dilute AVOPEF prior to intravenous infusion over 30- to 60-minutes. ( 2.5 ) 2.1 Important Dosage and Administration Information Dilute AVOPEF to a final concentration of 0.2 to 0.4 mg/mL prior to administration [see Dosage and Administration (2.5) ]. Administer diluted AVOPEF by intravenous infusion over 30 to 60 minutes to reduce the risk of infusion-related reactions including hypotension [see Dosage and Administration (2.5) ]. Before each AVOPEF administration and at appropriate intervals during and after therapy, monitor complete blood counts with differential and serum albumin [see Warnings and Precautions (5.1, 5.5) ]. If severe reactions occur, reduce the dosage or discontinue AVOPEF and take appropriate corrective measures according to the clinical judgment of the healthcare provider. 2.2 Recommended Dosage for Refractory Testicular Cancer The recommended dosage of AVOPEF is: 50 mg/m 2 to 100 mg/m 2 administered intravenously daily on Days 1 to 5, or 100 mg/m 2 administered intravenously daily on Days 1, 3 and 5 Repeat treatment cycles every 3 to 4 weeks. 2.3 Recommended Dosage for Small Cell Lung Cancer The recommended dosage of AVOPEF is: 35 mg/m 2 administered intravenously daily on Days 1 to 4, or 50 mg/m 2 administered intravenously daily on Days 1 to 5 Repeat treatment cycles every 3 to 4 weeks. 2.4 Recommended Dosage in Patients with Renal Impairment No dosage modification is recommended for patients with creatinine clearance (CLcr) > 50 mL/min. The recommended dosage of AVOPEF in patients with CLcr of 15 to 50 mL/min is listed in Table 1. Table 1: Recommended Dosage of AVOPEF in Patients with Creatine Clearance of 15 to 50 mL/min *Repeat treatment cycles every 3 to 4 weeks. Recommended AVOPEF Dosage * Refractory Testicular Cancer 37 mg/m 2 to 75 mg/m 2 Days 1 through 5 75 mg/m 2 Days 1, 3 and 5 Small Cell Lung Cancer 26 mg/m 2 Days 1 through 4 37 mg/m 2 Days 1 through 5 A recommended dosage of AVOPEF has not been established for patients with creatinine clearance < 15 mL/min. 2.5 Preparation for Intravenous Administration Preparation AVOPEF is a hazardous drug. Follow applicable special handling and disposal procedures. [see References (15) ]. Dilute AVOPEF with either 5% Dextrose Injection, USP, or 0.9% Sodium Chloride Injection, USP, to a final concentration of 0.2 to 0.4 mg/mL. If solutions of AVOPEF are prepared at concentrations above 0.4 mg/mL, precipitation may occur. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Administration Do not administer AVOPEF by rapid intravenous injection. To reduce the risk of infusion-related reactions including hypotension, administer diluted AVOPEF intravenously over 30 to 60 minutes. A longer duration of administration may be used if there is a large volume of fluid to be infused. Storage AVOPEF, diluted to a concentration of 0.2 mg/mL is stable for 96 hours or diluted to a concentration of 0.4 mg/mL is stable for 24 hours at room temperature (25°C) under normal room fluorescent light in polyvinyl chloride (PVC) container. After first use, store the partially used multiple-dose vial in the original carton at controlled room temperature, 20°C to 25° C (68°F to 77° F) for up to 28 days. Discard unused portion of the multiple-dose vial after 28 days.

4 CONTRAINDICATIONS AVOPEF is contraindicated in patients with hypersensitivity to etoposide or any of its excipients. Hypersensitivity to etoposide or any of its excipients. ( 4 )

