Etoposide

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)

Pharmacology

Mechanism of Action

Etoposide has been shown to delay transit of cells through the S phase and arrest cells in late S or early G₂ phase. The drug may inhibit mitochondrial transport at the NADH dehydrogenase level or inhibit uptake of nucleosides into HeLa cells. It is a topoisomerase II inhibitor and appears to cause DNA strand breaks. Etoposide does not inhibit microtubular assembly.

Pharmacokinetics/Pharmacodynamics

Absorption

Oral: Significant inter- and intrapatient variation

Distribution

Average V_d: 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%

Use in Specific Populations

Special Populations: Renal Function Impairment

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

Use: Labeled Indications

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).

Use: Off Label

Acute lymphoblastic leukemia, relapsed/refractoryc

Data from a small phase 2 study suggest that etoposide (in combination with mitoxantrone, ifosfamide, and mesna) may be an effective salvage regimen in adults with relapsed/refractory acute lymphoblastic leukemia (ALL) Schiller 1993. Data from another small study in patients ≤20 years of age with relapsed acute leukemias suggest that etoposide (in combination with clofarabine and cyclophosphamide) may be effective in treating relapsed or refractory ALL in heavily pretreated patients Miano 2012.

Acute myeloid leukemia, refractoryb

Data from a small study suggest that etoposide (in combination with mitoxantrone and cytarabine [MEC regimen]) may be beneficial in salvage treatment of refractory acute myeloid leukemia (AML) Amadori 1991. Data from a phase 2 study also suggest that etoposide (in combination with mitoxantrone) is effective and well tolerated in patients with refractory AML Ho 1988.

Adrenocortical carcinoma (advanced)a

Data from a randomized, phase 3 study support the use of etoposide (in combination with doxorubicin, cisplatin, and mitotane) for the treatment of advanced adrenocortical carcinoma Fassnacht 2012. A phase 2 study also supports the use of etoposide (in combination with doxorubicin, cisplatin, and mitotane) for the treatment of advanced adrenocortical carcinoma in patients not eligible for radical surgery Berruti 2005.

AIDS-related Kaposi sarcomac

Data from small phase 2 studies support the use of oral etoposide in the treatment of relapsed, refractory, or progressive AIDS-related Kaposi sarcoma Evans 2002, Sprinz 2001.

Brain metastases (due to breast or non-small cell lung cancers)b

Data from a study in patients with brain metastases due to breast cancer, non-small cell lung cancer (NSCLC), or melanoma support the use of etoposide (in combination with cisplatin) for the treatment of unresectable metastases due to breast cancer or NSCLC in patients who had not received radiation therapy to treat the metastases Franciosi 1999.

Breast cancer, metastaticb

Data from a phase 2 trial in patients with metastatic breast cancer support the use of oral etoposide for the treatment of this condition in patients with measurable disease who had received at least one prior chemotherapy regimen Martin 1994. Data from another phase 2 trial support the use of oral etoposide in metastatic breast cancer patients with good performance status Saphner 2000.

Gestational trophoblastic neoplasia (high risk)b

Data from several studies in patients with high-risk metastatic gestational trophoblastic neoplasia (GTN) support the use of etoposide (in combination with methotrexate, leucovorin, dactinomycin, cyclophosphamide, and vincristine [EMA-CO regimen] or with methotrexate, leucovorin, dactinomycin, and cisplatin [EMA-EP regimen or EP-EMA regimen]) in the treatment of high-risk disease Escobar 2003, Ghaemmaghami 2004, Lurain 2006, Newlands 2000. Data from a small study in heavily pretreated patients with high-risk GTN suggest that etoposide (in combination with paclitaxel and cisplatin [TP/TE regimen]) may be beneficial in relapsed/refractory disease Wang 2008. Data from a small study support the use of etoposide (in combination with bleomycin and cisplatin [BEP regimen] or ifosfamide, mesna, and carboplatin [ICE regimen]) in patients with high-risk refractory GTN Lurain 2005, Lurain 2012.

Hemophagocytic lymphohistiocytosisayes

Data from a prospective study (HLH-94 protocol) support the use of etoposide (in combination with dexamethasone, cyclosporine, and intrathecal methotrexate) for the management of hemophagocytic lymphohistiocytosis (HLH) Henter 1997, Henter 2002. Clinical experience also suggests the utility of etoposide in the management of adult-onset HLH La Rosée 2015, Ramos-Casals 2014.

