Fluorouracil injection is available in 10- and 20-mL single-dose vials2955; 2957 and in 50- and 100-mL pharmacy bulk vials for preparation of individual doses.2954; 2956 Each mL contains fluorouracil 50 mg with sodium hydroxide for pH adjustment.2954; 2955; 2956; 2957
pH
The pH is adjusted to approximately 9.2.2954; 2955; 2956; 2957
Fluorouracil is administered intravenously as a bolus injection into an intravenous line or as a continuous infusion through a central venous line using an infusion pump.2954; 2955; 2956; 2957 Dilution of the injection is not required for administration.2954; 2955; 2956; 2957 Fluorouracil also has been given by portal vein or hepatic artery infusion.4
In the event of spills or leaks, the use of sodium hypochlorite 5% (household bleach) to inactivate fluorouracil has been recommended.1200
Fluorouracil injection is a colorless to faint yellow2956; 2957 or yellow solution.2954; 2955 Intact vials should be stored in the original cartons at controlled room temperature and protected from light and freezing.2954; 2955; 2956; 2957 Unused portions of pharmacy bulk vials should be discarded within 4 hours of initial entry.2954; 2956
Manufacturers state diluted solutions of fluorouracil may be stored for up to 4 hours at 25°C prior to administration.2954; 2955; 2956; 2957
Solutions should be visually inspected for particulate matter and discoloration prior to use; if either is present, the solution should be discarded.2954; 2955; 2956; 2957
The stability and safety of fluorouracil injection are not affected by slight discoloration to a faint yellow that may occur during storage.3742 The color of the solution results from the presence of free fluorine. A dark yellow indicates greater decomposition. Such decomposition may result from storage for several months at temperatures above room temperature. It is suggested that solutions having a darker yellow color be discarded.398 Exposure to sunlight or intense incandescent light also has caused degradation. The solutions changed to dark amber to brown.760
A precipitate may form from exposure to low temperatures.662; 3742 Resolubilization of fluorouracil by heating to 60°C with vigorous shaking followed by cooling to body temperature prior to administration has been described by some manufacturers;662; 3742 however, current US manufacturers make no recommendations regarding resolubilization of fluorouracil.2954; 2955; 2956; 2957 Microwave radiation has been used to resolubilize fluorouracil precipitate.662 Ampuls of fluorouracil (no longer commercially available in the US) containing a precipitate were exposed to microwave radiation and shaken until clear.662 These ampuls were then compared to ampuls that were heated to 60°C and shaken until clear and also to unheated controls.662 The precipitate was redissolved by microwave radiation without significantly affecting the drug.662 No significant decrease in concentration was observed.662 There was a slight change in pH.662 The authors concluded that microwave radiation was a suitable method for solubilizing the precipitate that may form in fluorouracil ampuls.662 However, they warned that extreme care should be taken to avoid overheating and the resulting explosions from excessive pressure in the ampuls.662
Fluorouracil (Roche) 1 mg/mL in dextrose 5% was evaluated for stability in translucent containers (Perfupack Y, Baxter) and 5 opaque containers (green polyvinyl chloride [PVC] Opafuseur [Bruneau], white ethylene vinyl acetate [EVA] Perfu-opaque [Baxter], orange PVC PF170 [Cair], white PVC V86 [Codan], and white EVA Perfecran [Fandre]) when exposed to sunlight for 28 days. No photodegradation or sorption was found. However, an increase in concentration due to moisture permeation was detected after 2 weeks.1750
Immersion of a needle with an aluminum component in fluorouracil (Adria) 50 mg/mL resulted in no visually apparent reaction after 7 days at 24°C.988
Fluorouracil (Adria) 500 mg/10 mL did not support the growth of several microorganisms commonly implicated in nosocomial infections. The bacteriostatic properties were observed against Escherichia coli, Klebsiella pneumoniae, Staphylococcus epidermidis, Pseudomonas aeruginosa, Candida albicans, and Clostridium perfringens.828
