Etoposide

INDICATIONS AND USAGE ETOPOPHOS is a topoisomerase inhibitor indicated for the treatment of patients with: Refractory testicular tumors, in combination with other chemotherapeutic drugs. ( 1 ) Small cell lung cancer, in combination with cisplatin, as first-line treatment. ( 1 ) 1.1 Refractory Testicular Tumors ETOPOPHOS is indicated, in combination with other chemotherapeutic drugs, for treatment of patients with refractory testicular tumors. 1.2 Small Cell Lung Cancer ETOPOPHOS is indicated, in combination with cisplatin, for first-line treatment of patients with small cell lung cancer.

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.

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) ].

CONTRAINDICATIONS ETOPOPHOS is contraindicated in patients with a history of a severe hypersensitivity reaction to etoposide products [see Warnings and Precautions (5.3) ] . Hypersensitivity to etoposide products. ( 4 , 5.3 )

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).

ADVERSE REACTIONS The following data on adverse reactions are based on both oral and intravenous administration of etoposide injection as a single agent, using several different dose schedules for treatment of a wide variety of malignancies. Hematologic Toxicity Myelosuppression is dose related and dose limiting, with granulocyte nadirs occurring 7 to 14 days after drug administration and platelet nadirs occurring 9 to 16 days after drug administration. Bone marrow recovery is usually complete by day 20, and no cumulative toxicity has been reported. Fever and infection have also been reported in patients with neutropenia. Death associated with myelosuppression has been reported. The occurrence of acute leukemia with or without a preleukemic phase has been reported rarely in patients treated with etoposide injection in association with other antineoplastic agents (see WARNINGS section). Gastrointestinal Toxicity Nausea and vomiting are the major gastrointestinal toxicities. The severity of such nausea and vomiting is generally mild to moderate with treatment discontinuation required in 1% of patients. Nausea and vomiting can usually be controlled with standard antiemetic therapy. Mild to severe mucositis/esophagitis may occur. Gastrointestinal toxicities are slightly more frequent after oral administration than after intravenous infusion. Hypotension Transient hypotension following rapid intravenous administration has been reported in 1% to 2% of patients. It has not been associated with cardiac toxicity or electrocardiographic changes. No delayed hypotension has been noted. To prevent this rare occurrence, it is recommended that etoposide injection be administered by slow intravenous infusion over a 30- to 60-minute period. If hypotension occurs, it usually responds to cessation of the infusion and administration of fluids or other supportive therapy as appropriate. When restarting the infusion, a slower administration rate should be used. Allergic Reactions Anaphylactic-like reactions characterized by chills, fever, tachycardia, bronchospasm, dyspnea, and/or hypotension have been reported to occur in 0.7% to 2% of patients receiving intravenous etoposide injection and in less than 1% of the patients treated with the oral capsules. These reactions have usually responded promptly to the cessation of the infusion and administration of pressor agents, corticosteroids, antihistamines, or volume expanders as appropriate; however, the reactions can be fatal. Hypertension and/or flushing have also been reported. Blood pressure usually normalizes within a few hours after cessation of the infusion. Anaphylactic-like reactions have occurred during the initial infusion of etoposide injection. Facial/tongue swelling, coughing, diaphoresis, cyanosis, tightness in throat, laryngospasm, back pain, and/or loss of consciousness have sometimes occurred in association with the above reactions. In addition, an apparent hypersensitivity-associated apnea has been reported rarely. Rash, urticaria, and/or pruritus have infrequently been reported at recommended doses. At investigational doses, a generalized pruritic erythematous maculopapular rash, consistent with perivasculitis, has been reported. Alopecia Reversible alopecia, sometimes progressing to total baldness, was observed in up to 66% of patients. Other Toxicities The following adverse reactions have been infrequently reported: abdominal pain, aftertaste, constipation, dysphagia, asthenia, fatigue, malaise, somnolence, transient cortical blindness, optic neuritis, interstitial pneumonitis/pulmonary fibrosis, fever, seizure (occasionally associated with allergic reactions), Stevens-Johnson syndrome, and toxic epidermal necrolysis, pigmentation, and a single report of radiation recall dermatitis. Hepatic toxicity, generally in patients receiving higher doses of the drug than those recommended, has been reported with etoposide injection. Metabolic acidosis has also been reported in patients receiving higher doses. Reports of extravasation with swelling have been received postmarketing. Rarely extravasation has been associated with necrosis and venous induration. The incidences of adverse reactions in the table that follows are derived from multiple data bases from studies in 2,081 patients when etoposide injection was used either orally or by injection as a single agent. ADVERSE DRUG EFFECT PERCENT RANGE OF REPORTED INCIDENCE Hematologic toxicity Leukopenia (less than 1,000 WBC/mm 3 ) 3 to 17 Leukopenia (less than 4,000 WBC/mm 3 ) 60 to 91 Thrombocytopenia (less than 50,000 platelets/mm 3 ) 1 to 20 Thrombocytopenia (less than 100,000 platelets/mm 3 ) 22 to 41 Anemia 0 to 33 Gastrointestinal toxicity Nausea and vomiting 31 to 43 Abdominal pain 0 to 2 Anorexia 10 to 13 Diarrhea 1 to 13 Stomatitis 1 to 6 Hepatic 0 to 3 Alopecia 8 to 66 Peripheral neurotoxicity 1 to 2 Hypotension 1 to 2 Allergic reaction 1 to 2 To report SUSPECTED ADVERSE REACTIONS, contact Meitheal Pharmaceuticals, Inc. at 1-844-824-8426 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

