TY - JOUR
AU - Ahmed, Mohamed
AB - Abstract Objectives To identify the intravenous (IV) medications that are prepared in glass bottles at the institution and establish which of these medications can be prepared in flexible IV bags such as polyvinyl chloride (PVC) or non-PVC instead of glass bottles. The cost implication of switching from glass bottles to flexible IV bags was calculated. Methods A study using FOCUS-PDCA model to identify IV medications prepared in glass bottles and establish which of these medications could be prepared in IV bags (PVC or non-PVC). The cost impact of switching from glass bottles to IV plastic bags (including PVC or non-PVC) was calculated. The stability data obtained were used as a reference for updating pharmacy internal IV preparation charts. Key findings A total of 17 IV medications were found to be prepared in IV glass bottles. Of these 17 medications, only 8 (47%) were prepared in IV glass bottles due to incompatibility with PVC bags. For 7 (41%) of the medications, of which 6 were monoclonal antibodies (MABs), the reason for preparation in glass bottles was unclear as these medications are compatible with either PVC or non-PVC or both. The potential cost savings associated with switching all of the identified medications to IV plastic bags (either non-PVC or PVC) exceeded $200 000. Conclusions The elimination of glass bottles within the institution resulted in a significant cost saving. The use of FOCUS-PDCA model can help healthcare institution achieve significant improvements in process and realize significant cost savings. Intravenous, Glass bottles, PVC, non-PVC, FOCUS-PDCA Introduction The compounding of sterile products, such as intravenous (IV) admixture, within hospital pharmacies has become a fundamental part of pharmacy practice. The preparation of IV admixtures within hospital pharmacies reduces the risk of medication errors and the microbiological contamination of IV admixtures.[1] Several guidelines, such as the United States Pharmacopeia (USP) chapter 797 Pharmaceutical Compounding of Sterile Preparations, have been developed to ensure that procedural and environmental safeguards are in place for the preparation of sterile admixtures in hospitals.[1–3] A key component of these safeguards is the use of appropriate containers for the preparation of IV admixtures. Most IV admixtures are prepared in IV plastic bags made from polyvinyl chloride (PVC), which are cheap, flexible and readily available. However, there are a number of drawbacks to the use of IV PVC bags. The first is the fact that some IV medications are incompatible with PVC bags, due to adsorption of drugs into the inner plastic surface of the bag.[4] The other major drawback is the potential for the plasticizer, di-(2-ethylhexyl) phthalates (DEHP), to leach into IV solutions.[5] The negative effects of DEHP on animals and human health has been the subject of considerable discussion within the scientific community.[6–8] These concerns on human health have led to calls for the substitution of other materials for PVC in medical devices.[9] In its assessment into the safety of various medical devices containing DEHP, the US Food and Drug Administration (FDA) concluded that there is little to no risk posed by patient exposure to the amount of DEHP released from PVC bags used for infusion of crystalloid fluids (e.g. normal saline, dextrose in water, Ringers Lactate) or IV preparations for drugs that has no leaching properties.[10] Alternatives to PVC bags include IV glass bottles and IV bags made from non-PVC. Glass bottles are inert and therefore compatible with most drugs, and they are usually transparent, making it easier to detect particles in prepared IV solutions. Despite these advantages, there are several disadvantages associated, such as the risk of breakage, which can be extremely hazardous in the case of chemotherapy medications. In addition, glass bottles are considerably heavier than IV plastic bags, require a large storage space and are prone to leakage during priming. These inherent disadvantages have meant that glass bottles have been largely superseded by IV plastic bags. Another alternative to PVC bags are IV bags made from non-PVC materials, such as ethylene-vinyl acetate (EVA) or polyolefins, of which polyethylene and polypropylene are the most common. Compatibility of drugs in non-PVC bags is generally comparable to glass bottles and unlike PVC bags are DEHP free. Given the similarity in price between non-PVC and PVC bags, non-PVC bags would be the ideal for IV drug preparation. We describe a quality improvement study using FOCUS-PDCA model, to identify the IV medications that are prepared in glass bottles and establish which of these medications can be prepared in flexible IV bags (PVC or non-PVC) instead. The cost implications of switching from glass bottles to flexible IV bags were calculated. In addition, practical a stability reference guide was developed for the medications identified during this study. Methods FOCUS-PDCA is an acronym that describes the basic components of the improvement process. The steps include: Find a process to improve Organize an effort to work on improvement Clarify current knowledge of the process Understand process variation and capability Select a strategy for continued improvement PDCA is an acronym for Plan, Do, Check and Act. The PDCA cycle is a way of continuously checking progress in each step of the FOCUS process. Find a process to improve The widespread use of glass bottles for the preparation of IV medications was identified as part of the process to ensure adherence to USP 797. Organize an effort to work on improvement An audit was undertaken to identify all IV medications that were prepared in glass bottles and the reason behind this practice. The audit revealed discrepancies in practice between different pharmacies within the institution, as some medications were prepared in glass bottles within one area and in IV bags in another area. Clarify current knowledge of the process A literature search into the stability and compatibility of the identified medications in different IV containers was undertaken. A PubMed search was conducted from inception until August 2014 with the following terms stability, di-2-ethylhexyl phthalate (DEHP), ethylene-vinyl acetate (EVA), glass bottles, polyethylene, polyolefins, polypropylene and polyvinyl chloride (PVC), name of each medication identified. In addition, resources used to identify stability data included package insert of each medication, Micromedex, Trissel's IV-checkTM available through LEXICOMP. Recommendations for switching were made based on the stability data. Understand process variation and capability The over reliance on glass bottles at the institutions was due to the unavailability of non-PVC bags. There was a problem with the market access for non-PVC bags in the region. Select a strategy for continued improvement The stability data obtained during the literature search were used as a reference for updating pharmacy internal IV preparation charts with continuous education for pharmacy staff members and audit of practice. Plan, Do, Check and Act All data for compatibility and stability were updated and are summarized and listed in Table 1. After a thorough search and close collaboration with the purchasing department, the team selected non-PVC bags (Freeflex®) from Fresenius Kabi made from polyolefin. Table 1 Medications prepared in glass bottles in King Faisal Specialist Hospital & Research Center (KFSH&RC) Drug . Compatible with PVC bag . Compatible with non-PVC bag . Reasons prepared in glass bottles at KFSH&RC . Recommendations . Alemtuzumab ⊠YES □NO □NO DATA ⊠YES □NO □NO DATA Unclear why alemtuzumab was prepared in glass bottles. Compatible with PVC bags. Can be prepared in PVC bags. Amiodarone □YES ⊠NO □NO DATA ⊠YES □NO □NO