that concentration of infusion (or rate of infusion) plays in the development of anaphylactic-like reactions is uncertain. (see adverse reactions .) treatment is symptomatic. the infusion should be terminated immediately, followed by the administration of pressor agents, corticosteroids, antihistamines, or volume expanders at the discretion of the physician. for parenteral administration, etoposide should be given only by slow intravenous infusion (usually over a 30- to 60-minute period), since hypotension has been reported as a possible side effect of rapid intravenous injection. pregnancy teratogenic effects: pregnancy category d etoposide can cause fetal harm when administered to a pregnant woman. etoposide has been shown to be teratogenic in mice and rats. in rats, an intravenous etoposide dose of 0.4 mg/kg/day (about 1/20th of the human dose on a mg/m 2 basis) during organogenesis caused maternal toxicity, embryotoxicity, and teratogenicity (skeletal abnormalitites, exencephaly, encephalocele, and anophthalmia); higher doses of 1.2 and 3.6 mg/kg/day (about 1/7th and 1/2 of human dose on a mg/m 2 basis) resulted in 90 and 100% embryonic resorptions. in mice, a single 1 mg/kg (1/16th of human dose on a mg/m 2 basis) dose of etoposide administered intraperitoneally on days 6,7, or 8 of gestation caused embyotoxicity, cranial abnormalities, and major skeletal malformations. an ip dose of 1.5 mg/kg (about 1/10th of human dose on a mg/m 2 basis) on day 7 of gestation caused an increase in the incidence of intrauterine death and fetal malformations and a significant decrease in the average fetal body weight. women of childbearing potential should be advised to avoid becoming pregnant. if this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. etoposide should be considered a potential carcinogen in humans. the occurrence of acute leukemia with or without a preleukemic phase has been reported in rare instances in patients treated with etoposide alone or in association with other neoplastic agents. the risk of development of a preleukemic or leukemic syndrome is unclear. carcinogenicity tests with etoposide have not been conducted in laboratory animals.

ve compromised bone marrow reserve. administration precautions as with other potentially toxic compounds, caution should be exercised in handling and preparing the solution of etoposide. skin reactions associated with accidental exposure to etoposide may occur. the use of gloves is recommended. if etoposide solution contacts the skin or mucosa, immediately and thoroughly wash the skin with soap and water and flush the mucosa with water. preparation for intravenous administration etoposide injection must be diluted prior to use with either 5% dextrose injection, or 0.9% sodium chloride injection, to give a final concentration of 0.2 to 0.4 mg/ml. if solutions are prepared at concentrations above 0.4 mg/ml, precipitation may occur. hypotension following rapid intravenous administration has been reported; hence, it is recommended that the etoposide solution be administered over a 30- to 60-minute period. a longer duration of administration may be used if the volume of fluid to be infused is a concern. etoposide should not be given by rapid intravenous injection. parenteral drug products should be inspected visually for particulate matter and discoloration (see description ) prior to administration whenever solution and container permit. stability unopened vials of etoposide injection are stable for 24 months at room temperature (25°c). vials diluted as recommended to a concentration of 0.2 or 0.4 mg/ml are stable for 96 and 24 hours, respectively, at room temperature (25°c) under normal room fluorescent light in both glass and plastic containers. procedures for proper handling and disposal of anticancer drugs should be considered. several guidelines on this subject have been published. 1-8 there is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

y mild to moderate with treatment discontinuation required in 1% of patients. nausea and vomiting can usually be controlled with standard antiemetic therapy. mild to severe mucositis/esophagitis may occur. gastrointestinal toxicities are slightly more frequent after oral administration than after intravenous infusion. hypotension transient hypotension following rapid intravenous administration has been reported in 1% to 2% of patients. it has not been associated with cardiac toxicity or electrocardiographic changes. no delayed hypotension has been noted. to prevent this rare occurrence, it is recommended that etoposide be administered by slow intravenous infusion over a 30- to 60-minute period. if hypotension occurs, it usually responds to cessation of the infusion administration of fluids or other supportive therapy as appropriate. when restarting the infusion, a slower administration rate should be used. allergic reactions anaphylactic-like reactions characterized by chills, fever, tachycardia, bronchospasm, dyspnea, and/or hypotension have been reported to occur in 0.7% to 2% of patients receiving intravenous etoposide and in less than 1% of the patients treated with oral capsules. these reactions have usually responded promptly to the cessation of the infusion and administration of pressor agents, corticosteroids, antihistamines, or volume expanders as appropriate; however, the reactions can be fatal. hypertension and/or flushing have also been reported. blood pressure usually normalizes within a few hours after cessation of the infusion. anaphylactic-like reactions have occurred during the initial infusion of etoposide. facial/tongue swelling, coughing, diaphoresis, cyanosis, tightness in throat, laryngospasm, back pain, and/or loss of consciousness have sometimes occurred in association with the above reactions. in addition, an apparent hypersensitivity-associated apnea has been reported rarely. rash, urticaria, and/or pruritus have infrequently been reported at recommended doses. at investigational doses, a generalized pruritic erythematous maculopapular rash, consistent with perivasculitis, has been reported. alopecia reversible alopecia, sometimes progressing to total baldness was observed in up to 66% of patients. other toxicities the following adverse reactions have been infrequently reported: abdominal pain, aftertaste, constipation, dysphagia, asthenia, fatigue, malaise, somnolence, transient cortical blindness, optic neuritis, interstitial pneumonitis/pulmonary fibrosis, fever, seizure (occasionally associated with allergic reactions), stevens-johnson syndrome, and toxic epidermal necrolysis, pigmentation, and a single report of radiation recall dermatitis. hepatic toxicity, generally in patients receiving higher doses of the drug than those recommended, has been reported with etoposide. metabolic acidosis has also been reported in patients receiving higher doses. reports of extravasation with swelling have been received postmarketing. rarely extravasation has been associated with necrosis and venous induration. the incidences of adverse reactions in the table that follows are derived from multiple databases from studies in 2,081 patients when etoposide was used either orally or by injection as a single agent. adverse drug effect percent range of reported incidence hematologic toxicity leukopenia (less than 1,000 wbc/mm 3 ) 3 to 17 leukopenia (less than 4,000 wbc/mm 3 ) 60 to 91 thrombocytopenia (less than 50,000 platelets/mm 3 ) 1 to 20 thrombocytopenia (less than 100,000 platelets/mm 3 ) 22 to 41 anemia 0 to 33 gastrointestinal toxicity nausea and vomiting 31 to 43 abdominal pain 0 to 2 anorexia 10 to 13 diarrhea 1 to 13 stomatitis 1 to 6 hepatic 0 to 3 alopecia 8 to 66 peripheral neurotoxicity 1 to 2 hypotension 1 to 2 allergic reaction 1 to 2

