ETOPOSIDE — etoposide injection, solution
Fresenius Kabi USA, LLC
Must be diluted before intravenous infusion.
Etoposide should be administered under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents. Severe myelosuppression with resulting infection or bleeding may occur.
Etoposide (also commonly known as VP-16) is a semisynthetic derivative of podophyllotoxin used in the treatment of certain neoplastic diseases. It is 4’-demethylepipodophyllotoxin 9-[4,6-O-(R)-ethylidene-β-D-glucopyranoside]. It is very soluble in methanol and chloroform, slightly soluble in ethanol, and sparingly soluble in water and ether. It is made more miscible with water by means of organic solvents.
Etoposide Injection, USP is available for intravenous use as a 20 mg/mL solution in 100 mg (5 mL), 500 mg (25 mL), or 1 gram (50 mL) sterile, multiple dose vials. The pH of the clear, nearly colorless to yellow liquid is 3 to 4. Each mL contains 20 mg etoposide, 2 mg citric acid, 30 mg benzyl alcohol, 80 mg polysorbate 80/tween 80, 650 mg polyethylene glycol 300, and 30.5 percent (v/v) alcohol. Vial headspace contains nitrogen. The structural formula is:
C 29 H 32 O 13 M.W. 588.56
Etoposide has been shown to cause metaphase arrest in chick fibroblasts. Its main effect, however, appears to be at the G 2 portion of the cell cycle in mammalian cells. Two different dose-dependent responses are seen. At high concentrations (10 mcg/mL or more), lysis of cells entering mitosis is observed. At low concentrations (0.3 to 10 mcg/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.
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/m 2 and, like the terminal elimination half-life, are independent of dose over a range 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 (C max ) 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-O-(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, O-demethylation of the dimethoxyphenol ring occurs through the CYP450 3A4 isoenzyme pathway to produce the corresponding catechol.
After either intravenous infusion or oral capsule administration, the C max and AUC values exhibit marked intra- and inter-subject variability. This results in variability in the estimates of the absolute oral bioavailability of etoposide oral capsules.
C max and AUC values for orally administered etoposide capsules consistently fall in the same range as the C max and AUC values for an intravenous dose of one-half the size of the oral dose. The overall mean value of oral capsule bioavailability is approximately 50% (range 25 to 75%). The bioavailability of etoposide capsules appears to be linear up to a dose of at least 250 mg/m 2.
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.
Etoposide Injection, USP is indicated in the management of the following neoplasms:
Etoposide Injection, USP in combination therapy with other approved chemotherapeutic agents in patients with refractory testicular tumors who have already received appropriate surgical, chemotherapeutic, and radiotherapeutic therapy.
Adequate data on the use of etoposide capsules in the treatment of testicular cancer are not available.
Etoposide Injection, USP and/or capsules in combination with other approved chemotherapeutic agents as first line treatment in patients with small cell lung cancer.
Etoposide Injection, USP is contraindicated in patients who have demonstrated a previous hypersensitivity to etoposide or any component of the formulation.
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