Version January 2024
Etoposide should be administered under the supervision of a qualified health care provider experienced in the use of cancer chemotherapeutic agents.
Severe myelosuppression, with resulting infection or bleeding, may occur.
Acute lymphoblastic leukemia, relapsed/refractory (off-label use):
IV: 100 mg/m2 on days 1 to 5 (in combination with mitoxantrone, ifosfamide, and mesna) as induction therapy; if complete remission occurred following induction, one additional cycle as consolidation therapy was administered (Ref) or (adults <20 years of age) 100 mg/m2 on days 1 to 5 (in combination with clofarabine and cyclophosphamide) as induction (a second 5-day induction cycle may be administered if a partial response occurred), followed by 100 mg/m2 on days 1 to 4 (in combination with clofarabine and cyclophosphamide) as consolidation; a total of up to 4 cycles (induction and consolidation) may be administered (Ref).
Acute myeloid leukemia, refractory (off-label use):
IV: 80 mg/m2 on days 1 to 6 (in combination with mitoxantrone and cytarabine); if complete remission occurred following induction, an additional cycle of 80 mg/m2 on days 1 to 4 (in combination with mitoxantrone and cytarabine) as consolidation was administered (Ref) or 100 mg/m2 on days 1 to 5 (in combination with mitoxantrone); if complete remission occurred following induction, an additional cycle of 75 mg/m2 on days 1 to 5 (in combination with mitoxantrone and cytarabine) as consolidation was administered (Ref).
Adrenocortical carcinoma, advanced (off-label use):
IV: 100 mg/m2 on days 2, 3, and 4 every 4 weeks (in combination with doxorubicin, cisplatin, and mitotane) (Ref) or 100 mg/m2 on days 5, 6, and 7 every 4 weeks (in combination with doxorubicin, cisplatin, and mitotane) until disease progression or unacceptable toxicity up to a maximum of 6 cycles (Ref).
AIDS-related Kaposi sarcoma (off-label use; based on limited data):
Oral: 20 mg/m2 every 8 hours for 7 consecutive days every 21 days until persistent toxicity or a therapy delay beyond day 28 occurs (Ref) or 50 mg (flat dose) once daily for 7 consecutive days every 14 days; after 2 cycles, in patients without a response (complete or partial), may escalate the dose to 100 mg (flat dose) once daily for 7 consecutive days every 14 days (Ref).
Brain metastases, due to breast or non-small cell lung cancers (off-label use):
IV: 100 mg/m2 on days 1, 3, and 5 (or on days 4, 6, and 8) every 3 weeks (in combination with cisplatin) for up to 6 cycles in the absence of disease progression or unacceptable toxicity (Ref).
Intrathecal/Intraventricular (off- label route; based on limited data): 1 mg via Ommaya reservoir once weekly until disease progression or unacceptable toxicity (Ref) or 0.5 mg via Ommaya reservoir once daily for 5 consecutive days per week every other week for a total of 8 weeks (20 total doses), followed by maintenance intrathecal therapy of 0.5 mg via Ommaya reservoir once daily for 5 consecutive days every 4 weeks; continue until disease progression (Ref) or 0.5 mg via Ommaya or Rickham reservoir once daily for 5 consecutive days every 2 to 5 weeks (Ref). Refer to articles for further information. Note: Preservative-free etoposide formulations should be utilized.
Breast cancer, metastatic (off-label use):
Oral: 50 mg/m2 once daily for 21 days of a 28-day cycle; continue until disease progression or unacceptable toxicity (Ref).
Gestational trophoblastic neoplasia, high-risk (off-label use):
EMA-CO regimen: IV: 100 mg/m2 on days 1 and 2 every 2 weeks (in combination with methotrexate, leucovorin, dactinomycin, cyclophosphamide, and vincristine); continue for at least 2 treatment cycles after a normal hCG level (Ref).
EMA-EP regimen: IV: 100 mg/m2 on days 1, 2, and 8 every 2 weeks (in combination with methotrexate, leucovorin, dactinomycin, and cisplatin) for 2 to 4 treatment cycles after a normal hCG level (Ref).
EP-EMA regimen: EP: IV: 150 mg/m2 on day 1 (followed by cisplatin) alternating weekly with EMA: 100 mg/m2 on day 1 (in combination with methotrexate, leucovorin, and dactinomycin) (Ref).
BEP regimen (for refractory disease ): IV: 100 mg/m2 on days 1 to 4 every 3 weeks (in combination with bleomycin, cisplatin, and WBC growth factor support) for at least 2 treatment cycles after a normal hCG level (Ref).
ICE regimen (for refractory disease; based on limited data): IV: 75 mg/m2 on days 1, 2, and 3 every 3 weeks (in combination with ifosfamide, mesna, and carboplatin) for at least 2 treatment cycles after a normal hCG level (Ref).
TP/TE regimen (for refractory disease): IV: 150 mg/m2 on day 15 of a 28-day cycle (TE; in combination with paclitaxel) alternating every 2 weeks with TP (paclitaxel and cisplatin); continue until hCG level is normal for at least 8 weeks, or until treatment resistance (plateaued or rising hCG) or unacceptable toxicity (Ref).
Low-dose EP induction regimen (consider prior to EMA/CO in patients with high tumor burden): IV: 100 mg/m2 on days 1 and 2 every week (in combination with cisplatin) for 1 to 2 cycles, followed by the EMA-CO regimen until hCG levels normalize and then for a further 6 to 8 weeks; refer to protocol for further information (Ref).
Hematopoietic stem cell transplant conditioning regimen (off-label use):
IV: 100 mg/m2 or 200 mg/m2 once daily for 4 days on days −5, −4, −3, and −2 prior to autologous transplant (in combination with carmustine, cytarabine, and melphalan [BEAM regimen]) (Ref) or 60 mg/kg as a single dose on day −4 prior to autologous transplant (in combination with cyclophosphamide and total body irradiation) (Ref) or 60 mg/kg as a single dose on day −3 prior to allogeneic transplant (in combination with total body irradiation) (Ref).
Hemophagocytic lymphohistiocytosis (off-label use):
HLH-94 protocol:
Initial therapy: IV: 150 mg/m2 twice weekly for 2 weeks, then 150 mg/m2 once weekly for 6 weeks (in combination with dexamethasone) (Ref).
Continuation therapy (depending on clinical factors; refer to protocol for details): IV: 150 mg/m2 once every 2 weeks (in combination with dexamethasone pulses, cyclosporine, and intrathecal methotrexate) until hematopoietic stem cell transplant (Ref).
Note: Consider reducing the etoposide frequency from twice weekly to once weekly and/or a dose reduction from 150 mg/m2/dose to 50 to 100 mg/m2/dose in adults with comorbidities or organ dysfunction; in patients with hemophagocytic lymphohistiocytosis without malignancy, a maximum cumulative etoposide dose of 2 to 3 g/m2 should not be exceeded (Ref).
