Cyclosporine is available as a concentrate in 5-mL ampuls.2929 Each mL of the solution contains cyclosporine 50 mg, polyoxyethylated castor oil (Cremophor EL) 650 mg, and alcohol 278 mg (32.9%).874; 2929; 2930
Cyclosporine concentrate must be diluted prior to administration.874; 2929
Trade Name(s)
SandIMMUNE
Cyclosporine concentrate for injection is administered over 2 to 6 hours by intravenous infusion only after dilution.2929 Each mL of concentrate should be diluted in 20 to 100 mL of dextrose 5% or sodium chloride 0.9%.2929
Intact ampuls of cyclosporine concentrate should be stored below 30°C and protected from light.874; 2929 Light protection is not required for intravenous admixtures of cyclosporine.4; 1091 The manufacturer recommends that cyclosporine diluted for infusion be discarded after 24 hours.2929
Syringes
The stability of cyclosporine (Novartis) after dilution to a concentration of 0.2 or 2.5 mg/mL in dextrose 5% or sodium chloride 0.9% and packaged as 60 mL in 60-mL polypropylene syringes (Becton Dickinson) was evaluated at room temperature.2930 Although no physical changes were detected by visual inspection and chemical stability of cyclosporine did not appear to be affected, HPLC analysis revealed the development of an impurity after 1 day that substantially increased until termination of the study after 7 days.2930 This impurity was not detected in similar samples of cyclosporine that were stored in polypropylene-polyolefin bags.2930 The authors suggested that the diluted cyclosporine solution could have leached an ingredient used in the manufacture of the black rubber component of the syringe plunger.2930
Because such syringes are commonly used to transfer cyclosporine during preparation of IV solutions, an additional shorter test was conducted using 0.4 or 1 mL of undiluted cyclosporine concentrate 50 mg/mL in 1- or 5-mL polypropylene syringes.2930 The suspected leached component from the black rubber portion of the syringe plunger was not detected within the 10-minute study period.2930 Therefore, such short-term use of these syringes was considered appropriate provided the period of contact with the drug was less than 10 minutes.2930
Sorption
Simulated infusion studies of cyclosporine (Sandoz) 2 mg/mL in dextrose 5% and sodium chloride 0.9% were performed at a rate of 0.67 mL/minute over 75 minutes through 70-inch microdrip administration sets (Abbott). Significant amounts of cyclosporine were lost, presumably as a result of sorption to the tubing. Approximately 7% of the dose was lost from the dextrose 5% admixture, and about 13% was lost from the sodium chloride 0.9% admixture. The authors noted that as much as 30% of a pediatric dose could be lost.1091
In contrast, no significant cyclosporine loss occurred when 2.38 and 0.495 mg/mL in dextrose 5% and sodium chloride 0.9%, in either glass or polyvinyl chloride (PVC) containers, were delivered over 6 hours by an electronic infusion pump.1154
Cyclosporine 0.495 mg/mL in sodium chloride 0.9%, dextrose 5%, maltose 10%, and an electrolyte maintenance solution exhibited loss of delivered cyclosporine due to sorption when run through PVC administration tubing. The delivered cyclosporine concentrations were reduced to about 70% during the first 2 to 4 hours but rose to over 90% after 8 to 24 hours. The extent of sorption was somewhat higher in the electrolyte solutions compared with the sugar solutions. No loss occurred when the cyclosporine solutions were run through polybutadiene administration tubing.2443
Stability of cyclosporine 0.2 or 2.5 mg/mL diluted in dextrose 5% or sodium chloride 0.9% in ethylene vinyl acetate (EVA) containers was evaluated at 25°C.2931 The 2.5-mg/mL solution appeared to be stable for at least 2 weeks under the study conditions.2931 However, drug concentrations in the 0.2-mg/mL solution decreased to less than 90% within the 2-week study period.2931 The authors concluded that the absence of impurities detected within this study period combined with the drug loss suggest sorption to the EVA container as the cause for such decreases.2931
Plasticizer Leaching
Polyoxyethylated castor oil (Cremophor EL), a nonionic surfactant, may leach phthalate from PVC containers such as bags of infusion solutions.4; 2929 In 1996, an acceptability limit of no more than 5 parts per million (5 mcg/mL) for diethylhexyl phthalate (DEHP) plasticizer leached from PVC-containing devices (e.g., containers, administration sets, other equipment) was proposed based on a review of metabolic and toxicologic considerations.2185 FDA later evaluated the safety of DEHP exposure by comparing doses of DEHP received by patients undergoing various medical procedures with a defined tolerable intake value of DEHP, a value that was based upon the results of selected critical toxicity studies in experimental animals.3100 Based on the results of the safety assessment, FDA concluded that there is little risk posed by exposure to the amount of DEHP released from PVC bags used to store and administer drugs that require an excipient for solubilization when label instructions for preparation and administration are followed.3100 However, such conclusions do not take into account increased risk for adverse effects from DEHP exposure in certain patients (e.g., critically ill male neonates or infants, male infants less than 1 year of age, male offspring of pregnant or breast-feeding women undergoing certain medical treatments) or potential adverse effects related to aggregate exposure for patients exposed to multiple medical devices, procedures, or intravenous medications known to leach DEHP, for which there are varying levels of concern.3100; 3101
Cyclosporine (Sandoz) 3 mg/mL in dextrose 5% leached relatively large amounts of DEHP plasticizer from PVC bags. This leaching was due to the surfactant Cremophor EL in the formulation. After 4 hours at 24°C, the DEHP concentration in 50-mL bags of infusion solution was as much as 13 mcg/mL and it increased through 24 hours to 104 mcg/mL. This finding is consistent with the high surfactant concentration (3.9%) 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. Non-PVC containers and administration sets should be used to administer cyclosporine solutions.1683
Storage of cyclosporine (Sandoz) 3 mg/mL in dextrose 5% in PVC bags at 24°C was shown to cause leaching of significant amounts of DEHP due to the vehicle containing Cremophor EL and alcohol. Use of glass containers and tubing that does not contain DEHP to administer cyclosporine was recommended.1092
Cyclosporine 0.495 mg/mL in sodium chloride 0.9%, dextrose 5%, maltose 10%, and an electrolyte maintenance solution leached relatively large amounts of DEHP plasticizer when run through PVC administration tubing. The bulk of the leaching occurred during the first 4 hours but reached a plateau after 8 hours. About 94 mcg/mL was delivered over 12 hours in the saline solution. The cyclosporine admixtures in electrolyte solutions leached a greater amount of DEHP than those prepared in sugar-containing solutions.2443
Filtration
Use of either a 0.22- or 0.45-µm filter reduced the delivered cyclosporine concentration from 2.38- and 0.495-mg/mL solutions in dextrose 5% and sodium chloride 0.9%. A significant (but unspecified) decrease was found in the first sample, taken at 1 minute. At the 6-hour time point, the concentration had returned to the original concentration. The total amount of drug delivered over 6 hours was not quantified.1154
For a list of references cited in the text of this monograph, search the monograph titled References.