ETOPOPHOS (etoposide phosphate) for Injection is an antineoplastic agent which is available for intravenous infusion as a sterile lyophile in single-dose vials containing etoposide phosphate equivalent to 100 mg etoposide, 32.7 mg sodium citrate USP, and 300 mg dextran 40.

Etoposide phosphate is a water soluble ester of etoposide (commonly known as VP-16), a semi-synthetic derivative of podophyllotoxin. The water solubility of etoposide phosphate lessens the potential for precipitation following dilution and during intravenous administration.

The chemical name for etoposide phosphate is:

4'-Demethylepipodophyllotoxin 9-[4,6-O-(R)-ethylidene-β-D-glucopyranoside], 4'-(dihydrogen phosphate).

Etoposide phosphate has the following structure:

ETOPOPHOS for Injection is indicated in the management of the following neoplasms:

Refractory Testicular Tumors-ETOPOPHOS for Injection in combination therapy with other approved chemotherapeutic agents in patients with refractory testicular tumors who have already received appropriate surgical, chemotherapeutic, and radiotherapeutic therapy.

Small Cell Lung Cancer-ETOPOPHOS for Injection in combination with other approved chemotherapeutic agents as first-line treatment in patients with small cell lung cancer.

The usual dose of VePesid for Injection in testicular cancer in combination with other approved chemotherapeutic agents ranges from 50 to 100 mg/m²/day on days 1 through 5 to 100 mg/m²/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 approved chemotherapeutic drugs ranges from 35 mg/m²/day for 4 days to 50 mg/m²/day for 5 days. Equivalent doses of ETOPOPHOS should be used.

For recommended dosing adjustments in patients with renal impairment, see PRECAUTIONS.

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 from any toxicity.

The dosage should be modified to take into account the myelosuppressive effect of other drugs in the combination or the effects of prior x-ray therapy or chemotherapy which may have compromised bone marrow reserve.

Administration Precautions

As with other potentially toxic compounds, caution should be exercised in handling and preparing the solution of ETOPOPHOS. Skin reactions associated with accidental exposure to ETOPOPHOS may occur. The use of gloves is recommended. If ETOPOPHOS 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

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; Bacteriostatic Water for Injection with Benzyl Alcohol; or Bacteriostatic Sodium Chloride for Injection with Benzyl Alcohol to a concentration equivalent to 20 mg/mL or 10 mg/mL etoposide (22.7 mg/mL or 11.4 mg/mL etoposide phosphate, respectively). Use the quantity of diluent shown below to reconstitute the product.

Following reconstitution, ETOPOPHOS can be further diluted to concentrations as low as 0.1 mg/mL etoposide with either 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP.

Solutions of ETOPOPHOS should be prepared in an aseptic manner. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Stability

Unopened vials of ETOPOPHOS for Injection are stable until the date indicated on the package when stored under refrigeration 2°-8°C (36°-46°F) in the original package. When reconstituted as directed, ETOPOPHOS solutions can be stored in glass or plastic containers under refrigeration 2°-8°C (36°-46°F) for 7 days; at controlled room temperature 20°-25°C (68°-77°F) for 24 hours following reconstitution with Sterile Water for Injection, USP, 5% Dextrose Injection, USP, or 0.9% Sodium Chloride Injection, USP; or at controlled room temperature 20°-25°C (68°-77°F) for 48 hours following reconstitution with Bacteriostatic Water for Injection with Benzyl Alcohol or Bacteriostatic Sodium Chloride for Injection with Benzyl Alcohol. ETOPOPHOS solutions further diluted as directed can be stored under refrigeration 2°-8°C (36°-46°F) or at controlled room temperature 20°-25°C (68°-77°F) for 24 hours.

ETOPOPHOS (etoposide phosphate) for Injection is supplied as individual cartoned vials with white flip-off seals containing etoposide phosphate equivalent to 100 mg etoposide:

NDC 0015-3404-20 100 mg single-dose vial

Storage

Store the unopened vials under refrigeration 2°-8°C (36°-46°F). Retain in original package to protect from light.

Handling and Disposal

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.

To minimize the risk of dermal exposure, always wear impervious gloves when handling vials containing ETOPOPHOS for Injection. This includes all handling activities in clinical settings, pharmacies, storerooms, and home healthcare settings, including during unpacking and inspection, transport within a facility, and dose preparation and administration.

