Drug Facts
Composition & Profile
Identifiers & Packaging
HOW SUPPLIED Etoposide Injection, USP, 20 mg/mL, is supplied as follows: NDC 0143-9376-01 100 mg/5 mL, Sterile Multiple Dose Vial, individually boxed. Store at 20° to 25°C (68° to 77°F). See USP controlled room temperature. To report SUSPECTED ADVERSE REACTIONS, contact Hikm Pharmaceuticals USA Inc. at 1-877-845-0689, or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . For Product Inquiry call 1-877-845-0689.; VIAL LABEL 100 mg/5 mL NDC 0143-9376-01 Rx only ETOPOSIDE INJECTION, USP 100 mg/5 mL (20 mg/mL) Must be diluted before Intravenous infusion unit label
- HOW SUPPLIED Etoposide Injection, USP, 20 mg/mL, is supplied as follows: NDC 0143-9376-01 100 mg/5 mL, Sterile Multiple Dose Vial, individually boxed. Store at 20° to 25°C (68° to 77°F). See USP controlled room temperature. To report SUSPECTED ADVERSE REACTIONS, contact Hikm Pharmaceuticals USA Inc. at 1-877-845-0689, or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . For Product Inquiry call 1-877-845-0689.
- VIAL LABEL 100 mg/5 mL NDC 0143-9376-01 Rx only ETOPOSIDE INJECTION, USP 100 mg/5 mL (20 mg/mL) Must be diluted before Intravenous infusion unit label
Overview
Etoposide (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. It has a molecular weight of 588.58 and a molecular formula of C 29 H 32 O 13 . Etoposide Injection, USP is available for intravenous use as 20 mg/mL solution in 100 mg (5 mL), 500 mg (25 mL), and 1 g (50 mL) sterile, multiple-dose vials. The pH of the clear, nearly colorless to yellow liquid is 3 to 4. Each mL contains 20 mg etoposide USP, 2 mg citric acid, 30 mg benzyl alcohol, 80 mg modified polysorbate 80/tween 80, 650 mg polyethylene glycol 300, and 30.5 percent (v/v) alcohol. The structural formula is: Structural Formula Structural Formula
Indications & Usage
Etoposide Injection, USP 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.
Dosage & Administration
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 . 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. Skin reactions associated with accidental exposure to etoposide may occur. The use of gloves is recommended. If etoposide 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, or 0.9% Sodium Chloride Injection, 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 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 should not be given by rapid intravenous injection. Parenteral drug products should be inspected visually for particulate matter and discoloration (see DESCRIPTION ) prior to administration whenever solution and container permit. Stability Unopened vials of Etoposide Injection are stable for 24 months at room temperature (25°C). Vials diluted as recommended to a concentration of 0.2 or 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.
Warnings & Precautions
WARNINGS Patients being treated with etoposide must be frequently observed for myelosuppression both during and after therapy. Myelosuppression resulting in death has been reported. Dose-limiting bone marrow suppression is the most significant toxicity associated with etoposide therapy. Therefore, the following studies should be obtained at the start of therapy and prior to each subsequent cycle of etoposide: platelet count, hemoglobin, white blood cell count, and differential. The occurrence of a platelet count below 50,000/mm 3 or an absolute neutrophil count below 500/mm 3 is an indication to withhold further therapy until the blood counts have sufficiently recovered. Physicians should be aware of the possible occurrence of an anaphylactic reaction manifested by chills, fever, tachycardia, bronchospasm, dyspnea, and hypotension. Higher rates of anaphylactic-like reactions have been reported in children who received infusions at concentrations higher than those recommended. The role that concentration of infusion (or rate of infusion) plays in the development of anaphylactic-like reactions is uncertain. (See ADVERSE REACTIONS .) Treatment is symptomatic. The infusion should be terminated immediately, followed by the administration of pressor agents, corticosteroids, antihistamines, or volume expanders at the discretion of the physician. For parenteral administration, etoposide should be given only by slow intravenous infusion (usually over a 30- to 60-minute period), since hypotension has been reported as a possible side effect of rapid intravenous injection. Pregnancy Teratogenic Effects: Pregnancy Category D Etoposide can cause fetal harm when administered to a pregnant woman. Etoposide has been shown to be teratogenic in mice and rats. In rats, an intravenous etoposide dose of 0.4 mg/kg/day (about 1/20th of the human dose on a mg/m 2 basis) during organogenesis caused maternal toxicity, embryotoxicity, and teratogenicity (skeletal abnormalitites, exencephaly, encephalocele, and anophthalmia); higher doses of 1.2 and 3.6 mg/kg/day (about 1/7th and 1/2 of human dose on a mg/m 2 basis) resulted in 90 and 100% embryonic resorptions. In mice, a single 1 mg/kg (1/16th of human dose on a mg/m 2 basis) dose of etoposide administered intraperitoneally on days 6,7, or 8 of gestation caused embyotoxicity, cranial abnormalities, and major skeletal malformations. An IP dose of 1.5 mg/kg (about 1/10th of human dose on a mg/m 2 basis) on day 7 of gestation caused an increase in the incidence of intrauterine death and fetal malformations and a significant decrease in the average fetal body weight. Women of childbearing potential should be advised to avoid becoming pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Etoposide should be considered a potential carcinogen in humans. The occurrence of acute leukemia with or without a preleukemic phase has been reported in rare instances in patients treated with etoposide alone or in association with other neoplastic agents. The risk of development of a preleukemic or leukemic syndrome is unclear. Carcinogenicity tests with etoposide have not been conducted in laboratory animals.
Boxed Warning
WARNINGS Etoposide should be administered under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents. Severe myelosuppression with resulting infection or bleeding may occur.
Contraindications
Etoposide is contraindicated in patients who have demonstrated a previous hypersensitivity to etoposide or any component of the formulation.
Adverse Reactions
The following data on adverse reactions are based on intravenous administration of etoposide 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 in association with other antineoplastic agents. (See WARNINGS .) 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 be administered by slow intravenous infusion over a 30- to 60-minute period. If hypotension occurs, it usually responds to cessation of the infusion 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 and in less than 1% of the patients treated with 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. 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. 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 databases from studies in 2,081 patients when etoposide 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
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