Hodgkin lymphoma (off-label use):
BEACOPP (escalated) regimen: IV: 200 mg/m2 on days 1, 2, and 3 every 3 weeks (in combination with bleomycin, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) for 4 to 8 cycles (Ref).
Stanford V regimen: IV: 60 mg/m2 on days 1 and 2 of weeks 3, 7, and 11 of a 12-week cycle (in combination with mechlorethamine, vinblastine, vincristine, bleomycin, doxorubicin, and prednisone) (Ref).
Merkel cell carcinoma, high risk (off-label use):
IV: 80 mg/m2 on days 1 to 3 (in combination with carboplatin) during weeks 1 and 4 of concurrent synchronous radiation therapy and then 80 mg/m2 on days 1 to 3 during weeks 7 and 10 (in combination with carboplatin) (or every 28 days if blood counts not recovered) for a total of 4 cycles (Ref).
Multiple myeloma (off-label use):
DT-PACE regimen: IV: 40 mg/m2/day administered as a continuous infusion on days 1 to 4 of each cycle; repeat every 4 to 6 weeks (in combination with dexamethasone, thalidomide, cisplatin, doxorubicin, and cyclophosphamide) (Ref).
VDT-PACE regimen: IV: 40 mg/m2/day administered as a continuous infusion on days 1 to 4 of each cycle; repeat every 4 to 6 weeks (in combination with bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, and cyclophosphamide) (Ref).
Neuroendocrine tumors, metastatic carcinoma (off-label use):
IV: 100 mg/m2 on days 1, 2, and 3 every 4 weeks (in combination with cisplatin; refer to protocol for infusion information) until disease progression or unacceptable toxicity (Ref) or 130 mg/m2 as a continuous infusion on days 1, 2, and 3 every 4 weeks (in combination with cisplatin) until disease progression or unacceptable toxicity (Ref) or 100 mg/m2 on days 1, 2, and 3 every 3 weeks (in combination with cisplatin) for up to 6 cycles (Ref).
Non-Hodgkin lymphomas (off-label use):
Diffuse large B-cell lymphoma:
Dose-adjusted EPOCH-R regimen: IV: Initial: 50 mg/m2/day continuous infusion for 4 days (over 96 hours) (total 200 mg/m2/cycle) of a 21-day treatment cycle (in combination with prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) for 6 to 8 cycles; dose-adjusted for subsequent cycles based on neutrophil and platelet counts during nadir (Ref).
R-CEOP regimen: IV, Oral: 50 mg/m2 IV on day 1, followed by 100 mg/m2 orally on days 2 and 3 of a 21-day treatment cycle for 3 to 6 cycles (in combination with rituximab, cyclophosphamide, vincristine, and prednisone) (Ref).
R-ICE regimen: IV: 100 mg/m2 on days 3, 4, and 5 (in combination with rituximab, ifosfamide, mesna, and carboplatin) every 2 weeks for 3 cycles (Ref).
Peripheral T-cell lymphoma:
CHOEP regimen: IV: 100 mg/m2 on days 1, 2, and 3 of a 21-day treatment cycle (in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone) for 6 to 8 cycles (Ref).
Primary mediastinal B-cell lymphoma:
DA-EPOCH-R regimen: Initial: IV: 50 mg/m2/day as a continuous infusion on days 1 to 4 (over 96 hours) dose-adjusted for subsequent cycles based on neutrophil and platelet counts during nadir (in combination with vincristine, prednisone, cyclophosphamide, doxorubicin, rituximab, and filgrastim); repeat cycle every 3 weeks for a total of 6 to 8 cycles (Ref).
Other non-Hodgkin lymphoma regimens:
CEPP(B) regimen: Initial: IV: 70 mg/m2 on days 1, 2, and 3; may increase dose with subsequent cycles (refer to protocol for details) every 28 days (in combination with cyclophosphamide, procarbazine, prednisone, ± bleomycin) (Ref).
ESHAP regimen: IV: 40 mg/m2 on days 1 to 4 (in combination with methylprednisolone, cisplatin, and cytarabine) every 3 to 4 weeks for 6 to 8 cycles (Ref).
PEP-C regimen: Oral: 50 mg (flat dose) once daily after dinner (length of induction cycle depends on blood counts; frequency may vary based on tolerance in maintenance cycle; in combination with prednisone, procarbazine, and cyclophosphamide) (Ref).
Ovarian cancer, epithelial, refractory (off-label use):
Oral: 50 mg/m2 once daily for 21 days every 4 weeks until disease progression or unacceptable toxicity (Ref).
Ovarian germ cell tumors (off-label use):
BEP regimen: IV: 100 mg/m2 on days 1 to 5 every 21 days (in combination with bleomycin and cisplatin) for 3 cycles (Ref).
EP regimen: IV: 100 mg/m2 on days 1 to 5 every 21 days (in combination with cisplatin) for 4 cycles (Ref); while the BEP regimen is preferred in the treatment of ovarian germ cell tumors, EP may be considered if pulmonary toxicity is a concern. Note: Use of this regimen in ovarian germ cell tumors is extrapolated from data in the management of testicular germ cell tumors.
Carboplatin/etoposide regimen: IV: 120 mg/m2 days 1, 2, and 3 every 4 weeks (in combination with carboplatin) for 3 cycles (Ref).
Prostate cancer, metastatic, castration resistant (off-label use):
IV, Oral: 120 mg/m2 IV on days 1, 2, and 3 every 3 weeks (in combination with cisplatin, as second-line treatment following first-line treatment with carboplatin and docetaxel) for at least 4 cycles (Ref) or 80 mg/m2 IV on day 1, followed by 80 mg/m2 orally on days 2 and 3 (in combination with carboplatin) every 3 weeks until disease progression or unacceptable toxicity (Ref).
Sarcomas, rhabdomyosarcoma, Ewing sarcoma, osteosarcoma, refractory (off-label use):
Adults <22 years of age: IV: 100 mg/m2/day on days 1 to 5 every 3 weeks (in combination with ifosfamide, mesna, and carboplatin) (Ref).