REFERENCES

1. ONS Clinical Practice Committee. Cancer Chemotherapy Guidelines and Recommendations for Practice Pittsburgh, PA: Oncology Nursing Society; 1999:32-41.

2. Recommendations for the safe handling of parenteral antineoplastic drugs. Washington, DC: Division of Safety, National Institutes of Health; 1983. US Dept of Health and Human Services, Public Health Service publication NIH 83-2621.

3. AMA Council on Scientific Affairs. Guidelines for handling parenteral antineoplastics. JAMA.1985;253:1590-1591.

4. National Study Commission on Cytotoxic Exposure. Recommendations for handling cytotoxic agents. 1987. Available from Louis P. Jeffrey, Chairman, National Study Commission on Cytotoxic Exposure. Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, MA 02115.

5. Clinical Oncological Society of Australia. Guidelines and recommendations for safe handling of antineoplastic agents. Med J Australia. 1983;1:426-428.

6. Jones RB, Frank R, Mass T. Safe handling of chemotherapeutic agents: a report from the Mount Sinai Medical Center. CA-A Cancer J for Clin. 1983;33:258-263.

7. American Society of Hospital Pharmacists. ASHP technical assistance bulletin on handling cytotoxic and hazardous drugs. Am J Hosp Pharm. 1990;47:1033-1049.

8. Controlling Occupational Exposure to Hazardous Drugs. (OSHA Work-Practice Guidelines.). Am J Health SystPharm. 1996;53:1669-1685.

Manufactured by: Baxter Healthcare Corporation, Deerfield, IL 60015, USA. Made in Germany. Distributed by: Bristol-Myers Squibb Company, Princeton, NJ 08543 USA. Revised March 2005. FDA revision date: 11/5/2002

ETOPOPHOS has been found to be well tolerated as a single agent in clinical studies involving 206 patients with a wide variety of malignancies, and in combination with cisplatin in 60 patients with small cell lung cancer. The most frequent clinically significant adverse experiences were leukopenia and neutropenia.

The incidences of adverse experiences in the table that follows are derived from studies in which ETOPOPHOS was administered as a single agent. A total of 98 patients received total doses at or above 450 mg/m² on a 5 consecutive day or day 1, 3, and 5 schedule during the first course of therapy.

Summary of Adverse Events Reported With Single-Agent ETOPOPHOS Following Course 1 at Total Five Day Doses of ≥ 450 mg/m²

Since etoposide phosphate is converted to etoposide, those adverse experiences that are associated with VePesid can be expected to occur with ETOPOPHOS.

Hematologic Toxicity

Myelosuppression after ETOPOPHOS administration is dose related and dose limiting with the leukocyte nadir counts occurring from day 15 to day 22 after initiation of drug therapy, granulocyte nadir counts occurring day 12-19 after initiation of drug therapy, and platelet nadirs occurring from day 10-15. Bone marrow recovery usually occurs by day 21 but may be delayed, and no cumulative toxicity has been reported. Fever and infection have also been reported in patients with neutropenia. Death associated with myelosuppression has been reported following etoposide administration.

Gastrointestinal Toxicity

Nausea and vomiting are the major gastrointestinal toxicities. The severity of such nausea and vomiting is generally mild to moderate with treatment discontinuation required in 1% of patients. Nausea and vomiting can usually be controlled with standard antiemetic therapy.

Blood Pressure Changes

In clinical studies, 151 patients were treated with ETOPOPHOS with infusion times ranging from 30 minutes to 3.5 hours. Sixty-three patients received ETOPOPHOS as a 5-minute bolus infusion. Four patients experienced one or more episodes of hypertension and eight patients experienced one or more episodes of hypotension, which may or may not be drug related. One episode of hypotension was reported among those patients who received a 5-minute bolus infusion. If clinically significant hypotension or hypertension occurs with ETOPOPHOS, appropriate supportive therapy should be initiated.

Allergic Reactions

Anaphylactic-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 with ETOPOPHOS. Facial flushing was reported in 2% and skin rashes in 3% of patients receiving ETOPOPHOS. 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 initial infusion.

Anaphylactic-like reactions have occurred during the initial infusion of ETOPOPHOS (see WARNINGS). 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 44% of patients.

Other Toxicities

The following adverse reactions have been infrequently 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 a single report of radiation recall dermatitis. Rarely, hepatic toxicity may be seen.

The incidences of adverse reactions in the table that follows are derived from multiple data bases from studies in 2081 patients when VePesid was used either orally or by injection as a single agent.

