Rx onlyETOPOPHOS (etoposide phosphate)for INJECTIONWARNINGS ETOPOPHOS (etoposide phosphate) for Injection should be administered under thesupervision of a qualified physician experienced in the use of cancer chemotherapeuticagents. Severe myelosuppression with resulting infection or bleeding may occur.DESCRIPTIONETOPOPHOS (etoposide phosphate) for Injection is an antineoplastic agent which isavailable for intravenous infusion as a sterile lyophile in single-dose vials containingetoposide phosphate equivalent to 100 mg etoposide, 32.7 mg sodium citrate USP, and300 mg dextran 40.Etoposide phosphate is a water soluble ester of etoposide (commonly known as VP-16), asemi-synthetic derivative of podophyllotoxin. The water solubility of etoposide phosphatelessens the potential for precipitation following dilution and during intravenousadministration.The chemical name for etoposide phosphate is:4'-Demethylepipodophyllotoxin dihydrogen phosphate).Reference ID: 29193601

Etoposide phosphate has the following structure:CLINICAL PHARMACOLOGYThe in vitro cytotoxicity observed for etoposide phosphate is significantly less than that seenwith etoposide which is believed due to the necessity for conversion in vivo to the activemoiety, etoposide, by dephosphorylation. The mechanism of action is believed to be thesame as that of etoposide. Etoposide has been shown to cause metaphase arrest in chickfibroblasts. Its main effect, however, appears to be at the G2 portion of the cell cycle inmammalian cells. Two different dose-dependent responses are seen. At high concentrations(10 μg/mL or more), lysis of cells entering mitosis is observed. At low concentrations (0.3 10 μg/mL), cells are inhibited from entering prophase. It does not interfere with microtubularassembly. The predominant macromolecular effect of etoposide appears to be the inductionof DNA strand breaks by an interaction with DNA-topoisomerase II or the formation of freeradicals.ETOPOPHOS BioequivalenceFollowing intravenous administration of ETOPOPHOS, etoposide phosphate is rapidly andcompletely converted to etoposide in plasma. A direct comparison of the pharmacokineticparameters [area under the concentration time curve (AUC) and the maximum plasmaconcentration (Cmax)] of etoposide following intravenous administration of molar equivalent doses of ETOPOPHOS and VePesid was made in two randomized crossover studies inpatients with a variety of malignancies. In the first study of 41 evaluable patients, theetoposide mean S.D. AUC values were 168.3 48.2 μg hr/mL and 156.7 43.4 μg hr/mL2following administration of molar equivalent doses of 150 mg/m ETOPOPHOS or VePesidReference ID: 29193602

with a 3.5-hour infusion time; the corresponding mean S.D. Cmax values were 20.0 3.7 μg/mL and 19.6 4.2 μg/mL, respectively. The point estimate (90% confidence interval)for the bioavailability of etoposide from ETOPOPHOS, relative to VePesid, was 107%(105%, 110%) for AUC and 103% (99%, 106%) for Cmax. In the second study of 292evaluable patients following intravenous administration of 90, 100, and 110 mg/m molarequivalents of ETOPOPHOS or VePesid with a 60-minute infusion time, the etoposide mean2 S.D. AUC values (normalized to the 100 mg/m dose) were 96.1 22.6 μg hr/mL and86.5 25.8 μg hr/mL, respectively; the corresponding mean S.D. Cmax values (normalized2to the 100 mg/m dose) were 20.1 4.1 μg/mL and 19.0 5.1 μg/mL, respectively. Thepoint estimate (90% confidence interval) for the bioavailability of etoposide fromETOPOPHOS, relative to VePesid, was 113% (107%, 119%) for AUC and 107% (101%,113%) for Cmax indicating bioequivalence. Results from both studies demonstrated nostatistically significant differences in the AUC and Cmax parameters for etoposide whenadministered as ETOPOPHOS or VePesid. In addition, in the latter study, there were nostatistically significant differences in the pharmacodynamic parameters (hematologictoxicity) after administration of ETOPOPHOS or VePesid. Following VePesidadministration, the mean nadir values (expressed as percent decrease from baseline) forleukocytes, granulocytes, hemoglobin, and thrombocytes were 67.2 17.0%, 84.1 14.6%,22.6 9.8%, and 46.4 21.9%, respectively; the corresponding values after administrationof ETOPOPHOS were 67.3 14.2%, 81.0 16.5%, 21.4 9.9%, and 44.1 20.7%,respectively.Because of the similarity of pharmacokinetics and pharmacodynamics of etoposide afteradministration of either ETOPOPHOS or VePesid, the following information on VePesidshould be considered:VePesid PharmacokineticsOn intravenous administration, the disposition of etoposide is best described as a biphasicprocess with a distribution half-life of about 1.5 hours and terminal elimination half-liferanging from 4 to 11 hours. Total body clearance values range from 33 to 48 mL/min or 162to 36 mL/min/m and, like the terminal elimination half-life, are independent of dose over a2range 100 to 600 mg/m . Over the same dose range, the AUC and the Cmax values increaselinearly with dose. Etoposide does not accumulate in the plasma following daily2administration of 100 mg/m for 4 to 5 days. After intravenous infusion the Cmax and AUCvalues exhibit marked intra- and inter-subject variability.Reference ID: 29193603

