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ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Pronunciation
(e toe POE side)
Generic Available (U.S.)
Yes
Index Terms
U.S. Brand Names
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Treatment of refractory testicular tumors (injectable formulation); treatment of small cell lung cancer
Use: Unlabeled/Investigational
Treatment of acute lymphocytic leukemia (ALL), refractory acute myeloid leukemia (AML), recurrent or metastatic breast cancer, central nervous system tumors, Ewing's sarcoma, gestational trophoblastic disease, Hodgkin's lymphoma, merkel cell cancer, refractory multiple myeloma, neuroblastoma, neuroendocrine tumors (adrenal gland and carcinoid tumors), non-Hodgkin's lymphomas, nonsmall-cell lung cancer (NSCLC), osteosarcoma, ovarian cancer, prostate cancer, retinoblastoma, metastatic soft tissue sarcoma, thymic malignancies, unknown-primary adenocarcinoma, Wilms' tumor; conditioning regimen for hematopoietic cell transplantation
Pregnancy Risk Factor
D
Pregnancy Considerations
Animal studies have demonstrated teratogenicity and fetal loss. There are no adequate and well-controlled studies in pregnant women. Women of childbearing potential should be advised to avoid pregnancy.
Lactation
Excretion in breast milk unknown/not recommended
Contraindications
Hypersensitivity to etoposide or any component of the formulation
Warnings/Precautions
Boxed warnings:
• Bone marrow suppression: See “Concerns related to adverse effects” below.
• Experienced physician: See “Other warnings/precautions” below.
Special handling:
• Hazardous agent: Use appropriate precautions for handling and disposal.
Concerns related to adverse effects:
• Bone marrow suppression: [U.S. Boxed Warning]: Severe dose-limiting and dose-related myelosuppression with resulting infection or bleeding may occur. Treatment should be withheld for platelets <50,000/mm3 or absolute neutrophil count (ANC) <500/mm3.
• Hypersensitivity reaction: May cause anaphylactic-like reactions manifested by chills, fever, tachycardia, bronchospasm, dyspnea, and hypotension. In addition, facial/tongue swelling, coughing, chest tightness, cyanosis, laryngospasm, diaphoresis, hypertension, and flushing have also been reported less commonly. Incidence is primarily associated with intravenous administration (up to 2%) compared to oral administration (<1%). Infusion should be interrupted and medications for the treatment of anaphylaxis should be available for immediate use. High drug concentration and rate of infusion, as well as presence of polysorbate 80 and benzyl alcohol in the etoposide intravenous formulation, have been suggested as contributing factors to the development of hypersensitivity reactions. Etoposide intravenous formulations may contain polysorbate 80 and/or benzyl alcohol, while etoposide phosphate (the water soluble prodrug of etoposide) intravenous formulation does not contain either vehicle. Case reports have suggested that etoposide phosphate has been used successfully in patients with previous hypersensitivity reactions to etoposide (Collier, 2008; Siderov, 2002).
• Hypotension: Hypotension may occur due to rapid administration; infuse slowly over at least 30-60 minutes. If hypotension occurs, interrupt infusion and administer I.V. hydration and supportive care; decrease infusion upon reinitiation.
• Secondary malignancies: Secondary acute leukemias have been reported with etoposide, either as monotherapy or in combination with other chemotherapy agents.
Disease-related concerns:
• Hepatic impairment: Use with caution in patients with hepatic impairment; dosage should be adjusted.
• Hypoalbuminemia: Use with caution in patients with low serum albumin; may increase risk for toxicities.
• Renal impairment: Use with caution in patients with renal impairment; dosage should be adjusted.
Special populations:
• Elderly: Use with caution in elderly patients; may be more likely to develop severe myelosuppression and/or GI effects.
• Pediatrics: The use of concentrations higher than recommended were associated with higher rates of anaphylactic-like reactions in children.
