No

Antineoplastic Agent, Natural Source (Plant) Derivative

Treatment of lymphomas, ANLL, lung, testicular, bladder, and prostate carcinoma, hepatoma, rhabdomyosarcoma, uterine carcinoma, neuroblastoma, mycosis fungoides, Kaposi's sarcoma, histiocytosis, gestational trophoblastic disease, Ewing's sarcoma, Wilms' tumor, and brain tumors

D

Hypersensitivity to etoposide or any component; I.T. administration is contraindicated

The U.S. Food and Drug Administration (FDA) currently recommends that procedures for proper handling and disposal of antineoplastic agents be considered. Severe myelosuppression with resulting infection or bleeding may occur.

>10%:

Dermatologic: Alopecia (reversible)

Gastrointestinal: Occasional diarrhea and infrequent nausea and vomiting at standard doses; severe mucositis occurs with high (BMT) doses, anorexia

Emetic potential: Moderately low (10% to 30%)

Hematologic: Myelosuppressive: Principal dose-limiting toxicity of VP-16. White blood cell count nadir is 5-15 days after administration and is more frequent than thrombocytopenia. Recovery is usually within 24-28 days and cumulative toxicity has not been noted with VP-16 as a single agent. No difference in toxicity is seen when VP-16 is administered over a 24-hour period or over 2 hours on 5 consecutive days.

WBC: Mild to severe

Platelets: Mild

Onset (days): 10

Nadir (days): granulocytes 7-14 days; platelets 9-16 days

Recovery (days): 21-28

1% to 10%:

Cardiovascular: Hypotension: Related to drug infusion time; may be related to vehicle used in the I.V. preparation (polysorbate 80 plus polyethylene glycol); best to administer the drug over 1 hour

Central nervous system: Unusual fatigue

Gastrointestinal: Stomatitis, diarrhea, abdominal pain, hepatitic dysfunction

<1%: Irritant chemotherapy, tachycardia, unusual tiredness, thrombophlebitis has been reported, toxic hepatitis (with high-dose therapy), reports of flushing or bronchospasm, which did not reoccur in one report if patients were pretreated with corticosteroids and antihistamine, peripheral neuropathy

Symptoms of overdose include bone marrow depression, leukopenia, thrombocytopenia, nausea, vomiting

CYP3A3/4 enzyme substrate

Warfarin may elevate prothrombin time with concurrent use

Methotrexate: Alteration of MTX transport has been found as a slow efflux of MTX and its polyglutamated form out of the cell, leading to intercellular accumulation of MTX

Calcium antagonists: Increases the rate of VP-16-induced DNA damage and cytotoxicity in vitro

Carmustine: Reports of frequent hepatic dysfunction with hyperbilirubinemia, ascites, and thrombocytopenia

Cyclosporine: Additive cytotoxic effects on tumor cells

Store intact vials of injection at room temperature and protected from light; injection solution contains polyethylene glycol vehicle with absolute alcohol; store oral capsules under refrigeration

VP-16 should be further diluted in D₅W or NS for administration; diluted solutions have CONCENTRATION-DEPENDENT stability: More concentrated solutions have shorter stability times

At room temperature in D₅W or NS in polyvinyl chloride, the concentration is stable as follows:

0.2 mg/mL: 96 hours

0.4 mg/mL: 48 hours

0.6 mg/mL: 8 hours

1 mg/mL: 2 hours

2 mg/mL: 1 hour

20 mg/mL (undiluted): 24 hours

Y-site compatible with carboplatin, cytarabine, daunorubicin, mesna

Standard I.V. dilution:

Lower dose regimens (<1 g/dose):

Doses may be diluted in 100-1000 mL of D₅W or NS

If the concentration is less than or equal to 0.6 mg/mL, the bag should be mixed with the appropriate expiration dating

If the concentration is >0.6 mg/mL, the concentration is highly unstable and a syringe of UNDILUTED etoposide accompanied with the appropriate volume of diluent will be sent to the nursing unit to be mixed by the nursing staff just prior to administration