The mean volumes of distribution at steady state fall in the range of 18 to 29 liters or 7 to217 L/m . Etoposide enters the CSF poorly. Although it is detectable in CSF and intracerebraltumors, the concentrations are lower than in extracerebral tumors and in plasma. Etoposideconcentrations are higher in normal lung than in lung metastases and are similar in primarytumors 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 andetoposide renal clearance is found in children. In a study determining the effect of othertherapeutic agents on the in vitro binding of carbon-14 labeled etoposide to human serumproteins, only phenylbutazone, sodium salicylate, and aspirin displaced protein-boundetoposide at concentrations achieved in vivo.Etoposide binding ratio correlates directly with serum albumin in patients with cancer and innormal volunteers. The unbound fraction of etoposide significantly correlated with bilirubinin a population of cancer patients. Data have suggested a significant inverse correlationbetween serum albumin concentration and free fraction of etoposide (see PRECAUTIONS).After intravenous administration of142C-etoposide (100-124 mg/m ), mean recovery ofradioactivity in the urine was 56% of the dose at 120 hours, 45% of which was excreted asetoposide; fecal recovery of radioactivity was 44% of the dose at 120 hours.In children, approximately 55% of the dose of VePesid is excreted in the urine as etoposide2in 24 hours. The mean renal clearance of etoposide is 7 to 10 mL/min/m or 35% of the total2body clearance over a dose of 80 to 600 mg/m . Etoposide, therefore, is cleared by both renaland nonrenal processes, i.e., metabolism and biliary excretion. The effect of renal disease onplasma etoposide clearance is not known in children.Biliary excretion of unchanged drug and/or metabolites is an important route of etoposideelimination as fecal recovery of radioactivity is 44% of the intravenous dose. The hydroxyacid metabolite [4'-demethylepipodophyllic acid-9-(4,6-O-(R)-ethylidene-β-D-gluco pyranoside)], formed by opening of the lactone ring, is found in the urine of adults andchildren. It is also present in human plasma, presumably as the trans isomer. Glucuronideand/or sulfate conjugates of etoposide are also excreted in human urine. Only 8% or less of14an intravenous dose is excreted in the urine as radiolabeled metabolites of C-etoposide. Inaddition, O-demethylation of the dimethoxyphenol ring occurs through the CYP450 3A4isoenzyme pathway to produce the corresponding catechol.In adults, the total body clearance of etoposide is correlated with creatinine clearance, serumalbumin concentration, and nonrenal clearance. Patients with impaired renal functionReference ID: 29193604

