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    Etoposide, VP-16

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    Jan.11.2024

    Etoposide, VP-16

    Indications/Dosage

    Labeled

    • small cell lung cancer (SCLC)
    • testicular cancer

    Off-Label

    • acute lymphocytic leukemia (ALL)
    • acute myelogenous leukemia (AML)
    • bone marrow ablation
    • desmoid tumor
    • Ewing's sarcoma
    • Hodgkin lymphoma
    • neuroblastoma
    • non-Hodgkin's lymphoma (NHL)
    • non-small cell lung cancer (NSCLC)
    • stem cell transplant preparation
    • thymic carcinoma
    • thymoma
    • trophoblastic disease
    • Wilms' tumor
    † Off-label indication

    For the treatment of non-small cell lung cancer (NSCLC)†

    for the adjuvant treatment of resected stage IB to stage III non-small cell lung cancer (NSCLC) in combination with cisplatin†

    Intravenous dosage

    Adults

    100 mg/m2 IV on days 1, 2, and 3 in combination with cisplatin (100 mg/m2 IV) on day 1 every 21 days for 4 cycles. In a phase 3 trial of 1867 patients with stage IB to stage III NSCLC, cisplatin/etoposide was one of several regimens to collectively show a significant improvement in 5-year survival versus observation (44.5% vs. 40.4%) following complete resection.[34318]

    for the treatment of stage IIIB non-small cell lung cancer (NSCLC) in combination with cisplatin and concurrent radiotherapy†

    Intravenous dosage

    Adults

    50 mg/m2 IV on days 1, 2, 3, 4, and 5, and on days 29, 30, 31, 32, and 33 with cisplatin (50 mg/m2 IV) on days 1, 8, 29, and 36 plus concurrent radiotherapy for 25 days starting on day 1 has been studied. Responding patients proceeded to thoracotomy. Median overall survival ranged from 15 to 17 months. Grades 3 or 4 esophagitis and grade 4 neutropenia occurred.[34319] [51373]

    For the treatment of testicular cancer

    for the treatment of refractory testicular cancer, in combination with other chemotherapeutic agents

    Intravenous dosage

    Adults

    50 mg/m2 IV to 100 mg/m2 IV once daily on days 1 to 5 in combination with other approved chemotherapeutic agents, every 3 to 4 weeks. Alternatively, administer 100 mg/m2 IV once daily on days 1, 3, and 5 every 3 to 4 weeks. Etoposide injection should be administered over at least 30 to 60 minutes, while etoposide phosphate injection (Etopophos) may be infused over 5 minutes to 3.5 hours.[53552] [64884] Other doses and regimens have been used; consult the literature for specific protocols.

    for the treatment of testicular cancer, in combination with bleomycin and cisplatin (BEP regimen)

    Intravenous dosage

    Adults

    100 mg/m2 IV on days 1 to 5, in combination with cisplatin (20 mg/m2 IV on days 1 to 5) and bleomycin (30 units IV on days 1, 8, and 15), every 21 days for 3 cycles.[64341] [49371] Administer appropriate hydration prior to cisplatin administration and maintain hydration and adequate urinary output for 24 hours after cisplatin administration.[28393] In a randomized clinical trial, treatment with BEP resulted in a response rate of 94% of patients with disseminated germ cell tumors compared with 88% for those treated with etoposide plus cisplatin.[49371] In a randomized clinical trial of patients with favorable-prognosis germ-cell cancer, there was not a significant difference between 3 cycles of BEP and 4 cycles in terms of overall or disease-free survival.[64341]

    for the treatment of testicular cancer, in combination with cisplatin (EP regimen)

    Intravenous dosage

    Adults

    100 mg/m2 IV on days 1 to 5 in combination with cisplatin (20 mg/m2 IV on days 1 to 5), every 21 days for 4 cycles.[64338] [49372] [49375] Administer appropriate hydration prior to cisplatin administration and maintain hydration and adequate urinary output for 24 hours after cisplatin administration.[28393] In 2 consecutive randomized trials for good-risk metastatic germ cell tumors, 92% of patients treated with CP achieved a complete response (CR), with a relapse rate of 9% after a median follow-up of 7.6 years; the median time to relapse was 10 months.[64338] In another randomized trial of patients with good-risk disseminated germ cell tumor, treatment with EP resulted in a CR rate of 93% compared with 96% in patients treated with vinblastine, bleomycin, cisplatin, cyclophosphamide, and dactinomycin (VAB-6), with a relapse rate of 11% versus 12%, respectively; patients treated with EP had less toxicity than those who received VAB-6.[49372] Treatment with EP resulted in a 90% CR rate in a third randomized controlled trial compared with 88% for patients with good-risk germ cell tumors who received carboplatin plus etoposide (EC); after a median follow-up of 22.4 months, 3% of patients receiving EP relapsed compared with 12% of those who received EC.[49375]

    for the treatment of testicular cancer, in combination with cisplatin, ifosfamide, and mesna (VIP regimen)

    Intravenous dosage

    Adults

    75 mg/m2 IV on days 1 to 5, in combination with cisplatin (20 mg/m2 IV on days 1 to 5), ifosfamide (1,200 mg/m2 IV on days 1 to 5), and mesna (240 mg/m2 IV over 15 minutes before ifosfamide, then 240 mg/m2 IV at 4 and 8 hours from the start of each ifosfamide on days 1 to 5), every 21 days for 4 cycles. Patients who received previous radiation therapy had an initial 25% dose reduction of etoposide and ifosfamide.[29305] [49539] Administer appropriate hydration prior to cisplatin administration and maintain hydration and adequate urinary output for 24 hours after cisplatin administration.[28393] Due to a high risk of febrile neutropenia, colony-stimulating factors were administered in clinical trials. In a randomized clinical trial, treatment with VIP resulted in a complete response (CR) rate of 37% in patients with advanced, disseminated germ cell tumors compared with 31% in patients treated with bleomycin, etoposide, and cisplatin (BEP); 2-year failure-free survival (64% vs. 60%) and 2-year overall survival (74% vs. 71%) were not significantly different between treatment arms. Grade 3 or higher toxicity was significantly higher in patients who received VIP.[49539]

    For the treatment of high-risk gestational trophoblastic disease†

    in combination with methotrexate, leucovorin, actinomycin D, cyclophosphamide, and vincristine (EMA-CO regimen)†

    Intravenous dosage

    Adults

    100 mg/m2 IV once daily on days 1 and 2 in combination with methotrexate, leucovorin, actinomycin D, cyclophosphamide, and vincristine (EMA-CO regimen), repeated every 2 to 3 weeks depending on toxicity. Multiple studies have been reported with cure rates ranging from 70% to 90% in women with high-risk gestational trophoblastic disease. Results are typically better in women who receive EMA-CO as primary therapy and in women without metastatic disease. Consider growth-factor support to maintain dose-intensity and prevent hematological toxicity. Complete response is typically defined as 3 consecutive weekly human chorionic gonadotropin (hCG) levels that are undetectable or less than the upper limit of normal. In studies, treatment was continued for 2 to 3 additional courses after complete hCG response.[33966] [33967]

    in combination with methotrexate, leucovorin, actinomycin D, and cisplatin (EMA-EP regimen)†

    Intravenous dosage

    Adults

    100 mg/m2 IV once daily on days 1, 2, and 8 in combination with methotrexate, leucovorin, actinomycin D, and cisplatin (EMA-EP regimen), repeated every 2 to 3 weeks depending on toxicity. Studies in patients with chemorefractory high-risk gestational trophoblastic disease have shown response rates of greater than 90% with salvage treatment with EMA-EP. Consider growth-factor support to maintain dose-intensity and prevent hematological toxicity.[33965]

    For the treatment of acute lymphocytic leukemia (ALL)†

    for the treatment of relapsed or refractory ALL, in combination with cyclophosphamide and clofarabine†

    Intravenous dosage

    Adults 21 years and younger, Adolescents, and Children

    150 mg/m2 daily IV over 2 hours on days 1 to 5 plus cyclophosphamide 400 mg/m2 daily IV over 1 hour on days 1 to 5 and clofarabine 40 mg/m2 daily IV over 2 hours on days 1 to 5 were given in a clinical study. Clofarabine was administered before cyclophosphamide and etoposide. In patients with a blast count greater than 30 x 109 cells/L, prophylactic steroids were given.[49907] Alternately, etoposide 100 mg/m2 daily IV over 2 hours on days 1 to 5 plus cyclophosphamide 440 mg/m2 daily IV over 1 hour on days 1 to 5, and clofarabine 40 mg/m2 daily IV over 2 hours on days 1 to 5 has been studied. Each drug was given daily for 4 days if administered as consolidation treatment.[49910]

    for the treatment of relapsed or refractory acute lymphocytic leukemia (ALL) in combination with ifosfamide, carboplatin, and rituximab†

    Intravenous dosage

    Adults 21 years and younger, Adolescents, and Children

    Carboplatin 635 mg/m2 IV on day 3 in combination with ifosfamide 3,000 mg/m2 IV on days 3, 4 and 5 (each dose mixed with mesna 600 mg/m2 IV, followed by mesna 600 mg/m2 IV over 15 minutes at 3, 6, 9, and 12 hours after the start of ifosfamide) and etoposide 100 mg/m2 IV on days 3, 4, and 5 repeated for a maximum of 3 cycles. Rituximab 375 mg/m2 IV was given on days 1 and 3 of cycles 1 and 2, and on day 3 only of cycle 3. Colony-stimulating factors were initiated on day 6 of each cycle and intrathecal chemotherapy was also given as appropriate. Overall response rate was 60% and overall survival at 2 to 3 years was 37.5%.[44193]

    For the treatment of refractory acute myelogenous leukemia (AML)† in combination with mitoxantrone and cytarabine

    Intravenous dosage

    Children >= 5 years, Adolescents, and Adults

    80 mg/m2 IV over 1 hour, then cytarabine 1 g/m2 IV over 6 hours, then 3 hours later, mitoxantrone 6 mg/m2 IV bolus. All should be given daily for 6 days.[49914]

    Children < 5 years

    Safety and efficacy have not been established.

    For the treatment of Hodgkin lymphoma†

    for the treatment of Hodgkin lymphoma as part of the Stanford V regimen†

    Intravenous dosage

    Adolescents 15 years and older and Adults

    60 mg/m2 per day IV on 2 consecutive days in weeks 3, 7, and 11 in combination with mechlorethamine (6 mg/m2 IV on weeks 1, 5, and 9), doxorubicin (25 mg/m2 IV on weeks 1, 3, 5, 7, 9, and 11), vinblastine (6 mg/m2 IV on weeks 1, 3, 5, 7, 9, and 11), vincristine (1.4 mg/m2 (Max: 2 mg) IV on weeks 2, 4, 6, 8, 10, and 12), bleomycin (5 units/m2 IV on weeks 2, 4, 6, 8, 10, and 12) and prednisone (40 mg/m2 PO every other day for 10 weeks then tapered by 10 mg PO every other day between weeks 10 and 12). Total duration of Stanford V regimen is 12 weeks (three 4-week cycles).[40464] [40465] [36931] [40466] [40469] Doses of mechlorethamine, doxorubicin, vinblastine, and etoposide have been reduced to 65% if ANC less than 1,000 cells/mm3 (treatment delayed if ANC less than 500 cells/mm3). Prophylactic sulfamethoxazole-trimethoprim, acyclovir, and a H2-blocker were given throughout the treatment period.[40464] G-CSF has also been used to maintain dose intensity as needed after the first dose reduction.[40465] [40469] Alternative prophylactic medications have also been used.[36931]

    for the treatment of Hodgkin lymphoma as part of the BEACOPP regimen†

    Intravenous dosage

    Adolescents 15 years and older and Adults

    100 mg/m2 IV once daily on days 1 to 3 in combination with bleomycin (10 units/m2 IV on day 8), doxorubicin (25 mg/m2 IV on day 1), cyclophosphamide (650 mg/m2 IV on day 1), vincristine (1.4 mg/m2 [Max: 2 mg] IV on day 8), procarbazine (100 mg/m2 PO once daily on days 1 to 7), and prednisone (40 mg/m2 PO on days 1 to 14). Cycles are repeated every 21 days for up to 8 cycles. Filgrastim was administered beginning on day 8 of each cycle and continued until the leukocyte count returned to normal in some clinical trials.[12501] [40572] The escalated dose BEACOPP regimen includes etoposide 200 mg/m2 IV once daily on days 1 to 3, in combination with bleomycin (10 units/m2 IV on day 8), doxorubicin (35 mg/m2 IV on day 1), cyclophosphamide (1,200 mg/m2 IV on day 1), vincristine (1.4 mg/m2 [Max: 2 mg] IV on day 8), procarbazine (100 mg/m2 PO once daily on days 1 to 7), and prednisone (40 mg/m2 PO on days 1 to 14). Cycles are repeated every 21 days for up to 8 cycles. Filgrastim was administered beginning on day 8 of each cycle and continued until the leukocyte count returned to normal in some clinical trials.[12501] [40572]The standard dose BEACOPP and escalated dose BEACOPP regimens have shown benefit for the treatment of advanced Hodgkin lymphoma in clinical trials.[12501] [40572] [40568] Escalated dose BEACOPP has shown significantly better freedom from treatment failure at 10 years (82% vs. 70%) and overall survival at 10 years (86% vs. 80%) compared to standard dose BEACOPP.[49830] A regimen of 4 cycles of escalated dose BEACOPP followed by 4 cycles of standard-dose BEACOPP has also been used in patients who achieve a complete response after the initial 4 cycles of escalated dose BEACOPP.[40568]

    for the treatment of previously untreated, high-risk classical Hodgkin lymphoma, in combination with brentuximab vedotin, doxorubicin, vincristine, prednisone, and cyclophosphamide†

    Intravenous dosage

    Children 2 years and older and Adolescents

    125 mg/m2 IV on days 1, 2, and 3 in combination with brentuximab vedotin 1.8 mg/kg (not to exceed 180 mg/dose) IV on day 1; doxorubicin 25 mg/m2 IV on days 1 and 2; vincristine 1.4 mg/m2 IV on day 8; prednisone 20 mg/m2 PO twice daily on days 1 to 7; and cyclophosphamide 600 mg/m2 IV on days 1 and 2 repeated every 3 weeks for up to 5 cycles. Administer primary prophylaxis with a granulocyte colony-stimulating factor starting in cycle 1 due to the high incidence of febrile neutropenia.[45378] At a median follow-up time of 42.1 (range, 0.1 to 80.9) months, the 3-year event-free survival rate was significantly improved in patients (median age, 15.6 years; range, 3.4 to 21.99 years) with newly diagnosed, stage IIB with bulk tumor or stage IIIB, IVA, or IVB classic Hodgkin lymphoma who received brentuximab vedotin plus AVEPC compared with doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide (ABVE-PC) (92.1% vs. 82.5%; hazard ratio (HR) = 0.41; 95% CI, 0.25 to 0.67) in a multicenter, randomized, phase 3 trial (n = 587). The 3-year overall survival rates were 99.3% and 98.5% in the brentuximab vedotin plus AVEPC and ABVE-PC arms, respectively.[68172]