Dosage form specific issues:
• Benzyl alcohol: Injectable formulation may contain benzyl alcohol, which has been associated with "gasping syndrome" in neonates. Benzyl alcohol may also play a role in the development of hypersensitivity reactions occurring with intravenous administration.
• Polysorbate 80: Injectable formulation contains polysorbate 80; do not use in premature infants. Polysorbate 80 may also play a role in the development of hypersensitivity reactions occurring with intravenous administration.
Other warnings/precautions:
• Administration: Must be diluted; do not give I.V. push, infuse over at least 30-60 minutes; hypotension is associated with rapid infusion.
• Experienced physician: [U.S. Boxed Warning]: Should be administered under the supervision of an experienced cancer chemotherapy physician.
Adverse Reactions
Note: The following may occur with higher doses used in stem cell transplantation: Alopecia, ethanol intoxication, hepatitis, hypotension (infusion-related), metabolic acidosis, mucositis, nausea and vomiting (severe), secondary malignancy, skin lesions (resembling Stevens-Johnson syndrome).
>10%:
Dermatologic: Alopecia (8% to 66%)
Gastrointestinal: Nausea/vomiting (31% to 43%), anorexia (10% to 13%), diarrhea (1% to 13%)
Hematologic: Leukopenia (60% to 91%; grade 4: 3% to 17%; nadir: 7-14 days; recovery: by day 20), thrombocytopenia (22% to 41%; grades 3/4: 1% to 20%; nadir 9-16 days; recovery: by day 20), anemia (≤33%)
1% to 10%:
Cardiovascular: Hypotension (1% to 2%; due to rapid infusion)
Gastrointestinal: Stomatitis (1% to 6%), abdominal pain (up to 2%)
Hepatic: Hepatic toxicity (up to 3%)
Neuromuscular & skeletal: Peripheral neuropathy (1% to 2%)
Miscellaneous: Anaphylactic-like reaction (I.V. infusion 1% to 2%; oral capsules <1%; including chills, fever, tachycardia, bronchospasm, dyspnea)
<1%, postmarketing, and/or case reports: Amenorrhea, back pain, blindness (transient/cortical), constipation, cough, cyanosis, diaphoresis, dysphagia, erythema, esophagitis, extravasation (induration/necrosis), facial swelling, fatigue, fever, hyperpigmentation, hypersensitivity, hypersensitivity-associated apnea, interstitial pneumonitis, laryngospasm, maculopapular rash, malaise, metabolic acidosis, MI, mucositis, myocardial ischemia, optic neuritis, ovarian failure, perivasculitis, pruritus, pulmonary fibrosis, radiation-recall dermatitis, rash, reversible posterior leukoencephalopathy syndrome (RPLS), seizure, somnolence, Stevens-Johnson syndrome, tongue swelling, toxic epidermal necrolysis, toxic megacolon, urticaria, vasospasm, weakness
Metabolism/Transport Effects
Substrate of CYP1A2 (minor), CYP2E1 (minor), CYP3A4 (major), P-glycoprotein; Inhibits CYP2C9 (weak), 3A4 (weak)
Drug Interactions
Atovaquone: May increase the serum concentration of Etoposide. Management: Separate administration of atovaquone and etoposide by at least 1-2 days. Avoid concomitant administration of atovaquone and etoposide. Risk D: Consider therapy modification
Barbiturates: May decrease the serum concentration of Etoposide. Risk C: Monitor therapy
BCG: Immunosuppressants may diminish the therapeutic effect of BCG. Risk X: Avoid combination
Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Management: Upon completion/discontinuation of conivaptan, allow at least 7 days before initiating therapy with drugs that are CYP3A4 substrates. Risk D: Consider therapy modification
CycloSPORINE: May increase the serum concentration of Etoposide. Management: Consider reducing the dose of etoposide by 50% if the patient is receiving, or has recently received, cyclosporine. Monitor for increased toxic effects of etoposide if cyclosporine is initiated, the dose is increased, or it has been recently discontinued. Risk D: Consider therapy modification
CycloSPORINE (Systemic): May decrease the metabolism of Etoposide. Management: Consider reducing the dose of etoposide by 50% if the patient is receiving, or has recently received, cyclosporine. Monitor for increased toxic effects of etoposide if cyclosporine is initiated, the dose is increased, or it has been recently discontinued. Risk D: Consider therapy modification
CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Risk D: Consider therapy modification
Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Risk C: Monitor therapy
Echinacea: May diminish the therapeutic effect of Immunosuppressants. Risk D: Consider therapy modification
Fosphenytoin: May decrease the serum concentration of Etoposide. Risk C: Monitor therapy
Herbs (CYP3A4 Inducers): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Risk D: Consider therapy modification
Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Risk X: Avoid combination
P-Glycoprotein Inducers: May decrease the serum concentration of P-Glycoprotein Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy
P-Glycoprotein Inhibitors: May increase the serum concentration of P-Glycoprotein Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy
Phenytoin: May decrease the serum concentration of Etoposide. Risk C: Monitor therapy
Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Risk X: Avoid combination
Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Risk X: Avoid combination
Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Risk C: Monitor therapy
Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Risk X: Avoid combination
Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Risk C: Monitor therapy
Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Risk C: Monitor therapy
Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Vaccinial infections may develop. Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Risk X: Avoid combination
Vitamin K Antagonists (eg, warfarin): Antineoplastic Agents may enhance the anticoagulant effect of Vitamin K Antagonists. Antineoplastic Agents may diminish the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy
Vitamin K Antagonists (eg, warfarin): Etoposide may enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Ethanol: Avoid ethanol (may increase GI irritation).
Herb/Nutraceutical: Avoid concurrent St John's wort; may decrease etoposide levels.
Storage
Capsules: Store oral capsules under refrigeration at 2°C to 8°C (36°F to 46°F); do not freeze.
Injection: Store intact vials of injection at room temperature of 25°C (77°F); do not freeze. Protect from light. Diluted solutions for infusion, at room temperature, in D5W or NS in polyvinyl chloride, are stable as follows, depending on the concentration:
0.2 mg/mL: 96 hours
0.4 mg/mL: 24 hours
Etoposide injection contains polysorbate 80 which may cause leaching of diethylhexyl phthalate (DEHP), a plasticizer contained in polyvinyl chloride (PVC) bags and tubing. Higher concentrations and longer storage time after preparation in PVC bags may increase DEHP leaching. Preparation in glass or polyolefin containers will minimize patient exposure to DEHP. When undiluted etoposide injection is stored in acrylic or ABS (acrylonitrile, butadiene and styrene) plastic containers, may crack and leak.
Reconstitution
Etoposide should be diluted to a concentration of 0.2-0.4 mg/mL in D5W or NS for administration. Diluted solutions have concentration-dependent stability: More concentrated solutions have shorter stability times. Precipitation may occur with concentrations >0.4 mg/mL. Use appropriate precautions for handling and disposal.
Compatibility
Variable stability (consult detailed reference) in D5W, LR, NS.
Y-site administration: Compatible: Allopurinol, amifostine, aztreonam, cladribine, doxorubicin liposomal, fludarabine, gemcitabine, granisetron, melphalan, methotrexate, micafungin, mitoxantrone, ondansetron, paclitaxel, piperacillin/tazobactam, sargramostim, sodium bicarbonate, teniposide, thiotepa, topotecan, vinorelbine. Incompatible: Cefepime, filgrastim, gallium nitrate, 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 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. It is a topoisomerase II inhibitor and appears to cause DNA strand breaks. Etoposide does not inhibit microtubular assembly.
