Cisplatin is available as a 1-mg/mL solution in 50-, 100-, or 200-mL multiple-dose vials.3981 Each mL contains cisplatin 1 mg and sodium chloride 9 mg in water for injection with hydrochloric acid and/or sodium hydroxide for pH adjustment.3981
Cisplatin also is available as a lyophilized powder in single-dose vials containing 50 mg of cisplatin with sodium chloride 450 mg, mannitol 500 mg, and hydrochloric acid for pH adjustment.3982 Vials should be reconstituted with 50 mL of sterile water for injection to yield a solution containing cisplatin 1 mg/mL.3982
pH
The solution for injection has a pH of 3.8 to 5.9.3981
Sodium Content
Each 10 mg of cisplatin contains 1.54 mEq of sodium.846; 869
Cisplatin is administered by intravenous infusion.3981; 3982 Official product labeling recommends diluting the cisplatin dose in 2 L of compatible infusion solution containing mannitol 37.5 g and infusing over 6 to 8 hours3981 or diluting in 1 to 2 L of compatible infusion solution with or without mannitol 37.5 g.3982 Other dilutions and rates of administration have been used, including intravenous infusions over periods from 15 to 120 minutes and continuous infusion over 1 to 5 days.4 Intra-arterial infusion and intraperitoneal instillation have been used.4
Because of an interaction between cisplatin and aluminum resulting in precipitate formation and loss of drug potency, administration equipment (e.g., needles, intravenous sets) containing aluminum should not be used for the preparation or administration of this drug.3981; 3982 Aluminum displaces platinum from the cisplatin molecule, causing the formation of a black precipitate and loss of potency.4; 203; 204; 512; 988 Stainless steel needles and plated brass hubs do not elicit an observable reaction within 24 hours.4; 203; 204; 512; 988
Cisplatin injection is a clear, colorless solution packaged in amber vials.3981 Intact vials of the injection should be stored at controlled room temperature, protected from light, and should not be refrigerated.3981 After initial vial entry, cisplatin injection in amber vials is stable for 28 days if protected from light or for 7 days if exposed to fluorescent room light.3981 Solutions diluted for infusion should be protected from light if not intended to be used within 6 hours.3981
Cisplatin powder for injection is a white to light yellow lyophilized powder packaged in amber vials; upon reconstitution, the solution is clear and colorless to slight yellow.3982 Intact vials of the powder should be stored at controlled room temperature in the original carton to protect from light.3982 Reconstituted solutions should not be refrigerated and are stable for 20 hours at controlled room temperature.3982 Solutions removed from the amber vial should be protected from light if not intended to be used within 6 hours.3982
Concern has been expressed that storage of cisplatin solutions for several weeks might result in substantial amounts of the toxic mono- and di-aquo species.1199 However, the solution’s chloride content, rather than extended storage time periods, appears to determine the extent of aquated product formation. (See Effect of Chloride Ion below.)
Kristjansson et al. evaluated the long-term stability of cisplatin 1 mg/mL in an aqueous solution containing sodium chloride 9 mg/mL and mannitol 10 mg/mL in glass vials. After 22 months at 5°C, the 4% loss of cisplatin could be explained as the expected equilibrium between cisplatin and its aquated products. Furthermore, a precipitate formed and required sonication at 40°C for about 20 to 30 minutes to redissolve. Storage of the cisplatin solution at 40°C for 10 months resulted in no physical change. After an additional 1 year at 5°C, these samples exhibited an average 15% loss, which the authors concluded was not the result of the formation of aquated species or the toxic and inactive oligomeric species. These proposed degradation products were not present in the 40°C sample.1246
Theuer et al. reported little or no loss of cisplatin potency, after 27 days at room temperature with protection from light, from a solution of cisplatin 500 mcg/mL in sodium chloride 0.9% at pH 4.75 and 3.25.1605
Cisplatin may react with sodium thiosulfate, sodium metabisulfite, and sodium bisulfite in solution, rapidly and completely inactivating the cisplatin.4; 1089; 1175
Cisplatin 1 mg/mL did not support the growth of several microorganisms and may impart 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
pH Effects
The pH of maximum stability is 3.5 to 5.5. Alkaline media should be avoided because of increased hydrolysis.1379
In the dark at pH 6.3, cisplatin (Bristol) 1 mg/mL in sodium chloride 0.9% reached the maximum amount of decomposition product permitted in the USP in 34 days. Half of that amount was formed in 96 days at pH 4.3.1647
Cisplatin degradation results in ammonia formation, which increases the solution pH. Thus, the initial cisplatin degradation rate may be slow but increases with time.1647
Temperature Effects
