Can Beyond Use Dates be extended by using closed system transfer devices? If not, what is the BUD of 5-fluorouracil?

Can Beyond Use Dates be extended by using closed system transfer devices? If not, what is the BUD of 5-fluorouracil?

Comment by InpharmD Researcher

While evidence supports extending the BUD of 5-fluorouracil and other antineoplastic agents for up to 7 days after being punctured with a closed-system transfer device, The Joint Commission does not support extending the BUD past 6 hours. Limited data on the extended stability of 5-fluorouracil suggests frozen and thawed bags may be stable for up to 79 days or 28 days under refrigeration.

Background

Per a statement by The Joint Commission first published in 2018, the use of closed system transfer devices (CSTDs) should not be used to extend beyond use dates (BUD) of medications. While The Joint Commission is aware of published evidence supporting the use of CSTDs to extend the BUD longer than the 6 hours allowed for single-dose vials, this practice is not approved by the Food and Drug Administration (FDA) and should not be supported as a standard of practice. [1]

A systematic review identified 12 studies that evaluated the potential for microbial contamination of vials used for preparation with a CSTD. The studies evaluated microbial contamination according to different incubation times and different culture media, and nine studies (75%) did not have a control or comparator group. Five of the 12 studies (41.7%) found no contamination of vials punctured by CSTDs. The remaining studies found contamination rates to range from 0.3% to 27%, which were mainly attributed to handling errors or external contamination. Three studies that compared CSTD-punctured vials to conventional systems found no significant difference in microbial contamination. The low incidence of contamination observed in these studies supports extending the BUD of CSTD-punctured vials up to 7 days. Extending the BUD in this manner can help reduce waste and save costs. [2], [3]

Relevant Prescribing Information

Dosage and Administration: Do not administer in the same intravenous line concomitantly with other medicinal products. For bolus administration, store undiluted fluorouracil in the syringe for up to 4 hours at room temperature (25°C). Administer fluorouracil as an intravenous bolus through an established intravenous line. Store diluted solutions of fluorouracil for up to 4 hours at room temperature (25°C) prior to administration to the patient. For intravenous infusion regimens, administer through a central venous line using an infusion pump. [4]

Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

Can Beyond Use Dates be extended by using closed system transfer devices? If not, what is the BUD of 5-fluorouracil?

Level of evidence

C - Multiple studies with limitations or conflicting results Read more→

Please see Tables 1-2 for your response.

Long-Term Stability of 5-Fluorouracil in 0.9% Sodium Chloride after Freezing, Microwave Thawing, and Refrigeration
Design	Stability study
Objective	To investigate the stability of 5-fluorouracil diluted in 0.9% sodium chloride (normal saline [NS]) after freezing, microwave thawing, and storage for 28 days at 5°C ± 3°C
Methods	5-fluorouracil (Fluracedyl, 1,000 mg in 20 mL; Teva Pharma Belgium SA Wilrijk, Belgium, lot 06 H 28 PA) was diluted in 100 mL NS in a polyvinylchloride (PVC) bag under aseptic conditions to obtain an approximate final concentration of 800 mg/100 mL (8 mg/mL). The 5 infusion bags were initially frozen at -20°C and stored in the freezer for 79 days. After this storage period, the bags were thawed at 270 W power in a carousel-equipped microwave oven, consisting of thawing for 13 min, mixing, and thawing for an additional 7 min. The samples were then stored at 5°C ± 3°C for 28 days. Before sampling, each bag was inspected visually in room light without special equipment, and the color and appearance of the solution and the presence of any precipitate were also recorded. Afterward, a 2-mL sample was withdrawn from each bag after 1, 2, 5, 7, 9, 12, 15, 21, and 28 days of storage at 5°C ± 3°C to determine the final concentrations via high-performance liquid chromatography (HPLC).
Outcome Measures	Stability of 5-fluorouracil
Results	5-fluorouracil (800 mg in 100 mL NS; 8 mg/mL)	Mean concentration, mg/mL^§	Mean % of initial concentration	Mean pH^*
	0 days 1 day 2 days 5 days 7 days 9 days 12 days 15 days 21 days 28 days	6.78 ± 0.12 6.64 ± 0.10 6.52 ± 0.12 6.37 ± 0.16 6.61 ± 0.13 6.46 ± 0.10 6.52 ± 0.12 6.59 ± 0.11 6.46 ± 0.13 6.60 ± 0.10	100.00% 99.79% 99.58% 98.94% 98.52% 98.10% 97.46% 96.83% 95.56% 94.08%	8.86 ± 0.01 8.82 ± 0.01 8.84 ± 0.00 8.83 ± 0.00 8.82 ± 0.01 8.81 ± 0.00 8.80 ± 0.00 8.85 ± 0.01 8.84 ± 0.01 8.82 ± 0.01
	^§Initial concentration, before freezing: 6.44 ± 0.15 mg/mL. ^*Initial pH, before freezing: 8.75 ± 0.04. No color changes or precipitation were observed visually, and no crystallization was observed microscopically after thawing or after 28 days of storage at 5°C ± 3°C.
Study Author Conclusions	5-Fluorouracil 8 mg/mL in NS may be prepared in advance, frozen and stored in PVC bags, and thawed before use. The solutions remained stable after freezing at –20°C for 79 days, followed by storage at 5°C ± 3°C for up to 28 days.
InpharmD Researcher Critique	Study findings of current stability analysis may not readily apply to 5-fluorouracil prepared at different concentrations or stored under different conditions from the study settings.