Small cell lung cancer (combination chemotherapy):
Limited-stage disease (off-label dosing/combinations): IV: 120 mg/m2 on days 1, 2, and 3 every 3 weeks (in combination with cisplatin and concurrent radiation) for 4 courses (Ref) or 100 mg/m2 on days 1, 2, and 3 every 4 weeks (in combination with cisplatin and concurrent radiation) for 4 cycles (Ref) or 100 mg/m2 on days 1, 2, and 3 every 3 weeks (in combination with cisplatin and sequential radiation) for 4 cycles (Ref) or 100 mg/m2 on days 1, 2, and 3 every 3 weeks (in combination with carboplatin and radiation) up to a maximum of 6 cycles (Ref) or 100 mg/m2 IV on day 1 (in combination with cisplatin and concurrent radiation), followed by 200 mg/m2 orally on days 2 through 4 every 3 weeks for a maximum of 5 courses (Ref) or 100 mg/m2 on days 1, 2, and 3 every 3 to 4 weeks (in combination with cisplatin) for 6 cycles (Ref). According to American Society of Clinical Oncology (ASCO) guidelines, platinum-based therapy (cisplatin or carboplatin) in combination with either etoposide or irinotecan for 4 cycles is recommended over other regimens for limited-stage disease (Ref).
Extensive-stage disease (off-label dosing/combinations): IV: 100 mg/m2 IV on days 1, 2, and 3 every 3 weeks (in combination with carboplatin and atezolizumab) for 4 induction cycles, followed by atezolizumab maintenance therapy (Ref) or 100 mg/m2 IV on days 1, 2, and 3 every 3 weeks (in combination with cisplatin) for 4 cycles (Ref) or 100 mg/m2 IV on day 1 (in combination with cisplatin and concurrent radiation), followed by 200 mg/m2 orally on days 2 through 4 every 3 weeks for a maximum of 5 courses (Ref) or 80 mg/m2 on days 1, 2, and 3 every 3 weeks (in combination with cisplatin) up to 8 cycles (Ref) or 100 mg/m2 on days 1, 2, and 3 every 3 weeks (in combination with carboplatin) up to a maximum of 6 cycles (Ref) or 100 mg/m2 on days 1, 2, and 3 every 3 to 4 weeks (in combination with cisplatin) for 6 cycles (Ref). According to ASCO guidelines, platinum-based therapy (cisplatin or carboplatin) in combination with either etoposide or irinotecan for 4 to 6 cycles is recommended over other regimens for extensive-stage disease (Ref).
IV to oral conversion: Due to poor bioavailability, oral doses should be twice the IV dose (and rounded to the nearest 50 mg) according to the manufacturer.
Soft tissue sarcoma (off-label use):
EIA regimen: IV: 125 mg/m2 on days 1 and 4 (in combination with ifosfamide, doxorubicin, and regional hyperthermia) every 3 weeks until progression or unacceptable toxicity (Ref).
Testicular cancer, combination chemotherapy:
Testicular germ cell tumor, metastatic, good risk: IV: 100 mg/m2 on days 1 to 5 every 3 weeks (in combination with cisplatin) for 4 cycles (Ref).
Testicular germ cell tumor, metastatic, intermediate or poor risk: IV: 100 mg/m2 on days 1 to 5 every 3 weeks (in combination with bleomycin and cisplatin) for 4 cycles or 75 mg/m2 on days 1 to 5 every 3 weeks (in combination with cisplatin, ifosfamide, and mesna) for 4 cycles (Ref).
Testicular germ cell tumor, metastatic, high-dose regimens: IV: 750 mg/m2/day administered 5, 4, and 3 days before peripheral blood stem cell infusion (in combination with carboplatin); repeat for a second cycle after recovery of granulocyte and platelet counts (Ref) 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 (in combination with carboplatin) for 3 cycles (Ref).
Thymic carcinoma, locally advanced or metastatic (off-label use; based on limited data):
CODE regimen: IV: 80 mg/m2 on days 1, 2, and 3 (in combination with vincristine, doxorubicin, and cisplatin) during weeks 1, 3, 5, 7, and 9 (Ref).
VIP regimen: IV: 75 mg/m2 on days 1 to 4 (in combination with ifosfamide, mesna, cisplatin, and colony-stimulating growth factor support) every 3 weeks for up to 4 cycles or until disease progression or unacceptable toxicity (Ref).
Thymoma, locally advanced or metastatic (off-label use):
PE regimen: IV: 120 mg/m2 on days 1, 2, and 3 every 3 weeks (in combination with cisplatin) for up to 8 cycles (Ref).
VIP regimen: IV: 75 mg/m2 on days 1 to 4 (in combination with ifosfamide, mesna, cisplatin, and colony-stimulating growth factor support) every 3 weeks for up to 4 cycles or until disease progression or unacceptable toxicity (Ref).
Unknown primary adenocarcinoma (off-label use):
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) (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Oral, IV:
The manufacturer'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:
Hemodialysis: Reduce dose by 50%; not removed by hemodialysis so may be administered before or after dialysis (Ref).
Peritoneal dialysis: Administer 50% of dose; supplemental dose is not necessary (Ref).
Continuous renal replacement therapy (CRRT): Administer 75% of dose (Ref). A case report in a patient with metastatic testicular cancer on continuous hemodiafiltration (with concomitant hepatic dysfunction) receiving BEP (bleomycin, etoposide, and cisplatin) chemotherapy reported a 50% etoposide dosage reduction for the first cycle (Ref).
Aronoff 2007:
CrCl 10 to 50 mL/minute: Administer 75% of dose.
CrCl <10 mL minute: Administer 50% of dose.
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
There are no dosage adjustments provided in the manufacturer's labeling.
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
American Society of Clinical Oncology guidelines for appropriate chemotherapy dosing in adults with cancer with a BMI ≥30 kg/m2 (Note: Excludes hematopoietic stem cell transplantation dosing): Utilize patient's actual body weight for calculation of BSA- or weight-based dosing; manage regimen-related toxicities in the same manner as for patients with a BMI <30 kg/m2; if a dose reduction is utilized due to toxicity, may consider resumption of full, weight-based dosing (or previously tolerated dose level) with subsequent cycles only if dose escalations are allowed in the prescribing information, if contributing underlying factors (eg, hepatic or kidney impairment) are sufficiently resolved, AND if performance status has markedly improved or is considered adequate (Ref).
American Society for Blood and Marrow Transplantation practice guideline committee position statement on chemotherapy dosing in obesity: Utilize actual body weight for calculation of BSA for BSA-based dosing and utilize adjusted body weight 25% (ABW25) for mg/kg dosing for hematopoietic cell transplant conditioning regimens in adults (Ref).
ABW25: Adjusted weight (kg) = Ideal body weight (kg) + 0.25 [actual weight (kg) − ideal body weight (kg)]
Oral, IV:
ANC <500/mm3 or platelets <50,000/mm3: Withhold treatment until recovery.
Hypotension: Interrupt infusion and administer IV hydration and supportive care; decrease infusion rate upon reinitiation.
Infusion (hypersensitivity) reactions: Interrupt infusion (medications for the treatment of anaphylaxis should be available for immediate use during etoposide IV administration).
