|Toposar® Injection; VePesid®
Epipodophyllotoxin; VP-16; VP-16-213|
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
Hypersensitivity to etoposide or any component; I.T. administration is
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
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
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
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
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
Absorption: Oral: 32% to 57%
Distribution: Poor penetration across blood-brain barrier, with
concentrations in the CSF being <10% that of plasma; Average Vd:
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
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
Remission induction: 150 mg/m2/day for 2-3 days for 2-3 cycles
Intensification or consolidation: 250 mg/m2/day for 3 days,
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
Small cell lung cancer:
Oral: Twice the I.V. dose rounded to the nearest 50 mg given once daily if
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
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
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:
Clcr 10-50 mL/minute: Administer 75% of normal dose
Clcr <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
|Mental Health: Effects
on Mental Status|
May cause sedation
Effects on Psychiatric
May cause myelosuppression; use caution with clozapine and
|Dental Health: Local
No information available to require special precautions
Effects on Dental Treatment|
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
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)
Belani CP, Doyle LA, and Aisner J,
"Etoposide: Current Status and Future Perspectives in the Management of Malignant Neoplasms,"
Cancer Chemother Pharmacol, 1994, 34(Suppl): S118-26.
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.
"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.
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