VA Class:AN900

AHFS Class:

• Antineoplastic Agents 10:00

Generic Name(s):

• Etoposide

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

Etoposide is a semisynthetic podophyllotoxin-derivative antineoplastic agent.1,2,3

Testicular Neoplasms

Etoposide or etoposide phosphate may be used IV as a component of various chemotherapeutic regimens for the treatment of refractory testicular tumors in patients who have already received appropriate surgery, chemotherapy, and radiation therapy.1,256 Adequate data on the use of oral etoposide for the treatment of testicular tumors are currently not available.189

Nonseminomatous Testicular Carcinoma

In the treatment of disseminated nonseminomatous testicular carcinoma (Stage III), etoposide alone produces an objective response in about 35% of patients34,35,36,37,38,39,54 and is active in some patients whose disease is refractory to cisplatin-containing combination chemotherapy;38,39,40,41,164 however, combination chemotherapy for induction of remissions is superior to single-agent therapy.40 Various regimens have been used in combination therapy, and comparative efficacy is continually being evaluated.39,40,41,42 Most clinicians use cisplatin-containing combination chemotherapy regimens as initial therapy in patients with Stage III or unresectable Stage II nonseminomatous testicular carcinoma;39,40,41,42,206 if the patient has persistent, localized tumor following chemotherapy, the residual tumor is removed surgically, and if the disease contains malignant elements, additional chemotherapy is administered.40,41,42 Combination chemotherapy regimens containing etoposide and cisplatin have been evaluated in the treatment of disseminated nonseminomatous testicular carcinomas.34,45,46,198,213 For the initial treatment of advanced nonseminomatous testicular carcinoma, most clinicians recommend regimens containing cisplatin and bleomycin, in combination with etoposide rather than vinblastine, particularly because of the reduced neuromuscular toxicity and evidence suggesting greater efficacy in poor-risk patients.198,206,207,208,209,210,211,212,213 In addition, while a regimen of etoposide, cisplatin, and bleomycin appears to be as effective overall as a regimen of vinblastine, cisplatin, and bleomycin, the etoposide-containing regimen may be more effective than the vinblastine-containing regimen in a subgroup of patients with advanced disease (i.e., high tumor load).198 However, the best combination or sequential therapy in the treatment of advanced nonseminomatous testicular tumors has not been established, and comparative efficacy is continually being evaluated.212

Although studied less extensively than cisplatin-containing regimens, etoposide in combination with carboplatin with or without bleomycin has produced clinical response in the treatment of stage II or stage III nonseminomatous testicular cancer†.223,225,229 However, there is evidence that a regimen of etoposide and cisplatin is more effective than standard dosages of etoposide and carboplatin in the initial treatment of germ cell tumors, and treatment with a carboplatin regimen generally is reserved for patients who do not tolerate or refuse cisplatin.223,224,233,239,240 Limited data suggest that high-dose etoposide and carboplatin may be effective in the treatment of relapsed or refractory germ cell tumors in some patients.223,229,230 High-dose etoposide and carboplatin with autologous bone marrow transplant has been associated with complete remission in 10-20% of patients with cisplatin-resistant germ cell tumors.223,229,230

Etoposide also is used effectively in cisplatin-containing combination chemotherapy regimens for the treatment of those patients whose disease is refractory to chemotherapy, with or without surgery; a complete remission has been produced in about 50% of such patients treated with regimens that include etoposide and cisplatin, followed by surgery when feasible.2,38,43,44,165,182 Some data suggest that combination chemotherapy containing etoposide and cisplatin is effective in the treatment of refractory disease principally in those patients whose disease relapses after having achieved a complete remission with cisplatin-containing chemotherapy, followed by surgery when necessary.182 This combination does not appear to be very effective in patients with multiple tumor sites, increasing tumor markers, and refractory disease (as evidenced by incomplete response to conventional chemotherapy).182 Intensive combination chemotherapy regimens containing etoposide and high-dose cisplatin are currently being evaluated for the initial treatment of patients with disseminated disease associated with a poor prognosis.47,48

Etoposide also is used as a component of various other chemotherapeutic regimens for salvage therapy in patients with recurrent or refractory germ cell testicular cancer.215,223,241,242,243,244,245,246 A regimen of ifosfamide, cisplatin, and either etoposide or vinblastine has induced complete responses in 20-45% of patients who previously received other cisplatin-based chemotherapy regimens,223,243,244,245,246 and is considered by most clinicians to be the standard initial salvage (i.e., second-line) regimen in patients with recurrent testicular cancer.223,247 Patients with minimal or moderate disease have a more favorable outcome with this salvage regimen than those with extensive disease.223,244 In a clinical study in patients with recurrent germ cell tumors (who had previously received at least 2 cisplatin-based chemotherapy regimens and were considered to have cisplatin-responsive disease), a regimen of ifosfamide, cisplatin, and either etoposide or vinblastine resulted in disease-free status in 36% of patients (with or without surgery) and median duration of disease control ranged from 3 to more than 42 weeks, median survival was 53 weeks, and 20% of patients had survival of 2 years or longer.241,244 In patients with refractory disease, high-dose chemotherapy (e.g., etoposide and carboplatin with or without ifosfamide) with autologous bone marrow transplant (ABMT) or peripheral stem cell rescue may produce durable complete remissions in some patients.223,247,248 Patients with progressive tumors during initial or salvage therapy and those with refractory mediastinal germ cell tumors generally appear to benefit less from high-dose chemotherapy and ABMT or peripheral stem cell rescue than those whose disease relapses after a response.223 Salvage surgery also may be considered for certain highly selected patients (e.g., those with chemorefractory disease confined to a single site).223

The role of chemotherapy in the treatment of Stage I and resectable Stage II nonseminomatous testicular carcinoma has not been clearly established.39,40,49 Although most patients with Stage I disease are cured by surgery alone,40 combination chemotherapy regimens containing etoposide and cisplatin have been used successfully to induce complete remissions in a limited number of patients whose disease relapsed following surgical treatment.49

Seminoma Testis

Etoposide has been used successfully as a component of cisplatin-containing combination chemotherapy regimens in a limited number of patients for the initial treatment of disseminated seminoma testis45,50,51,198,214 and for the treatment of disseminated disease refractory to initial chemotherapy regimens,38,43 with complete remission rates comparable to those in patients with disseminated nonseminomatous disease.38,43,45,50,51,214 Further evaluation is needed to determine the optimum therapy.40,50

Extragonadal Germ-Cell Tumors

Data are limited, but etoposide-containing combination chemotherapy regimens (usually also containing cisplatin), followed by surgery when feasible, have reportedly been successful in the initial treatment of advanced extragonadal germ-cell tumors,52 but have generally produced only partial responses in the treatment of advanced extragonadal germ-cell tumors refractory to initial chemotherapy regimens.38,53,165

Lung Cancer

Etoposide has been widely used for the treatment of lung cancer, principally as a component of chemotherapeutic regimens in the treatment of small cell lung carcinoma.34,55,61,65,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,190,199,200,201,202,215

Small Cell Lung Cancer

Etoposide is used IV (either as etoposide or etoposide phosphate) in combination chemotherapy regimens for the treatment of small cell lung carcinoma; etoposide also has been used orally, either alone or as a component of combination therapy for this cancer.34,55,65,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,183,188,189,190,199,200,201,202,215,253,256 Combination chemotherapy regimens are superior to single-agent therapy in the treatment of this tumor and moderately intensive drug doses are superior to doses that produce minimal toxicity.34,55,56,68,70,190,253 Staging the cancer provides useful prognostic information and has implications for the specific course of therapy employed; all patients with small cell lung cancer generally should receive combination chemotherapy initially regardless of the extent of tumor dissemination since this cancer is the most aggressive form of lung cancer and some degree of metastasis is present in most patients regardless of whether it is detected at initial diagnosis.253

