Etoposide (DB00773): A Comprehensive Monograph on its Pharmacology, Clinical Utility, and Safety Profile

Executive Summary of Etoposide

Etoposide is a cornerstone chemotherapeutic agent widely utilized in the treatment of several solid tumors and hematologic malignancies.[1] A semi-synthetic derivative of the plant alkaloid podophyllotoxin, etoposide represents a critical advancement in natural product-based drug development, possessing a distinct mechanism of action from its parent compound.[2] It is classified as a topoisomerase II inhibitor, functioning not by direct DNA binding but as an enzyme "poison." Etoposide stabilizes a transient, covalent complex between the topoisomerase II enzyme and cleaved DNA, thereby preventing the re-ligation of DNA strands. This action introduces persistent, protein-linked double-strand breaks, which are highly cytotoxic and trigger apoptosis, particularly in rapidly proliferating cancer cells.[4]

The United States Food and Drug Administration (FDA) has approved etoposide for two primary indications: as a component of combination therapy for refractory testicular cancer and as a first-line treatment for small cell lung cancer (SCLC), typically in conjunction with a platinum agent.[7] Its broad-spectrum activity has also led to extensive off-label use in lymphomas, leukemias, and other solid tumors. The global importance of etoposide is underscored by its inclusion on the World Health Organization's List of Essential Medicines, recognizing its efficacy and value in oncology.[1]

The pharmacokinetic profile of etoposide is characterized by significant inter-patient variability, stemming from incomplete and erratic oral bioavailability and extensive hepatic metabolism, primarily mediated by the cytochrome P450 3A4 (CYP3A4) isoenzyme.[4] This reliance on CYP3A4 renders etoposide highly susceptible to numerous drug-drug and drug-food interactions, which can profoundly impact its therapeutic window.

Clinically, the utility of etoposide is balanced by a significant and predictable toxicity profile. The drug's mechanism of action directly accounts for its primary dose-limiting toxicity: severe myelosuppression, which manifests as profound neutropenia, thrombocytopenia, and anemia.[5] Other common adverse effects include alopecia, nausea, vomiting, and mucositis. A critical long-term risk associated with etoposide therapy is the development of secondary malignancies, particularly treatment-related acute myeloid leukemia (t-AML). This has been mechanistically linked to the drug's activity against the topoisomerase II beta isoform, distinguishing it from the anti-tumor effects mediated via the alpha isoform.[4] Consequently, the safe and effective administration of etoposide requires careful patient selection, vigilant monitoring, and judicious management of its toxicities and interactions.

Physicochemical Properties and Synthesis

Chemical Identification and Nomenclature

Etoposide is a complex organic molecule with a well-defined chemical identity. Its primary common name is Etoposide, which is recognized as an International Nonproprietary Name (INN).[1] Its chemical structure is complex, leading to several systematic names under the International Union of Pure and Applied Chemistry (IUPAC) nomenclature, depending on the specific conventions used. One commonly cited IUPAC name is

(5S,5aR,8aR,9R)- 9- (4- hydroxy- 3,5- dimethoxyphenyl)- 8- oxo- 5,5a,6,8,8a,9- hexahydrofuro[3',4':6,7]naphtho[2,3- d]dioxol- 5- yl 4,6- O-- \beta- D- glucopyranoside.[1] An alternative systematic name is

(5S,5aR,8aR,9R)-5-dioxin-6-yl]oxy]-9-(4-hydroxy-3,5-dimethoxyphenyl)-5a,6,8a,9-tetrahydro-5H-benzofuro[6,5-f]benzodioxol-8-one.[10]

For unambiguous identification in scientific databases and regulatory documents, etoposide is assigned several unique identifiers. These include the CAS (Chemical Abstracts Service) Registry Number 33419-42-0 [1], the DrugBank Accession Number DB00773 [1], the PubChem Compound ID (CID) 36462 [2], and the ChEBI (Chemical Entities of Biological Interest) ID CHEBI:4911.[1] In early research and clinical development, it was often referred to by the codes VP-16 or VP-16-213, which are still used colloquially.[1]

The drug is marketed under various brand names globally, including Vepesid®, Toposar®, Etopophos® (for the phosphate prodrug), and Lastet®.[1] It also has numerous chemical synonyms, the most descriptive of which is

4'-Demethylepipodophyllotoxin 9-(4,6-O-ethylidene-beta-D-glucopyranoside), highlighting its structural relationship to its parent compounds.[1]

Molecular Structure and Properties

Etoposide's molecular formula is C29​H32​O13​, with a corresponding molecular weight of approximately 588.56 g/mol.[14] Minor variations in the reported molecular weight, such as 588.55 g/mol or 588.6 g/mol, are due to differences in atomic weight averaging and precision.[15]

Its structure is defined by a rigid, organic heterotetracyclic aglycone core linked to a sugar moiety. Chemically, it is classified as a furonaphthodioxole and a β-D-glucoside.[1] The molecule is functionally derived from its natural precursor, podophyllotoxin, and its immediate synthetic parent, 4'-demethylepipodophyllotoxin.[1] For precise computational and database use, its structure is represented by unique identifiers such as the InChIKey (VJJPUSNTGOMMGY-MRVIYFEKSA-N) and the SMILES string (

C[C@@H]1OC[C@@H]2[C@@H](O1)[C@@H]([C@H]([C@@H](O2)O[C@H]3[C@H]4COC(=O)[C@@H]4[C@@H](C5=CC6=C(C=C35)OCO6)C7=CC(=C(C(=C7)OC)O)OC)O)O).[14]

Physical Characteristics and Formulation

In its solid state, etoposide appears as a white to yellow-brown crystalline powder.[2] A key physicochemical property that profoundly influences its clinical formulation is its solubility. It is very soluble in organic solvents like methanol and chloroform but only slightly soluble in ethanol and is sparingly soluble in water, with an aqueous solubility of approximately 0.08 mg/mL.[14] Its melting point is recorded over a range of 236–251 °C.[14]

This poor water solubility presents a significant pharmaceutical challenge. To address this, etoposide is formulated in two primary forms for clinical use:

1. Oral Formulation: Available as 50 mg liquid-filled gelatin capsules for oral administration.[7]
2. Intravenous (IV) Formulation: Provided as a sterile, non-aqueous concentrate for injection (e.g., 20 mg/mL) that must be diluted prior to administration. This formulation contains organic solvents, such as ethanol and polysorbate 80, to solubilize the lipophilic drug.[7] The presence of these excipients, particularly polysorbate 80, is associated with infusion-related hypersensitivity reactions.[23]
3. Etoposide Phosphate (Etopophos®): To overcome the challenges associated with the conventional IV formulation, a water-soluble prodrug, etoposide phosphate, was developed. It is supplied as a sterile, lyophilized powder that can be reconstituted with aqueous solutions. Upon intravenous administration, it is rapidly and completely converted to the active etoposide moiety by endogenous plasma phosphatases.[9] This formulation allows for easier preparation, smaller infusion volumes, and faster administration times, mitigating some of the risks associated with the organic solvent vehicle.[23]

The development trajectory from the parent drug to its phosphate prodrug exemplifies a classic pharmaceutical solution to a problem rooted in the drug's intrinsic physicochemical properties. The poor aqueous solubility of etoposide necessitated the use of excipients that contribute to adverse events, which in turn drove the innovation of a more soluble prodrug to improve patient safety and administration convenience.