High dose regimens (>1g/dose):

Total dose should be drawn into an empty viaflex container and the appropriate amount of diluent (for a final concentration of 1 mg/mL) will be sent

Use the 2-Channel Pump Method: Instill all of the etoposide dose into one viaflex container (concentration = 20 mg/mL). Infuse this into one channel (Baxter Flow-Guard 6300 Dual Channel Volumetric Infusion Pump - or any 2-channel infusion pump that does not require a "hard" plastic cassette). Infuse the indicated diluent (ie, D₅W or NS) at a rate of at least 20 times the infusion rate of the etoposide to simulate a 1 mg/mL concentration in the line. The etoposide should be Y-sited into the port most proximal to the patient. A 0.22 micron filter should be attached to the line after the Y-site and before entry into the patient.

Inhibits mitotic activity; inhibits cells from entering prophase; inhibits DNA synthesis. Initially thought to be mitotic inhibitors similar to podophyllotoxin, but actually have no effect on microtubule assembly. However, later shown to induce DNA strand breakage and inhibition of topoisomerase II (an enzyme which breaks and repairs DNA); etoposide acts in late S or early G2 phases.

Absorption: Oral: 32% to 57%

Distribution: Poor penetration across blood-brain barrier, with concentrations in the CSF being <10% that of plasma; Average V_d: 3-36 L/m²

Protein binding: 94% to 97%

Metabolism: In the liver (with a biphasic decay)

Half-life: Terminal: 4-15 hours; Children: 6-8 hours with normal renal and hepatic function

Time to peak serum concentration: Oral: 1-1.5 hours

Elimination: Both unchanged drug and metabolites are excreted in the urine and a small amount (2% to 16%) excreted in feces; up to 55% of an I.V. dose is excreted unchanged in urine in children

Refer to individual protocols:

Children: I.V.: 60-120 mg/m²/day for 3-5 days every 3-6 weeks

AML:

Remission induction: 150 mg/m²/day for 2-3 days for 2-3 cycles

Intensification or consolidation: 250 mg/m²/day for 3 days, courses 2-5

Brain tumor: 150 mg/m²/day on days 2 and 3 of treatment course

Neuroblastoma: 100 mg/m²/day over 1 hour on days 1-5 of cycle; repeat cycle every 4 weeks

BMT conditioning regimen used in patients with rhabdomyosarcoma or neuroblastoma: I.V. continuous infusion: 160 mg/m²/day for 4 days

Conditioning regimen for allogenic BMT: 60 mg/kg/dose as a single dose

Adults:

Small cell lung cancer:

Oral: Twice the I.V. dose rounded to the nearest 50 mg given once daily if tolerated

I.V.: 35 mg/m²/day for 4 days or 50 mg/m²/day for 5 days every 3-4 weeks total dose less than or equal to 400 mg/day or in divided doses if >400 mg/day

IVPB: 60-100 mg/m²/day for 3 days (with cisplatin)

CIV: 500 mg/m² over 24 hours every 3 weeks

Testicular cancer:

IVPB: 50-100 mg/m²/day for 5 days repeated every 3-4 weeks

I.V.: 100 mg/m² every other day for 3 doses repeated every 3-4 weeks

BMT/relapsed leukemia: I.V.: 2.4-3.5 g/m² or 25-70 mg/kg administered over 4-36 hours

Dosing adjustment in renal impairment:

Cl_cr 10-50 mL/minute: Administer 75% of normal dose

Cl_cr <10 mL minute: Administer 50% of normal dose

Hemodialysis: Supplemental dose is not necessary

Peritoneal dialysis: Supplemental dose is not necessary

CAPD effects: Unknown

CAVH effects: Unknown

Dosing adjustment in hepatic impairment:

Bilirubin 1.5-3 mg/dL or AST 60-180 units: Reduce dose by 50%

Bilirubin 3-5 mg/dL or AST >180 units: Reduce by 75%

Bilirubin >5 mg/dL: Do not administer

Administration of food does not affect GI absorption with doses less than or equal to 200 mg of injection

