Etoposide

L01C - Plant alkaloids and other natural products ATC L01CB01 Small molecule approved 1983 Oral Parenteral Natural product Black-box warning

JFDA label: ETOPOSID "Ebewe"

⚠ Black-Box Warning

Experienced physician:
Bone marrow suppression:

Mechanism of Action

Inhibitor of DNA topoisomerase II — DNA topoisomerase II inhibitor

Target	Action	Gene / class
DNA topoisomerase II efficacy	INHIBITOR

Indications

Approved

Small cell lung cancer (oral and IV)
Testicular cancer (IV)

Off-label

Acute lymphocytic leukemia (ALL)
Acute myeloid leukemia (AML) induction (Children)
Acute myeloid leukemia (AML), refractory
Breast cancer, recurrent or metastatic
Central nervous system tumors
Ewing sarcoma
Gestational trophoblastic disease
Hematopoietic stem cell transplant conditioning regimen (Children)
Hematopoietic stem cell transplant conditioning regimen, lymphoid malignancies
Hodgkin lymphoma (Children)
Merkel cell cancer
Multiple myeloma, refractory
Neuroblastoma (Children)
Neuroendocrine tumors (adrenal gland and carcinoid tumors)
Non-Hodgkin lymphomas
Non-small cell lung cancer
Osteosarcoma
Ovarian cancer, refractory
Prostate cancer
Retinoblastoma
Sarcoma, refractory (Children)
Soft tissue sarcoma, metastatic
Thymic malignancies (locally advanced or metastatic)
Thymoma, locally advanced or metastatic
Unknown primary adenocarcinoma
Wilms tumor

Class profile

mechanismClass	Plant alkaloid (podophyllotoxin, topoisomerase II inhibitor)
targetMolecule	Topoisomerase II (DNA double-strand break stabilization)
targetPathway	DNA replication/S phase
generation	Classic
primaryTumors	Testicular,SCLC,Lymphoma,AML,Kaposi sarcoma
resistanceMechanisms	MDR1/P-gp efflux,Topoisomerase II mutation or downregulation,Altered apoptosis (p53 mutation)
source	NCCN/OncoKB/Goodman&Gilman13ed

Contraindications

Source: Lexicomp

Additional contraindications (not in the US labeling): Severe leukopenia or thrombocytopenia Absolute
Hypersensitivity to etoposide or any component of the formulation Absolute
severe hepatic impairment Absolute
severe renal impairment Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (1)

Common Hypotension

Nervous system disorders (1)

Common Peripheral neuropathy

Hepatobiliary disorders (1)

Common Hepatotoxicity

Blood and lymphatic system disorders (3)

Very Common anemia · Leukopenia · thrombocytopenia

Immune system disorders (1)

Common Anaphylactoid reaction (intravenous: 1% to 2%; oral capsules:

Gastrointestinal disorders (5)

Very Common anorexia · diarrhea · Nausea and vomiting

Common abdominal pain · Stomatitis

Skin and subcutaneous tissue disorders (1)