receiving etoposide have exhibited reduced total body clearance, increased AUC, and alower volume of distribution at steady state (see PRECAUTIONS). Use of cisplatin therapyis associated with reduced total body clearance. In children, elevated serum SGPT levels areassociated with reduced drug total body clearance. Prior use of cisplatin may also result in adecrease of etoposide total body clearance in children.Although some minor differences in pharmacokinetic parameters between age and genderhave been observed, these differences were not considered clinically significant.Clinical StudiesA total of seven clinical trials with 365 patients treated (368 entered) provide the databasefor the human experience summarized in this insert. Five phase I trials evaluated etoposidephosphate given on a days 1, 3, and 5 or days 1 through 5 schedule. In two trials the drugwas given over 5 minutes and in three over 30 minutes. The following table summarizes thedoses, schedules, infusion times, and numbers of patients entered in the phase I experience.Dose Escalation (Phase I) Trials of Etoposide PhosphateStudyScheduleQ 21 daysInfusionTimeDose Range2(mg/m )Number ofPatientsEntered002Days 1-530 minutes25-11068005Days 1,3,530 minutes50-17539006Days 1-530 minutes50-12528008Days 1,3,55 minutes50-20036009Days 1-55 minutes50-12527Two trials evaluated the pharmacokinetic equivalence of etoposide and etoposide phosphate.A phase I study (002) was expanded at the higher doses to compare the pharmacokineticprofile of etoposide following administration of etoposide or etoposide phosphate. Another2multi-institutional trial (012) was conducted at a dose of 150 mg/m using a day 1, 3, and 5schedule and a crossover design.The seventh trial (011) was a randomized study in which patients with limited or extensivesmall cell lung cancer and no prior therapy were treated with either cisplatin plus etoposide2or cisplatin plus etoposide phosphate. Patients received 20 mg/m /day of cisplatin for 5 days2and 80 mg/m /day of etoposide or etoposide phosphate. A total of 121 patients wererandomized and 120 treated (60 per group). Response rates, time to response, duration ofresponse, time to progression, time to worsening performance status, and survival wereReference ID: 29193605

similar in the two groups whether the analysis was done for patients with limited orextensive disease or for the entire population. The following table summarizes the resultsregardless of disease extent.Response to Treatment for All PatientsComplete Responses:Partial Responses:Overall Response Rate:Median Time to Response:Median Response Duration:Median Time to Progression:Median Time to WorseningPerformance Status:Median Survival:Etoposide Phosphateplus CisplatinEtoposideplus CisplatinP-value15%46%61%48 days273 days211 days15%43%58%46 days241 days213 days1.000*0.855*0.854*0.596**0.141***0.500***210 days348 days149 days318 days0.472***0.780****Fisher's Exact test**Wilcoxon Rank Sum test***Logrank testThe most prominent side effects were myelosuppression and GI toxicity. Sixty-eight percent3of patients treated with etoposide phosphate plus cisplatin had neutrophils less than 500/mmat some time during treatment as did 88% of those getting etoposide and cisplatin. Over 85%in each group had nausea and/or vomiting. No differences in the pattern or severity of sideeffects were observed.INDICATIONS AND USAGEETOPOPHOS for Injection is indicated in the management of the following neoplasms:Refractory Testicular Tumors-ETOPOPHOS for Injection in combination therapy withother approved chemotherapeutic agents in patients with refractory testicular tumors whohave already received appropriate surgical, chemotherapeutic, and radiotherapeutic therapy.Small Cell Lung Cancer-ETOPOPHOS for Injection in combination with other approvedchemotherapeutic agents as first-line treatment in patients with small cell lung cancer.CONTRAINDICATIONSETOPOPHOS for Injection is contraindicated in patients who have demonstrated a previoushypersensitivity to etoposide, etoposide phosphate, or any other component of theformulations.Reference ID: 29193606

