Etoposide

Class: Antineoplastic Agents
VA Class: AN900
Chemical Name: [5R - [5α,5aβ,8aα,9β(R*)]] - 9 - [4,6 - O - ethylidene - β - d - glucopyranosyl)oxy]5,8,8a,9 - tetrahydro - 5 - (4 - hydroxy - 3,5 - dimethoxyphenyl)furo[3′,4′:6,7]naphtho[2,3 - d] - 1,3 - dioxol - 6(5aH) - one
Molecular Formula: C₂₉H₃₂O₁₃
CAS Number: 33419-42-0
Brands: Etopophos, Toposar, VePesid

• Experience of Supervising Clinician


• 
  

  For administration only under the supervision of a qualified clinician experienced in the use of antineoplastic agents.^{c d}

  
  

• Myelosuppression


• 
  

  Severe myelosuppression with resulting infection or bleeding may occur. (See Myelosuppression under Cautions.)^{c d}

  
  

Introduction

Antineoplastic agent; semisynthetic podophyllotoxin-derivative.^{1 2 3}

Uses for Etoposide

Testicular Cancer

Component of various combination chemotherapeutic regimens for treatment of refractory testicular tumors in patients who have already received appropriate surgery, chemotherapy, and radiation therapy.^{1 256}

Component of various combination chemotherapeutic regimens with cisplatin for first-line treatment of stage III or unresectable stage II nonseminomatous testicular carcinoma^{39 40 41 42 206} and for chemotherapy-refractory disease.^{2 38 39 43 44 165 182}

Combination chemotherapy with etoposide, cisplatin, and bleomycin (BEP) is recommended for initial treatment of advanced nonseminomatous testicular carcinoma.^{198 206 207 208 209 210 211 212 213}

Component of a combination chemotherapeutic regimen (ifosfamide, cisplatin, and either etoposide or vinblastine) as second-line therapy for recurrent nonseminomatous testicular carcinoma.^{223 241 243 244 245 246 247}

Component of combination chemotherapeutic regimens (with cisplatin) for initial treatment of disseminated seminoma testis^{45 50 51 198 214} and treatment-refractory disease.^{38 43}

Component of combination chemotherapeutic regimens (usually with cisplatin) for initial treatment of advanced extragonadal germ-cell tumors.⁵²

Small Cell Lung Cancer

Component of a combination chemotherapeutic regimen with etoposide and cisplatin or carboplatin (PE) as a preferred first-line treatment of small-cell lung cancer.^{a 65 79 80 81 82 83 84 180 183 215 253}

In combination with ifosfamide with mesna and cisplatin (VIP) or carboplatin (ICE)^{215 249 250 252 253 254 255} as second-line therapy for the treatment of refractory small-cell lung cancer.^{65 81 82 83 183 215 249 250 252 253 254 255}

In combination with cyclophosphamide and doxorubicin (or vincristine)^{61 69 70 71 72 73 86 190 199 200 201} for treatment of extensive-stage disease.²⁵³

Non-small Cell Lung Cancer

Combination chemotherapy with etoposide and cisplatin has been used for second-line treatment of advanced non-small cell lung cancer†,^{93 94 95 96 204 205} but paclitaxel-containing ^{215 237 301 302} or other platinum-based regimens^{215 237} currently are preferred.

Hodgkin's Disease

Component of combination chemotherapeutic regimens for treatment of advanced or refractory Hodgkin's lymphoma†.^{a 14 64 100 101 110 116 118 119 121 123 129}

Non-Hodgkin's Lymphoma

Component of various combination chemotherapeutic regimens for treatment of advanced non-Hodgkin's lymphoma†.^{13 14 54 64 100 101 115 116 117 118 119 120}

Component of combination chemotherapeutic regimens (e.g., etoposide, ifosfamide, and methotrexate) for treatment of advanced diffuse lymphomas of unfavorable histology (e.g., diffuse histiocytic lymphoma)†.^{54 100 101 115 117 118 120 121 122 123 124 125 126 127}

Cutaneous T-cell Lymphoma

Has been used with transient responses in patients with cutaneous T-cell lymphoma (mycosis fungoides†).¹²⁸

Acute Myeloid Leukemia

Used alone^{54 100 101 102 103 104 105 106 107 108 109 110} and in various combination chemotherapeutic regimens^{11 107 108 111 112} for treatment of refractory acute myeloid (myelogenous, nonlymphocytic) leukemia (AML, ANLL)† in adults and children.^{14 34 54 67 100 101 102 103 104 105 106 107 108 109 110}