Caution should be exercised when administering ETOPOPHOS with drugs that are known to inhibit phosphatase activities (e.g. levamisole hydrochloride). High-dose cyclosporin A resulting in concentrations above 2000 ng/mL administered with oral etoposide has led to an 80% increase in etoposide exposure with a 38% decrease in total body clearance of etoposide compared to etoposide alone.

Patients being treated with ETOPOPHOS must be frequently observed for myelosuppression both during and after therapy. Myelosuppression resulting in death has been reported following etoposide administration. Dose-limiting bone marrow suppression is the most significant toxicity associated with ETOPOPHOS therapy. Therefore, the following studies should be obtained at the start of therapy and prior to each subsequent cycle of ETOPOPHOS: platelet count, hemoglobin, white blood cell count, and differential. The occurrence of a platelet count below 50,000/mm³ or an absolute neutrophil count below 500/mm³ is an indication to withhold further therapy until the blood counts have sufficiently recovered. The toxicity of rapidly infused ETOPOPHOS in patients with impaired renal or hepatic function has not been adequately evaluated. The toxicity profile of ETOPOPHOS when infused at doses > 175 mg/m² has not been delineated.

Physicians should be aware of the possible occurrence of an anaphylactic reaction manifested by chills, fever, tachycardia, bronchospasm, dyspnea, and hypotension. Higher rates of anaphylactic-like reactions have been reported in children who received infusions of etoposide at concentrations higher than those recommended. The role 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.

ETOPOPHOS can cause fetal harm when administered to a pregnant woman. Etoposide has been shown to be teratogenic in mice and rats, and it is therefore likely that ETOPOPHOS is also teratogenic.

In rats, an intravenous etoposide dose of 0.4 mg/kg/day (about 1/20 of the human dose on a mg/m² basis) during organogenesis caused maternal toxicity, embryotoxicity, and teratogenicity (skeletal abnormalities, exencephaly, encephalocele, and anophthalmia); higher doses of 1.2 and 3.6 mg/kg/day (about 1/7 and 1/2 of the human dose on a mg/m² basis) resulted in 90 and 100% embryonic resorptions. In mice, a single 1.0 mg/kg (1/16 of the human dose on a mg/m² basis) dose of etoposide administered intraperitoneally on days 6, 7, or 8 of gestation caused embryotoxicity, cranial abnormalities, and major skeletal malformations. An i.p. dose of 1.5 mg/kg (about 1/10 of the human dose on a mg/m² 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.

If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be warned of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.

ETOPOPHOS 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 ETOPOPHOS have not been conducted in laboratory animals.

General

In all instances where the use of ETOPOPHOS is considered for chemotherapy, the physician must evaluate the need and usefulness of the drug against the risk of adverse reactions. Most such adverse reactions are reversible if detected early. If severe reactions occur, the drug should be reduced in dosage or discontinued and appropriate corrective measures should be taken according to the clinical judgement of the physician. Reinstitution of ETOPOPHOS therapy should be carried out with caution, and with adequate consideration of the further need for the drug and alertness as to possible recurrence of toxicity.

Patients with low serum albumin may be at an increased risk for etoposide associated toxicities.

Laboratory Tests

Periodic complete blood counts should be done during the course of ETOPOPHOS treatment. They should be performed prior to each cycle of therapy and at appropriate intervals during and after therapy.

Renal Impairment

In patients with impaired renal function, the following initial dose modification should be considered based on measured creatinine clearance:

Subsequent 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 dose reduction should be considered in these patients.

Carcinogenesis (see WARNINGS), Mutagenesis, Impairment of Fertility

ETOPOPHOS was non-mutagenic in in vitro Ames microbial mutagenicity assay and the E. coli WP2 uvrA reverse mutation assay. Since ETOPOPHOS is rapidly and completely converted 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 on a mg/m² basis) or above administered for 5 consecutive days resulted in irreversible testicular atrophy. Irreversible testicular atrophy was also present in rats treated with ETOPOPHOS intravenously for 30 days at 5.11 mg/kg/day (about 1/2 of the human dose on a mg/m² basis).

Pregnancy

Pregnancy Category D. (See WARNINGS.)

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ETOPOPHOS, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established. Anaphylactic reactions have been reported in pediatric patients who received etoposide (see WARNINGS).

