Etoposide

Source and Pharmacology

Etoposide (also called VePesid, VP-16, NSC #141540) is a semisynthetic derivative of podophyllotoxin that forms a complex with topoisomerase II and DNA resulting in single or double strand DNA breaks. Its main effect appears to be in the S and G₂ phases of the cell cycle. The initial half-life is 1.5 hours and the mean terminal half-life is 4 to 11 hours. It is primarily excreted in the urine. There is poor diffusion into the CSF. The maximum plasma concentration and area under the concentration time curve (AUC) exhibit a high degree of patient variability. Etoposide is highly bound to plasma proteins (~94%), primarily serum albumin. Pharmacodynamic studies have shown that etoposide systemic exposure is related to toxicity. Preliminary data suggest that systemic exposure to unbound etoposide correlates better than to total (bound and unbound) etoposide. The pharmacokinetic data in infants suggest that a decrease in dosage is not necessary to avoid increased systemic exposure [McLeod 1994].

Toxicity

(L) = Toxicity may also occur later.

Formulation and Stability

A yellow solution with a pH of 3-4, available in 100 mg (5 mL) or 500 mg (25 mL) multiple-dose sterile vials containing 20 mg/mL of etoposide. Store at room temperature. Unopened vials of etoposide are stable for 24 months at room temperature (25_C). Stability of the reconstituted etoposide depends on the dilution. Dilute with 0.9% sodium chloride injection or D₅W. At room temperature, the solution diluted with 0.9% sodium chloride is thought to be stable for 48 hours at a concentration of 0.4 mg/mL, and for 96 hours at a concentration of 0.2 mg/mL in both glass and plastic containers. At a concentration above 0.4 mg/mL, the stability of the solution is highly unpredictable and precipitation may occur. Therefore dilutions to a concentrations of >0.4 mg/mL is not recommended. Discard if precipitation is noted. Do not refrigerate solution. Keep the agitation to a minimum after reconstitution. However, it is important to mix the etoposide well in the diluting 0.9% sodium chloride at the time of reconstitution, to avoid the ìRed Man Syndromeî from a ìbolus injectionî of the polyethylene glycol vehicle of etoposide.

Guidelines for Intravenous Administration

Give the etoposide solution reconstituted to a final concentration of 0.4 mg/mL intravenously over 30 minutes. For the purpose of this protocol, we have found that it is safe to give the etoposide infusion and vincristine intravenous push as well as all flushes over 30 minutes. Caution: severe hypotension may occur if etoposide is given too rapidly. Etoposide should never be given by rapid intravenous push. Watch for anaphylaxis.