    For the treatment of relapsed or refractory non-Hodgkin's lymphoma (NHL)† in combination with ifosfamide and carboplatin

    Intravenous dosage

    Adults

    Etoposide 100 mg/m2 IV once daily on days 1 to 3, ifosfamide 5 g/m2 IV mixed with equal dose of mesna via continuous intravenous infusion over 24 hours beginning on day 2, carboplatin AUC 5 IV on day 2 (Max: 800 mg), every 2 weeks (ICE regimen) for 3 cycles, was developed to treated relapsed NHL and allow for adequate stem cell collection prior to transplant.[29307] Alternative dosage regimens have been used, including some in the outpatient setting.[51026]

    For stem cell transplant preparation and bone marrow ablation†

    for stem cell mobilization in combination with ifosfamide and carboplatin, in transplant eligible patients with non-Hodgkin's lymphoma

    Intravenous dosage

    Adults

    Etoposide 100 mg/m2/day IV on days 1, 2, and 3 in combination with carboplatin AUC 5 (Max: 800 mg) IV on day 2 and ifosfamide 5 g/m2 mixed with an equal dose of mesna administered via continuous IV infusion for 24 hours beginning day 2. Filgrastim was administered at 10 mcg/kg/day starting on day 5 until completion of leukapheresis.[29307]

    for stem cell transplant preparation and bone marrow ablation for allogeneic hematopoietic stem cell transplantation, in combination with total body irradiation†

    Intravenous dosage

    Adults, Adolescents, and Children

    Etoposide 60 mg/kg IV on day -3 in combination with total body irradiation with 1320 cGy (11 fractions of 120 cGy delivered between days -7 and -4).[44348]

    For the treatment of neuroblastoma†

    for the treatment of intermediate-risk neuroblastoma in combination with carboplatin, cyclophosphamide, doxorubicin†

    Intravenous dosage

    Infants and Children

    Etoposide has been given in combination with carboplatin, cyclophosphamide, and doxorubicin. In Cycles 1 and 7: Carboplatin 560 mg/m2 IV on day 1 (18 mg/kg per day in children less than 12 kg) plus etoposide 120 mg/m2 per day IV on days 1 to 3 (4 mg/kg per day in children less than 12 kg). Cycles 2 and 6: Carboplatin 560 mg/m2 IV on day 1 (18 mg/kg per day in children less than 12 kg) plus cyclophosphamide 1,000 mg/m2 IV on day 1 (33 mg/kg per day in children less than 12 kg), and doxorubicin 30 mg/m2 IV on day 1 (1 mg/kg per day in children less than 12 kg). Cycles 3 and 5: Cyclophosphamide 1,000 mg/m2 IV on day 1 (33 mg/kg per day in children less than 12 kg) plus etoposide 120 mg/m2 per day IV on days 1 to 3 (4 mg/kg per day in children less than 12 kg). Cycle 4: Carboplatin 560 mg/m2 IV on day 1 (18 mg/kg per day in children less than 12 kg) plus etoposide 120 mg/m2 per day IV on days 1 to 3 (4 mg/kg per day in children less than 12 kg), and doxorubicin 30 mg/m2 IV on day 1 (1 mg/kg per day in children less than 12 kg). Cycle 8: Cyclophosphamide 1,000 mg/m2 IV on day 1 (33 mg/kg per day in children less than 12 kg) plus doxorubicin 30 mg/m2 IV on day 1 (1 mg/kg per day in children less than 12 kg). All cycles given at 3 week intervals. Patients with favorable biologic features received 4 cycles; if incomplete response after 4 cycles, patients given an additional 4 cycles. Patients with unfavorable biologic features received 8 cycles. Infants younger than 60 days of age received granulocyte colony-stimulating factor after each cycle.[49848]

    for the treatment of localized and unresectable neuroblastoma in combination with cisplatin, alternating with cyclophosphamide, vincristine, and doxorubicin†

    Intravenous dosage

    Adolescents and Children

    100 mg/m2 per day IV on days 1 to 5 in combination with cisplatin 40 mg/m2 per day IV on days 1 to 5 (CVP regimen), alternating with cyclophosphamide, vincristine, and doxorubicin (CADO regimen). Two cycles of each regimen should be given as induction therapy, followed by surgery. The administration of cisplatin as a 1-hour infusion reduced the incidence of neutropenia compared to administration as a continuous infusion.[50270]

    For the treatment of refractory desmoid tumor† and fibromatosis†

    Intravenous dosage

    Adults

    A small series of patients with recurrent desmoid tumors were treated with combination chemotherapy including a regimen of etoposide 100 mg/m2 per day IV on days 1 to 3, in combination with ifosfamide (2,500 mg/m2 per day IV with mesna on days 1 to 3), repeated every 3 to 4 weeks. Two patients received a combination of mitomycin/doxorubicin/cisplatin in sequence with etoposide/ifosfamide. Clinical benefit was reported in 6 of 7 patients and objective responses were noted in 3 patients.[27474]

    For the first-line treatment of unresectable, advanced thymoma†

    for the first-line treatment of unresectable, advanced thymoma in combination with cisplatin†

    Intravenous dosage

    Adults

    120 mg/m2 per day IV over at least 30 minutes on days 1 to 3 plus cisplatin 60 mg/m2 IV over 1 hour (with hydration) on day 1 repeated every 3 weeks for up to 8 cycles (median of 6 cycles; range, 2 to 9 cycles) has been studied in 16 patients in a phase 2 study. Overall response rate was 56%.[41519]

    for the first-line treatment of unresectable, advanced thymoma in combination with cisplatin and ifosfamide†

    Intravenous dosage

    Adults

    75 mg/m2 per day IV on days 1 to 4 plus cisplatin 20 mg/m2 per day IV (with hydration) on days 1 to 4 and ifosfamide 1,200 mg/m2 per day IV (with mesna 240 mg/m2 IV push prior to and at 4 and 8 hours after each ifosfamide dose) on days 1 to 4 repeated every 3 weeks for 4 cycles (median of 4 cycles; range, 1 to 6 cycles) or until disease progression or unacceptable toxicity resulted in favorable overall response rates in a nonrandomized study of 28 patients (20 with thymoma). All patients received granulocyte colony-stimulating factor 5 mcg/kg/day subcutaneously on days 5 to 15 or until a postnadir white blood cell count of 10,000 cells/mm3.[41521]

    For the first-line treatment of unresectable, advanced thymic carcinoma†, in combination with cisplatin and ifosfamide

    Intravenous dosage

    Adults

    75 mg/m2 per day IV on days 1 to 4 plus cisplatin 20 mg/m2 per day IV (with hydration) on days 1 to 4 and ifosfamide 1,200 mg/m2 per day IV (with mesna 240 mg/m2 IV push prior to and at 4 and 8 hours after each ifosfamide dose) on days 1 to 4 repeated every 3 weeks for 4 cycles or until disease progression or unacceptable toxicity (median of 4 cycles; range, 1 to 6 cycles) resulted in an overall response rate (ORR) of 32% (all partial responses; median duration of response, 11.9 months) in 28 patients with advanced thymoma or thymic carcinoma in a nonrandomized study. All patients received granulocyte colony-stimulating factor 5 mcg/kg per day subcutaneously on days 5 to 15 or until a postnadir white blood cell count of 10,000 cells/mm3. At a median follow-up of 43 months, the median overall survival (OS) time was 31.6 months and the 1- and 2-year OS rates were 89% and 70%, respectively. In the 8 patients with advanced thymic carcinoma, the ORR was 25% and the 1- and 2-year OS rates were 75% and 50%, respectively. Serious toxicity reported in this study included grade 3 or 4 thrombocytopenia (18%), leukopenia (16%), and anemia (15%).[41521]

    For the treatment of poor-risk relapsed Wilms' tumor in combination with ifosfamide and carboplatin†

    Intravenous dosage

    Adults <= 21 years, Adolescents, and Children

    Ifosfamide 1,800 mg/m2 per day IV for 5 days (on days 0 to 4), carboplatin 400 mg/m2 per day IV for 2 days (on day 0 to 1) and etoposide 100 mg/m2 per day IV for 5 days (on days 0 to 4), repeated every 21 days.[50019]

    For the treatment of small cell lung cancer (SCLC)

    for the first-line treatment of SCLC, in combination with other approved chemotherapeutic agents

    Intravenous dosage

    Adults

    35 mg/m2 IV once daily on days 1 to 4 in combination with other approved chemotherapeutic agents, every 3 to 4 weeks. Alternatively, administer etoposide 50 mg/m2 IV once daily on days 1 to 5 in combination with other approved chemotherapeutic agents, every 3 to 4 weeks. Etoposide injection should be administered over at least 30 to 60 minutes, while etoposide phosphate injection (Etopophos) may be infused over 5 minutes to 3.5 hours.[64884] [53552] Other doses and regimens have been used; consult the literature for specific protocols.

    Oral dosage

    Adults

    70 mg/m2 PO once daily on days 1 to 4 in combination with other approved chemotherapeutic agents, every 3 to 4 weeks. Alternatively, administer etoposide 100 mg/m2 PO once daily on days 1 to 5 in combination with other approved chemotherapeutic agents, every 3 to 4 weeks. Round the dose to the nearest capsule strength. The recommended dose of etoposide capsules is two times the IV dose, rounded to the nearest 50 mg.[53551] Other doses and regimens have been used; consult the literature for specific protocols.

    for the treatment of limited-stage SCLC, in combination with cisplatin

    Intravenous dosage

    Adults

    100 mg/m2 IV on days 1 to 3, in combination with cisplatin (75 mg/m2 IV on day 1) and concurrent radiation therapy, every 3 weeks for up to 4 to 6 cycles (EP); cisplatin has also been administered at a dose of 25 mg/m2 IV on days 1 to 3.[64886] [34315] An alternative cisplatin/etoposide dosing regimen for the treatment of limited-stage SCLC is etoposide 120 mg/m2 IV on days 1 to 3 in combination with cisplatin 60 mg/m2 IV on day 1, every 3 weeks for 4 cycles.[34312] Administer appropriate hydration prior to cisplatin administration and maintain hydration and adequate urinary output for 24 hours after cisplatin administration.[28393] The use of colony-stimulating factors is not recommended during concurrent EP plus radiation therapy.[64887] In an open-label, phase 3 trial comparing twice-daily radiation therapy versus once-daily radiation therapy and a backbone of concurrent EP in patients with limited-stage SCLC, treatment with EP plus twice-daily radiotherapy resulted in a median overall survival of 30 months, 2-year overall survival of 56%, and median progression-free survival of 15.4 months. Once-daily radiation therapy was not superior to twice-daily radiation.[64886]

    for the treatment of limited-stage SCLC, in combination with carboplatin and radiation therapy†

    Intravenous dosage

    Adults

    100 mg/m2 daily IV on days 1, 2, 3 in combination with carboplatin (AUC 6 IV on day 1), every 3 weeks for up to 6 cycles. Hyperfractionated thoracic radiation therapy should be given concurrently with chemotherapy. Treatment with carboplatin and etoposide with concurrent HTRT resulted in an overall response rate of 76% to 92.5% (complete response, 40.5% to 56.5%), median time to progression of 9.5 to 10.5 months, and overall survival of 17 to 17.5 months.[50248]

    for the first-line treatment of extensive-stage SCLC, in combination with carboplatin and atezolizumab†

    Intravenous dosage

    Adults

    100 mg/m2 IV on days 1, 2, and 3, every 3 weeks for 4 cycles. Administer in combination with carboplatin (AUC 5 IV on day 1, every 3 weeks for 4 cycles) and atezolizumab (840 mg IV every 2 weeks; OR 1,200 mg IV every 3 weeks; OR 1,680 mg IV every 4 weeks). Administer atezolizumab prior to chemotherapy when given on the same day. In a randomized, double-blind, phase 3 clinical trial (IMpower133), the addition of atezolizumab to carboplatin plus etoposide significantly improved overall survival (12.3 months vs. 10.3 months) and progression-free survival (5.2 months vs. 4.3 months) compared with placebo plus carboplatin/etoposide. Survival at 1 year was 51.7% versus 38.2%, respectively. Treatment was well-tolerated, with 56.5% of patients in the atezolizumab arm experiencing grade 3 or 4 adverse reactions compared with 56.1% of those in the placebo arm. Immune-related adverse reactions occurred in 39.9% versus 24.5% of patients, respectively.[63611] [60793]

    for the first-line treatment of extensive-stage SCLC, in combination with carboplatin and durvalumab

    Intravenous dosage

    Adults weighing more than 30 kg

    80 to 100 mg/m2 IV on days 1 to 3 plus carboplatin (AUC 5 to 6 IV on day 1), following administration of durvalumab (1,500 mg IV over 60 minutes on day 1), every 3 weeks for 4 cycles; administer durvalumab prior to chemotherapy when given on the same day. After completion of 4 cycles of durvalumab plus chemotherapy, continue durvalumab 1,500 mg IV every 4 weeks as a single agent until disease progression or unacceptable toxicity. Durvalumab significantly improved overall survival by approximately 3 months when added to platinum-etoposide chemotherapy compared with platinum-etoposide alone in patients with extensive-stage SCLC in a randomized clinical trial.[64736] [61913]

    Adults weighing 30 kg or less

    80 to 100 mg/m2 IV on days 1 to 3 plus carboplatin (AUC 5 to 6 IV on day 1), following administration of durvalumab (20 mg/kg IV over 60 minutes on day 1), every 3 weeks for 4 cycles; administer durvalumab prior to chemotherapy when given on the same day. After completion of 4 cycles of durvalumab plus chemotherapy, continue durvalumab 20 mg/kg IV every 4 weeks as a single agent until disease progression or unacceptable toxicity. Durvalumab significantly improved overall survival by approximately 3 months when added to platinum-etoposide chemotherapy compared with platinum-etoposide alone in patients with extensive-stage SCLC in a randomized clinical trial.[64736] [61913]

    for the first-line treatment of extensive-stage SCLC, in combination with cisplatin and durvalumab

    Intravenous dosage

    Adults weighing more than 30 kg

    80 to 100 mg/m2 IV on days 1 to 3 plus cisplatin (75 to 80 mg/m2 IV on day 1), following administration of durvalumab (1,500 mg IV over 60 minutes on day 1), every 3 weeks for 4 cycles; administer durvalumab prior to chemotherapy when given on the same day.[64736] [61913] Administer appropriate hydration prior to cisplatin administration and maintain hydration and adequate urinary output for 24 hours after cisplatin administration.[28393] After completion of 4 cycles of durvalumab plus chemotherapy, continue durvalumab 1,500 mg IV every 4 weeks as a single agent until disease progression or unacceptable toxicity. Durvalumab significantly improved overall survival by approximately 3 months when added to platinum-etoposide chemotherapy compared with platinum-etoposide alone in patients with extensive-stage SCLC in a randomized clinical trial.[64736] [61913]

