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Published on 29 April 2009

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Stability of 5-fluorouracil and sodium folinate admixture


This study demonstrated that an admixture of 5-fluorouracil and sodium folinate remained stable in two different ambulatory infusion systems over a two-week period

Julie Cadrobbi
Pharmacist, Medical Laboratory

Jean-Daniel Hecq
Pharmacist, Hospital Pharmacy

Danielle Vanbeckbergen
Medical Laboratory

Jacques Jamart
Centre of Biostatistics and Medical Documentation

Laurence Galanti
Medical Laboratory, Cliniques Universitaires
UCL, Yvoir, Belgium

The aim of this study was to evaluate the chemical stability of an admixture of 5-fluorouracil (5-FU) and sodium folinate in two ambulatory infusion systems placed in simulated clinical conditions. Concentrations were measured by high-performance liquid chromatography (HPLC). The solution concentrations remained stable in the infusion systems for at least two weeks, the lower confidence limits of the results value for each drug remaining superior to 90% of the initial concentration. This has practical importance for both the patient and medical staff because it determines the suitability of administration at home.

The simultaneous administration of 5-FU and sodium folinate, used to treat a wide variety of malignancies, [1-12] in one infusion system rather than via separate infusion lines, would be more convenient and less expensive, especially for home care and ambulatory patients.[13] Little is known about the stability of this ready-to-use injectable solution.[14,15] The aim of the study was to evaluate the stability of this admixture in two type of reservoir stored at 32°C, temperature reached by the solution when the containers are carried close to the body.

Main discussion
The Easypump® (Braun, Boulogne, France) and the Infusor® (Baxter, Lessines, Belgium) were filled in a vertical laminar-airflow hood with 250 ml of a 5% dextrose solution containing 24 mg/ml 5-FU and 3.2 mg/ml sodium folinate prepared from commercially available vials of 5-FU (FLURACEDYL® 5000 mg/100 ml) and sodium folinate (VORINA® 500 mg/20 ml) (Teva Pharma, Wilrijk, Belgium). A standard solution containing 25 mg/ml 5-FU and 3.12 mg/ml sodium folinate was extemporaneously diluted in sterile water for injection each day. Concentrations were measured by HPLC (Alliance system, DAD detector, Empower 2 software, Waters Association, Milford, MA, USA) using a reversed-phase column (Hypersil ODS column C18, Waters Association). The flow rate of the 5% methanol (v/v) in KH2PO4 buffer 0.01 M mobile phase was 1 ml/min, the column temperature was set at 35°C and the wavelength at 300 nm. Solutions were visually inspected and pH was measured with a pH-meter (Radiometer PHM82, Copenhagen, Denmark). The within-day variation calculated from three concentrations of 5-FU (10, 25 and 35 mg/ml) and sodium folinate (1, 3.12 and 5 mg/ml) remained below 1.1%, the between-day variation below 3.3%. The method was linear (r2 > 0.99) from 1 mg/ml to 35 mg/ml for 5-FU and 0.1 mg/ml to 7.5 mg/ml for sodium folinate. After alkaline (pH = 12.0) and acidic (pH = 1.2) treatment and heating at 100°C for 60 min, the degradation products remained separate from each parent molecule.

Five Easypump and five Infusor reservoirs were stored at 32°C for two weeks. At day 0, 1, 2, 3, 4, 7, 9 and 11, 2 ml aliquots from each reservoir were placed in glass containers to be visually inspected. pH and concentration were measured in triplicate. After injection (10 Microlitres) of standard and samples, the concentrations were automatically calculated by interpolation of a single-level calibration curve (linear trough zero) using peak areas versus standard concentrations. Data were expressed as mean ± standard deviation.

Statistical analysis demonstrated that the pH remained stable, varying from 8.86 to 8.94. No significant change was observed in the concentrations of the admixture in the two infusion pumps, the slope of the regression line was not statistically different from 0 and, as recommended by the US Food and Drug Administration,[16,17] the lower 95% confidence limit of the estimated common regression line for the two systems remained above 90% of the initial concentration during the two-week period (see Tables 1 and 2).