Pharmacodynamics/Kinetics
Absorption: Oral: Significant inter- and intrapatient variation
Distribution: Average Vd: 7-17 L/m2; poor penetration across the blood-brain barrier; CSF concentrations <5% of plasma concentrations
Protein binding: 94% to 98%
Metabolism: Hepatic, via CYP3A4 and 3A5, to various metabolites; in addition, conversion of etoposide to the O-demethylated metabolites (catechol and quinine) via prostaglandin synthases or myeloperoxidase occurs, as well as glutathione and glucuronide conjugation via GSTT1/GSTP1 and UGT1A1 (Yang, 2009)
Bioavailability: Oral: ~50% (range: 25% to 75%)
Half-life elimination: Terminal: I.V.: 4-11 hours; Children: Normal renal/hepatic function: 6-8 hours
Excretion:
Children: I.V.: Urine (~55% as unchanged drug) in 24 hours
Adults: I.V.: Urine (56%; 45% as unchanged drug) within 120 hours; feces (44%) within 120 hours
Dosage
Details concerning dosing in combination regimens should also be consulted:
Children (unlabeled uses): I.V.:
AML induction (Woods, 1996):
<3 years: 3.3 mg/kg/day continuous infusion for 4 days
≥3 years: 100 mg/m2/day continuous infusion for 4 days
Brain tumor:
<3 years: 6.5 mg/kg/dose days 3 and 4 of each 28-day “B” treatment cycle (Duffner, 1993)
≥3 years: 100 mg/m2/day on days 1, 2, and 3 of a 3-week treatment cycle (Taylor, 2003)
≥6 years: 150 mg/m2/day on days 3 and 4 of a 3-week treatment course (Kovnar, 1990)
Conditioning regimen for hematopoietic stem cell transplantation: 60 mg/kg/dose over 4 hours as a single dose 3 or 4 days prior to transplantation (Horning, 1994; Snyder, 1993)
Hodgkin's lymphoma: 200 mg/m2/day on days 1, 2, and 3 every 3 weeks (Kelly, 2002)
Neuroblastoma:
Induction: 100 mg/m2/day on days 1-5 of each cycle (Kaneko, 2002)
Preconditioning regimen (prior to transplantation): 200 mg/m2/day for 4 days beginning 8 or 9 days prior to transplantation (Kaneko, 2002)
Sarcoma, refractory: 100 mg/m2/day on days 1-5 of cycle; repeat cycle every 21 days (Van Winkle, 2005)
Adults:
Small cell lung cancer (in combination with other chemotherapy agents):
I.V.: 35 mg/m2/day for 4 days, up to 50 mg/m2/day for 5 days every 3-4 weeks
Oral: Due to poor bioavailability, oral doses should be twice the I.V. dose (and rounded to the nearest 50 mg)
Small cell lung cancer, limited stage (unlabeled combination chemotherapy dosing): I.V.: 120 mg/m2/day on days 1, 2, and 3 every 3 weeks for 4 courses (Turrisi, 1999) or 100 mg/m2/day on days 1, 2, and 3 for induction therapy, followed by consolidation chemotherapy (Saito, 2006) or 100 mg/m2/day on days 1, 2, and 3 every 3 weeks up to a maximum of 6 cycles (Skarlos, 2001) or 100 mg/m2/day I.V. on day 1, followed by 200 mg/m2/day orally on days 2 through 4 every 3 weeks for a maximum of 5 courses (Sundstrom, 2002)
Small cell lung cancer, extensive stage (unlabeled combination chemotherapy dosing): 100 mg/m2/day I.V. on day 1, followed by 200 mg/m2/day orally on days 2 through 4 every 3 weeks for a maximum of 5 courses (Sundstrom, 2002) or I.V.: 80 mg/m2/day on days 1, 2, and 3 every 3 weeks up to 8 cycles (Ihede, 1994)
Testicular cancer (in combination with other chemotherapy agents): I.V.: 50-100 mg/m2/day for 1-5 days or 100 mg/m2/day on days 1, 3, and 5 repeated every 3-4 weeks
Testicular cancer (unlabeled combination chemotherapy dosing):
Nonseminoma: I.V.: 100 mg/m2/day on days 1 through 5 every 21 days for 3-4 courses (Saxman, 1998)
Nonseminoma, metastatic (high-dose regimens): I.V.: 750 mg/m2/day administered 5, 4, and 3 days before peripheral blood stem cell infusion, repeat for a second cycle after recovery of granulocyte and platelet counts (Einhorn, 2007) or 400 mg/m2/day (beginning on cycle 3) on days 1, 2, and 3, with peripheral blood stem cell support, administered at 14- to 21-day intervals for 3 cycles (Kondagunta, 2007)
Lymphoid malignancies, conditioning regimen for hematopoietic cell transplantation (unlabeled use): I.V.: 60 mg/kg over 4 hours as a single dose 3 or 4 days prior to transplantation (Horning, 1994; Snyder, 1993; Weaver, 2004)
Dosing adjustment in renal impairment:
The FDA-approved labeling recommends the following adjustments:
Clcr >50 mL/minute: No adjustment required.
