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Etoposide

Pronunciation

Pronunciation

(e toe POE side)

Index Terms

  • EPEG
  • Epipodophyllotoxin
  • VePesid
  • VP - 16
  • VP - 16 - 213
  • VP16

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral:

Generic: 50 mg

Solution, Intravenous:

Toposar: 100 mg/5 mL (5 mL); 500 mg/25 mL (25 mL); 1 g/50 mL (50 mL) [contains alcohol, usp, polyethylene glycol 300, polysorbate 80]

Generic: 100 mg/5 mL (5 mL); 500 mg/25 mL (25 mL); 1 g/50 mL (50 mL)

Brand Names: U.S.

  • Toposar

Pharmacologic Category

  • Antineoplastic Agent, Podophyllotoxin Derivative
  • Antineoplastic Agent, Topoisomerase II Inhibitor

Pharmacology

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.

Absorption

Oral: Significant inter- and intrapatient variation

Distribution

Average Vd: 7 to 17 L/m2; poor penetration across the blood-brain barrier; CSF concentrations <5% of plasma concentrations

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)

Excretion

Children: IV: Urine (~55% as unchanged drug) in 24 hours

Adults: IV: Urine (56%; 45% as unchanged drug) within 120 hours; feces (44%) within 120 hours

Half-Life Elimination

Terminal: IV: Normal renal/hepatic function: Children: 6 to 8 hours: Adults: 4 to 11 hours

Protein Binding

94% to 98%

Special Populations: Renal Function Impairment

Total body clearance is reduced, AUC is increased, and Vd is lower.

Use: Labeled Indications

Small cell lung cancer (oral and IV): Treatment (first-line) of small cell lung cancer (SCLC)

Testicular cancer (IV): Treatment of refractory testicular tumors (injectable formulation)

Canadian labeling: Treatment of small cell lung cancer (SCLC; first- and second-line); treatment of non-small cell lung cancer (NSCLC); treatment of non-Hodgkin lymphomas (first-line); treatment of testicular cancer (first-line [injectable formulation] and refractory)

Use: Unlabeled

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 lymphoma, merkel cell cancer, refractory multiple myeloma, neuroblastoma, neuroendocrine tumors (adrenal gland and carcinoid tumors), non-Hodgkin lymphomas, non-small cell lung cancer (NSCLC), osteosarcoma, ovarian cancer (refractory), prostate cancer, retinoblastoma, metastatic soft tissue sarcoma, thymic malignancies (locally advanced or metastatic), unknown-primary adenocarcinoma, Wilms' tumor; conditioning regimen for hematopoietic cell transplantation

Contraindications

Hypersensitivity to etoposide or any component of the formulation

Canadian labeling: Additional contraindications (not in U.S. labeling): Severe leukopenia or thrombocytopenia; severe hepatic impairment; severe renal impairment

Dosage

Note: Oral etoposide is associated with a low (adults) or moderate (children) emetic potential; antiemetics may be recommended to prevent nausea and vomiting (Dupuis, 2011; Roila, 2010).

Children (off-label uses):

Acute myeloid leukemia (AML) induction (combination chemotherapy; Woods, 1996): IV:

<3 years: 3.3 mg/kg/day continuous infusion for 4 days

≥3 years: 100 mg/m2/day continuous infusion for 4 days

Central nervous system tumors (combination chemotherapy): IV:

<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)

Hematopoietic stem cell transplant conditioning regimen: IV: 60 mg/kg/dose over 4 hours as a single dose 3 or 4 days prior to transplantation (Horning, 1994; Snyder, 1993)

Hodgkin lymphoma: IV: 200 mg/m2/day on days 1, 2, and 3 every 3 weeks (Kelly, 2002)

Neuroblastoma: IV:

Induction: 100 mg/m2/day on days 1-5 of each cycle (Kaneko, 2002)

Hematopoietic stem cell transplant conditioning regimen: 200 mg/m2/day for 4 days beginning 8 or 9 days prior to transplantation (Kaneko, 2002)

Sarcoma, refractory: IV: 100 mg/m2/day on days 1-5 of cycle; repeat cycle every 21 days (Van Winkle, 2005)

Adults:

U.S. labeling:

Small cell lung cancer (combination chemotherapy):

IV: 35 mg/m2/day for 4 days, up to 50 mg/m2/day for 5 days every 3 to 4 weeks

Oral: Due to poor bioavailability, oral doses should be twice the IV dose (and rounded to the nearest 50 mg)

Testicular cancer (combination chemotherapy): IV: 50 to 100 mg/m2/day for days 1 to 5 or 100 mg/m2/day on days 1, 3, and 5 repeated every 3 to 4 weeks

Canadian labeling: Non-Hodgkin lymphoma (in combination with other agents), non-small cell lung cancer (alone or in combination), small cell lung cancer (first-line in combination; second-line alone or in combination), testicular cancer (in combination; oral therapy for refractory disease):

IV: 50 to 100 mg/m2/day for 5 days

Oral: 100 to 200 mg/m2/day for 5 days; administer daily doses >200 mg in 2 divided doses.