nt decrease in the average fetal body weight. women of childbearing potential should be advised to avoid becoming pregnant. if this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. etoposide should be considered a potential carcinogen in humans. the occurrence of acute leukemia with or without a preleukemic phase has been reported in rare instances in patients treated with etoposide alone or in association with other neoplastic agents. the risk of development of a preleukemic or leukemic syndrome is unclear. carcinogenicity tests with etoposide have not been conducted in laboratory animals.

independent of dose over a range of 100 to 600 mg/m 2 . over the same dose range, the areas under the plasma concentration vs. time curves (auc) and the maximum plasma concentration (cmax) values increase linearly with dose. etoposide does not accumulate in the plasma following daily administration of 100 mg/m 2 for 4 to 5 days. the mean volumes of distribution at steady state fall in the range of 18 to 29 liters or 7 to 17 l/m 2 . etoposide enters the csf poorly. although it is detectable in csf and intracerebral tumors, the concentrations are lower than in extracerebral tumors and in plasma. etoposide concentrations are higher in normal lung than in lung metastases and are similar in primary tumors and normal tissues of the myometrium. in vitro , etoposide is highly protein bound (97%) to human plasma proteins. an inverse relationship between plasma albumin levels and etoposide renal clearance is found in children. in a study determining the effect of other therapeutic agents on the in vitro binding of carbon-14 labeled etoposide to human serum proteins, only phenylbutazone, sodium salicylate, and aspirin displaced protein-bound etoposide at concentrations achieved in vivo . etoposide binding ratio correlates directly with serum albumin in patients with cancer and in normal volunteers. the unbound fraction of etoposide significantly correlated with bilirubin in a population of cancer patients. data have suggested a significant inverse correlation between serum albumin concentration and free fraction of etoposide. (see precautions .) after intravenous administration of 14 c-etoposide (100 to 124 mg/m 2 ), mean recovery of radioactivity in the urine was 56% of the dose at 120 hours, 45% of which was excreted as etoposide: fecal recovery of radioactivity was 44% of the dose at 120 hours. in children, approximately 55% of the dose is excreted in the urine as etoposide in 24 hours. the mean renal clearance of etoposide is 7 to 10 ml/min/m 2 or about 35% of the total body clearance over a dose range of 80 to 600 mg/m 2 . etoposide, therefore, is cleared by both renal and nonrenal processes, i.e., metabolism and biliary excretion. the effect of renal disease on plasma etoposide clearance is not known. biliary excretion of unchanged drug and/or metabolites is an important route of etoposide elimination as fecal recovery of radioactivity is 44% of the intravenous dose. the hydroxy acid metabolite [4’-demethylepipodophyllic acid-9-(4,6-0-(r)-ethylidene-β-d-glucopyranoside)], formed by opening of the lactone ring, is found in the urine of adults and children. it is also present in human plasma, presumably as the trans isomer. glucuronide and/or sulfate conjugates of etoposide are also excreted in human urine. only 8% or less of an intravenous dose is excreted in the urine as radiolabeled metabolites of 14 c-etoposide. in addition, 0-demethyulation of the dimethoxyphenol ring occurs through the cyp450 3a4 isoenzyme pathway to produce the corresponding catechol. after intravenous infusion, the cmax and auc values exhibit marked intra- and inter-subject variability. there is no evidence of a first-pass effect for etoposide. for example, no correlation exists between the absolute oral bioavailability of etoposide capsules and nonrenal clearance. no evidence exists for any other differences in etoposide metabolism and excretion after administration of oral capsules as compared to intravenous infusion. in adults, the total body clearance of etoposide is correlated with creatinine clearance, serum albumin concentration, and nonrenal clearance. patients with impaired renal function receiving etoposide have exhibited reduced total body clearance, increased auc and a lower volume of distribution at steady state. (see precautions .) use of cisplatin therapy is associated with reduced total body clearance. in children, elevated serum sgpt levels are associated with reduced drug total body clearance. prior use of cisplatin may also result in a decrease of etoposide total body clearance in children. although some minor differences in pharmacokinetic parameters between age and gender have been observed, these differences were not considered clinically significant.