    Adults weighing 30 kg or less

    80 to 100 mg/m2 IV on days 1 to 3 plus cisplatin (75 to 80 mg/m2 IV on day 1), following administration of durvalumab (20 mg/kg IV over 60 minutes on day 1), every 3 weeks for 4 cycles; administer durvalumab prior to chemotherapy when given on the same day.[64736] [61913] Administer appropriate hydration prior to cisplatin administration and maintain hydration and adequate urinary output for 24 hours after cisplatin administration.[28393] After completion of 4 cycles of durvalumab plus chemotherapy, continue durvalumab 20 mg/kg IV every 4 weeks as a single agent until disease progression or unacceptable toxicity. Durvalumab significantly improved overall survival by approximately 3 months when added to platinum-etoposide chemotherapy compared with platinum-etoposide alone in patients with extensive-stage SCLC in a randomized clinical trial.[64736] [61913]

    for the treatment of extensive-stage SCLC, in combination with carboplatin†

    Intravenous dosage

    Adults

    80 mg/m2 daily IV on days 1, 2, 3 in combination with carboplatin AUC 5 IV on day 1, every 3 to 4 weeks up to 4 courses. [50232]

    for the treatment of newly-diagnosed small cell lung cancer (SCLC), in combination with cyclophosphamide and doxorubicin (CDE)

    Intravenous dosage

    Adults

    Etoposide 100 mg/m2 daily IV on days 1, 2, 3 in combination with cyclophosphamide 1,000 mg/m2 IV on day 1 and doxorubicin 45 mg/m2 IV on day 1, every 3 weeks for 5 cycles.[50310] [51057]

    For the treatment of newly diagnosed Ewing's sarcoma† family tumors, in combination with ifosfamide, alternating with vincristine, doxorubicin, and cyclophosphamide

    Intravenous dosage

    Adults 30 years or younger, Adolescents, and Children

    100 mg/m2 per day IV on days 1 to 5 in combination with ifosfamide 1,800 mg/m2 per day IV on days 1 to 5 (with equal dose mesna) repeated every 3 weeks; alternating with vincristine 2 mg/m2 (maximum dose of 2 mg) on day 1 with doxorubicin 75 mg/m2 IV bolus on day 1, and cyclophosphamide 1,200 mg/m2 on day 1 repeated every 3 weeks. Dactinomycin 1.25 mg/m2 IV on day 1 was substituted for doxorubicin once a cumulative doxorubicin dose of 375 mg/m2 IV was reached.[29312]

    Therapeutic Drug Monitoring

    Maximum Dosage Limits

    • Adults

      IV: 200 mg/m2 per day.[12501][40572]

      PO: 100 mg/m2 per day.

    • Geriatric

      IV: 200 mg/m2 per day.[12501][40572]

      PO: 100 mg/m2 per day.

    • Adolescents

      IV: 200 mg/m2 per day.[12501][40572]

    • Children

      IV: 150 mg/m2 per day.[49907]

    • Infants

      IV: 120 mg/m2 per day.[49848]

    Patients with Hepatic Impairment Dosing

    Specific guidelines for dosage adjustments in hepatic impairment are not provided by the manufacturer. However, biliary excretion of unchanged drug and/or metabolites is an important route of etoposide elimination and the unbound (free) fraction of etoposide significantly correlates with increased bilirubin in cancer patients.[61465][53551][53552]

     

    Dosage adjustments based on bilirubin levels have been suggested as follows:

    • Bilirubin 1.5 to 3 mg/dL or AST greater than 3 times the upper limit of normal (ULN): Reduce the etoposide dose by 50%.[53549]
    • Bilirubin 3 to 5 mg/dL: Reduce the etoposide dose by 75%.
    • Bilirubin greater than 5 mg/dL: Hold etoposide.[53550]

    Patients with Renal Impairment Dosing

    • CrCl 15 to 50 mL/min: Reduce the etoposide dose by 25%.
    • CrCl less than 15 mL/min: Consider further dose reduction; data are not available.[53552][53551][64884]
    † Off-label indication
    Revision Date: 01/11/2024, 04:54:00 PM

    References

    12501 - Diehl V, Franklin J, Pfreundschuh M, et al. Standard and increased-dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin's disease. N Engl J Med 2003;348:2386-9527474 - Okuno SH, Edmonoson JH. Combination chemotherapy for desmoid tumors. Cancer 2003;97:1134-5.28393 - Platinol (cisplatin) for injection package insert. Paramus, NJ: WG Critical Care, LLC; 2022 March.29305 - Nichols CR, Catalano P, Loehrer PJ, et al. Randomized comparison of cisplatin and etoposide and either bleomycin or ifosfamide in treatment of advanced disseminated germ cell tumors: an Eastern Cooperative Oncology Group, Southwest Oncology Group, and Cancer and Leukemia Group B Study. J Clin Oncol 1998;16:1287-93.29307 - Moskowitz CH, Bertino JR, Glassman JR, et al. Ifosfamide, carboplatin and etoposide: A highly effective cytoreduction and peripheral-blood progenitor-cell mobilization regimen for transplant-eligible patients with non-Hodgkins lymphoma. J Clin Oncol 1999;17:3776-85.29312 - Grier HE, Krailo MD, Tarbel NJ, et al. Addition of ifosfamide and etoposide to standard chemotherapy for Ewing's sarcoma and primitive neuroectodermal tumor of bone. N Engl J Med 2003;348:694-701.33965 - Xiang Y, Sun Z, Wan X, et al. EMA/EP chemotherapy for chemorefractory gestational trophoblastic tumor. J Reprod Med 2004;49:443-6.33966 - Lurain JR, Singh DK, Schink JC. Primary treatment of metastatic high-risk gestational trophoblastic neoplasia with EMA-CO chemotherapy. J Reprod Med 2006;51:767-72.33967 - Bower M, Newlands ES, Holden L, et al. EMA/CO for high-risk gestational trophoblastic tumors: results from a cohort of 272 patients. J Clin Oncol 1997;15:2636-43.34312 - Turrisi AT, Kim K, Blum R, et al. Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med 1999;340:265-71.34315 - Evans WK, Shepherd FA, Feld R, et al. VP-16 and cisplatin as first-line therapy for small-cell lung cancer. J Clin Oncol 1985;3:1471-7.34318 - The International Adjuvant Lung Cancer Trial Collaborative Group. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med 2004;350:351-60.34319 - Albain KS, Crowley JJ, Turrisi AT, et al. Concurrent cisplatin, etoposide, and chest radiotherapy in pathologic stage IIIB non-small cell lung cancer: a Southwest Oncology Group phase II study, SWOG 9019. J Clin Oncol 2002;20:3454-60.36931 - Gobbi PG, Levis A, Chisesi T. ABVD versus modified Stanford V versus MOPPEBVCAD with optional and limited radiotherapy in intermediate- and advanced-stage Hodgkin's lymphoma: final results of a multicenter randomized trial by the Intergruppo Italiano Linfomi. J Clin Oncol. 2005;23:9198-20740464 - Horning SJ, Hoppe RT, Breslin S, et al. Stanford V and radiotherapy for locally extensive and advanced Hodgkin's disease: mature results of a prospective clinical trial. J Clin Oncol 2002;20:630-637.40465 - Horning SJ, Hoppe RT, Advani R, et al. Efficacy and late effects of Stanford V chemotherapy and radiotherapy in untreated Hodgkin's disease: mature data in early and advanced stage patients. Presented at ASH Annual Meeting; 2004. Abstract 308.40466 - Hoskin PJ, Lowry L, Horwich A, et al. Randomized comparison of the Stanford V regimen and ABVD in the treatment of advanced Hodgkin's lymphoma: United Kingdom National Cancer Research Institute Lymphoma Group Study ISRCTN 64141244. J Clin Oncol 2009;27:5390-5396.40469 - Edwards-Bennett SM, Jacks LM, Moskowitz CH, et al. Stanford V program for locally extensive and advanced Hodgkin's lymphoma: the Memorial Sloan-Kettering Cancer Center experience. Ann Oncol 2010;21:574-581.40568 - Diehl V, Haverkamp H, Mueller R, et al. Eight cycles of BEACOPP escalated compared with 4 cycles of BEACOPP escalated followed by 4 cycles of BEACOPP baseline with or without radiotherapy in patients in advanced stage Hodgkin lymphoma: final analysis of the HD12 trial of the German Hodgkin Study Group. Presented at ASCO Annual Meeting. Orlando, FL; 2009. Abstract 8544.40572 - Diehl V, Franklin J, Pfistner B, et al. Ten-year results of a German Hodgkin Study Group randomized trial of standard and increased dose BEACOPP chemotherapy for advanced Hodgkin lymphoma (HD9). Presented at ASCO Annual Meeting. 2007:Abstract LBA8014.41519 - Giaccone G, Ardizzoni A, Kirkpatrick A, et al. Cisplatin and etoposide combination chemotherapy for locally advanced or metastatic thymoma: a phase II study of the European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group. J Clin Oncol 1996;14:814-820.41521 - Loehrer PJ, Jiroutek M, Alsner S, et al. Combined etoposide, ifosfamide, and cisplatin in the treatment of patients with advanced thymoma and thymic carcinoma. Cancer 2001;91:2010-2015.44193 - Griffin TC, Weitzman S, Weinstein H, Chang M, et al; Children's Oncology Group. A study of rituximab and ifosfamide, carboplatin, and etoposide chemotherapy in children with recurrent/refractory B-cell (CD20+) non-Hodgkin's lymphoma and mature B-cell acute lymphoblastic leukemia: a report from the Children's Oncology Group. Pediat Blood Cancer. 2009;52(2):177-181.44348 - Blume KG, Kopecky KJ, Henslee-Downey JP, et al. A prospective randomized comparison of total body irradiation-etoposide versus busulfan-cyclophosphamide as preparatory regimens for bone marrow transplantation in patients with leukemia who were not in first remission: a Southwest OncologyGroup study. Blood 1993;81(8):2187-93.45378 - Adcetris (brentuximab vedotin) injection package insert. Bothell, WA: Seagen Inc; 2023 June.49371 - Loehrer PJ Sr, Johnson D, Elson P, Einhorn LH, Trump D. Importance of bleomycin in favorable-prognosis disseminated germ cell tumors: an Eastern Cooperative Oncology Group trial. J Clin Oncol. 1995;13:470-649372 - Bosl GJ, Geller NL, Bajorin D, et al. A randomized trial of etoposide + cisplatin versus vinblastine + bleomycin + cisplatin + cyclophosphamide + dactinomycin in patients with good-prognosis germ cell tumors. J Clin Oncol. 1988;6:1231-849375 - Bajorin DF, Sarosdy MF, Pfister DG, et al. Randomized trial of etoposide and cisplatin versus etoposide and carboplatin in patients with good-risk germ cell tumors: a multi-institutional study. J Clin Oncol. 1993;11:598-60649539 - Mesnex (mesna) tablet package insert. Deerfield, IL: Baxter Healthcare; 2018 Dec.49830 - Engert A, Diehl V, Franklin J, et al. Escalated-dose BEACOPP in the treatment of patients with advanced-stage Hodgkin's lymphoma: 10 years of follow-up of the GHSG HD9 study. J Clin Oncol 2009; 27(27):4548-4554.49848 - Baker DL, Schmidt ML, Cohn SL, et al. Outcome after reduced chemotherapy for intermediate-risk neuroblastoma. N Eng J Med 2010;363:1313-1323.49907 - Locatelli F, Testi AM, Bernardo ME, et al. Clofarabine, cyclophosphamide and etoposide as single-course re-induction therapy for children with refractory/multiple relapsed acute lymphoblastic leukaemia. Br J Haematol 2009;147:371-37849910 - Hijiya N, Thomson B, Isakoff MS, et al. Phase 2 trial of clofarabine in combination with etoposide and cyclophosphamide in pediatric patients with refractory or relapsed acute lymphoblastic leukemia. Blood 2011;118:6043-6049.49914 - Amadori S, Arcese W, Isacchi G et al. Mitoxantrone, etoposide and intermediate-dose cytarabine: an effective and tolerable regimen for the treatment of refractory acute myeloid leukemia. J Clin Oncol 1991;9:1210-121450019 - Abu-Ghosh AM, Krailo MD, Goldman SC, et al. Ifosfamide, carboplatin and etoposide in children with poor-risk relapsed Wilms' tumor: a Children's Cancer Group report. Ann Oncol 2002;13:460-469.50232 - Okamoto H, Watanabe K, Kunikane H et al. Randomized phase III trial of carboplatin plus etoposide vs split doses of cisplatin plus etoposide in elderly or poor-risk patients with extensive disease small-cell lung cancer: JCOG 9702. Br J Cancer 2007;97:162-16950248 - Skarlos DV, Samantas E, Briassoulis E et al. Randomized comparison of early versus late hyperfractionated thoracic irradiation concurrently with chemotherapy in limited disease small-cell lung cancer: a randomized phase II study of the Hellenic Cooperative Oncology Group (HeCOG). Ann Oncol 2001;123:1231-1238.50270 - Coze C, Hartmann O, Michon J et al. NB87 induction protocol for stage 4 neuroblastoma in children over 1 year of age: a report from the French Society of Pediatric Oncology. J Clin Oncol 1997;12:3433-3440.50310 - De Jong Wk, Groen JH, Koolen MG et al. Phase III study of cyclophosphamide, doxorubicin, and etoposide compared with carboplatin and paclitaxel in patients with extensive disease small-cell lung cancer. Eur J Cancer 2007;16:2345-2350.51026 - Hertzberg MS, Crombie C, Benson W, et al. Outpatient fractionated ifosfamide, carboplatin and etoposide as salvage therapy in relapsed and refractory non-Hodgkin’s and Hodgkin’s lymphoma. Annals of Oncology 2006;17 (Suppl 4):iv25-iv30.51057 - Ardizzoni A, Tjan-Heijnen VCG, Postmus PE, Buchholz E, Biesma B, Karnicka-Mlodkowska H, et al. Standard versus intensified chemotherapy with granulocyte colony-stimulating factor support in small-cell lung cancer: a prospective European Organization for Research and Treatment of Cancer – Lung Cancer Group phase III trial - 08923. J Clin Oncol 2002; 20: 3947 - 55.51373 - Albain KS, Rusch VW, Crowley JJ, et al. Concurrent cisplatin / etoposide plus chest radiotherapy followed by surgery for stages IIIA (N2) and IIIB non-small-cell lung cancer: mature results of Southwest Oncology Group phase II study 8805. J Clin Oncol 1995; 13 (8): 1880-1892.53549 - Floyd J, Mirza I, Sachs B, et al. Hepatotoxicity of chemotherapy. Semin Oncol 2006;33(1):50-67.53550 - Macdonald JS. Cancer chemotherapy and the liver. Clin Liver Dis 1998;2(3):631-642.53551 - Etoposide capsules package insert. Morgantown, WV: Mylan Pharmaceuticals Inc; 2016 April.53552 - Etopophos (etoposide phosphate) injection package insert. Princeton, NJ: Bristol-Myers Squibb Company; 2019 May.60793 - Tecentriq (atezolizumab) injection package insert. South San Francisco, CA: Genentech, Inc.; 2024 Apr.61465 - Etoposide injection package insert. Lake Zurich, IL: Fresenius Kabi USA, LLC; 2016 Feb.61913 - Imfinzi (durvalumab) injection package insert. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2024 June.63611 - Horn L, Mansfield AS, Szczesna A, et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. NEJM. 2018;379:2220-2229.64338 - Xiao H, Mazumdar M, Bajorin DF, et al. Long-term follow-up of patients with good-risk germ cell tumors treated with etoposide and cisplatin. J Clin Oncol. 1997;15(7):2553-2558.64341 - Saxman SB, Finch D, Gonin R, et al. Long-term follow-up of a phase III study of three versus four cycles of bleomycin, etoposide, and cisplatin in favorable-prognosis germ-cell tumors: the Indiana University experience. J Clin Oncol. 1998;16(2):702-706.64736 - Paz-Ares L, Dvorkin M, Chen Y, et al. Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. The Lancet. 2019;394:1929-1939.64884 - Etoposide injection package insert. Eatontown, NJ: Hikma Pharmaceuticals USA Inc.; 2019 Aug.64886 - Faivre-Finn C, Snee M, Ashcroft L, et al. Concurrent once-daily versus twice-daily chemoradiotherapy in patients with limited-stage small-cell lung cancer (CONVERT): an open-label, phase 3, randomised, superiority trial. Lancet Oncology. 2017;18:1116-1125.64887 - Bunn PA, Crowley J, Kelly K, et al. Chemoradiotherapy with or without granulocyte-macrophage colony-stimulating factor in the treatment of limited-stage small-cell lung cancer: a prospective phase III randomized study of the Southwest Oncology Group. J Clin Oncol. 1995;13:1632-1641.68172 - Castellino SM, Pei Q, Parsons SK, et al. Brentuximab vedotin with chemotherapy in pediatric high-risk Hodgkin's lymphoma. N Engl J Med 2022;387(18):1649-1660.

