Etoposide

Trade Names:
Etopophos
- Injection, lyophilized powder for solution 100 mg vial

Trade Names:
Etoposide
- Capsules 50 mg

Trade Names:
Toposar
- Injection, solution, concentrate 20 mg/mL

Pharmacology

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Etoposide's main effect appears to be at the G ₂ portion of the cell cycle. At high concentrations (10 mcg/mL or more), lysis of cells entering mitosis is seen; at low concentrations (0.3 to 10 mcg/mL), cells are inhibited from entering prophase. Predominant macromolecular effect appears to be DNA synthesis inhibition.

Pharmacokinetics

Absorption

Bioavailability is approximately 50% (oral).

Distribution

Distribution half-life is approximately 1.5 h. Vd is approximately 18 to 29 L (at steady state). 97% is protein bound.

Metabolism

Etoposide phosphate is rapidly dephosphonylated to etoposide in the plasma. Etoposide is extensively metabolized in the liver (including CYP3A4).

Elimination

The half-life is approximately 4 to 11 h. Cl is 33 to 48 mL/min. 42% to 67% is excreted in the urine, and 0% to 16% is excreted in the feces. Less than 50% is excreted in the urine, and less than 6% is excreted in bile as etoposide.

Special Populations

Total body Cl is reduced, AUC is increased, and Vd is lower.

Indications and Usage

In combination with other chemotherapeutic agents in patients with small cell lung cancer.

In combination with other chemotherapeutic agents in patients with refractory testicular tumors.

Unlabeled Uses

Bladder carcinoma, lymphomas, leukemias, Ewing sarcoma, Kaposi sarcoma, brain tumors, gestational trophoblastic tumors, ovarian germ cell tumors, rhabdomyosarcomas, Wilms tumor, bone marrow transplantation.

Contraindications

Standard considerations.

Dosage and Administration

IV Dosage ranges from 35 mg/m ² /day for 4 days to 50 mg/m ² /day for 5 days. Repeat chemotherapy courses at 3- to 4-week intervals after adequate recovery from any toxicity. PO Two times the IV dose rounded to the nearest 50 mg.

IV Dosage 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. Repeat chemotherapy courses at 3- to 4-week intervals after adequate recovery from any toxicity.

For patients with CrCl of 15 to 50 mL/min, give 75% of the usual dose. Consider further dose reduction for those with CrCl less than 15 mL/min.

General Advice

• Modify dose to take into account the myelosuppressive effects of other drugs in the combination or the effects of prior x-ray therapy or chemotherapy that may have compromised bone marrow reserve.

• Etoposide solution for injection can be mixed to a final concentration 0.4 mg/mL or less with orange juice, apple juice, or lemonade for oral administration.
• Stable for 3 h at room temperature.

• Dilute prior to use with dextrose 5% or sodium chloride 0.9% to final concentration of 0.2 or 0.4 mg/mL. Concentrations less than 0.4 mg/mL may precipitate.
• Infuse over 30 to 60 min. Do not give by rapid IV injection because of the risk of hypotension.

Storage/Stability

Refrigerate; can be stored at room temperature for 3 mo.

Store unopened vials refrigerated at 36° to 46°F. Protect from light. Reconstituted solutions can be stored in glass or plastic containers refrigerated at 36° to 46°F for 7 days; following reconstitution with sterile water for injection, dextrose 5% injection, or sodium chloride 0.9%, store at 68° to 77°F for 24 hours; or following reconstitution with bacteriostatic water for injection with benzyl alcohol or bacteriostatic sodium chloride for injection with benzyl alcohol, store at 68° to 77°F for 48 hours.

Store refrigerated at 36° to 46°F. Do not freeze.

Store at 59° to 86°F. Do not freeze. Vials diluted as recommended to 0.2 mg/mL or 0.4 mg/mL may be stored at 77°F for 96 hours and 24 hours, respectively.

Drug Interactions

Etoposide plasma concentrations may be elevated, increasing the risk of adverse reactions.

High-dose cyclosporine has increased etoposide exposure 89% and decreased Cl 38%. The risk of etoposide toxicity may be increased.

Etoposide plasma concentrations may be reduced, decreasing the pharmacologic effect.

Etoposide may increase the hypoprothrombinemic effects of warfarin.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Hypotension (2%).

CNS

Peripheral neurotoxicity (2%).

Dermatologic

Alopecia (66%).

GI

Nausea and vomiting (43%); anorexia, diarrhea (13%); stomatitis (6%); abdominal pain (2%).

Hematologic-Lymphatic

Leukopenia (less than 1,000 WBC/mm ³ [17%], less than 4,000 WBC/mm ³ [91%]); thrombocytopenia (less than 50,000 platelets/mm ³ [20%], less than 1,000,000 platelets/mm ³ [41%]); anemia (33%).

Hepatic

Hepatic toxicity (3%).

Hypersensitivity

Allergic reactions, including anaphylactic-type reactions (2%).

Precautions

Pregnancy

Category D .

Lactation

Undetermined.

Children

Safety and efficacy in children not established.

Elderly

Use with caution because elderly patients are more likely to have decreased renal function. Postmarketing experience suggests that elderly patients may be more sensitive to some etoposide adverse reactions, including alopecia, GI effects, infections, myelosuppression.

Renal Function

Dosage adjustments may be needed.

Albumin

Patients with low serum albumin may be at increased risk of etoposide toxicity.

Anaphylaxis

Anaphylaxis manifested by chills, fever, tachycardia, bronchospasm, dyspnea, facial flushing, hypertension, or hypotension may occur.

Hypotension

Administer by slow IV infusion because hypotension may occur with rapid IV injection.

Extravasation

Can cause local irritation or phlebitis. Refer to your institution-specific protocol.

Overdosage

Symptoms

Bone marrow suppression.

Patient Information

• Contraceptive measures are recommended during treatment.
• Notify health care provider of any of the following: chills, difficult breathing, fever, rapid heartbeat.

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