Etoposide is available as a 20-mg/mL concentrate for injection in 5-, 25-, or 50-mL multiple-dose vials containing etoposide 100 mg, 500 mg, or 1 g, respectively.2951 Each mL also contains polyethylene glycol 300 650 mg, ethanol 30.5% (v/v), polysorbate 80 80 mg, benzyl alcohol 30 mg, and citric acid 2 mg.2951 The concentrate must be diluted prior to administration; a final etoposide concentration of 0.2 to 0.4 mg/mL is recommended.2951 Precipitation may occur at concentrations above 0.4 mg/mL.2951
pH
From 3 to 4.2951
Etoposide is recommended to be administered by intravenous infusion over 30 to 60 minutes; however, a longer duration of administration may be considered if the volume of the infusion solution is a concern.2951
Continuous intravenous infusion also has been used.4 Etoposide should not be given by rapid intravenous injection.2951
The surfactant content of the etoposide formulation decreases surface tension and has been found to produce a 30% reduction in drop size compared to simple aqueous solutions. The altered drop size may interfere with accurate infusion rates if infusion devices that rely on drop counting are used. The use of infusion devices that operate independently of drop size has been recommended.181
The manufacturer notes that accidental exposure to this potentially toxic agent may cause skin reactions.2951 Therefore, protective gloves should be used during preparation of solutions.2951 A soap and water wash should be employed after accidental contact with the skin and accidentally exposed mucosa should be flushed with water.2951
In the event of spills or leaks, the use of sodium hypochlorite 5% (household bleach) or potassium permanganate 1% to inactivate etoposide has been recommended.1200
Etoposide concentrate for injection is a clear, nearly colorless to yellow solution.2951 Intact vials should be stored at controlled room temperature.2951 Stability is not affected by exposure to normal room fluorescent light.1374
Diluted solutions at recommended concentrations of 0.2 and 0.4 mg/mL in dextrose 5% or sodium chloride 0.9% are stated to be stable for 96 and 24 hours, respectively, at 25°C under normal room fluorescent light in either glass or plastic containers.2951
Plastic devices composed of acrylic or a polymer of acrylonitrile, butadiene, and styrene (ABS) may crack and leak when used with undiluted etoposide.2951 In one study, a multiport disposable infusion cassette (Omni-Flow) developed cracks within 5 minutes after infusion was started and leakage was evident within 15 minutes. This phenomenon did not occur when etoposide was diluted to concentrations up to 1 mg/mL. In addition, a venting pin and a connector on an extension set reportedly cracked. Exposure to the polyethylene glycol 300 content of the etoposide formulation can cause cracks in minutes. However, dehydrated alcohol did not cause any cracks within 1 hour.1261
Immersion of a needle with an aluminum component in etoposide (Bristol) 20 mg/mL resulted in no visually apparent reaction after 7 days at 24°C.988
Precipitation
Dextrose 5% and sodium chloride 0.9% are recommended diluents for preparation of etoposide for infusion.2951 Unlike etoposide phosphate, the aqueous solubility of etoposide is poor (0.03 mg/mL), but the formulation temporarily increases its miscibility in an aqueous medium. Nevertheless, the drug will eventually crystallize in varying time periods, and the crystallization is reported to be exacerbated by peristaltic pumps.1949 At concentrations of 0.2 and 0.4 mg/mL in dextrose 5% or sodium chloride 0.9%, the solutions are stated to be stable for 96 and 24 hours, respectively, at 25°C under normal fluorescent light in either glass or plastic containers.2951 However, precipitation in shorter time periods has been observed. At concentrations of 0.2 and 0.4 mg/mL in Ringer’s injection, lactated, or mannitol 10% in glass containers under the same conditions, the solutions are stable for 8 hours. No precipitate formed in 72 hours at 20°C in solutions of etoposide 0.4 mg/mL in dextrose 5% in sodium chloride 0.45%.1162 However, at 1 mg/mL, crystallization may occur in 30 minutes in a standing solution or 5 minutes if the solution is stirred. Occasionally, 1-mg/mL concentrations may remain in solution for extended periods.1374 Nevertheless, concentrations greater than 0.4 mg/mL are not recommended by the manufacturer.2951 Because of the poor solubility of etoposide in aqueous media, monitor closely for precipitation before and during administration.915; 916
The rate of precipitation of a supersaturated etoposide solution depends on the presence of crystalline nuclei, agitation, contact with incompatible surfaces, and possibly other factors.1374
Etoposide 1 mg/mL in sodium chloride 0.9% in polypropylene syringes (Braun Omnifix) developed a pure etoposide precipitate in about 10% of the prefilled syringes. It also precipitated at various locations in subclavian lines.1564
pH Effects
Etoposide is most stable at a pH of about 3.5 to 6, with a calculated minimum degradation rate occurring at pH 4.8.1262 Epimerization to the less active cis-etoposide may occur at pH values above 6. Hydrolysis may occur in alkaline solutions.1379
Syringes
When etoposide 1 mg/mL in sodium chloride 0.9% was stored in plastic syringes (Gillette), seizing of the syringes occurred.1564