Very Common Alopecia

Dosing

Source: Lexicomp

Small cell lung cancer (combination chemotherapy): IV: 35 mg/m2/day for 4 days, up to 50 mg/m2/day for 5 days every 3 to 4 weeks Oral: Due to poor bioavailability, oral doses should be twice the IV dose (and rounded to the nearest 50 mg) Testicular cancer (combination chemotherapy): IV: 50 to 100 mg/m2/day for days 1 to 5 or 100 mg/m2/day on days 1, 3, and 5 repeated every 3 to 4 weeks Adult off-label uses and/or dosing: Hematopoietic stem cell transplant conditioning regimen, lymphoid malignancies: IV: 60 mg/kg over 4 hours as a single dose 3 or 4 days prior to transplantation (Horning 1994; Snyder 1993; Weaver 1994) Non-small cell lung cancer: IV: 100 mg/m2 days 1, 2, and 3 every 3 weeks for 4 cycles or every 4 weeks for 3 to 4 cycles (in combination with cisplatin) (Arriagada 2004) or 50 mg/m2 days 1 to 5 and days 29 to 33 (in combination with cisplatin and radiation therapy) (Albain 2009) Ovarian cancer, refractory: Oral: 50 mg/m2 once daily for 21 days every 4 weeks until disease progression or unacceptable toxicity (Rose 1998) Small cell lung cancer, limited stage: IV: 120 mg/m2 on days 1, 2, and 3 every 3 weeks (in combination with cisplatin) for 4 courses (Turrisi 1999) or 100 mg/m2 on days 1, 2, and 3 for induction therapy (in combination with cisplatin), followed by consolidation chemotherapy (Saito 2006) or 100 mg/m2 on days 1, 2, and 3 every 3 weeks (in combination with carboplatin) up to a maximum of 6 cycles (Skarlos 2001) or 100 mg/m2 IV on day 1 (in combination with cisplatin), followed by 200 mg/m2 orally on days 2 through 4 every 3 weeks for a maximum of 5 courses (Sundstrom 2002). According to American Society of Clinical Oncology (ASCO) guidelines, platinum-based therapy (cisplatin or carboplatin) in combination with either etoposide or irinotecan for 4 cycles is recommended over other regimens for limited stage disease (Rudin 2015). Small cell lung cancer, extensive stage: 100 mg/m2 IV on days 1, 2, and 3 every 3 weeks (in combination with cisplatin) for 4 cycles (Lara 2009) or 100 mg/m2 IV on day 1 (in combination with cisplatin), followed by 200 mg/m2 orally on days 2 through 4 every 3 weeks for a maximum of 5 courses (Sundstrom 2002) or IV: 80 mg/m2 on days 1, 2, and 3 every 3 weeks (in combination with cisplatin) up to 8 cycles (Ihede 1994). According to ASCO guidelines, platinum-based therapy (cisplatin or carboplatin) in combination with either etoposide or irinotecan for 4 to 6 cycles is recommended over other regimens for extensive stage disease (Rudin 2015). Testicular cancer (combination chemotherapy): Nonseminoma: IV: 100 mg/m2/day on days 1 through 5 every 21 days for 3 to 4 courses (Saxman 1998) Nonseminoma, metastatic (high-dose regimens): IV: 750 mg/m2/day administered 5, 4, and 3 days before peripheral blood stem cell infusion, repeat for a second cycle after recovery of granulocyte and platelet counts (Einhorn 2007) or 400 mg/m2/day (beginning on cycle 3) on days 1, 2, and 3, with peripheral blood stem cell s

(For additional information see "Etoposide: Pediatric drug information") Note: Oral etoposide is associated with a moderate emetic potential; antiemetics may be recommended to prevent nausea and vomiting (Dupuis 2011). Acute myeloid leukemia (AML) induction (off-label use; combination chemotherapy) (Woods 1996): IV: ≥3 years: 100 mg/m2/day continuous infusion for 4 days Central nervous system tumors (off-label use; combination chemotherapy): IV: ≥3 years: 100 mg/m2/day on days 1, 2, and 3 of a 3-week treatment cycle (Taylor 2003) ≥6 years: 150 mg/m2/day on days 3 and 4 of a 3-week treatment course (Kovnar 1990) Hematopoietic stem cell transplantation conditioning regimen: IV: 60 mg/kg/dose over 4 hours as a single dose 3 or 4 days prior to transplantation (Horning 1994; Snyder 1993) Hodgkin lymphoma (off-label use): IV: 200 mg/m2/day on days 1, 2, and 3 every 3 weeks (Kelly 2002) Neuroblastoma (off-label use): IV: Induction: 100 mg/m2/day on days 1 to 5 of each cycle (Kaneko 2002) Hematopoietic stem cell transplantation conditioning regimen: 200 mg/m2/day for 4 days beginning 8 or 9 days prior to transplantation (Kaneko 2002) Sarcoma, refractory (off-label use): IV: 100 mg/m2/day on days 1 to 5 of cycle; repeat cycle every 21 days (Van Winkle 2005)

Refer to adult dosing.

Oral, IV: The manufacturer’s labeling recommends the following adjustments: CrCl >50 mL/minute: No adjustment required. CrCl 15 to 50 mL/minute: Administer 75% of dose CrCl The following adjustments have also been recommended: Aronoff, 2007: Adults: CrCl 10 to 50 mL/minute: Administer 75% of dose. CrCl Hemodialysis: Administer 50% of dose; supplemental posthemodialysis dose is not necessary. Peritoneal dialysis: Administer 50% of dose; supplemental dose is not necessary. Continuous renal replacement therapy (CRRT): Administer 75% of dose. Children: CrCl 10 to 50 mL/minute/1.73 m2: Administer 75% of dose. CrCl 2: Administer 50% of dose. Hemodialysis: Administer 50% of dose. Peritoneal dialysis: Administer 50% of dose. Continuous renal replacement therapy (CRRT): Administer 75% of dose and reduce for hyperbilirubinemia. Janus, 2010: Hemodialysis: Reduce dose by 50%; not removed by hemodialysis so may be administered before or after dialysis Kintzel, 1995: CrCl 46 to 60 mL/minute: Administer 85% of dose CrCl 31 to 45 mL/minute: Administer 80% of dose CrCl ≤30 mL/minute: Administer 75% of dose