An interdisciplinary work group consensus panel on adult HLH (sponsored by the Histiocyte Society) recommend HLH-94 treatment components, including etoposide, to manage hyperinflammation in adults with HLH La Rosée 2019.

Hematopoietic stem cell transplant conditioning regimenb

Data from studies in patients with Hodgkin and non-Hodgkin lymphoma undergoing hematopoietic stem cell transplantation support the use of etoposide (in combination with carmustine, cytarabine, and melphalan [BEAM regimen]) administered prior to stem cell or bone marrow transplantation Chopra 1993, Mills 1995. Data from 3 studies in recurrent or refractory Hodgkin disease, non-Hodgkin lymphoma, or acute leukemia treated with high-dose etoposide (in combination with total body irradiation ± cyclophosphamide) support the use of etoposide as a transplant conditioning regimen Horning 1994, Snyder 1993, Weaver 1994.

Hodgkin lymphomaa

Data from a large randomized study support the use of etoposide (in combination with bleomycin, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone [BEACOPP escalated regimen]) for the treatment of advanced-stage Hodgkin lymphoma Diehl 2003, Engert 2009. Data from another study in patients <21 years of age (at diagnosis) support the use of etoposide (in combination with bleomycin, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone [BEACOPP regimen]) for the treatment of advanced-stage Hodgkin lymphoma Kelly 2002.

Data from a prospective clinical study support the use of etoposide (in combination with mechlorethamine, vinblastine, vincristine, bleomycin, doxorubicin, and prednisone [Stanford V regimen]) for the treatment of locally extensive and advanced Hodgkin lymphoma Horning 2002.

Merkel cell carcinoma (high risk)b

Data from a phase 2 trial suggest the use of etoposide (in combination with carboplatin and synchronous radiation) results in high levels of locoregional and distant control, as well as survival in patients with high-risk Merkel cell carcinoma Poulsen 2003.

Multiple myelomaa

Data from large, randomized, phase 3 trials support the use of etoposide (in combination with cisplatin, dexamethasone, thalidomide, doxorubicin, and cyclophosphamide ± bortezomib) as induction therapy for the management of multiple myeloma Lee 2003, Pineda-Roman 2008.

Neuroendocrine tumors (metastatic carcinoma)b

Data from 3 small studies suggest that etoposide (in combination with cisplatin) could be of benefit for the treatment of metastatic neuroendocrine carcinoma, including foregut, pancreatic, and lung carcinoid tumors Fjällskog 2001, Le Treut 2013, Moertel 1991.

Non-Hodgkin lymphomab

Data from a small study support the use of etoposide (in combination with rituximab, ifosfamide and carboplatin [R-ICE regimen]) for the treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL) prior to proceeding to autologous transplant Kewalramani 2004. Data from a phase 2 study support the use of etoposide in combination with cisplatin, methylprednisolone, and cytarabine (ESHAP regimen) for the treatment of relapsed/refractory non-Hodgkin lymphoma Velasquez 1994. Data from a small prospective, observational study support the use of etoposide (in combination with rituximab, prednisone, vincristine, cyclophosphamide, and doxorubicin [DA-EPOCH-R regimen]) in patients with previously untreated poor prognosis DLBCL García-Suárez 2007. Furthermore, data from a phase 2 study support the use of etoposide (as a component of the DA-EPOCH-R regimen) in the treatment of primary mediastinal B-cell lymphoma Dunleavy 2013. Data from a small retrospective study support the use of etoposide (in combination with rituximab, cyclophosphamide, vincristine, and prednisone) in patients with DLBCL and who cannot receive anthracyclines Moccia 2009.

Data from studies in patients with aggressive non-Hodgkin lymphoma (including patients with peripheral T-cell lymphoma) support the use of etoposide (in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone) in the treatment of this condition Pfreundschuh 2004, Schmitz 2010. Data from a study evaluating the use of CEPP (B) (cyclophosphamide, etoposide, procarbazine, and prednisone [with or without bleomycin]) in patients with recurrent or resistant non-Hodgkin lymphoma who are ineligible for hematopoietic stem cell transplantation or who cannot tolerate standard chemotherapy regimens support the use of etoposide (as a component of the CEPP regimen) for the treatment of this condition Chao 1990. Data from a study evaluating the use of PEP-C (prednisone, etoposide, procarbazine, cyclophosphamide) regimen in patients with recurrent non-Hodgkin lymphoma support the use of etoposide (as part of the PEP-C regimen) for the treatment of recurrent or refractory non-Hodgkin lymphoma Coleman 2008.