Origin and Synthesis

Etoposide is a semi-synthetic derivative of podophyllotoxin, a potent cytotoxic lignan naturally occurring in the rhizome of the American mayapple plant, Podophyllum peltatum.[2] The development of etoposide was part of a broader effort to create derivatives of podophyllotoxin with an improved therapeutic index, specifically aiming for reduced toxicity compared to the parent compound.

This research led to a pivotal shift in the drug's mechanism of action. While the natural product podophyllotoxin exerts its cytotoxic effects as an anti-mitotic agent by binding to tubulin and disrupting microtubule formation, the semi-synthetic modifications that produced etoposide altered its primary molecular target to topoisomerase II.[5] This fundamental change in mechanism underpins etoposide's distinct pharmacological and clinical profile.

The drug was first synthesized in 1966, and the key patent for its preparation was granted in 1970.[2] The synthesis involves a multi-step chemical modification of the naturally extracted podophyllotoxin.[22]

Identifier/Property	Value	Source(s)
Common Name	Etoposide	1
DrugBank ID	DB00773	4
CAS Number	33419-42-0	1
IUPAC Name	(5S,5aR,8aR,9R)- 9- (4- hydroxy- 3,5- dimethoxyphenyl)- 8- oxo- 5,5a,6,8,8a,9- hexahydrofuro[3',4':6,7]naphtho[2,3- d]dioxol- 5- yl 4,6- O-- \beta- D- glucopyranoside	1
Molecular Formula	C29​H32​O13​	16
Molecular Weight	588.56 g/mol	16
InChIKey	VJJPUSNTGOMMGY-MRVIYFEKSA-N	14
SMILES	C[C@@H]1OC[C@@H]2[C@@H](O1)[C@@H]([C@H]([C@@H](O2)O[C@H]3[C@H]4COC(=O)[C@@H]4[C@@H](C5=CC6=C(C=C35)OCO6)C7=CC(=C(C(=C7)OC)O)OC)O)O	14
Physical Form	Crystalline Solid	14
Color	White to yellow-brown
Melting Point	236-251 °C	14
Water Solubility	Sparingly soluble (approx. 0.08 mg/mL)	14

Comprehensive Pharmacological Profile

Mechanism of Action: Topoisomerase II "Poison"

The primary antineoplastic effect of etoposide is achieved through its interaction with DNA topoisomerase II (Topo II), a critical nuclear enzyme.[3] Topo II plays an indispensable role in managing the complex topology of DNA during essential cellular processes such as replication, transcription, and chromosomal segregation at mitosis. It functions by catalyzing a transient, enzyme-mediated double-strand break (DSB) in the DNA backbone, allowing a separate, intact DNA duplex to pass through the gap. Following this strand-passage event, the enzyme re-ligates the broken DNA strands, restoring the integrity of the genome.[3]

Etoposide is classified as a non-intercalating Topo II inhibitor, meaning it does not bind directly into the DNA helix in the manner of drugs like doxorubicin.[5] Instead, it functions as a "Topo II poison." Its mechanism involves the formation of a stable ternary complex composed of the Topo II enzyme, the DNA substrate, and the drug molecule itself.[2] Etoposide specifically intervenes in the enzyme's catalytic cycle after the DNA cleavage step but before the re-ligation step. By binding to and stabilizing this "cleavable complex," etoposide prevents the enzyme from rejoining the DNA strands it has just broken.[3]

This action effectively traps the Topo II enzyme on the DNA, converting it from an essential cellular tool into a potent cellular toxin that generates persistent, protein-linked DSBs.[11] The accumulation of these unrepaired DSBs is the ultimate cytotoxic lesion. These breaks are recognized by the cell's DNA damage response machinery, which triggers a cascade of events including cell cycle arrest and, ultimately, programmed cell death (apoptosis).[4]

Isoform Specificity and Clinical Implications

Mammalian cells express two distinct but highly homologous isoforms of Topo II: alpha (encoded by the TOP2A gene) and beta (encoded by the TOP2B gene). These isoforms have different expression patterns and physiological roles, a distinction that is fundamental to understanding both the therapeutic efficacy and the long-term toxicity of etoposide.[3]

Topoisomerase II Alpha (TOP2A): The expression of the alpha isoform is tightly regulated and linked to the cell cycle. Its concentration increases significantly during the G2 and M phases and is orders of magnitude higher in rapidly proliferating cells compared to quiescent, non-dividing cells.[25] This proliferative dependency makes TOP2A an ideal target for anticancer therapy, as cancer cells are characterized by uncontrolled proliferation and thus have a greater reliance on this enzyme. The primary anti-tumor activity of etoposide is directly attributed to its inhibition of the TOP2A isoform.[4]

Topoisomerase II Beta (TOP2B): In contrast, the expression of the beta isoform is relatively constant throughout the cell cycle and is present in both proliferating and terminally differentiated, post-mitotic cells. It is believed to play roles in transcriptional regulation and cellular differentiation programs.[3] Etoposide also inhibits TOP2B. However, this interaction is not associated with the drug's primary therapeutic effect. Instead, it is critically implicated in the drug's most serious long-term adverse effect: the development of treatment-related secondary malignancies, particularly acute myeloid leukemia (t-AML).[4] The inhibition of TOP2B is thought to facilitate illegitimate DNA recombination events, leading to specific chromosomal translocations, most notably involving the Myeloid-Lymphoid Leukemia (

MLL) gene located on chromosome 11q23.[5]

This dual-isoform activity represents a therapeutic paradox. The drug's efficacy and its carcinogenicity are mechanistically intertwined, arising from the inhibition of two different isoforms of the same enzyme family. This understanding provides a compelling scientific rationale for the development of next-generation, TOP2A-specific inhibitors, which could potentially uncouple the desired anti-tumor benefit from the life-threatening risk of secondary leukemia.[3]

Pharmacodynamics: Cellular and Molecular Consequences

The accumulation of etoposide-induced DSBs triggers a series of profound cellular responses.