There are no dosage adjustments provided in the manufacturer’s labeling. The following adjustments have also been recommended: Donelli 1998: Liver dysfunction may reduce the metabolism and increase the toxicity of etoposide. Normal doses of IV etoposide should be given to patients with liver dysfunction (dose reductions may result in subtherapeutic concentrations); however, use caution with concomitant liver dysfunction (severe) and renal dysfunction as the decreased metabolic clearance cannot be compensated by increased renal clearance. Floyd 2006: Bilirubin 1.5 to 3 mg/dL or AST >3 times ULN: Administer 50% of dose King 2001; Koren, 1992: Bilirubin 1.5 to 3 mg/dL or AST >180 units/L: Administer 50% of dose

Warnings & Precautions

Source: Lexicomp

Bone marrow suppression

Severe dose-limiting and dose-related myelosuppression with resulting infection or bleeding may occur. Treatment should be withheld for platelets 3 or absolute neutrophil count (ANC) 3.

Gastrointestinal toxicity

Oral etoposide is associated with a low (adults) or moderate (children) emetic potential; antiemetics may be recommended to prevent nausea and vomiting (Dupuis 2011; Roila 2016).

Hypersensitivity reaction

May cause anaphylactic-like reactions manifested by chills, fever, tachycardia, bronchospasm, dyspnea, and hypotension. In addition, facial/tongue swelling, coughing, chest tightness, cyanosis, laryngospasm, diaphoresis, hypertension, back pain, loss of consciousness, and flushing have also been reported less commonly. Incidence is primarily associated with intravenous administration (up to 2%) compared to oral administration (• Hypotension: Hypotension may occur due to rapid administration; infuse slowly over at least 30 to 60 minutes. If hypotension occurs, interrupt infusion and administer IV hydration and supportive care; decrease infusion upon reinitiation.

Secondary malignancies

Secondary acute leukemias have been reported with etoposide, either as monotherapy or in combination with other chemotherapy agents. Disease-related concerns:

Hepatic impairment

Use with caution in patients with hepatic impairment; dosage should be adjusted.

Hypoalbuminemia

Use with caution in patients with low serum albumin; may increase risk for toxicities.

Renal impairment

Use with caution in patients with renal impairment; dosage should be adjusted. Concurrent drug therapy issues:

Drug-drug interactions

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

Elderly

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

Pediatric

The use of concentrations higher than recommended were associated with higher rates of anaphylactic-like reactions in children. Dosage form specific issues:

Alcohol

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

Benzyl alcohol and derivatives

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

Polysorbate 80

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

Administration

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

Experienced physician

Should be administered under the supervision of an experienced cancer chemotherapy physician.

Pregnancy & Lactation

Pregnancy

FDA category D

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

Lactation

Etoposide is present in breast milk. Based on data from one case report, concentrations are below the limit of detection 24 hours after the last dose (Azuno 1995). Due to the potential for serious adverse reactions in the breastfed infant, the manufacturer recommends a decision be made whether to discontinue breastfeeding or to discontinue the drug, taking into account the importance of treatment to the mother.

Monitoring

Efficacy	Tumour response (RECIST criteria, tumour markers, imaging); progression-free survival; performance status (ECOG/Karnofsky)
Toxicity	CBC with differential (nadir timing depends on agent); LFTs; renal function; ECG (QT for relevant agents); echocardiogram for cardiotoxic agents (anthracyclines, trastuzumab); cumulative dose tracking for dose-limited toxicities
Clinical pearl	Treatment response is assessed after 2–3 cycles. Grade 3–4 toxicities typically require dose reduction or interruption per protocol-defined criteria.
Counseling	Attend all scheduled blood tests and imaging appointments. Report fever > 38°C (risk of neutropaenic sepsis — medical emergency), unusual bleeding, or new pain immediately.