Various regimens have been used in combination therapy, and many 2- to 4-drug regimens, including etoposide-containing regimens, have produced response rates of 65-90 or 70-85% and complete response rates of 45-75 or 20-30% in patients with limited-stage or extensive-stage disease, respectively; however, comparative efficacy is continually being evaluated.34,55,72,76,77,190,253 Etoposide-containing regimens are used in chemotherapy for extensive-stage small cell lung cancer and in combined modality treatment (i.e., combination chemotherapy with concurrent thoracic irradiation administered early in the course of treatment) for limited-stage disease.253,300

Etoposide used in combination with cisplatin or carboplatin is a preferred regimen for the treatment of small cell lung cancer;65,79,80,81,82,83,84,180,183,215,253 this combination also may be of some value for the treatment of small cell lung carcinoma refractory to other chemotherapy regimens (particularly when relapse occurs more than 6 months following completion of initial treatment).65,81,82,83,183,253 Etoposide also has been employed in conjunction with a platinum agent (i.e., cisplatin or carboplatin) and ifosfamide with mesna.215,249,250,252,253,254,255 Other etoposide-containing combination chemotherapy regimens (e.g., etoposide, cyclophosphamide, and doxorubicin; etoposide, cyclophosphamide, and vincristine)61,69,70,71,72,73,86,190,199,200,201 have been used less commonly for the treatment of extensive-stage small cell lung cancer.253

Concomitant administration of granulocyte colony-stimulating factor has been used in some patients with small cell lung carcinoma but is not routinely used to reduce the incidence and severity of myelosuppression associated with therapy.184

Monotherapy with oral etoposide is inferior to combination therapy, and even geriatric and/or debilitated patients should be offered standard IV combination chemotherapy regimens for the treatment of advanced small cell lung cancer.180,253,297,299,304 In a randomized trial involving patients with poor-prognosis extensive-stage small cell lung cancer and geriatric patients (older than 75 years of age) with any stage of small cell lung cancer, fewer complete responses, reduced survival, and comparable or worse toxicity were observed among patients who received oral etoposide alone compared with those who received IV combination chemotherapy with alternating cycles of cisplatin/etoposide and cyclophosphamide/doxorubicin/vincristine.297 A randomized trial involving patients with previously untreated extensive-stage small cell lung cancer and poor performance status (WHO grade performance status 2-4) was stopped when interim analysis showed reduced survival and increased hematologic toxicity for those receiving oral etoposide alone compared with those receiving IV combination chemotherapy with etoposide/vincristine or cyclophosphamide/doxorubicin/vincristine.304

Etoposide currently is considered one of the most active antineoplastic agents in the treatment of small cell lung carcinoma, producing an objective response in about 35-40% of previously untreated patients when used alone†.14,34,54,55,56,57,58,59,60,61,62,63,64,65,66,67 Although results of initial studies suggested that etoposide alone had substantial activity in patients whose disease was refractory to initial combination chemotherapy,57,67 more extensive studies have shown that monotherapy with the drug generally is of little benefit in these patients.62,64,65,66

Although optimum duration of chemotherapy has not been clearly defined, additional improvement in survival has not been observed when the duration of drug administration exceeds 3-6 or 6 months in patients with limited-stage or extensive-stage small cell lung cancer, respectively.253 Because the current prognosis for small cell lung carcinoma is unsatisfactory regardless of stage and despite considerable diagnostic and therapeutic advances, all patients with this cancer are candidates for inclusion in clinical trials at the time of diagnosis.253

Non-small Cell Lung Carcinoma

In the treatment of non-small cell lung carcinoma†, etoposide alone appears to be of little benefit.14,64,90,91,92 A small survival benefit has been demonstrated for the use of platinum-based (cisplatin) chemotherapy in selected patients with unresectable, locally advanced or metastatic non-small cell lung cancer who have a good performance status.237,238 Etoposide has been used in combination with cisplatin for the treatment of advanced non-small cell lung cancer.93,94,95,96,204,205 However, in randomized trials, patients with stage IIIB or IV non-small cell lung cancer receiving paclitaxel combined with cisplatin301 or gemcitabine combined with cisplatin89 had higher response rates and similar median survival compared with those receiving combination therapy with etoposide and cisplatin;85,301 consequently, paclitaxel-containing regimens215,237,301,302 or other platinum-based regimens215,237 currently are preferred in the treatment of patients with advanced non-small cell lung cancer. Some clinicians consider etoposide and cisplatin an alternative regimen for the treatment of advanced non-small cell lung cancer.215

Various chemotherapy regimens used alone or in combination with other treatment modalities, such as radiation therapy, are continually being evaluated for the treatment of advanced non-small cell lung cancer.237,238 A randomized trial is under way to determine the comparative efficacy and toxicity of combination therapy with etoposide and cisplatin versus paclitaxel and carboplatin in patients with advanced non-small cell lung cancer.302,303 Because current treatment is not satisfactory for almost all patients with non-small cell lung cancer except selected patients with early-stage, resectable disease, all patients may be considered for enrollment in clinical trials at the time of diagnosis.237

Malignant Lymphomas and Hodgkin's Disease

Etoposide appears to be one of the more active antineoplastic agents in the treatment of advanced non-Hodgkin's lymphomas†.13,14,54,64,100,101,115,116,117,118,119,120 The drug appears to be particularly effective for the treatment of advanced diffuse lymphomas of unfavorable histology such as diffuse histiocytic lymphoma, producing an objective response in about 30-40% of previously treated patients.54,100,101,115,117,118,120 Etoposide has been used in effective combination chemotherapy regimens (e.g., etoposide, ifosfamide, and methotrexate)124,125 for the treatment of refractory advanced diffuse lymphomas of unfavorable histology.121,122,123,124,125,126 Etoposide has also been used in effective alternating combination chemotherapy regimens for the initial treatment of advanced diffuse lymphomas of unfavorable histology.127

Data are limited, but etoposide has produced transient responses in a few patients with mycosis fungoides†.128

Etoposide has shown some activity in the treatment of advanced Hodgkin's disease†,14,64,100,101,110,116,118,119 and combination chemotherapy regimens containing the drug are currently being evaluated in the treatment of refractory disease.121,123,129

Leukemias

Although the exact role of etoposide has not been established,34,106,107,108 the drug has been shown to be active in the 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 When used alone in patients whose disease is refractory to initial chemotherapy, etoposide induces complete remission in about 10-15% of patients;54,100,101,102,103,104,105,106,107,108,109,110 response rates appear to be higher in patients with acute monocytic and myelomonocytic leukemias.34,54,100,101,102,103,104,107,110 Since etoposide appears to be particularly effective for the treatment of acute monocytic and myelomonocytic leukemias, the drug may be useful when monocytoid cells are not cleared with conventional combination chemotherapy.100,101,102,103,104,107,110 Because of its antileukemic activity, etoposide also has been employed in various combination chemotherapy regimens for remission induction in adults and children with refractory AML;11,107,108,111,112 while some of these regimens are effective (e.g., etoposide and azacitidine),11,112 the role of etoposide in these regimens remains to be clearly established.107,108,111 Additional studies are needed to evaluate the role of etoposide as a single agent and in combination chemotherapy for the treatment of AML.34,106,107,108

Data are limited, but etoposide has shown activity alone and in combination chemotherapy for remission induction in the treatment of refractory acute lymphocytic (lymphoblastic) leukemia† in children;108,109,110 in adults with acute lymphocytic leukemia, etoposide appears to have little, if any, activity.100,101,107