Clcr 15-50 mL/minute: Administer 75% of dose
Clcr <15 mL minute: Data not available; consider further dose reductions
The following guidelines have been used by some clinicians:
Aronoff, 2007:
Clcr 10-50 mL/minute: Children and Adults: Administer 75% of dose
Clcr <10 mL minute: Children and Adults: Administer 50% of dose
Hemodialysis:
Children: Administer 50% of dose
Adults: Supplemental dose is not necessary
Peritoneal dialysis:
Children: Administer 50% of dose
Adults: Supplemental dose is not necessary
Continuous renal replacement therapy (CRRT):
Children: Administer 75% of dose and reduce for hyperbilirubinemia
Adults: Administer 75% of dose
Kintzel, 1995:
Clcr 46-60 mL/minute: Administer 85% of dose
Clcr 31-45 mL/minute: Administer 80% of dose
Clcr ≤30 mL/minute: Administer 75% of dose
Dosing adjustment in hepatic impairment: The FDA-approved labeling does not contain dosing adjustment guidelines. The following adjustments have been used by some clinicians:
Donelli, 1998: Liver dysfunction may reduce the metabolism and increase the toxicity of etoposide. Normal doses of I.V. etoposide should be given to patients with liver dysfunction (dose reductions may result in subtherapeutic concentrations); however, use caution with concomitant liver dysfunction (severe) and renal dysfunction as the decreased metabolic clearance cannot be compensated by increased renal clearance.
Floyd, 2006: Bilirubin 1.5-3 mg/dL or AST >3 times ULN: Administer 50% of dose
King, 2001; Koren, 1992: Bilirubin 1.5-3 mg/dL or AST >180 units/L: Administer 50% of dose
Dosage: Combination Regimens
Brain tumors:
CDDP/VP-16
COPE
Breast cancer: ICE-T
Gestational trophoblastic tumor:
EMA/CO
EP/EMA
Leukemia, acute lymphocytic: Hyper-CVAD (Leukemia, Acute Lymphocytic)
Leukemia, acute myeloid:
7 + 3 + 7
EMA 86
MV
Lung cancer (small cell):
CAVE
EC (Small Cell Lung Cancer)
EP (Small Cell Lung Cancer)
VIP (Small Cell Lung Cancer)
VP (Small Cell Lung Cancer)
Lung cancer (nonsmall cell):
Cisplatin-Etoposide (NSCLC)
EC (NSCLC)
EP (NSCLC)
EP/PE
Lymphoma, Hodgkin's disease:
BEACOPP-14 (Hodgkin's Lymphoma)
BEACOPP Escalated (Hodgkin's Lymphoma)
BEACOPP Standard (Hodgkin's Lymphoma)
mini-BEAM
Stanford V Regimen
VIM-D (Hodgkin's Lymphoma)
Lymphoma, non-Hodgkin's:
CEPP(B)
CODOX-M/IVAC
EPOCH Dose-Adjusted (AIDS-Related Lymphoma)
EPOCH Dose-Adjusted (NHL)
EPOCH (Dose-Adjusted)-Rituximab (NHL)
EPOCH (NHL)
EPOCH-Rituximab (NHL)
ESHAP
ICE (Lymphoma, non-Hodgkin's)
IMVP-16
MINE
MINE-ESHAP
Pro-MACE-CytaBOM
RICE
Lymphoma, non-Hodgkin's (Burkitt's): CODOX-M/IVAC
Multiple myeloma: DTPACE
Neuroblastoma:
CAV-P/VP
CDDP/VP-16
CE-CAdO
CE (Neuroblastoma)
HIPE-IVAD
N6 Protocol
Regimen A2
Osteosarcoma: ICE (Sarcoma)
Ovarian cancer:
BEP (Ovarian Cancer)
BEP (Ovarian Cancer, Testicular Cancer)
Etoposide-Carboplatin (Ovarian Cancer)
