EtoposideU.S. Brand Names: Toposar�(r); VePesid�(r)
Synonyms: Epipodophyllotoxin; VP-16; VP-16-213
Generic Available: Yes
Canadian Brand Names: VePesid�(r)
Use: 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
Pregnancy Risk Factor: D
Lactation: Enters breast milk/contraindicated
Contraindications: Hypersensitivity to etoposide or any component of the formulation; intrathecal administration; pregnancy
Warnings/Precautions: 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. Dosage should be adjusted in patients with hepatic or renal impairment. Etoposide preparation should be performed in a Class II laminar flow biologic safety cabinet. Personnel should be wearing surgical gloves and a closed front surgical gown with knit cuffs. Appropriate safety equipment is recommended for preparation, administration, and disposal of antineoplastics. If etoposide contacts the skin, wash and flush thoroughly with water.
Adverse Reactions: >10%: Cardiovascular: Hypotension if the drug is infused too fast Dermatologic: Alopecia (22% to 93%) Endocrine & metabolic: Ovarian failure (38%), amenorrhea Gastrointestinal: Mild to moderate nausea and vomiting; mucositis, especially at high doses; anorexia (10% to 13%) Hematologic: Myelosuppression, leukopenia (91%), thrombocytopenia (41%), anemia Onset: 5-7 days Nadir: 7-14 days Recovery: 21-28 days 1% to 10%: Gastrointestinal: Stomatitis (1% to 6%), diarrhea (1% to 13%), abdominal pain Neuromuscular & skeletal: Peripheral neuropathies (0.7% to 2%) <1%: Tachycardia, CHF, MI, somnolence, fatigue, headache, anovulatory cycles, hypomenorrhea, hepatitis, thrombophlebitis, anaphylactoid reactions (chills, fever, bronchospasm, dyspnea, hypotension); possibly related to rapid infusion (0.7% to 2%)
Overdosage/Toxicology: Symptoms of overdose include bone marrow suppression, leukopenia, thrombocytopenia, nausea, and vomiting. Treatment is supportive.
Drug Interactions: Substrate of CYP1A2 (minor), 2E1 (minor), 3A4 (major); Inhibits CYP2C8/9 (weak), 3A4 (weak) 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. CYP3A4 inducers: CYP3A4 inducers may decrease the levels/effects of etoposide. Example inducers include aminoglutethimide, carbamazepine, nafcillin, nevirapine, phenobarbital, phenytoin, and rifamycins. CYP3A4 inhibitors: May increase the levels/effects of etoposide. Example inhibitors include azole antifungals, ciprofloxacin, clarithromycin, diclofenac, doxycycline, erythromycin, imatinib, isoniazid, nefazodone, nicardipine, propofol, protease inhibitors, quinidine, and verapamil. Methotrexate: Alteration of methotrexate transport has been found as a slow efflux of methotrexate and its polyglutamated form out of the cell, leading to intercellular accumulation of methotrexate. Warfarin may elevate prothrombin time with concurrent use.
Ethanol/Nutrition/Herb Interactions: Ethanol: Avoid ethanol (may increase GI irritation). Food: Administration of food does not affect GI absorption with doses
200 mg of injection. Herb/Nutraceutical: St John's wort may decrease etoposide levels.
Stability: 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�(r) 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.
Compatibility: Stable in D5W, LR; variable stability (consult detailed reference) in NS Y-site administration: Compatible: Allopurinol, amifostine, aztreonam, cladribine, doxorubicin liposome, fludarabine, gemcitabine, granisetron, melphalan, ondansetron, paclitaxel, piperacillin/tazobactam, sargramostim, sodium bicarbonate, teniposide, thiotepa, topotecan, vinorelbine. Incompatible: Cefepime, filgrastim, idarubicin Compatibility when admixed: Compatible: Carboplatin, cisplatin, cisplatin with cyclophosphamide, cisplatin with floxuridine, cytarabine, cytarabine with daunorubicin, floxuridine, fluorouracil, hydroxyzine, ifosfamide, ifosfamide with carboplatin, ifosfamide with cisplatin, ondansetron. Variable (consult detailed reference): Cisplatin with mannitol and potassium chloride, doxorubicin with vincristine
Mechanism of Action: Etoposide does not inhibit microtubular assembly. It has been shown to delay transit of cells through the S phase and arrest cells in late S or early G2 phase. The drug may inhibit mitochondrial transport at the NADH dehydrogenase level or inhibit uptake of nucleosides into HeLa cells. Etoposide is a topoisomerase II inhibitor and appears to cause DNA strand breaks.