Wilms' Tumor

Etoposide has shown activity in the management of Wilms' tumor and has been used with encouraging results in conjunction with carboplatin in a limited number of children with recurrent (relapsed or refractory) disease.231,232,234,235 Etoposide also has been used as an alternative215 to standard preferred regimens (e.g., combined vincristine and dactinomycin with or without doxorubicin) in patients with less severe stages of Wilms' tumor.215 Second-line (salvage) therapy with etoposide and carboplatin may be considered for patients with recurrent tumors of unfavorable histology, abdominal recurrence after radiation therapy, or recurrence within 6 months of nephrectomy or after initial 3-drug combination chemotherapy (e.g., vincristine, dactinomycin, and doxorubicin).231,232,239 In a study in a limited number of children with recurrent Wilms' tumor, most of whose tumors were of favorable histology, second-line therapy (2 courses separated by 21 days) with etoposide (100 mg/m² daily for 5 days) and carboplatin (160 mg/m² daily for 5 days) resulted in complete or partial responses in 73% of patients; complete response was maintained for a median follow-up of 40 months (range: 24-56 months) in about 30% of patients.232 The principal toxicity in these children was high-grade hematologic toxicity, particularly thrombocytopenia.231,232 Second-line therapy with high-dose chemotherapy followed by autologous bone marrow transplantation also has been used effectively in patients with recurrent disease, occasionally resulting in long-term survival.231,232 Patients with recurrent disease failing to respond to such attempts with salvage therapy should be offered treatment under protocol conditions in ongoing clinical trials.231

Neuroblastoma

Etoposide also has been used in the treatment of disseminated neuroblastoma†,64,109,110,157,215,226,227,228 and combination regimens using cyclophosphamide, doxorubicin, cisplatin, and/or etoposide or teniposide generally are preferred in children with this tumor.215,226,239 For localized resectable neuroblastoma, complete gross surgical excision produces disease-free survival that is indistinguishable from that obtained with surgery and adjuvant chemotherapy or adjuvant radiation therapy and therefore is preferred; however, the importance of certain tumor biologic properties (e.g., N-myc amplification and DNA ploidy) and other prognostic factors should be considered in evaluating the possible need for adjuvant therapy.226 For localized unresectable tumor, subtotal resection followed by chemotherapy is used for initial treatment, and short-term treatment (e.g., 4-6 months) usually is adequate.226 For regional neuroblastoma in children younger than 1 year of age, chemotherapy generally is limited to relatively resistant tumors since prognosis in less resistant tumors treated with surgery alone is good.226 In older children with regional neuroblastoma, chemotherapy may be employed for tumor reduction prior to surgery or may be employed aggressively following surgery; the role of aggressive therapy that includes high-dose chemotherapy, radiation therapy, and bone marrow transplant is being evaluated for children older than 1 year of age and/or those with poor prognostic characteristics (e.g., N-myc amplification).226 For disseminated neuroblastoma, intensive conventional chemotherapy, with or without surgery and radiation therapy (depending on clinical presentation and course), currently is the preferred initial therapy, although the relative efficacy of such therapy compared with myeloablative chemotherapy and autologous bone marrow transplant is being evaluated.226 For infants with stage IVS (special) neuroblastoma, chemotherapy often is unnecessary, but the management course should be individualized.226

AIDS-related Kaposi's Sarcoma

Etoposide has been used alone133,215,258 or in combination257,258,259 chemotherapy for the palliative treatment of AIDS-related Kaposi's sarcoma†. Single-agent therapy with etoposide is an alternative regimen for treatment of such sarcoma.215 Combination chemotherapy that includes bleomycin, doxorubicin, and a vinca alkaloid (vinblastine or vincristine) has been considered a regimen of choice for the disease,215,258,259,260 but many clinicians currently consider a liposomal anthracycline (doxorubicin or daunorubicin) the first-line therapy of choice for advanced AIDS-related Kaposi's sarcoma (see Uses: AIDS-related Kaposi's Sarcoma in Doxorubicin 10:00 or Daunorubicin 10:00).215,258,307,308,309

Although single-agent therapy with conventional (i.e., nonencapsulated) cytotoxic agents generally has been used in the early stage of disease, Kaposi's sarcoma in patients with human immunodeficiency virus (HIV) infection often is rapidly progressive.258,261,262,263,264,265,266,267,268,305 AIDS-related Kaposi's sarcoma often progresses to multifocal, widespread lesions that may involve the skin, oral mucosa, and lymph nodes as well as visceral organs such as the GI tract, lung, liver, and spleen;261,263,264,268,269,270,271,272,273,305 such lesions often are numerous and may be cosmetically unattractive or disfiguring and accompanied by lymphedema.264,274,305 Appropriate evaluation of the effects of drug therapies on survival in patients with Kaposi's sarcoma must include assessment of the effects of such therapies on the development of infection as well as on tumor regression.264,273,305 Although treatment may result in disappearance or reduction in the size of Kaposi's sarcoma skin lesions and thereby alleviate the discomfort associated with chronic edema and ulcerations that often accompany multiple skin lesions on the lower extremities and in symptomatic control of mucosal and visceral lesions, there currently are no data demonstrating unequivocal evidence of improved survival with any therapy.258,275,276,277,305 Small localized Kaposi's sarcomalesions may be treated with electrodesiccation and curettage cryotherapy or by surgical excision; the lesions also generally are responsive to local radiation, and excellent palliation often can be achieved.258,305 Localized palatal lesions have been treated effectively with intralesional† injections of vinblastine.258,278,305 Alitretinoin gel (Panretin^®, Ligand Pharmaceuticals), a topical retinoid, is used for the treatment of localized cutaneous lesions in patients with AIDS-related Kaposi's sarcoma; responses of cutaneous lesions to topical therapy with alitretinoin have been reported in patients who have received prior systemic and/or topical therapy for Kaposi's sarcoma as well as in those with previously untreated disease.306

Response rates observed with single-agent chemotherapy (e.g., doxorubicin, etoposide, vinblastine, vincristine) appear to be similar to those observed with interferon alfa; however, studies directly comparing the efficacy of doxorubicin alone with that of interferon alfa have not been performed.279 Any differences in response rates reported in clinical studies generally appear to reflect differences in patient selection and in the criteria used to evaluate response rather than in drug activity.258 In one study in patients with AIDS-related Kaposi's sarcoma who received etoposide in an IV dosage of 150 mg/m² daily for 3 consecutive days at the beginning of a 28-day cycle for a median of 6 or 7 cycles (range: 2-26 cycles), complete or partial response was observed in about 30 or 46% of evaluable patients, respectively.133,259 Combined treatment with etoposide and interferon alfa generally appears to result in enhanced systemic toxicity without added therapeutic benefit.268,290,310,311

Combination chemotherapy with conventional antineoplastic agents (e.g., bleomycin, conventional doxorubicin, etoposide, vinblastine, vincristine) usually has been used for more advanced disease (e.g., extensive mucocutaneous disease, lymphedema, symptomatic visceral disease).258,259,260,305 Doxorubicin hydrochloride liposomal injection (Doxil^® by Alza Pharmaceuticals) is approved for use277 in the palliative treatment of AIDS-related Kaposi's sarcoma in adults who are intolerant to combination chemotherapy or whose disease has progressed while receiving such therapy.275,276,277,280,281,282,283,284,285,286,287,288,289 Liposomal daunorubicin citrate (DaunoXome^®by NeXstar) is approved for use as first-line therapy for advanced AIDS-related Kaposi's sarcoma.291 The results of several randomized, multicenter trials indicate that patients receiving a liposomal anthracycline for the treatment of advanced AIDS-related Kaposi's sarcoma experience similar or higher response rates with a more favorable toxic effects profile than those receiving combination therapy with conventional chemotherapeutic agents.258,307,308,309 Preliminary evidence suggests that the mean survival period in patients with AIDS-related pulmonary Kaposi's sarcoma receiving liposomal doxorubicin may be increased compared with those receiving conventional chemotherapy (bleomycin and/or vincristine).287 The comparative efficacy of liposomal daunorubicin relative to liposomal doxorubicin has not been established.291,292,293,294

Although treatment may result in the reduction or disappearance of lesions and alleviation of the associated symptoms, no treatment has been shown conclusively to alter the natural history of AIDS-related Kaposi's sarcoma258,264,268,275,276,280,290,305 and additional study and experience are needed to establish the optimal regimen.275,276,280

Ovarian Neoplasms

Epithelial Ovarian Cancer

Etoposide currently is being investigated as an active agent for use in the treatment of advanced epithelial ovarian cancer†.215,312,313,314,315,316 In phase II studies, objective responses were observed in 6-26% of patients receiving low-dose oral etoposide as salvage therapy for previously treated advanced epithelial ovarian cancer; responses occurred in patients with platinum- and paclitaxel-resistant disease.312,313,314,315,316