Non-small cell lung cancerbyes

Data from a randomized study in patients with NSCLC treated with etoposide (in combination with cisplatin) support the use of etoposide for the treatment of this condition Arriagada 2004. Additional data from a phase 3 trial in patients with stage IIIA NSCLC with ipsilateral mediastinal nodal metastases also supports the use of etoposide (in combination with cisplatin and radiation therapy) for the treatment of this condition Albain 2009.

Based on American Society of Clinical Oncology guidelines for systemic therapy for stage IV NSCLC, etoposide (in combination with platinum therapy) may be considered for stage IV NSCLC patients with large-cell neuroendocrine carcinoma.

Ovarian cancer, epithelial, refractoryb

Data from a phase 2 trial in patients with refractory epithelial ovarian cancer support the use of oral etoposide for the treatment of this condition Rose 1998.

Ovarian germ cell tumorsb

Data from a prospective study in patients with surgically resected ovarian germ cell tumors support the use of etoposide (in combination with bleomycin and cisplatin [BEP regimen]) as adjuvant therapy Williams 1994. While the BEP regimen is preferred in the treatment of ovarian germ cell tumors, etoposide and cisplatin (EP regimen) may be considered if pulmonary toxicity is a concern; use of this regimen in the treatment of ovarian germ cell tumors is extrapolated from data in the management of testicular germ cell tumors Culine 2007. Data from a small study support the use of etoposide (in combination with carboplatin) for the treatment of stages IB to III ovarian germ cell tumors following complete surgical resection Williams 2004.

Prostate cancer, castration resistant, metastaticb

Data from a small phase 2 study support the use of etoposide (in combination with cisplatin) for second-line treatment (following first-line treatment with carboplatin and docetaxel) of metastatic prostate cancer that is castration resistant and has at least one anaplastic feature or is small-cell variant Aparicio 2013. Data from a small prospective study in patients with castration-resistant prostate cancer with disease progression after docetaxel-based chemotherapy suggest etoposide (in combination with carboplatin) may have activity in the treatment of this condition Loriot 2009.

Sarcomas (rhabdomyosarcoma, Ewing sarcoma, osteosarcoma), refractoryb

Data from a study evaluating patients ≤22 years of age with recurrent or refractory sarcomas (rhabdomyosarcoma, Ewing sarcoma, and osteosarcoma) treated with etoposide (in combination with ifosfamide and carboplatin) in one of three phase 1/2 trials support the use of etoposide for these refractory sarcomas Van Winkle 2005.

Soft tissue sarcomaa

Data from a prospective, randomized, phase 3 trial support the use of etoposide (in combination with ifosfamide, mesna, and doxorubicin) with regional hyperthermia in patients with localized high-risk soft-tissue sarcoma Issels 2010, Issels 2018.

Thymic carcinoma, locally advanced or metastaticc

Data from a small, prospective study suggest that etoposide (in combination with cisplatin, ifosfamide, and mesna [VIP regimen]) may be of benefit for the treatment of thymic carcinoma Loehrer 2001. Data from a retrospective review also suggest the utility of etoposide (in combination with vincristine, doxorubicin, and cisplatin [CODE regimen]) for managing advanced or unresectable thymic carcinoma Yoh 2003.

Thymoma, locally advanced or metastaticb

Data from 2 prospective studies support the use of etoposide (in combination with cisplatin [PE regimen] or ifosfamide, mesna, and cisplatin [VIP regimen]) for the treatment of advanced, recurrent, or metastatic malignant thymoma Giaccone 1996, Loehrer 2001.

Unknown primary adenocarcinomab

Data from a phase 2 trial in patients with metastatic carcinoma of unknown primary site support the use of oral etoposide (in combination with paclitaxel and carboplatin) for the treatment of this condition Greco 2000. Additional data from a multicenter, phase 2 study in patients with metastatic poorly-differentiated neuroendocrine carcinoma (62% had unknown primary site) who had received no prior treatment demonstrated that etoposide (in combination with paclitaxel and carboplatin) also supports the use of etoposide in this condition Hainsworth 2006.