Prostate cancer:
Estramustine + Etoposide
Paclitaxel + Estramustine + Etoposide
Retinoblastoma:
CCCDE (Retinoblastoma)
CE (Retinoblastoma)
Sarcoma: VAC Alternating With IE (Ewing's Sarcoma)
Sarcoma, soft tissue:
ICE (Sarcoma)
ICE-T
IE
Testicular cancer:
BEP (Ovarian Cancer, Testicular Cancer)
BEP (Testicular Cancer)
EP (Testicular Cancer)
VIP (Etoposide) (Testicular Cancer)
Unknown primary, adenocarcinoma: Paclitaxel-Carboplatin-Etoposide (Unknown Primary)
Administration: Oral
Doses ≤400 mg/day as a single once daily dose; doses >400 mg should be given in 2-4 divided doses. If necessary, the injection may be used for oral administration (see Extemporaneously Prepared).
Administration: I.M.
Do not administer I.M. or SubQ (severe tissue necrosis).
Administration: I.V.
Irritant.
Administer standard doses over at least 30-60 minutes to minimize the risk of hypotension. Higher (unlabeled) doses used in transplantation may be infused over longer time periods depending on the protocol. Etoposide injection contains polysorbate 80 which may cause leaching of diethylhexyl phthalate (DEHP), a plasticizer contained in polyvinyl chloride (PVC) tubing. Administration through non-PVC (low sorbing) tubing will minimize patient exposure to DEHP.
Concentrations >0.4 mg/mL are very unstable and may precipitate within a few minutes. For large doses, where dilution to ≤0.4 mg/mL is not feasible, consideration should be given to slow infusion of the undiluted drug through a running normal saline, dextrose or saline/dextrose infusion; or use of etoposide phosphate. Etoposide solutions of 0.1-0.4 mg/mL may be filtered through a 0.22 micron filter without damage to the filter; etoposide solutions of 0.2 mg/mL may be filtered through a 0.22 micron filter without significant loss of drug.
Administration: I.V. Detail
pH: 3-4
Monitoring Parameters
CBC with differential, platelet count, hemoglobin; liver function (bilirubin, ALT, AST), albumin, renal function tests; vital signs (blood pressure)
Patient Education
This medication may be administered by infusion. Report immediately any swelling, pain, burning, or redness at infusion site; swelling of extremities; palpitations, rapid heartbeat, sudden difficulty breathing or swallowing; chest pain; or chills. It is important to maintain adequate nutrition and hydration, unless instructed to restrict fluid intake. You will be more susceptible to infection. May cause nausea, vomiting, diarrhea, loss of hair (reversible), or mouth sores. Report extreme fatigue, pain or numbness in extremities, severe GI upset or diarrhea, bleeding or bruising, fever, sore throat, vaginal discharge, yellowing of eyes or skin, or any changes in color of urine or stool.
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Mucositis (especially at high doses) and stomatitis.