Infusion Pumps
Precipitation of etoposide from infusion solutions is reportedly exacerbated by the use of peristaltic pumps, especially at concentrations of 0.4 mg/mL or above. Use of volumetric pumps has been recommended to reduce this problem.1832; 1949
In a study evaluating the effect of volumetric pumps on the stability of etoposide solutions, etoposide (Mylan) solutions at concentrations up to 1.26 mg/mL that were determined to be physically stable were passed through an administration set with a 0.2-µm inline filter using a Volumat Agilia volumetric pump (Fresenius Kabi).3933 No change in physical stability of the etoposide solutions was observed.3933 The investigators concluded that the volumetric pump did not cause physical instability in the etoposide solutions.3933
Ambulatory Pumps
Etoposide (Bristol-Myers Squibb) 0.5 mg/mL in sterile water for injection was evaluated for stability and compatibility in polyvinyl chloride (PVC) reservoirs of Graseby 9000 ambulatory pumps. Etoposide was chemically stable at 37°C for 7 days with no loss of drug. However, refrigerated storage at 4°C resulted in precipitation of the etoposide in some samples. In addition, substantial amounts of diethylhexyl phthalate (DEHP) plasticizer (up to 90 mcg/mL) were leached from the PVC reservoirs. The authors concluded that etoposide was unsuitable for use in this pump reservoir and recommended consideration of etoposide phosphate, which should not be subject to precipitation and leaching of plasticizer.2288
Sorption
No loss of etoposide because of sorption to PVC containers has been observed.1374
In an admixture composed of cytarabine (Upjohn) 0.157 mg/mL, daunorubicin hydrochloride (Bellon) 15.7 mcg/mL, and etoposide (Sandoz) 0.157 mg/mL in dextrose 5%, little or no loss of the drugs due to sorption occurred when delivered through PVC, PVC with polyethylene-lined sets, and silicone central catheter.1955
Plasticizer Leaching
The surfactant in the etoposide formulation leaches DEHP plasticizer from PVC containers and tubing. The amount of DEHP leached is variable, depending on surfactant concentration, container size, tubing diameter and length, ambient temperature, DEHP concentration in the plastic, and contact time. The use of non-PVC containers and tubing has been recommended to reduce patient exposure to DEHP. If there is sufficient concern, the use of the water-soluble ester form, etoposide phosphate, which does not leach DEHP plasticizer, could be used.
Etoposide 0.4 mg/mL in PVC bags of dextrose 5% leached relatively minor amounts of DEHP plasticizer from PVC bags. This leaching was due to the surfactant polysorbate 80 (Tween 80) in the formulation. After 24 hours at 24°C, the DEHP concentration in 50-mL bags of infusion solution was 2.6 mcg/mL. This finding is consistent with the low surfactant concentration (0.16%) in the final admixture solution. The actual amount of DEHP leached from PVC containers and administration sets may vary in clinical situations, depending on surfactant concentration, bag size, and contact time.1683
Etoposide (Sandoz) 0.4 mg/mL in sodium chloride 0.9% in PVC containers leached DEHP plasticizer from the container material. This leaching increased with storage time from about 12 mcg/mL in 8 hours to over 50 mcg/mL in 96 hours at 24°C. Refrigeration reduced, but did not eliminate, DEHP leaching.1833
Etoposide (Novartis) 0.4 mg/mL in dextrose 5% and sodium chloride 0.9% was evaluated for the leaching of DEHP plasticizer from PVC bags of the infusion solution from 4 manufacturers (Aguettant, Baxter, Biosedra-Fresenius, and Macopharma) over 24 hours stored at 24°C. Both solutions from all manufacturers leached DEHP in amounts near 20 mcg/mL.2447
The low-density polyethylene inner linings of trilayer Vygon tubing and bilayer Cair tubing have been reported not to act as effective barriers to DEHP leaching from the outer PVC layers. Leached DEHP was nearly identical to plain PVC tubing.2587; 2605
Filtration
Etoposide 0.1 to 0.4 mg/mL in dextrose 5% or sodium chloride 0.9% has been filtered through several commercially available filters (such as the 0.22-µm Millex-GS or Millex GV) without filter decomposition.4
Etoposide (Sandoz) 0.2 mg/mL in dextrose 5% and sodium chloride 0.9% was filtered through a 0.22-µm cellulose ester membrane filter (Ivex-HP, Millipore) over 6 hours. No significant drug loss due to binding to the filter was noted.1034
Central Venous Catheter
Etoposide infused undiluted at a rate of 30 mL/hr for 24 hours through a polyurethane central catheter caused substantial damage to the catheter. In addition to cracking the catheter, a 36% decrease in elasticity, a 3.7% increase in catheter length, and damage similar to melting on the internal catheter wall were found. The damage also occurred with the etoposide vehicle and ethanol alone. Consequently, the damage was attributed to the ethanol component of the formulation.2286
The damage to polyurethane catheters caused by the etoposide formulation did not extend to silicone central catheters. Administration of undiluted etoposide could be performed using silicone catheters.2286
For a list of references cited in the text of this monograph, search the monograph titled References.