VePesid

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VePesid

Classes

Podophyllotoxin Derivatives

Administration

Hazardous Drugs Classification
NIOSH 2016 List: Group 1
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.
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.]
Emetic Risk
IV Doses: Low
Administer routine antiemetic prophylaxis prior to treatment.
Oral Doses: Minimal/Low
Administer prn antiemetics as necessary.
Extravasation Risk
Etoposide: Irritant
Etoposide phosphate: Nonvesicant

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.

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.
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.
 
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.
 
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.
 
Intravenous Infusion:
Administer IV over 5 minutes to 3.5 hours.
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.
 
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.

Adverse Reactions
Severe

thrombocytopenia / Delayed / 1.0-20.0
leukopenia / Delayed / 3.0-17.0
Stevens-Johnson syndrome / Delayed / 1.0-10.0
toxic epidermal necrolysis / Delayed / 1.0-10.0
seizures / Delayed / 1.0-10.0
optic neuritis / Delayed / 1.0-10.0
pulmonary fibrosis / Delayed / 1.0-10.0
anaphylactoid reactions / Rapid / 0-2.0
bronchospasm / Rapid / 0-2.0
new primary malignancy / Delayed / 0-1.0
skin necrosis / Early / 0-1.0
apnea / Delayed / 0-1.0
vasculitis / Delayed / Incidence not known
angioedema / Rapid / Incidence not known
cyanosis / Early / Incidence not known
laryngospasm / Rapid / Incidence not known
hepatotoxicity / Delayed / Incidence not known
renal failure (unspecified) / Delayed / Incidence not known

Moderate

anemia / Delayed / 0-33.0
constipation / Delayed / 1.0-10.0
dysphagia / Delayed / 1.0-10.0
pneumonitis / Delayed / 1.0-10.0
stomatitis / Delayed / 1.0-6.0
hypotension / Rapid / 1.0-2.0
sinus tachycardia / Rapid / 0-2.0
dyspnea / Early / 0-2.0
peripheral neuropathy / Delayed / 1.0-2.0
bone marrow suppression / Delayed / Incidence not known
esophagitis / Delayed / Incidence not known
radiation recall reaction / Delayed / Incidence not known
metabolic acidosis / Delayed / Incidence not known
hypertension / Early / Incidence not known

Mild

alopecia / Delayed / 8.0-66.0
vomiting / Early / 31.0-43.0
nausea / Early / 31.0-43.0
diarrhea / Early / 1.0-13.0
anorexia / Delayed / 10.0-13.0
fever / Early / 1.0-10.0
dysgeusia / Early / 1.0-10.0
skin hyperpigmentation / Delayed / 1.0-10.0
urticaria / Rapid / 1.0-10.0
rash / Early / 1.0-10.0
pruritus / Rapid / 1.0-10.0
asthenia / Delayed / 1.0-10.0
fatigue / Early / 1.0-10.0
malaise / Early / 1.0-10.0
drowsiness / Early / 1.0-10.0
abdominal pain / Early / 0-2.0
chills / Rapid / 0-2.0
infection / Delayed / Incidence not known
injection site reaction / Rapid / Incidence not known
maculopapular rash / Early / Incidence not known
diaphoresis / Early / Incidence not known
cough / Delayed / Incidence not known
back pain / Delayed / Incidence not known
flushing / Rapid / Incidence not known
throat irritation / Early / Incidence not known

Boxed Warning
Bleeding, bone marrow suppression, infection, neutropenia, 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. 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.

Common Brand Names

Etopophos, Toposar, VePesid

Dea Class

Rx

Description

Topoisomerase inhibitor that causes DNA strand breaks and cell cycle arrest
IV formulations used as part of combination therapy for refractory testicular tumors and as first-line treatment for small-cell lung cancer (SCLC); oral formulation used as first-line treatment for SCLC in combination with other chemotherapeutic agents
Black Box Warning for severe myelosuppression with risk of infection or bleeding

Dosage And Indications
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. 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. Administer appropriate hydration prior to cisplatin administration and maintain hydration and adequate urinary output for 24 hours after cisplatin administration. 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. 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.