DATA Incompatible with PVC bags and risk of leaching of DEHP. Can be prepared in non-PVC bags. Basiliximab ⊠YES □NO □NO DATA ⊠YES □NO □NO DATA Unclear why Basiliximab was prepared in glass bottles. Compatible with PVC bags. Can be prepared in PVC bags. Bevacizumab ⊠YES □NO □NO DATA ⊠YES □NO □NO DATA Unclear why Bevacizumab was prepared in glass bottles. Compatible with PVC bags. Can be prepared in PVC bags. Carmustine (BiCNU®) □YES ⊠NO □NO DATA ⊠YES □NO □NO DATA Exhibits sorption to polyvinyl chloride (PVC). Prepare in non-PVC bags. Cetuximab ⊠YES □NO □NO DATA ⊠YES □NO □NO DATA Unclear as to why Cetuximab was prepared in glass bottles. Compatible with PVC bags. Can be prepared in PVC bags. Ciprofloxacin Not applicable Not applicable The only dosage strength available at KFSH&RC is the 200 mg/100 ml. Adult dose of 400 mg is prepared by decanting 2 bottles of 200 mg into an evacuated glass bottle. Add 400 mg/200 ml solution for infusion dosage forms to the hospital formulary. Cyclosporine □YES ⊠NO □NO DATA ⊠YES □NO □NO DATA Subject to sorption to PVC bags and leaching of DHEP from PVC bags. Can be prepared in non-PVC bags. Docetaxel □YES ⊠NO □NO DATA ⊠YES □NO □NO DATA Subject to leaching of DHEP from PVC bags. Can be prepared in non-PVC bags. Etoposide □YES ⊠NO[1–3] □NO DATA ⊠YES □NO □NO DATA Subject to leaching of DHEP from PVC bags. Can be prepared in non-PVC bags. Fluconazole Not applicable Not applicable The only dosage strength available at KFSH&RC is the 200 mg/100 ml. Doses other than 200 mg are transferred into an evacuated glass bottle. Add 100 mg/50 ml and 400 mg/200 ml solution for infusion dosage forms to the hospital formulary. Foscarnet ⊠YES □NO □NO DATA □YES □NO ⊠NO DATA Unclear as to why Foscarnet was prepared in glass bottles. Compatible with PVC bags. Can be prepared in PVC bags. Infliximab ⊠YES □NO □NO DATA □YES □NO ⊠NO DATA Unclear as to why Infliximab was prepared in glass bottles. Compatible with PVC bags. Can be prepared in PVC bags. Nitroglycerine □YES ⊠NO □NO DATA ⊠YES[1–3] □NO □NO DATA Subject to adsorption to PVC bags. Can be prepared in PVC bags. Paclitaxel □YES ⊠NO □NO DATA ⊠YES □NO □NO DATA Subject to leaching of DEHP by polyoxyl castor oil (Cremophor)® from PVC bags. Can be prepared in non-PVC bags. Rituximab ⊠YES □NO □NO DATA ⊠YES □NO □NO DATA Unclear as to why rituximab was prepared in glass bottles. Compatible with PVC bags. Can be prepared in PVC bags. Tacrolimus □YES ⊠NO □NO DATA ⊠YES □NO □NO DATA Tacrolimus has demonstrated some loss due to sorption to PVC containers and sets. Can be prepared in non-PVC bags. Drug . Compatible with PVC bag . Compatible with non-PVC bag . Reasons prepared in glass bottles at KFSH&RC . Recommendations . Alemtuzumab ⊠YES □NO □NO DATA ⊠YES □NO □NO DATA Unclear why alemtuzumab was prepared in glass bottles. Compatible with PVC bags. Can be prepared in PVC bags. Amiodarone □YES ⊠NO □NO DATA ⊠YES □NO □NO DATA Incompatible with PVC bags and risk of leaching of DEHP. Can be prepared in non-PVC bags. Basiliximab ⊠YES □NO □NO DATA ⊠YES □NO □NO DATA Unclear why Basiliximab was prepared in glass bottles. Compatible with PVC bags. Can be prepared in PVC bags. Bevacizumab ⊠YES □NO □NO DATA ⊠YES □NO □NO DATA Unclear why Bevacizumab was prepared in glass bottles. Compatible with PVC bags. Can be prepared in PVC bags. Carmustine (BiCNU®) □YES ⊠NO □NO DATA ⊠YES □NO □NO DATA Exhibits sorption to polyvinyl chloride (PVC). Prepare in non-PVC bags. Cetuximab ⊠YES □NO □NO DATA ⊠YES □NO □NO DATA Unclear as to why Cetuximab was prepared in glass bottles. Compatible with PVC bags. Can be prepared in PVC bags. Ciprofloxacin Not applicable Not applicable The only dosage strength available at KFSH&RC is the 200 mg/100 ml. Adult dose of 400 mg is prepared by decanting 2 bottles of 200 mg into an evacuated glass bottle. Add 400 mg/200 ml solution for infusion dosage forms to the hospital formulary. Cyclosporine □YES ⊠NO □NO DATA ⊠YES □NO □NO DATA Subject to sorption to PVC bags and leaching of DHEP from PVC bags. Can be prepared in non-PVC bags. Docetaxel □YES ⊠NO □NO DATA ⊠YES □NO □NO DATA Subject to leaching of DHEP from PVC bags. Can be prepared in non-PVC bags. Etoposide □YES ⊠NO[1–3] □NO DATA ⊠YES □NO □NO DATA Subject to leaching of DHEP from PVC bags. Can be prepared in non-PVC bags. Fluconazole Not applicable Not applicable The only dosage strength available at KFSH&RC is the 200 mg/100 ml. Doses other than 200 mg are transferred into an evacuated glass bottle. Add 100 mg/50 ml and 400 mg/200 ml solution for infusion dosage forms to the hospital formulary. Foscarnet ⊠YES □NO □NO DATA □YES □NO ⊠NO DATA Unclear as to why Foscarnet was prepared in glass bottles. Compatible with PVC bags. Can be prepared in PVC bags. Infliximab ⊠YES □NO □NO DATA □YES □NO ⊠NO DATA Unclear as to why Infliximab was prepared in glass bottles. Compatible with PVC bags. Can be prepared in PVC bags. Nitroglycerine □YES ⊠NO □NO DATA ⊠YES[1–3] □NO □NO DATA Subject to adsorption to PVC bags. Can be prepared in PVC bags. Paclitaxel □YES ⊠NO □NO DATA ⊠YES □NO □NO DATA Subject to leaching of DEHP by polyoxyl castor oil (Cremophor)® from PVC bags. Can be prepared in non-PVC bags. Rituximab ⊠YES □NO □NO DATA ⊠YES □NO □NO DATA Unclear as to why rituximab was prepared in glass bottles. Compatible with PVC bags. Can be prepared in PVC bags. Tacrolimus □YES ⊠NO □NO DATA ⊠YES □NO □NO DATA Tacrolimus has demonstrated some loss due to sorption to PVC containers and sets. Can be prepared in non-PVC bags. For detailed information on stability data for the above medications please refer to Table 2. DEHP, diethylhexyl phthalate; D5W, dextrose 5%; EVA, ethylene-vinyl acetate; NS, normal saline; PVC, polyvinyl chloride. Open in new tab Table 1 Medications prepared in glass bottles in King Faisal Specialist Hospital & Research Center (KFSH&RC) Drug . Compatible with PVC bag . Compatible with non-PVC bag . Reasons prepared in glass bottles at KFSH&RC . Recommendations . Alemtuzumab ⊠YES □NO □NO DATA ⊠YES □NO □NO DATA Unclear why alemtuzumab was prepared in glass bottles. Compatible with PVC bags. Can be prepared in PVC bags. Amiodarone □YES ⊠NO □NO DATA ⊠YES □NO □NO DATA Incompatible with PVC bags and risk of leaching of DEHP. Can be prepared in non-PVC bags. Basiliximab ⊠YES □NO □NO DATA ⊠YES □NO □NO DATA Unclear why Basiliximab was prepared in glass bottles. Compatible with PVC bags. Can be prepared in PVC bags. Bevacizumab ⊠YES □NO □NO DATA ⊠YES □NO □NO DATA Unclear why Bevacizumab was prepared in glass bottles. Compatible with PVC bags. Can be prepared in PVC bags. Carmustine (BiCNU®) □YES ⊠NO □NO DATA ⊠YES □NO □NO DATA Exhibits sorption to polyvinyl chloride (PVC). Prepare in non-PVC bags. Cetuximab ⊠YES □NO □NO DATA ⊠YES □NO □NO DATA Unclear as to why Cetuximab was prepared in glass bottles. Compatible with PVC bags. Can be prepared in PVC bags. Ciprofloxacin Not applicable Not applicable The only dosage strength available at KFSH&RC is the 200 mg/100 ml. Adult dose of 400 mg is prepared by decanting 2 bottles of 200 mg into an evacuated glass bottle. Add 400 mg/200 ml solution for infusion dosage forms to the hospital formulary. Cyclosporine □YES ⊠NO □NO DATA ⊠YES □NO □NO DATA Subject to sorption to PVC bags and leaching of DHEP from PVC bags. Can be prepared in non-PVC bags. Docetaxel □YES ⊠NO □NO DATA ⊠YES □NO □NO DATA Subject to leaching of DHEP from PVC bags. Can be prepared in non-PVC bags. Etoposide □YES ⊠NO[1–3] □NO DATA ⊠YES □NO □NO DATA Subject to leaching of DHEP from PVC bags. Can be prepared in non-PVC bags. Fluconazole Not applicable Not applicable The only dosage strength available at KFSH&RC is the 200 mg/100 ml. Doses other than 200 mg are transferred into an evacuated glass bottle. Add 100 mg/50 ml and 400 mg/200 ml solution for infusion dosage forms to the hospital formulary. Foscarnet ⊠YES □NO □NO DATA □YES □NO ⊠NO DATA Unclear as to