ETOPOSIDE

Etoposide Injection, USP (also commonly known as VP-16) is a semisynthetic derivative of podophyllotoxin used in the treatment of certain neoplastic diseases. It is 4'-demethylepipodophyllotoxin 9-[4,6-0-(R)-ethylidene-β-D-glucopyranoside]. It is very soluble in methanol and chloroform, slightly soluble in ethanol, and sparingly soluble in water and ether. It is made more miscible with water by means of organic solvents. Etoposide Injection, USP is available for intravenous use as a sterile 20 mg per mL solution in 100 mg (5 mL), 500 mg (25 mL), or 1 g (50 mL) sterile, multiple dose vials. The pH of the clear, colorless to yellow solution is 3.0 to 4.0. Each mL contains: 20 mg etoposide, USP, 2 mg citric acid anhydrous, 80 mg polysorbate 80, 650 mg polyethylene glycol 300 (57.5% v/v and 65.0% w/v), and 262 mg dehydrated alcohol (33.2% v/v and 26.2% w/v). The structural formula is: Structural Formula

Etoposide Injection is indicated in the management of the following neoplasms: Refractory Testicular Tumors Etoposide Injection in combination therapy with other approved chemotherapeutic agents in patients with refractory testicular tumors who have already received appropriate surgical, chemotherapeutic, and radiotherapeutic therapy. Small Cell Lung Cancer Etoposide Injection and/or capsules in combination with other approved chemotherapeutic agents as first line treatment in patients with small cell lung cancer.

Note: Plastic devices made of acrylic or ABS (a polymer composed of acrylonitrile, butadiene, and styrene) have been reported to crack and leak when used with undiluted etoposide injection. Etoposide Injection The usual dose of etoposide injection in testicular cancer in combination with other approved chemotherapeutic agents ranges from 50 to 100 mg/m 2 /day on days 1 through 5 to 100 mg/m 2 /day on days 1, 3, and 5. In small cell lung cancer, the etoposide injection dose in combination with other approved chemotherapeutic drugs ranges from 35 mg/m 2 /day for 4 days to 50 mg/m 2 /day for 5 days. For recommended dosing adjustments in patients with renal impairment see PRECAUTIONS section. Chemotherapy courses are repeated at 3- to 4-week intervals after adequate recovery from any toxicity. The dosage should be modified to take into account the myelosuppressive effects of other drugs in the combination or the effects of prior x-ray therapy or chemotherapy which may have compromised bone marrow reserve. Administration Precautions As with other potentially toxic compounds, caution should be exercised in handling and preparing the solution of etoposide injection. Skin reactions associated with accidental exposure to etoposide injection may occur. The use of gloves is recommended. If etoposide injection solution contacts the skin or mucosa, immediately and thoroughly wash the skin with soap and water and flush the mucosa with water. Preparation for Intravenous Administration Etoposide injection must be diluted prior to use with either 5% Dextrose Injection, USP, or 0.9% Sodium Chloride Injection, USP, to give a final concentration of 0.2 to 0.4 mg/mL. If solutions are prepared at concentrations above 0.4 mg/mL, precipitation may occur. Hypotension following rapid intravenous administration has been reported, hence, it is recommended that the etoposide injection solution be administered over a 30- to 60-minute period. A longer duration of administration may be used if the volume of fluid to be infused is a concern. Etoposide injection should not be given by rapid intravenous injection. Parenteral drug products should be inspected visually for particulate matter and discoloration (see DESCRIPTION section) prior to administration whenever solution and container permit. Stability Unopened vials of etoposide injection are stable until the date indicated on the package at room temperature (25°C). Vials diluted as recommended to a concentration of 0.2 to 0.4 mg/mL are stable for 96 and 24 hours, respectively, at room temperature (25°C) under normal room fluorescent light in both glass and plastic containers. Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published. 1-8 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

Etoposide injection is contraindicated in patients who have demonstrated a previous hypersensitivity to etoposide or any component of the formulation.

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 .

High-dose cyclosporin A resulting in concentrations above 2000 ng/mL administered with oral etoposide has led to an 80% increase in etoposide exposure with a 38% decrease in total body clearance of etoposide compared to etoposide alone.