Etoposide

Etoposide concentrate for injection should be stored at room temperature.

PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practical to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen & date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured & the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed & labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/

SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational exposure or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in soil or water; effects on animal, aquatic, and plant life; and conformance with environmental and public health regulations.

PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds & specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... summary of avail methods & recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous & organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp & carcinogenic wastes generated by this treatment conducted to & burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter & misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/

For more Disposal Methods (Complete) data for ETOPOSIDE (6 total), please visit the HSDB record page.

PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food & beverage containers or utensils, & the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, & rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes & wear protective suits (preferably disposable, one-piece & close-fitting at ankles & wrists), gloves, hair covering & overshoes. ... Clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves & gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, & disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth & purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care & vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... & when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, & contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) & label fixed to it, giving date of test & avg air-flow measured. This test should be repeated periodically & after any structural changes. /Chemical Carcinogens/

For more Preventive Measures (Complete) data for ETOPOSIDE (10 total), please visit the HSDB record page.

PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece & close-fitting at ankles & wrists), gloves, hair covering & overshoes. ... In chemical laboratory, gloves & gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, & disposable plastic aprons might provide addnl protection. ... Gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/

Additive bone marrow depression may occur; dosage reduction may be required when two or more bone marrow depressants, including radiation, are used concurrently or consecutively.

Multidrug resistance is one of the mechanisms of resistance to multiple cytotoxic drugs and is mediated by the expression of a membrane pump called the P-glycoprotein. Nifedipine is one of the calcium channel blocking agents which reverses multidrug resistance in vitro. Fifteen patients with various malignancies received nifedipine at three dose levels: 40 mg, 60 mg and 80 mg orally twice daily for 6 days. Etoposide was administered intravenously on day 2 in a dose of 150-250 mg/sq m and orally 150-300 mg twice daily on days 3 and 4. Cardiovascular effects of nifedipine were dose limiting and the maximum tolerated dose was 60 mg twice a day. Mean area under the plasma concentration curve and plasma half-life of nifedipine and its major metabolite MI at the highest dose level were 7.87 uM.hr, 7.97 hr and 4.97 uM.hr, 14.0 hr respectively. Nifedipine did not interfere with the pharmacokinetics of etoposide.

Dipyridamole has chemical characteristics similar to other known modulators of etoposide, doxorubicin, and vinblastine sensitivity. When compared to verapamil, dipyridamole was as efficacious but twice as potent in its synergistic enhancement of etoposide sensitivity. These results demonstrate that dipyridamole can markedly increase the cytotoxicity of etoposide, doxorubicin, and vinblastine and suggest possible clinical applications.

Enhanced antineoplastic action of etoposide in the presence of cyclosporin A, was investigated in several in vitro and in vivo tumor systems. Macromolecular DNA damage induced by etoposide at drug levels comparable to plasma area under the curve values achieved in patients was increased not only in leukemic peripheral blood cells from patients but also in mononuclear peripheral blood cells from a healthy donor. Intracellular retention of radioactivity from (3)H etoposide was increased by a factor of 1.5 at the most in the presence of cyclosporin A. The cytotoxicity of etoposide and adriamycin to L 1210 leukemic cells was clearly enhanced, whereas cyclosporin A had no effect on the action of cisplatin or ionizing irradiation. At cyclosporin A blood levels not exceeding 1.44 ug/ml, increased tumor inhibition of etoposide was observed in a human embryonal cancer xenograft, but there was also higher lethality in normal mice. With respect to chemosensitization the effects of cyclosporin A resemble those of calcium channel blockers or anticalmodulin agents. In contrast to calcium channel blockers, however, adequate plasma levels of cyclosporin A can well be achieved in patients.

For more Interactions (Complete) data for ETOPOSIDE (7 total), please visit the HSDB record page.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 51(SRC), determined from a log Kow of 0.60(2) and a regression-derived equation(3), indicates that etoposide is expected to have high mobility in soil(SRC). Volatilization of etoposide from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 1.7X10-30 atm-cu m/mole(SRC), using a fragment constant estimation method(4). Etoposide is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 5.4X10-23 mm Hg(SRC), determined from a fragment constant method(5). No biodegradation was located for etoposide(SRC). The antineoplastic agents vindesine, vincristine, and vinblastine were all shown to fail the closed bottle test and Zahn-Wellens tests for ready and inherent biodegradability(6). These data suggest that etoposide may also be slow to biodegrade in the environment.