Severe adverse reactions (nonhematologic): Reduce dose or discontinue treatment.
Intrathecal/Intraventricular (off-label route): Arachnoiditis: May be managed with corticosteroids (Ref). Corticosteroids were administered prophylactically in some reports (Ref).
Refer to adult dosing.
(For additional information see "Etoposide: Pediatric drug information")
Note: Dose, frequency, number of doses, and start date may vary by protocol and treatment phase; refer to individual protocols. Pediatric dosing units (eg, mg/kg, mg/m2) and routes (eg, IV, continuous IV infusion, intraventricular) are variable depending upon protocol/regimen; use caution. Etoposide is associated with a low emetic risk (intravenous) and moderate emetic risk (oral); antiemetics may be recommended to prevent nausea and vomiting (Ref).
Acute lymphoblastic leukemia (ALL), relapsed/refractory: Limited data available:
Hijiya 2011: Induction and Consolidation: Children and Adolescents: IV: 100 mg/m2 over 2 hours for 5 consecutive days in Induction (in combination with cyclophosphamide and clofarabine) and 4 consecutive days in Consolidation (in combination with cyclophosphamide and clofarabine).
Parker 2010: ALL R3 Protocol:
Children and Adolescents:
Phase 2 Consolidation: IV: 100 mg/m2 once daily on days 15 to 19 (in combination with other chemotherapeutic agents).
Phase 5 before continuation: IV: 150 mg/m2 once daily on days 42, 49, 99, and 106 (in combination with other chemotherapeutic agents).
Acute lymphoblastic leukemia (ALL) of infancy: Limited data available:
Dreyer 2011; Dreyer 2015: Infants and Children <1 year at diagnosis: IV: 100 mg/m2 over 2 hours once daily for 5 consecutive days; specific regimen days and combination chemotherapeutic agents variable dependent on protocol phase; refer to specific protocols.
Tomizawa 2020: Note: Specific regimen days and combination chemotherapeutic agents variable dependent on protocol phase.
Infants and Children <1 year at diagnosis:
Low risk; Regimen A:
Early consolidation and re-induction: Note: Used in combination with other chemotherapy; varies with phase of the regimen (refer to specific protocols).
Infants <2 months: IV: 66.7 mg/m2 over 2 hours once daily for 4 consecutive days.
Infants ≥2 to 3 months: IV: 75 mg/m2 over 2 hours once daily for 4 consecutive days.
Infants >3 months and Children: IV: 100 mg/m2 over 2 hours once daily for 4 consecutive days.
Maintenance:
Infants <2 months: IV: 100 mg/m2 over 2 hours once daily on days 14 and 42.
Infants ≥2 to 3 months: IV: 112.5 mg/m2 over 2 hours once daily on days 14 and 42.
Infants >3 months and Children: IV: 150 mg/m2 over 2 hours once daily on days 14 and 42.
Intermediate and high risk; Regimen B:
Early and late consolidation and maintenance B-I (cycles 2 and 4):
Infants <2 months: IV: 66.7 mg/m2 over 2 hours once daily for 5 consecutive days.
Infants ≥2 to 3 months: IV: 75 mg/m2 over 2 hours once daily for 5 consecutive days.
Infants >3 months and Children: IV: 100 mg/m2 over 2 hours once daily for 5 consecutive days.
Acute myeloid leukemia (AML): Limited data available:
Gamis 2014: Note: Some aspects of protocol dosing presented in previous reports (Ref).
Infants, Children, and Adolescents:
Remission Induction: ADE (10 + 3 + 5) and ADE (8 + 3 + 5) regimens:
BSA <0.6 m2: IV: 3.3 mg/kg once daily for 5 days (in combination with cytarabine and daunorubicin).
BSA ≥0.6 m2: IV: 100 mg/m2 once daily for 5 days (in combination with cytarabine and daunorubicin).
Intensification I: AE regimen:
BSA <0.6 m2: IV: 5 mg/kg once daily for 5 days (in combination with cytarabine).
BSA ≥0.6 m2: IV: 150 mg/m2 once daily for 5 days (in combination with cytarabine).
Gibson 2011:
Infants, Children, and Adolescents <17 years: Note: For infants, the full dose was reduced by 25%:
Induction Course 1 (ADE 10 + 3 + 5, MAE 3 + 10 + 5 regimens):
Infants: IV: 75 mg/m2 once daily for 5 days (in combination with cytarabine and daunorubicin or mitoxantrone).
Children and Adolescents <17 years: IV: 100 mg/m2 once daily for 5 days (in combination with cytarabine and daunorubicin or mitoxantrone).
Induction Course 2 (ADE 8 + 3 + 5, MAE 3 + 8 + 5 regimens):
Infants: IV: 75 mg/m2 once daily for 5 days (in combination with cytarabine and daunorubicin or mitoxantrone).
Children and Adolescents <17 years: IV: 100 mg/m2 once daily for 5 days (in combination with cytarabine and daunorubicin or mitoxantrone).
CNS tumors, malignant (medulloblastoma, primitive neuroectodermal tumors [PNET], ependymoma, and brainstem glioma): Limited data available; multiple regimens reported:
Chi 2004; Fangusaro 2008: Head Start II regimen:
Infants and Children <10 years:
Induction: IV: 4 mg/kg once daily for 2 days on day 2 and 3 of a 21-day cycle (cycle starts on day 0) for 4 to 5 cycles (in combination with cisplatin, vincristine, cyclophosphamide/mesna and high-dose methotrexate/leucovorin).
Consolidation with autologous peripheral blood stem cell rescue: IV: 250 mg/m2 for 3 doses on day −5 to −3 (in combination with carboplatin and thiotepa).
Taylor 2003: Children ≥3 years and Adolescents: IV: 100 mg/m2/dose once daily on days 1, 2, and 3 (in combination with vincristine and carboplatin or cyclophosphamide) every 3 weeks for 4 cycles prior to radiation.
CNS nongerminomatous germ cell tumor (NGGCT): Limited data available:
Children ≥3 years and Adolescents:
Induction Cycles 1, 3, and 5: IV: 90 mg/m2 once daily for 3 days on days 1 to 3 in combination with carboplatin (Ref).
Induction Cycles 2, 4, and 6: IV: 90 mg/m2 once daily for 5 days on days 1 to 5 in combination with ifosfamide (Ref).
CNS tumors; relapsed, metastatic: Limited data available (Ref):
Infants: Intraventricular (using preservative-free formulation): 0.25 mg. Administer via an Ommaya or Rickham reservoir once daily for 5 consecutive days.
Children and Adolescents: Intraventricular (using preservative-free formulation): 0.5 mg Administer via an Ommaya or Rickham reservoir once daily for 5 consecutive days.