Pharmacodynamics/Kinetics: Absorption: Oral: 25% to 75%; significant inter- and intrapatient variation Distribution: Average Vd: 3-36 L/m2; poor penetration across the blood-brain barrier; CSF concentrations <10% of plasma concentrations Protein binding: 94% to 97% Metabolism: Hepatic to hydroxy acid and cislactone metabolites Half-life elimination: Terminal: 4-15 hours; Children: Normal renal/hepatic function: 6-8 hours Time to peak, serum: Oral: 1-1.5 hours Excretion: Children: Urine (
55% as unchanged drug) Adults: Urine (42% to 67%; 8% to 35% as unchanged drug) within 24 hours; feces (up to 16%)
Dosage: 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 total dose
400 mg or in divided doses if >400 mg I.V.: 35 mg/m2/day for 4 days or 50 mg/m2/day for 5 days every 3-4 weeks total dose
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: 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: Oral: Doses should be rounded to the nearest 50 mg; doses
400 mg/day should be given as a single daily dose. Doses
400 mg/day should be given in 2-4 divided doses. I.V.: As a bolus or 24-hour continuous infusion; bolus infusions are usually administered over at least 45-60 minutes. Infusion of doses in
30 minutes greatly increases the risk of hypotension. Extravasation management: Inject 150-900 units of hyaluronidase SubQ 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.
Monitoring Parameters: CBC with differential, platelet count, and hemoglobin, vital signs (blood pressure), bilirubin, and renal function tests
Patient Education: Inform prescriber of all prescriptions, OTC medications, or herbal products you are taking, and any allergies you have. Do not take any new medication during therapy unless approved by prescriber. This medication may be administered by infusion. Report immediately any swelling, pain, burning, or redness at infusion site. Avoid alcohol. It is important to maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake, and adequate nutrition (small, frequent meals may help). You will be more susceptible to infection (avoid crowds and exposure to infection and do not have any vaccinations without consulting prescriber). May cause nausea or vomiting (small, frequent meals, frequent mouth care, sucking lozenges, or chewing gum may help); diarrhea (buttermilk, boiled milk, or yogurt may help); loss of hair (reversible); or mouth sores (use soft toothbrush or cotton swabs for oral care and rinse mouth frequently). Report immediately chest pain, swelling of extremities, respiratory difficulty, palpitations, or rapid heartbeat. Report extreme fatigue, pain or numbness in extremities, severe GI upset or diarrhea, bleeding or bruising, fever, chills, sore throat, vaginal discharge, respiratory difficulty, yellowing of eyes or skin, or any changes in color of urine or stool. Pregnancy/breast-feeding precautions: Do not get pregnant while taking this medication. Consult prescriber for appropriate contraceptive measures to use during and for 1 month following therapy. Do not breast-feed.
Dental Health: Effects on Dental Treatment: Key adverse event(s) related to dental treatment: Mucositis (especially at high doses).
Dental Health: Vasoconstrictor/Local Anesthetic Precautions: No information available to require special precautions
Mental Health: Effects on Mental Status: May cause sedation
Mental Health: Effects on Psychiatric Treatment: May cause myelosuppression; use caution with clozapine and carbamazepine
Oncology: Emetic Potential: Mild (10% to 30%)
Oncology: Vesicant: No; considered an irritant
Oncology: Bone Marrow Comments: The etoposide formulation contains ethanol 30.3% (v/v). Etoposide 2.4 mg/m2 delivers ethanol 45 g/m2 I.V. Adverse effects may be increased with administration of etoposide to patients with decreased creatinine clearance. Etoposide 400-1600 mg/m2 has been drawn into plastic syringes undiluted (20 mg/mL) for administration over 3-4 hours. Etoposide 800 mg/m2 was pharmacokinetically equivalent to etoposide phosphate 910 mg/m2 in patients with refractory hematologic malignancies.
Oncology: Bone Marrow - High Dose: I.V.: 750-2400 mg/m2; 10-60 mg/kg; duration of infusion is 1-4 hours to 24 hours; generally combined with other high-dose chemotherapeutic drugs or total body irradiation (TBI).