Ovarian Germ Cell Tumors

Etoposide is used in combination with cisplatin and bleomycin for the treatment of ovarian germ cell tumors†.215,317

Other Uses

The use of high-dose† etoposide regimens in conjunction with autogenous (autologous) bone marrow transplantation is currently being evaluated for the treatment of various refractory advanced malignant neoplasms (e.g., nonseminomatous testicular carcinoma).63,158,164 Etoposide has been used with encouraging results in the treatment of gestational trophoblastic tumors† (choriocarcinoma and chorioadenoma destruens) in women.130,185 The drug has also shown some activity in the treatment of hepatoma†,110,131,132 Ewing's sarcoma†,54,110,157 rhabdomyosarcoma†,64,109,110 and brain tumors†.14,64 The role of etoposide in the treatment of these neoplasms has not been fully elucidated.54,64,109,110,131,132,133

Administration

Etoposide is administered orally189 and by slow IV infusion.1,189 Etoposide phosphate is administered by IV infusion.256

Etoposide solutions should not be administered by rapid IV injection .1(See Cautions: Cardiovascular Effects.)Because delayed, severe (sometimes fatal) toxicity has occurred in animals following intraperitoneal and intrapleural administration of etoposide ,155it is recommended that the drug not be administered by these routes .139,155

The toxicity of rapidly infused etoposide phosphate in patients with impaired renal or hepatic function has not been adequately evaluated,256 and the toxicity profile of etoposide phosphate when infused at doses exceeding 175 mg/m² has not been delineated.256

To minimize the risk of hypotensive reactions, IV infusions of etoposide should be administered over a period of at least 30-60 minutes.1 The manufacturer states that a longer duration of administration may be used if the volume of fluid to be infused is a concern.189 Patients should be observed closely for possible hypotensive or anaphylactoid reactions during administration of the drug.1 (See Cautions: Precautions and Contraindications.) When a hypotensive reaction occurs and the infusion is discontinued and then restarted after appropriate treatment of the reaction, a slower rate of infusion should be employed.1,2 Etoposide has been administered by continuous IV infusion over 5 days,134,135,136 but this method of administration has not been shown to date to have any therapeutic advantage over intermittent IV infusions of the drug.156

Etoposide phosphate solutions may be administered over 5-210 minutes.256

The manufacturer recommends that protective gloves be used during handling of etoposide concentrate for injection and preparation of etoposide and etoposide phosphate solutions, since skin reactions associated with accidental exposure to the drug may occur.1 If etoposide concentrate for injection or a solution of the drug comes in contact with the skin, the affected area should be washed immediately and thoroughly with soap and water.1 If solutions of etoposide phosphate come in contact with the skin or mucosa, the affected skin should be washed immediately and thoroughly with soap and water, and the affected mucosa should be rinsed thoroughly with water.256

Etoposide concentrate for injection must be diluted before administration .1,2,5,189 It is recommended that syringes with Luer-Lok^® fittings be used for handling of etoposide concentrate for injection;2 when under pressure, needles have become displaced from etoposide-containing syringes without Luer-Lok^® fittings, an effect which may be related to the drug's vehicle.2 The manufacturer recommends that the required dose of etoposide concentrate for injection be diluted to a final concentration of 0.2 or 0.4 mg/mL in 0.9% sodium chloride or 5% dextrose injection prior to slow IV infusion.1,2 (See Chemistry and Stability: Stability.) Etoposide concentrate for injection and the diluted solution for infusion should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.1,256

Etoposide phosphate powder for injection should be reconstituted with 5 or 10 mL of 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), resulting in a concentration equivalent to 20 or 10 mg of etoposide per mL (22.7 or 11.4 mg of etoposide phosphate per mL), respectively.256 Following reconstitution, the solution may be administered without further dilution, or it may be further diluted to concentrations as low as 0.1 mg of etoposide per mL with either 5% dextrose injection or 0.9% sodium chloride injection.256

Dosage

Dosage of etoposide must be based 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 Clinicians should consult published protocols for the dosage of etoposide and other chemotherapeutic agents and the method and sequence of administration. A repeat course of etoposide should not be administered until the patient's hematologic function is within acceptable limits .1 (See Cautions: Precautions and Contraindications.) When etoposide phosphate is used, dosage is expressed in terms of etoposide; 113.6 mg of etoposide phosphate is equivalent to 100 mg of etoposide.296

Testicular Neoplasms

For remission induction in the treatment of refractory testicular neoplasms, the usual IV dosage of etoposide in combination chemotherapy regimens is 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 Carcinoma

For the treatment of small cell lung carcinoma, the usual IV dosage of etoposide in combination chemotherapy regimens 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 The recommended oral dosage of the drug is twice the IV dosage rounded to the nearest 50 mg.189

Other Malignant Neoplasms

For the treatment of other malignant neoplasms†, the optimum dosage of etoposide remains to be clearly established.34,54,59,106,107,108,115,116,117,118,139 Various dosage schedules and regimens of etoposide, alone or in combination with other antineoplastic agents, have been used.34,54,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,139 While the dosage of etoposide employed for the treatment of other malignant neoplasms has generally been similar to that used for the treatment of refractory testicular neoplasms,54,60,65,70,72,73,100,105,107,108,115,120,134 dosage has varied widely.34,54,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,139 Some high-dose† IV etoposide regimens (e.g., 400-800 mg/m² daily for 3 consecutive days for 1 or 2 courses of therapy in conjunction with autogenous bone marrow transplantation for the treatment of various advanced malignant neoplasms) have been investigated.21,63,106,158,164 Clinicians should consult published protocols for the dosage of etoposide and other chemotherapeutic agents and the method and sequence of administration.

For the treatment of Kaposi's sarcoma† in patients with AIDS, etoposide has been given in an IV dosage of 150 mg/m² daily for 3 consecutive days every 4 weeks, with cycles of therapy repeated as necessary depending on the patient's response and dosage reduced as necessary depending on the myelosuppressive effect of the drug.133

Dosage in Renal and Hepatic Impairment

The effects of renal or hepatic impairment on the elimination of etoposide have not been fully evaluated.20,21,28,163,176,197 Because a substantial fraction of the drug is excreted unchanged in urine,18,20,29,30,176 it is suggested that dosage reductions be considered in patients with impaired renal function.20,21,161,256 In patients with a measured creatinine clearance of greater than 50 mL/minute, no initial dose modification is required.256 In patients with a measured creatinine clearance of 15-50 mL/minute, 75% of the initial recommended etoposide dose should be administered.256 Although specific data are not available in patients with a measured creatinine clearance less than 15 mL/minute, further dose reduction should be considered.256 Subsequent etoposide dosing should be based on patient tolerance and clinical effect.256 Since etoposide-induced hematologic toxicity appeared to be more severe in patients with elevated serum bilirubin concentrations in one study163 and there is some evidence that total plasma clearance and elimination of the drug may be reduced in patients with impaired hepatic function,28,176 etoposide should probably be used with caution and the need for dosage reduction considered in patients with hepatic impairment.159,163,176

Because etoposide phosphate is converted rapidly and completely in vivo to etoposide, the adverse effects associated with etoposide can be expected to occur with etoposide phosphate.256

