Stability of High Concentration Etoposide (10mg/ml) in Physiologic Saline for Use in Conditioning Regimens

Background.High-dose etoposide (60 mg/kg) is used in conditioning regimens for allogeneic stem cell transplantation. As solubilizing excipients are present in commercially available non-aqueous formulations (20 mg/ml), dilution is needed before administration. Licensed final concentration ranges are 0.2-0.4 mg/ml, while crystallization is likely to occur with concentrations higher than 0.4 mg/ml. Consequently, high-dose etoposide regimens require huge quantities of dilution fluids. So far, most centres use a concentration of 1 mg/ml with limited stability of only one hour which means a practical hurdle for pharmacists, nurses and patients.

Aim. To define stability of Etoposide (Sandoz) at a concentration of 10.0mg/ml for 48h (5°C) followed by  8h (25°C) (n=3), at 25°C for 24h.

Methodology and results. Aspect was performed by visual examination and the analytical assay by High Performance Liquid Chromatography according to the USP monograph. Samples were stored for 48h at 5°C with sampling testing after 24h and 48h. Samples were consecutively stored for an additional 8h at 25°C (relative humidity of 60%) with sampling and testing at the end of this extra storage period. Samples dilutions stored at 25°C/60% RH for 24h were sampled and tested after 24h.

Visual aspects revealed a clear, colourless solution at all test points for all dilutions. Evolution of the mean assay of samples with regard to initial concentration at time zero (= 100.0 %) revealed for t = 24h, 5°C = 101.9%; t = 48h, 5°C = 101.3%; t = 48h,5°C + 8h,25°C = 101.4%. For the samples stored for 24h at 25°C, a value of 104.2% was obtained.

Conclusion.  Etoposide solutions of 10.0 mg/ml in NaCl 0.9% are stable when stored for 48h at 5°C followed by storage for 8h at 25°C, and for 24h at 25°C. Its use might be an added-value for pharmacists, nurses and patients during high-dose etoposide conditioning regimens. Monitoring for hypotension and strict control of the administration rate (below 10mg/kg/h) during infusion remains necessary.