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. Administer appropriate hydration prior to cisplatin administration and maintain hydration and adequate urinary output for 24 hours after cisplatin administration. 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. 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. 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.

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. Administer appropriate hydration prior to cisplatin administration and maintain hydration and adequate urinary output for 24 hours after cisplatin administration. 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.

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. 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. Other doses and regimens have been used; consult the literature for specific protocols.

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.

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.

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.

For the first-line treatment of extensive-stage SCLC, in combination with carboplatin and atezolizumab†.
NOTE: Atezolizumab is FDA-approved in combination with carboplatin and etoposide for this indication.
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.

For the first-line treatment of extensive-stage SCLC, in combination with carboplatin and durvalumab.
NOTE: Durvalumab is FDA-approved in combination with carboplatin and etoposide for this indication.
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.

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.

For the first-line treatment of extensive-stage SCLC, in combination with cisplatin and durvalumab.
NOTE: Durvalumab is FDA-approved in combination with cisplatin and etoposide for this indication.
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.  Administer appropriate hydration prior to cisplatin administration and maintain hydration and adequate urinary output for 24 hours after cisplatin administration. 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.

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.  Administer appropriate hydration prior to cisplatin administration and maintain hydration and adequate urinary output for 24 hours after cisplatin administration. 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.

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. 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. Administer appropriate hydration prior to cisplatin administration and maintain hydration and adequate urinary output for 24 hours after cisplatin administration. The use of colony-stimulating factors is not recommended during concurrent EP plus radiation therapy. 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.

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.

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.

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.

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. 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.

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%.

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.

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). 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. G-CSF has also been used to maintain dose intensity as needed after the first dose reduction. Alternative prophylactic medications have also been used.

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. 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. The standard dose BEACOPP and escalated dose BEACOPP regimens have shown benefit for the treatment of advanced Hodgkin lymphoma in clinical trials. 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. 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.

For the treatment of previously untreated, high-risk classical Hodgkin lymphoma, in combination with brentuximab vedotin, doxorubicin, vincristine, prednisone, and cyclophosphamide†.
NOTE: Brentuximab vedotin is FDA approved for this indication.
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. 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.

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. Alternative dosage regimens have been used, including some in the outpatient setting.

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.

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).

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.

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.

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.

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%.

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.

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%).

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.

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.

†Indicates off-label use

Dosing Considerations
Hepatic Impairment

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.
 
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%.
Bilirubin 3 to 5 mg/dL: Reduce the etoposide dose by 75%.
Bilirubin greater than 5 mg/dL: Hold etoposide.

Renal Impairment

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.

Drug Interactions

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.
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.
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.
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.
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.
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.
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.
Warfarin: (Moderate) Frequently measure the PT/INR if coadministration of etoposide with warfarin is necessary; concomitant use can increase the INR.

How Supplied

Etopophos/Etoposide/Etoposide Phosphate Intravenous Inj Pwd F/Sol: 100mg
Etoposide/Toposar/VePesid Intravenous Inj Sol: 1mL, 20mg
Etoposide/VePesid Oral Cap: 50mg

Maximum Dosage
Adults

IV: 200 mg/m2 per day.
PO: 100 mg/m2 per day.

Geriatric

IV: 200 mg/m2 per day.
PO: 100 mg/m2 per day.

Adolescents

IV: 200 mg/m2 per day.

Children

IV: 150 mg/m2 per day.

Infants

IV: 120 mg/m2 per day.

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. Etoposide has also been shown to cause metaphase arrest in chick fibroblasts. Etoposide phosphate is a prodrug that is converted to its active moiety, etoposide, by dephosphorylation.

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.
 
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).

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.

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. There is marked intra- and inter-subject variability following IV etoposide administration. 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).

Pregnancy And Lactation
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.

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.