Geriatric Use

Clinical studies of etoposide for the treatment of refractory testicular tumors did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients. Of more than 600 patients in four clinical studies in the NDA databases who received ETOPOPHOS (etoposide phosphate) or etoposide in combination with other chemotherapeutic agents for the treatment of small cell lung cancer (SCLC), about one third were older than 65 years. When advanced age was determined to be a prognostic factor for response or survival in these studies, comparisons between treatment groups were performed for the elderly subset. In the one study (etoposide in combination with cyclophosphamide and vincristine compared with cyclophosphamide and vincristine or cyclophosphamide, vincristine, and doxorubicin) where age was a significant prognostic factor for survival, a survival benefit for elderly patients was observed for the etoposide regimen compared with the control regimens. No differences in myelosuppression were seen between elderly and younger patients in these studies except for an increased frequency of WHO Grade III or IV leukopenia among elderly patients in a study of etoposide phosphate or etoposide in combination 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 some of the known adverse effects of etoposide, including myelosuppression, gastrointestinal effects, infectious complications, and alopecia.

Although some minor differences in pharmacokinetic parameters between elderly and non-elderly patients have been observed, these differences were not considered clinically significant.

Etoposide and its metabolites are known to be substantially excreted by the kidney, and the risk of adverse reactions to ETOPOPHOS may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see PRECAUTIONS: Renal Impairment, for recommended dosing adjustments in patients with renal impairment).

No proven antidotes have been established for ETOPOPHOS overdosage in humans. In mice, a single intravenous dose of rapidly administered ETOPOPHOS was lethal at or above 120 mg/kg (about 7 times human dose on a mg/m² basis) and was associated with clinical signs of neurotoxicity.

ETOPOPHOS for Injection is contraindicated in patients who have demonstrated a previous hypersensitivity to etoposide, etoposide phosphate, or any other component of the formulations.

The in vitro cytotoxicity observed for etoposide phosphate is significantly less than that seen with etoposide which is believed due to the necessity for conversion in vivo to the active moiety, etoposide, by dephosphorylation. The mechanism of action is believed to be the same as that of etoposide. Etoposide has been shown to cause metaphase arrest in chick fibroblasts. Its main effect, however, appears to be at the G₂ portion of the cell cycle in mammalian 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 to 10 μg/mL), cells are inhibited from entering prophase. It does not interfere with microtubular assembly. The predominant macromolecular effect of etoposide appears to be the induction of DNA strand breaks by an interaction with DNA-topoisomerase II or the formation of free radicals.

ETOPOPHOS Bioequivalence

Following intravenous administration of ETOPOPHOS, etoposide phosphate is rapidly and completely converted to etoposide in plasma. A direct comparison of the pharmacokinetic parameters [area under the concentration time curve (AUC) and the maximum plasma concentration (CMAX)] of etoposide following intravenous administration of molar equivalent doses of ETOPOPHOS and VePesid was made in two randomized crossover studies in patients with a variety of malignancies. In the first study of 41 evaluable patients, the etoposide mean ± S.D. AUC values were 168.3 ± 48.2 μg•hr/mL and 156.7 ± 43.4 μg hr/mL following administration of molar equivalent doses of 150 mg/m² ETOPOPHOS or VePesid 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 29 evaluable patients following intravenous administration of 90, 100, and 110 mg/m² molar equivalents of ETOPOPHOS or VePesid with a 60-minute infusion time, the etoposide mean ± S.D. AUC values (normalized to the 100 mg/m² dose) were 96.1 ± 22.6 μg &bull;hr/mL and 86.5 ± 25.8 μg •hr/mL, respectively; the corresponding mean ± S.D. CMAX values (normalized to the 100 mg/m² dose) were 20.1 ± 4.1 μg/mL and 19.0 ± 5.1 μg/mL, respectively. The point estimate (90% confidence interval) for the bioavailability of etoposide from ETOPOPHOS, relative to VePesid, was 113% (107%, 119%) for AUC and 107% (101%, 113%) for CMAX indicating bioequivalence. Results from both studies demonstrated no statistically significant differences in the AUC and CMAX parameters for etoposide when administered as ETOPOPHOS or VePesid. In addition, in the latter study, there were no statistically significant differences in the pharmacodynamic parameters (hematologic toxicity) after administration of ETOPOPHOS or VePesid. Following VePesid administration, the mean nadir values (expressed as percent decrease from baseline) for leukocytes, 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 administration of 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 after administration of either ETOPOPHOS or VePesid, the following information on VePesid should be considered:

VePesid Pharmacokinetics

On intravenous administration, the disposition of etoposide is best described as a biphasic process with a distribution half-life of about 1.5 hours and terminal elimination half-life ranging from 4 to 11 hours. Total body clearance values range from 33 to 48 mL/min or 16 to 36 mL/min/m² and, like the terminal elimination half-life, are independent of dose over a range 100-600 mg/m². Over the same dose range, the AUC and the CMAX values increase linearly with dose. Etoposide does not accumulate in the plasma following daily administration of 100 mg/m² for 4 to 5 days. After intravenous infusion the CMAX and AUC values exhibit marked intra- and inter-subject variability.