References:
[1] Galanti L, Lebitasy MP, Hecq JD, Cadrobbi J, Vanbeckbergen D, Jamart J. Long-term stability of 5-Fluorouracil in 0.9% sodium chloride after freezing, microwave thawing, and refrigeration. Can J Hosp Pharm. 2009;62(1):34-38. doi:10.4212/cjhp.v62i1.115

Cost savings realized by use of the PhaSeal® closed-system transfer device for preparation of antineoplastic agents
Design	Observational, pharmacoeconomic analysis
Objective	To determine whether using a closed system transfer device (CSTD), Phaseal®, to extend the beyond-use date (BUD) of single-use vials of antineoplastic medications would result in a measurable cost saving
Inclusion Criteria	Single-use vials of antineoplastic agents; medications whose stability was 48 hours or more
Exclusion Criteria	N/A
Methods	This was a single-center study conducted by oncology services in Maryland. At this institution, Phaseal CSTDs were attached per the manufacturer's instructions in the clean room. Prior to this study, the oncology pharmacy discarded all unpreserved vials following their initial use. For this study, all partially used single-use vials of antineoplastic agents were saved following their initial use. When possible, these partially filled vias were used to prepare subsequent doses within 2-7 days. A data collection form was used to record the initial dose used, any additional dose(s) prepared, and any drug not used from each vial. For each vial, the actual amount and percent of drug salvaged were recorded. Since the amount of drug used varied depending on patient-specific variables, the total amount of drug used from the initial entry into the vials of that drug was calculated by adding the individual dose from each vial. Medications supplied as injectable solutions were assumed to be stable for 7 days with a CSTD. Medications whose stability following reconstitution is greater than 7 days were listed as stable for 7 days for the purpose of this study.
Duration	April 30 to June 18, 2012
Outcome Measures	Amount wasted (% of vial dose), amount saved by using CSTD (% of overall amount of drug used), cost savings (calculated by determining the number of vials not used due to reuse of the original vial)
Results		Stability	Amount Wasted	Amount Saved	Cost Savings
	Bleomycin	7 days	18.62%	32.10%	$383.49
	Bortezomib	7 days	18.92%	31.65%	$21,897.92
	Cyclophosphamide	6 days	22.12%	46.20%	$6,468.25
	Cytarabine	7 days (Liquid)	90.52%	1.64%	$20.36
	Dacarbazine	4 days	92.55%	0	$0.00
	Docetaxel	7 days (Liquid)	4.19%	45%	$17,050.86
	Doxorubicin (liposomal)	7 days (Liquid)	7.07%	25.67%	$5,508.72
	Eribulin	7 days (Liquid)	25%	0	$0.00
	Fludarabine	7 days (Liquid)	30%	25%	$84.76
	Fluorouracil	7 days (Liquid)	12.88%	46.49%	$1,070.88
	Gemcitabine	7 days	6.78%	79.80%	$5,399.34
	Idarubicin	7 days (Liquid)	39%	9%	$66.20
	Ifosfamide	7 days	35.70%	33.42%	$208.32
	Irinotecan	7 days (Liquid)	27.77%	11.14%	$50.88
	Methotrexate	7 days (Liquid)	63.29%	14.22%	$132.84
	Oxaliplatin	7 days (Liquid)	8.21%	30.36%	$17,951.83
	Pemetrexed	7 days	4.69%	42.15%	$18,799.60
	Topotecan	7 days	50%	30%	$620.58
	Vincristine	7 days (Liquid)	3.91%	60.65%	$329.68
	The mean initial use of the vials was 43.45%; leaving a mean of 57.03% of the drug potentially salvageable. The average overall waste avoidance was 51.35%, which represents an average of 29% per vial.
Study Author Conclusions	Significant reductions in drug waste and cost savings were realized through use of the Phaseal CSTD to extend the BUD of single-dose vials of selected antineoplastic medications. This cost reduction represents a potential annual saving of more than $700,000.
InpharmD Researcher Critique	This was a short-term cost-saving analysis. Not all eligible antineoplastic agents on formulary were used during the study period, which may have decreased the expected cost-savings by using a CSTD. Microbial testing of opened vials was not conducted, but the authors state a policy will be put in place to have an aliquot withdrawn and sent for sterility testing periodically when emptied, or at the end of 7 days after first use, whichever is earlier.

References:
[1] Edwards MS, Solimando DA Jr, Grollman FR, et al. Cost savings realized by use of the PhaSeal(®) closed-system transfer device for preparation of antineoplastic agents. J Oncol Pharm Pract. 2013;19(4):338-347. doi:10.1177/1078155213499387