Contraindications

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

Dosage and Administration

Dosing: Adult

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 (Schiller 1993) 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 (Miano 2012).

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 (Amadori 1991) 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 (Ho 1988).

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) (Fassnacht 2012) 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 (Berruti 2005).

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 (Sprinz 2001) 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 (Evans 2002).

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 (Franciosi 1999).

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 (Martin 1994; Saphner 2000).

Gestational trophoblastic neoplasia, high-risk metastatic disease (off-label use):

IV:

BEP regimen: 100 mg/m² on days 1 to 4 every 3 weeks (in combination with bleomycin and cisplatin) for at least 2 treatment cycles after a normal hCG level (Lurain 2005; Lurain 2012).

EMA-CO regimen: 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 (Escobar 2003; Lurain 2006).

EMA-EP regimen: 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 (Ghaemmaghami 2004).

EP-EMA regimen: EP: 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) (Newlands 2000).

ICE regimen (based on limited data): 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 (Lurain 2005; Lurain 2012).

TP/TE regimen: 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 failure (rising hCG) or unacceptable toxicity (Wang 2008).

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]) (Chopra 1993; Mills 1995) or 60 mg/kg as a single dose on day −4 prior to autologous transplant (in combination with cyclophosphamide and total body irradiation) (Horning 1994; Weaver 1994) or 60 mg/kg as a single dose on day −3 prior to allogeneic transplant (in combination with total body irradiation) (Snyder 1993).

Hemophagocytic lymphohistiocytosis (off-label use):

HLH-94 protocol: IV:

Initial therapy: 150 mg/m² twice weekly for 2 weeks, then 150 mg/m² once weekly for 6 weeks (in combination with dexamethasone) (Henter 1997; Henter 2002).

Continuation therapy (depending on clinical factors; refer to protocol for details): 150 mg/m² once every 2 weeks (in combination with dexamethasone pulses, cyclosporine, and intrathecal methotrexate) until hematopoietic stem cell transplant (Henter 1997; Henter 2002).

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 (La Rosée 2019).

Hodgkin lymphoma (off-label use):

IV:

BEACOPP (escalated) regimen: 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 (Diehl 2003; Engert 2009; Kelly 2002).

Stanford V regimen: 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) (Horning 2002).

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 (Poulsen 2003).

Multiple myeloma (off-label use):

IV:

DT-PACE regimen: 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) (Lee 2003).

VDT-PACE regimen: 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) (Lee 2003; Pineda-Roman 2008).

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 (Fjällskog 2001) 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 (Moertel 1991) or 100 mg/m² on days 1, 2, and 3 every 3 weeks (in combination with cisplatin) for up to 6 cycles (Le Treut 2013).

Non-Hodgkin lymphoma (off-label use):

Diffuse large B-cell lymphoma:

Dose-adjusted EPOCH-R regimen: IV: 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 (García-Suárez 2007).

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) (Moccia 2009).

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 (Kewalramani 2004).

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 (Pfreundschuh 2004; Schmitz 2010).

Primary mediastinal B-cell lymphoma:

DA-EPOCH-R regimen: 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 (Dunleavy 2013).

Other non-Hodgkin lymphoma regimens:

CEPP(B) regimen: IV: Initial: 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) (Chao 1990).

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 (Velasquez 1994).

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) (Coleman 2008).

Non-small cell lung cancer (off-label use):

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, epithelial, refractory (off-label use):

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

Ovarian germ cell tumors (off-label use):

IV:

BEP regimen: 100 mg/m² on days 1 to 5 every 21 days (in combination with bleomycin and cisplatin) for 3 cycles (Williams 1994).

EP regimen: 100 mg/m² on days 1 to 5 every 21 days (in combination with cisplatin) for 4 cycles (Culine 2007); 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: 120 mg/m² days 1, 2, and 3 every 4 weeks (in combination with carboplatin) for 3 cycles (Williams 2004).

Prostate cancer, castration resistant, metastatic (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 (Aparicio 2013) 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 (Loriot 2009).