    How Supplied

    Etoposide Oral capsule

    Etoposide 50mg Capsule (51079-0965) (Mylan Institutional LLC) (off market)

    Etoposide Oral capsule

    Etoposide 50mg Capsule (00378-3266) (Mylan Pharmaceuticals Inc.) nullEtoposide 50mg Capsule package photo

    Etoposide Oral capsule

    Vepesid 50mg Capsule (00015-3091) (Bristol Myers Squibb Oncology Products) (off market)

    Etoposide Phosphate Lyophilisate for solution for injection

    Etopophos 100mg Powder for Injection (00015-3404) (Bristol Myers Squibb Oncology Products) nullEtopophos 100mg Powder for Injection package photo

    Etoposide Phosphate Lyophilisate for solution for injection

    Etopophos 100mg Powder for Injection (61269-0410) (H2-Pharma, LLC) null

    Etoposide Solution for injection

    Etoposide 100mg/5ml Solution for Injection (16729-0114) (Accord Healthcare, Inc.) nullEtoposide 100mg/5ml Solution for Injection package photo

    Etoposide Solution for injection

    Etoposide 100mg/5ml Solution for Injection (63323-0104) (Fresenius Kabi USA, LLC ) null

    Etoposide Solution for injection

    Etoposide 100mg/5mL Solution for Injection (68001-0265) (BluePoint Lab Injectables) null

    Etoposide Solution for injection

    Etoposide 100mg/5mL Solution for Injection (00143-9510) (Hikma Pharmaceuticals USA inc.) null

    Etoposide Solution for injection

    Etoposide 100mg/5ml Solution for Injection (NOVAPLUS) (16729-0262) (Accord Healthcare, Inc.) null

    Etoposide Solution for injection

    Etoposide 100mg/5mL Solution for Injection (NOVAPLUS) (00143-9376) (Hikma Pharmaceuticals USA inc.) null

    Etoposide Solution for injection

    Etoposide 1g/50ml Solution for Injection (16729-0114) (Accord Healthcare, Inc.) null

    Etoposide Solution for injection

    Etoposide 1g/50ml Solution for Injection (63323-0104) (Fresenius Kabi USA, LLC ) null

    Etoposide Solution for injection

    Etoposide 1g/50mL Solution for Injection (68001-0265) (BluePoint Lab Injectables) null

    Etoposide Solution for injection

    Etoposide 1g/50mL Solution for Injection (00143-9512) (Hikma Pharmaceuticals USA inc.) null

    Etoposide Solution for injection

    Etoposide 20mg/ml Solution for Injection (10019-0930) (Baxter Anesthesia/Critical Care Oncology) (off market)

    Etoposide Solution for injection

    Etoposide 20mg/ml Solution for Injection (55390-0291) (Bedford Laboratories, a Hikma Company) (off market)

    Etoposide Solution for injection

    Etoposide 20mg/ml Solution for Injection (55390-0293) (Bedford Laboratories, a Hikma Company) (off market)

    Etoposide Solution for injection

    Etoposide 20mg/ml Solution for Injection (55390-0292) (Bedford Laboratories, a Hikma Company) (off market)Etoposide 20mg/ml Solution for Injection package photo

    Etoposide Solution for injection

    Etoposide 20mg/ml Solution for Injection (63323-0104) (Fresenius Kabi USA, LLC ) null

    Etoposide Solution for injection

    Etoposide 20mg/ml Solution for Injection (00074-1485) (Hospira Worldwide, Inc., a Pfizer Company) (off market)

    Etoposide Solution for injection

    Etoposide 20mg/ml Solution for Injection (00703-5646) (Teva Pharmaceuticals USA) (off market)

    Etoposide Solution for injection

    Etoposide 20mg/ml Solution for Injection (00703-5643) (Teva Pharmaceuticals USA) (off market)

    Etoposide Solution for injection

    Etoposide 20mg/ml Solution for Injection (00703-5667) (Teva Pharmaceuticals USA) (off market)

    Etoposide Solution for injection

    Etoposide 20mg/ml Solution for Injection (NOVAPLUS) (55390-0491) (Bedford Laboratories, a Hikma Company) (off market)

    Etoposide Solution for injection

    Etoposide 20mg/ml Solution for Injection (NOVAPLUS) (55390-0492) (Bedford Laboratories, a Hikma Company) (off market)

    Etoposide Solution for injection

    Etoposide 20mg/ml Solution for Injection (NOVAPLUS) (55390-0493) (Bedford Laboratories, a Hikma Company) (off market)

    Etoposide Solution for injection

    Etoposide 500mg/25ml Solution for Injection (16729-0114) (Accord Healthcare, Inc.) null

    Etoposide Solution for injection

    Etoposide 500mg/25ml Solution for Injection (63323-0104) (Fresenius Kabi USA, LLC ) null

    Etoposide Solution for injection

    Etoposide 500mg/25mL Solution for Injection (68001-0265) (BluePoint Lab Injectables) null

    Etoposide Solution for injection

    Etoposide 500mg/25mL Solution for Injection (00143-9511) (Hikma Pharmaceuticals USA inc.) null

    Etoposide Solution for injection

    Toposar 1g/50ml Solution for Injection (NOVAPLUS) (00703-5657) (Teva Pharmaceuticals USA) (off market)

    Etoposide Solution for injection

    Toposar 20mg/ml Solution for Injection (00013-7336) (Pfizer Inc.) (off market)

    Etoposide Solution for injection

    Toposar 20mg/ml Solution for Injection (00013-7346) (Pfizer Inc.) (off market)

    Etoposide Solution for injection

    Toposar 20mg/ml Solution for Injection (00013-7356) (Pfizer Inc.) (off market)

    Etoposide Solution for injection

    Toposar 20mg/ml Solution for Injection (00703-5653) (Teva Pharmaceuticals USA) (off market)

    Etoposide Solution for injection

    Toposar 20mg/ml Solution for Injection (00703-5656) (Teva Pharmaceuticals USA) (off market)Toposar 20mg/ml Solution for Injection package photo

    Etoposide Solution for injection

    Toposar 20mg/ml Solution for Injection (00703-5657) (Teva Pharmaceuticals USA) (off market)

    Etoposide Solution for injection

    Toposar 500mg/25ml Solution for Injection (NOVAPLUS) (00703-5656) (Teva Pharmaceuticals USA) (off market)

    Etoposide Solution for injection

    Vepesid 100mg/5ml Solution for Injection (00015-3095) (Bristol Myers Squibb Oncology Products) (off market)

    Etoposide Solution for injection

    Vepesid 150mg/7.5ml Solution for Injection (00015-3084) (Bristol Myers Squibb Oncology Products) (off market)

    Etoposide Solution for injection

    Vepesid 1g/50ml Solution for Injection (00015-3062) (Bristol Myers Squibb Oncology Products) (off market)Vepesid 1g/50ml Solution for Injection package photo

    Etoposide Solution for injection

    Vepesid 500mg/25ml Solution for Injection (00015-3061) (Bristol Myers Squibb Oncology Products) (off market)

    Description/Classification

    Description

    Etoposide is available as an injectable or a liquid-filled, soft gelatin capsule formulation. Etopophos (etoposide phosphate) is an IV prodrug that is converted to etoposide by dephosphorylation. Etoposide works by causing induction of DNA strand breaks by an interaction with DNA-topoisomerase II or the formation of free radicals. These actions lead to cell cycle arrest, mostly at the G2 stage of the cell cycle, and cell death. Etoposide capsules are indicated for the first-line treatment of small-cell lung cancer (SCLC) in combination with other chemotherapeutic agents.[53551] IV etoposide and etoposide phosphate are indicated for the first-line treatment of SCLC in combination with other chemotherapeutic agents and for the treatment of refractory testicular tumors as part of combination therapy.[53552][64884] Etoposide was approved by the FDA in 1983.

    Classifications

    • Antineoplastic and Immunomodulating Agents
      • Antineoplastics
        • Antineoplastic Plant Alkaloids and Other Natural Agents
          • Podophyllotoxin Derivatives
    Revision Date: 01/11/2024, 04:54:00 PM

    References

    53551 - Etoposide capsules package insert. Morgantown, WV: Mylan Pharmaceuticals Inc; 2016 April.53552 - Etopophos (etoposide phosphate) injection package insert. Princeton, NJ: Bristol-Myers Squibb Company; 2019 May.64884 - Etoposide injection package insert. Eatontown, NJ: Hikma Pharmaceuticals USA Inc.; 2019 Aug.

    Administration Information

    General Administration Information

    For storage information, see the specific product information within the How Supplied section.

    Hazardous Drugs Classification

    • NIOSH 2016 List: Group 1 [63664]
    • NIOSH (Draft) 2020 List: Table 1
    • Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
    • Oral Tablets/Capsules: Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure.[63664]
    • Injectables: Use double chemotherapy gloves and a protective gown. Prepare in a biological safety cabinet or compounding aseptic containment isolator with a closed system drug transfer device. Eye/face and respiratory protection may be needed during preparation and administration.[63664]

    Emetic Risk

    IV Doses: Low

    • Administer routine antiemetic prophylaxis prior to treatment.[67389]

    Oral Doses: Minimal/Low

    • Administer prn antiemetics as necessary.[67389]

    Extravasation Risk

    • Etoposide: Irritant
    • Etoposide phosphate: Nonvesicant [67387]

    Route-Specific Administration

    Oral Administration

    • Store capsules in the refrigerator (2 to 8 degrees C or 36 to 46 degrees F); capsules are stable for 36 months under refrigerated conditions.[53551]

    Injectable Administration

    • Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    • Administer as an IV infusion; do NOT give as a bolus injection.
    • If etoposide injection comes into contact with the skin or mucosa, immediately and thoroughly wash the skin with soap and water and flush the mucosa with water.[53552][64884]
    • Plastic devices made of acrylic or ABS (a polymer composed of acrylonitrile, butadiene, and styrene) have been reported to crack and leak when used with undiluted etoposide injection.[64884]

     

    Etoposide Phosphate for Injection

    Reconstitution:

    • Reconstitute with Sterile Water for Injection, Dextrose 5% Injection, 0.9% Sodium Chloride Injection, Bacteriostatic Water for Injection (with benzyl alcohol), or Bacteriostatic Sodium Chloride for Injection (with benzyl alcohol).
    • For a final concentration of 20 mg/mL: add 5 mL of diluent.
    • For a final concentration of 10 mg/mL: add 10 mL of diluent.
    • Storage of reconstituted solution: Store refrigerated at 2 to 8 degrees C (36 to 46 degrees F) for up to 7 days. Also stable at room temperature (20 to 25 degrees C; 68 to 77 degrees F) for 24 hours when diluted with Sterile Water for Injection, Dextrose 5% Injection, or 0.9% Sodium Chloride Injection and for 48 hours when diluted with Bacteriostatic Water for Injection or Bacteriostatic Sodium Chloride for Injection.[53552]

     

    Dilution:

    • Dilute with either Dextrose 5% Injection or 0.9% Sodium Chloride Injection to achieve a final concentration of 0.1 mg/mL or more.
    • Storage of diluted admixture: Store refrigerated (2 to 8 degrees C; 36 to 46 degrees F) or at room temperature (20 to 25 degrees C; 68 to 77 degrees F) for up to 24 hours.[53552]

     

    Intravenous Infusion:

    • Administer IV over 5 minutes to 3.5 hours.[53552]


    Etoposide Injection

    Dilution:

    • Dilute with either Dextrose 5% Injection or 0.9% Sodium Chloride Injection to a final concentration of 0.2 mg/mL to 0.4 mg/mL; precipitation may occur if the concentration exceeds 0.4 mg/mL.
    • Storage of diluted admixture: For final concentrations of 0.2 mg/mL, store at room temperature (25 degrees C) for up to 96 hours. For final concentrations of 0.4 mg/mL, store at room temperature (25 degrees C) for up to 24 hours.[64884]

     

    Intravenous Infusion:

    • Administer IV over 30 to 60 minutes; hypotension has been reported following rapid IV administration.
    • A longer duration of administration may be used for larger volumes of fluid.[64884]