Ewing sarcoma: Limited data available; multiple regimens reported:
IE regimen: Children and Adolescents: IV: 100 mg/m2 over 1 hour once daily for 5 days on days 1 to 5 of a 21-day cycle in combination with ifosfamide; frequency of cycles, and alternating chemotherapy combinations vary based on protocol (eg, cyclophosphamide, vincristine, doxorubicin) (Ref).
VAC/IE regimen: Children and Adolescents: IV: 150 mg/m2 once daily for 3 doses on days 1 to 3 in combination with ifosfamide every 3 weeks alternating with VAC (vincristine, doxorubicin, and cyclophosphamide) (Ref).
Relapsed, refractory: ICE regimen: Children and Adolescents: IV: 100 mg/m2 for 5 days every 3 to 4 weeks for up to 12 cycles in combination with carboplatin, ifosfamide, and mesna; or may follow with 2 courses of CAV (cyclophosphamide, doxorubicin, and vincristine) (Ref).
Hematopoietic stem cell transplant (HSCT) conditioning regimen: Limited data available:
Infant ALL conditioning regimen: Infants and Children diagnosed at <1 year: IV: 60 mg/kg/dose over 12 hours on day −4 (in combination with busulfan and cyclophosphamide) (Ref).
ALL conditioning regimen: Infants ≥6 months, Children, and Adolescents: IV: 20 mg/kg once daily on days −4 to −2 (in combination with busulfan and fludarabine) (Ref).
Medulloblastoma conditioning regimen: Children ≥7 years and Adolescents: IV: 250 mg/m2 on days −5, −4, and −3 (in combination with thiotepa and high-dose carboplatin) (Ref).
Hemophagocytic lymphohistiocytosis (HLH): Limited data available:
Infants, Children, and Adolescents:
Initial therapy: IV: 150 mg/m2 twice weekly for weeks 1 and 2 then once weekly for 8 weeks, in combination with cyclosporine and dexamethasone (Ref).
Continuation therapy: IV: 150 mg/m2 every 2 weeks until HSCT or for 40 weeks, in combination with cyclosporine and dexamethasone (Ref).
Hodgkin lymphoma: Limited data available:
High risk: BEACOPP regimen: Children and Adolescents: IV: 200 mg/m2 on days 0, 1, and 2 of a 21-day treatment cycle for 4 cycles (in combination with bleomycin, cyclophosphamide, doxorubicin, vincristine, prednisone, and procarbazine) (Ref).
Intermediate or high risk: ABVE-PC regimen: Children and Adolescents: IV: 125 mg/m2 over 1 hour once daily for 3 days of a 21-day cycle for 2 to 4 cycles (in combination with doxorubicin, vincristine, cyclophosphamide, prednisone, and bleomycin) (Ref).
Lymphoma, primary mediastinal B-cell (PMLBL): Limited data available:
Dose adjusted (DA)-EPOCH regimen (Ref):
Children and Adolescents:
Initial: Dose level 1: IV: 50 mg/m2/day on days 1 to 4 as a continuous infusion in combination with doxorubicin, vincristine, cyclophosphamide, and prednisone.
Dosage adjustment: Dose-adjusted for subsequent course every 3 weeks based on neutrophil and platelet counts during nadir to ensure highest tolerated doses are given while minimizing toxicity; within the protocol the dose ranges from 50 mg/m2/day (Level 1) to 124.4 mg/m2/day (Level 6). Measure blood counts twice weekly (3 days apart) (Ref).
Malignant solid tumors, relapsed or metastatic disease:
IE regimen: Children and Adolescents: IV: 100 mg/m2 over 1 hour once daily for 3 to 5 days every 3 weeks in combination with ifosfamide (Ref).
ICE regimen: Children and Adolescents: IV: 100 mg/m2/day for 5 days on days 0 to 4 every 3 weeks for up to 12 cycles in combination with carboplatin, ifosfamide, and mesna (Ref).
Neuroblastoma, high-risk: Limited data available:
Children ≥1 year and Adolescents:
Induction: IV: 100 to 200 mg/m2/dose infused over 1 to 2 hours once daily for 3 to 5 consecutive days (in combination with other chemotherapy agents) (Ref); other reported regimens include 100 mg/m2/dose on day 2 and 5 (in combination with cisplatin, doxorubicin, and cyclophosphamide) every 28 days for 5 cycles (Ref).
Myeloablative therapy with stem cell rescue (tandem transplant):
Children <12 kg:
GFR ≥100 mL/minute/1.73 m2: IV: 10 mg/kg over 24 hours × 4 doses in combination with carboplatin and melphalan beginning 7 days prior to stem cell infusion, administered in tandem with thiotepa and cyclophosphamide regimen followed by stem cell rescue (Ref).
GFR ≥60 and <100 mL/minute/1.73 m2: IV: 6.7 mg/kg over 24 hours × 4 doses in combination with carboplatin and melphalan beginning 7 days prior to stem cell infusion, administered in tandem with thiotepa and cyclophosphamide regimen followed by stem cell rescue (Ref).
Children ≥12 kg and Adolescents:
GFR ≥100 mL/minute/1.73 m2: IV: 300 mg/m2 over 24 hours × 4 doses in combination with carboplatin and melphalan beginning 7 days prior to stem cell infusion, administered in tandem with thiotepa and cyclophosphamide regimen followed by stem cell rescue (Ref).
GFR ≥60 and <100 mL/minute/1.73 m2: IV: 200 mg/m2 over 24 hours × 4 doses in combination with carboplatin and melphalan beginning 7 days prior to stem cell infusion, administered in tandem with thiotepa and cyclophosphamide regimen followed by stem cell rescue (Ref).
Retinoblastoma, extraocular: Limited data available:
Infants and Children:
Patient weight <10 kg: IV: 3.3 mg/kg once daily on days 1, 2, and 3 of a 21-day treatment cycle (in combination with carboplatin) alternating cycles with idarubicin and vincristine for a total of 8 cycles (Ref).
Patient weight ≥10 kg: IV: 100 mg/m2 once daily on days 1, 2, and 3 of a 21-day treatment cycle (in combination with carboplatin) alternating cycles with idarubicin and vincristine for a total of 8 cycles (Ref).
Wilms tumor: Limited data available: ICE regimen: Children and Adolescents: IV: 100 mg/m2 once daily for 3 to 5 doses (in combination with ifosfamide and carboplatin); repeat cycle every 21 days (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Dosage adjustment for toxicity: The presented dosing adjustments are based on experience in adult patients; specific recommendations for pediatric patients are limited. Refer to specific protocol for management in pediatric patients if available.
Adult:
ANC <500/mm3 or platelets <50,000/mm3: Withhold treatment until recovery.
Hypotension: Interrupt infusion and administer IV hydration and supportive care; decrease infusion rate upon reinitiation.