why Foscarnet was prepared in glass bottles. Compatible with PVC bags. Can be prepared in PVC bags. Infliximab ⊠YES □NO □NO DATA □YES □NO ⊠NO DATA Unclear as to why Infliximab was prepared in glass bottles. Compatible with PVC bags. Can be prepared in PVC bags. Nitroglycerine □YES ⊠NO □NO DATA ⊠YES[1–3] □NO □NO DATA Subject to adsorption to PVC bags. Can be prepared in PVC bags. Paclitaxel □YES ⊠NO □NO DATA ⊠YES □NO □NO DATA Subject to leaching of DEHP by polyoxyl castor oil (Cremophor)® from PVC bags. Can be prepared in non-PVC bags. Rituximab ⊠YES □NO □NO DATA ⊠YES □NO □NO DATA Unclear as to why rituximab was prepared in glass bottles. Compatible with PVC bags. Can be prepared in PVC bags. Tacrolimus □YES ⊠NO □NO DATA ⊠YES □NO □NO DATA Tacrolimus has demonstrated some loss due to sorption to PVC containers and sets. Can be prepared in non-PVC bags. Drug . Compatible with PVC bag . Compatible with non-PVC bag . Reasons prepared in glass bottles at KFSH&RC . Recommendations . Alemtuzumab ⊠YES □NO □NO DATA ⊠YES □NO □NO DATA Unclear why alemtuzumab was prepared in glass bottles. Compatible with PVC bags. Can be prepared in PVC bags. Amiodarone □YES ⊠NO □NO DATA ⊠YES □NO □NO DATA Incompatible with PVC bags and risk of leaching of DEHP. Can be prepared in non-PVC bags. Basiliximab ⊠YES □NO □NO DATA ⊠YES □NO □NO DATA Unclear why Basiliximab was prepared in glass bottles. Compatible with PVC bags. Can be prepared in PVC bags. Bevacizumab ⊠YES □NO □NO DATA ⊠YES □NO □NO DATA Unclear why Bevacizumab was prepared in glass bottles. Compatible with PVC bags. Can be prepared in PVC bags. Carmustine (BiCNU®) □YES ⊠NO □NO DATA ⊠YES □NO □NO DATA Exhibits sorption to polyvinyl chloride (PVC). Prepare in non-PVC bags. Cetuximab ⊠YES □NO □NO DATA ⊠YES □NO □NO DATA Unclear as to why Cetuximab was prepared in glass bottles. Compatible with PVC bags. Can be prepared in PVC bags. Ciprofloxacin Not applicable Not applicable The only dosage strength available at KFSH&RC is the 200 mg/100 ml. Adult dose of 400 mg is prepared by decanting 2 bottles of 200 mg into an evacuated glass bottle. Add 400 mg/200 ml solution for infusion dosage forms to the hospital formulary. Cyclosporine □YES ⊠NO □NO DATA ⊠YES □NO □NO DATA Subject to sorption to PVC bags and leaching of DHEP from PVC bags. Can be prepared in non-PVC bags. Docetaxel □YES ⊠NO □NO DATA ⊠YES □NO □NO DATA Subject to leaching of DHEP from PVC bags. Can be prepared in non-PVC bags. Etoposide □YES ⊠NO[1–3] □NO DATA ⊠YES □NO □NO DATA Subject to leaching of DHEP from PVC bags. Can be prepared in non-PVC bags. Fluconazole Not applicable Not applicable The only dosage strength available at KFSH&RC is the 200 mg/100 ml. Doses other than 200 mg are transferred into an evacuated glass bottle. Add 100 mg/50 ml and 400 mg/200 ml solution for infusion dosage forms to the hospital formulary. Foscarnet ⊠YES □NO □NO DATA □YES □NO ⊠NO DATA Unclear as to why Foscarnet was prepared in glass bottles. Compatible with PVC bags. Can be prepared in PVC bags. Infliximab ⊠YES □NO □NO DATA □YES □NO ⊠NO DATA Unclear as to why Infliximab was prepared in glass bottles. Compatible with PVC bags. Can be prepared in PVC bags. Nitroglycerine □YES ⊠NO □NO DATA ⊠YES[1–3] □NO □NO DATA Subject to adsorption to PVC bags. Can be prepared in PVC bags. Paclitaxel □YES ⊠NO □NO DATA ⊠YES □NO □NO DATA Subject to leaching of DEHP by polyoxyl castor oil (Cremophor)® from PVC bags. Can be prepared in non-PVC bags. Rituximab ⊠YES □NO □NO DATA ⊠YES □NO □NO DATA Unclear as to why rituximab was prepared in glass bottles. Compatible with PVC bags. Can be prepared in PVC bags. Tacrolimus □YES ⊠NO □NO DATA ⊠YES □NO □NO DATA Tacrolimus has demonstrated some loss due to sorption to PVC containers and sets. Can be prepared in non-PVC bags. For detailed information on stability data for the above medications please refer to Table 2. DEHP, diethylhexyl phthalate; D5W, dextrose 5%; EVA, ethylene-vinyl acetate; NS, normal saline; PVC, polyvinyl chloride. Open in new tab The annual consumption of glass bottles for each medication was generated from the pharmacy computer system. This allowed the team to accurately estimate the quantity of non-PVC bags required for purchase and calculate the cost implications of switching from glass bottles to plastic bags. The cost implication will be presented as a total cost rather than the cost of each medication to ensure both commercial and pharmacy confidentiality. Results Number and types of medications prepared in glass bottles As shown in Table 1, a total of 17 IV medications were found to be prepared in IV glass bottles. Of these 17 medications, only 8 (47%) were prepared in IV glass bottles due to incompatibility with PVC bags. For 7 (41%) of the medications, of which 6 were monoclonal antibodies (MABs), the reason for preparation in glass bottles was unclear as these medications are compatible with either PVC or non-PVC or both. The remaining 2 (12%) medications, ciprofloxacin and fluconazole, are only available as one strength in the hospital formulary, although there are other strengths available in the market. Consequently, doses other than the available strength at the institution have to be transferred into an evacuated IV glass bottle. Data on compatibility and stability There was compatibility date available for all the medications in this study. For the medications that were found to be incompatible with PVC bags, available data regarding stability in non-PVC bags are shown in Table 2. In general, the stability in non-PVC or PVC bags was comparable or longer duration compared to glass bottles. Most of the medications in this study, such as cyclosporine and amiodarone, have been around for many years consequently some of the stability data was published in the 1990s. However, more recent studies for the same medications have yielded similar stability data. Table 2 Stability data of medications identified during the FOCUS-PDCA process as well as both formulary and non-formulary MABs Drug . Material . Solutions . Concentration . Temperature . Stability . Ref . Comments . Amiodarone Polyolefin (VISIV® Hospira) D5W 1 mg/ml Room 24 h [11,12] The polysorbate surfactant content in the amiodarone hydrochloride formulation leaches DEHP plasticizer from PVC containers and administration sets. Conflicting data with regard to stability in NS. Polyolefin D5W 2 mg/ml Refrigerated Room 38 days 21 days [13] Glass bottle D5W & NS 2 mg/ml Refrigerated Room 32 days [14] Carmustine Polyethylene D5W 0.2 mg/ml Refrigerated Room 48 h 2.5 h (protected from light) [15] Carmustine exhibits sorption to PVC and EVA containers and administration tubing. Polyethylene D5W 0.1–0.5 mg/ml and 1 mg/ml Refrigerated Room 48 h 4 h [16] Polyolefin (VISV® Hospira) D5W 1 mg/ml Room 6 h [11] Polyethylene-lined multi-layer bags Glass bottles NS &D5W 0.96 mg/ml Refrigerated Room 48 h 3 h (protected from light) [17] Glass bottles D5W 0.2 mg/ml Refrigerated Room 48 h 5.5 h (protected from light) [15] Cyclosporine Polypropylene-polyolefin (Aviva® Baxter) NS & D5W 0.2, 2.5 mg/ml Room 14 days [18] Subject to sorption to PVC bags and leaching of DHEP from PVC bags. Ethylene-vinyl acetate (EVA) NS & D5W 0.2 mg/ml 2.5 mg/ml Room 7 days 14 days [19] Glass bottle D5W 2 mg/ml Refrigerated and Room 48 h [20] Docetaxel (1-vial) Polyolefin plastic bags (Macoflex-N, Macopharma® Polyolefin plastic bags (Macoflex-N, Macopharma) NS & D5W 0.24–0.32, 0.77, 0.95 mg/ml Refrigerated and Room 28 days [21] The polysorbate 80 surfactant content of both the 1-vial docetaxel formulations as well as the 2-vial formulation leaches DEHP plasticizer from PVC containers and administration set tubing. All infusions should be carefully examined for visual precipitation prior to use and at intervals during infusion.[23] There are conflicting data with regard to the stability of docetaxel, especially with regard to the formation of precipitation when stored at room temperature.