In treating various types of carcinoma, 5-FU may be combined with folinate salts justifying the investigation of the stability of the mixture to find out whether their prolonged administration in the same infusion system is feasible. We demonstrated that 5-FU and sodium folinate concentrations when mixed together in the same ambulatory infusion system remained stable in two types of currently used reservoirs when used for at least two weeks at 32°C. This has practical importance for both patient and medical staff because it determines the suitability of administration of this admixture in the same infusion device.


1. Peters GJ, Kohne CH. Fluoropyrimidines as antifolate drugs. In Jackman JL, Ed. Antifolate drugs in cancer therapy. Totowa, NJ: Humana Press. 1999;101-45.
2. Van der Wilt CL, Van Groeningen CJ, Pinedo HM, Smid K, Hoekman K, Meijer S, Peters GF. 5-Fluorouracil/leucovorin-induced inhibition of thymidilate synthase in normal tissues of mouse and man. J Cancer Res Clin Oncol 1997; 23:595-601.
3. Cameron DA, Gabra H, Leonard RC. Continuous 5-fluorouracil in the treatment of breast cancer. Br J Cancer 1994;70(1):120-4.
4. Noordhuis P, Holwerda U, Van der Wilt CL, Van Groeningen CJ, Smid K, Meijer S, et al. 5-Fluorouracil incorporation into RNA and DNA in relation to thymidilate synthase inhibition of human colorectal cancers. Ann Oncol 2004;15:1025-32.
5. Bathe OF, Dowden S, Sutherland F, Dixon E, Butts C, Bigam D, et al. Phase II study of neoadjuvant 5-FU + leucovorin + CPT-II in patients with resectable liver metastases from colorectal adenocarcinoma. BMC Cancer 2004;4:32.
6. Boussen H, Cvitkovic E, Wendling JL, Azli N, Bachouchi M, Mahjoubi R, et al. Chemotherapy of metastatic and/or recurrent undifferentiated nasopharyngeal carcinoma with cisplatin, bleomycin, and fluorouracil. J Clin Oncol 1991;9(9):1675-81.
7. Pinedo HM, Peters GF. Fluorouracil: biochemistry and pharmacology. J Clin Oncol 1988;6(10):1653-64.
8. Danenberg PV, Danenberg KD. Effect of 5,10- methylenetetrahydrofolate on the dissociation of 5-fluoro- 2’-deoxyuridilate from thymidilate synthetase: evidence of an ordered mechanism. Biochemistry 1978;17:4018-24.
9. Moran RG, Scanlon KI. Schedule-dependent enhancement of the cytotoxicity of fluoropyrimidines to human carcinoma cells in the presence of folinic acid. Cancer Res 1991;51:4618-23.
10. Machover D, Schwartzenberg L, Goldschmidt E, Tourani JM, Michalski B, Hayat M, et al. Treatment of advanced colorectal and gastric carcinomas with 5- fluorouracil combined with high-dose folinic acid. A pilot study. Cancer Treat Rep 1982;66:1803-7.
11. QUASAR Collaborative Group. Comparison of fluorouracil with additional levamisole, higher-dose folinic acid, or both, as adjuvant chemotherapy for colorectal cancer: a randomised trial. Lancet 2000;355:1588-96.
12. The Meta-Analysis Group in Cancer. Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: an update meta-analysis. J Clin Oncol 2004;22:3766-75.
13. Fluorouracil, uses and administration. MICROMEDEX(R) Healthcare Series Volume 128.
14. Milano G, Etienne MC, Cassuto-Viguier E, Renée N, Bousselet M, Guillot T, Lecompte D. Long-term stability of 5-fluorouracil and folinic acid admixtures. Eur J Cancer 1993;29A(1):129-32.
15. Smith JA, Morris A, Duafala ME, Bertino JR, Markman M, Kleinberg M. Stability of floxuridine and leucovorin calcium admixtures for intraperitoneal administration. Am J Hosp Pharm 1989;46:985-9.
16. Food and Drug Administration. Guideline for submitting documentation for the stability of human drugs and biologics. 1987.
17. Ruberg SJ, Stegeman JW. Pooling data for stability studies: testing the equality of batch degradation slopes. Biometrics 1991;47:1059-69.

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