    Clinical Pharmaceutics Information

    From Trissel's 2‚Ñ¢ Clinical Pharmaceutics Database

    Etoposide

    pH Range
    pH 3 to 4
    ReferencesAnon. Manufacturer's information and labeling. (Package insert).
    Osmolality/Osmolarity
    Etoposide concentrated injection 20 mg/mL has an osmolality exceeding 2000 mOsm/kg.
    ReferencesTrissel LA. Drug information- osmolalities. Data on file.
    Stability
    Etoposide in intact vials stored as directed by the manufacturer is stable until the labeled expiration date. Martel et al. reported that the stability of etoposide in intact vials stored at an elevated temperature of 33 degree C protected from exposure to light for 12 months exhibited little or no loss of drug when tested by stability-indicating HPLC analysis. The authors stated such temperatures might be reached during transportation of the vials during summer months. Packaged in Syringes: Adams et al. reported that etoposide 1 mg/mL in sodium chloride 0.9% packaged in Braun Omnifix polypropylene syringes developed precipitation in about 10% of the syringes and in subclavian lines. In Gillette plastic syringes, seizing of the syringes occurred. Infusion Solutions: Etoposide has very poor aqueous solubility of only 0.03 mg/mL. Consequently, the formulation relies on organic surfactants and surfactants to increase miscibility and keep the insoluble drug dispersed in infusion solutions sufficiently long to complete administration. However, this dispersion is always temporary making precipitation inevitable but unpredictable in timing. At a concentration of 0.4 mg/mL or above, precipitation may occur rapidly; the manufacturer does not recommend concentrations above 0.4 mg/mL. Beijnen et al. reported that at a concentration of 1 mg/mL, precipitation may occur in as little as 30 minutes (5 minutes if stirred) or may not occur for extended periods. Gras et a. reported etoposide 0.4 mg/mL in dextrose 5% and in sodium chloride 0.9% developed precipitation after 6 hours but before 24 hours. The timing of precipitation is influenced by factors such as the presence of crystallization nuclei, agitation, surface characteristics and probably other factors over which little or no control can be exerted. Some types of pumping mechanisms in peristaltic pumps can accelerate precipitation. The use of volumetric pumps has been recommended. Priston and Sewell reported that etoposide 0.5 mg/mL in sterile water for injection in polyvinyl chloride (PVC) ambulatory pump reservoirs was chemically stable with HPLC analysis showing no drug loss over 7 days at 37 degree C. However, some refrigerated samples developed precipitation. The manufacturer indicates that in dextrose 5% and in sodium chloride 0.9%, etoposide 0.2 mg/mL is stable for 96 hours and at 0.4 mg/mL is stable for 24 hours at room temperature exposed to normal fluorescent room light. However, precipitation may occur in shorter time intervals as Gras et al. reported; etoposide admixtures should always be observed and monitored closely and frequently for precipitation development. Gras et al. as well as Brigas et al. reported etoposide 0.05 and 0.2 mg/mL in dextrose 5% and in sodium chloride 0.9% remained physically and chemically stable for up to 192 hours (8 days) at ambient room temperature and under refrigeration. However, Gras et al. also reported that etoposide 0.4 mg/mL in these intravenous solutions stored at room and refrigeration temperatures were physically and chemically stable for only 6 hours but developed a white precipitation of etoposide by 24 hours with an accompanying loss of drug content from solution. Lepage et al. reported that etoposide stability in sodium chloride 0.9% was concentration-dependent and temperature-dependent over a wide range of concentrations from 0.2 to 12 mg/mL. At the highest concentrations, extended stability periods were observed. However, the precipitation of etoposide remains unpredictable, and close monitoring for precipitation remains important. The stability periods observed by Lepage et al. are shown below: Concentration 24 degree C 4 degree C 0.2 mg/mL 22 days 14 days* 0.3 mg/mL 2 days 7 days 0.4 mg/mL 1 day 2 days 0.5 mg/mL 1 day 1 day 1 to 8 mg/mL Ppt in hours Ppt in hours 9.5 mg/mL 1 day 2 days 10 mg/mL 5 days 7 days 11 mg/mL 7 days* 22 days 12 mg/mL 7 days* 14 days* *22-day study was not completed for this sample. Not tested beyond this time point. Joel et al. documented similar precipitation concentration-dependency. At etoposide concentrations of 0.25 and 0.4 mg/mL in both dextrose 5% and sodium chloride 0.9%, precipitation and loss of etoposide did not occur until 8 and 7 days, respectively. At concentrations of 0.5 and 0.6 mg/mL in these solutions, precipitation generally was observed in 24 to 30 hours. At higher concentrations of 0.75 and 1 mg/mL, precipitation was observed in as little as 6 hours. Precipitation was found to be highly variable at all concentrations with some admixtures precipitating earlier than others of the same concentration.
    ReferencesAnon. Manufacturer's information and labeling. (Package insert).
    ReferencesAdams PS, Haines-Nutt RF, Bradford E, et al. Pharmaceutical aspects of home infusion therapy for cancer patients. Pharm J. 1987; 238
    ReferencesBeijnen JH, Beijnen-Bandhoe AU, Dubbelman AC, et al. Chemical and physical stability of etoposide and teniposide in commonly used infusion fluids. J Parenter Sci Tech. 1991; 45
    ReferencesBrigas F, Sautou-Miranda V, Vanheherswynghels S, et al. Stabilite de l'etoposide dans Ecoflac contenant en polyethylene basse densite (Stability of etoposide in Ecoflac low density polyethylene containers). J Pharm Clin. 1999; 18
    ReferencesGras C, Sautou-Miranda V, Bagel-Boithias S, et al. Compatibility of etoposide solution with polyvinyl chloride and low density polyethylene containers and its stability in different storage conditions. Eur J Hosp Pharm. 2002; 8
    ReferencesJoel SP, Clark PI, Slevin ML. Stability of the i.v. and oral formulations of etoposide in solution. Cancer Chemother Pharmacol. 1995; 37
    ReferencesLepage R, Walker SE, Godin J. Stability and compatibility of etoposide in normal saline. Can J Hosp Pharm. 2000; 53
    ReferencesMartel P, Pinguet F, Petit I, et al. Stability of the principal cytostatic agents during storage at unusual temperatures. Int J Pharm. 1997; 149
    ReferencesMcCollum PL, Garrison TJ. Etoposide: a new chemotherapeutic agent. Am J IV Ther Clin Nutr. 1984; 11
    ReferencesPhillips NC, Lauper RD. Review of etoposide. Clin Pharm. 1983; 2
    ReferencesPriston MJ, Sewell GJ. Stability of three cytotoxic drug infusions in the Graseby 9000 ambulatory infusion pump. J Oncol Pharm Pract. 1998; 4
    ReferencesWoloschuk DMM, Nazeravich DR. Etoposide precipitation. Can J Hosp Pharm. 1992; 45
    ReferencesWoloschuk DMM. Drug precipitation and peristaltic pumps. Am J Hosp Pharm. 1994; 51
    pH Effects
    Etoposide exhibits maximum stability at pH 4.8 with good stability in the pH range of 3.5 to 6. Hydrolysis and epimerization may occur above pH 6.
    ReferencesBeijnen JH, Holthuis JJM, Kerkdijk HG, et al. Degradation kinetics of etoposide in solution. Int J Pharm. 1988; 41
    ReferencesWilliams DA. Stability and compatibility of admixtures of antineoplastic drugs, in Lokich JJ (ed), Cancer chemotherapy by infusion, 2nd ed. Chicago: Precept Press. 1990.
    Light Exposure
    Etoposide stability is not adversely affected by exposure to normal fluorescent room light.
    ReferencesBeijnen JH, Beijnen-Bandhoe AU, Dubbelman AC, et al. Chemical and physical stability of etoposide and teniposide in commonly used infusion fluids. J Parenter Sci Tech. 1991; 45
    ReferencesGras C, Sautou-Miranda V, Bagel-Boithias S, et al. Compatibility of etoposide solution with polyvinyl chloride and low density polyethylene containers and its stability in different storage conditions. Eur J Hosp Pharm. 2002; 8
    Filtration
    Etoposide 0.1 to 0.4 mg/mL in dextrose 5% or in sodium chloride 0.9% has been delivered through 0.22-micron Millex GV and Millex GS filters without damaging the filters. Khue and Jung reported that Sandoz etoposide 0.2 mg/mL in dextrose 5% and in sodium chloride 0.9% delivered through a Millipore 0.22-micron Ivex-HP cellulose ester membrane filter did not demonstrate substantial drug loss due to binding to the filter. Pall reported that etoposide underwent no loss due to filtration through a Supor membrane filter.
    ReferencesAnon. Pall Medical Supor-membrane IV filter device drug-adsorption data. Data on file. 2004; 8
    ReferencesKhue NV, Jung L. Study of the retention of child-dose drugs on cellulose ester membrane filters during inline filtration. S-T-P Pharma. 1985; 1
    ReferencesMcEvoy GK (ed). AHFS Drug Information (current edition). Bethesda, MD: American Society of Health-System Pharmacists.
    Sorption Leaching
    Sorption: Etoposide has not been found to undergo substantial sorption to polyvinyl chloride (PVC) containers and administration set tubing, polyethylene containers and sets, glass containers, or to elastomeric pump reservoirs. However, see Leaching of Plasticizer below. Leaching of Plasticizer: The polysorbate 80 surfactant in the etoposide formulation leaches diethylhexyl phthalate (DEHP) plasticizer from PVC containers and administration set tubing. The amount of DEHP leached is variable depending on surfactant concentration, container size, tubing diameter and length, ambient temperature, DEHP concentration in the plastic, and contact time. At etoposide concentrations of 0.4 to 0.5 mg/mL, reports of leached DEHP have varied from 2.6 mcg/mL (Trissel et al.), to 20 mcg/mL (Demore et al.), to 50 mcg/mL (Barthes et al.), to about 60 mcg/mL (Bourdeaux et al. and Gras et al.), to a high of 90 mcg/mL (Priston and Sewell). More troubling, Bourdeaux et al. reported (and was repeated in Bagel-Boithias et al.) that the low-density polyethylene inner linings of tri-layer Vygon tubing and bi-layer Cair tubing were not effective barriers to the leaching of DEHP from the outer PVC layers of the two products. Amounts of leached DEHP were about 25 mcg/mL in 2 hours and 60 mcg/mL in 24 hours and were nearly identical to pure PVC tubing. The use of non-PVC containers and tubing has been recommended by de Lemos and other authors to reduce patient exposure to DEHP. Gras et al. reported no leaching of DEHP from low-density polyethylene containers (Ecoflac, B. Braun). If there is sufficient concern, the use of the water-soluble ester form, etoposide phosphate, which does not leach DEHP plasticizer could be used. Jobet-Hermelin et al. proposed a maximum DEHP acceptability limit of 5 mcg/mL from PVC containers and administration equipment based on metabolic and toxicologic evaluations. Tickner et al. have reviewed the health concerns associated with leached DEHP in patients. Trevis et al. reported that polysorbate 80 (a component of the etoposide formulation) in concentrations from 0.05 to 2 mcg/mL at temperatures of 4, 25, and 37 degree C did not leach substantial amounts of tris(2-ethylhexyl)trimellitate (also known as TOTM and TETM) plasticizer from PVC plastic tubing plasticized with TOTM. Also See Other information.
    ReferencesAllwood M, Stanley A, Wright P. The cytotoxics handbook, 3rd ed., Oxford, England: Radcliffe Medical Press, 1997.
    ReferencesAnon. Guidelines for the administration of drugs using the Homepump Eclipse and C-Series disposable elastomeric infusion systems. Lake Forest, CA: I-Flow Corporation. 2004;
    ReferencesBagel-Boithias S, Sautou-Miranda V, Bourseaux D, et al. Leaching of diethyl hexyl phthalate from multilayer tubing into etoposide infusion solutions. Am J Health-Syst Pharm. 2005; 62
    ReferencesBarthes DMC, Rochard EB, Pouliquen IJ, et al. Stability and compatibility of etoposide in 0.9% sodium chloride injection in three containers. Am J Hosp Pharm. 1994; 51
    ReferencesBeijnen JH, Beijnen-Bandhoe AU, Dubbelman AC, et al. Chemical and physical stability of etoposide and teniposide in commonly used infusion fluids. J Parenter Sci Tech. 1991; 45
    ReferencesBourdeaux D, Sautou-Miranda V, Bagel-Boithias S, et al. Analysis by liquid chromatography and infrared spectrometry of di(2-ethylhexyl)phthalate released by multilayer infusion tubing. J Pharm Biomed Anal. 2004; 35
    ReferencesBrigas F, Sautou-Miranda V, Vanheherswynghels S, et al. Stabilite de l'etoposide dans Ecoflac contenant en polyethylene basse densite (Stability of etoposide in Ecoflac low density polyethylene containers). J Pharm Clin. 1999; 18
    ReferencesChevrier R, Sautou V, Pinon V, et al. Stability and compatibility of a mixture of the anti-cancer drugs etoposide, cytarabine and daunorubicine for infusion. Pharm Acta Helv. 1995; 70
    Referencesde Lemos ML, Hamata L, Vu T. Leaching of diethylhexyl phthalate from polyvinyl chloride materials into etoposide intravenous solutions. J Oncol Pharm Pract. 2005; 11
    ReferencesDemore B, Vigneron J, Perrin A, et al. Leaching of diethylhexyl phthalate from polyvinyl chloride bags into intravenous etoposide solution. J Clin Pharm Ther. 2002; 27
    ReferencesGras C, Sautou-Miranda V, Bagel-Boithias S, et al. Compatibility of etoposide solution with polyvinyl chloride and low density polyethylene containers and its stability in different storage conditions. Eur J Hosp Pharm. 2002; 8
    ReferencesHamon M, Plas-Remoissenet D, Kubab-Alajati S. Study on the stability in dilute solutions destined for perfusion of two antimitotics derived from podophyllotoxin: etoposide (VP16) and teniposide (VM26). STP Pharma. 1987; 3
    ReferencesHanawa T, Muramatsu E, Asakawa K, et al. Investigation of the release behavior of diethylhexyl phthalate from the polyvinyl-chloride tubing for intravenous administration. Int J Pharm. 2000; 210
    ReferencesHanawa T, Endoh N, Suzuki M, et al. Release behavior of diethylhexyl phthalate from polyvinyl-chloride tubing used for intravenous administration and the plasticized PVC membrane. Int J Pharm. 2005; 297
    ReferencesJobet-Hermelin I, Mallvais ML, Jacquot C, et al. Proposition d'une concentration limite acceptable du plastifiant librere par le poly(chlorure de vinyle) dans les solutions injectables aqueuses.[Proposal of an acceptability limit concentration of released plasticizer from polyvinyl chloride in infusion]. J Pharm Clin. 1996; 15
    ReferencesPearson SD, Trissel LA. Leaching of diethylhexyl phthalate from polyvinyl chloride containers by selected drugs and formulation components. Am J Hosp Pharm. 1993; 50
    ReferencesPriston MJ, Sewell GJ. Stability of three cytotoxic drug infusions in the Graseby 9000 ambulatory infusion pump. J Oncol Pharm Pract. 1998; 4
    ReferencesTrevis S, Santou-Miranda V, Bagel-Boithias S, et al. Release of plasticizer, tri-2-ethylhexyl trimellitate, from polyvinyl chloride tubings. Pharm World Sci. 2009; 31
    ReferencesTickner JA, Schettler T, Guidotti T, et al. Health risks posed by use of di-2-ethylhexyl phthalate (DEHP) in PVC medical devices: a critical review. Am J Indust Med. 2001; 39
    Other Information
    Etoposide is cited by NIOSH as a drug that should be handled as hazardous. Aluminum: In a test of the compatibility of etoposide 20mg/mL with an immersed needle having an aluminum component, Ogawa et al. reported no visually observable reaction in 7 days at 24 degree C. Damage to Plastics: The manufacturer indicates that undiluted etoposide may damage acrylic and ABS plastic devices. Schwinghammer et al. reported that the polyethylene glycol content of undiluted etoposide 20 mg/mL damages hard ABS plastic components. An Omni-Flow multiport cassette developed cracks within 5 minutes of initial contact and began leaking within 15 minutes. A venting pin and extension set connector also developed cracks. Dilution to an etoposide concentration of 1 mg/mL did not result in damage to the plastic. Also see Sorption/Leaching. Yokoyama et al. reported that undiluted etoposide damaged a polyurethane central catheter including development of cracks, decrease in elasticity, and "melting" of the internal catheter surface. This damage was attributed to the ethanol content of the formulation. However, silicone central catheters were undamaged by undiluted etoposide. Drop Size: The polysorbate 80 surfactant content of the formulation decreases surface tension and reduces drop size by about 30% in devices that use drop counting interfering with the accuracy of drug delivery. The use of infusion devices that do not rely on drop counting is recommended. Microbial Growth Potential: Hamilton-Miller reported that etoposide exhibited little or no antimicrobial activity against 28 strains of microbes including Gram-positive aerobic bacterial, Gram-negative aerobic bacteria, anaerobic bacteria, and yeasts.
    ReferencesAnon. Manufacturer's information and labeling. (Package insert).
    ReferencesAnon. Preventing occupational exposure to antineoplastic and other hazardous drugs in health care settings. NIOSH Publication No. 2004-165. 2004; 165
    ReferencesOgawa GS, Young R, Munar M. Dispensing-pin problems. Am J Hosp Pharm. 1985; 42
    ReferencesHamilton-Miller JMY. Antimicrobial activity of 21 anti-neoplastic agents. Br J Cancer. 1984; 49
    ReferencesSchlicht JR. Adjustments in etoposide infusion flow rates when using controllers. Am J Hosp Pharm. 1990; 47
    ReferencesSchwinghammer TL, Reilly M, Rosenfeld CS. Cracking of ABS plastic devices used to infuse undiluted etoposide injection. Am J Hosp Pharm. 1988; 45
    ReferencesYokoyama H, Aoyama T, Matsuyama T, et al. The cause of polyurethane catheter cracking during constant infusion of etoposide (VP-16) injection. Yakugaku Zasshi. 1998; 118
    Stability Max
    Maximum reported stability periods. See Stability regarding precipitation: In D5W- Variable up to 8 days depending on concentration. See Infusion Solutions in Stability section. In NS- Variable up to 22 days depending on concentration. See Infusion Solutions in Stability section.
    ReferencesBeijnen JH, Beijnen-Bandhoe AU, Dubbelman AC, et al. Chemical and physical stability of etoposide and teniposide in commonly used infusion fluids. J Parenter Sci Tech. 1991; 45
    ReferencesJoel SP, Clark PI, Slevin ML. Stability of the i.v. and oral formulations of etoposide in solution. Cancer Chemother Pharmacol. 1995; 37
    ReferencesLepage R, Walker SE, Godin J. Stability and compatibility of etoposide in normal saline. Can J Hosp Pharm. 2000; 53