Cell Cycle Arrest: Etoposide is a cell cycle-dependent and phase-specific agent. By inducing DNA damage, it prevents cells from successfully navigating the cell cycle checkpoints, leading to arrest primarily in the late S (DNA synthesis) and G2 (pre-mitotic) phases.[4] This arrest prevents cells with damaged DNA from entering mitosis, a crucial mechanism to maintain genomic stability. The clinical effectiveness of etoposide is therefore schedule-dependent; administration over several consecutive days is more effective than a single large dose because it increases the probability of targeting more cells as they cycle through the susceptible S and G2 phases.[22]

Dose-Dependent Effects: The cellular response to etoposide is also dose-dependent. At high concentrations (10 µg/mL or more), the drug causes the lysis of cells as they attempt to enter mitosis. At lower, more clinically relevant concentrations (0.3 to 10 µg/mL), it effectively inhibits cells from entering prophase, the first stage of mitosis.[4]

Induction of Apoptosis: The principal mechanism by which etoposide kills cancer cells is the induction of apoptosis.[5] The DNA damage serves as a potent trigger for the intrinsic apoptotic pathway. This involves the activation of key signaling networks, including the p53 tumor suppressor pathway. Upon sensing DNA damage, p53 accumulates and functions as a transcription factor, activating genes that promote cell cycle arrest and apoptosis, thereby amplifying the death signal.[6] The apoptotic cascade proceeds through the activation of effector caspases, such as caspase-3, which then cleave critical cellular substrates like poly (ADP-ribose) polymerase-1 (PARP-1), leading to the systematic dismantling of the cell.[16] Studies have also demonstrated that etoposide can trigger mitochondria-dependent apoptotic signals, involving mitochondrial dysfunction and the phosphorylation of signaling kinases like JNK and ERK1/2.[21]

Importantly, etoposide's mechanism is distinct from that of its parent compound, podophyllotoxin, and other anti-mitotic agents like the vinca alkaloids. Etoposide does not interfere with the assembly or function of microtubules.[4]

Pharmacokinetic Profile: Absorption, Distribution, Metabolism, and Excretion (ADME)

Absorption and Bioavailability

Etoposide can be administered both orally and intravenously, with distinct pharmacokinetic characteristics for each route.

Following oral administration via capsules, etoposide is well absorbed, with the time to reach peak plasma concentration (Tmax) occurring between 1 and 1.5 hours.[4] However, the absolute bioavailability of oral etoposide is notably incomplete and highly variable. The mean bioavailability is approximately 50%, but it exhibits a wide range, from as low as 25% to as high as 75%.[4] This variability is observed not only between different patients (inter-subject) but also within the same patient on different occasions (intra-subject), making precise dose-to-exposure predictions challenging.[4] There is no evidence of a significant first-pass metabolic effect contributing to this incomplete bioavailability.[4] While food does not appear to significantly alter absorption, some clinical guidelines recommend administration on an empty stomach to ensure consistency.[23]

Distribution

Once in the systemic circulation, etoposide's disposition follows a biphasic process, with an initial distribution half-life of about 1.5 hours.[4] A defining characteristic of its distribution is its extensive binding to plasma proteins, with approximately 97% of the drug bound, primarily to serum albumin.[4] This high degree of protein binding results in a low fraction of unbound, pharmacologically active drug and limits its distribution into tissues. The steady-state volume of distribution (Vd) is relatively small, reported to be in the range of 18 to 29 L.[4]

The high protein binding has significant clinical implications. It restricts the drug's ability to penetrate certain physiological compartments, most notably the central nervous system. Concentrations of etoposide in the cerebrospinal fluid (CSF) are typically less than 5% of concurrent plasma concentrations, rendering it largely ineffective for treating CNS malignancies at standard doses.[4] Furthermore, the unbound fraction of etoposide is clinically important. In patients with conditions that lower serum albumin (e.g., malnutrition) or increase serum bilirubin (which can displace etoposide from its binding sites), the fraction of free, active drug can increase significantly. This can lead to a disproportionate increase in toxicity even if the total plasma concentration remains unchanged.[5]

Metabolic Pathways and Genetic Considerations

Etoposide undergoes extensive metabolism, which occurs primarily in the liver.[4] The principal metabolic pathway is O-demethylation, which is mediated by the

cytochrome P450 3A4 (CYP3A4) isoenzyme.[4] This reaction produces catechol and quinone metabolites, which are themselves biologically active and possess Topo II inhibitory properties, thus contributing to the drug's overall effect.[5]

In addition to this primary oxidative pathway, etoposide and its metabolites are subject to Phase II conjugation reactions, which typically serve to inactivate the compounds and facilitate their excretion. These pathways include:

• Glucuronidation: Catalyzed by the enzyme UDP-glucuronosyltransferase 1A1 (UGT1A1).[4]
• Glutathione Conjugation: Catalyzed by glutathione S-transferases, specifically GSTT1 and GSTP1.[4]

The genes that encode these critical metabolic enzymes (CYP3A4, UGT1A1, GSTT1) and drug transporters like P-glycoprotein (ABCB1) are known to be polymorphic in the human population. Genetic variations in these genes can lead to significant differences in enzyme or transporter activity between individuals. This pharmacogenomic variability is a major contributor to the observed inter-patient differences in etoposide clearance, drug exposure, and, consequently, clinical response and toxicity.[12] The pharmacokinetic profile of etoposide is thus a cascade of variability, beginning with erratic absorption and compounded by genetically variable metabolism and transport, making standardized dosing a challenge.

Excretion and Elimination

The elimination of etoposide from the body is a biphasic process with a terminal elimination half-life in adults ranging from 4 to 11 hours.[2] Clearance occurs via both renal and non-renal (hepatic and biliary) routes.[5]

Approximately 35% to 45% of an administered intravenous dose is excreted unchanged in the urine, highlighting the importance of renal function in the drug's clearance.[4] The total body clearance of etoposide has been shown to correlate with creatinine clearance, and dose adjustments are necessary in patients with renal impairment.[9] The remaining portion of the drug is eliminated through non-renal mechanisms. Biliary excretion of both unchanged drug and its metabolites is a significant route, with fecal recovery of radioactivity accounting for as much as 44% of an IV dose in some studies.[4]

Clinical Applications and Dosing Regimens

FDA-Approved Indications and Efficacy

Etoposide is a widely used antineoplastic agent with well-established efficacy in specific cancer types. The U.S. Food and Drug Administration (FDA) has approved its use for two primary indications, in both cases as part of a combination chemotherapy regimen.[7]

1. Refractory Testicular Cancer: Etoposide is a standard-of-care component in combination regimens for patients with refractory testicular tumors who have not responded to or have relapsed after initial surgery, chemotherapy, or radiotherapy.[4] It is most famously used in the BEP (bleomycin, etoposide, and cisplatin) and EP (etoposide and cisplatin) regimens, which have achieved high cure rates in this disease setting.[22]
2. Small Cell Lung Cancer (SCLC): Etoposide is indicated as a first-line treatment for patients with SCLC, where it is almost always administered in combination with a platinum agent, either cisplatin or carboplatin.[4] The combination of etoposide and cisplatin has long been a global standard for the initial management of extensive-stage SCLC.

Off-Label and Investigational Uses

Beyond its approved indications, the broad-spectrum cytotoxic activity of etoposide has led to its extensive off-label use in the treatment of a wide variety of other cancers.[1] These uses are often supported by substantial clinical evidence and inclusion in major treatment guidelines.