5 WARNINGS AND PRECAUTIONS Severe Myelosuppression : Monitor complete blood counts before each AVOPEF administration and at appropriate intervals during and after therapy. Interrupt AVOPEF for absolute neutrophil counts below 500 cells/mm 3 or platelet counts below 50,000 cells/mm 3 . ( 5.1 ) Hypersensitivity and Infusion-Related Reactions : At the first sign of hypersensitivity, stop the infusion and administer volume expanders, corticosteroids, antihistamines, and pressor agents as appropriate. Permanently discontinue AVOPEF in patients who experience a severe hypersensitivity reaction. Hypotension has occurred after rapid intravenous injection. ( 5.2 ) Extravasation Resulting in Tissue Necrosis : Extravasation of etoposide can result in swelling, pain, cellulitis, and tissue necrosis. ( 5.3 ) Secondary Leukemia : Secondary leukemia has occurred with use of etoposide. ( 5.4 ) Risk of Increased AVOPEF Toxicity with Low Serum Albumin : Monitor serum albumin during treatment with AVOPEF. Patients with low serum albumin may have increased concentrations of unbound etoposide and may be at an increased risk for etoposide associated adverse reactions. ( 5.5 ) Alcohol Content : The alcohol content in a dose of AVOPEF may affect the central nervous system. This may include impairment of a patient's ability to drive or use machines immediately after infusion. ( 5.6 ) Embryo-Fetal Toxicity : AVOPEF can cause fetal harm. Advise patients of the potential risk to a fetus and to use effective contraception. ( 5.7 ) 5.1 Severe Myelosuppression AVOPEF can cause severe and fatal myelosuppression, including neutropenia, febrile neutropenia, anemia, and thrombocytopenia. Monitor complete blood counts with differential before each AVOPEF administration and at appropriate intervals during and after treatment with AVOPEF. Do not administer AVOPEF to patients with absolute neutrophil counts of less than 500 cells/mm 3 or platelets less than 50,000 cells/mm 3 . 5.2 Hypersensitivity and Infusion-Related Reactions AVOPEF can cause severe and fatal infusion-related reactions including anaphylactic reactions characterized by chills, fever, tachycardia, bronchospasm, dyspnea and hypotension [see Adverse Reactions (6.1) ] . Hypertension and flushing have occurred. At the first sign of hypersensitivity, stop the infusion and administer volume expanders, corticosteroids, antihistamines, and pressor agents as appropriate. Permanently discontinue AVOPEF in patients who experience a severe hypersensitivity reaction. Hypotension due to rapid intravenous injection has also occurred. To reduce the risk of hypotension due to an infusion-related reaction, administer AVOPEF by intravenous infusion over 30 to 60 minutes [see Dosage and Administration (2.5) ]. 5.3 Extravasation Resulting in Tissue Necrosis Extravasation of etoposide can result in swelling, pain, cellulitis, and tissue necrosis. 5.4 Secondary Leukemia Secondary leukemia has occurred with use of etoposide. 5.5 Risk of Increased AVOPEF Toxicity with Low Serum Albumin Etoposide is highly protein-bound. Patients with low serum albumin may have increased concentrations of unbound etoposide and may be at an increased risk for etoposide associated adverse reactions. Monitor for increased adverse reactions during treatment with AVOPEF in patients with low serum albumin. 5.6 Alcohol Content The alcohol content in a dose of AVOPEF may affect the central nervous system and should be taken into account for patients in whom alcohol intake should be avoided or minimized. Consideration should be given to the alcohol content in AVOPEF on the ability to drive or use machines immediately after the infusion. Each administration of AVOPEF at 100 mg/m 2 delivers 1.5 g/m 2 of ethanol. For a patient with a BSA of 2.0 m 2 this would deliver 3.0 grams of ethanol [see Description (11) ]. Other etoposide products may have a different amount of alcohol or no alcohol. 5.7 Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, AVOPEF can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, intravenous or intraperitoneal administration of etoposide to pregnant animals during the period of organogenesis caused embryo-fetal mortality and structural abnormalities at doses below the recommended human dose of 50 mg/m 2 based on body surface area (BSA). Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise female patients of reproductive potential to use effective contraception during treatment with AVOPEF and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with AVOPEF and for 4 months after the last dose [see Use in Specific Populations (8.1, 8.3) ].

7 DRUG INTERACTIONS CYP3A Inhibitors and CYP3A Inducers : Avoid concomitant use of strong CYP3A inhibitors and strong CYP3A inducers with AVOPEF. ( 7.1 ) Vitamin K Antagonists : Monitor INR more frequently and modify the dosage of the vitamin K antagonists as appropriate. Co-administration of AVOEPF with warfarin can result in elevated international normalized ratio (INR). ( 7.2 ) 7.1 Effect of Other Drugs on AVOPEF CYP3A Inhibitors Avoid concomitant use of strong CYP3A inhibitors. Etoposide is a CYP3A4 substrate. Strong CYP3A inhibitors may increase etoposide exposure, which may increase the risk of AVOPEF-associated adverse reactions [see Clinical Pharmacology (12.3) ]. CYP3A Inducers Avoid concomitant use of strong CYP3A inducers. Etoposide is a CYP3A4 substrate. Strong CYP3A inducers may reduce etoposide exposure, which may decrease the effectiveness of AVOPEF [see Clinical Pharmacology (12.3) ]. 7.2 Effect of AVOPEF on Other Drugs Vitamin K Antagonists Monitor INR more frequently and modify the dosage of the vitamin K antagonists as appropriate. Co-administration of AVOEPF with warfarin can result in elevated international normalized ratio (INR).