Hematologic Effects

The major and dose-limiting adverse effect of etoposide is hematologic toxicity.1,2,17,59,64,106,110,116,118,120,133,134,135,136,256 Myelosuppression, which is dose related, is manifested mainly by leukopenia (principally granulocytopenia).1,2,17,57,59,64,67,91,100,101,256 Myelosuppression resulting in death has been reported in patients receiving etoposide. 256 Thrombocytopenia occurs less frequently,1,2,17,64,67,91,100,101 and anemia may also occur;17,60,64,133,189 pancytopenia has occurred in some patients.100,101 Myelosuppression apparently is not cumulative1,2,57,59,120 but may be more severe in patients previously treated with other antineoplastic agents or radiation therapy.1,2,135 Leukopenia has reportedly occurred in 60-91% of patients receiving etoposide and was severe (leukocyte count less than 1000/mm³) in 3-17% of patients.1,2,189,256 Neutropenia (less than 2000/mm³) occurred in 88% of patients treated with etoposide phosphate; severe neutropenia (less than 500/mm³) occurred in 37% of patients treated.256 Thrombocytopenia has reportedly occurred in 22-41% of patients receiving the drug and was severe (platelet count less than 50,000/mm³) in 1-20% of patients.1,2,189 Anemia has occurred in up to 33% of patients receiving etoposide.17,60,64,189 Anemia (hemoglobin less than 11 g/dL) occurred in 72% of patients treated with etoposide phosphate; severe anemia (hemoglobin less than 8 g/dL) occurred in 19% of patients treated.256 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 has been reported to occur 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 Fever and infection have been reported in patients with drug-induced neutropenia.189,256

GI Effects

Nausea and vomiting are the principal adverse GI effects of etoposide, occurring in about 30-40% of patients receiving the drug.1,2,17,60,67,91,100,109,189,256 Etoposide-induced nausea and vomiting do not appear to be dose related17,64 and are usually mild to moderate in severity17,56,57,64,91,100,106,116,133 and readily controlled by conventional antiemetics.60,117,136 Nausea and vomiting have required discontinuance of the drug in about 1% of patients.189 There is some evidence that the incidence of nausea and vomiting may be reduced with 5-day continuous IV infusions of etoposide compared with intermittent IV administration.134,135,136

Other adverse GI effects of etoposide include abdominal pain, anorexia, and diarrhea, which have occurred in up to 7%,189,256 about 10-16%,1,2,67,92,101,116,134,256 and about 1-13%1,2,109,134,136,256 of patients, respectively. Stomatitis has reportedly occurred in about 1-6% of patients receiving usual dosages of etoposide1,2,133,135,189 and may be more likely to occur and/or be more severe in patients previously treated with radiation therapy to the head and neck region;135 in studies evaluating high-dose† etoposide regimens, stomatitis occurred more frequently106,136,158 and was found to be the dose-limiting adverse effect.158 Mucositis, constipation, and taste alteration have been reported in 11%,256 8%,256 and 6%,256 respectively, of patients treated with etoposide phosphate. Aftertaste,1,2,189 dysphagia,189 and parotitis133 have also been reported rarely.

Adverse GI effects appear to occur slightly more frequently following oral administration of etoposide than following IV administration.14,15,58,59,189

Cardiovascular Effects

Transient hypotension has occurred in about 1-2% of patients following rapid IV administration of etoposide,1,2,57,110 but has not been associated with cardiotoxicity or ECG changes to date.1,2 Hypotension also has been reported following administration of etoposide phosphate solution.256 While delayed hypotension has not been reported with recommended doses and rates of administration,1,2 it has occurred following slow IV infusion of higher than recommended doses.106 Geriatric patients may be particularly susceptible to etoposide-induced hypotension.137 While etoposide does not consistently induce hypotension following rapid IV administration,137 to minimize the risk of this adverse effect, etoposide solutions should be infused slowly over a period of at least 30-60 minutes.1,2 If hypotension occurs during administration of etoposide or etoposide phosphate solutions, it usually subsides with discontinuance of the infusion and administration of IV fluids or other supportive therapy as necessary.1,2,256 In some patients, etoposide and etoposide phosphate have reportedly caused a transient increase in blood pressure.1,2,100,137,256 Blood pressure usually normalizes within a few hours after discontinuance of the infusion.189

Etoposide has been associated with myocardial infarction136,138 or congestive heart failure134,135,136 in a small number of patients; however, these effects occurred almost exclusively in patients receiving etoposide by continuous IV infusion over 5 days, some of whom had preexisting cardiovascular disease, and were attributed to the large volumes of sodium chloride injection used as the diluent for administration of the drug.134,135,136

Sensitivity 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 hypotension1,2,92,178,256 have occurred during or immediately after administration of etoposide or etoposide phosphate in 0.7-3% of patients receiving the drug.1,2,67,92,134,178,256 Other manifestations have included flushing,178,189,256 rash,256 substernal chest pain,178 lacrimation,140 sneezing,140 coryza,140 throat pain,140 back pain,64 generalized body pain,64 abdominal cramps,64 and auditory impairment.64 Anaphylactoid reactions have occurred during the initial infusion of etoposide in some patients.189 Facial/lingual swelling, coughing, diaphoresis, cyanosis, tightness in the throat, laryngospasm, back pain, and/or loss of consciousness have sometimes occurred in association with the above reactions in patients receiving etoposide.189,256 Rarely, an apparent hypersensitivity-associated apnea has been reported.189,256 Anaphylactoid reactions are usually controlled by discontinuance of the drug infusion1,2,92,140,256 and administration of vasopressors,1,2,134,256 corticosteroids,1,2,134,256 antihistamines,1,2,134,256 and/or plasma volume expanders1,2,256 as necessary; however, these reactions can be fatal.189,256 In one patient who had experienced several acute anaphylactoid reactions to the drug, prolonging the infusion over 4-6 hours prevented further occurrences of the reactions.140

Bronchospasm with severe wheezing, responsive to antihistamine therapy, has been reported,141 and at least one fatal acute reaction associated with etoposide-induced bronchospasm has occurred.1,2,139,189 Acute pulmonary dysfunction, with or without hypertension, which may progress to pulmonary edema has also occurred.139

Dermatologic and Local Effects

Reversible alopecia, sometimes progressing to complete baldness, has occurred in 8-66% of patients receiving etoposide.1,2,17,60,64,67,100,101,109,133,134,189,256 The degree of alopecia may be dose related.17 Stevens-Johnson syndrome256 has been reported infrequently in patients receiving etoposide.256 Rash,1,2,189,256 pigmentation,189 urticaria,189,256 and severe pruritus64,189,256 have occurred infrequently, and cutaneous radiation-recall reactions associated with etoposide have been reported.1,2,142,179 At investigational doses, a generalized pruritic erythematous maculopapular rash, consistent with perivasculitis, has been reported.189,256 Localized herpes zoster infections have occurred in a few patients with AIDS during therapy with the drug.133

Swelling of the forearm and upper arm with erythema was reported in one patient receiving an IV infusion of etoposide via a hand vein.110 Phlebitis has occurred following IV administration of undiluted etoposide concentrate for injection,115 and local pain has occurred following rapid IV injection of the drug diluted with 0.9% sodium chloride injection to a final concentration of 10 mg/mL;137 these irritant effects may be related to the solubilizing agents in the drug's vehicle.139 While etoposide and its vehicle have been shown to produce ulceration in mice following intradermal injection,143 only one case of soft-tissue ulceration following extravasation of an etoposide infusion has been reported to date.144 In mice, local infiltration of 0.9% sodium chloride injection or hyaluronidase was an effective local antidote, probably by diluting the local tissue concentration of the drug.143

Nervous System Effects

Peripheral neuropathy has occurred in about 1-2% of patients receiving etoposide.1,2,14,189 Although not clearly established,145 it has been suggested that the risk and/or severity of peripheral neuropathy may be increased when etoposide is administered concurrently with other potentially neurotoxic agents (e.g., vincristine).34,146,147

Adverse CNS effects, including somnolence and fatigue, have been reported to occur in up to 3% of patients receiving etoposide.1,2 Seizure, occasionally associated with allergic reactions, has been reported infrequently in patients receiving etoposide.256 Headache,100 transient cortical blindness,189 optic neuritis,189 and transient vertigo115 have been reported rarely. Transient mental confusion during administration of etoposide has been reported in a few patients receiving high-dose regimens of the drug; this effect appeared to be consistent with alcohol intoxication resulting from the large volume of the drug's vehicle necessary to administer the dose.158

Other Adverse Effects

Hepatotoxicity has been reported in patients receiving etoposide.189 Hepatic toxicity generally has occurred in those patients receiving doses of the drug higher than recommended.189 Metabolic acidosis also has been reported in patients receiving such doses of etoposide.189