In another study, fluorouracil (Adria) 1 g/20 mL transferred to PVC containers did not support the growth of several microorganisms and may have imparted an antimicrobial effect at this concentration. Loss of viability was observed for Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Pseudomonas cepacia, Candida albicans, and Aspergillus niger.1187
Fluorouracil eliminated the viability of Staphylococcus epidermidis (106 to 107 CFU/mL) in varying time periods, depending on concentration and diluent, when stored at near-body temperature (35°C). At 50 mg/mL, no viability was found after 5 days of incubation. At 10 mg/mL in sodium chloride 0.9% and dextrose 5%, no viability was found after 7 and 5 days, respectively. Following dilution to 10 mg/mL with bacteriostatic sodium chloride 0.9%, no viability was found after 2 days.1659
pH Effects
At a pH greater than 11, slow hydrolysis of fluorouracil occurs. At a pH less than 8, solubility is reduced and precipitation may or may not occur, depending on the concentration.1369; 1379
Fluorouracil 50 mg/mL (Lyphomed, Roche, and SoloPak) exhibited precipitation in 2 to 4 hours at pH 8.6 to 8.68; precipitation occurred immediately at pH 8.52 or less. The precipitate consisted of needle-shaped crystals at pH 8.26 to 8.68. Cluster-shaped crystals formed at pH 8.18 and below.1489
Admixture with acidic drugs or drugs that decompose in an alkaline environment should be avoided.524
A color change to deep purple was reported for the mixtures of doxorubicin hydrochloride (Adria) 10 mg/L with fluorouracil (Roche) 250 mg/L in dextrose 5%.296 This color change is indicative of decomposition occurring in solutions with an alkaline pH. It also occurs with other anthracyclines.394
Freezing Solutions
Fluorouracil (Abic) 5 mg/0.5 mL in sodium chloride 0.9% in polypropylene syringes (Plastipak, Becton Dickinson) was stored frozen at -20°C. No fluorouracil loss occurred in 8 weeks. Refreezing and further storage at -20°C for another 2 weeks also did not result in a fluorouracil loss.1666
Fluorouracil (Teva) near 6.8 mg/mL in sodium chloride 0.9% in PVC bags was stored frozen at -20°C for 79 days, thawed in a microwave oven, and stored for an additional 28 days under refrigeration. No precipitation or crystallization occurred. No fluorouracil loss occurred after frozen storage and about 6% loss occurred after the subsequent refrigerated storage.2807
Syringes
Manufacturers state undiluted fluorouracil may be stored in syringes for up to 4 hours at 25°C.2954; 2955; 2956; 2957
Fluorouracil 25 mg/mL in polypropylene syringes (Braun Omnifix) was stable for 28 days at 4 and 20°C.1564
Fluorouracil (Roche) 50 mg/mL was packaged as 3 mL in 10-mL polypropylene infusion pump syringes (Pharmacia Deltec). Little or no loss occurred during 21 days of storage at 30°C.1967
Fluorouracil (Roche) 12 and 40 mg/mL diluted with sodium chloride 0.9% and dextrose 5% was packaged in 60-mL polypropylene syringes and stored at 25°C protected from light. Losses of 5% or less occurred in the solutions after storage for 72 hours. Furthermore, the solutions had no visually apparent precipitate or discoloration.1983
Ambulatory Pumps
The stability of undiluted fluorouracil 50 mg/mL from 3 manufacturers (Lyphomed, Roche, and SoloPak) in the reservoirs of 4 portable infusion pumps (Pharmacia Deltec CADD-1, Model 5100; Cormed II, Model 10500; Medfusion Infumed 200; and Pancretec Provider I.V., Model 2000) was evaluated. The fluorouracil was delivered by the pumps at a rate of 10 mL/day over a 7-day cycle at 25 and 37°C. All fluorouracil samples in all pump reservoirs were stable over the 7-day study period, exhibiting little or no drug loss and only minimal leached plasticizer, diethylhexyl phthalate (DEHP), at either temperature.1489
