Etoposide

ETOPOSIDE- etoposide capsule
Mylan Pharmaceuticals Inc.

DESCRIPTION

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. It has a molecular weight of 588.56 and a molecular formula of C₂₉ H₃₂ O₁₃ .

Etoposide may be administered either intravenously or orally. Etoposide capsules, USP are available as 50 mg opaque dark pink, oblong capsules. Each liquid filled, soft gelatin capsule contains 50 mg of etoposide, USP in a vehicle consisting of citric acid anhydrous, glycerol and polyethylene glycol. The soft gelatin capsules contain anidrisorb, gelatin and glycerol with the following dye system: red iron oxide and titanium dioxide; the capsules are printed with edible black ink containing FD&C Blue No. 1 Aluminum Lake, FD&C Red No. 40 Aluminum Lake, hypromellose and propylene glycol.

The structural formula is:

CLINICAL PHARMACOLOGY

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 mcg/mL or more), lysis of cells entering mitosis is observed. At low concentrations (0.3 mcg/mL 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.

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 mL/min to 48 mL/min or 16 mL/min/m² to 36 mL/min/m² and, like the terminal elimination half-life, are independent of dose over a range 100 mg/m² to 600 mg/m². 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/m² for 4 to 5 days.

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

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-ß-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. Glucoronide 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-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/m².

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.

INDICATIONS AND USAGE

Etoposide capsules are indicated in the management of the following neoplasms:

Small Cell Lung Cancer

Etoposide capsules in combination with other approved chemotherapeutic agents as first line treatment in patients with small cell lung cancer.

CONTRAINDICATIONS

Etoposide capsules are contraindicated in patients who have demonstrated a previous hypersensitivity to etoposide or any component of the formulation.

WARNINGS

Patients being treated with etoposide 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 therapy. Therefore, the following studies should be obtained at the start of therapy and prior to each subsequent cycle of etoposide: 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.