Sarcomas (rhabdomyosarcoma, Ewing sarcoma, osteosarcoma), refractory (off-label use):

IV: Adults <22 years of age: 100 mg/m²/day on days 1 to 5 every 3 weeks (in combination with ifosfamide, mesna, and carboplatin) (Van Winkle 2005).

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 (Turrisi 1999) or 100 mg/m² on days 1, 2, and 3 every 4 weeks (in combination with cisplatin and concurrent radiation) for 4 cycles (Takada 2002) or 100 mg/m² on days 1, 2, and 3 every 3 weeks (in combination with cisplatin and sequential radiation) for 4 cycles (Takada 2002) 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 (Skarlos 2001) or 100 mg/m² IV on day 1 (in combination with cisplatin and concurrent radiation), followed by 200 mg/m²orally on days 2 through 4 every 3 weeks for a maximum of 5 courses (Sundstrom 2002) or 100 mg/m² on days 1, 2, and 3 every 3 to 4 weeks (in combination with cisplatin) for 6 cycles (Evans 1985). 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 (ASCO [Rudin 2015]).

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 (Horn 2018) or 100 mg/m² IV on days 1, 2, and 3 every 3 weeks (in combination with cisplatin) for 4 cycles (Lara 2009) or 100 mg/m² IV on day 1 (in combination with cisplatin and concurrent radiation), followed by 200 mg/m²orally on days 2 through 4 every 3 weeks for a maximum of 5 courses (Sundstrom 2002) or 80 mg/m² on days 1, 2, and 3 every 3 weeks (in combination with cisplatin) up to 8 cycles (Ihde 1994) or 100 mg/m² on days 1, 2, and 3 every 3 weeks (in combination with carboplatin) up to a maximum of 6 cycles (Socinski 2009) or 100 mg/m² on days 1, 2, and 3 every 3 to 4 weeks (in combination with cisplatin) for 6 cycles (Evans 1985). 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 (ASCO [Rudin 2015]).

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

Soft tissue sarcoma (off-label use):

IV: 125 mg/m² on days 1 and 4 (in combination with ifosfamide, doxorubicin, and regional hyperthermia [EIA regimen]) every 3 weeks until progression or unacceptable toxicity (Issels 2010; Issels 2018).

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 (Culine 2007; Kondagunta 2005).

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 (Nichols 1998).

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 (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 (in combination with carboplatin) for 3 cycles (Kondagunta 2007).

Thymic carcinoma, locally advanced or metastatic (off-label use; based on limited data):

IV:

CODE regimen: 80 mg/m² on days 1, 2, and 3 (in combination with vincristine, doxorubicin, and cisplatin) during weeks 1, 3, 5, 7, and 9 (Yoh 2003).

VIP regimen: 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 (Loehrer 2001).

Thymoma, locally advanced or metastatic (off-label use):

IV:

PE regimen: 120 mg/m² on days 1, 2, and 3 every 3 weeks (in combination with cisplatin) for up to 8 cycles (Giaccone 1996).

VIP regimen: 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 (Loehrer 2001).

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) (Greco 2000; Hainsworth 2006).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

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 extra precaution. Etoposide is associated with a low emetic risk (Dupuis 2011); antiemetics are recommended to prevent nausea and vomiting (Dupuis 2013)

Acute lymphocytic leukemia (ALL), relapsed or 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 2010; Dreyer 2015): Infant <1 year at diagnosis: 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

Acute myeloid leukemia (AML): Limited data available:

Gamis 2014: Note: Some aspects of protocol dosing presented in previous reports (Cooper 2012)

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 over 1 hour daily for 5 days (in combination with cytarabine)

BSA ≥0.6 m²: IV: 150 mg/m² over 1 hour 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 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)

Consolidation MACE or LAME 89/91 (Perel 2002):

Infants: 75 mg/m² over 1 hour once daily for 5 days (in combination with amsacrine and cytarabine)

Children and Adolescents <17 years: IV: 100 mg/m² over 1 hour once daily for 5 days (in combination with cytarabine and daunorubicin or amsacrine)

Salvage treatment for refractory/recurrent disease: MEC regimen:

Intermittent IV: Children ≥5 years and Adolescents: IV: 80 mg/m² over 1 hour once daily for 6 days (in combination with cytarabine and mitoxantrone) (Amadori 1991)