However, precipitation of the Roche fluorouracil was observed with all pumps; a fine white precipitate originated close to the connection junction and migrated in both directions until it occupied most of the tubing and was in the drug reservoir. In some cases, the pumps stopped due to the extent of precipitation. The authors noted that various factors, including solution pH, temperature, drug concentration and solubility, and the manipulative techniques used could contribute to precipitate formation.1489
Undiluted fluorouracil (Roche) 50 mg/mL in EVA bags for use with portable infusion pumps remained stable, with little or no loss after 28 days at 4, 22, and 35°C. The containers at 35°C did sustain approximately a 3% water loss due to evaporation during storage, increasing the fluorouracil concentration slightly.1548
Fluorouracil (David Bull Laboratories) 25 mg/mL was stable in PVC reservoirs (Parker Micropump) for 14 days at 4 and 37°C, exhibiting no loss.1696
The stability of undiluted fluorouracil injection (Roche) 50 mg/mL in EVA reservoirs (Celsa) and PVC reservoirs (Pharmacia) for use with ambulatory infusion pumps was evaluated. The filled reservoirs were stored for 14 days at 4°C and at 33°C to simulate the conditions of prolonged infusion from the reservoirs kept under patients’ clothing. No loss of fluorouracil due to decomposition was found. However, the refrigerated samples exhibited substantial (up to 15%) loss of drug content from solution due to gross precipitation. Flocculent precipitation was observed in as little as 3 days, though subvisible precipitation may occur earlier. At the elevated temperature, substantial increases in concentration of fluorouracil occurred in the EVA reservoirs due to water loss from permeation through the plastic reservoir. Approximately 5% increase in drug concentration occurred in 14 days. No change in concentration occurred in the PVC reservoirs during this time frame.2004
Implantable Pumps
Fluorouracil 50 mg/mL was filled into an implantable infusion pump (Fresenius VIP 30) and associated capillary tubing and stored at 37°C. No fluorouracil loss and no contamination from components of pump materials occurred during 8 weeks of storage.1903
Fluorouracil combined with leucovorin calcium for repeated administration using a Fresenius implanted port resulted in blockage of the pump catheter and necessitated surgical removal of the port. The blockage was caused by precipitation of calcium carbonate in the catheter.2504
Sorption
Fluorouracil was shown not to exhibit sorption to PVC bags and tubing, polyethylene bags or tubing, Silastic tubing, and polypropylene and polyethylene syringes.536; 606; 760; 2420; 2430
Fluorouracil may be more extensively adsorbed to glass surfaces than to plastic. In one report, significant loss occurred from solutions in glass vials, but almost quantitative recovery was obtained from polyethylene and polypropylene plastic vials. The loss was attributed to adsorption to the glass surface.663 This difference was also observed in dextrose 5% in glass and PVC infusion containers. A 10% loss of fluorouracil occurred in 43 hours in the PVC containers but in only 7 hours in the glass containers.519
Filtration
Fluorouracil 10 to 75 mcg/mL exhibited little or no loss due to sorption to either cellulose nitrate/cellulose acetate ester (Millex OR) or Teflon (Millex FG) filters.1415; 1416
Central Venous Catheter
Fluorouracil (Roche) 5 mg/mL in dextrose 5% was found to be compatible with the ARROWg+ard Blue Plus (Arrow International) chlorhexidine-bearing triple-lumen central catheter. Essentially complete delivery of the drug was found with little or no drug loss occurring. Furthermore, chlorhexidine delivered from the catheter remained at trace amounts with no substantial increase due to the delivery of the drug through the catheter.2335
Drugs in Syringe Compatibility
Y-Site Injection Compatibility (1:1 Mixture)
Additional Compatibility Information
Leucovorin Calcium and Levoleucovorin Calcium
Because of the risk of precipitation, leucovorin calcium should not be mixed in the same infusion as fluorouracil.3845
Manufacturers state fluorouracil and levoleucovorin calcium should be administered separately to avoid formation of a precipitate.3196; 3197
For a list of references cited in the text of this monograph, search the monograph titled References.