Particularly effective for the treatment of acute monocytic and myelomonocytic leukemias†;^{34 54 100 101 102 103 104 107 110} may be useful when monocytoid cells are not cleared with conventional combination chemotherapy.^{100 101 102 103 104 107 110}

Acute Lymphocytic Leukemia

Has been used alone and in combination chemotherapy for remission induction in refractory acute lymphocytic (lymphoblastic) leukemia (ALL)† in a limited number of children;^{108 109 110} little, if any, activity in adults.^{100 101 107}

Wilms' Tumor

Component of a combination chemotherapeutic regimen (e.g., carboplatin with etoposide) as second-line (salvage) therapy for treatment of recurrent (relapsed or refractory) Wilms' tumor†^{231 232 234 235} including recurrent tumors of unfavorable histology, abdominal recurrence after radiation therapy, or recurrence within 6 months of nephrectomy or after initial combination chemotherapy.^{231 232 239}

Alternative to standard preferred regimens in patients with less severe stages of Wilms’ tumor†.²¹⁵

Second-line high-dose therapy followed by autologous bone marrow transplantation also has been used effectively in recurrent disease.^{231 232}

Offer patients with recurrent disease (i.e., salvage therapy failure) treatment under protocol conditions in ongoing clinical trials.²³¹

Neuroblastoma

Component of combination chemotherapeutic regimens (cyclophosphamide, doxorubicin, cisplatin, and/or etoposide or teniposide) as preferred first-line therapy for neuroblastoma†.^{a 64 109 110 157 215 226 227 228 239}

Kaposi's Sarcoma

Used alone or in combination chemotherapeutic regimens^{257 258 259} as second-line therapy^{a 133 215 258} for palliative treatment of AIDS-related Kaposi's sarcoma†. ²¹⁵

Ovarian Cancer

Has been used orally as second-line therapy for advanced epithelial ovarian cancer†.^{a 215 312 313 314 315 316}

Component of a combination chemotherapeutic regimen with bleomycin and cisplatin (BEP) as first-line therapy for ovarian germ cell tumors†.^{215 317 a}

Other Uses

Component of alternating chemotherapeutic regimens (vincristine, doxorubicin and cyclophosphamide alternating with ifosfamide and mesna and etoposide) as first-line therapy for Ewing's sarcoma†.^{a 54 110 157}

Component of a chemotherapeutic regimen with methotrexate, dactinomycin, cyclophosphamide, and vincristine (EMA-CO), or with cisplatin as second-line therapy for gestational trophoblastic tumors† (choriocarcinoma†).^a Also has been used for treatment of chorioadenoma destruens†.^{130 185 a}

May be useful for treatment of hepatoma†.^{110 131 132}

May be useful as second-line therapy for treatment of rhabdomyosarcoma†.^{a 64 109 110}

Etoposide Dosage and Administration

General

• 
  

  Consult specialized references for procedures for proper handling and disposal of antineoplastics.^{b c d} (See IV Administration under Dosage and Administration.)

  
  

Administration

Administer orally¹⁸⁹ or IV.^{1 189 256}

Intraperitoneal and intrapleural administration is not recommended; delayed, severe (sometimes fatal) toxicity has occurred in animals following administration by these routes. ^{139 155}

Observe closely for possible hypotensive or anaphylactoid reactions during administration of the drug.¹ (See Hypotension and also see Sensitivity Reactions, under Cautions.)

Oral Administration

Administer etoposide capsules orally.^c

IV Administration

Administer diluted etoposide concentrate for injection by slow IV infusion.^{1 189}

Administer etoposide phosphate by IV infusion.²⁵⁶

Use syringes with Luer-Lok fittings for handling of etoposide concentrate for injection;² under pressure, needles have become displaced from etoposide-containing syringes without Luer-Lok fittings.²

Plastic devices composed of acrylic or ABS (a polymer composed of acrylonitrile, butadiene, and styrene) may crack and leak when used with undiluted etoposide injection.¹⁸⁹

Etoposide solutions containing 0.1–0.4 mg/mL in 0.9% sodium chloride or 5% dextrose injection have been filtered through several commercially available filters (e.g., 0.22-mcm Millex-GS or Millex-GV) without filter decomposition.^{2 159}

Reconstitution

Reconstitute vial containing 100 mg of etoposide phosphate powder with 5 or 10 mL sterile water for injection, 5% dextrose injection, 0.9% sodium chloride, bacteriostatic water for injection (with benzyl alcohol), or bacteriostatic sodium chloride for injection (with benzyl alcohol) to provide a solution containing 20 mg etoposide per mL (22.7 etoposide phosphate per mL) or 10 mg etoposide per mL (11.4 mg etoposide phosphate per mL), respectively.²⁵⁶

May administer reconstituted etoposide phosphate with or without further dilution.²⁵⁶

Dilution

Etoposide concentrate for injection must be diluted before administration.^{1 2 5 189}

Dilute required dose of concentrate for injection to a final concentration of 0.2 or 0.4 mg/mL in 0.9% sodium chloride or 5% dextrose injection.^{1 2}

Reconstituted etoposide phosphate solutions may be further diluted with either 5% dextrose injection or 0.9% sodium chloride injection to concentrations as low as 0.1 mg of etoposide per mL.²⁵⁶

Rate of Administration

Do not administer etoposide solutions by rapid IV injection.¹ (See Hypotension under Cautions.)