Infusion (hypersensitivity) reactions: Interrupt infusion (medications for the treatment of anaphylaxis should be available for immediate use during etoposide IV administration).
Severe adverse reactions (nonhematologic): Reduce dose or discontinue treatment.
Note: Dosage adjustment may be indication specific; consult institutional protocols.
Infants, Children, and Adolescents: Dosage adjustments are not provided in the manufacturer's labeling for pediatric patients; however, the manufacturer recommends the following for adult patients.
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.
Alternate adjustments have been recommended (Ref):
GFR >50 mL/minute/1.73 m2: No dosage adjustment necessary.
GFR 10 to 50 mL/minute/1.73 m2: Administer 75% of dose.
GFR <10 mL/minute/1.73 m2: Administer 50% of dose.
Hemodialysis/peritoneal dialysis (PD) (after dialysis on dialysis days): Administer 50% of dose.
Continuous renal replacement therapy (CRRT): Administer 75% of dose and reduce for hyperbilirubinemia.
Infants, Children, and Adolescents: The following adjustment has been recommended based primarily on experience in adult patients (Ref):
Bilirubin 1.5 to 3 mg/dL or AST >3 times ULN: Administer 50% of dose.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
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 and vomiting (31% to 43%), anorexia (10% to 13%), diarrhea (1% to 13%)
Hematologic & oncologic: Leukopenia (60% to 91%; grade 4: 3% to 17%; nadir: 7 to 14 days; recovery: by day 20), thrombocytopenia (22% to 41%; grades 3/4: 1% to 20%; nadir: 9 to 16 days; recovery: by day 20), anemia (≤33%)
1% to 10%:
Cardiovascular: Hypotension (1% to 2%; due to rapid infusion)
Central nervous system: Peripheral neuropathy (1% to 2%)
Gastrointestinal: Stomatitis (1% to 6%), abdominal pain (≤2%)
Hepatic: Hepatotoxicity (≤3%)
Hypersensitivity: Anaphylactoid reaction (intravenous: 1% to 2%; oral capsules: <1%; including bronchospasm, chills, dyspnea, fever, tachycardia)
<1%, postmarketing, and/or case reports: Amenorrhea, apnea (hypersensitivity-associated), back pain, constipation, cortical blindness (transient), cough, cyanosis, diaphoresis, drowsiness, dysphagia, erythema, esophagitis, extravasation (induration/necrosis), facial swelling, fatigue, fever, hyperpigmentation, hypersensitivity reaction, interstitial pneumonitis, ischemic heart disease, laryngospasm, maculopapular rash, malaise, metabolic acidosis, mucositis, myocardial infarction, optic neuritis, ovarian failure, pruritic erythematous rash, pruritus, pulmonary fibrosis, radiation-recall phenomenon (dermatitis), reversible posterior leukoencephalopathy syndrome (RPLS), seizure, skin rash, Stevens-Johnson syndrome, tongue edema, toxic epidermal necrolysis, toxic megacolon, urticaria, vasospasm, weakness
Hypersensitivity to etoposide or any component of the formulation
Canadian labeling: Additional contraindications (not in the US labeling): Severe leukopenia or thrombocytopenia; severe hepatic impairment; severe renal impairment
Concerns related to adverse effects:
• Bone marrow suppression: Severe myelosuppression with resulting infection or bleeding may occur. Myelosuppression is dose related and dose limiting. Granulocyte and platelet nadirs typically occur 7 to 14 days or 9 to 16 days, respectively, after administration; hematologic recovery usually occurs by day 20.
• Extravasation: Etoposide IV is an irritant (Pérez Fidalgo 2012); tissue irritation and inflammation have occurred following extravasation.
• Hypersensitivity: 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 IV administration (up to 2%) compared to oral administration (<1%). High drug concentration and rate of infusion, as well as presence of polysorbate 80 and benzyl alcohol in the etoposide IV formulation, have been suggested as contributing factors to the development of hypersensitivity reactions. Etoposide IV formulations may contain polysorbate 80 and/or benzyl alcohol, while etoposide phosphate (the water-soluble prodrug of etoposide) IV 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.
• Secondary malignancies: Secondary acute leukemias have been reported with etoposide, either as monotherapy or in combination with other chemotherapy agents.
Disease-related concerns:
• Hypoalbuminemia: Use with caution in patients with low serum albumin; may increase risk for toxicities.
Special populations:
• Older adult: Patients ≥65 years of age 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:
• Alcohol: Injectable formulation contains alcohol (~30% to 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.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Capsule, Oral:
Generic: 50 mg
Solution, Intravenous:
Toposar: 100 mg/5 mL (5 mL [DSC]); 500 mg/25 mL (25 mL [DSC]); 1 g/50 mL (50 mL [DSC]) [contains alcohol, usp, polyethylene glycol 300 (peg-6), polysorbate 80]
Generic: 100 mg/5 mL (5 mL); 500 mg/25 mL (25 mL); 1 g/50 mL (50 mL)
Yes
Capsules (Etoposide Oral)
50 mg (per each): $100.44
Solution (Etoposide Intravenous)
1 gm/50 mL (per mL): $1.82 - $2.99
100 mg/5 mL (per mL): $1.20 - $2.99
500 mg/25 mL (per mL): $1.82 - $2.99
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral:
VePesid: 50 mg [contains ethylparaben, propylparaben]
Solution, Intravenous:
Generic: 20 mg/mL (5 mL, 10 mL, 20 mL, 25 mL, 50 mL)
Oral: Doses ≤200 mg/day may be administered as a single once daily dose; doses >200 mg should be given in 2 divided doses. Based on a small pharmacokinetic study, food does not appear to significantly interfere with the bioavailability of a 100 mg etoposide dose (oral capsules); therefore, etoposide capsules may be administered in a fed or fasted state (with or without food) (Ref). If necessary, the injection may be used to prepare an oral solution for oral administration (see Extemporaneously Prepared).
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 (refer to protocol for infusion duration). Etoposide injection contains polysorbate 80 which may cause leaching of DEHP, a plasticizer contained in PVC tubing (Ref). Administration through non-PVC (low sorbing) tubing will minimize patient exposure to DEHP (Ref). Etoposide is an irritant; tissue irritation and inflammation have occurred following extravasation; avoid extravasation.
IV 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.
Intrathecal/Intraventricular (off-label route): In clinical reports, etoposide was administered over 2 minutes via an Ommaya or Rickham reservoir. Prior to administration, 5 to 6 mL of CSF fluid was drained for discarding (Ref). Corticosteroids were administered as prophylaxis for chemical arachnoiditis in some reports (Ref).
Note: Etoposide is associated with a low emetic risk (intravenous) and moderate emetic risk (oral); antiemetics may be recommended to prevent nausea and vomiting (Ref).