Oncology: Bone Marrow - Unique Toxicity: Cardiovascular: Hypotension (infusion-related) Central nervous system: Confusion, somnolence, seizure activity increased Dermatologic: Skin lesions resembling Stevens-Johnson syndrome, alopecia Endocrine & metabolic: Metabolic acidosis, parotitis Gastrointestinal: Severe nausea and vomiting, mucositis Hepatic: Hepatitis Neuromuscular & skeletal: Peripheral neuropathy, motor deficits exacerbated Miscellaneous: Secondary malignancy, ethanol intoxication
Dosage Forms: Capsule, softgel (VePesid�(r)): 50 mg Injection, solution: 20 mg/mL (5 mL, 25 mL, 50 mL) [may contain benzyl alcohol or alcohol] Toposar�(r): 20 mg/mL (5 mL, 10 mL, 25 mL) [contains benzyl alcohol] VePesid�(r): 20 mg/mL (5 mL, 7.5 mL, 25 mL, 50 mL) [contains benzyl alcohol and alcohol 30%]
References: 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):118-26. 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. Dorr RT, Briggs A, Kintzel P, et al, "Comparative Pharmacokinetic Study of High-Dose Etoposide and Etoposide Phosphate in Patients With Lymphoid Malignancy Receiving Autologous Stem Cell Transplantation,"Bone Marrow Transplant, 2003, 31(8):643-9. Hainsworth JD and Greco FA, "Etoposide: Twenty Years Later,"Ann Oncol, 1995, 6(4):325-41. Joel SP, Shah R, and Slevin ML, "Etoposide Dosage and Pharmacodynamics,"Cancer Chemother Pharmacol, 1994, 34(Suppl):69-75. 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.
International Brand Names: Asta Medica Etoposido�(r) (BR); Celltop�(r) (FR); Citodox�(r) (AR); Cytosafe Etoposide�(r) (ID); DBL Etoposide�(r) (TH); Eposin�(r) (BE, ES, GB, NL, NO, SE, TH, TR); Etocris�(r) (AR); Eto CS�(r) (DE); Eto-GRY�(r) (DE); Etomedac�(r) (DE); Etopofos�(r) (AR, AT, DK, FI, NO, SE); Etopophos�(r) (AU, CH, DE, FR, GB, IL, NL, NZ, PL, YU, ZA); Etoposide Abbott�(r) (ID); Etoposide Abic�(r) (TH); Etoposide�(r) (AU, GB, HR, IL, NZ, PL, RO, RU, TR, YU); Etoposid Ebewe�(r) (AT, CH, CZ, DK, HU, ID, PL, RO, RU, TH, TR, YU); Etoposide Bigmar�(r) (CH); Etoposide DBL�(r) (ID, SG); Etoposide Fidia�(r) (IT); Etoposide Pharmacia and Upjohn�(r) (CZ); Etoposide Pharmacia�(r) (AT, CH, DK, FI, SG); Etoposide Pierre Fabre�(r) (CZ, LU, PL, RO); Etoposide Teva�(r) (CZ, FR, HU, IT, PL, TR); Etoposid Hexal�(r) (DE); Etoposid Mayne�(r) (DK); Etoposido Biocrom�(r) (AR); Etoposido�(r) (CL, CO); Etoposido Delta Farma�(r) (AR); Etoposido D.W.�(r) (AR); Etoposido Farmitalia�(r) (AR); Etoposido Ferrer Farma�(r) (ES); Etoposido Filaxis�(r) (AR); Etoposido Varifarma�(r) (AR); Etoposid Pharmacia & Upjohn�(r) (AT); Etopos�(r) [inj.] (BR, MX, RU, TH); Etosid�(r) (IN); Euvaxon�(r) (AR); Exitop�(r) (AT, DE, FI, NO, SE); Fytosid�(r) (TH); Kebedil�(r) (AR); Labimion�(r) (AR); Lastet�(r) (CL, CZ, ES, HU, ID, IN, IT, JP, MX, PL, TR); Neoplaxol�(r) (AR); Onkoposid�(r) (DE); Optasid�(r) (AR); Percas�(r) (AR); Posyd�(r) (ID); Riboposid�(r) (DE); Sintopozid�(r) (PL, RO); VepeGal�(r) (YU); VePesid�(r) (AR, AT, AU, BE); Vepesid�(r) (BG); VePesid�(r) (BR, CA, CH, CN, CZ, DE); Vepesid�(r) (DK); Vepeside-Sandoz�(r) (FR); VePesid�(r) (ES, FI); Vepesid�(r) (GB, HR); VePesid�(r) (HU, ID, IL, IT, LU, MX, NL, NO, NZ, PL, PT, RO); Vepesid�(r) (RU); VePesid�(r) (SE); Vepesid�(r) (SG); VePesid�(r) (SI); Vepesid�(r) (TH); VePesid�(r) (TR); Vepesid�(r) (YU, ZA); VP-16�(r) (CL); VP-Gen�(r) (AR); Vp-Tec�(r) (MX)
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