Adult off-label uses and/or dosing:

Hematopoietic stem cell transplant conditioning regimen, lymphoid malignancies: IV: 60 mg/kg over 4 hours as a single dose 3 or 4 days prior to transplantation (Horning, 1994; Snyder, 1993; Weaver, 1994)

Non-small cell lung cancer: IV: 100 mg/m2 days 1, 2, and 3 every 3 weeks for 4 cycles or every 4 weeks for 3 to 4 cycles (in combination with cisplatin) (Arriagada, 2004) or 50 mg/m2 days 1 to 5 and days 29 to 33 (in combination with cisplatin and radiation therapy) (Albain, 2009)

Ovarian cancer, refractory: Oral: 50 mg/m2 once daily for 21 days every 4 weeks until disease progression or unacceptable toxicity (Rose, 1998)

Small cell lung cancer, limited stage (combination chemotherapy): IV: 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 IV 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 (combination chemotherapy): 100 mg/m2/day IV on days 1, 2, and 3 every 3 weeks for 4 cycles (Lara, 2009) or 100 mg/m2/day IV 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 IV: 80 mg/m2/day on days 1, 2, and 3 every 3 weeks up to 8 cycles (Ihede, 1994)

Testicular cancer (combination chemotherapy):

Nonseminoma: IV: 100 mg/m2/day on days 1 through 5 every 21 days for 3 to 4 courses (Saxman, 1998)

Nonseminoma, metastatic (high-dose regimens): IV: 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)

Thymoma, locally advanced or metastatic: IV: 120 mg/m2 days 1, 2, and 3 every 3 weeks (in combination with cisplatin) for up to 8 cycles (Giaccone, 1996)

Unknown primary adenocarcinoma: Oral: 50 mg once daily on days 1, 3, 5, 7, and 9 alternating with 100 mg once daily on days 2, 4, 6, 8, and 10 every 3 weeks (in combination with paclitaxel and carboplatin) (Greco, 2000; Hainsworth, 2006)

Dosage adjustment for toxicity: Oral, IV:

Infusion (hypersensitivity) reactions: Interrupt infusion.

ANC <500/mm3 or platelets <50,000/mm3: Withhold treatment until recovery.

Severe adverse reactions (nonhematologic): Reduce dose or discontinue treatment.

WBC 2000-3000/mm3 or platelets 75,000 to 100,000/mm3: Canadian labeling (not in U.S. labeling): Reduce dose by 50%.

Dosage adjustment in renal impairment: Oral, IV:

The manufacturer’s U.S. labeling recommends the following adjustments:

CrCl >50 mL/minute: No adjustment required.

CrCl 15 to 50 mL/minute: Administer 75% of dose.

CrCl <15 mL minute: Data not available; consider further dose reductions.

The following adjustments have also been recommended:

Aronoff, 2007:

Children:

CrCl 10 to 50 mL/minute/1.73 m2: Administer 75% of dose.

CrCl <10 mL minute/1.73 m2: Administer 50% of dose.

Hemodialysis: Administer 50% of dose.

Peritoneal dialysis: Administer 50% of dose.

Continuous renal replacement therapy (CRRT): Administer 75% of dose and reduce for hyperbilirubinemia.

Adults:

CrCl 10 to 50 mL/minute: Administer 75% of dose.

CrCl <10 mL minute: Administer 50% of dose.

Hemodialysis: Administer 50% of dose; supplemental posthemodialysis dose is not necessary.

Peritoneal dialysis: Administer 50% of dose; supplemental dose is not necessary.

Continuous renal replacement therapy (CRRT): Administer 75% of dose.

Janus, 2010: Hemodialysis: Reduce dose by 50%; not removed by hemodialysis so may be administered before or after dialysis.

Kintzel, 1995:

CrCl 46 to 60 mL/minute: Administer 85% of dose.

CrCl 31 to 45 mL/minute: Administer 80% of dose.

CrCl ≤30 mL/minute: Administer 75% of dose.