[25–27] Furthermore, agitation of docetaxel may promote the formation of precipitate material. Docetaxel (2-vials) Polyethylene (Ecoflac® plus), and Polypropylene (Plasco®, B Braun) Glass bottle NS & D5W 0.3, 0.9 mg/ml Refrigerated and Room 28 days (protected from light) [22] Polyelofin (Viaflo® Baxter) NS & D5W 0.3, 0.7 mg/ml Refrigerated and Room 56 days (protected from light) [23] Polypropylene–Polyethylene Copolymer (B Braun) NS 0.4, 0.8 mg/ml Room 35 days [24] Etoposide Polypropylene NS 0.2 mg/ml 0.4 mg/ml Room 96 h 24 h [28] The polysorbate 80 surfactant in the etoposide formulation leaches DEHP plasticizer from PVC containers and administration set tubing. Etoposide has poor aqueous solubility, and precipitation from aqueous solutions has occurred irregularly, even in low concentrations. Time to precipitation is variable, but at concentrations above 0.4 mg/ml precipitation can occur rapidly. Polyethylene (Ecoflac®, B Braun) NS & D5W 0.05, 0.4, 0.2 mg/ml Refrigerated (protected from light) and Room (in ambient light) 8 days [29] Glass D5W NS 0.4 mg/ml 0.05-0.3 mg/ml Room 4 days [30] Glass NS 0.2–0.5 mg/ml 10–12 mg/ml (For other concentrations see comments) Refrigerated and Room 24 h 7 days [31] Solution of 2, 4, and 6 mg/ml precipitated within 2 h. Solutions from 1-8 mg/ml lost more than 10% of the initial concentration within 24 h.[31] Etoposide phosphate Polyethylene (Ecoflac, B. Braun) and Glass NS & D5W 0.08, 3 mg/ml Room 7 days (protected from light) [32] PVC NS & D5W 0.1, 10 mg/ml Refrigerated and Room 31 days [33] Foscarnet PVC NS & D5W 12 mg/ml Refrigerated and Room 35 days [34,35] Nitroglycerine Polyolefin & Glass NS & D5W 0.2, 0.4 mg/ml Refrigerated (protected from light) and Room 28 days [36] Nitroglycerine will undergo substantial loss from aqueous solutions due to sorption to PVC containers and administration sets. Paclitaxel Polyolefin (Freeflex® Fresinus Kabi) NS 0.3 mg/ml Refrigerated Room 28 days 6 days protected from light [37] The Cremophor EL surfactant in paclitaxel formulation leaches large amounts of DEHP plasticizer from PVC containers and administration sets. D5W Refrigerated Room 28 days 8 days protected from light NS 0.75 mg/ml Refrigerated Room 20 days 6 days protected from light D5W Refrigerated Room 20 days 4 days protected from light NS 1.2 mg/ml Refrigerated Room 12 days 4 days protected from light D5W Refrigerated Room 12 days 4 days protected from light Polyolefin (Viaflo® B-Braun) NS & D5W 0.3 mg/ml Refrigerated Room 13 days 3 days protected from light [38] NS 1.2 mg/ml Refrigerated Room 9 days 3 days protected from light D5W 1.2 mg/ml Refrigerated Room 10 days 3 days protected from light Polyethylene (Ecoflac® B. Braun) NS 0.3 mg/ml Refrigerated Room 16 days 3 days protected from light D5W 0.3 mg/ml Refrigerated Room 18 days 3 days protected from light NS & D5W 1.2 mg/ml Refrigerated Room 12 days 3 days protected from light Glass bottles NS 0.3 mg/ml Refrigerated Room 13 days 3 days protected from light D5W 0.3 mg/ml Refrigerated Room 15 days 7 days protected from light NS 1.2 mg/ml Refrigerated Room 8 days 5 days protected from light D5W 1.2 mg/ml Refrigerated Room 10 days 7 days protected from light Tacrolimus Polyolefin NS & D5W 0.1 mg/ml Room 48 h [39] Tacrolimus has demonstrated some loss due to sorption to PVC containers and sets. Glass bottle D5W 0.1 mg/ml Room 48 h Stability of Monoclonal Antibodies Drug Material Solutions Concentration Temperature Stability Ref Comments Alemtuzumab* Polyolefin NS 0.28 mg/ml Refrigerated Room 14 days [40] Concerns have been raised about the method used to determine the stability of alemtuzumab in this study. The formation of large molecular weight species, which can occur as a result of protein degradation and aggregation during preparation, may not be adequately detected by the method used in this study.[41] PVC NS 0.1–41 mcg/ml Refrigerated 28 days [42] Basiliximab* PVC NS & D5W 0.4 mg/ml Refrigerated Room 24 h 4 h [43] Follow SPC recommendations. Belimumab PVC or Polyolefin NS 0.1–0.5 mg/ml and 1 mg/ml Refrigerated 8 h [44] Follow SPC recommendations. Bevacizumab* Polyolefin NS 2 mg/ml & 16 mg/ml Refrigerated Room 90 days [45] BrentuximabVedotin Not specified NS & D5W 0.4–1.8 mg/ml Refrigerated 24 h [46] Follow SPC recommendations. Cetuximab* PVC Glass vials NS 2 mg/ml Refrigerated 14 days [47] Concerns have been raised about the method used to determine the stability of Cetuximab in this study. The formation of large molecular weight species, which can occur as a result of protein degradation and aggregation during preparation, may not be adequately detected by the method used in this study.[41] Eculizumab Not specified NS & D5W 5 mg/ml Refrigerated Room 24 h protected from light [48] Follow SPC recommendations. Golimumab (Simponi Aria®) Not specified NS Room 4 h [49] Follow SPC recommendations. Infliximab* PVC NS 0.4 mg/ml Refrigerated 14 days [50] Ipilimumab Polyolefin NS 2 mg/ml Refrigerated Room 30 days [51] Manufacturer recommends 24 h in room temperature or refrigerated.[52] Natalizumab Not specified NS 2.6 mg/ml Refrigerated 8 h [53] Follow SPC recommendations. Ofatumumab Polyolefin PVC NS 0.3, 2 mg/ml Refrigerated 24 h [54] Follow SPC recommendations. Panitumumab PVC NS 2.5 mg/ml Refrigerated 14 days [47] Concerns have been raised about the method used to determine the stability of Panitumumab in this study. The formation of large molecular weight species, which can occur as a result of protein degradation and aggregation during preparation, may not be adequately detected by the method used in this study.[41] Glass Undiluted 20 mg/ml Refrigerated 14 days Pertuzumab Polyolefin PVC NS 1.68, 3.36 mg/ml Refrigerated Room 24 h [55] RiTUXimab* Polyolefin (Freeflex® Fresinus Kabi) NS 1 mg/ml Refrigerated 180 days (protected from light) [56] PVC, Polyethylene NS & D5W 1–4 mg/ml Refrigerated 24 h [57] Trastuzumab* PVC Polyolefin NS 1.68, 2.88 mg/ml Refrigerated Room 24 h [55] Polyolefin (Freeflex® Fresinus Kabi) NS 0.8, 2.4 mg/ml Refrigerated 180 days (protected from light) [58] Ado-Trastuzumab Emtansine PVC Polyethylene NS 250 ml of NS Refrigerated 24 h [59] Follow SPC recommendation Drug . Material . Solutions . Concentration . Temperature . Stability . Ref . Comments . Amiodarone Polyolefin (VISIV® Hospira) D5W 1 mg/ml Room 24 h [11,12] The polysorbate surfactant content in the amiodarone hydrochloride formulation leaches DEHP plasticizer from PVC containers and administration sets. Conflicting data with regard to stability in NS. Polyolefin D5W 2 mg/ml Refrigerated Room 38 days 21 days [13] Glass bottle D5W & NS 2 mg/ml Refrigerated Room 32 days [14] Carmustine Polyethylene D5W 0.2 mg/ml Refrigerated Room 48 h 2.5 h (protected from light) [15] Carmustine exhibits sorption to PVC and EVA containers and administration tubing. Polyethylene D5W 0.1–0.5 mg/ml and 1 mg/ml Refrigerated Room 48 h 4 h [16] Polyolefin (VISV® Hospira) D5W 1 mg/ml Room 6 h [11] Polyethylene-lined multi-layer bags Glass bottles NS &D5W 0.96 mg/ml Refrigerated Room 48 h 3 h (protected from light) [17] Glass bottles D5W 0.2 mg/ml Refrigerated Room 48 h 5.5 h (protected from light) [15] Cyclosporine Polypropylene-polyolefin (Aviva® Baxter) NS & D5W 0.2, 2.5 mg/ml Room 14 days [18] Subject to sorption to PVC bags and leaching of DHEP from PVC bags. Ethylene-vinyl acetate (EVA) NS & D5W 0.2 mg/ml 2.5 mg/ml Room 7 days 14 days [19] Glass bottle D5W 2 mg/ml Refrigerated and Room 48 h [20] Docetaxel (1-vial) Polyolefin plastic bags (Macoflex-N, Macopharma® Polyolefin plastic bags (Macoflex-N, Macopharma) NS & D5W 0.24–0.32, 0.77, 0.95 mg/ml Refrigerated and Room 28 days [21] The polysorbate 80 surfactant content of both the 1-vial docetaxel formulations as well as the 2-vial formulation leaches DEHP plasticizer from PVC containers and administration set tubing. All infusions should be carefully examined for visual precipitation prior to use and at intervals during infusion.