Interstitial pneumonitis256 or pulmonary fibrosis256 has been reported infrequently in patients receiving etoposide.256 Fever100,109 and intermittent muscle cramps120 have been reported rarely in patients receiving etoposide. Although a causal relationship has not been established, etoposide has been associated with increases in serum bilirubin (sometimes resulting in jaundice),106,116,166 AST (SGOT),106,166 and alkaline phosphatase concentrations; these effects were transient and resolved without sequelae and occurred almost exclusively in patients in studies evaluating high-dose† regimens of the drug.106,166 Transient compensated metabolic acidosis has also occurred in patients receiving high-dose† etoposide regimens and was presumably caused by the agents contained in the drug's vehicle.158

Precautions and Contraindications

Etoposide is a toxic drug with a low therapeutic index, and a therapeutic response is not likely to occur without evidence of toxicity.1,2,34,139 The drug must be used only under constant supervision by clinicians experienced in therapy with cytotoxic agents and only when the potential benefits of etoposide therapy are thought to outweigh the possible risks.1 Most adverse effects of etoposide are reversible if detected promptly.1 When severe adverse effects occur during etoposide therapy, the drug should be discontinued or dosage reduced and appropriate measures instituted as necessary.1 Etoposide therapy should be reinstituted with caution, with adequate consideration of further need for the drug and awareness of possible recurrence of toxicity.1

Patients receiving etoposide should be observed closely for possible hypotensive or anaphylactoid reactions, and 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 Higher rates of anaphylactoid reactions have been reported in children who received etoposide infusions at concentrations higher than those recommended.189,256 The role that the concentration of the infusion (or rate of infusion) plays in the development of anaphylactoid reactions is uncertain.189,256 If hypotension occurs during administration of etoposide, it usually subsides with discontinuance of the infusion and administration of IV fluids or other supportive therapy as necessary.1,2 If an anaphylactoid reaction occurs during administration of the drug, the infusion should be discontinued and appropriate therapy (e.g., antihistamines, epinephrine, oxygen, corticosteroids) instituted as necessary.1 Etoposide and etoposide phosphate are contraindicated in patients who are hypersensitive to either etoposide or etoposide phosphate or any ingredient in the formulation.1,2,189,256

Hematologic function must be frequently and carefully monitored during and after etoposide therapy.1,2 The manufacturer states that complete blood cell counts (leukocyte count with differential, platelet count, hemoglobin) should be performed prior to initiation of etoposide therapy, at appropriate intervals during the course of treatment (e.g., twice weekly),180 and before each subsequent course of treatment with the drug.1,2 The manufacturer also states that therapy should be suspended if the platelet count is less than 50,000/mm³ or the absolute neutrophil count is less than 500/mm³;1,2 when blood counts have returned to an acceptable level, therapy may be resumed if indicated.1,2 Severe myelosuppression with resulting infection or bleeding may occur in patients receiving the drug.1,2,92,100,105,118,120,133,134,135,136 Treatment of severe hematologic toxicity may consist of supportive therapy, antibiotics for complicating infections, and blood product transfusions.105,133,135,136

Pediatric Precautions

Safety and efficacy of etoposide in children have not been established.1,256 The drug has been used with encouraging results in children for the treatment of refractory acute myelogenous leukemia†,11,108,109,110,112 principally in combination chemotherapy regimens,11,108,112 and has shown some activity in the treatment of refractory acute lymphocytic leukemia†108,110 and other pediatric malignancies†,109,110,157 but additional evaluation is needed.108,109,110,157

Higher rates of anaphylactoid reactions have been reported in children who received infusions of etoposide at higher-than-recommended concentrations.189,256 The role that the concentration or rate of infusion plays in the development of anaphylactoid reactions is uncertain.189,256

Each mL of etoposide concentrate for injection and etoposide for injection pharmacy bulk package contains 30 mg of benzyl alcohol as a preservative. Although a causal relationship has not been established, administration of injections preserved with benzyl alcohol has been associated with toxicity in neonates.216,217,218,219,220,221 Toxicity appears to have resulted from administration of large amounts (i.e., 100-400 mg/kg daily) of benzyl alcohol in these neonates.216,217,218,219,220,221 Although use of drugs preserved with benzyl alcohol should be avoided in neonates whenever possible, the American Academy of Pediatrics states that the presence of small amounts of the preservative in a commercially available injection should not proscribe its use when indicated in neonates.216

A complex, potentially fatal syndrome including thrombocytopenia, ascites, and renal, pulmonary, and hepatic failure has occurred in several premature infants who received IV therapy with an injectable vitamin E product containing polysorbate 80; etoposide injection contains polysorbate 80.189

Mutagenicity and Carcinogenicity

Etoposide is mutagenic and potentially carcinogenic; the occurrence of acute leukemia (with or without a preleukemic phase) has been reported rarely in patients receiving etoposide in association with other antineoplastic agents.189,256 Etoposide has been shown to induce chromosomal aberrations in embryonic murine cells1 and in human hematopoietic cell lines in vitro;14 gene mutations in Chinese hamster ovary cells;189 and DNA damage via strand breakage and DNA-protein crosslinks in mouse leukemia cells.189 The drug also caused a dose-related increase in sister chromatid exchanges in Chinese hamster ovary cells.189 Although etoposide phosphate was nonmutagenic in the in vitro Ames microbial mutagenicity assay and the E. coli WP2 uvrA reverse mutation assay, because it is rapidly and completely converted to etoposide in vivo, etoposide phosphate also should be considered as a potential mutagen.256

Studies in animals to determine the carcinogenic potential of etoposide have not been performed to date;1,256 however, because of its mechanism of action, the drug should be considered a potential carcinogen.1

Pregnancy, Fertility, and Lactation

Pregnancy

Etoposide may cause fetal harm when administered to pregnant women,1,256 but potential benefits from use of the drug may be acceptable in certain conditions despite possible risks to the fetus.149,159 Etoposide has been shown to be teratogenic and embryocidal in mice and rats at doses of 1-5% of the recommended human dose based on body surface area.1,256 In rats, etoposide caused dose-related maternal toxicity, embryotoxicity, and teratogenicity with IV dosages of 0.4-3.6 mg/kg daily.1 Embryonic resorptions, decreased fetal weights, and fetal abnormalities including major skeletal anomalies, exencephaly, encephalocele, and anophthalmia, were observed;1 even at an IV dosage of 0.13 mg/kg daily, a substantial increase in retarded ossification occurred.1 In mice, intraperitoneal etoposide doses of 1-2 mg/kg caused dose-related embryotoxicity, cranial abnormalities, and major skeletal malformations.1,181 There are no adequate and controlled studies to date using etoposide in pregnant women.1 Women of childbearing potential should be advised to avoid becoming pregnant while receiving the drug.1 Etoposide should be used during pregnancy only in life-threatening situations or severe disease for which safer drugs cannot be used or are ineffective.149,159 When the drug is administered during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be informed of the potential hazard to the fetus.1

Fertility

The effect of etoposide on fertility in humans is not known.159 In rats, oral doses of etoposide phosphate at 86 mg (of etoposide) per kg daily (approximately 10 times the human dosage based on body surface area) or greater for 5 consecutive days resulted in irreversible testicular atrophy also was observed in rats given IV etoposide phosphate at a dosage of 5.11 mg (of etoposide) per kg daily for 30 days (approximately 50% the human dosage based on body surface area).256

Lactation

It is not known whether etoposide is distributed into milk.1 Because of the potential for serious adverse reactions to etoposide in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.1

Antineoplastic Agents

Studies in animals150,151,152 and clinical trials in humans43,44,65,79,80,81,82,83,93,95,99 indicate that the antineoplastic activity of etoposide and cisplatin may be synergistic against some tumors. In mice implanted with P388150,151,152 or L1210151,152 leukemia or B16 melanoma,152 a combination of etoposide and cisplatin was shown to act synergistically in reducing the body burden of tumor cells and/or increasing survival.150,151,152 Response rates in humans receiving combination chemotherapy with etoposide and cisplatin suggest that the combination has synergistic antineoplastic activity against testicular carcinomas,43,44 small cell carcinoma of the lung,65,79,80,81,82,83 or non-small cell carcinoma of the lung.93,95,99 Studies in animals also indicate that the antineoplastic activity of etoposide and some other antineoplastic agents (e.g., carmustine, cytarabine, cyclophosphamide) is potentially additive or synergistic.152,153,154