• Hematologic Malignancies: Etoposide is frequently used for non-Hodgkin lymphoma, acute lymphoblastic leukemia (ALL), and acute myeloid leukemia (AML).[1] It is also a key component of high-dose chemotherapy conditioning regimens administered prior to autologous or allogeneic hematopoietic stem cell transplantation (HSCT) for various hematologic cancers.[2]
• Solid Tumors: Its off-label applications in solid tumors include ovarian cancer, non-small cell lung cancer (NSCLC), glioblastoma multiforme, Kaposi's sarcoma, Ewing's sarcoma, neuroblastoma, and Wilms' tumor.[1]
• Non-Malignant Conditions: Etoposide has also found a role in treating severe, life-threatening non-malignant disorders of immune dysregulation, such as hemophagocytic lymphohistiocytosis (HLH).[1]

Dosing, Administration, and Formulation-Specific Considerations

The safe and effective use of etoposide requires strict adherence to administration protocols and careful consideration of patient-specific factors for dose adjustments.

Administration Precautions: Etoposide is classified as a hazardous drug, and healthcare personnel must exercise caution during handling and preparation, including the use of protective gloves.[7] For intravenous administration, the concentrate must be diluted with either 5% Dextrose Injection or 0.9% Sodium Chloride Injection to a final concentration between 0.2 and 0.4 mg/mL to prevent precipitation.[7] A critical administration precaution is the rate of infusion. Rapid IV injection can cause severe, life-threatening hypotension. Therefore, etoposide must be administered as a slow intravenous infusion, typically over a period of 30 to 60 minutes, with monitoring of the patient's blood pressure.[2] This hypotension is believed to be related to the excipients in the formulation vehicle, such as polysorbate 80, rather than a direct effect of the drug itself.[23] The development of the water-soluble prodrug, etoposide phosphate (Etopophos®), mitigates this issue, as it can be administered more rapidly (e.g., over as little as 5 minutes) without the same risk of vehicle-induced hypotension.[9]

Dose Adjustments:

• Renal Impairment: Since a significant fraction of etoposide is cleared by the kidneys, dose reduction is necessary in patients with renal dysfunction. For patients with a creatinine clearance (CrCl) between 15 and 50 mL/min, a 25% dose reduction (i.e., administration of 75% of the standard dose) is recommended. Data are limited for patients with a CrCl below 15 mL/min, and further dose reductions should be considered.[9]
• Hepatic Impairment: Dose adjustments are also recommended for patients with hepatic dysfunction, particularly those with elevated serum bilirubin levels. Hyperbilirubinemia can decrease etoposide's protein binding, increasing the fraction of free, active drug and thereby elevating the risk of toxicity. A dose reduction of 50% may be appropriate for patients with total bilirubin levels between 1.5 and 3.0 mg/dL. Etoposide is contraindicated in patients with severe hepatic impairment.[5]
• Myelosuppression: Dosing in subsequent cycles should always be guided by the patient's hematologic recovery from the previous cycle. Treatment should be delayed or doses reduced if blood counts (neutrophils and platelets) have not recovered to safe levels.[7]

Indication	Regimen Example	Etoposide Dose & Schedule	Combination Agents	Cycle Length	Source(s)
Testicular Cancer (Refractory)	EP	IV: 100 mg/m²/day on Days 1-5	Cisplatin: 20 mg/m²/day on Days 1-5	Repeat q21 days	31
	BEP	IV: 100 mg/m²/day on Days 1-5	Bleomycin: 30 units on Days 1, 8, 15Cisplatin: 20 mg/m²/day on Days 1-5	Repeat q21 days	31
	Alternate	IV: 100 mg/m²/day on Days 1, 3, 5	Varies	Repeat q21-28 days	7
Small Cell Lung Cancer (First-Line)	Etoposide + Cisplatin	IV: 35 mg/m²/day for 4 daysORIV: 50 mg/m²/day for 5 days	Cisplatin	Repeat q21-28 days	7
	Etoposide + Carboplatin	IV: 100 mg/m² on Day 1Oral: 200 mg/m²/day on Days 2, 3	Carboplatin: AUC 5 on Day 1	Repeat q21 days	41
	Oral Regimen	Oral: 70 mg/m²/day for 4 daysOROral: 100 mg/m²/day for 5 days(Note: Oral dose is ~2x IV dose)	Varies	Repeat q21-28 days	28

Safety Profile, Adverse Events, and Toxicology

Common and Severe Adverse Reactions

The clinical use of etoposide is associated with a wide range of adverse effects, many of which are predictable consequences of its cytotoxic mechanism of action. The toxicity profile is well-documented across numerous sources.[1]

Dose-Limiting Toxicity: Myelosuppression: The most significant and dose-limiting toxicity of etoposide is severe bone marrow suppression. This effect can be life-threatening and manifests as:

• Leukopenia and Neutropenia: A profound decrease in white blood cells is very common, with Grade 4 neutropenia (Absolute Neutrophil Count < 500/mm³) occurring in a significant percentage of patients.[26] The nadir, or lowest point of the blood count, typically occurs 7 to 14 days after treatment administration.[27] This severely compromises the patient's immune system, leading to a high risk of serious and potentially fatal infections.[13]
• Thrombocytopenia: A significant decrease in platelet counts is also very common, increasing the risk of spontaneous and severe bleeding.[13]
• Anemia: A decrease in red blood cells and hemoglobin occurs frequently, leading to symptoms of fatigue, weakness, and shortness of breath.[2]

The on-target effect of etoposide on rapidly dividing cells is the direct cause of its most frequent toxicities. The cells of the bone marrow, hair follicles, and gastrointestinal mucosa are among the most rapidly proliferating in the body. It is therefore biologically inevitable that a drug designed to kill such cells will also damage these normal tissues. This explains why myelosuppression, alopecia, and gastrointestinal toxicities are not merely side effects but are intrinsically linked to the drug's therapeutic mechanism. This understanding reinforces why myelosuppression is the dose-limiting toxicity: the dose is escalated to the maximum level the bone marrow can tolerate to achieve the greatest anti-tumor effect.

Other Common Adverse Reactions:

• Gastrointestinal Effects: Nausea and vomiting are very common, affecting up to 43% of patients. Diarrhea and anorexia are also frequent, each occurring in about 13% of patients. Mucositis (inflammation and ulceration of the mouth and throat) is another common effect, occurring in about 6% of patients and becoming more severe with high-dose regimens.[1]
• Dermatologic Effects: Alopecia (hair loss) is an extremely common and psychologically distressing side effect, affecting up to 66% of patients. It is typically reversible, with hair regrowth occurring after treatment completion.[1] Skin rashes and itching can also occur.[42]
• Hypersensitivity/Anaphylactoid Reactions: These occur in approximately 2% of patients and can be severe and life-threatening. Symptoms include chills, fever, tachycardia, bronchospasm, dyspnea, and hypotension. These reactions are often related to the rate of infusion and may be caused by the polysorbate 80 vehicle in the IV formulation.[23]
• Hypotension: A drop in blood pressure can occur, particularly with rapid intravenous infusion.[2]
• Neurologic Effects: While less common, peripheral neuropathy (numbness or tingling in the hands and feet) can occur in about 2% of patients. Rare but serious neurologic events, including seizures and transient cortical blindness, have been reported.[26]
• Injection Site Reactions: Pain, burning, and inflammation (phlebitis) at the intravenous site can occur.[2]