The mean volumes of distribution at steady state fall in the range of 18 to 29 liters or 7 to 17 L/m². 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 ¹⁴C-etoposide (100-124 mg/m²), 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 of VePesid is excreted in the urine as etoposide in 24 hours. The mean renal clearance of etoposide is 7 to 10 mL/min/m² or 35% of the total body clearance over a dose of 80 to 600 mg/m². 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 in children.

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-O-(R)-ethylidene-β-D-gluco-pyranoside)], 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 ¹⁴C-etoposide. In addition, O-demethylation of the dimethoxyphenol ring occurs through the CYP450 3A4 isoenzyme pathway to produce the corresponding catechol.

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.

Clinical Studies

A total of seven clinical trials with 365 patients treated (368 entered) provide the data base for the human experience summarized in this insert. Five phase I trials evaluated etoposide phosphate given on a days 1, 3, and 5 or days 1 through 5 schedule. In two trials the drug was given over 5 minutes and in three over 30 minutes. The following table summarizes the doses, schedules, infusion times, and numbers of patients entered in the phase I experience.

Dose Escalation (Phase I) Trials of Etoposide Phosphate

Two trials evaluated the pharmacokinetic equivalence of etoposide and etoposide phosphate. A phase I study (002) was expanded at the higher doses to compare the pharmacokinetic profile of etoposide following administration of etoposide or etoposide phosphate. Another multi-institutional trial (012) was conducted at a dose of 150 mg/m² using a day 1, 3, and 5 schedule and a crossover design.

The seventh trial (011) was a randomized study in which patients with limited or extensive small cell lung cancer and no prior therapy were treated with either cisplatin plus etoposide or cisplatin plus etoposide phosphate. Patients received 20 mg/m²/day of cisplatin for 5 days and 80 mg/m²/day of etoposide or etoposide phosphate. A total of 121 patients were randomized and 120 treated (60 per group). Response rates, time to response, duration of response, time to progression, time to worsening performance status, and survival were similar in the two groups whether the analysis was done for patients with limited or extensive disease or for the entire population. The following table summarizes the results regardless of disease extent.

Response to Treatment for All Patients

The most prominent side effects were myelosuppression and GI toxicity. Sixty-eight percent of patients treated with etoposide phosphate plus cisplatin had neutrophils less than 500/mm³ at 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 side effects were observed.

No information provided. Please refer to the WARNINGS and PRECAUTIONS sections.

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

ETOPOSIDE PHOSPHATE - INJECTION

(ee-TOE-poe-side)

COMMON BRAND NAME(S): Etopophos

WARNING: This medication may cause certain severe blood and bone marrow problems (low red blood cells/white blood cells/platelets). This can affect your body's ability to stop bleeding or fight infection. Tell your doctor immediately if you develop easy bleeding/bruising or signs of infection (e.g., fever, chills, persistent sore throat).

USES: This medication is used to treat cancer. Etoposide works by slowing or stopping the growth of cancer cells.

HOW TO USE: Follow all instructions for proper mixing with the correct IV fluids. Before using, check the product visually for particles or discoloration. If either is present, do not use the liquid.

This medication is given by slow injection into a vein by a health care professional, usually over 30 to 60 minutes or as directed by your doctor. This medication is usually given every day or every other day for a total of 3 to 5 doses. This cycle may be repeated every 3 to 4 weeks. This medication may cause low blood pressure. Tell your doctor or other health care professional if you feel dizzy. Your injection may need to be stopped or given more slowly.

Dosage is based on your medical condition, body size, and response to treatment. Your doctor will check your blood counts to make sure you can receive your next cycle. Be sure to keep all medical/lab appointments.

Wear gloves when handling this medication. If this medication touches your skin, immediately wash the area well with soap and water. If this medication gets in your eye, open the eyelids and flush with water, then seek immediate medical attention.

Learn how to store and discard needles, medical supplies, and medical waste safely. Consult your pharmacist for details.