Continuous IV infusion: Adolescents ≥15 years: IV: 200 mg/m²/day as a continuous infusion for 3 days (Day 8 to 10) (in combination with mitoxantrone and cytarabine) as a single course; may administer a second course if needed (Archimbaud 1991; Archimbaud 1995)

CNS tumors, malignant (medulloblastoma, PNET, ependymoma, 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)

Duffner 1993: Infants and Children <3 years: IV: 6.5 mg/kg once daily administered on days 3 and 4 (in combination with cisplatin as Cycle B regimen) for a 28-day cycle alternating with Cycle A regimen (cyclophosphamide and vincristine); therapy initiated 2 to 4 weeks after tumor resection

Kovnar 1990: Children ≥6 years and Adolescents: IV: 150 mg/m²/dose once daily on days 3 and 4 (in combination with cisplatin) every 3 weeks for 4 cycles prior to radiation

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 (Goldman 2015): 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

Induction Cycles 2, 4, and 6: IV: 90 mg/m² once daily for 5 days on days 1 to 5 in combination with ifosfamide

CNS tumors; relapsed, metastatic: Limited data available (Fleischhack 2001; Pajtler 2016; Peyrl 2014): Intraventricular (using preservative-free formulation): Administer via an Ommaya-Rickham reservoir once daily for 5 consecutive days

Infants: 0.25 mg

Children and Adolescents: 0.5 mg

Retinoblastoma, extraocular: Limited data available (Chantada 2003): 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

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

Hematopoietic stem cell transplantation (HSCT), conditioning regimen: Limited data available: Children ≥1 year and Adolescents: IV: 30 or 60 mg/kg administered over 4 to 8 hours as a single dose 3 or 4 days prior to transplantation (Biagi 2000; Duerst 2000; Horning 1994; Snyder 1993; Zander 1997)

ALL conditioning regimen: IV: Infants ≥6 months, Children, and Adolescents: IV: 20 mg/kg once daily on days -4 to -2 (in combination with busulfan and fludarabine) (Lee 2015)

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 (Dunkel 2010)

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 (Kelly 2011)

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) (Dharmarajan 2015; Friedman 2014; Schwartz 2009)

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) (Kaneko 2002; Kushner 2004; Simon 2007; Simon 2007a); 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 (Matthay 1999)

Myeloablative therapy with stem cell rescue:

IV: 100 to 200 mg/m²/day for 4 to 5 days beginning 8 to 9 days prior to transplantation was used in 301 patients (Kaneko 2002)

Continuous IV infusion: 640 mg/m² infused over 96 hours beginning 8 days prior to transplant (Matthany 1999; Park 2009)

Salvage therapy: HD-ICE regimen: IV: 100 mg/m² over 1 hour once daily for 5 days in combination with ifosfamide and carboplatin with or without autologous peripheral blood stem cell support (depending on hematologic reserve) (Kushner 2013)

Ewing sarcoma: Limited data available; multiple regimens reported:

HD-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 (cyclophosphamide, vincristine, doxorubicin) (Grier 2003; Kushner 1995; Miser 2007)

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, cyclophosphamide) (Navid 2006)

Relapsed, refractory: ICE regimen: 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) (Milano 2006; Van Winkle 2005)

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 (Kung 1993; Marina 2016)

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 (Van Winkle 2005)

Wilms tumor: Limited data available (Abu-Ghosh 2002; Daw 2009): 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

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:

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

Dosing: 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.

Dosing: Obesity

American Society of Clinical Oncology Guidelines for appropriate chemotherapy dosing in obese adults with cancer (Note:Excludes hematopoietic stem cell transplantation and leukemia dosing): Utilize patient's actual body weight (full weight) for calculation of body surface area (BSA)- 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 (ASCO [Griggs 2012]).

American Society for Blood and Marrow Transplantation practice guideline committee position statement on chemotherapy dosing in obesity: Utilize actual body weight (full weight) for calculation of 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 (ASBMT [Bubalo 2014]).

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

Reconstitution

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. Preparation in glass or polyolefin containers will minimize patient exposure to DEHP (de Lemos 2005; Demoré 2002).