6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed in more detail in other sections of the labeling. Severe Myelosuppression [see Warnings and Precautions (5.1) ] Hypersensitivity and Infusion-Related Reactions [see Warnings and Precautions (5.2) ] Extravasation Resulting in Tissue Necrosis [see Warnings and Precautions (5.3) ] Secondary Leukemia [see Warnings and Precautions (5.4) ] Risk of Increased AVOPEF Toxicity with Low Serum Albumin [see Warnings and Precautions (5.5) ] Alcohol Content [see Warnings and Precautions (5.6) ] The most common adverse reactions are, myelosuppression, hypersensitivity, nausea/vomiting, and alopecia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Avyxa Pharma, LLC at 1-888-520-0954 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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 clinical practice. Blood and lymphatic system disorders : acute leukemia, myelosuppression Eye disorders : transient cortical blindness Gastrointestinal disorders : abdominal pain, anorexia, constipation, diarrhea, dysgeusia, dysphagia, esophagitis, mucositis, nausea, stomatitis and vomiting General disorders and administration site conditions : fatigue, fever, and infusion site extravasation with necrosis Hepatobiliary disorders : hepatoxicity, metabolic acidosis Immune system disorders : allergic reaction, anaphylactic reaction (including chills, fever, tachycardia, bronchospasm, dyspnea, hypotension, hypertension, flushing, facial swelling, tongue swelling, coughing, diaphoresis, cyanosis, tightness in throat, laryngospasm, back pain, loss of consciousness, hypersensitivity-associated apnea), hypersensitivity, infusion-related reaction. Infections : febrile neutropenia Nervous system disorders : optic neuritis, peripheral neuropathy and seizure Respiratory, thoracic and mediastinal disorders : interstitial pneumonitis and pulmonary fibrosis Skin and subcutaneous tissue disorders : alopecia, pigmentation changes (including pigmented bands in nails, skin darkening and discoloration of tongue and teeth), pruritic erythematous maculopapular rash, pruritus, radiation recall dermatitis, rash, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and urticaria Vascular disorders : hypotension following rapid intravenous administration [see Dosage and Administration (2.5) ] , perivasculitis

8.1 Pregnancy Risk Summary Based on findings in animal studies and its mechanism of action [see Clinical Pharmacology (12.1) ], AVOPEF can cause fetal harm when administered to a pregnant woman. There are no available data on the use of AVOPEF in pregnant women to inform a drug-associated risk. AVOPEF contains alcohol which can interfere with neurobehavioral development [see Clinical Considerations] . In animal reproduction studies, intravenous or intraperitoneal administration of etoposide to pregnant animals during the period of organogenesis caused embryo-fetal mortality and structural abnormalities at doses below the recommended human dose of 50 mg/m 2 based on body surface area (BSA). Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise female patients of reproductive potential to use effective contraception during treatment with AVOPEF and for 6 months after the last dose [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1) ] . In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and of miscarriage is 15% to 20%, respectively. Clinical Considerations AVOPEF contains alcohol [see Warnings and Precautions (5.6) ] . Published studies have demonstrated that alcohol is associated with fetal harm including central nervous system abnormalities, behavioral disorders, and impaired intellectual development. Data Animal Data In rats, an intravenous etoposide dose of 0.4 mg/kg/day (approximately 0.05 times the human dose of 50 mg/m 2 based on BSA) during organogenesis caused maternal toxicity, embryotoxicity, and teratogenicity (skeletal abnormalities, exencephaly, encephalocele, and anophthalmia); higher doses of 1.2 and 3.6 mg/kg/day (approximately 0.14- and 0.5-times the human dose of 50 mg/m 2 based on BSA) resulted in 90% and 100% embryonic resorptions, respectively. In mice, a single etoposide dose of 1.0 mg/kg (approximately 0.06 times the human dose of 50 mg/m 2 based on BSA) administered intraperitoneally on Days 6, 7, or 8 of gestation caused embryotoxicity, cranial abnormalities, and major skeletal malformations. An intraperitoneal dose of 1.5 mg/kg (approximately 0.10-times the human dose 50 mg/m 2 based on BSA) on Day 7 of gestation caused an increase in the incidence of intrauterine death, fetal malformations, and a significant decrease in the average fetal body weight.