Physicians' Cancer Chemotherapy Drug Manual 2004
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E

Etoposide


Generic Drug Name
Etoposide

 

 



 

Trade Names
VePesid, VP-16
 


 

Classification
Epipodophyllotoxin, topoisomerase II inhibitor


 

Category
Chemotherapy drug


 

Drug Manufacturer
Bristol-Myers Squibb


 

Mechanism of Action
 

  • Plant alkaloid extracted from the Podophyllum peltatum mandrake plant.
  • Cell cycle–specific agent with activity in the late S- and G2-phase of the cell cycle.
  • Inhibits topoisomerase II by stabilizing the topoisomerase II-DNA complex and preventing the unwinding of DNA.

 


 

Mechanism of Resistance
 

  1. Multidrug-resistant phenotype with increased expression of P170 glycoprotein. Results in enhanced drug efflux and decreased intracellular accumulation of drug. Cross-resistant to vinca alklaloids, anthracyclines, taxanes, and other natural products.
  2. Decreased expression of topoisomerase II.
  3. Mutations in topoisomerase II with decreased binding affinity to drug.
  4. Enhanced activity of DNA repair enzymes.

 


 

Absorption
Bioavailability of oral capsules is approximately 50%, requiring an oral dose to be twice that of an IV dose. However, oral bioavailability is nonlinear and decreases with higher doses of drug (> 200 mg). Presence of food and/or other anticancer agents does not alter drug absorption.


 

Distribution
Rapidly distributed into all body fluids and tissues. Large fraction of etoposide (90%–95%) is protein-bound, mainly to albumin. Decreased albumin levels result in a higher fraction of free drug and a potentially higher incidence of host toxicity.


 

Metabolism
Metabolized primarily by the liver via glucuronidation to hydroxy acid metabolites, which are less active than the parent compound. About 30%–50% of etoposide is excreted in urine and about 2%–6% is excreted in stool via biliary excretion. The elimination half-life ranges from 3 to 10 hours.


 

Indications
 

  1. Germ cell tumors.
  2. Small cell lung cancer.
  3. Non–small cell lung cancer.
  4. Non-Hodgkin's lymphoma.
  5. Relapsed Hodgkin's lymphoma.
  6. Gastric cancer.
  7. High-dose therapy in transplant setting for various malignancies, including breast cancer, lymphoma, and ovarian cancer.

 


 

Dosage Range
 

  1. IV: Testicular cancer―As part of the PEB regimen, 100 mg/m2 IV on days 1–5 with cycles repeated every 3 weeks.
  2. IV: Small cell lung cancer―As part of cisplatin/VP-16 regimen, 100–120 mg/m2 IV on days 1–3 with cycles repeated every 3 weeks.
  3. Small cell lung cancer―50 mg/m2/day PO for 21 days.

 


 

Drug Preparation
 

  • Available in 50 or 100 mg capsules for oral use and in 100 mg vials for IV use.
  • Vial is reconstituted with 5 mL or 10 mL normal saline, 5% dextrose, or sterile water with benzyl alcohol to 20 mg/mL or 10 mg/mL, respectively.
  • May be further diluted to 0.9% sodium chloride or 5% dextrose to a final concentration of 0.1 mg/mL.

 


 

Drug Interactions
Warfarin―Etoposide may alter the anticoagulant effect of warfarin by prolonging the prothrombin time and INR. Coagulation parameters (PT and INR) need to be closely monitored and dose of warfarin may require adjustment.


 

Special Considerations
 

  1. Use with caution in patients with abnormal renal function. Dose reduction is recommended in patients with renal dysfunction. Baseline creatinine clearance should be obtained and renal status should be carefully monitored during therapy.
  2. Use with caution in patients with abnormal liver function. Dose reduction is recommended in this setting.
  3. Administer drug over a period of at least 30–60 minutes to avoid the risk of hypotension. Should the blood pressure drop, immediately discontinue the drug and administer IV fluids. Rate of administration must be reduced upon restarting therapy.
  4. Carefully monitor for anaphylactic reactions. More commonly observed during the initial infusion of therapy and probably related to the polysorbate 80 vehicle in which the drug is formulated. In rare instances, such an allergic reaction can be fatal. The drug should be immediately stopped and treatment with antihistamines, steroids, H2 blockers such as cimetidine, and pressor agents should be administered.
  5. Closely monitor injection site for signs of phlebitis and avoid extravasation.
  6. Pregnancy category D.

 


 

Toxicity 1
Myelosuppression. Dose-limiting toxicity with leukopenia more common than thrombocytopenia. Nadir usually occurs 10–14 days after therapy with recovery by day 21.
 


 

Toxicity 2
Nausea and vomiting. Occur in about 30%–40% of patients and generally mild to moderate. More commonly observed with oral administration.
 


 

Toxicity 3
Anorexia.
 


 

Toxicity 4
Alopecia observed in nearly two-thirds of patients.
 


 

Toxicity 5
Mucositis and diarrhea are unusual with standard doses but more often observed with high doses in transplant setting.
 


 

Toxicity 6
Hypersensitivity reaction with chills, fever, bronchospasm, dyspnea, tachycardia, facial and tongue swelling, and hypotension. Occurs in less than 2% of patients.
 


 

Toxicity 7
Metallic taste during infusion of drug.
 


 

Toxicity 8
Local inflammatory reaction at injection site.
 


 

Toxicity 9
Radiation recall skin changes.
 


 

Toxicity 10
Increased risk of secondary malignancies, especially acute myelogenous leukemia. Associated with 11:23 translocation. Typically develops within 5–8 years of treatment and in the absence of preceding myelodysplastic syndrome.
 


 

Toxicity 11
Peripheral neuropathy is rare.