ETOPOSIDE MYLAN

A semisynthetic derivative of podophyllotoxin that exhibits antitumor activity.

Etoposide inhibits

DNA synthesis by forming a complex with topoisomerase II and DNA.

This complex induces breaks in double stranded DNA and prevents repair by topoisomerase II binding.

Accumulated breaks in

DNA prevent entry into the mitotic phase of cell division, and lead to cell death.

Etoposide acts primarily in the

G2 and S phases of the cell cycle.

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.

Etoposide is an antineoplastic agent and an epipodophyllotoxin (a semisynthetic derivative of the podophyllotoxins).

It inhibits DNA topoisomerase

II, thereby ultimately inhibiting DNA synthesis.

Etoposide is cell cycle dependent and phase specific, affecting mainly the S and G2 phases.

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 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.

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

Oral administered etoposide capsules display intra.

• and inter-subject variability.

There is no evidence of first-pass effect for etoposide.

The disposition of etoposide is a biphasic process with a distribution half-life of 1.5 hours.

It does not cross into cerebrospinal fluid well.

Volume of distribution, steady state = 18-29 L.

Primarily hepatic (through O-demethylation via the CYP450 3A4 isoenzyme pathway) with 40% excreted unchanged in the urine.

Etoposide also undergoes glutathione and glucuronide conjugation which are catalyzed by GSTT1/GSTP1 and UGT1A1, respectively.

Prostaglandin synthases are also responsible for the conversion of etoposide to O-demethylated metabolites (quinone).

Hover over products below to view reaction partners Etoposide 3'-demethyletoposide Etoposide glucuronide Etoposide catechol Etoposide ortho-quinone.

Etoposide is cleared by both renal and nonrenal processes, i.e., metabolism and biliary excretion.

Glucuronide and/or sulfate conjugates of etoposide are also excreted in human urine.

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. 56% of the dose was in the urine, 45% of which was excreted as etoposide.

Total body clearance = 33-48 mL/min Mean renal clearance = 7-10 mL/min/m^2.

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Side effects include alopecia, constipation, diarrhea, nausea and vomiting and secondary malignancies (leukemia).

Patients being treated with etoposide Injection

USP must be frequently observed for myelosuppression both during and after therapy.

Myelosuppression resulting in death has been reported.

Dose-limiting bone marrow suppression is the most significant toxicity associated with etoposide Injection USP therapy.

Therefore, the following studies should be obtained at the start of therapy and prior to each subsequent cycle of etoposide Injection USP: platelet count, hemoglobin, white blood cell count, and differential.

The occurrence of a platelet count below 50,000/mm 3 or an absolute neutrophil count below 500/mm is an indication to withhold further therapy until the blood counts have sufficiently recovered.

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 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.

For parenteral administration, etoposide Injection USP 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 Category D Etoposide Injection USP 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 abnormalities, 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 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 of gestation caused embryotoxicity, 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 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.

USP 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 Injection

USP have not been conducted in laboratory animals.

USP is contraindicated in patients who have demonstrated a previous hypersensitivity to etoposide or any component of the formulation.

Plastic devices made of acrylic or

ABS (a polymer composed of acrylonitrile, butadiene, and styrene) have been reported to crack and leak when used with undiluted Etoposide Injection USP.

The usual dose of Etoposide Injection

USP in testicular cancer in combination with other approved chemotherapeutic agents ranges from to 100 mg/m 2 /day on days 1 through to 100 mg/m 2 /day on days 1, 3, and 5.

In small cell lung cancer, the Etoposide Injection USP dose in combination with other approved chemotherapeutic drugs ranges from 35 mg/m 2 /day for 4 days to 50 mg/m 2 /day for 5 days.

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

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 effects of other drugs in the combination or the effects of prior X-ray therapy or chemotherapy which may have compromised bone marrow reserve.

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 Injection USP 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

USP 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 Injection USP 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.

USP 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

USP 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 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. 1–7 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

USP, 20 mg/mL, is supplied as follows: NDC Etoposide Injection, USP Volume 68001-265-22 20 mg/mL 100 mg/5 mL 68001-265-23 20 mg/mL 500 mg/25 mL 68001-265-24 20 mg/mL 1 g/50 mL 5 mL vials are packed individually per shelf pack with NDC 68001-265-25. 25 mL vials are packed individually per shelf pack with NDC 68001-265-26. 50 mL vials are packed individually per shelf pack with NDC 68001-265-27.

Store between 20° to 25°C (68° to 77°F).

USP controlled room temperature.

USP 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 abnormalities, 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 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 of gestation caused embryotoxicity, 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 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.

USP 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 Injection

USP have not been conducted in laboratory animals.

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 etoposide Injection USP, 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.

Safety and effectiveness in pediatric patients have not been established.

USP contains polysorbate 80.

In premature infants, a life-threatening syndrome consisting of liver and renal failure, pulmonary deterioration, thrombocytopenia, and ascites has been associated with an injectable vitamin E product containing polysorbate 80.

Anaphylactic reactions have been reported in pediatric patients See WARNINGS.

Clinical studies of etoposide Injection

USP did not include sufficient numbers of subjects aged and over to determine whether they respond differently from younger subjects.

Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.