Limited data indicate that patients previously treated with cisplatin may have impaired elimination of etoposide.176 Although further documentation is needed, the potential effect should be considered when etoposide is administered to patients who received prior cisplatin therapy.176

Other Drugs

Caution should be exercised when administering etoposide phosphate with drugs that are known to inhibit phosphatase activity (e.g., levamisole hydrochloride).256

High-dose cyclosporine administration, resulting in blood cyclosporine concentrations greater than 2000 ng/mL, with concomitant oral etoposide administration, resulted in an 80% increase in etoposide exposure with a 38% decrease in total body clearance of etoposide compared with etoposide alone.256

Pharmacology

The exact mechanism(s) of action of etoposide is not known, but the drug appears to produce its cytotoxic effects by damaging DNA3,6,7,169 and thereby inhibiting or altering DNA synthesis.1,2,3,8,169 Although the in vitro cytotoxicity of etoposide phosphate is significantly less than that seen with etoposide, once the drug has undergone dephosphorylation in vivo to the active etoposide moiety, the mechanism of action is believed to be the same as that of etoposide.256 Etoposide appears to be cell-cycle dependent and cycle-phase specific, inducing G₂-phase arrest and preferentially killing cells in the G₂ and late S phases.8,9,10,11,169

Etoposide has been shown to arrest metaphase in chick fibroblasts,1 but its principal effect in mammalian cells appears to be in the G₂ phase.1,8,9,10,11,169 At etoposide concentrations of 0.3-10 mcg/mL in vitro, cells are inhibited from entering prophase;1 at concentrations of 10 mcg/mL or higher, lysis of cells entering mitosis occurs.1 Unlike podophyllotoxin, etoposide does not inhibit microtubule assembly.1,2,3,12,167 Etoposide has been shown to induce single-stranded DNA breaks in HeLa cells7 and in murine leukemia L1210 cells6 in vitro; the drug also induces double-stranded DNA breaks and DNA-protein crosslinks in L1210 cells.6 Etoposide-induced DNA damage appears to correlate well with the cytotoxicity of the drug.6,170 While the exact mechanism remains to be determined, etoposide appears to induce single-stranded DNA breaks indirectly, possibly through endonuclease activation,6,7 inhibition of intranuclear type II topoisomerase,170,171,172 or formation of a free-radical metabolite via an enzymatic reaction involving the hydroxyl group at the C-4' position of the E ring.6,7 Etoposide also reversibly inhibits the facilitated diffusion of nucleosides into HeLa cells in a concentration-dependent manner in vitro;12 however, the relative importance of this effect to the cytotoxicity of the drug is unclear.3,12

Pharmacokinetics

Although some minor differences in etoposide pharmacokinetic parameters between age and gender have been observed, these differences were not considered clinically important.256,296

Absorption

Etoposide is variably absorbed following oral administration.13,14,15,16,17,18,19,160,161,189,190,191,192,193,194,195,196,197 The extent of absorption of etoposide is not affected by food.160,196 Several oral dosage preparations of the drug have been evaluated.13,14,15,16,17,18,19,160,161,189,190,191,192,193,194,195,196,197 Lipophilic capsules containing etoposide were found to be erratically absorbed13,14,15 and produced dose-limiting adverse GI effects.14 An oral solution of the drug (known as the “drink ampul”) was about 50-90% absorbed but was unpalatable.13,14,15,16,18 The absolute bioavailability of the currently available hydrophilic liquid-filled soft gelatin capsules containing the drug averages about 50% (range: 25-75%).17,18,19,160,161,189,190,191,192,193,194,195,196,197 Following oral administration of the commercially available capsules, peak plasma etoposide concentrations are generally attained within 1-1.5 hours (range: 0.75-4 hours)18,190,191,192 and peak plasma concentration and area under the plasma concentration-time curve (AUC) exhibit marked intraindividual and interindividual variation.18,189,190,191,192,193,194,195,196,197 However, peak plasma concentrations and AUCs for a given oral dose consistently fall in the same range as those following an IV dose one half as large.189,190,191,192,193 There is some evidence that the extent of absorption of etoposide does not increase proportionately with doses greater than 200 mg and may plateau at doses of 400 mg or more,160,194 but further studies are needed to evaluate the dose-bioavailability relationship of the drug.190,194 Following oral administration of 160 or 200 mg/m² as the commercially available capsules, peak plasma etoposide concentrations of 9 mcg/mL (range: 3-19 mcg/mL)191 and 9.6 mcg/mL (range: 2.1-15.9 mcg/mL),192 respectively, were attained. There is no evidence that the drug undergoes first-pass metabolism.189

Following IV administration of etoposide phosphate, the drug is rapidly and completely converted to etoposide in plasma. A direct comparison of the pharmacokinetic parameters (area under the plasma concentration-time curve [AUC] and maximum plasma concentration) of etoposide following IV administration of molar equivalent doses of etoposide phosphate and etoposide was made in 2 randomized, crossover studies in patients with a variety of malignancies.256,296 Results from both studies demonstrated no statistically significant differences in the AUC and maximum plasma concentration of etoposide when administered as either etoposide phosphate or etoposide.256,296 Therefore, the pharmacokinetic data reported for etoposide apply also to etoposide phosphate.256,296

Peak plasma concentrations and AUCs following IV administration of etoposide exhibit marked interindividual variation,189,190,191,192,193 but possibly less intraindividual variation than after oral administration.197 Over the dose range of 100-600 mg/m², peak plasma concentration and AUC increase linearly with dose.189 Following IV infusion of an 80-mg/m² dose of etoposide over 1 hour in adults with normal renal and hepatic function, peak plasma drug concentrations occurred at the end of the infusion and averaged 14.9 mcg/mL (range: 7.8-19.3 mcg/mL).20,161,191 Following 500-mg/hour IV infusions of 400, 500, or 600 mg/m² in adults with normal renal function in one study, peak plasma etoposide concentrations of 26-53, 27-73, and 42-114 mcg/mL, respectively, were attained.21 When etoposide was administered as a 72-hour continuous IV infusion in a dosage of 100 mg/m² daily in several patients with normal renal and hepatic function, plasma drug concentrations of about 2-5 mcg/mL were attained 2-3 hours after beginning the infusion and were maintained until the end of the infusion.18 In a limited number of children 3 months to 16 years of age with normal renal and hepatic function who were given IV infusions of 200-250 mg/m² over 0.5-2.25 hours, peak serum etoposide concentrations ranged from 17-88 mcg/mL.22

Distribution

Distribution of etoposide into human body tissues and fluids has not been fully characterized.18,21,24,27,28 Following IV administration of etoposide in mice and rats, highest concentrations of the drug are attained in the small intestine, kidneys, and liver, with lower concentrations in the lungs, stomach, pancreas, spleen, heart, and skin.2,23

Following IV administration in humans, etoposide undergoes rapid distribution.18,21,22,24,25 The apparent steady-state volume of distribution of the drug averages 20-28% of body weight1,24,161 or 18-29 L21,24,189 or 7-17 L/m²21,24,191,197 in adults and 5-10 L/m² in children.25,176,197 The major metabolite of etoposide appears to be distributed into a volume approximately equal to total body water.26 Following IV administration, etoposide is distributed minimally into pleural fluid21,27 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 Limited data suggest that distribution of the drug into bile is minimal.28,173,174,197 It is not known if etoposide is distributed into milk.1 The drug apparently crosses the placenta in animals.1,2