Administer etoposide IV infusions over at least 30–60 minutes to minimize the risk of hypotensive reactions.¹ If hypotensive reaction occurs, use slower rate of infusion if restarting after discontinuance and appropriate treatment.^{1 2}

A longer duration of administration may be used if the volume of fluid to be infused is a concern.¹⁸⁹

Has been administered by continuous IV infusion over 5 days,^{134 135 136} but no therapeutic advantage with this method over intermittent IV infusions.¹⁵⁶

May administer etoposide phosphate solutions over 5–210 minutes.²⁵⁶

Dosage

Available as etoposide and etoposide phosphate; dosage is expressed in terms of etoposide; 113.6 mg of etoposide phosphate is equivalent to 100 mg of etoposide.²⁹⁶

Base dosage on the clinical and hematologic response and tolerance of the patient and whether or not other chemotherapy or radiation therapy has been or is also being used in order to obtain optimum therapeutic results with minimum adverse effects.^{1 2}

Consult published protocols for the dosage, method, and sequence of administration of etoposide and other chemotherapeutic agents used in combination chemotherapeutic regimens.^b

Do not administer a repeat course until the patient’s hematologic function is within acceptable limits.¹

Toxicity profile of etoposide phosphate infused at doses exceeding 175 mg/m² has not been delineated.²⁵⁶

Adults

Testicular Cancer

Induction of Remission for Refractory Testicular Neoplasms

IV

Combination chemotherapy regimens: Usually, 50–100 mg/m² daily for 5 consecutive days every 3–4 weeks or 100 mg/m² daily on days 1, 3, and 5 every 3–4 weeks,¹ for 3 or 4 courses of therapy.^{38 43 44}

When the consecutive-day dosage regimen is employed, some clinicians administer etoposide for 3–5 days, depending on the patient’s hematologic tolerance.^{38 43}

Small Cell Lung Cancer

Oral

Twice the IV dosage rounded to the nearest 50 mg is recommended.¹⁸⁹

IV

Combination chemotherapy regimens: Usually, ranges from 35 mg/m² daily for 4 consecutive days to 50 mg/m² daily for 5 consecutive days, every 3–4 weeks.^{188 256}

Optimum duration not clearly defined; no additional improvement in survival when duration of therapy >3–6 months for limited-stage or >6 months for extensive-stage disease.²⁵³

Kaposi's Sarcoma

AIDS-Related Kaposi's Sarcoma†

IV

150 mg/m² daily for 3 consecutive days every 4 weeks; repeat cycles of therapy and reduce dosage as necessary depending on the patient’s response and the myelosuppressive effect of the drug.¹³³

Special Populations

Hepatic Impairment

Use with caution; consider the need for dosage reduction.^{159 163 176}

Renal Impairment

Cl_cr >50 mL/minute: no initial dose modification required.²⁵⁶

Cl_cr 15–50 mL/minute: administer 75% of the initial recommended dose.²⁵⁶

Cl_cr <15 mL/minute: consider further dose reduction; specific data are not available.²⁵⁶

Base subsequent doses on patient tolerance and clinical effect.²⁵⁶

Cautions for Etoposide

Contraindications

• 
  

  Known hypersensitivity to etoposide, etoposide phosphate, or any ingredient in the formulations.^{1 2 189 256}

  
  

Warnings/Precautions

Warnings

Myelosuppression

Risk of dose-limiting and potentially fatal myelosuppression,^{1 2 17 59 64 106 110 116 118 120 133 134 135 136 256} manifested commonly by leukopenia (principally granulocytopenia);^{1 2 17 57 59 64 67 91 100 101 256} thrombocytopenia ^{1 2 17 64 67 91 100 101} and anemia may also occur.^{17 60 64 133 189} Severe myelosuppression with resulting infection or bleeding may occur.^{1 2 92 100 105 118 120 133 134 135 136}