Warnings, Precautions, and Contraindications

Black Box Warning: The FDA requires a boxed warning on the prescribing information for etoposide, highlighting its most serious risk: severe myelosuppression. This warning emphasizes that the drug can cause life-threatening infections or bleeding and should only be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents.[7]

Contraindications: Etoposide is contraindicated in patients with:

• A known history of hypersensitivity to etoposide, the related drug teniposide, or any component of the formulation (e.g., polysorbate 80).[7]
• Pre-existing severe myelosuppression.[26]
• Severe hepatic impairment.[26]
• The presence of an acute, uncontrolled infection.[32]
• Pregnancy and lactation.[13]

Pregnancy and Fertility: Etoposide is classified as Pregnancy Category D. It is known to be teratogenic in animal studies and can cause fetal harm when administered to a pregnant woman.[1] Both male and female patients of reproductive potential must use effective contraception during treatment and for at least 6 months after the final dose.[26] The drug can also impair fertility in both sexes, causing oligospermia or azoospermia in males and amenorrhea or premature menopause in females.[26]

Management of Overdose and Acute Toxicity

There is no specific antidote available for an etoposide overdose.[37] Management is therefore entirely supportive and is directed at the anticipated toxicities. Total doses of 2.4 to 3.5 g/m² administered over three days have resulted in severe mucositis and myelosuppression. In the event of an overdose, the primary concerns are profound and prolonged bone marrow suppression and severe gastrointestinal toxicity. Management strategies include intensive supportive care with blood product transfusions (platelets and red blood cells), administration of granulocyte colony-stimulating factors (G-CSF) to shorten the duration of severe neutropenia, and aggressive management of any infectious complications with broad-spectrum antibiotics.[7]

For acute anaphylactoid reactions that occur during infusion, the infusion must be stopped immediately. Treatment is symptomatic and may include the administration of corticosteroids, pressor agents for hypotension, antihistamines, and intravenous fluids.[23]

Long-Term Toxicology: Secondary Malignancies

A critical and well-documented long-term toxicity of etoposide is the development of treatment-related acute myeloid leukemia (t-AML).[5] This secondary cancer typically presents 2 to 4 years after the completion of etoposide-containing chemotherapy.[26] The risk is mechanistically linked to etoposide's inhibitory activity against the Topoisomerase II beta isoform, which can lead to aberrant DNA recombination and the formation of specific chromosomal translocations. The most common of these is a translocation involving the

MLL gene on chromosome 11q23, a hallmark of etoposide-induced leukemia.[5] This risk must be discussed with patients, particularly those being treated for curable diseases like testicular cancer.

System Organ Class	Frequency	Adverse Reaction	Source(s)
Blood and lymphatic system	Very Common (≥10%)	Myelosuppression (dose-limiting), Leukopenia/Neutropenia, Thrombocytopenia, Anemia	26
	Late (months to years)	Secondary Acute Myeloid Leukemia (t-AML)	5
Gastrointestinal	Very Common (≥10%)	Nausea and vomiting (43%), Anorexia (13%), Diarrhea (13%)	26
	Common (1-10%)	Mucositis/Stomatitis (6%), Abdominal pain (2%), Constipation	26
	Rare (<0.1%)	Dysphagia (difficulty swallowing), Dysgeusia (taste alteration)	42
Dermatological	Very Common (≥10%)	Alopecia (reversible) (66%)	26
	Common (1-10%)	Rash, Urticaria (hives), Pruritus (itching)	42
	Rare (<0.1%)	Stevens-Johnson syndrome, Toxic epidermal necrolysis, Radiation recall dermatitis	26
Immune system	Common (1-10%)	Anaphylactoid/Hypersensitivity reaction (2%) (chills, fever, bronchospasm, dyspnea, hypotension)	26
Cardiovascular	Common (1-10%)	Hypotension (with rapid IV infusion) (2%)	26
	Rare (<0.1%)	Myocardial infarction, Arrhythmia	26
Nervous system	Common (1-10%)	Dizziness	42
	Uncommon (0.1-1%)	Peripheral neuropathy	42
	Rare (<0.1%)	Seizure, Transient cortical blindness, Optic neuritis	42
General / Administration site	Common (1-10%)	Asthenia (weakness/fatigue)	26
	Rare (<0.1%)	Phlebitis (injection site inflammation)	26
Hepatobiliary	Common (1-10%)	Elevated liver function tests (LFTs) (3%)	26
	Rare (<0.1%)	Hepatotoxicity (severe with high doses)	9
Metabolic	Rare (<0.1%)	Tumor lysis syndrome	26

Significant Drug-Drug and Drug-Food Interactions

The safe administration of etoposide is highly dependent on the careful management of concomitant medications due to its narrow therapeutic index and its reliance on common metabolic pathways. The drug is susceptible to a large number of clinically significant interactions that can alter its plasma concentration, leading to either increased toxicity or reduced efficacy.[47]

Interactions Involving Cytochrome P450 Enzymes (CYP3A4)

Etoposide is a major substrate of the cytochrome P450 3A4 (CYP3A4) enzyme, which is responsible for its primary metabolic clearance pathway.[4] This makes it particularly vulnerable to interactions with drugs that inhibit or induce this enzyme.

CYP3A4 Inhibitors: When etoposide is co-administered with drugs that are strong or moderate inhibitors of CYP3A4, its metabolism is decreased. This leads to higher plasma concentrations (increased AUC) and a prolonged half-life, significantly increasing the risk of severe toxicity, especially myelosuppression.

• Examples of Inhibitors: Potent inhibitors include azole antifungals (e.g., ketoconazole, itraconazole), certain macrolide antibiotics (e.g., clarithromycin), HIV protease inhibitors (e.g., ritonavir), and nefazodone.[4]
• Clinical Management: The combination of etoposide with strong CYP3A4 inhibitors should be avoided whenever possible. If co-administration is medically necessary, patients must be monitored with extreme vigilance for signs of increased toxicity (e.g., more frequent complete blood counts). A proactive reduction in the etoposide dose should be strongly considered.[37]

CYP3A4 Inducers: Conversely, co-administration with drugs that are potent inducers of CYP3A4 will accelerate the metabolism of etoposide. This results in lower plasma concentrations and reduced systemic exposure, which can lead to diminished anti-tumor efficacy and potential treatment failure.

• Examples of Inducers: Common inducers include certain anticonvulsants (e.g., phenytoin, carbamazepine, phenobarbital), rifampin, and the herbal supplement St. John's Wort.[5] Mitotane, a drug used for adrenocortical carcinoma, is also a powerful CYP3A4 inducer, and its co-administration has been shown to more than double the clearance of etoposide, providing a clear clinical example of this interaction's impact.[50]
• Clinical Management: This combination should also be avoided. If a CYP3A4 inducer must be used, clinicians should anticipate a potential decrease in etoposide's effectiveness. Monitoring for therapeutic response is crucial, and an increase in the etoposide dose may be required to achieve the target exposure.[49]

Interactions Involving P-glycoprotein (P-gp/ABCB1)

Etoposide is also a substrate for the P-glycoprotein (P-gp) efflux pump, an ATP-binding cassette (ABC) transporter encoded by the ABCB1 gene.[12] P-gp is expressed in the intestine, liver, kidneys, and blood-brain barrier, where it actively transports substrates out of cells.