WARNINGSPatients being treated with ETOPOPHOS must be frequently observed for myelosuppressionboth during and after therapy. Myelosuppression resulting in death has been reportedfollowing etoposide administration. Dose-limiting bone marrow suppression is the mostsignificant toxicity associated with ETOPOPHOS therapy. Therefore, the following studiesshould be obtained at the start of therapy and prior to each subsequent cycle ofETOPOPHOS: platelet count, hemoglobin, white blood cell count, and differential. The3occurrence of a platelet count below 50,000/mm or an absolute neutrophil count below3500/mm is an indication to withhold further therapy until the blood counts have sufficientlyrecovered. The toxicity of rapidly infused ETOPOPHOS in patients with impaired renal orhepatic function has not been adequately evaluated. The toxicity profile of ETOPOPHOS2when infused at doses 175 mg/m has not been delineated.Physicians should be aware of the possible occurrence of an anaphylactic reactionmanifested by chills, fever, tachycardia, bronchospasm, dyspnea, and hypotension. Higherrates of anaphylactic-like reactions have been reported in children who received infusions ofetoposide at concentrations higher than those recommended. The role that concentration ofinfusion (or rate of infusion) plays in the development of anaphylactic-like reactions isuncertain. (See ADVERSE REACTIONS.) Treatment is symptomatic. The infusion shouldbe terminated immediately, followed by the administration of pressor agents, corticosteroids,antihistamines, or volume expanders at the discretion of the physician.Injection site reactions may occur during the administration of ETOPOPHOS (seeADVERSE REACTIONS). Closely monitor the infusion site for possible infiltration duringdrug administration. No specific treatment for extravasation reactions is known.ETOPOPHOS can cause fetal harm when administered to a pregnant woman. Etoposide hasbeen shown to be teratogenic in mice and rats, and it is therefore likely that ETOPOPHOS isalso teratogenic.In rats, an intravenous etoposide dose of 0.4 mg/kg/day (about 1/20 of the human dose on a2mg/mbasis) during organogenesis caused maternal toxicity, embryotoxicity, andteratogenicity (skeletal abnormalities, exencephaly, encephalocele, and anophthalmia);2higher doses of 1.2 and 3.6 mg/kg/day (about 1/7 and 1/2 of the human dose on a mg/mbasis) resulted in 90% and 100% embryonic resorptions. In mice, a single 1.0 mg/kg (1/16 of2the human dose on a mg/m basis) dose of etoposide administered intraperitoneally on daysReference ID: 29193607

6, 7, or 8 of gestation caused embryotoxicity, cranial abnormalities, and major skeletalmalformations. An intraperitoneal dose of 1.5 mg/kg (about 1/10 of the human dose on a2mg/m basis) on day 7 of gestation caused an increase in the incidence of intrauterine deathand fetal malformations and a significant decrease in the average fetal body weight.If this drug is used during pregnancy, or if the patient becomes pregnant while receiving thisdrug, the patient should be warned of the potential hazard to the fetus. Women ofchildbearing potential should be advised to avoid becoming pregnant.ETOPOPHOS should be considered a potential carcinogen in humans. The occurrence ofacute leukemia with or without a preleukemic phase has been reported in rare instances inpatients treated with etoposide alone or in association with other neoplastic agents. The riskof development of a preleukemic or leukemic syndrome is unclear. Carcinogenicity testswith ETOPOPHOS have not been conducted in laboratory animals.PRECAUTIONSGeneralIn all instances where the use of ETOPOPHOS is considered for chemotherapy, thephysician must evaluate the need and usefulness of the drug against the risk of adversereactions. Most such adverse reactions are reversible if detected early. If severe reactionsoccur, the drug should be reduced in dosage or discontinued and appropriate correctivemeasures should be taken according to the clinical judgement of the physician. Reinstitutionof ETOPOPHOS therapy should be carried out with caution, and with adequateconsideration of the further need for the drug and alertness as to possible recurrence oftoxicity.Patients with low serum albumin may be at an increased risk for etoposide associatedtoxicities.Drug InteractionsCaution should be exercised when administering ETOPOPHOS with drugs that are known toinhibit phosphatase activities (e.g., levamisole hydrochloride). High-dose cyclosporin Aresulting in concentrations above 2000 ng/mL administered with oral etoposide has led to an80% increase in etoposide exposure with a 38% decrease in total body clearance of etoposidecompared to etoposide alone.Reference ID: 29193608