SIDE EFFECTS: See also Warning section.

Nausea, vomiting, diarrhea, muscle aches, tiredness, loss of appetite, and pain/redness at the injection site may occur. Nausea and vomiting can be severe. In some cases, your doctor may prescribe medication to prevent or relieve nausea and vomiting. Eating several small meals, not eating before treatment, or limiting activity may help lessen some of these effects. If these effects persist or worsen, tell your doctor or pharmacist promptly.

Temporary hair loss may occur. Normal hair growth should return after treatment has ended.

Many people using this medication may have serious side effects. However, your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. To lower your risk of serious side effects, your doctor will follow your condition closely and order lab tests.

Pain or sores in the mouth and throat may occur. Brush your teeth gently/carefully, avoid using mouthwash that contains alcohol, and rinse your mouth frequently with cool water mixed with baking soda or salt. It may also be best to eat soft, moist foods.

Tell your doctor immediately if any of these unlikely but serious side effects occur: numbness/tingling of hands/feet, bloody/black/tarry stool, coughing up blood, fast/irregular heartbeat.

Tell your doctor immediately if any of these rare but very serious side effects occur: severe abdominal pain, dark urine, yellowing eyes/skin.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any of the following symptoms of a serious allergic reaction: rash, itching, swelling (especially of the face/lips/throat), severe dizziness, trouble breathing, fever/chills.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before using etoposide, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies.

Tell your doctor your medical history, especially of: current infections, certain virus illnesses (herpes, chickenpox), blood disorders (e.g., anemia, clotting problems), liver problems, kidney problems, previous radiation/chemotherapy treatment.

Do not have immunizations/vaccinations without the consent of your doctor, and avoid contact with people who have recently received oral polio vaccine or flu vaccine inhaled through the nose.

Wash your hands well to prevent the spread of infections. Avoid contact with people who have illnesses that may spread to others (e.g., flu, chickenpox).

To lower your chance of getting cut, bruised, or injured, use caution with sharp objects like razors and nail cutters, and avoid activities such as contact sports.

Kidney function declines as you grow older. This medication is removed by the kidneys. Therefore, elderly people may be at greater risk for side effects (e.g., dizziness, infection, bleeding) while using this drug.

This drug is not recommended for use during pregnancy. It may harm the unborn baby. If you become pregnant or think you may be pregnant, tell your doctor immediately. To avoid pregnancy, both males and females using this drug should use reliable form(s) of birth control (e.g., birth control pills, condoms) during treatment. Consult your doctor for details and to discuss effective forms of birth control.

It is not known whether this medication passes into breast milk. However, it may have undesirable effects on a nursing infant. Therefore, breast-feeding while using this medication is not recommended. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with them first.

This drug should not be used with the following medications because very serious interactions may occur: live vaccines (e.g., flu vaccine inhaled through the nose, typhoid/polio vaccine taken by mouth).

If you are currently receiving or planning any vaccinations, tell your doctor or pharmacist before starting etoposide.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: "blood thinners" (e.g., warfarin, enoxaparin), salicylates/NSAIDs (e.g., aspirin, ibuprofen, naproxen), cyclosporine, levamisole, St John's wort.

Check all prescription and nonprescription medicine labels carefully since many contain pain relievers/fever reducers (NSAIDs such as ibuprofen, naproxen, or aspirin) that can increase your risk of bleeding. Low-dose aspirin should be continued if prescribed by your doctor for heart attack or stroke prevention (usually at dosages of 81-325 milligrams a day). Consult your doctor or pharmacist for more details.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center.

NOTES: Do not share this medication with others.

Laboratory and/or medical tests (e.g., complete blood count) should be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

MISSED DOSE: For the best possible benefit, it is important to receive each scheduled dose of this medication as directed. If you miss a dose, contact your doctor to establish a new dosing schedule. Do not double the dose to catch up.

STORAGE: Store the unmixed vials in the original package in the refrigerator between 36-46 degrees F (2-8 degrees C). Protect from light. The Canadian product may be stored at room temperature between 59-77 degrees F (15-25 degrees C). Check the package labeling for storage directions for your product.

For directions on storing mixed solutions of etoposide, read the package labeling or contact your pharmacist.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

MEDICAL ALERT: Your condition can cause complications in a medical emergency. For information about enrolling in MedicAlert, call 1-800-854-1166 (USA) or 1-800-668-1507 (Canada).

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.