    Etoposide phosphate

    pH Range
    Approximately pH 2.9
    ReferencesMcEvoy GK (ed). AHFS Drug Information (current edition). Bethesda, MD: American Society of Health-System Pharmacists.
    Osmolality/Osmolarity
    Etoposide phosphate reconstituted to a 10-mg/mL concentration with sterile water for injection is hypotonic having an osmolality of 62 mOsm/mg.
    ReferencesTrissel LA. Drug information- osmolalities. Data on file.
    Stability
    Etoposide phosphate injection in intact containers stored as directed by the manufacturer is stable until the labeled expiration date. The manufacturer indicates that etoposide phosphate reconstituted with a non-preserved diluent like sterile water for injection is stable for 24 hours at room temperature. If reconstituted with a preserved diluent like sterile bacteriostatic water for injection, etoposide phosphate is stable for 48 hours at room temperature. Etoposide phosphate is stable for 7 days if refrigerated. Infusion Solutions: The manufacturer indicates that etoposide phosphate at concentrations down to 0.1 mg/mL is stable in dextrose 5% and in sodium chloride 0.9% for 24 hours at both room temperature and under refrigeration. Etoposide phosphate is very water soluble (solubility over 100 mg/mL) and does not exhibit the potential for precipitation that the conventional formulation of etoposide has. Webster et al. reported on storage of etoposide phosphate in concentrations equivalent to etoposide 15 mg/mL and 1.5 mg/mL in sodium chloride 0.9% in polyvinyl chloride (PVC) Pharmacia-Deltec ambulatory pump reservoirs for 7 days at 20 degree C and 37 degree C protected from light. Hydrolysis resulted in an increase in free etoposide of 2% at 20 degree C and 7% at 37 degree C, which was deemed acceptable for multiple-day ambulatory infusion. Ostermann-Kraljevic et al. reported the stability of etoposide phosphate 0.08 and 3 mg/mL in dextrose 5% and sodium chloride 0.9% in glass and polyethylene containers. The solutions were physically stable, and HPLC analysis found no loss of etoposide phosphate within 7 days at room temperature of 22 to 24 degree C. Packaged in Syringes: Zhang and Trissel reported the stability of etoposide phosphate 10 mg/mL and 20 mg/mL reconstituted with benzyl alcohol-preserved bacteriostatic water for injection and packaged in Becton Dickinson 5-mL polypropylene syringes sealed with Red Cap tip seals. The solutions were physically stable with no visible haze or particulates or increase in measured microparticulates. HPLC analysis found up to 4% loss in 7 days at near body temperature of 32 degree C, about 7% loss in 31 days at room temperature, and up to 4% loss in 31 days under refrigeration.
    ReferencesAnon. Manufacturer's information and labeling. (Package insert).
    ReferencesMcEvoy GK (ed). AHFS Drug Information (current edition). Bethesda, MD: American Society of Health-System Pharmacists.
    ReferencesOstermann-Kraljevic S, Berger M, Voeffray M, et al. Stability and compatibility studies of antineoplastic agents in glass and polyethylene containers. Eur J Hosp Pharm. 1999; 5
    ReferencesWebster LK, Crinis NA, Davis JR, et al. Conversion of etoposide phosphate to etoposide under ambulatory infusion conditions. J Oncol Pharm Pract. 1995; 1
    ReferencesZhang Y, Trissel LA. Physical and chemical stability of etoposide phosphate solutions. J Am Pharm Assoc. 1999; 39
    Light Exposure
    Yuan et al. reported no etoposide phosphate loss after 124 hours of constant exposure to fluorescent light in a multi-drug admixture that included etoposide phosphate 2 mg/mL.
    ReferencesYuan P, Grimes GJ, Shankman SE, et al. Compatibility and stability of vincristine sulfate, doxorubicin hydrochloride, and etoposide phosphate in 0.9% sodium chloride injection. Am J Health-Syst Pharm. 2001; 58
    Sorption Leaching
    Etoposide phosphate has not been found to undergo substantial sorption to polyvinyl chloride (PVC) containers, polyolefin containers, including polyethylene containers and polypropylene (in syringes), or glass containers.
    ReferencesAnon. Manufacturer's information and labeling. (Package insert).
    ReferencesOstermann-Kraljevic S, Berger M, Voeffray M, et al. Stability and compatibility studies of antineoplastic agents in glass and polyethylene containers. Eur J Hosp Pharm. 1999; 5
    ReferencesWebster LK, Crinis NA, Davis JR, et al. Conversion of etoposide phosphate to etoposide under ambulatory infusion conditions. J Oncol Pharm Pract. 1995; 1
    ReferencesYuan P, Grimes GJ, Shankman SE, et al. Compatibility and stability of vincristine sulfate, doxorubicin hydrochloride, and etoposide phosphate in 0.9% sodium chloride injection. Am J Health-Syst Pharm. 2001; 58
    ReferencesZhang Y, Trissel LA. Physical and chemical stability of etoposide phosphate solutions. J Am Pharm Assoc. 1999; 39
    Other Information
    Etoposide is cited by NIOSH as a drug that should be handled as hazardous. Microbial Growth Potential: Hamilton-Miller reported that etoposide exhibited little or no antimicrobial activity against 28 strains of microbes including Gram-positive aerobic bacterial, Gram-negative aerobic bacteria, anaerobic bacteria, and yeasts. Yuan et al. reported that an etoposide phosphate-containing admixture was unable to pass the USP test for antimicrobial growth effectiveness. The growth promotion capacity of etoposide phosphate should be included into decisions regarding beyond use dating. Karstens and Kramer reported that etoposide phosphate 0.09 mg/mL (90 mcg/mL) in sodium chloride 0.9% did not result in the loss of viability of Staphylococcus aureus, Enterococcus faecium, Pseudomonas aeruginosa, and Candida albicans at room temperature of 22 degree C. Admixtures should be refrigerated whenever possible, and the potential for inadvertent contamination and microbial growth should be incorporated into decisions regarding beyond use periods.
    ReferencesAnon. Preventing occupational exposure to antineoplastic and other hazardous drugs in health care settings. NIOSH Publication No. 2004-165. 2004; 165
    ReferencesHamilton-Miller JMY. Antimicrobial activity of 21 anti-neoplastic agents. Br J Cancer. 1984; 49
    ReferencesBell MS, Nolt DH. Visual compatibility of doxapram hydrochloride with drugs commonly administered via a Y-site in the intensive care nursery. Am J Health-Syst Pharm. 2003; 60
    ReferencesYuan P, Grimes GJ, Shankman SE, et al. Compatibility and stability of vincristine sulfate, doxorubicin hydrochloride, and etoposide phosphate in 0.9% sodium chloride injection. Am J Health-Syst Pharm. 2001; 58
    Stability Max
    Maximum reported stability periods: Reconstituted- 48 hours at room temperature and 7 days refrigerated. In D5W- 31 days at room temperature and refrigerated. In NS- 31 days at room temperature and refrigerated.
    ReferencesAnon. Manufacturer's information and labeling. (Package insert).
    ReferencesZhang Y, Trissel LA. Physical and chemical stability of etoposide phosphate solutions. J Am Pharm Assoc. 1999; 39
    Revision Date: 01/11/2024, 04:54:00 PMCopyright 2004-2024 by Lawrence A. Trissel. All Rights Reserved.

    References

    53551 - Etoposide capsules package insert. Morgantown, WV: Mylan Pharmaceuticals Inc; 2016 April.53552 - Etopophos (etoposide phosphate) injection package insert. Princeton, NJ: Bristol-Myers Squibb Company; 2019 May.63664 - CDC National Institute for Occupational Safety and Health (NIOSH). NIOSH List of Antineoplastic and Other Hazardous Drugs in Healthcare Settings 2016. DHHS (NIOSH) Publication Number 2016-161, September 2016. Available on the World Wide Web at https://www.cdc.gov/niosh/docs/2016-161/pdfs/2016-161.pdf?id=10.26616/NIOSHPUB201616164884 - Etoposide injection package insert. Eatontown, NJ: Hikma Pharmaceuticals USA Inc.; 2019 Aug.67387 - Perez Fidalgo, JA, Garcia Fabregat L, Cervantes A, et al. Management of chemotherapy extravasation: ESMO-EONS Clinical Practice Guidelines. Ann Oncol. 2012 Oct;23 Suppl; vii167-73.67389 - Hesketh PJ, Kris MG, Basch E, et al. Antiemetics: ASCO Guideline Update. J Clin Oncol. 2020 Aug 20;38(24):2782-2797.

    Adverse Reactions

    Mild

    • abdominal pain
    • alopecia
    • anorexia
    • asthenia
    • back pain
    • chills
    • cough
    • diaphoresis
    • diarrhea
    • drowsiness
    • dysgeusia
    • fatigue
    • fever
    • flushing
    • infection
    • injection site reaction
    • maculopapular rash
    • malaise
    • nausea
    • pruritus
    • rash
    • skin hyperpigmentation
    • throat irritation
    • urticaria
    • vomiting

    Moderate

    • anemia
    • bone marrow suppression
    • constipation
    • dysphagia
    • dyspnea
    • esophagitis
    • hypertension
    • hypotension
    • leukopenia
    • metabolic acidosis
    • neutropenia
    • peripheral neuropathy
    • pneumonitis
    • radiation recall reaction
    • sinus tachycardia
    • stomatitis
    • thrombocytopenia

    Severe

    • anaphylactoid reactions
    • angioedema
    • apnea
    • bronchospasm
    • cyanosis
    • hepatotoxicity
    • laryngospasm
    • leukopenia
    • new primary malignancy
    • optic neuritis
    • pulmonary fibrosis
    • renal failure (unspecified)
    • seizures
    • skin necrosis
    • Stevens-Johnson syndrome
    • thrombocytopenia
    • toxic epidermal necrolysis
    • vasculitis

    Fever has infrequently been reported in patients treated with both IV and oral etoposide; both fever and infection have also been reported in neutropenic patients.[53551] [64884] [53552] Postmarketing experience indicates that elderly patients may be more sensitive to the infectious complications of etoposide treatment.[53551] [64884]

    Bone marrow suppression is a dose-related and dose-limiting toxicity of etoposide, with myelosuppression-related fatalities reported. Leukopenia with white blood cell counts (WBC) less than 4,000 cells/mm3 occurred in 60% to 91% of patients from multiple databases who received etoposide oral or IV monotherapy (n = 2,081); grade 4 leukopenia (less than 1,000 cells/mm3) occurred in 3% to 17% of patients. Thrombocytopenia with platelet counts below 100,000 cells/mm3 occurred in 22% to 41% of patients receiving etoposide monotherapy in these databases; grade 3 or 4 thrombocytopenia (less than 50,000 cells/mm3) occurred in 1% to 20% of patients. Anemia also occurred in 33% or fewer database patients.[53551] [64884] In clinical studies where etoposide phosphate was administered as monotherapy (n = 206) or in combination with cisplatin (n = 60) for various malignancies, neutropenia was the most common adverse reaction.[53552] Granulocyte nadirs typically occur 7 to 14 days after administration and platelet nadirs occur 9 to 16 days after administration. Bone marrow recovery is usually complete by day 20 and is not cumulative. Myelosuppression was more common in elderly patients in postmarketing experience with etoposide. Grade 3 or 4 leukopenia and granulocytopenia were more frequent among elderly patients (age 65 or older) compared to younger patients in various clinical trials.[53551] [64884]