Laboratory TestsPeriodic complete blood counts should be done during the course of ETOPOPHOStreatment. They should be performed prior to each cycle of therapy and at appropriateintervals during and after therapy.Renal ImpairmentIn patients with impaired renal function, the following initial dose modification should beconsidered based on measured creatinine clearance:MeasuredCreatinine Clearance 50 mL/min15-50 mL/minetoposide100% of dose75% of doseSubsequent etoposide dosing should be based on patient tolerance and clinical effect.Equivalent dose adjustments of ETOPOPHOS should be used.Data are not available in patients with creatinine clearances 15 mL/min and further dosereduction should be considered in these patients.Carcinogenesis (see WARNINGS), Mutagenesis, Impairment ofFertilityETOPOPHOS was non-mutagenic in in vitro Ames microbial mutagenicity assay and theE. coli WP2 uvrA reverse mutation assay. Since ETOPOPHOS is rapidly and completelyconverted to etoposide in vivo and etoposide has been shown to be mutagenic in Ames assay,ETOPOPHOS should be considered as a potential mutagen in vivo.In rats, an oral dose of ETOPOPHOS at 86.0 mg/kg/day (about 10 times the human dose on2a mg/m basis) or above administered for 5 consecutive days resulted in irreversibletesticular atrophy. Irreversible testicular atrophy was also present in rats treated withETOPOPHOS intravenously for 30 days at 5.11 mg/kg/day (about 1/2 of the human dose on2a mg/m basis).PregnancyPregnancy Category D. (See WARNINGS.)Reference ID: 29193609

Nursing MothersIt is not known whether this drug is excreted in human milk. Because many drugs areexcreted in human milk and because of the potential for serious adverse reactions in nursinginfants from ETOPOPHOS, a decision should be made whether to discontinue nursing or todiscontinue the drug, taking into account the importance of the drug to the mother.Pediatric UseSafety and effectiveness in pediatric patients have not been established. Anaphylacticreactions have been reported in pediatric patients who received etoposide (seeWARNINGS).Geriatric UseClinical studies of etoposide for the treatment of refractory testicular tumors did not includesufficient numbers of patients aged 65 years and over to determine whether they responddifferently from younger patients. Of more than 600 patients in four clinical studies in theNDA databases who received ETOPOPHOS or etoposide in combination with otherchemotherapeutic agents for the treatment of small cell lung cancer, about one third wereolder than 65 years. When advanced age was determined to be a prognostic factor forresponse or survival in these studies, comparisons between treatment groups were performedfor the elderly subset. In the one study (etoposide in combination with cyclophosphamideand vincristine compared with cyclophosphamide and vincristine or cyclophosphamide,vincristine, and doxorubicin) where age was a significant prognostic factor for survival, asurvival benefit for elderly patients was observed for the etoposide regimen compared withthe control regimens. No differences in myelosuppression were seen between elderly andyounger patients in these studies except for an increased frequency of WHO Grade III or IVleukopenia among elderly patients in a study of etoposide phosphate or etoposide incombination with cisplatin. Elderly patients in this study also had more anorexia, mucositis,dehydration, somnolence, and elevated BUN levels than younger patients.In five single-agent studies of etoposide phosphate in patients with a variety of tumor types,34% of patients were aged 65 years or more. WHO Grade III or IV leukopenia,granulocytopenia, and asthenia were more frequent among elderly patients.Postmarketing experience also suggests that elderly patients may be more sensitive to someof the known adverse effects of etoposide, including myelosuppression, gastrointestinaleffects, infectious complications, and alopecia.Reference ID: 291936010

Although some minor differences in pharmacokinetic parameters between elderly and nonelderly patients have been observed, these differences were not considered clinicallysignificant.Etoposide and its metabolites are known to be substantially excreted by the kidney, and therisk of adverse reactions to ETOPOPHOS may be greater in patients with impaired renalfunction. Because elderly patients are more likely to have decreased renal function, careshould be taken in dose selection, and it may be useful to monitor renal function (seePRECAUTIONS: Renal Impairment, for recommended dosing adjustments in patientswith renal impairment).ADVERSE REACTIONSETOPOPHOS has been found to be well tolerated as a single agent in clinical studiesinvolving 206 patients with a wide variety of malignancies, and in combination withcisplatin in 60 patients with small cell lung cancer. The most frequent clinically significantadverse experiences were leukopenia and neutropenia.The incidences of adverse experiences in the table that follows are derived from studies inwhich ETOPOPHOS was administered as a single agent. A total of 98 patients received total2doses at or above 450 mg/m on a 5 consecutive day or day 1, 3, and 5 schedule during thefirst course of therapy.Reference ID: 291936011