Chemistry & Properties

Formula	C29H32O13
Molecular weight	588.56 g/mol
IUPAC name	(5S,5aR,8aR,9R)-5-[[(2R,4aR,6R,7R,8R,8aS)-7,8-dihydroxy-2-methyl-4,4a,6,7,8,8a-hexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy]-9-(4-hydroxy-3,5-dimethoxyphenyl)-5a,6,8a,9-tetrahydro-5H-[2]benzofuro[6,5-f][1,3]benzodioxol-8-one
CAS	33419-42-0
PubChem CID	36462
InChIKey	`VJJPUSNTGOMMGY-MRVIYFEKSA-N`
logP	1.34 (XLogP 0.6)
Polar surface area	160.83 Å²
H-bond acceptors / donors	13 / 3
Drug-likeness (QED)	0.43
Lipinski violations	2

SMILES

COc1cc([C@@H]2c3cc4c(cc3[C@@H](O[C@@H]3O[C@@H]5CO[C@@H](C)O[C@H]5[C@H](O)[C@H]3O)[C@H]3COC(=O)[C@H]23)OCO4)cc(OC)c1O

Biology & Pharmacokinetics

Pharmacokinetics

BBB penetrant	No (logBB -1.5)

Enzyme interactions

Enzyme	Role	Detail
CYP2B6	Inhibitor	—
CYP2C19	Substrate	—
CYP3A4	Inhibitor	—
CYP3A4	Substrate	—

Receptor binding (top 1)

Target	Action	Affinity
DNA topoisomerase II alpha (TOP2A)	Inhibitor	pIC50 7.3

Transporters

BCRP (Inhibitor)BCRP (Inhibitor)BSEP (Inhibitor)BSEP (Inhibitor)MATE1 (Inhibitor)MDR1 (Inhibitor)MRP (Inhibitor)MRP1 (Inhibitor)MRP1 (Inhibitor)MRP2 (Inhibitor)MRP3 (Inhibitor)MRP4 (Inhibitor)MRP7 (Inhibitor)OATP1B1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)OATP1B3 (Inhibitor)OATP2B1 (Inhibitor)OCT1 (Inhibitor)P-gp (Inhibitor)BCRP (Substrate)MDR1 (Substrate)MRP1 (Substrate)MRP2 (Substrate)OATP1B1 (Substrate)OATP1B3 (Substrate)OATP2B1 (Substrate)P-gp (Substrate)

Drug–drug interactions (100+, DDInter)

Interacting drug	Severity	Management
Adalimumab	major
Bacillus calmette-guerin substrain tice live antigen	major
Baricitinib	major
Certolizumab pegol	major
Cladribine	major
Clozapine	major
Deferiprone	major
Etanercept	major
Fingolimod	major
Golimumab	major
Infliximab	major
Leflunomide	major
Measles virus vaccine live attenuated	major
Mumps virus strain B level jeryl lynn live antigen	major
Natalizumab	major
Ozanimod	major
Rotavirus vaccine	major
Rubella virus vaccine	major
Samarium (153Sm) lexidronam	major
Siponimod	major
Smallpox (Vaccinia) Vaccine, Live	major
Talimogene laherparepvec	major
Teriflunomide	major
Thalidomide	major
Tofacitinib	major
Typhoid vaccine (live)	major
Upadacitinib	major
Varicella Zoster Vaccine (Recombinant)	major
Yellow Fever Vaccine	major
Abametapir (topical)	moderate
Aldesleukin	moderate
Alefacept	moderate
Alemtuzumab	moderate
Alpelisib	moderate
Amiodarone	moderate
Anakinra	moderate
Anisindione	moderate
Anthrax vaccine	moderate
Apalutamide	moderate
Aprepitant	moderate

Showing 40 of 100+.

Registered Products (6)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Zuvitop-50	Capsule 50 mg	8 cap	ÙØ³ØªÙØ¯Ø¹ Ø£Ø¯ÙÙØ© Ø§ÙÙÙÙÙÙÙ	28.000
ETOPOSID "Ebewe"	Suspension 100 mg/5 ml	1 vial	Sabbagh Drug Store	—
Eotocid 100mg /5ml Sol For Inf	Solution 100 mg/5 ml	1 vial	Hikma Pharmaceuticals Co.Ltd/Jordan	—
Eotocid 200mg /10ml Sol For Inf	Solution 200 mg/10 ml	1 vial	Hikma Pharmaceuticals Co.Ltd/Jordan	—
Eotocid 400mg /20ml Sol For Inf	Solution 400 mg/20 ml	1 vial	Hikma Pharmaceuticals Co.Ltd/Jordan	—
Fytosid	Injection 100 mg/5 ml	1 vial	Sun Set Drug Store	—