Oral: In adults, doses ≤200 mg/day should be given as a single daily dose; doses >200 mg should be given in 2 divided doses. If necessary, the injection may be used for oral administration either as an extemporaneous preparation or by mixing dose with orange juice, apple juice, or lemonade at a final concentration not to exceed 0.4 mg/mL (to improve palatability) (Ref). Based on a small pharmacokinetic study, food does not appear to significantly interfere with the bioavailability of a 100 mg etoposide dose (oral capsules); therefore, etoposide capsules may be administered in a fed or fasted state (with or without food) (Ref).
Parenteral:
IV: For IV infusion only; do not administer by rapid IV injection or by intrathecal, intraperitoneal, or intrapleural routes due to possible severe toxicity. Etoposide injection contains polysorbate 80 which may cause leaching of diethylhexyl phthalate (DEHP), a plasticizer contained in polyvinyl chloride (PVC) tubing (Ref). Administration through non-PVC (low sorbing) tubing will minimize patient exposure to DEHP (Ref). Etoposide is an irritant; tissue irritation and inflammation have occurred following extravasation; avoid extravasation.
Administer by continuous IV infusion or IV intermittent infusion over at least 60 minutes at a rate not to exceed 100 mg/m2/hour (or 3.3 mg/kg/hour) to minimize the risk of hypotension. Due to risk for precipitation, a 0.22-micron inline filter may be used. Hematopoietic stem cell transplantation conditioning regimens have infused etoposide through a central venous catheter over 4 to 8 hours (Ref). Higher than recommended concentrations of etoposide infusions may crack hard plastic in chemo venting pins and infusion lines; inspect infusion solution for particulate matter and plastic devices for cracks and leaks.
Intraventricular: In pediatric patients, doses were injected over 2 minutes (Ref).
Hazardous agent (NIOSH 2016 [group 1]).
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).
Small cell lung cancer (oral and IV): Treatment (first-line) of small cell lung cancer (in combination with other chemotherapeutic agents).
Testicular cancer (IV): Treatment of refractory testicular tumors (injectable formulation) (in combination with other chemotherapeutic agents).
Acute lymphoblastic leukemia, relapsed/refractory; Acute myeloid leukemia, refractory; Adrenocortical carcinoma (advanced); AIDS-related Kaposi sarcoma; Brain metastases (due to breast or non-small cell lung cancers); Breast cancer, metastatic; Gestational trophoblastic neoplasia (high risk); Hemophagocytic lymphohistiocytosis; Hematopoietic stem cell transplant conditioning regimen; Hodgkin lymphoma; Merkel cell carcinoma (high risk); Multiple myeloma; Neuroendocrine tumors (metastatic carcinoma); Non-Hodgkin lymphoma; Non-small cell lung cancer; Ovarian cancer, epithelial, refractory; Ovarian germ cell tumors; Prostate cancer, castration resistant, metastatic; Sarcomas (rhabdomyosarcoma, Ewing sarcoma, osteosarcoma), refractory; Soft tissue sarcoma; Thymic carcinoma, locally advanced or metastatic; Thymoma, locally advanced or metastatic; Unknown primary adenocarcinoma
Etoposide may be confused with teniposide
Etoposide may be confused with etoposide phosphate (a prodrug of etoposide which is rapidly converted in the plasma to etoposide)
VePesid may be confused with Versed
This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.
Substrate of CYP1A2 (minor), CYP2E1 (minor), CYP3A4 (major), P-glycoprotein/ABCB1 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
5-Aminosalicylic Acid Derivatives: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy
Abrocitinib: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid combination
Antithymocyte Globulin (Equine): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Antithymocyte Globulin (Equine). Specifically, these effects may be unmasked if the dose of cytotoxic chemotherapy is reduced. Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Antithymocyte Globulin (Equine). Specifically, infections may occur with greater severity and/or atypical presentations. Risk C: Monitor therapy
Atovaquone: May increase the serum concentration of Etoposide. Management: Consider separating the administration of atovaquone and etoposide by at least 1 to 2 days. Risk C: Monitor therapy
Baricitinib: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Baricitinib. Risk X: Avoid combination
BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Risk X: Avoid combination
BCG Products: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of BCG Products. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of BCG Products. Risk X: Avoid combination
Brincidofovir: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Brincidofovir. Risk C: Monitor therapy
Brivudine: May enhance the adverse/toxic effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid combination
Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Risk C: Monitor therapy
Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk X: Avoid combination
Cladribine: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Cladribine. Risk X: Avoid combination
CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Risk C: Monitor therapy
Coccidioides immitis Skin Test: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the diagnostic effect of Coccidioides immitis Skin Test. Management: Consider discontinuing cytotoxic chemotherapy several weeks prior to coccidioides immitis skin antigen testing to increase the likelihood of accurate diagnostic results. Risk D: Consider therapy modification
COVID-19 Vaccine (Adenovirus Vector): Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of COVID-19 Vaccine (Adenovirus Vector). Management: Administer a 2nd dose using an mRNA COVID-19 vaccine (at least 4 weeks after the primary vaccine dose) and a bivalent booster dose (at least 2 months after the additional mRNA dose or any other boosters). Risk D: Consider therapy modification
COVID-19 Vaccine (Inactivated Virus): Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of COVID-19 Vaccine (Inactivated Virus). Risk C: Monitor therapy
COVID-19 Vaccine (mRNA): Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of COVID-19 Vaccine (mRNA). Management: Give a 3-dose primary series for all patients aged 6 months and older taking immunosuppressive medications or therapies. Booster doses are recommended for certain age groups. See CDC guidance for details. Risk D: Consider therapy modification
COVID-19 Vaccine (Subunit): Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of COVID-19 Vaccine (Subunit). Risk C: Monitor therapy
COVID-19 Vaccine (Virus-like Particles): Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of COVID-19 Vaccine (Virus-like Particles). Risk C: Monitor therapy
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 (Moderate): May decrease the serum concentration of Etoposide. Risk C: 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 combined, monitor patients closely for diminished etoposide response and need for etoposide dose increases. Risk D: Consider therapy modification
Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Risk D: Consider therapy modification
Dengue Tetravalent Vaccine (Live): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Dengue Tetravalent Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Dengue Tetravalent Vaccine (Live). Risk X: Avoid combination
Denosumab: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Management: Consider the risk of serious infections versus the potential benefits of coadministration of denosumab and cytotoxic chemotherapy. If combined, monitor patients for signs/symptoms of serious infections. Risk D: Consider therapy modification
Deucravacitinib: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid combination
Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Risk X: Avoid combination
Fexinidazole: Myelosuppressive Agents may enhance the myelosuppressive effect of Fexinidazole. Risk X: Avoid combination
Filgotinib: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid combination
Grapefruit Juice: May decrease the serum concentration of Etoposide. Risk C: Monitor therapy
Inebilizumab: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Inebilizumab. Risk C: Monitor therapy