It is recommended that cisplatin solutions not be refrigerated3981; 3982 because of the formation of a crystalline precipitate.4; 633; 636; 1246 In a study of cisplatin at concentrations of 0.4 to 1 mg/mL in sodium chloride 0.9%, it was found that at 0.6 mg/mL or greater a precipitate formed on refrigeration at 2 to 6°C. At 1 mg/mL the precipitation was noted in 1 hour. However, the 0.6-mg/mL solution did not have a precipitate until after 48 hours under refrigeration. The 0.5-mg/mL and lower solutions did not precipitate for up to 72 hours at 2 to 6°C. In solutions where precipitate did form, redissolution occurred very slowly with warming back to room temperature.317 Sonication at 40°C has been used to redissolve the precipitate in about 20 to 30 minutes.1246 The warming of precipitated cisplatin solutions to effect redissolution is not recommended, however. Solutions containing a precipitate should not be used.4; 633
Freezing Solutions
Cisplatin (Bristol) 50 and 200 mg/L in dextrose 5% in sodium chloride 0.45% in polyvinyl chloride (PVC) bags and admixed with either mannitol 18.75 g/L or magnesium sulfate 1 or 2 g/L is reportedly stable for 30 days when frozen at -15°C followed by an additional 48 hours at 25°C.1088
Light Effects
Although changes in the UV spectra of cisplatin solutions on exposure to intense light have long been recognized,317 their significance was questioned. It was reported that exposure to normal laboratory light for 72 hours had no significant effect on cisplatin’s stability.635
More recently, however, Zieske et al. reported substantial cisplatin decomposition after exposure to typical laboratory light, a mixture of incandescent and fluorescent illumination. As much as 12% degraded to trichloroammineplatinate (II) after 25 hours. Cisplatin was most sensitive to light in the UV to blue region and had little sensitivity to yellow or red light. It was protected from light-induced degradation by low-actinic amber glass flasks but not by PVC bags, clear glass vials, or polyethylene syringes. The authors concluded that exposure to moderately intense white light for more than 1 hour should be avoided.1647
Cisplatin injection in amber vials is stable for 7 days if exposed to fluorescent room light, and solutions removed from amber vials should be protected from light if not intended to be used within 6 hours.3981; 3982
Chloride Ion Effects
The stability of cisplatin in solution is dependent on the chloride ion concentration present. Cisplatin is stable in solutions containing an adequate amount of chloride ion but is incompatible in solutions having a low chloride content.4; 316; 317; 634; 635; 637 In solutions with an inadequate chloride content, one or both chloride ions in the cisplatin molecule are displaced by water, forming mono- and di-aquo species. The minimum acceptable chloride ion concentration is about 0.040 mol/L, the equivalent of about 0.2% sodium chloride.317; 634; 635
At a cisplatin concentration of 200 mg/L in sodium chloride 0.9% with the pH adjusted to 4, about 3% decomposition occurs in less than 1 hour at room temperature. An equilibrium is then reached, with the cisplatin remaining stable thereafter. At lesser concentrations of chloride ion, greater decomposition of cisplatin occurs. In sodium chloride 0.45 and 0.2%, approximately 4 and 7% decomposition occurred at equilibrium, respectively. In very low chloride-containing solutions, most of the drug may be decomposed. The decomposition appears to be reversible, with cisplatin being reformed in the presence of high chloride concentrations.317
In another study, the stability of cisplatin 50 and 500 mg/L was evaluated in aqueous solutions containing sodium chloride 0.9, 0.45, and 0.1% and also in water over 24 hours at 25°C exposed to light. Approximately 2 and 4% of the cisplatin were lost in the sodium chloride 0.9 and 0.45% solutions, respectively. In the 0.1% solution, about 4 to 10% decomposition occurred in 4 to 6 hours, increasing to approximately 11 to 15% at both 12 and 24 hours. In aqueous solution with no chloride content, cisplatin decomposed rapidly, with about a 30 to 35% loss in 4 hours increasing to a 70 to 80% loss in 24 hours.635
Ambulatory Pumps
Cisplatin (David Bull) reconstituted to concentrations of 1 and 1.6 mg/mL with sterile water for injection was evaluated for stability for 14 days protected from light in Pharmacia Deltec medication cassettes at 24 and 37°C. The 1.6-mg/mL concentration developed a yellow crystalline precipitate rendering it unfit for use. For the 1-mg/mL concentration, little change in cisplatin concentration was found, but water loss due to evaporation was found to be about 1% at 24°C and 3% at 37°C in 14 days.2319
Filtration
Cisplatin 10 to 300 mcg/mL exhibited no loss due to sorption to cellulose nitrate/cellulose acetate ester (Millex OR) or Teflon (Millex FG) filters.1415; 1416
For a list of references cited in the text of this monograph, search the monograph titled References.