CBC with differential, platelet count, and hemoglobin, vital signs (blood pressure), bilirubin, and renal function tests

May cause sedation

May cause myelosuppression; use caution with clozapine and carbamazepine

No information available to require special precautions

No effects or complications reported

During therapy, do not use alcohol, aspirin-containing products, and OTC medications without consulting prescriber. It is important to maintain adequate nutrition and hydration (2-3 L/day of fluids unless instructed to restrict fluid intake) during therapy; frequent small meals may help. You may experience mild nausea or vomiting (frequent small meals, frequent mouth care, sucking lozenges, or chewing gum may help). You may experience loss of hair (reversible); you will be more susceptible to infection (avoid crowds and exposure to infection as much as possible). Yogurt or buttermilk may help reduce diarrhea. Frequent mouth care and use of a soft toothbrush or cotton swabs may help prevent mouth sores. This drug may cause sterility or birth defects. Report extreme fatigue, pain or numbness in extremities, severe GI upset or diarrhea, bleeding or bruising, fever, chills, sore throat, vaginal discharge, difficulty breathing, yellowing of eyes or skin, and any changes in color of urine or stool. Pregnancy/breast-feeding precautions: Do not get pregnant while taking this medication; use appropriate barrier contraceptive measures. Do not breast-feed while taking this medication and for several weeks after last dose.

Extravasation treatment:

Inject 150-900 units of hyaluronidase S.C. clockwise into the infiltrated area using a 25-gauge needle; change the needle with each injection; apply heat immediately for 1 hour, repeat 4 times/day for 3-5 days

Application of cold or hydrocortisone is contraindicated.

If necessary, the injection may be used for oral administration; mix with orange juice, apple juice, or lemonade to a concentration of 0.4 mg/mL or less, and use within a 3-hour period

Capsule: 50 mg

Injection: 20 mg/mL (5 mL, 10 mL, 25 mL, 50 mL)

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Berg SL, Grisell DL, DeLaney TF, et al, "Principles of Treatment of Pediatric Solid Tumors," Pediatr Clin North Am, 1991, 38(2):249-67.

Boos J, Krümpelmann S, Schulze-Westhoff P, et al, "Steady-State Levels and Bone Marrow Toxicity of Etoposide in Children and Infants: Does Etoposide Require Age-Dependent Dose Calculation?" J Clin Oncol, 1995, 13(12):2954-60.

Clark PL and Slevin ML, "The Clinical Pharmacology of Etoposide and Teniposide," Clin Pharmacokinet, 1987, 12(4):223-52.

Comis RL, "Oral Etoposide in Oncology: An Evolving Role," Ann Oncol, 1992, 3(Suppl 3):63-7.

Hainsworth JD and Greco FA, "Etoposide: Twenty Years Later," Ann Oncol, 1995, 6(4):325-41.

Jeffrey LP, Chairman, National Study Commission on Cytotoxic Exposure. Position Statement. "The Handling of Cytotoxic Agents by Women Who Are Pregnant, Attempting to Conceive, or Breast-Feeding," January 12, 1987.

Joel SP, Shah R, and Slevin ML, "Etoposide Dosage and Pharmacodynamics," Cancer Chemother Pharmacol, 1994, 34(Suppl):S69-75.

Lazarus HM, Creger RJ, and Diaz D, "Simple Method for the Administration of High-Dose Etoposide During Autologous Bone Marrow Transplantation," Cancer Treat Rep, 1985, 70(6):819-20.

Nishikawa A, Nakamura Y, Nobori U, et al, "Acute Monocytic Leukemia in Children. Response to VP-16-213 as a Single Agent," Cancer, 1987, 60(9):2146-9.

O'Dwyer PJ, Leyland-Jones B, Alonso MT, et al, "Etoposide (VP-16-213): Current Status of an Active Anticancer Drug," N Engl J Med, 1985, 312(11):692-700.