[23] There are conflicting data with regard to the stability of docetaxel, especially with regard to the formation of precipitation when stored at room temperature.[25–27] Furthermore, agitation of docetaxel may promote the formation of precipitate material. Docetaxel (2-vials) Polyethylene (Ecoflac® plus), and Polypropylene (Plasco®, B Braun) Glass bottle NS & D5W 0.3, 0.9 mg/ml Refrigerated and Room 28 days (protected from light) [22] Polyelofin (Viaflo® Baxter) NS & D5W 0.3, 0.7 mg/ml Refrigerated and Room 56 days (protected from light) [23] Polypropylene–Polyethylene Copolymer (B Braun) NS 0.4, 0.8 mg/ml Room 35 days [24] Etoposide Polypropylene NS 0.2 mg/ml 0.4 mg/ml Room 96 h 24 h [28] The polysorbate 80 surfactant in the etoposide formulation leaches DEHP plasticizer from PVC containers and administration set tubing. Etoposide has poor aqueous solubility, and precipitation from aqueous solutions has occurred irregularly, even in low concentrations. Time to precipitation is variable, but at concentrations above 0.4 mg/ml precipitation can occur rapidly. Polyethylene (Ecoflac®, B Braun) NS & D5W 0.05, 0.4, 0.2 mg/ml Refrigerated (protected from light) and Room (in ambient light) 8 days [29] Glass D5W NS 0.4 mg/ml 0.05-0.3 mg/ml Room 4 days [30] Glass NS 0.2–0.5 mg/ml 10–12 mg/ml (For other concentrations see comments) Refrigerated and Room 24 h 7 days [31] Solution of 2, 4, and 6 mg/ml precipitated within 2 h. Solutions from 1-8 mg/ml lost more than 10% of the initial concentration within 24 h.[31] Etoposide phosphate Polyethylene (Ecoflac, B. Braun) and Glass NS & D5W 0.08, 3 mg/ml Room 7 days (protected from light) [32] PVC NS & D5W 0.1, 10 mg/ml Refrigerated and Room 31 days [33] Foscarnet PVC NS & D5W 12 mg/ml Refrigerated and Room 35 days [34,35] Nitroglycerine Polyolefin & Glass NS & D5W 0.2, 0.4 mg/ml Refrigerated (protected from light) and Room 28 days [36] Nitroglycerine will undergo substantial loss from aqueous solutions due to sorption to PVC containers and administration sets. Paclitaxel Polyolefin (Freeflex® Fresinus Kabi) NS 0.3 mg/ml Refrigerated Room 28 days 6 days protected from light [37] The Cremophor EL surfactant in paclitaxel formulation leaches large amounts of DEHP plasticizer from PVC containers and administration sets. D5W Refrigerated Room 28 days 8 days protected from light NS 0.75 mg/ml Refrigerated Room 20 days 6 days protected from light D5W Refrigerated Room 20 days 4 days protected from light NS 1.2 mg/ml Refrigerated Room 12 days 4 days protected from light D5W Refrigerated Room 12 days 4 days protected from light Polyolefin (Viaflo® B-Braun) NS & D5W 0.3 mg/ml Refrigerated Room 13 days 3 days protected from light [38] NS 1.2 mg/ml Refrigerated Room 9 days 3 days protected from light D5W 1.2 mg/ml Refrigerated Room 10 days 3 days protected from light Polyethylene (Ecoflac® B. Braun) NS 0.3 mg/ml Refrigerated Room 16 days 3 days protected from light D5W 0.3 mg/ml Refrigerated Room 18 days 3 days protected from light NS & D5W 1.2 mg/ml Refrigerated Room 12 days 3 days protected from light Glass bottles NS 0.3 mg/ml Refrigerated Room 13 days 3 days protected from light D5W 0.3 mg/ml Refrigerated Room 15 days 7 days protected from light NS 1.2 mg/ml Refrigerated Room 8 days 5 days protected from light D5W 1.2 mg/ml Refrigerated Room 10 days 7 days protected from light Tacrolimus Polyolefin NS & D5W 0.1 mg/ml Room 48 h [39] Tacrolimus has demonstrated some loss due to sorption to PVC containers and sets. Glass bottle D5W 0.1 mg/ml Room 48 h Stability of Monoclonal Antibodies Drug Material Solutions Concentration Temperature Stability Ref Comments Alemtuzumab* Polyolefin NS 0.28 mg/ml Refrigerated Room 14 days [40] Concerns have been raised about the method used to determine the stability of alemtuzumab in this study. The formation of large molecular weight species, which can occur as a result of protein degradation and aggregation during preparation, may not be adequately detected by the method used in this study.[41] PVC NS 0.1–41 mcg/ml Refrigerated 28 days [42] Basiliximab* PVC NS & D5W 0.4 mg/ml Refrigerated Room 24 h 4 h [43] Follow SPC recommendations. Belimumab PVC or Polyolefin NS 0.1–0.5 mg/ml and 1 mg/ml Refrigerated 8 h [44] Follow SPC recommendations. Bevacizumab* Polyolefin NS 2 mg/ml & 16 mg/ml Refrigerated Room 90 days [45] BrentuximabVedotin Not specified NS & D5W 0.4–1.8 mg/ml Refrigerated 24 h [46] Follow SPC recommendations. Cetuximab* PVC Glass vials NS 2 mg/ml Refrigerated 14 days [47] Concerns have been raised about the method used to determine the stability of Cetuximab in this study. The formation of large molecular weight species, which can occur as a result of protein degradation and aggregation during preparation, may not be adequately detected by the method used in this study.[41] Eculizumab Not specified NS & D5W 5 mg/ml Refrigerated Room 24 h protected from light [48] Follow SPC recommendations. Golimumab (Simponi Aria®) Not specified NS Room 4 h [49] Follow SPC recommendations. Infliximab* PVC NS 0.4 mg/ml Refrigerated 14 days [50] Ipilimumab Polyolefin NS 2 mg/ml Refrigerated Room 30 days [51] Manufacturer recommends 24 h in room temperature or refrigerated.[52] Natalizumab Not specified NS 2.6 mg/ml Refrigerated 8 h [53] Follow SPC recommendations. Ofatumumab Polyolefin PVC NS 0.3, 2 mg/ml Refrigerated 24 h [54] Follow SPC recommendations. Panitumumab PVC NS 2.5 mg/ml Refrigerated 14 days [47] Concerns have been raised about the method used to determine the stability of Panitumumab in this study. The formation of large molecular weight species, which can occur as a result of protein degradation and aggregation during preparation, may not be adequately detected by the method used in this study.[41] Glass Undiluted 20 mg/ml Refrigerated 14 days Pertuzumab Polyolefin PVC NS 1.68, 3.36 mg/ml Refrigerated Room 24 h [55] RiTUXimab* Polyolefin (Freeflex® Fresinus Kabi) NS 1 mg/ml Refrigerated 180 days (protected from light) [56] PVC, Polyethylene NS & D5W 1–4 mg/ml Refrigerated 24 h [57] Trastuzumab* PVC Polyolefin NS 1.68, 2.88 mg/ml Refrigerated Room 24 h [55] Polyolefin (Freeflex® Fresinus Kabi) NS 0.8, 2.4 mg/ml Refrigerated 180 days (protected from light) [58] Ado-Trastuzumab Emtansine PVC Polyethylene NS 250 ml of NS Refrigerated 24 h [59] Follow SPC recommendation DEHP, diethylhexyl phthalate; D5W, dextrose 5%; EVA, ethylene-vinyl acetate; NS, normal Saline; PVC, polyvinyl chloride; SPC, summary of product characteristics. * Available at KFSH&RC. Open in new tab Table 2 Stability data of medications identified during the FOCUS-PDCA process as well as both formulary and non-formulary MABs Drug . Material . Solutions . Concentration . Temperature . Stability . Ref . Comments . Amiodarone Polyolefin (VISIV® Hospira) D5W 1 mg/ml Room 24 h [11,12] The polysorbate surfactant content in the amiodarone hydrochloride formulation leaches DEHP plasticizer from PVC containers and administration sets. Conflicting data with regard to stability in NS. Polyolefin D5W 2 mg/ml Refrigerated Room 38 days 21 days [13] Glass bottle D5W & NS 2 mg/ml Refrigerated Room 32 days [14] Carmustine Polyethylene D5W 0.2 mg/ml Refrigerated Room 48 h 2.5 h (protected from light) [15] Carmustine exhibits sorption to PVC and EVA containers and administration tubing. Polyethylene D5W 0.1–0.5 mg/ml and 1 mg/ml Refrigerated Room 48 h 4 h [16] Polyolefin (VISV® Hospira) D5W 1 mg/ml Room 6 h [11] Polyethylene-lined multi-layer bags Glass bottles NS &D5W 0.96 mg/ml Refrigerated Room 48 h 3 h (protected from light) [17] Glass bottles D5W 0.2 mg/ml Refrigerated Room 48 h 5.5 h (protected from light) [15] Cyclosporine Polypropylene-polyolefin (Aviva® Baxter) NS & D5W 0.2, 2.5 mg/ml Room 14 days [18] Subject to sorption to PVC bags and leaching of DHEP from PVC bags. Ethylene-vinyl acetate (EVA) NS & D5W 0.2 mg/ml 2.5 mg/ml Room 7 days 14 days [19] Glass bottle D5W 2 mg/ml Refrigerated and Room 48 h [20] Docetaxel (1-vial) Polyolefin plastic bags (Macoflex-N, Macopharma® Polyolefin plastic bags (Macoflex-N, Macopharma) NS & D5W 0.24–0.32, 0.77, 0.95 mg/ml Refrigerated and Room 28 days [21] The polysorbate 80 surfactant content of both the 1-vial docetaxel formulations as well as the 2-vial formulation leaches DEHP plasticizer from PVC containers and administration set tubing. All infusions should be carefully examined for visual precipitation prior to use and at intervals during infusion.