Granulocyte and platelet nadirs usually occur within 7–14 and 9–16 days, respectively, after administration of etoposide,^{1 2 59 67 106 134 136} and within 12–19 and 10–15 days, respectively, after administration of etoposide phosphate;²⁵⁶ leukocyte nadir usually occurs within 15–22 days after administration of etoposide phosphate.²⁵⁶ Bone marrow recovery is usually complete within 20 days after administration,^{1 2 56 60 67 134 135} but may occasionally require longer periods.^{17 106 136}

Monitor hematologic function frequently during and after treatment.^{1 2} Perform CBC (leukocyte count with differential, platelet count, hemoglobin) prior to initiation of therapy, at appropriate intervals during the course of treatment (e.g., twice weekly),¹⁸⁰ and before each subsequent course of treatment.^{1 2}

Suspend therapy if the platelet count is <50,000/mm³ or absolute neutrophil count is <500/mm³.^{1 2} Resume therapy when blood counts have returned to an acceptable level, if indicated.^{1 2}

If severe hematologic toxicity occurs, consider supportive therapy, antibiotics for complicating infections, and blood product transfusions.^{105 133 135 136}

Hypotension

Transient hypotension reported following rapid IV administration of etoposide.^{1 2 57 110}

Observe closely for possible hypotensive reactions.¹

Administer IV infusions slowly (i.e., over at least 30–60 minutes) to minimize the risk of hypotensive reactions.¹

Hypotension occurring during administration usually subsides with infusion discontinuance, administration of IV fluids or other supportive therapy as necessary.^{1 2}

Use slower rate of infusion if restarting after discontinuance and appropriate treatment.^{1 2}

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; teratogenicity and embryolethality demonstrated in animals.^{c d} Avoid pregnancy during therapy.^{c d} If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.^{c d}

Carcinogenicity

Acute leukemia (with or without a preleukemic phase) has been reported rarely in patients receiving etoposide in association with other antineoplastic agents.^{189 256}

Animal studies to determine the carcinogenic potential of etoposide have not been performed to date;^{1 256} however, the drug should be considered a potential carcinogen.¹

Sensitivity Reactions

Hypersensitivity Reactions

Anaphylactoid reactions consisting principally of chills,^{1 2 67 92 256} rigors,²⁵⁶ diaphoresis,^{64 256} pruritus,²⁵⁶ loss of consciousness,²⁵⁶ nausea,²⁵⁶ vomiting,²⁵⁶ fever,^{1 2} bronchospasm,^{1 2 178 256} dyspnea,^{1 2 141 178 256} tachycardia,^{1 2 256} hypertension,^{189 256} and/or hypotension^{1 2 92 178 256} reported.^{1 2 67 92 134 178 256}

Observe closely for possible anaphylactic reactions.¹

Appropriate equipment for maintenance of an adequate airway and other supportive measures and agents for the treatment of these reactions should be readily available whenever etoposide is administered.¹

Stevens-Johnson syndrome,²⁵⁶ rash,^{1 2 189 256} pigmentation,¹⁸⁹ urticaria,^{189 256} and severe pruritus^{64 189 256} occur infrequently.^{1 2 142 179}

If a hypersensitivity reaction occurs during administration, discontinue infusion and institute appropriate therapy (e.g., antihistamines, epinephrine, oxygen, corticosteroids) as necessary.¹

The role of infusion concentration or rate in the development of hypersensitivity reactions is uncertain.^{189 256}

General Precautions

Toxicity

Highly toxic drug with a low therapeutic index; therapeutic response is not likely to occur without some evidence of toxicity.^{1 2 34 139}

Administer only under constant supervision by clinicians experienced in therapy with cytotoxic agents and only when the potential benefits outweigh the possible risks.¹

Most adverse effects are reversible if detected promptly.¹

Discontinue or reduce dosage and institute appropriate measures as necessary when severe adverse effects occur.¹

Reinstitute therapy with caution, considering further need for the drug and possible toxicity recurrence.¹

Specific Populations

Pregnancy

Category D.^c (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether etoposide is distributed into milk.¹ Discontinue nursing or the drug.¹

Pediatric Use

Safety and efficacy not established.^{1 256}

Higher rates of anaphylactoid reactions reported in children receiving infusions at higher than recommended concentrations.^{189 256} (See Hypersensitivity Reactions under Cautions.)