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 51(SRC), determined from a log Kow of 0.60(2) and a regression-derived equation(3), indicates that etoposide is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 1.7X10-30 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5),an estimated BCF of 3(SRC), from its log Kow(2)and a regression-derived equation(6), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Etoposide has a UV absorption band that extends beyond 290 nm(7) and contains functional groups that may potentially be susceptible to hydrolysis(3); however, the rates of photolysis in surface water and hydrolysis are not known. No biodegradation was located for etoposide(SRC). The antineoplastic agents vindesine, vincristine, and vinblastine were all shown to fail the closed bottle test and Zahn-Wellens tests for ready and inherent biodegradability(8). These data suggest that etoposide may also be slow to biodegrade in the environment.

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), etoposide, which has an estimated vapor pressure of 5.4X10-24 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase etoposide may be removed from the air by wet and dry deposition(SRC). Etoposide has a UV absorption band that extends beyond 290 nm(3) making it potentially susceptible to direct photolysis; however, photolysis of particulate phase compounds is generally much slower than for vapor phase compounds(SRC).

Etoposide is a relatively well-tolerated chemotherapeutic agent. Common adverse effects include alopecia and gastrointestinal toxicity. GI toxicity includes nausea, vomiting, and stomatitis. The GI toxicity is relatively mild compared to other antineoplastic medications and can be well controlled with antiemetic therapy. Alopecia is commonly observed at standard doses and becomes a universal side effect at doses of 500 mg/m^2 or higher. The dose-limiting side effect of etoposide is myelosuppression.

Absorbed well, time to peak plasma concentration is 1-1.5 hrs. Mean bioavailability is 50% (range of 25% - 75%). Cmax and AUC values for orally administered etoposide capsules display intra- and inter-subject variability. There is no evidence of first-pass effect for etoposide.

Excretion of etoposide in breast milk was demonstrated in a woman with acute promyelocytic leukemia receiving daily doses of 80 mg/sq m (route not stated). Peak concentrations of 0.6-0.8 ug/mL were measured immediately after dosing but had decreased to undetectable levels by 24 hr.

Myelosuppression is the dose-limiting toxicity of etoposide. Research data showed alopecia, nausea, vomiting, and stomatitis occurring in 20 to 30% of patients.

Etoposide inhibits DNA topoisomerase II, thereby inhibiting DNA re-ligation. This causes critical errors in DNA synthesis at the premitotic stage of cell division and can lead to apoptosis of the cancer cell. Etoposide is cell cycle dependent and phase specific, affecting mainly the S and G2 phases of cell division. Inhibition of the topoisomerase II alpha isoform results in the anti-tumour activity of etoposide. The drug is also capable of inhibiting the beta isoform but inhibition of this target is not associated with the anti-tumour activity. It is instead associated with the carcinogenic effect.

PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/

The Koc of etoposide is estimated as 51(SRC), using a log Kow of 0.60(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that etoposide is expected to have high mobility in soil(SRC).

/HUMAN EXPOSURE STUDIES/ An Italian cohort consisted of 241 patients (132 boys and 109 girls) who were treated between 1977 and 1995 for newly diagnosed or relapsed Langerhans cell histiocytosis. The median length of follow-up was 5.8 years. The expected number of cases of leukemia was estimated from age- and sex-specific incidence rates derived from the Varese Cancer Registry in Italy. The standardized incidence ratio (SIR) of acute myeloid leukemia for the extended Italian cohort was 520 (95% CI, 168-1213). Eighty-two patients had received etoposide as a single agent or in combination with other drugs not known to be leukaemogenic, while 31 patients had received etoposide in combination with one or more agents with possible leukaemogenic activity (vincristine, prednisone, vinblastine, doxorubicin and cyclophosphamide); 128 patients were not treated with etoposide. The cumulative dose of etoposide ranged between 100 and 30 000 mg/sq m (median, 5200 mg/sq m); 70 children received more than 4000 mg/sq m. Five cases of acute promyelocytic leukemia were diagnosed, all in etoposide-treated patients (four girls, one boy; latency, 27-106 months). Four of the five patients had not been exposed to alkylating agents, intercalating agents or radiotherapy; the SIR for this group was 1600 (95% CI, 435-4096). The fifth case occurred in the group that had received both etoposide and alkylating agents, intercalating agents or radiotherapy (SIR, 776; 95% CI, 19-4325). All of the patients with acute promyelocytic leukemia had received a cumulative dose of etoposide exceeding 4000 mg/sq m, and the SIR for this group was 1782 (95% CI, 574-4159). No cases of acute promyelocytic leukemia were observed in patients who had not received etoposide.