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
Nursing: Physical Assessment/Monitoring
Patient should be monitored closely for anaphylactic reaction (chills, fever, tachycardia, bronchospasm, dyspnea, hypotension). Emergency equipment should be available. Assess renal function prior to each treatment and on a regular basis.
Oncology: Emetic Potential
Oral: Low (10% to 30%)
I.V.: Low (10% to 30%)
Oncology: Vesicant
May be 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.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, softgel, oral: 50 mg
Injection, solution: 20 mg/mL (5 mL, 25 mL, 50 mL)
Toposar®: 20 mg/mL (5 mL, 25 mL, 50 mL) [contains dehydrated ethanol 33.2%, polyethylene glycol 300, polysorbate 80]
Extemporaneously Prepared
Etoposide 10 mg/mL oral solution: Dilute etoposide for injection 1:1 with normal saline to a concentration of 10 mg/mL. This solution is stable in plastic oral syringes for 22 days at room temperature. Prior to oral administration, further mix with fruit juice (orange, apple, or lemon; NOT grapefruit juice) to a concentration of <0.4 mg/mL; once mixed with fruit juice, use within 3 hours. Note: Use appropriate handling precautions during preparation.
McLeod HL and Relling MV, “Stability of Etoposide Solution for Oral Use,” Am J Hosp Pharm, 1992, 49(11):2784-5.
References
Aronoff GR, Bennett WM, Berns JS, et al, Drug Prescribing in Renal Failure: Dosing Guidelines for Adults and Children, 5th ed. Philadelphia, PA: American College of Physicians; 2007, p 99, 171.
Collier K, Schink C, Young AM, et al, “Case Report: Successful Treatment With Etoposide Phosphate in Patients With Previous Etoposide Hypersensitivity,” J Oncol Pharm Pract, 2008, 14(1):51-5.
de Lemos ML, Hamata L, and Vu T, “Leaching of Diethylhexyl Phthalate from Polyvinyl Chloride Materials into Etoposide Intravenous Solutions,” J Oncol Pharm Pract, 2005, 11(4):155-7.
Demoré B, Vigneron J, Perrin A, et al, “Leaching of Diethylhexyl Phthalate from Polyvinyl Chloride Bags into Intravenous Etoposide Solution,” J Clin Pharm Ther, 2002, 27(2):139-42.
Donelli MG, Zucchetti M, Munzone E, et al, “Pharmacokinetics of Anticancer Agents in Patients With Impaired Liver Function,” Eur J Cancer, 1998, 34(1):33-46.
Duffner PK, Horowitz ME, Krischer JP, et al “Postoperative Chemotherapy and Delayed Radiation in Children Less Than Three Years of Age With Malignant Brain Tumors,” N Engl J Med, 1993, 328(24):1725-31.
Einhorn LH, Williams SD, Chamness A, et al, “High-Dose Chemotherapy and Stem-Cell Rescue for Metastatic Germ-cell Tumors,” N Engl J Med, 2007, 357(4):340-8.
Floyd J, Mirza I, Sachs B, et al, "Hepatotoxicity of Chemotherapy," Semin Oncol, 2006, 33(1):50-67.
Floyd JD, Nguyen DT, Lobins RL, et al, “Cardiotoxicity of Cancer Therapy,” J Clin Oncol, 2005, 23(30):7685-96.
Horning SJ, Negrin RS, Chao JC, et al, “Fractionated Total-Body Irradiation, Etoposide, and Cyclophosphamide and Non-Hodgkin's Lymphoma,” J Clin Oncol, 1994, 12(12):2552-8.
Ihde DC, Mulshine JL, Kramer BS, et al, “Prospective Randomized Comparison of High-Dose and Standard-Dose Etoposide and Cisplatin Chemotherapy in Patients With Extensive-Stage Small-Cell Lung Cancer,” J Clin Oncol, 1994, 12(10):2022-34.
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