    Nausea and vomiting are the major gastrointestinal toxicities associated with etoposide treatment, occurring in 31% to 43% of patients treated with IV or oral etoposide monotherapy in multiple databases from clinical trials (n = 2,081).[53552] [64884] [53551] Both are generally mild-to-moderate in severity, requiring treatment discontinuation in 1% of patients. GI toxicities are slightly more frequent after oral administration compared to IV administration. Postmarketing experience with etoposide indicates that elderly patients may be more sensitive to GI toxicities.[53551] [64884]

    Diarrhea (1% to 13%) and abdominal pain (2% or less) have been reported in patients treated with IV or oral etoposide monotherapy in multiple databases from clinical trials (n = 2,081).[53551] [64884] Constipation has also been infrequently reported.[53552] [53551] [64884] GI toxicities are slightly more frequent after oral administration compared to IV administration. Postmarketing experience with etoposide indicates that elderly patients may be more sensitive to GI toxicities.[53551] [64884]

    Anorexia has been reported in 10% to 13% of patients treated with IV or oral etoposide monotherapy in multiple databases from clinical trials (n = 2,081).[53551] [64884] Dysphagia and dysgeusia have also been infrequently reported with etoposide treatment.[53552] [53551] [64884] GI toxicities are slightly more frequent after oral administration compared to IV administration. Postmarketing experience with etoposide indicates that elderly patients may be more sensitive to GI toxicities.[53551] [64884]

    Stomatitis has been reported in 1% to 6% of patients treated with IV or oral etoposide monotherapy in multiple databases from clinical trials (n = 2,081); mucositis/esophagitis has been reported as mild to severe. GI toxicities are slightly more frequent after oral administration compared to IV administration. Postmarketing experience with etoposide indicates that elderly patients may be more sensitive to GI toxicities.[53552] [53551] [64884]

    Transient hypotension has been reported in 1% to 2% of patients following the rapid IV administration of etoposide; delayed hypotension has not been noted. Administer etoposide by slow IV infusion over 30 to 60 minutes to prevent hypotension. If hypotension occurs, stop the infusion and give fluids or other supportive therapy as necessary; restart the infusion at a slower rate when therapy is resumed.[64884]

    New primary malignancy, specifically acute leukemia with or without a preleukemic phase, has been reported rarely in patients treated with IV or oral etoposide alone or in combination with other chemotherapy agents. The risk of development of a preleukemic or leukemic syndrome is unclear.[61465] [53551] Secondary leukemias have occurred with long-term use of IV etoposide phosphate.[53552]

    Extravasation resulting in an injection site reaction including local soft tissue toxicity, swelling, pain, and cellulitis has been reported in postmarketing experience with IV etoposide and etoposide phosphate. Rarely, extravasation has been associated with skin necrosis and venous induration.[64884] [53552]

    Rash, urticaria, and/or pruritus have infrequently been reported in patients receiving IV or oral etoposide at recommended doses. At investigational doses, a generalized pruritic erythematous maculopapular rash consistent with peri-vasculitis has been reported. Additionally, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and skin hyperpigmentation occurred infrequently with IV or oral etoposide monotherapy with several different dose schedules for treatment of a wide variety of malignancies; there was a single report of radiation recall dermatitis.[64884] [53551] Pigmentation, radiation recall reaction, SJS, and TEN also occurred in patients with a variety of malignancies treated with etoposide phosphate monotherapy in clinical trials.[53552]

    Seizures, occasionally associated with allergic reactions, have been infrequently reported in patients treated with IV or oral etoposide monotherapy using several different dose schedules for treatment of a wide variety of malignancies.[53551] [64884] Seizures also occurred in patients with a variety of malignancies treated with etoposide phosphate monotherapy in clinical trials.[53552]

    Asthenia, fatigue, and malaise were reported infrequently in patients treated with IV or oral etoposide monotherapy using several different dose schedules for treatment of a wide variety of malignancies. Grade 3 or 4 asthenia was more frequent in elderly patients (age 65 years or more) compared to younger patients in 5 monotherapy studies of etoposide phosphate in patients with a variety of tumor types.[64884] [53551]

    Transient cortical blindness and optic neuritis were infrequently reported in patients treated with IV or oral etoposide monotherapy using several different dose schedules for treatment of a wide variety of malignancies.[64884] [53551] [53552]

    Interstitial pneumonitis/pulmonary fibrosis occurred infrequently in patients treated with IV or oral etoposide monotherapy using several different dose schedules for treatment of a wide variety of malignancies.[64884] [53551] [53552]

    Metabolic acidosis has been reported in patients who received IV or oral etoposide monotherapy for the treatment of a wide variety of malignancies at doses higher than the recommended dose.[64884] [53551]

    Anaphylactoid reactions characterized by chills, fever, sinus tachycardia, bronchospasm, dyspnea, and/or hypotension have been reported in 0.7% to 2% of patients who received IV etoposide and in less than 1% of the patients who received oral etoposide in clinical trials; reactions have occurred during the initial infusion of etoposide. Reactions typically respond to stopping the infusion and administration of pressor agents, corticosteroids, antihistamines, or volume expanders as necessary; however, these reactions can be fatal. Hypertension and/or flushing have also been reported; blood pressure usually normalizes within a few hours after stopping the infusion. Sometimes, facial/tongue swelling (angioedema), cough, diaphoresis, cyanosis, throat irritation/tightness, laryngospasm, back pain, and/or loss of consciousness have occurred in association with allergic reactions; rarely, an apparent hypersensitivity-associated apnea has been reported.[64884] [53551] Anaphylactoid reactions have also been reported with IV etoposide phosphate. Permanently discontinue etoposide phosphate in patients who develop a severe hypersensitivity reaction.[53552]

    Hepatotoxicity has been reported with IV or oral etoposide monotherapy using several different dose schedules for treatment of a wide variety of malignancies, generally in patients receiving higher than the recommended dose.[64884] [53551] Hepatotoxicity was also reported in patients with a variety of malignancies treated with etoposide phosphate monotherapy in clinical trials.[53552] Hepatic adverse reactions occurred in 3% or fewer patients treated with IV or oral etoposide monotherapy in multiple databases from clinical trials (n = 2,081).[64884] [53551]

    Reversible cases of acute renal failure (unspecified) have been reported with administration of high-dose etoposide phosphate (2,220 mg/m2) with total body irradiation used for stem cell transplantation. The etoposide phosphate formulation contains dextran 40, which has been associated with acute renal failure when administered in high doses.[53552] Elevated BUN was reported more often in elderly patients treated with etoposide or etoposide phosphate in combination with cisplatin.[53551] [64884]

    Reversible alopecia, sometimes progressing to total baldness, was observed in 8% to 66% of patients treated with IV or oral etoposide monotherapy in multiple databases from clinical trials (n = 2,081). Postmarketing experience suggests that elderly patients may experience more alopecia compared to younger patients.[64884] [53551]

    Somnolence/drowsiness was infrequently reported in patients treated with IV or oral etoposide monotherapy using several different dose schedules for treatment of a wide variety of malignancies. Somnolence was reported more often in elderly patients treated with etoposide or etoposide phosphate in combination with cisplatin.[53551] [64884]

    Peripheral neuropathy was reported in 1% to 2% of patients treated with IV or oral etoposide monotherapy in multiple databases from clinical trials (n = 2,081).[64884] [53551]

    Revision Date: 01/11/2024, 04:54:00 PM

    References

    53551 - Etoposide capsules package insert. Morgantown, WV: Mylan Pharmaceuticals Inc; 2016 April.53552 - Etopophos (etoposide phosphate) injection package insert. Princeton, NJ: Bristol-Myers Squibb Company; 2019 May.61465 - Etoposide injection package insert. Lake Zurich, IL: Fresenius Kabi USA, LLC; 2016 Feb.64884 - Etoposide injection package insert. Eatontown, NJ: Hikma Pharmaceuticals USA Inc.; 2019 Aug.

    Contraindications/Precautions

    Absolute contraindications are italicized.

    • bleeding
    • bone marrow suppression
    • breast-feeding
    • children
    • contraception requirements
    • extravasation
    • geriatric
    • hypoalbuminemia
    • infants
    • infection
    • infertility
    • infusion-related reactions
    • male-mediated teratogenicity
    • neutropenia
    • new primary malignancy
    • pregnancy
    • reproductive risk
    • requires an experienced clinician
    • thrombocytopenia

    Bone marrow suppression (e.g., neutropenia, thrombocytopenia) is a dose-limiting toxicity with etoposide therapy and has resulted in severe infection, bleeding, and death. The use of etoposide requires an experienced clinician knowledgeable in administering chemotherapy. Obtain complete blood cell counts prior to each cycle of therapy with etoposide and more frequently as clinically indicated. After administration of etoposide, granulocyte nadirs generally occur in 7 to 14 days and platelet nadirs within 9 to 16 days; bone marrow recovery is usually complete by day 20.[53552] [64884] [53551] Do not administer a new course of therapy until the ANC has recovered above 500 cells/mm3 and the platelet count above 50,000 cells/mm3.[64884] [53551]

    Closely monitor patients during IV infusions for signs and symptoms of extravasation. Extravasation has been reported in postmarketing surveillance of both etoposide and etoposide phosphate and may result in skin necrosis, venous induration, swelling, pain, and cellulitis. If dermal contact occurs, immediately and thoroughly wash areas of skin contact with soap and water and flush mucosa with water.[53552] [64884]

    Closely monitor patients with hypoalbuminemia for etoposide-associated toxicities, as they may be at increased risk. Lower levels of albumin are associated with higher free fractions of etoposide.[64884] [53551]

    New primary malignancy, specifically acute leukemia, has been reported rarely in patients who received etoposide in combination with other antineoplastic agents.[61465] [53551] New primary leukemias have also occurred following long-term use of etoposide phosphate.[53552]

    Geriatric patients (aged 65 years and older) may be at increased risk for etoposide-associated toxicity. Because elderly patients are more likely to have decreased renal function and etoposide and its metabolites are primarily excreted by the kidney, consider monitoring renal function in these patients during therapy. In postmarketing surveillance, myelosuppression, gastrointestinal effects, infectious complications, and alopecia have been reported more often in geriatric patients who received etoposide. In a clinical study, severe leukopenia, anorexia, mucositis, dehydration, somnolence, and elevated BUN levels occurred in more geriatric patients who received etoposide or etoposide phosphate in combination with cisplatin compared with younger patients. In pooled results from 5 lung cancer trials, geriatric patients who received single-agent etoposide phosphate experienced a higher incidence of severe leukopenia, granulocytopenia, and asthenia compared with younger patients.[53551] [64884]

    Use etoposide solution for injection with caution in infants as it contains polysorbate 80. In premature infants, a life-threatening syndrome consisting of liver and renal failure, pulmonary deterioration, thrombocytopenia, and ascites has been associated with an injectable vitamin E product containing polysorbate 80.[64884]

    Infusion-related reactions and hypersensitivity reactions including rash, urticaria, pruritus, and anaphylaxis can occur with intravenous administration of etoposide or etoposide phosphate.[53552] [64884] Higher rates of anaphylactic-like reactions have been reported in children who received infusions at concentrations higher than those recommended. The role of concentration or rate of infusion in the development of anaphylactic-like reactions is uncertain.[64884] If hypersensitivity reactions occur, immediately interrupt the etoposide infusion and institute supportive management. Permanently discontinue etoposide or etoposide phosphate in patients who experience a severe hypersensitivity reaction.[53552] [64884]

    Etoposide may cause fetal harm in pregnant women based on its mechanism of action and data from animal studies. Females of reproductive potential should be advised to avoid pregnancy while taking etoposide. If a woman becomes pregnant during therapy with etoposide, she should be informed of the potential risk to the fetus. Intrauterine death and fetal toxicity (e.g., reduced fetal weight, skeletal abnormalities, cranial abnormalities, exencephaly, encephalocele, and anophthalmia) occurred in rats and mice when etoposide was administered during organogenesis; doses given in these studies were much less than the recommended human dose.[61465] [53552] [53551]

    Counsel patients about the reproductive risk and contraception requirements during etoposide treatment. Females of reproductive potential should avoid pregnancy and use effective contraception during and for at least 6 months after the last etoposide dose. Women who become pregnant while receiving etoposide should be apprised of the potential hazard to the fetus. Due to the potential for male-mediated teratogenicity, males with female sexual partners of reproductive potential should use effective contraception during treatment with etoposide and for at least 4 months after the last dose. Infertility may occur with etoposide use. In females, etoposide may cause amenorrhea and premature menopause; recovery of menses and ovulation is related to age at treatment. In males, etoposide may cause oligospermia, azoospermia, and permanent loss of fertility; sperm counts have returned to normal several years after the end of therapy in some cases.[53552]

    It is not known if etoposide is secreted in human milk or if it has effects on the breast-fed infant or on milk production. Due to the risk of serious adverse reactions in nursing infants, women should discontinue breast-feeding during etoposide or etoposide phosphate therapy.[53552] [53551] [61465]

    Revision Date: 01/11/2024, 04:54:00 PM

    References

    53551 - Etoposide capsules package insert. Morgantown, WV: Mylan Pharmaceuticals Inc; 2016 April.53552 - Etopophos (etoposide phosphate) injection package insert. Princeton, NJ: Bristol-Myers Squibb Company; 2019 May.61465 - Etoposide injection package insert. Lake Zurich, IL: Fresenius Kabi USA, LLC; 2016 Feb.64884 - Etoposide injection package insert. Eatontown, NJ: Hikma Pharmaceuticals USA Inc.; 2019 Aug.

    Mechanism of Action

    Etoposide is a topoisomerase inhibitor that is a semisynthetic derivative of podophyllotoxin. Two different dose-dependent responses are seen at the G2 portion of the cell cycle in mammalian cells, leading to cell cycle arrest and cell death. At high concentrations (10 mcg/mL or more), lysis of cells entering mitosis is observed; at low concentrations (0.3 mcg/mL to 10 mcg/mL), cells are inhibited from entering prophase. Etoposide does not interfere with microtubular assembly. The predominant macromolecular effect of etoposide appears to be the induction of DNA strand breaks by an interaction with DNA topoisomerase II or the formation of free radicals.[53552][53551][64884] Etoposide has also been shown to cause metaphase arrest in chick fibroblasts.[53551][64884] Etoposide phosphate is a prodrug that is converted to its active moiety, etoposide, by dephosphorylation.[53552]

    Revision Date: 01/11/2024, 04:54:00 PM

    References

    53551 - Etoposide capsules package insert. Morgantown, WV: Mylan Pharmaceuticals Inc; 2016 April.53552 - Etopophos (etoposide phosphate) injection package insert. Princeton, NJ: Bristol-Myers Squibb Company; 2019 May.64884 - Etoposide injection package insert. Eatontown, NJ: Hikma Pharmaceuticals USA Inc.; 2019 Aug.