Dosage adjustment in hepatic impairment:

Manufacturer’s U.S. labeling: There are no dosage adjustments provided in the manufacturer’s labeling.

Canadian labeling:

Mild-to-moderate impairment: There are no dosage adjustments provided in the manufacturer’s labeling.

Severe impairment: Use is contraindicated.

The following adjustments have also been recommended:

Donelli, 1998: Liver dysfunction may reduce the metabolism and increase the toxicity of etoposide. Normal doses of IV 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 to 3 mg/dL or AST >3 times ULN: Administer 50% of dose

King, 2001; Koren, 1992: Bilirubin 1.5 to 3 mg/dL or AST >180 units/L: Administer 50% of dose

Dosing in obesity:

American Society of Clinical Oncology (ASCO) Guidelines for appropriate chemotherapy dosing in obese adults with cancer (Note: Excludes HSCT dosing): Utilize patient’s actual body weight (full weight) for calculation of body surface area- or weight-based dosing, particularly when the intent of therapy is curative; manage regimen-related toxicities in the same manner as for nonobese patients; if a dose reduction is utilized due to toxicity, consider resumption of full weight-based dosing with subsequent cycles, especially if cause of toxicity (eg, hepatic or renal impairment) is resolved (Griggs, 2012).

American Society for Blood and Marrow Transplantation (ASBMT) practice guideline committee position statement on chemotherapy dosing in obesity: Utilize actual body weight (full weight) for calculation of body surface area (BSA) for BSA-based dosing and utilize adjusted body weight 25% (ABW25) for mg/kg dosing for hematopoietic stem cell transplant conditioning regimens in adults (Bubalo, 2014).

ABW25: Adjusted wt (kg) = Ideal body weight (kg) + 0.25 [actual wt (kg) - ideal body weight (kg)]

Reconstitution

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]). Etoposide should be diluted to a concentration of 0.2 to 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.

Extemporaneously Prepared

Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

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.

McLeod HL and Relling MV, “Stability of Etoposide Solution for Oral Use,” Am J Hosp Pharm, 1992, 49(11):2784-5.1471649

Administration

Oral etoposide is associated with a low (adults) or moderate (children) emetic potential; antiemetics may be recommended to prevent nausea and vomiting (Dupuis, 2011; Roila, 2010).

Oral: Doses ≤200 mg/day as a single once daily dose; doses >200 mg should be given in 2 divided doses. If necessary, the injection may be used for oral administration (see Extemporaneously Prepared). Canadian labeling recommends administering capsule on an empty stomach.

IV: Administer standard doses over at least 30 to 60 minutes to minimize the risk of hypotension. Higher (off-label) 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. Etoposide is an irritant; tissue irritation and inflammation have occurred following extravasation; avoid extravasation.

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. Due to the risk for precipitation, an inline filter may be used; etoposide solutions of 0.1 to 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.

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

Compatibility

Variable stability (consult detailed reference) in D5W, LR, NS.

Y-site administration: Incompatible with cefepime, filgrastim, gallium nitrate, idarubicin.

Storage

Capsules: Store oral capsules at 2°C to 8°C (36°F to 46°F); do not freeze. Dispense in a light-resistant container.

Injection: Store intact vials of injection at 20°C to 25°C (68°F to 77°F; do not freeze. According to the manufacturer’s labeling, stability for solutions diluted for infusion in D5W or NS (in glass or plastic containers) varies based on concentration; 0.2 mg/mL solutions are stable for 96 hours at room temperature and 0.4 mg/mL solutions are stable for 24 hours at room temperature (precipitation may occur at concentrations above 0.4 mg/mL).

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, the containers may crack and leak.

Drug Interactions

Aprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

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. Consider therapy modification

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

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. Consider therapy modification

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Etoposide. Management: When possible, seek alternatives to strong CYP3A4-inducing medications in patients receiving etoposide. If these combinations cannot be avoided, monitor patients closely for diminished etoposide response. Consider therapy modification

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates. Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Ivacaftor: May increase the serum concentration of CYP3A4 Substrates. 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. Consider therapy modification

Luliconazole: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Mifepristone: May increase the serum concentration of CYP3A4 Substrates. Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

Mitotane: May decrease the serum concentration of CYP3A4 Substrates. Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Netupitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Osimertinib: May increase the serum concentration of CYP3A4 Substrates. Osimertinib may decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of P-glycoprotein/ABCB1 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.). Monitor therapy

P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of P-glycoprotein/ABCB1 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.). Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Ranolazine: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

St Johns Wort: May decrease the serum concentration of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Avoid combination