Etoposide and its metabolites apparently do not readily penetrate the CNS.1,18,21,22,27,29,30,197 While variable, CSF etoposide concentrations generally range from undetectable18,22 to less than 5% of concurrent plasma concentrations21,29,30,162 during the initial 24 hours after IV administration of the drug, even after administration of very high doses.21,162 Limited data suggest that etoposide distributes into brain tumor tissue more readily than into healthy brain tissue.27 Concentrations of the drug are higher in healthy lung tissue than in lung metastases but those achieved in primary myometrial tumors are similar to those achieved in healthy myometrial tissues.189,197

In vitro, etoposide is approximately 94% bound to serum proteins at a concentration of 10 mcg/mL.1,24

Elimination

Following IV infusion of etoposide, plasma concentrations of the drug have generally been reported to decline in a biphasic manner;18,21,22,24,25,27,29,30,31,176,197 however, some data indicate that the drug may exhibit triphasic elimination with a prolonged terminal phase.19,197 In adults with normal renal and hepatic function, the half-life of etoposide averages 0.6-2 hours (range: 0.2-2.5 hours) in the initial phase and 5.3-10.8 hours (range: 2.9-19 hours) in the terminal phase.18,20,21,24,29,161,189,191,192 In one adult with impaired hepatic function, the terminal elimination half-life was reportedly 78 hours.28 In children with normal renal and hepatic function, the half-life of etoposide averages 0.6-1.4 hours in the initial phase and 3-5.8 hours in the terminal phase.18,22,25,31

The metabolic fate of etoposide has not been completely determined.20,21,25,26,27,30,32,33 Etoposide appears to be metabolized principally at the D ring to produce the resulting hydroxy acid21,25,26,30,32,33 (probably the trans -hydroxy acid);33 this metabolite appears to be pharmacologically inactive.25,177 The picrolactone isomer of etoposide has been detected in low concentrations in the plasma and urine of some patients21,25 but not in others.20 The aglycone of etoposide and/or its conjugates have not been detected to date in patients receiving the drug.20,25 In vitro, the picrolactone isomer and aglycone of etoposide have minimal cytotoxic activity.25,177

Metabolism and excretion of etoposide appear to be similar following oral or IV administration of the drug.189 Etoposide and its metabolites are excreted principally in urine;18,20,21,26,27,29,30,32 fecal excretion of the drug is variable.29,30 Following IV infusion of etoposide in patients with normal renal and hepatic function, approximately 40-60% of a dose is excreted in urine as unchanged drug and metabolites within 48-72 hours20,29,30 and from less than 2 to 16% is excreted in feces within 72 hours;29,30 about 20-30% of the dose is excreted in urine unchanged within 24 hours18,29,30 and 30-45% within 48 hours.20,161 The principal urinary metabolite is the hydroxy acid of the drug.25,26,30,32 Following oral administration in patients with normal renal and hepatic function, about 5-25% of the dose is excreted in urine within 24-48 hours.191,194,195,196,197

Total plasma clearance of etoposide reportedly averages 19-28 mL/minute per m² in adults18,20,21,161,191,192 and 18-39 mL/minute per ² in children18,22,25 with normal renal and hepatic function; renal clearance of the drug is approximately 30-40% of the total plasma clearance.19,21,29,161,191,197 The effects of renal impairment on the elimination of the drug and its metabolites have not been fully evaluated;20,21,176,197 individuals with decreased renal function may have impaired elimination.20,21,176 Patients with impaired renal function receiving etoposide have exhibited reduced total body clearance, increased AUC, and a lower volume of distribution at steady state.256,296 Limited evidence suggests that total plasma clearance and elimination of etoposide may be reduced in patients with impaired hepatic function.28,163,176

Limited data suggest that etoposide is not appreciably dialyzable.197

Chemistry and Stability

Chemistry

Etoposide is a semisynthetic podophyllotoxin-derivative antineoplastic agent.1,2,3 Etoposide differs structurally from podophyllotoxin by having a glucoside moiety and the epimeric configuration at the C-4 position of the C ring and by the presence of a hydroxyl group, rather than a methoxy group, at the C-4' position of the E ring.3 The presence of the hydroxyl group at the C-4' position is associated with the drug's ability to induce single-stranded DNA breaks,3,7 and the presence of the glucoside moiety is associated with the drug's inability to inhibit microtubule assembly.3,167,168 Etoposide also is commercially available as etoposide phosphate, a water-soluble ester; this chemical modification decreases the potential for precipitation following dilution of the drug in aqueous solution, while maintaining pharmacologic activity in vivo.256,296 Etoposide phosphate undergoes dephosphorylation in vivo to etoposide, the active moiety.256,296 Each single-dose vial of etoposide phosphate contains 100 mg of etoposide, equivalent to 113.6 mg of etoposide phosphate.296

Etoposide occurs as a white to yellow-brown crystalline powder4 and is sparingly soluble in water1 (approximately 0.03 mg/mL)159 and slightly soluble in alcohol1 (approximately 0.76 mg/mL);159 the water miscibility of the drug is increased by the presence of organic solvents.1 Etoposide phosphate occurs as a white to off-white crystalline powder296 and is freely soluble in water (exceeding 100 mg/mL)296 and slightly soluble in alcohol.296 Etoposide concentrate for injection is a sterile, nonaqueous solution of the drug in a vehicle consisting of dehydrated alcohol, benzyl alcohol, citric acid, polyethylene glycol 300, and polysorbate (Tween^®) 80.1,2,159 Etoposide phosphate for injection is a sterile, nonpyrogenic, lyophilized powder containing sodium citrate and dextran 40;256,296 following reconstitution of etoposide phosphate with water for injection to a concentration of 1 mg/mL, the solution has a pH of 2.9.296 The concentrate for injection occurs as a clear, yellow solution and has a pH of 3-4.1,2 Etoposide is also commercially available as soft gelatin capsules containing the drug in a vehicle consisting of citric acid, glycerin, purified water, and polyethylene glycol 400; the soft gelatin capsules contain gelatin, glycerin, sorbitol, purified water, and parabens.189

Stability

Etoposide concentrate for injection should be stored at room temperature.1 Unopened vials of the drug are stable for 2 years when stored at room temperature (25°C).1 Etoposide phosphate powder for injection should be stored in unopened vials at 2-8°C and retained in the original package to protect from light;256,296 such unopened vials of the drug are stable at least 36 months when refrigerated at 2-8°C.296 Etoposide liquid-filled capsules should be refrigerated at 2-8°C.189 The capsules are stable for 2 years when refrigerated at 2-8°C.189

Etoposide concentrate for injection must be diluted before administration.1,2,5,189 The manufacturer states that, following dilution in 0.9% sodium chloride or 5% dextrose injection, etoposide solutions containing 0.2 or 0.4 mg/mL are stable for 96 or 24 hours, respectively, at room temperature (25°C) in glass or plastic (PVC) containers under exposure to normal room fluorescent light;189 following dilution in lactated Ringer's or 10% mannitol injection, solutions of the drug containing 0.2 or 0.4 mg/mL are stable for 8 hours at 25°C in glass containers under exposure to normal room fluorescent light.187 Because etoposide is sparingly soluble in water,1,2 the drug may crystallize following dilution in the above diluents;5 if crystallization occurs, the solution should be discarded.5 Crystallization of etoposide in aqueous solutions appears to be concentration dependent.5 At a concentration of 1 mg/mL in 0.9% sodium chloride or 5% dextrose injection, crystallization has occurred within 5 minutes upon stirring the solution or within 30 minutes upon allowing the solution to stand;5 therefore, this concentration is not recommended for IV administration.5 If solutions of etoposide are prepared at concentrations above 0.4 mg/mL, precipitation may occur,189 and the manufacturer recommends that the concentration not exceed 0.4 mg/mL.1,2,189

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-µm Millex^®-GS or Millex^®-GV) without filter decomposition.2,159

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

When reconstituted and/or diluted as directed, solutions of etoposide phosphate can be stored in glass or plastic containers at controlled room temperature (20-25°C) or under refrigeration (2-8°C) for 24 hours.256,296 Refrigerated solutions of etoposide phosphate should be used immediately following return to room temperature.256,296

Additional Information

For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].

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