Influenza Virus Vaccines: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Influenza Virus Vaccines. Management: Administer influenza vaccines at least 2 weeks prior to initiating chemotherapy if possible. If vaccination occurs less than 2 weeks prior to or during chemotherapy, revaccinate at least 3 months after therapy discontinued if immune competence restored. Risk D: Consider therapy modification
Leflunomide: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Leflunomide. Management: Increase the frequency of chronic monitoring of platelet, white blood cell count, and hemoglobin or hematocrit to monthly, instead of every 6 to 8 weeks, if leflunomide is coadministered with immunosuppressive agents, such as cytotoxic chemotherapy. Risk D: Consider therapy modification
Lenograstim: Antineoplastic Agents may diminish the therapeutic effect of Lenograstim. Management: Avoid the use of lenograstim 24 hours before until 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Risk D: Consider therapy modification
Lipegfilgrastim: Antineoplastic Agents may diminish the therapeutic effect of Lipegfilgrastim. Management: Avoid concomitant use of lipegfilgrastim and myelosuppressive cytotoxic chemotherapy. Lipegfilgrastim should be administered at least 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Risk D: Consider therapy modification
Mumps- Rubella- or Varicella-Containing Live Vaccines: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Mumps- Rubella- or Varicella-Containing Live Vaccines. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Mumps- Rubella- or Varicella-Containing Live Vaccines. Risk X: Avoid combination
Nadofaragene Firadenovec: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Nadofaragene Firadenovec. Specifically, the risk of disseminated adenovirus infection may be increased. Risk X: Avoid combination
Natalizumab: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Natalizumab. Risk X: Avoid combination
Ocrelizumab: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Ocrelizumab. Risk C: Monitor therapy
Ofatumumab: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Ofatumumab. Risk C: Monitor therapy
Olaparib: Myelosuppressive Agents may enhance the myelosuppressive effect of Olaparib. Risk C: Monitor therapy
Palifermin: May enhance the adverse/toxic effect of Antineoplastic Agents. Specifically, the duration and severity of oral mucositis may be increased. Management: Do not administer palifermin within 24 hours before, during infusion of, or within 24 hours after administration of myelotoxic chemotherapy. Risk D: Consider therapy modification
P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of Etoposide. Risk C: Monitor therapy
Pidotimod: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Pidotimod. Risk C: Monitor therapy
Pimecrolimus: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid combination
Pneumococcal Vaccines: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Pneumococcal Vaccines. Risk C: Monitor therapy
Poliovirus Vaccine (Live/Trivalent/Oral): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Risk X: Avoid combination
Polymethylmethacrylate: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the potential for allergic or hypersensitivity reactions to Polymethylmethacrylate. Management: Use caution when considering use of bovine collagen-containing implants such as the polymethylmethacrylate-based Bellafill brand implant in patients who are receiving immunosuppressants. Consider use of additional skin tests prior to administration. Risk D: Consider therapy modification
Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy
Rabies Vaccine: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Rabies Vaccine. Management: Complete rabies vaccination at least 2 weeks before initiation of immunosuppressant therapy if possible. If combined, check for rabies antibody titers, and if vaccination is for post exposure prophylaxis, administer a 5th dose of the vaccine. Risk D: Consider therapy modification
Ritlecitinib: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Ritlecitinib. Risk X: Avoid combination
Ropeginterferon Alfa-2b: Myelosuppressive Agents may enhance the myelosuppressive effect of Ropeginterferon Alfa-2b. Management: Avoid coadministration of ropeginterferon alfa-2b and other myelosuppressive agents. If this combination cannot be avoided, monitor patients for excessive myelosuppressive effects. Risk D: Consider therapy modification
Ruxolitinib (Topical): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Ruxolitinib (Topical). Risk X: Avoid combination
Sipuleucel-T: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Sipuleucel-T. Management: Consider reducing the dose or discontinuing the use of immunosuppressants, such as cytotoxic chemotherapy, prior to initiating sipuleucel-T therapy. Risk D: Consider therapy modification
Sphingosine 1-Phosphate (S1P) Receptor Modulator: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk C: Monitor therapy
Tacrolimus (Topical): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Tacrolimus (Topical). Risk X: Avoid combination
Talimogene Laherparepvec: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Talimogene Laherparepvec. Specifically, the risk of infection from the live, attenuated herpes simplex virus contained in talimogene laherparepvec may be increased. Risk X: Avoid combination
Tertomotide: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Tertomotide. Risk X: Avoid combination
Tofacitinib: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Tofacitinib. Risk X: Avoid combination
Typhoid Vaccine: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Typhoid Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Typhoid Vaccine. Risk X: Avoid combination
Ublituximab: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Ublituximab. Risk C: Monitor therapy
Upadacitinib: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Upadacitinib. Risk X: Avoid combination
Vaccines (Inactivated/Non-Replicating): Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating). Management: Give inactivated vaccines at least 2 weeks prior to initiation of chemotherapy when possible. Patients vaccinated less than 14 days before initiating or during chemotherapy should be revaccinated at least 3 months after therapy is complete. Risk D: Consider therapy modification
Vaccines (Live): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Vaccines (Live). Specifically, the risk of vaccine-associated infection may be increased. Vaccines (Live) may diminish the therapeutic effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid combination
Vitamin K Antagonists (eg, warfarin): Etoposide may enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy
Yellow Fever Vaccine: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Yellow Fever Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Yellow Fever Vaccine. Risk X: Avoid combination
In females 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 at least 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 at least 4 months after the last dose.
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; ESMO [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 (ESMO [Peccatori 2013]).
Etoposide is present in breast milk.
Based on data from one case report, concentrations are below the limit of detection 24 hours after the last dose (Azuno 1995). Due to the potential for serious adverse reactions in the breastfed infant, the manufacturer recommends a decision be made whether to discontinue breastfeeding or to discontinue the drug, taking into account the importance of treatment to the mother.
CBC with differential at baseline, prior to each cycle, and as clinically necessary; liver function (bilirubin, ALT, AST), albumin, renal function tests; monitor vital signs (BP); monitor for signs of an infusion reaction. Monitor for secondary malignancies. Intrathecal/intraventricular etoposide (off-label route): Monitor for signs/symptoms of arachnoiditis. Oral etoposide: Monitor adherence.
The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.
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: Children: 10 L/m2; Adults: 7 to 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: IV: Normal renal/hepatic function: Children: 6 to 8 hours: Adults: 4 to 11 hours
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
Altered kidney function: Total body clearance is reduced, AUC is increased, and Vd is lower.
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