[23] There are conflicting data with regard to the stability of docetaxel, especially with regard to the formation of precipitation when stored at room temperature.[25–27] Furthermore, agitation of docetaxel may promote the formation of precipitate material. Docetaxel (2-vials) Polyethylene (Ecoflac® plus), and Polypropylene (Plasco®, B Braun) Glass bottle NS & D5W 0.3, 0.9 mg/ml Refrigerated and Room 28 days (protected from light) [22] Polyelofin (Viaflo® Baxter) NS & D5W 0.3, 0.7 mg/ml Refrigerated and Room 56 days (protected from light) [23] Polypropylene–Polyethylene Copolymer (B Braun) NS 0.4, 0.8 mg/ml Room 35 days [24] Etoposide Polypropylene NS 0.2 mg/ml 0.4 mg/ml Room 96 h 24 h [28] The polysorbate 80 surfactant in the etoposide formulation leaches DEHP plasticizer from PVC containers and administration set tubing. Etoposide has poor aqueous solubility, and precipitation from aqueous solutions has occurred irregularly, even in low concentrations. Time to precipitation is variable, but at concentrations above 0.4 mg/ml precipitation can occur rapidly. Polyethylene (Ecoflac®, B Braun) NS & D5W 0.05, 0.4, 0.2 mg/ml Refrigerated (protected from light) and Room (in ambient light) 8 days [29] Glass D5W NS 0.4 mg/ml 0.05-0.3 mg/ml Room 4 days [30] Glass NS 0.2–0.5 mg/ml 10–12 mg/ml (For other concentrations see comments) Refrigerated and Room 24 h 7 days [31] Solution of 2, 4, and 6 mg/ml precipitated within 2 h. Solutions from 1-8 mg/ml lost more than 10% of the initial concentration within 24 h.[31] Etoposide phosphate Polyethylene (Ecoflac, B. Braun) and Glass NS & D5W 0.08, 3 mg/ml Room 7 days (protected from light) [32] PVC NS & D5W 0.1, 10 mg/ml Refrigerated and Room 31 days [33] Foscarnet PVC NS & D5W 12 mg/ml Refrigerated and Room 35 days [34,35] Nitroglycerine Polyolefin & Glass NS & D5W 0.2, 0.4 mg/ml Refrigerated (protected from light) and Room 28 days [36] Nitroglycerine will undergo substantial loss from aqueous solutions due to sorption to PVC containers and administration sets. Paclitaxel Polyolefin (Freeflex® Fresinus Kabi) NS 0.3 mg/ml Refrigerated Room 28 days 6 days protected from light [37] The Cremophor EL surfactant in paclitaxel formulation leaches large amounts of DEHP plasticizer from PVC containers and administration sets. D5W Refrigerated Room 28 days 8 days protected from light NS 0.75 mg/ml Refrigerated Room 20 days 6 days protected from light D5W Refrigerated Room 20 days 4 days protected from light NS 1.2 mg/ml Refrigerated Room 12 days 4 days protected from light D5W Refrigerated Room 12 days 4 days protected from light Polyolefin (Viaflo® B-Braun) NS & D5W 0.3 mg/ml Refrigerated Room 13 days 3 days protected from light [38] NS 1.2 mg/ml Refrigerated Room 9 days 3 days protected from light D5W 1.2 mg/ml Refrigerated Room 10 days 3 days protected from light Polyethylene (Ecoflac® B. Braun) NS 0.3 mg/ml Refrigerated Room 16 days 3 days protected from light D5W 0.3 mg/ml Refrigerated Room 18 days 3 days protected from light NS & D5W 1.2 mg/ml Refrigerated Room 12 days 3 days protected from light Glass bottles NS 0.3 mg/ml Refrigerated Room 13 days 3 days protected from light D5W 0.3 mg/ml Refrigerated Room 15 days 7 days protected from light NS 1.2 mg/ml Refrigerated Room 8 days 5 days protected from light D5W 1.2 mg/ml Refrigerated Room 10 days 7 days protected from light Tacrolimus Polyolefin NS & D5W 0.1 mg/ml Room 48 h [39] Tacrolimus has demonstrated some loss due to sorption to PVC containers and sets. Glass bottle D5W 0.1 mg/ml Room 48 h Stability of Monoclonal Antibodies Drug Material Solutions Concentration Temperature Stability Ref Comments Alemtuzumab* Polyolefin NS 0.28 mg/ml Refrigerated Room 14 days [40] Concerns have been raised about the method used to determine the stability of alemtuzumab in this study. The formation of large molecular weight species, which can occur as a result of protein degradation and aggregation during preparation, may not be adequately detected by the method used in this study.[41] PVC NS 0.1–41 mcg/ml Refrigerated 28 days [42] Basiliximab* PVC NS & D5W 0.4 mg/ml Refrigerated Room 24 h 4 h [43] Follow SPC recommendations. Belimumab PVC or Polyolefin NS 0.1–0.5 mg/ml and 1 mg/ml Refrigerated 8 h [44] Follow SPC recommendations. Bevacizumab* Polyolefin NS 2 mg/ml & 16 mg/ml Refrigerated Room 90 days [45] BrentuximabVedotin Not specified NS & D5W 0.4–1.8 mg/ml Refrigerated 24 h [46] Follow SPC recommendations. Cetuximab* PVC Glass vials NS 2 mg/ml Refrigerated 14 days [47] Concerns have been raised about the method used to determine the stability of Cetuximab in this study. The formation of large molecular weight species, which can occur as a result of protein degradation and aggregation during preparation, may not be adequately detected by the method used in this study.[41] Eculizumab Not specified NS & D5W 5 mg/ml Refrigerated Room 24 h protected from light [48] Follow SPC recommendations. Golimumab (Simponi Aria®) Not specified NS Room 4 h [49] Follow SPC recommendations. Infliximab* PVC NS 0.4 mg/ml Refrigerated 14 days [50] Ipilimumab Polyolefin NS 2 mg/ml Refrigerated Room 30 days [51] Manufacturer recommends 24 h in room temperature or refrigerated.[52] Natalizumab Not specified NS 2.6 mg/ml Refrigerated 8 h [53] Follow SPC recommendations. Ofatumumab Polyolefin PVC NS 0.3, 2 mg/ml Refrigerated 24 h [54] Follow SPC recommendations. Panitumumab PVC NS 2.5 mg/ml Refrigerated 14 days [47] Concerns have been raised about the method used to determine the stability of Panitumumab in this study. The formation of large molecular weight species, which can occur as a result of protein degradation and aggregation during preparation, may not be adequately detected by the method used in this study.[41] Glass Undiluted 20 mg/ml Refrigerated 14 days Pertuzumab Polyolefin PVC NS 1.68, 3.36 mg/ml Refrigerated Room 24 h [55] RiTUXimab* Polyolefin (Freeflex® Fresinus Kabi) NS 1 mg/ml Refrigerated 180 days (protected from light) [56] PVC, Polyethylene NS & D5W 1–4 mg/ml Refrigerated 24 h [57] Trastuzumab* PVC Polyolefin NS 1.68, 2.88 mg/ml Refrigerated Room 24 h [55] Polyolefin (Freeflex® Fresinus Kabi) NS 0.8, 2.4 mg/ml Refrigerated 180 days (protected from light) [58] Ado-Trastuzumab Emtansine PVC Polyethylene NS 250 ml of NS Refrigerated 24 h [59] Follow SPC recommendation Drug . Material . Solutions . Concentration . Temperature . Stability . Ref . Comments . Amiodarone Polyolefin (VISIV® Hospira) D5W 1 mg/ml Room 24 h [11,12] The polysorbate surfactant content in the amiodarone hydrochloride formulation leaches DEHP plasticizer from PVC containers and administration sets. Conflicting data with regard to stability in NS. Polyolefin D5W 2 mg/ml Refrigerated Room 38 days 21 days [13] Glass bottle D5W & NS 2 mg/ml Refrigerated Room 32 days [14] Carmustine Polyethylene D5W 0.2 mg/ml Refrigerated Room 48 h 2.5 h (protected from light) [15] Carmustine exhibits sorption to PVC and EVA containers and administration tubing. Polyethylene D5W 0.1–0.5 mg/ml and 1 mg/ml Refrigerated Room 48 h 4 h [16] Polyolefin (VISV® Hospira) D5W 1 mg/ml Room 6 h [11] Polyethylene-lined multi-layer bags Glass bottles NS &D5W 0.96 mg/ml Refrigerated Room 48 h 3 h (protected from light) [17] Glass bottles D5W 0.2 mg/ml Refrigerated Room 48 h 5.5 h (protected from light) [15] Cyclosporine Polypropylene-polyolefin (Aviva® Baxter) NS & D5W 0.2, 2.5 mg/ml Room 14 days [18] Subject to sorption to PVC bags and leaching of DHEP from PVC bags. Ethylene-vinyl acetate (EVA) NS & D5W 0.2 mg/ml 2.5 mg/ml Room 7 days 14 days [19] Glass bottle D5W 2 mg/ml Refrigerated and Room 48 h [20] Docetaxel (1-vial) Polyolefin plastic bags (Macoflex-N, Macopharma® Polyolefin plastic bags (Macoflex-N, Macopharma) NS & D5W 0.24–0.32, 0.77, 0.95 mg/ml Refrigerated and Room 28 days [21] The polysorbate 80 surfactant content of both the 1-vial docetaxel formulations as well as the 2-vial formulation leaches DEHP plasticizer from PVC containers and administration set tubing. All infusions should be carefully examined for visual precipitation prior to use and at intervals during infusion.