Summary of Adverse Events Reported With Single-Agent ETOPOPHOS Following Course 1 at2Total Five Day Doses of 450 mg/mPercent of PatientsHematologic a 4000/mm3 1000/mm3 2000/mm3 500/mm3 100,000/mm3 50,000/mm3 11 g/dL 8 g/dL911788372397219Gastrointestinal toxicityNausea and/or vomitingAnorexiaMucositisConstipationAbdominal PainDiarrheaTaste Alteration3716118766Asthenia/MalaiseAlopeciaChills and/or FeverDizzinessExtravasation/Phlebitis39332455Since etoposide phosphate is converted to etoposide, those adverse experiences that areassociated with VePesid can be expected to occur with ETOPOPHOS.Hematologic ToxicityMyelosuppression after ETOPOPHOS administration is dose related and dose limiting withthe leukocyte nadir counts occurring from day 15 to day 22 after initiation of drug therapy,granulocyte nadir counts occurring day 12 to 19 after initiation of drug therapy, and plateletnadirs occurring from day 10 to 15. Bone marrow recovery usually occurs by day 21 but maybe delayed, and no cumulative toxicity has been reported. Fever and infection have also beenreported in patients with neutropenia. Death associated with myelosuppression has beenreported following etoposide administration.Reference ID: 291936012

Gastrointestinal ToxicityNausea and vomiting are the major gastrointestinal toxicities. The severity of such nauseaand vomiting is generally mild to moderate with treatment discontinuation required in 1% ofpatients. Nausea and vomiting can usually be controlled with standard antiemetic therapy.Blood Pressure ChangesIn clinical studies, 151 patients were treated with ETOPOPHOS with infusion times rangingfrom 30 minutes to 3.5 hours. Sixty-three patients received ETOPOPHOS as a 5-minutebolus infusion. Four patients experienced one or more episodes of hypertension and eightpatients experienced one or more episodes of hypotension, which may or may not be drugrelated. One episode of hypotension was reported among those patients who received a5-minute bolus infusion. If clinically significant hypotension or hypertension occurs withETOPOPHOS, appropriate supportive therapy should be initiated.Allergic ReactionsAnaphylactic-type reactions characterized by chills, rigors, tachycardia, bronchospasm,dyspnea, diaphoresis, fever, pruritus, hypertension or hypotension, loss of consciousness,nausea, and vomiting have been reported to occur in 3% (7/245) of all patients treated withETOPOPHOS. Facial flushing was reported in 2% and skin rashes in 3% of patientsreceiving ETOPOPHOS. These reactions have usually responded promptly to the cessationof the infusion and administration of pressor agents, corticosteroids, antihistamines, orvolume expanders as appropriate; however, the reactions can be fatal. Hypertension and/orflushing have also been reported. Blood pressure usually normalizes within a few hours aftercessation of the initial infusion.Anaphylactic-like reactions have occurred during the initial infusion of ETOPOPHOS (seeWARNINGS). Facial/tongue swelling, coughing, diaphoresis, cyanosis, tightness in throat,laryngospasm, back pain, and/or loss of consciousness have sometimes occurred inassociation with the above reactions. In addition, an apparent hypersensitivity-associatedapnea has been reported.Rash, urticaria, and/or pruritus have been reported at recommended doses. At investigationaldoses, a generalized pruritic erythematous maculopapular rash, consistent with perivasculitis,has been reported.Reference ID: 291936013