    Pharmacokinetics

    Etoposide is administered orally or intravenously (IV); etoposide phosphate is administered IV and is completely converted to etoposide in plasma. Etoposide is highly protein-bound (97%), primarily to albumin; the unbound fraction may increase in patients with low serum albumin (hypoalbuminemia) and elevated bilirubin levels (hyperbilirubinemia). Patients with higher unbound fractions may be at increased risk for etoposide-related adverse effects; in one study, phenylbutazone, sodium salicylate, and aspirin displaced protein-bound etoposide at concentrations achieved in vivo. Etoposide has poor cerebral spinal fluid (CSF) penetration; although it is detectable in CSF and intracerebral tumors, the concentrations are lower than in extracerebral tumors and in plasma. Etoposide concentrations are higher in normal lung than in lung metastases and are similar in primary tumors and normal tissues of the myometrium. The mean steady-state volume of distribution is 18 to 29 liters (7 to 17 liters/m2). Etoposide disposition is a biphasic process after IV administration, with a distribution half-life of 1.5 hours and terminal elimination half-life of 4 to 11 hours, independent of dose; total body clearance ranges from 33 to 48 mL/min (16 to 36 mL/min/m2). Total body clearance correlates with creatinine clearance, serum albumin levels, and nonrenal clearance. Etoposide is metabolized in the liver by the opening of the lactone ring, O-demethylation, and conjugation (glucuronidation and sulfation); O-demethylation of the dimethoxyphenol ring occurs through the CYP3A4 isoenzyme pathway to produce the active catechol metabolite. After IV administration of radiolabeled etoposide (dose range, 100 to 124 mg/m2), the mean recovery of radioactivity in the urine was 56% of the dose at 120 hours (unchanged drug, 45%; 8% or less of the dose was excreted as metabolites). Biliary excretion of unchanged drug and metabolites is an important route of etoposide elimination; fecal recovery of radioactivity was 44% of the dose at 120 hours.[53551][53552][64884]

     

    Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4/5

    O-demethylation of the dimethoxyphenol ring via cytochrome CYP3A4 is a major pathway of etoposide metabolism, with CYP3A5 also contributing at clinically relevant free etoposide concentrations; CYP2E1 and CYP1A2 may have a minor role in etoposide metabolism, but the relevance is unknown. In vitro, etoposide may also be a substrate of P-glycoprotein (P-gp).[60075][34509][57989]

    Route-Specific Pharmacokinetics

    Oral Route

    There is no evidence of a first-pass effect with oral etoposide administration; a correlation does not exist between the absolute oral bioavailability of etoposide capsules and nonrenal clearance. Significant intra- and intersubject variability exists in Cmax values after either IV or oral administration of etoposide, resulting in variable bioavailability of 25% to 75% (mean, 50%) following an oral dose; however, Cmax and AUC values for oral etoposide consistently fall in the same range as the Cmax and AUC values for an IV dose of one-half the size of the oral dose. The bioavailability of etoposide capsules appears to be linear up to a dose of at least 250 mg/m2.[53551]

    Intravenous Route

    With IV administration, AUC and Cmax values increase linearly with dose of etoposide in the range of 100 to 600 mg/m2. Additionally, there is no accumulation in the plasma when etoposide is administered as 100 mg/m2 daily for 4 to 5 days.[53552][64884] There is marked intra- and inter-subject variability following IV etoposide administration.[64884] Etoposide phosphate is rapidly and completely converted to etoposide in plasma, and has similar pharmacokinetics and pharmacodynamics as etoposide. The pharmacokinetics of etoposide and etoposide phosphate were compared in 2 randomized crossover studies. In the first (n = 41), patients with a variety of malignancies were given etoposide phosphate or etoposide 150 mg/m2 IV over 3.5 hours. The mean AUC values were 168.3 +/- 48.2 micrograms (mcg) x hr/mL and 156.7 +/- 43.4 mcg x hr/mL, respectively; the Cmax values were 20 +/- 3.7 mcg/mL for etoposide phosphate and 19.6 +/- 4.2 mcg/mL for etoposide. Bioavailability of etoposide from etoposide phosphate was 107% (90% CI, 105% to 110%) for AUC and 103% (90% CI, 99% to 106%) for Cmax. In the second study, the mean AUC after a 1 hour infusion of etoposide phosphate or etoposide (dose-normalized to 100 mg/m2) was 96.1 +/- 22.6 mcg x hr/mL and 86 +/- 25.8 mcg x hr/mL, with Cmax values of 20.1 +/- 4.1 mcg/mL and 19 +/- 5.1 mcg/mL, respectively. Bioavailability of etoposide from etoposide phosphate was 113% (90% CI, 107% to 119%) for AUC and 107% (90% CI, 101% to 113%) for Cmax. There were no statistically significant differences in AUC or Cmax or in pharmacodynamic parameters (hematologic toxicity).[61467]

    Special Populations

    Renal Impairment

    Patients with renal impairment have a reduced total body clearance, increased AUC, and lower volume of distribution at steady state.[64884][53551]

    Pediatrics

    In children, an inverse relationship exists between plasma albumin levels and etoposide renal clearance. Over a dose range of 80 to 600 mg/m2, the mean renal clearance is 7 to 10 mL/min/m2 (35% of total body clearance); the effect of renal disease on etoposide clearance in children is not known. Elevated ALT is associated with reduced total body clearance of etoposide in children.[53551] [64884]

    Geriatric

    Age does not have a clinically significant effect on the pharmacokinetics of etoposide.[53552][64884][53551]

    Gender Differences

    Gender does not have a clinically significant effect on the pharmacokinetics of etoposide.[53552][64884][53551]

    Revision Date: 01/11/2024, 04:54:00 PM

    References

    34509 - Kang YH, Lee E, Youk HJ, et al. Potentiation by alpha-tocopheryl succinate of the etoposide response in multidrug resistance protein 1-expressing glioblastoma cells. Cancer Lett 2005;217:181-190.53551 - Etoposide capsules package insert. Morgantown, WV: Mylan Pharmaceuticals Inc; 2016 April.53552 - Etopophos (etoposide phosphate) injection package insert. Princeton, NJ: Bristol-Myers Squibb Company; 2019 May.57989 - Leu BL, Huang JD. Inhibition of intestinal p-glycoprotein and effects on etoposide absorption. Cancer Chemother Pharmacol 1995;35:432-436.60075 - Zhuo X, Zheng N, Felix CA, et al. Kinetics and regulation of cytochrome p450-mediated etoposide metabolism. Drug Metabolism and Disposition. 2004;32(9):993-1000.61467 - Etopophos (etoposide phosphate) injection package insert. Deerfield, IL: Baxter Healthcare Corporation; 2015 July.64884 - Etoposide injection package insert. Eatontown, NJ: Hikma Pharmaceuticals USA Inc.; 2019 Aug.

    Pregnancy/Breast-feeding

    pregnancy

    Etoposide may cause fetal harm in pregnant women based on its mechanism of action and data from animal studies. Females of reproductive potential should be advised to avoid pregnancy while taking etoposide. If a woman becomes pregnant during therapy with etoposide, she should be informed of the potential risk to the fetus. Intrauterine death and fetal toxicity (e.g., reduced fetal weight, skeletal abnormalities, cranial abnormalities, exencephaly, encephalocele, and anophthalmia) occurred in rats and mice when etoposide was administered during organogenesis; doses given in these studies were much less than the recommended human dose.[61465] [53552] [53551]

    breast-feeding

    It is not known if etoposide is secreted in human milk or if it has effects on the breast-fed infant or on milk production. Due to the risk of serious adverse reactions in nursing infants, women should discontinue breast-feeding during etoposide or etoposide phosphate therapy.[53552] [53551] [61465]

    Revision Date: 01/11/2024, 04:54:00 PM

    References

    53551 - Etoposide capsules package insert. Morgantown, WV: Mylan Pharmaceuticals Inc; 2016 April.53552 - Etopophos (etoposide phosphate) injection package insert. Princeton, NJ: Bristol-Myers Squibb Company; 2019 May.61465 - Etoposide injection package insert. Lake Zurich, IL: Fresenius Kabi USA, LLC; 2016 Feb.

    Interactions

    Level 2 (Major)

    • grapefruit juice

    Level 3 (Moderate)

    • Cholera Vaccine
    • Cyclosporine
    • Dengue Tetravalent Vaccine, Live
    • Dichlorphenamide
    • Gadobenate Dimeglumine
    • SARS-CoV-2 (COVID-19) vaccines
    • SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine
    • SARS-CoV-2 Virus (COVID-19) mRNA Vaccine
    • SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine
    • Tuberculin Purified Protein Derivative, PPD
    • Warfarin
    Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine. [60871] cycloSPORINE: (Moderate) Monitor for an increase in etoposide-related adverse reactions if concomitant use of cyclosporine results in cyclosporine levels greater than 2,000 ng/mL. Concomitant administration of high-dose cyclosporine (concentrations greater than 2,000 ng/mL) with oral etoposide increased etoposide exposure by 80% with a 38% decrease in total body clearance of etoposide compared to etoposide alone. [53551] [53552] [61465] Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine. [60092] [64100] [65107] Dichlorphenamide: (Moderate) Use dichlorphenamide and etoposide, VP-16 together with caution. Metabolic acidosis is associated with the use of dichlorphenamide and has been reported in patients who received higher doses of single agent etoposide given orally or as an IV injection. Concurrent use may increase the severity of metabolic acidosis. Measure sodium bicarbonate concentrations at baseline and periodically during dichlorphenamide treatment. If metabolic acidosis occurs or persists, consider reducing the dose or discontinuing dichlorphenamide therapy. [53551] [60122] Gadobenate Dimeglumine: (Moderate) Gadobenate dimeglumine is a substrate for the canalicular multi-specific organic anion transporter (MOAT). Use with other MOAT substrates, such as etoposide, VP-16, may result in prolonged systemic exposure of the coadministered drug. Caution is advised if these drugs are used together. [58462] Grapefruit juice: (Major) Monitor for an increased incidence of etoposide-related adverse effects if used concomitantly with grapefruit juice. Grapefruit juice is a strong inhibitor of CYP3A4 as well as a P-glycoprotein (P-gp) inhibitor; etoposide, VP-16 is a CYP3A4 and P-gp substrate. Coadministration may cause accumulation of etoposide and decreased metabolism, resulting in increased etoposide concentrations. In a small crossover, randomized trial, 6 patients receiving etoposide for non-small cell lung cancer were treated with 50 mg IV etoposide, 50 mg PO etoposide, or 50 mg PO etoposide following grapefruit juice. Pretreatment with grapefruit juice resulted in a decrease in the AUC of etoposide (average 26.2%) after oral administration; interindividual variability was large in all treatment arms. One suggested mechanism for this interaction is a possible alteration of intestinal p-glycoprotein mediated transport. Due to the small number of patients in this study, no definite conclusions may be drawn. [27612] [29087] [34509] [43788] [51394] [57989] [58104] SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine. [65107] [66080] SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine. [65107] [66080] SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine. [65107] [66080] SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine. [65107] [66080] Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy. [43298] [43299] Warfarin: (Moderate) Frequently measure the PT/INR if coadministration of etoposide with warfarin is necessary; concomitant use can increase the INR. [53552]
    Revision Date: 01/11/2024, 04:54:00 PM

    References

    27612 - Reif S, Nichloson MC, Bisset D, et al. Effect of grapefruit juice intake on etoposide bioavailability. Eur J Clin Pharmacol 2002;58:491-4.29087 - Dahan A, Altman H. Food-drug interaction: grapefruit juice augments drug bioavailability-mechanism, extent, and relevance. Eur J Clin Nutr 2004;58:1-9.34509 - Kang YH, Lee E, Youk HJ, et al. Potentiation by alpha-tocopheryl succinate of the etoposide response in multidrug resistance protein 1-expressing glioblastoma cells. Cancer Lett 2005;217:181-190.43298 - Aplisol (tuberculin purified protein derivative, diluted) package insert. Chestnut Ridge, NY: Par Pharmaceuticals; 2016 Mar.43299 - Tubersol (tuberculin purified protein derivative, mantoux) package insert. Swiftwater, PA: Sanofi Pasteur, Inc.; 2020 Nov.43788 - Etoposide injection USP package insert. Bedford, OH: Ben Venue Laboratories, Inc.; 2006 Feb.51394 - Vepesid (etoposide) package insert. Princeton, NJ: Bristol-Myers Squibb Company, February 2006.53551 - Etoposide capsules package insert. Morgantown, WV: Mylan Pharmaceuticals Inc; 2016 April.53552 - Etopophos (etoposide phosphate) injection package insert. Princeton, NJ: Bristol-Myers Squibb Company; 2019 May.57989 - Leu BL, Huang JD. Inhibition of intestinal p-glycoprotein and effects on etoposide absorption. Cancer Chemother Pharmacol 1995;35:432-436.58104 - Girennavar B, Jayaprakasha GK, and Patil BS. Potent inhibition of human cytochrome P450 3A4, 2D6, and 2C9 isoenzymes by grapefruit juice and its furocoumarins. Journal of Food Science. 2007;72(8):C417-C421.58462 - MultiHance (gadobenate dimeglumine) injection package insert. Monroe Township, NJ: Bracco Diagnostics, Inc.; 2024 Jan.60092 - Rubin LG, Levin MJ, Ljungman P, et al. 2013 IDSA clinical practice guideline for vaccination of the immunocompromised host. Clin Infect Dis. 2014; 58: e44-100.60122 - Keveyis (dichlorphenamide) tablets package insert. Trevose, PA: Strongbridge US Inc.; 2019 Nov.60871 - Vaxchora (Cholera Vaccine, live, oral) package insert. Redwood City, CA: Emergent Travel Health Inc.; 2024 Jan.61465 - Etoposide injection package insert. Lake Zurich, IL: Fresenius Kabi USA, LLC; 2016 Feb.64100 - Dengvaxia (dengue tetravalent vaccine, live) package insert. Swiftwater, PA: Sanofi Pasteur Inc.; 2023 August.65107 - Kroger A, Bahta L, Hunter P. General Best Practice Guidelines for Immunization. Best Practices Guidance of the Advisory Committee on Immunization Practices (ACIP). Accessed April 25, 2024. Available at https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/index.html.66080 - Food and Drug Administration (FDA). Fact Sheet for Healthcare Providers Administering Vaccine: Emergency Use Authorization (EUA) of Pfizer-BioNTech COVID-19 Vaccine to Prevent Coronavirus Disease 2019 (COVID-19) for 12 years and older. Purple cap and purple border. Retrieved November 22, 2022.

    Monitoring Parameters

    • CBC with differential
    • LFTs
    • serum creatinine/BUN

    US Drug Names

    • Etopophos
    • Toposar
    • VePesid
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