Etoposide

Description

DESCRIPTION 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-O-( 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 588.56 and a molecular formula of C 29 H 32 O 13 . Etoposide may be administered either intravenously or orally. Etoposide capsules, USP are available as 50 mg opaque dark pink, oblong capsules. Each liquid filled, soft gelatin capsule contains 50 mg of etoposide, USP in a vehicle consisting of citric acid anhydrous, glycerol and polyethylene glycol. The soft gelatin capsules contain anidrisorb, gelatin and glycerol with the following dye system: red iron oxide and titanium dioxide; the capsules are printed with edible black ink containing FD&C Blue No. 1 Aluminum Lake, FD&C Red No. 40 Aluminum Lake, hypromellose and propylene glycol. The structural formula is: Etoposide Structural Formula

What Is Etoposide Used For?

INDICATIONS AND USAGE Etoposide capsules are indicated in the management of the following neoplasms: Small Cell Lung Cancer Etoposide capsules in combination with other approved chemotherapeutic agents as first line treatment in patients with small cell lung cancer.

Dosage and Administration

DOSAGE AND ADMINISTRATION Etoposide Capsules In small cell lung cancer, the recommended dose of etoposide capsules is two times the IV dose rounded to the nearest 50 mg (i.e., Two times 35 mg/m 2 /day for 4 days to 50 mg/m 2 /day for 5 days). 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. Stability Etoposide capsules must be stored under refrigeration 2° to 8°C (36° to 46°F). The capsules are stable for 36 months under such refrigeration conditions. 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.

Side Effects (Adverse Reactions)

ADVERSE REACTIONS The following data on adverse reactions are based on both oral and 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 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 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. 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. The incidences of adverse reactions in the table...

Drug Interactions

Drug Interactions 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.

Contraindications

CONTRAINDICATIONS Etoposide capsules are contraindicated in patients who have demonstrated a previous hypersensitivity to etoposide or any component of the formulation.

Pregnancy and Breastfeeding

Pregnancy Teratogenic Effects Pregnancy Category D (see WARNINGS ).

Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from etoposide, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Overdosage

OVERDOSAGE No proven antidotes have been established for etoposide overdosage.

How Supplied

HOW SUPPLIED Etoposide Capsules, USP are available containing 50 mg of etoposide, USP. The 50 mg capsule is an opaque dark pink, soft gelatin capsule printed with E50 in black ink. They are available as follows: NDC 0378-3266-94 20 Capsules - Unit Dose Capsules are to be stored under refrigeration, between 2° to 8°C (36° to 46°F). Protect from freezing. Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.