AlopeciaReversible alopecia, sometimes progressing to total baldness, was observed in up to 44% ofpatients.Other ToxicitiesThe following adverse reactions have been reported: abdominal pain, aftertaste, constipation,dysphagia, fever, transient cortical blindness, interstitial pneumonitis/pulmonary fibrosis,optic neuritis, pigmentation, seizure (occasionally associated with allergic reactions),Stevens-Johnson syndrome, toxic epidermal necrolysis, and radiation recall dermatitis.Hepatic toxicity may be seen.Local soft tissue toxicity has been reported following extravasation of ETOPOPHOS.Infiltration of ETOPOPHOS may result in swelling, pain, cellulitis, and necrosis includingskin necrosis.The incidences of adverse reactions in the table that follows are derived from multipledatabases from studies in 2081 patients when VePesid was used either orally or by injectionas a single agent.Adverse Drug Effects Observed With Single-Agent VePesidPercent Range of ReportedIncidenceHematologic toxicityLeukopenia ( 1000/mm3)Leukopenia ( 4000/mm3)Thrombocytopenia ( 50,000/mm3)Thrombocytopenia ( stinal toxicityNausea and vomitingAbdominal 1-131-60-3AlopeciaPeripheral neurotoxicityHypotensionAllergic Reaction8-661-21-21-2Reference ID: 291936014

OVERDOSAGENo proven antidotes have been established for ETOPOPHOS overdosage in humans. Inmice, a single intravenous dose of rapidly administered ETOPOPHOS was lethal at or above2120 mg/kg (about 7 times human dose on a mg/m basis) and was associated with clinicalsigns of neurotoxicity.DOSAGE AND ADMINISTRATIONThe usual dose of VePesid for Injection in testicular cancer in combination with other2approved chemotherapeutic agents ranges from 50 to 100 mg/m /day on days 1 through 5 to2100 mg/m /day on days 1, 3, and 5. Equivalent doses of ETOPOPHOS should be used.In small cell lung cancer, the VePesid for Injection dose in combination with other approved22chemotherapeutic drugs ranges from 35 mg/m /day for 4 days to 50 mg/m /day for 5 days.Equivalent doses of ETOPOPHOS should be used.For recommended dosing adjustments in patients with renal impairment, seePRECAUTIONS.ETOPOPHOS SHOULD NOT BE GIVEN BY BOLUS INTRAVENOUS INJECTION.ETOPOPHOS solutions may be administered at infusion rates from 5 to 210 minutes.Chemotherapy courses are repeated at 3- to 4-week intervals after adequate recovery fromany toxicity.The dosage should be modified to take into account the myelosuppressive effect of otherdrugs in the combination or the effects of prior x-ray therapy or chemotherapy which mayhave compromised bone marrow reserve.Administration PrecautionsAs with other potentially toxic compounds, caution should be exercised in handling andpreparing the solution of ETOPOPHOS. Skin reactions associated with accidental exposureto ETOPOPHOS may occur. The use of gloves is recommended. If ETOPOPHOS solutioncontacts the skin or mucosa, immediately and thoroughly wash the skin with soap and waterand flush the mucosa with water.Preparation for Intravenous AdministrationReference ID: 291936015

Prior to use, the content of each vial must be reconstituted with Sterile Water for Injection,USP; 5% Dextrose Injection, USP; 0.9% Sodium Chloride Injection, USP; BacteriostaticWater for Injection with Benzyl Alcohol; or Bacteriostatic Sodium Chloride for Injectionwith Benzyl Alcohol to a concentration equivalent to 20 mg/mL or 10 mg/mL etoposide(22.7 or 11.4 mg/mL etoposide phosphate, respectively). Use the quantity of diluent shownbelow to reconstitute the product.Vial Strength100 mgVolume of Diluent5 mL10 mLFinal Concentration20 mg/mL10 mg/mLFollowing reconstitution, ETOPOPHOS can be further diluted to concentrations as low as0.1 mg/mL etoposide with either 5% Dextrose Injection, USP or 0.9% Sodium ChlorideInjection, USP.Solutions of ETOPOPHOS should be prepared in an aseptic manner. Parenteral drugproducts should be inspected visually for particulate matter and discoloration prior toadministration whenever solution and container permit.StabilityUnopened vials of

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 p