/HUMAN EXPOSURE STUDIES/ A study in Japan included 119 women who were treated for recurrent breast cancer between 1985 and 1994. Before recurrence, the patients had been treated with 5-fluorouracil, cyclophosphamide, doxorubicin, tamoxifen or radiation. All of the patients with recurrences were first treated with doxorubicin (or pirarubicin), vindesine and cyclophosphamide or cisplatin (or carboplatin). Twenty four patients received etoposide (orally at 50 or 100 mg per day for five to seven days at four-week intervals); the cumulative doses were < 2000 mg for seven patients, 2000-5000 mg for 10 and > 5000 mg for seven. The length of follow-up from the start of etoposide treatment ranged from 1 to 40 months. The cumulative risk for acute myeloid leukemia and myelodysplastic syndrome on the basis of three cases among the 119 patients was 9.1% (SE, 5.6%) 91-120 months after the operation. Two cases of acute myeloid leukemia and one of myelodysplastic syndrome developed in the subgroup of 24 patients who had received etoposide orally, and no cases occurred in the group that did not receive etoposide (p < 0.01; Fisher's exact test). The latency from start of etoposide treatment was 31 months, 25 months and seven months, and the cumulative doses of etoposide were 1750 mg, 11900 mg and 4550 mg, respectively.

Etoposide's production and use as an antineoplastic chemotherapy agent(1) may result in its release to the environment through various waste streams(SRC). Etoposide is expected to be released primarily to wastewater from the urinary excretion of patients using this medication(2).

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl etoposide and etoposide phosphate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

Antineoplastic

MEDICATION

Use (kg; approx.) in Germany (2009): >25

For use in combination with other chemotherapeutic agents in the treatment of refractory testicular tumors and as first line treatment in patients with small cell lung cancer. Also used to treat other malignancies such as lymphoma, non-lymphocytic leukemia, and glioblastoma multiforme.

... Semisynthetic glycoside derivative of podophyllotoxin.

Etoposide can be synthesized from naturally occurring podophyllotoxin by first treating the podophyllotoxin with hydrogen bromide to produce 1-bromo-1-deoxyepipodophyllotoxin, which is demethylated to 1-bromo-4'-demethylepipodophyllotoxin. The bromine is replaced by a hydroxy group, resulting in 4'-demethylepipodophyllotoxin. After protection of the phenolic hydroxyl, the 4-hydroxy group is coupled with 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranose. The protecting group at the 4'- hydroxy is removed by hydrogenolysis and the acyl groups by hydrolysis, and the cyclic O-4,6 acetal is formed by reaction with acetaldehyde dimethyl acetal.

Oral: Capsules, liquid-filled: 50 mg Etoposide Capsules, (Mylan), Vepesid (with parabens), (Bristol-Myers Squibb.

Parenteral: For injection concentrate, for IV infusion only: 20 mg/mL (100, 150, 200, 250, and 500 mg) Etoposide for Injection (with alcohol 30.5% v/v benzyl alcohol 3%), (Abbott, Bedford, GensiaSicor, SuperGen), Toposar, (Pfizer), VePesid, (with alcohol 30.5% v/v benzyl alcohol 3%), (Bristol-Myers Squibb); 20 mg/mL (1 g) pharmacy bulk package, Etoposide for Injection (with alcohol 30.5% and benzyl alcohol 3%), (Abbott, Bedford, GensiaSicor), VePesid (with alcohol 30.5% and benzyl alcohol 3%), (Bristol-Myers Squibb).

Etoposide Phosphate: Parenteral: For injection: 500 mg (of etoposide) pharmacy bulk package, Etopophos, (Bristol-Myers Squibb); 1 g (of etoposide ) pharmacy bulk package, Etopophos, (Bristol-Myers Squibb). For Injection, for IV infusion: 100 mg (of etoposide),Etopophos, (Bristol-Myers Squibb). /Etoposide phosphate/

Trade names for etoposide include Abiposid, Cehaposid, Celltop, Citodox, Eposin, Etocris, Etomedac, Etopol, Etoposid Ebewe, Etoposid Pharmacia Upjohn, Etoposid Austropharm, Etoposida Filaxis, Etoposid, Etoposide Dakota, Etoposide Injection, Etoposide P&U, Etoposide Pierre Fabre, Etoposido Asofarma, Etoposido Dakota Farma, Etoposido Farmitalia, Etosid Euvaxon, Exitop, Kebedil, Labimion, Lastet, Optasid, Toposar, VePesid and Vépéside-Sandoz.