CLINICAL PHARMACOLOGY Etoposide has been shown to cause metaphase arrest in chick fibroblasts. Its main effect, however, appears to be at the G 2 portion of the cell cycle in mammalian cells. Two different dose dependent responses are seen. At high concentrations (10 mcg/mL or more), lysis of cells entering mitosis is observed. At low concentrations (0.3 mcg/mL to 10 mcg/mL), cells are inhibited from entering prophase. It does not interfere with microtubular assembly. The predominant macromolecular effect of etoposide appears to be the induction of DNA strand breaks by an interaction with DNA topoisomerase II or the formation of free radicals. Pharmacokinetics On intravenous administration, the disposition of etoposide is best described as a biphasic process with a distribution half-life of about 1.5 hours and terminal elimination half-life ranging from 4 to 11 hours. Total body clearance values range from 33 mL/min to 48 mL/min or 16 mL/min/m 2 to 36 mL/min/m 2 and, like the terminal elimination half-life, are independent of dose over a range 100 mg/m 2 to 600 mg/m 2 . Over the same dose range, the areas under the plasma concentration vs. time curves (AUC) and the maximum plasma concentration (C max ) values increase linearly with dose. Etoposide does not accumulate in the plasma following daily administration of 100 mg/m 2 for 4 to 5 days. The mean volumes of distribution at steady-state fall in the range of 18 to 29 liters or 7 L/m 2 to 17 L/m 2 . Etoposide enters the CSF poorly. Although it is detectable in CSF and intracerebral tumors, the concentrations are lower than in extracerebral tumors and in plasma. Etoposide concentrations are higher in normal lung than in lung metastases and are similar in primary tumors and normal tissues of the myometrium. In vitro , etoposide is highly protein bound (97%) to human plasma proteins. An inverse relationship between plasma albumin levels and etoposide renal clearance is found in children. In a study determining the effect of other therapeutic agents on the in vitro binding of 14 C-etoposide to human serum proteins, only phenylbutazone, sodium salicylate and aspirin displaced protein bound etoposide at concentrations achieved in vivo . Etoposide binding ratio correlates directly with serum albumin in patients with cancer and in normal volunteers. The unbound fraction of etoposide significantly correlated with bilirubin in a population of cancer patients. Data have suggested a significant inverse correlation between serum albumin concentration and free fraction of etoposide (see PRECAUTIONS ). After intravenous administration of 14 C-etoposide (100 mg/m 2 to 124 mg/m 2 ), mean recovery of radioactivity in the urine was 56% of the dose at 120 hours, 45% of which was excreted as etoposide; fecal recovery of radioactivity was 44% of the dose at 120 hours. In children, approximately 55% of the dose is excreted in the urine as etoposide in 24 hours. The mean renal clearance of etoposide is 7 mL/min/m 2 to 10 mL/min/m 2 or about 35% of the total body clearance over a dose range of 80 mg/m 2 to 600 mg/m 2 . Etoposide, therefore, is cleared by both renal and nonrenal processes, i.e., metabolism and biliary excretion. The effect of renal disease on plasma etoposide clearance is not known. Biliary excretion of unchanged drug and/or metabolites is an important route of etoposide elimination as fecal recovery of radioactivity is 44% of the intravenous dose. The hydroxy acid metabolite [4’-demethylepipodophyllic acid-9-(4,6-0-( R )-ethylidene-ß-D-glucopyranoside)], formed by opening of the lactone ring, is found in the urine of adults and children. It is also present in human plasma, presumably as the trans isomer. Glucoronide and/or sulfate conjugates of etoposide are also excreted in human urine. Only 8% or less of an intravenous dose is excreted in the urine as radiolabeled metabolites of 14 C-etoposide. In addition, 0-demethylation of the dimethoxyphenol ring occurs through the CYP450 3A4 isoenzyme pathway to produce the corresponding catechol. After either intravenous infusion or oral capsule administration, the C max and AUC values exhibit marked intra- and inter-subject variability. This results in variability in the estimates of the absolute oral bioavailability of etoposide oral capsules. C max and AUC values for orally administered etoposide capsules consistently fall in the same range as the C max and AUC values for an intravenous dose of one-half the size of the oral dose. The overall mean value of oral capsule bioavailability is approximately 50% (range 25% to 75%). The bioavailability of etoposide capsules appears to be linear up to a dose of at least 250 mg/m 2 . There is no evidence of a first-pass effect for etoposide. For example, no correlation exists between the absolute oral bioavailability of etoposide capsules and nonrenal clearance. No evidence exists for any other differences in etoposide metabolism and excretion after administration of oral capsules as compared to intravenous infusion. In adults, the total body clearance of etoposide is correlated with creatinine clearance, serum albumin concentration and nonrenal clearance. Patients with impaired renal function receiving etoposide have exhibited reduced total body clearance, increased AUC and a lower volume of distribution at steady-state (see PRECAUTIONS ). Use of cisplatin therapy is associated with reduced total body clearance. In children, elevated serum SGPT levels are associated with reduced drug total body clearance. Prior use of cisplatin may also result in a decrease of etoposide total body clearance in children. Although some minor differences in pharmacokinetic parameters between age and gender have been observed, these differences were not considered clinically significant.