• P-gp Inhibitors: Drugs that inhibit P-gp, such as cyclosporine, verapamil, and quinidine, can increase the absorption and decrease the clearance of etoposide, leading to higher plasma concentrations.[4] This interaction has been explored therapeutically in clinical trials as a strategy to overcome P-gp-mediated multidrug resistance in cancer cells.[36]
• P-gp Inducers: Many CYP3A4 inducers (e.g., rifampin, St. John's Wort) are also potent inducers of P-gp, leading to a synergistic effect that further reduces etoposide exposure.[48]

Drug-Food Interactions

Grapefruit and Grapefruit Juice: This is the most significant food interaction for etoposide. Grapefruit juice is a well-known, potent inhibitor of intestinal CYP3A4. Consumption of grapefruit products during oral etoposide therapy can significantly increase the drug's bioavailability and plasma concentrations, thereby increasing the risk of toxicity. Patients should be explicitly counseled to avoid grapefruit and its juice during treatment.[27]

Other Clinically Relevant Interactions

• Warfarin: Etoposide can potentiate the anticoagulant effect of warfarin, leading to an elevated International Normalized Ratio (INR) and an increased risk of bleeding. Patients on concurrent therapy require close monitoring of their INR.[38]
• Live Vaccines: As an immunosuppressive agent, etoposide significantly increases the risk of developing disseminated infections from live or live-attenuated vaccines. Therefore, the administration of such vaccines (e.g., measles, mumps, rubella; varicella; yellow fever) is contraindicated during and for a period following etoposide treatment.[26]
• Other Myelosuppressive Agents: The bone marrow-suppressing effects of etoposide are additive with those of other cytotoxic chemotherapy drugs and with radiation therapy. When used in combination, doses must be carefully selected and adjusted to account for this cumulative toxicity.[5]

The clinical management of a patient receiving etoposide is therefore a complex exercise in managing polypharmacy. A thorough medication reconciliation, which includes prescription drugs, over-the-counter products, herbal supplements, and dietary habits, is a critical safety intervention to prevent potentially life-threatening interactions.

Interacting Agent/Class	Example Drugs	Mechanism of Interaction	Clinical Consequence	Management Recommendation	Source(s)
Strong CYP3A4 Inhibitors	Ketoconazole, Itraconazole, Clarithromycin, Ritonavir	Inhibition of CYP3A4-mediated metabolism of etoposide	Increased etoposide concentration; increased risk of severe toxicity (e.g., myelosuppression)	Avoid combination. If necessary, monitor closely for toxicity and consider etoposide dose reduction.	4
Strong CYP3A4 Inducers	Rifampin, Phenytoin, Carbamazepine, St. John's Wort, Mitotane	Induction of CYP3A4-mediated metabolism of etoposide	Decreased etoposide concentration; risk of therapeutic failure	Avoid combination. If necessary, monitor for lack of efficacy and consider etoposide dose increase.	5
P-glycoprotein (P-gp) Inhibitors	Cyclosporine, Verapamil, Quinidine	Inhibition of P-gp efflux pump	Increased etoposide absorption and/or decreased clearance, leading to higher exposure	Use with caution. Monitor for increased toxicity. May be used intentionally in some protocols.	4
Warfarin	Warfarin	Pharmacodynamic interaction (mechanism not fully defined)	Increased anticoagulant effect (elevated INR); increased risk of bleeding	Monitor INR frequently and adjust warfarin dose as needed.	38
Live Vaccines	MMR, Varicella, Yellow Fever vaccines	Pharmacodynamic antagonism (immunosuppression)	Risk of serious or fatal disseminated infection from the vaccine virus	Contraindicated during and for at least 3 months after etoposide therapy.	26
Grapefruit Juice	Grapefruit, Grapefruit Juice	Potent inhibition of intestinal CYP3A4	Increased bioavailability and concentration of oral etoposide; increased risk of toxicity	Patients must avoid consumption of grapefruit products during therapy.	27

Regulatory Status and Future Directions

Regulatory History and Global Standing

Etoposide has a long and established history as a regulated pharmaceutical agent. Following its initial synthesis in 1966, it underwent extensive preclinical and clinical development.[2] The U.S. Food and Drug Administration (FDA) granted its initial approval on

November 10, 1983, under the brand name VePesid®, for the treatment of refractory testicular tumors.[54] Subsequently, its indication was expanded to include the first-line treatment of small cell lung cancer in combination with other chemotherapy agents.[7]

The drug's global importance and established role in oncology are further solidified by its inclusion on the World Health Organization's (WHO) Model List of Essential Medicines. This designation signifies that etoposide is considered a highly effective, safe, and cost-effective medication necessary to meet the priority healthcare needs of a population.[1] Its status as a fundamental chemotherapeutic is also confirmed by the availability of official reference standards from major international pharmacopoeias, including the United States Pharmacopeia (USP), European Pharmacopoeia (EP), and British Pharmacopoeia (BP), which are used to ensure the quality and purity of pharmaceutical preparations.[18]

Current Research and Clinical Trials

While etoposide is a mature drug, research into its use continues to evolve. A review of current clinical trials indicates that the focus has largely shifted from investigating etoposide as a single agent or in new formulations to exploring its role as a foundational "backbone" for novel combination therapies.[35] This reflects a broader paradigm shift in oncology toward multi-modal treatment strategies.

New Combination Therapies: The frontier of etoposide research lies in combining its broad cytotoxic effects with the precision of newer therapeutic classes.

• Immunotherapy Combinations: Several ongoing trials are evaluating the synergy of standard etoposide/platinum chemotherapy with immune checkpoint inhibitors. For instance, trials are investigating combinations with atezolizumab for large-cell neuroendocrine carcinoma of the lung and with camrelizumab for SCLC.[58] The underlying rationale is that the DNA damage and cell death induced by etoposide can lead to the release of tumor-associated antigens, a process known as immunogenic cell death. This may enhance the tumor's visibility to the immune system, thereby priming it for a more robust response to checkpoint blockade.
• Targeted Therapy Combinations: Researchers are also exploring combinations with targeted agents. One trial is studying etoposide with the mTOR inhibitor temsirolimus in children with relapsed acute lymphoblastic leukemia and non-Hodgkin lymphoma, aiming to attack cancer cells through two distinct signaling pathways simultaneously.[59]

Overcoming Drug Resistance: A persistent challenge in chemotherapy is drug resistance. Some research is focused on strategies to overcome this, such as by inhibiting the P-glycoprotein efflux pump that actively removes etoposide from cancer cells. A clinical trial investigated the use of the P-gp inhibitor cyclosporine in combination with etoposide and mitoxantrone for patients with relapsed or refractory acute myeloid leukemia (AML).[36]

New Applications and Regimens: Etoposide continues to be evaluated in different hematologic malignancies and solid tumors, often as part of refined, dose-adjusted regimens like DA-EPOCH (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) for acute lymphoblastic leukemia and lymphoblastic lymphoma.[35]

This evolution in clinical research demonstrates that etoposide has transitioned from a novel compound to a reliable, foundational component of modern cancer treatment. The innovation is no longer centered on the drug itself but on how it can be strategically integrated with the next generation of therapies to improve patient outcomes. Its ability to induce widespread DNA damage makes it a valuable partner for targeted agents and immunotherapies, securing its relevance in the contemporary oncologic arsenal.