Extemporaneously Prepared

Etoposide 10 mg/mL oral solution: Dilute etoposide for injection 1:1 with normal saline to a concentration of 10 mg/mL. This solution is stable in plastic oral syringes for 22 days at room temperature (McLeod 1992). Prior to oral administration, further mix with fruit juice (orange or apple NOT grapefruit juice) or lemonade to a concentration of <0.4 mg/mL; once mixed with fruit juice, use within 3 hours (Lam 2011).

Lam MS. Extemporaneous compounding of oral liquid dosage formulations and alternative drug delivery methods for anticancer drugs. Pharmacotherapy. 2011;31(2):164-92.21275495McLeod 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) emetic potential; antiemetics may be recommended to prevent nausea and vomiting (Roila 2016).

Oral: Doses ≤200 mg/day may be administered 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).

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 (de Lemos 2005; Demoré 2002). Administration through non-PVC (low sorbing) tubing will minimize patient exposure to DEHP (de Lemos 2005; Demoré 2002). 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.

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 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). Follow USP 797 recommendations for beyond use dates based on the level of risk for preparation.

Etoposide injection contains polysorbate 80 which may cause leaching of DEHP, a plasticizer contained in 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 (de Lemos 2005; Demoré 2002). When undiluted etoposide injection is stored in acrylic or ABS (acrylonitrile, butadiene and styrene) plastic containers, the containers may crack and leak.

Drug Interactions

Atovaquone: May increase the serum concentration of Etoposide. Management: Consider separating the administration of atovaquone and etoposide by at least 1 to 2 days. Monitor therapy

Baricitinib: Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted. 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 (High risk with Inducers). Monitor therapy

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Monitor therapy

Cladribine: May enhance the immunosuppressive effect of Immunosuppressants. Avoid combination

Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Avoid combination

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

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 (High risk with Inducers). 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. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). 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

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

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. Consider therapy modification

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 (High risk with Inducers). 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

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

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

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

Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Lasmiditan: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Avoid combination

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

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. 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. Consider therapy modification

Lorlatinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences. Consider therapy modification

Mesalamine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Mitotane: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). 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

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

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

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

Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy

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

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

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

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

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Siponimod: Immunosuppressants may enhance the immunosuppressive effect of Siponimod. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy. Consider therapy modification

Smallpox and Monkeypox Vaccine (Live): Immunosuppressants may diminish the therapeutic effect of Smallpox and Monkeypox Vaccine (Live). Monitor therapy

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

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). 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. Consider therapy modification

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

Upadacitinib: Immunosuppressants may enhance the immunosuppressive effect of Upadacitinib. Avoid combination

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. Exceptions: Smallpox and Monkeypox Vaccine (Live). Avoid combination

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

Adverse Reactions

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

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: [US Boxed Warning]: 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. Treatment should be withheld for platelets <50,000/mm³ or ANC <500/mm³. Monitor blood counts at baseline and prior to each cycle.
• Extravasation: Etoposide IV is an irritant (Pérez Fidalgo 2012); tissue irritation and inflammation have occurred following extravasation.
• GI toxicity: Oral etoposide is associated with a moderate emetic potential in pediatric patients (the emetic potential in adults is low); antiemetics may be recommended to prevent nausea and vomiting (Dupuis 2011; Hesketh 2017; Roila 2016). Mild to severe mucositis/esophagitis may occur.
• 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%). 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 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; infuse slowly over at least 30 to 60 minutes (do not administer IV push). 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.
• 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.

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 (~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.

Other warnings/precautions:

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

Monitoring Parameters

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 (blood pressure); monitor for signs of an infusion reaction. Oral etoposide: Monitor adherence.

Pregnancy

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 (Peccatori 2013).

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.

Patient Education

What is this drug used for?

• It is used to treat lung cancer.
• It is used to treat testicular cancer.
• It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Nausea
• Vomiting
• Lack of appetite
• Diarrhea
• Mouth irritation
• Mouth sores
• Hair loss

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Infection
• Bleeding like vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding.
• Shortness of breath
• Severe loss of strength and energy
• Vision changes
• Severe dizziness
• Passing out
• Fast heartbeat
• Severe headache
• Flushing
• Sweating a lot
• Blue/gray skin discoloration
• Back pain
• Severe injection site burning, pain, edema, or irritation
• Signs of a significant reaction like 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. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.