[23] There are conflicting data with regard to the stability of docetaxel, especially with regard to the formation of precipitation when stored at room temperature.[25–27] Furthermore, agitation of docetaxel may promote the formation of precipitate material. Docetaxel (2-vials) Polyethylene (Ecoflac® plus), and Polypropylene (Plasco®, B Braun) Glass bottle NS & D5W 0.3, 0.9 mg/ml Refrigerated and Room 28 days (protected from light) [22] Polyelofin (Viaflo® Baxter) NS & D5W 0.3, 0.7 mg/ml Refrigerated and Room 56 days (protected from light) [23] Polypropylene–Polyethylene Copolymer (B Braun) NS 0.4, 0.8 mg/ml Room 35 days [24] Etoposide Polypropylene NS 0.2 mg/ml 0.4 mg/ml Room 96 h 24 h [28] The polysorbate 80 surfactant in the etoposide formulation leaches DEHP plasticizer from PVC containers and administration set tubing. Etoposide has poor aqueous solubility, and precipitation from aqueous solutions has occurred irregularly, even in low concentrations. Time to precipitation is variable, but at concentrations above 0.4 mg/ml precipitation can occur rapidly. Polyethylene (Ecoflac®, B Braun) NS & D5W 0.05, 0.4, 0.2 mg/ml Refrigerated (protected from light) and Room (in ambient light) 8 days [29] Glass D5W NS 0.4 mg/ml 0.05-0.3 mg/ml Room 4 days [30] Glass NS 0.2–0.5 mg/ml 10–12 mg/ml (For other concentrations see comments) Refrigerated and Room 24 h 7 days [31] Solution of 2, 4, and 6 mg/ml precipitated within 2 h. Solutions from 1-8 mg/ml lost more than 10% of the initial concentration within 24 h.[31] Etoposide phosphate Polyethylene (Ecoflac, B. Braun) and Glass NS & D5W 0.08, 3 mg/ml Room 7 days (protected from light) [32] PVC NS & D5W 0.1, 10 mg/ml Refrigerated and Room 31 days [33] Foscarnet PVC NS & D5W 12 mg/ml Refrigerated and Room 35 days [34,35] Nitroglycerine Polyolefin & Glass NS & D5W 0.2, 0.4 mg/ml Refrigerated (protected from light) and Room 28 days [36] Nitroglycerine will undergo substantial loss from aqueous solutions due to sorption to PVC containers and administration sets. Paclitaxel Polyolefin (Freeflex® Fresinus Kabi) NS 0.3 mg/ml Refrigerated Room 28 days 6 days protected from light [37] The Cremophor EL surfactant in paclitaxel formulation leaches large amounts of DEHP plasticizer from PVC containers and administration sets. D5W Refrigerated Room 28 days 8 days protected from light NS 0.75 mg/ml Refrigerated Room 20 days 6 days protected from light D5W Refrigerated Room 20 days 4 days protected from light NS 1.2 mg/ml Refrigerated Room 12 days 4 days protected from light D5W Refrigerated Room 12 days 4 days protected from light Polyolefin (Viaflo® B-Braun) NS & D5W 0.3 mg/ml Refrigerated Room 13 days 3 days protected from light [38] NS 1.2 mg/ml Refrigerated Room 9 days 3 days protected from light D5W 1.2 mg/ml Refrigerated Room 10 days 3 days protected from light Polyethylene (Ecoflac® B. Braun) NS 0.3 mg/ml Refrigerated Room 16 days 3 days protected from light D5W 0.3 mg/ml Refrigerated Room 18 days 3 days protected from light NS & D5W 1.2 mg/ml Refrigerated Room 12 days 3 days protected from light Glass bottles NS 0.3 mg/ml Refrigerated Room 13 days 3 days protected from light D5W 0.3 mg/ml Refrigerated Room 15 days 7 days protected from light NS 1.2 mg/ml Refrigerated Room 8 days 5 days protected from light D5W 1.2 mg/ml Refrigerated Room 10 days 7 days protected from light Tacrolimus Polyolefin NS & D5W 0.1 mg/ml Room 48 h [39] Tacrolimus has demonstrated some loss due to sorption to PVC containers and sets. Glass bottle D5W 0.1 mg/ml Room 48 h Stability of Monoclonal Antibodies Drug Material Solutions Concentration Temperature Stability Ref Comments Alemtuzumab* Polyolefin NS 0.28 mg/ml Refrigerated Room 14 days [40] Concerns have been raised about the method used to determine the stability of alemtuzumab in this study. The formation of large molecular weight species, which can occur as a result of protein degradation and aggregation during preparation, may not be adequately detected by the method used in this study.[41] PVC NS 0.1–41 mcg/ml Refrigerated 28 days [42] Basiliximab* PVC NS & D5W 0.4 mg/ml Refrigerated Room 24 h 4 h [43] Follow SPC recommendations. Belimumab PVC or Polyolefin NS 0.1–0.5 mg/ml and 1 mg/ml Refrigerated 8 h [44] Follow SPC recommendations. Bevacizumab* Polyolefin NS 2 mg/ml & 16 mg/ml Refrigerated Room 90 days [45] BrentuximabVedotin Not specified NS & D5W 0.4–1.8 mg/ml Refrigerated 24 h [46] Follow SPC recommendations. Cetuximab* PVC Glass vials NS 2 mg/ml Refrigerated 14 days [47] Concerns have been raised about the method used to determine the stability of Cetuximab in this study. The formation of large molecular weight species, which can occur as a result of protein degradation and aggregation during preparation, may not be adequately detected by the method used in this study.[41] Eculizumab Not specified NS & D5W 5 mg/ml Refrigerated Room 24 h protected from light [48] Follow SPC recommendations. Golimumab (Simponi Aria®) Not specified NS Room 4 h [49] Follow SPC recommendations. Infliximab* PVC NS 0.4 mg/ml Refrigerated 14 days [50] Ipilimumab Polyolefin NS 2 mg/ml Refrigerated Room 30 days [51] Manufacturer recommends 24 h in room temperature or refrigerated.[52] Natalizumab Not specified NS 2.6 mg/ml Refrigerated 8 h [53] Follow SPC recommendations. Ofatumumab Polyolefin PVC NS 0.3, 2 mg/ml Refrigerated 24 h [54] Follow SPC recommendations. Panitumumab PVC NS 2.5 mg/ml Refrigerated 14 days [47] Concerns have been raised about the method used to determine the stability of Panitumumab in this study. The formation of large molecular weight species, which can occur as a result of protein degradation and aggregation during preparation, may not be adequately detected by the method used in this study.[41] Glass Undiluted 20 mg/ml Refrigerated 14 days Pertuzumab Polyolefin PVC NS 1.68, 3.36 mg/ml Refrigerated Room 24 h [55] RiTUXimab* Polyolefin (Freeflex® Fresinus Kabi) NS 1 mg/ml Refrigerated 180 days (protected from light) [56] PVC, Polyethylene NS & D5W 1–4 mg/ml Refrigerated 24 h [57] Trastuzumab* PVC Polyolefin NS 1.68, 2.88 mg/ml Refrigerated Room 24 h [55] Polyolefin (Freeflex® Fresinus Kabi) NS 0.8, 2.4 mg/ml Refrigerated 180 days (protected from light) [58] Ado-Trastuzumab Emtansine PVC Polyethylene NS 250 ml of NS Refrigerated 24 h [59] Follow SPC recommendation DEHP, diethylhexyl phthalate; D5W, dextrose 5%; EVA, ethylene-vinyl acetate; NS, normal Saline; PVC, polyvinyl chloride; SPC, summary of product characteristics. * Available at KFSH&RC. Open in new tab The MABs, that are currently prepared in IV glass bottles at the institution, are all compatible with PVC bags. Cost implications The process of switching from IV glass bottles to IV plastic bags (either PVC or non-PVC) was associated with a cost saving of $212 672, see Table 3. As shown in Table 3, there are possible cost savings for each medication. Ciprofloxacin, cyclosporine, foscarnet and