Concluding Analysis and Recommendations

Etoposide stands as a paradigm of successful natural product-derived drug development, a highly effective antineoplastic agent that has been a mainstay of cancer treatment for decades. Its mechanism as a topoisomerase II poison, which introduces lethal double-strand DNA breaks in rapidly dividing cells, is the source of both its profound therapeutic efficacy and its significant, predictable toxicity profile. This inherent duality is the central theme of its clinical pharmacology. The drug's value is undisputed, as evidenced by its FDA-approved indications in testicular cancer and SCLC, its widespread off-label use, and its designation as an essential medicine by the WHO.

However, its optimal and safe use is contingent upon a deep understanding of its complex characteristics. The clinical application of etoposide demands adherence to several key principles:

1. Rational Combination Therapy: Etoposide's greatest successes have been as part of multi-drug regimens that exploit mechanistic synergy. Its future utility, as suggested by ongoing research, lies in its continued role as a cytotoxic backbone for novel immunotherapy and targeted therapy combinations.
2. Vigilant Hematologic Monitoring: The dose-limiting toxicity of severe myelosuppression is an unavoidable, on-target effect. Its management requires strict adherence to pre-treatment blood count parameters, with proactive dose delays and reductions to mitigate the risk of life-threatening infections and bleeding.
3. Comprehensive Medication Management: Etoposide's reliance on the CYP3A4 metabolic pathway and its susceptibility to P-gp transport place it at high risk for clinically significant drug interactions. Meticulous medication reconciliation, including over-the-counter products and dietary factors like grapefruit juice, is not an ancillary task but a critical clinical intervention to ensure patient safety and therapeutic efficacy.
4. Informed Patient Counseling and Risk Assessment: Clinicians must engage in transparent discussions with patients regarding the high likelihood of acute toxicities, such as alopecia, nausea, and fatigue, as well as the rare but serious long-term risk of developing treatment-related secondary leukemia.

In conclusion, while the landscape of oncology is being rapidly transformed by precision medicine and immunotherapy, etoposide remains an indispensable tool. Its power lies in its broad, potent cytotoxicity, and its continued value is assured by the clinician's ability to harness this power while skillfully navigating its pharmacokinetic variability and managing its inherent risks. The legacy of etoposide is a testament to the enduring importance of foundational cytotoxic agents in the multi-modal fight against cancer.