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). 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. Avoid combination

Vitamin K Antagonists (eg, warfarin): Etoposide may enhance the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

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 (IV infusion 1% to 2%; oral capsules <1%; including chills, fever, tachycardia, bronchospasm, dyspnea)

<1% (Limited to important or life-threatening): Amenorrhea, blindness (transient/cortical), cyanosis, extravasation (induration/necrosis), facial swelling, hypersensitivity, hypersensitivity-associated apnea, interstitial pneumonitis, laryngospasm, maculopapular rash, metabolic acidosis, MI, mucositis, myocardial ischemia, optic neuritis, perivasculitis, pruritus, pulmonary fibrosis, radiation-recall dermatitis, rash, reversible posterior leukoencephalopathy syndrome (RPLS), seizure, Stevens-Johnson syndrome, tongue swelling, toxic epidermal necrolysis, toxic megacolon, vasospasm

ALERT: U.S. Boxed Warning

Experienced physician:

Administer etoposide under the supervision of a qualified health care provider who is experienced in the use of cancer chemotherapeutic agents.

Bone marrow suppression:

Severe myelosuppression, with resulting infection or bleeding, may occur.

Warnings/Precautions

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.

• Gastrointestinal toxicity: Oral etoposide is associated with a low (adults) or moderate (children) emetic potential; antiemetics may be recommended to prevent nausea and vomiting (Dupuis, 2011; Roila, 2010).

• 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, back pain, loss of consciousness, 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 to 60 minutes. If hypotension occurs, interrupt infusion and administer IV 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. Canadian labeling contraindicates use in severe impairment.

• 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. Canadian labeling contraindicates use in severe impairment.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: Use with caution in elderly patients; may be more likely to develop severe myelosuppression and/or GI effects.

• Pediatric: The use of concentrations higher than recommended were associated with higher rates of anaphylactic-like reactions in children.

Dosage form specific issues:

• Alcohol: Injectable formulation contains alcohol (~33% v/v); may contribute to adverse reactions, especially with higher etoposide doses.

• Benzyl alcohol and derivatives: Some dosage forms may contain benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC, 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors, 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer’s labeling.

• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson, 2002; Lucente 2000; Shelley, 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade, 1986; CDC, 1984). See manufacturer’s labeling.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

Other warnings/precautions:

• Administration: Must be diluted; do not give IV push, infuse over at least 30 to 60 minutes; hypotension is associated with rapid infusion. Etoposide is an irritant; tissue irritation and inflammation have occurred following extravasation. Do not administer IM or SubQ.

• Experienced physician: [U.S. Boxed Warning]: Should be administered under the supervision of an experienced cancer chemotherapy physician.

Monitoring Parameters

CBC with differential; liver function (bilirubin, ALT, AST), albumin, renal function tests; vital signs (blood pressure); signs of an infusion reaction

Pregnancy Risk Factor

D

Pregnancy Considerations

Adverse events were observed in animal reproduction studies. Fetal growth restriction and newborn myelosuppression have been observed following maternal use of regimens containing etoposide during pregnancy (NTP 2013; Peccatori 2013). The European Society for Medical Oncology has published guidelines for diagnosis, treatment, and follow-up of cancer during pregnancy. The guidelines recommend referral to a facility with expertise in cancer during pregnancy and encourage a multidisciplinary team (obstetrician, neonatologist, oncology team). In general, if chemotherapy is indicated, it should be avoided during in the first trimester, there should be a 3-week time period between the last chemotherapy dose and anticipated delivery, and chemotherapy should not be administered beyond week 33 of gestation. Guidelines for the treatment of SCLC are not provided (Peccatori 2013).

In women of reproductive potential, product labeling for etoposide phosphate notes that it may cause amenorrhea, infertility, or premature menopause; effective contraception should be used during therapy and for ≥6 months after the last dose. In males, azoospermia, oligospermia, or permanent loss of fertility may occur. In addition, spermatozoa and testicular tissue may be damaged. Males with female partners of reproductive potential should use condoms during therapy and for ≥4 months after the last dose.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience lack of appetite, stomatitis, or alopecia. Have patient report immediately to prescriber signs of infection, signs of hepatic impairment, paresthesia, severe dyspepsia, dyspnea, significant nausea, considerable diarrhea, ecchymosis, hemorrhaging, intolerable asthenia, vision changes, severe dizziness, syncope, tachycardia, considerable headache, flushing, signs of Stevens-Johnson syndrome/toxic epidermal necrolysis, or injection site pain or irritation (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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