Has been used with encouraging results for refractory acute myelogenous leukemia†,^{11 108 109 110 112} has shown some activity against refractory acute lymphocytic leukemia†^{108 110} and other pediatric malignancies†,^{109 110 157} but additional evaluation is needed.^{108 109 110 157}

Each mL of etoposide concentrate for injection contains 30 mg of benzyl alcohol.^c Although a causal relationship has not been established, injections preserved with benzyl alcohol have been associated with toxicity in neonates.^{216 217 218 219 220 221}

Concentrate for injection contains polysorbate 80A complex; potentially fatal syndrome (e.g., thrombocytopenia, ascites, and renal, pulmonary, and hepatic failure) has occurred in several premature infants who received a vitamin E product (IV) with polysorbate 80.¹⁸⁹

Hepatic Impairment

Effects of hepatic impairment on etoposide elimination have not been fully evaluated.^{20 21 28 163 176 197}

Toxicity of rapidly infused etoposide phosphate in hepatic impairment has not been adequately evaluated.²⁵⁶

Use with caution, consider the need for dosage reduction; more severe hematologic toxicity reported with elevated serum bilirubin concentrations in one study.¹⁶³ Some evidence of reduced total plasma clearance and elimination.^{28 159 163 176}

Renal Impairment

Dosage adjustments recommended based on degree of renal impairment.^{20 21 161 256} (See Renal Impairment under Dosage and Administration.)

Toxicity of rapidly infused etoposide phosphate in renal impairment has not been adequately evaluated.²⁵⁶

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether safety and efficacy for treatment of testicular tumors in geriatric patients differ from safety and efficacy in younger adults.^f

Response in patients ≥65 years of age with small cell lung cancer similar to that in younger adults.^f

Substantially eliminated by kidneys; assess renal function periodically since geriatric patients more likely to have decreased renal function.^f Dosage adjustments may be required.^f (See Renal Impairment under Dosage and Administration.)

Geriatric patients may be particularly susceptible to etoposide-induced adverse effects.¹³⁷

Common Adverse Effects

Leukopenia,^{1 2 17 57 59 64 67 91 100 101 256} thrombocytopenia,^{1 2 17 64 67 91 100 101} neutropenia,²⁵⁶ anemia,^{17 60 64 133 189} nausea,^{1 2 17 60 67 91 100 109 189 256} vomiting,^{1 2 17 60 67 91 100 109 189 256} anorexia,^{1 2 67 92 101 116 134 256} mucositis,²⁵⁶ diarrhea,^{1 2 109 134 136 256} alopecia,^{1 2 17 60 64 67 100 101 109 133 134 189 256} asthenia/malaise,^c fatigue,^{1 2} chills and/or fever.^c

Interactions for Etoposide

Specific Drugs

Drug	Interaction	Comments
Antineoplastic agents (cisplatin, carmustine, cytarabine, cyclophosphamide)	Potential additive or synergistic antineoplastic activity43 44 65 79 80 81 82 83 152 153 154
Cisplatin	Possible decreased etoposide elimination176	Limited data, further documentation needed; consider potential effect when administering etoposide to patients who received prior cisplatin therapy176
Cyclosporine (high-dose)	Possible decreased total body clearance of etoposide with concomitant use of oral etoposide and high-dose cyclosporine 256
Inhibitors of phosphatase activity (e.g., levamisole HCl)		Use caution with etoposide phosphate256

Etoposide Pharmacokinetics

Absorption

Bioavailability

Oral capsules: about 50% (range: 25–75%).^{17 18 19 160 161 189 190 191 192 193 194 195 196 197}

Distribution

Extent

Not fully characterized.^{18 21 24 27 28} Following IV administration, distributed minimally into pleural fluid^{21 27} and has been detected in the saliva,¹⁹⁷ liver,¹⁷³ spleen,¹⁷³ kidney,¹⁷³ myometrium,^{189 197} healthy brain tissue,²⁷ and brain tumor tissue.^{27 175}

Does not readily penetrate the CNS;^{1 18 21 22 27 29 30 197} variable CSF concentrations generally ranging from undetectable^{18 22} to <5% of concurrent plasma concentrations^{21 29 30 162}

Apparently crosses the placenta in animals,^{1 2} not known whether distributed into milk.¹

Plasma Protein Binding

Approximately 97% at 10 mcg/mL in vitro.^{c f}

Elimination

Metabolism

Metabolized principally to inactive hydroxy acid^{21 25 26 30 32 33 177} (probably the trans-hydroxy acid).³³

Elimination Route

Following IV infusion, excreted principally (40–60%) in urine as unchanged drug (20–30% within 24 hours,^{18 29 30} 30–45% within 48 hours)^{20 161} and metabolites in 48–72 hours.^{18 20 21 26 27 29 30 32} 2–16% is excreted in feces within 72 hours;^{29 30} .^{28 173 174 197}

Following oral administration, about 5–25% of the dose is excreted in urine within 24–48 hours.^{191 194 195 196 197}

Half-life

Biphasic,^{18 21 22 24 25 27 29 30}