Works cited

1. CHEBI:4911 - etoposide - EMBL-EBI, accessed July 8, 2025, https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:4911
2. en.wikipedia.org, accessed July 8, 2025, https://en.wikipedia.org/wiki/Etoposide
3. Molecular mechanisms of etoposide - PMC, accessed July 8, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC4652635/
4. Etoposide: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed July 8, 2025, https://go.drugbank.com/drugs/DB00773
5. Topoisomerase Inhibitors Type II: Epipodophyllotoxins: Etoposide (VP-16, Etopophos, Toposar) - Oncology, accessed July 8, 2025, https://www.pharmacology2000.com/Oncology/oncology475.htm
6. What is the mechanism of Etoposide? - Patsnap Synapse, accessed July 8, 2025, https://synapse.patsnap.com/article/what-is-the-mechanism-of-etoposide
7. Etoposide: Package Insert / Prescribing Information - Drugs.com, accessed July 8, 2025, https://www.drugs.com/pro/etoposide.html
8. Etoposide - NCI, accessed July 8, 2025, https://www.cancer.gov/about-cancer/treatment/drugs/etoposide
9. Reference ID: 4101905 1 - accessdata.fda.gov, accessed July 8, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020457s016lbl.pdf
10. etoposide | Ligand page - IUPHAR/BPS Guide to PHARMACOLOGY, accessed July 8, 2025, https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6815
11. Etoposide as a Key Therapeutic Agent in Lung Cancer: Mechanisms, Efficacy, and Emerging Strategies - MDPI, accessed July 8, 2025, https://www.mdpi.com/1422-0067/26/2/796
12. Etoposide Pathway, Pharmacokinetics/Pharmacodynamics, accessed July 8, 2025, https://www.pharmgkb.org/pathway/PA2025
13. Etoposide: MedlinePlus Drug Information, accessed July 8, 2025, https://medlineplus.gov/druginfo/meds/a684055.html
14. Etoposide | C29H32O13 | CID 36462 - PubChem, accessed July 8, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Etoposide
15. Etoposide, Topoisomerase II inhibitor (CAS 33419-42-0) (ab120227) - Abcam, accessed July 8, 2025, https://www.abcam.com/en-us/products/biochemicals/etoposide-topoisomerase-ii-inhibitor-ab120227
16. Etoposide (VP-16) | CAS 33419-42-0 | SCBT - Santa Cruz Biotechnology, accessed July 8, 2025, https://www.scbt.com/p/etoposide-vp-16-33419-42-0
17. Etoposide (EPE, NSC 141540, VP-16-123, CAS Number: 33419-42-0) | Cayman Chemical, accessed July 8, 2025, https://www.caymanchem.com/product/12092/etoposide
18. CAS 33419-42-0 - Sigma-Aldrich, accessed July 8, 2025, https://www.sigmaaldrich.com/US/en/search/33419-42-0?focus=products&page=1&perpage=30&sort=relevance&term=33419-42-0&type=cas_number
19. Etoposide, accessed July 8, 2025, https://www.drugfuture.com/chemdata/etoposide.html
20. [Etoposide (300 mg)] - CAS [33419-42-0] - USP Store, accessed July 8, 2025, https://store.usp.org/product/1268808
21. Etoposide | CAS#33419-42-0 | Topoisomerase II Inhibitor - MedKoo Biosciences, accessed July 8, 2025, https://www.medkoo.com/products/4642
22. ETOPOSIDE 1. Exposure Data - IARC Publications, accessed July 8, 2025, https://publications.iarc.fr/_publications/media/download/2512/7723a4da2763bd47f9f507aa61942546b1620d4c.pdf
23. DNA Topoisomerase II Inhibitors - PRINCIPLES OF ANTINEOPLASTIC THERAPY, accessed July 8, 2025, https://hemonc.medicine.ufl.edu/files/2013/07/TopoII.pdf
24. ETOPOPHOS - accessdata.fda.gov, accessed July 8, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020457s013lbl.pdf
25. Topoisomerase II inhibitors | BIOCEV, accessed July 8, 2025, https://biocev.lf1.cuni.cz/file/182/inhibitory-topoizomerazy-ii-hande-2008.pdf
26. etoposide - Cancer Care Ontario, accessed July 8, 2025, https://www.cancercareontario.ca/en/drugformulary/drugs/monograph/43711
27. Etoposide Patient Handout Oral - BC Cancer, accessed July 8, 2025, http://www.bccancer.bc.ca/drug-database-site/Drug%20Index/Etoposide_oral_handout.pdf
28. Etoposide Dosage Guide + Max Dose, Adjustments - Drugs.com, accessed July 8, 2025, https://www.drugs.com/dosage/etoposide.html
29. Population pharmacokinetics and pharmacodynamics of oral etoposide - PubMed Central, accessed July 8, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC2014597/
30. PHARMACOLOGY OF Etoposide (VP 16) ; Overview, Pharmacokinetics, Uses, Mechanism of action, Effects - YouTube, accessed July 8, 2025, https://www.youtube.com/watch?v=oO3YDapzxXQ
31. TESTICULAR CANCER TREATMENT REGIMENS (Part 1 of 2), accessed July 8, 2025, http://media.chemotherapyadvisor.com/documents/32/testicular_r0412_7930.pdf
32. ETOPOSIDE® - Pfizer, accessed July 8, 2025, https://labeling.pfizer.com/ShowLabeling.aspx?id=15276
33. Etoposide (intravenous route) - Mayo Clinic, accessed July 8, 2025, https://www.mayoclinic.org/drugs-supplements/etoposide-intravenous-route/description/drg-20063769
34. Etoposide | Drug Lookup | Pediatric Care Online | American ..., accessed July 8, 2025, https://publications.aap.org/pediatriccare/drug-monograph/18/5280/Etoposide
35. Study Details | Etoposide, Prednisone, Vincristine Sulfate ..., accessed July 8, 2025, https://clinicaltrials.gov/study/NCT02538926
36. Study Details | Cyclosporine, Pravastatin Sodium, Etoposide, and Mitoxantrone Hydrochloride in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia | ClinicalTrials.gov, accessed July 8, 2025, https://clinicaltrials.gov/study/NCT01342887
37. VePesid, Toposar (etoposide) dosing, indications, interactions, adverse effects, and more, accessed July 8, 2025, https://reference.medscape.com/drug/vepesid-toposar-etoposide-342098
38. Etoposide - Mechanism, Indication, Contraindications, Dosing, Adverse Effect, Interaction, Renal Dose, Hepatic Dose | Drug Index | Pediatric Oncall, accessed July 8, 2025, https://www.pediatriconcall.com/drugs/etoposide/564
39. New Zealand Datasheet 1 PRODUCT NAME Etoposide Injection 2 QUALITATIVE AND QUANTITATIVE COMPOSITION 3 PHARMACEUTICAL FORM 4 CLI - Medsafe, accessed July 8, 2025, https://www.medsafe.govt.nz/profs/datasheet/e/EtoposideinjRex.pdf
40. Appendix 4. EAU Guidelines on Testicular Cancer: Chemotherapy Protocols - Cloudfront.net, accessed July 8, 2025, https://d56bochluxqnz.cloudfront.net/documents/guideline-appendices/testicular-cancer/Appendix-4.-Chemotherapy-Protocols.pdf
41. Small cell lung cancer extensive disease cARBOplatin and ... - eviQ, accessed July 8, 2025, https://www.eviq.org.au/getmedia/819fc01c-adac-46f1-ae6d-92b488ab9d82/ID-340-Respiratory-Small-Cell-Lung-Cancer-extensive-disease-Carboplatin-and-Oral-Etoposide-protocol-and-PI.pdf.aspx
42. Etoposide Side Effects: Common, Severe, Long Term - Drugs.com, accessed July 8, 2025, https://www.drugs.com/sfx/etoposide-side-effects.html
43. etoposide | Cancer Care Ontario, accessed July 8, 2025, https://www.cancercareontario.ca/en/system/files_force/etoposide.pdf?download=1
44. Etoposide: Side Effects, Uses, Dosage, Interactions, Warnings - RxList, accessed July 8, 2025, https://www.rxlist.com/etoposide/generic-drug.htm
45. Etoposide Oral: Uses, Side Effects, Interactions, Pictures, Warnings & Dosing - WebMD, accessed July 8, 2025, https://www.webmd.com/drugs/2/drug-8781/etoposide-oral/details
46. DRUG NAME: Etoposide - BC Cancer, accessed July 8, 2025, http://www.bccancer.bc.ca/drug-database-site/Drug%20Index/Etoposide_monograph.pdf
47. Etoposide Interactions Checker - Drugs.com, accessed July 8, 2025, https://www.drugs.com/drug-interactions/etoposide.html
48. Drug Interactions with CYP3A4: An Update - Pharmacy Times, accessed July 8, 2025, https://www.pharmacytimes.com/view/drug-interactions-with-cyp3a4-an-update
49. Small cell lung cancer extensive disease cARBOplatin and etoposide - eviQ, accessed July 8, 2025, https://www.eviq.org.au/medical-oncology/respiratory/small-cell-lung-cancer/215-sclc-extensive-disease-carboplatin-and-etoposi
50. Pharmacokinetic interaction between mitotane and etoposide in adrenal carcinoma: a pilot study - PMC, accessed July 8, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC6301193/
51. Pharmacokinetic interaction between mitotane and etoposide in adrenal carcinoma: a pilot study in - Endocrine Connections, accessed July 8, 2025, https://ec.bioscientifica.com/view/journals/ec/7/12/EC-18-0428.xml
52. Etoposide Food, Alcohol, Supplements and Drug Interactions - ScriptSave WellRx, accessed July 8, 2025, https://www.wellrx.com/etoposide/lifestyle-interactions/
53. Etoposide (oral route) - Mayo Clinic, accessed July 8, 2025, https://www.mayoclinic.org/drugs-supplements/etoposide-oral-route/description/drg-20074443
54. A pharmacovigilance study of etoposide in the FDA adverse event reporting system (FAERS) database, what does the real world say?, accessed July 8, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10637489/
55. Company history timeline - Bristol Myers Squibb, accessed July 8, 2025, https://www.bms.com/about-us/our-company/history-timeline.html
56. Etoposide (Vepesid) | HemOnc.org - A Hematology Oncology Wiki, accessed July 8, 2025, https://hemonc.org/wiki/Etoposide_(Vepesid)
57. Study of Etoposide in Breast Cancer Patients | ClinicalTrials.gov, accessed July 8, 2025, https://clinicaltrials.gov/study/NCT00026949
58. Study Details | A Single-arm Trial of Atezolizumab/Platinum/Etoposide for the Treatment of Advanced Large-cell Neuroendocrine Cancer of the Lung | ClinicalTrials.gov, accessed July 8, 2025, https://www.clinicaltrials.gov/study/NCT05470595
59. Study Details | A Trial of Temsirolimus With Etoposide and Cyclophosphamide in Children With Relapsed Acute Lymphoblastic Leukemia and Non-Hodgkins Lymphoma | ClinicalTrials.gov, accessed July 8, 2025, https://clinicaltrials.gov/study/NCT01614197
60. Study Details | Camrelizumab Combined With Apatinib, Etoposide and Cisplatin Treat Small-cell Lung Cancer. | ClinicalTrials.gov, accessed July 8, 2025, https://www.clinicaltrials.gov/study/NCT04490421