fluconazole are associated with the largest cost saving. As stated above, ciprofloxacin and fluconazole are only available in one dosage strength of 200 mg/100 ml premixed solution for infusion. The purchase of different dosage strengths will negate the need to prepare these medications in glass bottles. Cyclosporine and foscarnet had a high-cost saving due to high-usage frequency. Table 3 Cost implication of switching from glass bottles to either PVC or non-PVC plastic bags Medications . Total cost saving ($) . Alemtuzumab≠ 49 Amiodarone* 5335 Basiliximab≠ 1378 Bevacizumab≠ 2936 Carmustine* 90 Cetuximab≠ 1027 Ciprofloxacin¥ 77 992 Cyclosporine* 54 155 Docetaxel* 3612 Etoposide* 6800 Fluconazole¥ 13 418 Foscarnet≠ 16 600 Infliximab≠ 3182 Nitroglycerine* 6550 Paclitaxel* 4510 Rituximab≠ 5736 Tacrolimus* 3174 Trastuzumab≠ 6128 Total 212 672 Medications . Total cost saving ($) . Alemtuzumab≠ 49 Amiodarone* 5335 Basiliximab≠ 1378 Bevacizumab≠ 2936 Carmustine* 90 Cetuximab≠ 1027 Ciprofloxacin¥ 77 992 Cyclosporine* 54 155 Docetaxel* 3612 Etoposide* 6800 Fluconazole¥ 13 418 Foscarnet≠ 16 600 Infliximab≠ 3182 Nitroglycerine* 6550 Paclitaxel* 4510 Rituximab≠ 5736 Tacrolimus* 3174 Trastuzumab≠ 6128 Total 212 672 * Cost in non-PVC bags versus cost in glass IV bottles. ≠ Cost in PVC bags versus cost in glass IV bottles. ¥ Cost of 400 mg dosage form versus 2 × 200 mg & 1 evacuated glass bottle. Open in new tab Table 3 Cost implication of switching from glass bottles to either PVC or non-PVC plastic bags Medications . Total cost saving ($) . Alemtuzumab≠ 49 Amiodarone* 5335 Basiliximab≠ 1378 Bevacizumab≠ 2936 Carmustine* 90 Cetuximab≠ 1027 Ciprofloxacin¥ 77 992 Cyclosporine* 54 155 Docetaxel* 3612 Etoposide* 6800 Fluconazole¥ 13 418 Foscarnet≠ 16 600 Infliximab≠ 3182 Nitroglycerine* 6550 Paclitaxel* 4510 Rituximab≠ 5736 Tacrolimus* 3174 Trastuzumab≠ 6128 Total 212 672 Medications . Total cost saving ($) . Alemtuzumab≠ 49 Amiodarone* 5335 Basiliximab≠ 1378 Bevacizumab≠ 2936 Carmustine* 90 Cetuximab≠ 1027 Ciprofloxacin¥ 77 992 Cyclosporine* 54 155 Docetaxel* 3612 Etoposide* 6800 Fluconazole¥ 13 418 Foscarnet≠ 16 600 Infliximab≠ 3182 Nitroglycerine* 6550 Paclitaxel* 4510 Rituximab≠ 5736 Tacrolimus* 3174 Trastuzumab≠ 6128 Total 212 672 * Cost in non-PVC bags versus cost in glass IV bottles. ≠ Cost in PVC bags versus cost in glass IV bottles. ¥ Cost of 400 mg dosage form versus 2 × 200 mg & 1 evacuated glass bottle. Open in new tab Discussion We were able to shift all the medications found to be prepared in a glass bottle into an IV bags (either PVC or non-PVC), which resulted in significant cost saving. Stability data showed that medications prepared in plastic bags had a similar or better stability compared with glass bottles. Other publications have looked into the stability of different cytotoxic medications in a variety of IV containers.[62] However, our study was more comprehensive and included the stability of other IV medications (both cytotoxic and non-cytotoxic) in a variety of IV containers. The study was first commenced in 2009 with the aim of minimizing the use of IV glass bottles. The original study was abandoned due to leakages from the non-PVC bags purchased by the hospital. In hindsight, that original study was flawed because the team did not use a systematic approach throughout each aspect of the study. However, in the second attempt, the team was fully involved in each step of the process, including the purchase of the non-PVC bags. The team used FOCUS-PDCA approach which is a commonly used tool in quality improvement projects.[60,61] The use of the FOCUS-PDCA model helped to avoid the missing elements from the initial study and ensure preparedness for different eventualities. For example, the team developed detailed stability data (see Table 1) in different IV materials that can be used as an alternative in the event of shortage of supply. The team also identified the current market availability of non-PVC bags required for medications that are incompatible with PVC bags. The quality, availability and cost of all non-PVC bags from different manufacturers were evaluated thoroughly. It became apparent that there were difficulties in obtaining non-PVC bags for export to the Middle East. This was likely to have ramifications when it came to select appropriate non-PVC bags. However, as this is a single centre study, some of the challenges such as marketing dynamic may not exist in different places of the world. The switching from glass bottle to IV plastic bags was achieved using a systematic approach and will be associated with significant benefits such as ease of preparation, storage and lack of breakage. In addition, studies have demonstrated that switching from IV glass bottles to IV plastic bags for intravenous solution can reduce the risk of central line–associated bloodstream infection in Intensive Care Unit (ICU) setting.[63,64] The culture of widespread use of IV glass bottles stems from the fact that IV glass bottles are inert and is, therefore, compatible with a wide variety of drugs. The stability data obtained during the course of this study, clearly demonstrates that IV drug stability in plastic bags (PVC or non-PVC) is comparable to those in glass bottles. However, there are key differences in stability among different non-PVC bags, for example, carmustine can exhibit sorption in EVA but is compatible with polyolefin bags.[65] The MABs evaluated in this study were all prepared in glass bottles although they are all compatible with PVC bags. This suggests that there is a preconception that MABs are incompatible with PVC bags. The lack of long-term stability data, beyond manufacture recommendations, for many of the MABs was striking. Given the cost of MABs and their increased importance in the treatment of many conditions, the lack of long-term stability data beyond manufacturers recommendations has to be addressed as a matter of urgency. The stability data obtained during the literature search were used as a reference for updating pharmacy internal IV preparation charts. The cost impact of switching from glass bottles to IV plastic bags (including PVC or non-PVC) was substantial. Ciprofloxacin, cyclosporine, foscarnet and fluconazole were associated with the largest cost saving. The purchase of different strengths of medication, such as ciprofloxacin and fluconazole, were associated with the highest cost saving. Furthermore, there was a potential for greater cost savings if other hidden costs were evaluated. These costs include but were not limited to preparation time, solutions used for dilution when transferring into glass bottles, and auxiliary equipment (e.g. dispensing luer slip connector, transfer set, etc.). Conclusion We describe a study using a FOCUS-PDCA process to eliminate the use of IV glass bottles for the preparation of IV medications. Our study shows that the use of plastic bags for IV admixture offer a significant advantage over IV glass bottles and can result in significant cost savings without any detrimental effects on drug stability. Declarations Conflict of interest The Author(s) declare(s) that they have no conflicts of interest to disclose. Funding This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. Authors' contributions All authors state that they had complete access to the study data that support the publication. All authors contributed equally to the publication. 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TI - Eliminating the use of intravenous glass bottles using a FOCUS-PDCA model and providing a practical stability reference guide
JF - International Journal of Pharmacy Practice
DO - 10.1111/ijpp.12245
DA - 2016-07-26
UR - https://www.deepdyve.com/lp/oxford-university-press/eliminating-the-use-of-intravenous-glass-bottles-using-a-focus-pdca-kP7QaWHuz3
SP - 271
EP - 282
VL - 24
IS - 4
DP - DeepDyve
ER -