Natural disasters can have a detrimental impact on the drug supply chain, affecting both immediate and long-term product availability. When the product affected is a critical medication or a sole-source product—ie, only one manufacturer is capable of production (see FIGURE 11)—the disruption is particularly distressing.2 On September 20, 2017, Maria, a Category 4 hurricane, made landfall in the southeastern region of Puerto Rico. In its wake, thousands of homes and businesses were damaged, and the electricity grid was decimated, bringing pharmaceutical and health care device manufacturing to a temporary halt.3
Because pharmaceutical products manufactured in Puerto Rico comprise approximately 10% of all drugs utilized in the US, the manufacturing disruptions following Hurricane Maria are of grave concern.4,5 According to a statement by the commissioner of the FDA on October 23, 2017, concern for potential shortages was due to limited plant operation capacity, with most manufacturers operating below 50% and some plants still using only generator power. Some of the ongoing production challenges include damage to transportation infrastructure, access to fuel to power generators and to transport for employees, and availability of secondary supplies used in manufacturing processes.6
Sample Critical Medications List1
- All medicines used in emergency situations (eg, resuscitation and anaphylaxis drugs, reversal agents /antidotes, glucagon, oxygen, vasopressors, inotropes, fluids)
- Anticoagulants used for prophylaxis and treatment (eg, enoxaparin, heparin, warfarin, rivaroxaban, apixaban, dabigatran)
- Anti-infectives (eg, antibiotics, antivirals, antifungals, antiretrovirals, antimalarials)
- Anti-Parkinson medications
- Bronchodilators and respiratory stimulants
- Corticosteroids (oral and parenteral)
- Disease-modifying antirheumatics
- Insulin and oral hypoglycemics
Small-Volume Parenteral Shortages
Since the impact of Hurricane Maria, the FDA and the ASHP have reported several drug products affected by the manufacturing disruption in Puerto Rico,7,8 including antibiotics, parenteral nutrition products, and IV fluids.9 Perhaps one of the most alarming shortages involves sodium chloride 0.9% small-volume injection bags. Although these small-volume (50 mL and 100 mL) parenteral (SVP) infusion bags are not typically considered critical medications themselves, they are used to compound or admix medications, including critical medications such as anti-infectives.10 Moreover, ASHP considers SVPs the foundation of basic IV compounding for hundreds of drugs that need further dilution.11
As a result, hospitals and infusion centers across the US are scrambling to identify ways to address the shortage. Alternative administration techniques, including IV push administration and continuous infusion, are useful strategies for continuing patient care. ASHP also recommends conservation, inventory control, pharmacy operational strategies, and device and informatics optimization (eg, infusion pumps), and provides useful drug shortage resources (see SIDEBAR on page 24). To successfully navigate the SVP shortage, organizations must dedicate time and resources to fleshing out these alternative strategies and management techniques.
Alternative Administration Techniques
IV Push Administration
One medication administration strategy that has garnered renewed attention as a result of the SVP shortage is IV push administration. The Institute for Safe Medication Practices (ISMP) defines IV push as direct manual administration of a medication using a syringe, usually under pressure and connected to an IV access device, which includes a manually administered IV dose.
Benefits to IV push administration include increased nursing unit availability, greater accuracy of dose and delivery without residual drug left in the tubing, a simplified administration method, reduced expense, less equipment required, less waste produced, and increased patient mobility. However, this practice requires extensive knowledge, references, and training. Additional disadvantages include the possibility of an incorrect rate of administration, the risk of adverse events and adverse drug reactions, the possibility of vein irritation, and a lack of oversight and guidance for administration practices, leading to practice variability.12,13
To address the limited published evidence and lack of established safe practices for IV push medication administration, ISMP has published a safe practice guideline for adult IV push medications.13 Review this guideline prior to implementing an IV push policy to prevent potential medication errors associated with preparation and administration of IV push medications.
Limited data suggests there is no difference in tolerability of some medications when assessing IV push versus infusion.12,14-16 Ensuring that the preparation to be administered by IV push has an osmolality of 560 mOsm per kg or less may reduce intolerance during peripheral vein administration.17 Standard doses of medications that can be given via IV push in ≤5 minutes are noted in TABLE 1. Information within the table is based on product information when available, and/or primary literature demonstrating safety when product information is unavailable.
Concern regarding IV push administration of beta-lactams has arisen due to the pharmacodynamic properties of these medications. Beta-lactams exhibit time-dependent bactericidal activity with the percent of time the serum concentration is maintained above the minimum inhibitory concentration (T>MIC), as the pharmacodynamic parameter that determines efficacy.18 When reducing the time of infusion from intermittent (eg, 30 minutes) to IV push (eg, 3-5 minutes), there may be concern for reducing the T>MIC and not achieving the pharmacodynamic target. However, literature suggests minimal pharmacokinetic or pharmacodynamic variability between intermittent infusion and IV push administration.19,20 This suggests that IV push administration of beta-lactams does not diminish the bactericidal activity and can be considered equally efficacious to intermittent infusion.19,20
Overall, IV push administration appears to be a safe, effective, and economical administration option compared with intermittent infusion. Institutions implementing IV push administration should work closely with nursing staff to ensure aseptic preparation and appropriate administration through utilization of the ISMP guidelines.
In light of SVP shortages, continuous infusion (CI) of some beta-lactams may be a viable alternative administration method for agents that cannot be administered by IV push but are stable at room temperature for at least 24 hours. CI, the continuous administration of the total daily dose of an IV antibiotic over a 24-hour duration, is a safe and effective alternative to intermittent or prolonged infusion dosing regimens.21-29 As described earlier, beta-lactams exhibit time-dependent bactericidal activity indicating that efficacy is dependent on the amount of time the bacteria are exposed to the antibiotic. CI administration of beta-lactams may enhance this exposure time and has been shown to be at least as effective as intermittent infusion.21-29 Antibiotics lacking data for ≤5 minutes as IV push but have stability data for at least 24 hours at room temperature within the product information (depending on diluent and concentration) include piperacillin/tazobactam, nafcillin, and oxacillin.
Stability and Sterility Considerations
One important issue to incorporate into policies and procedures is the USP <797> requirement concerning beyond-use dates (BUDs). The BUD of any compounded sterile preparation (CSP) must be the shorter of either the stability of the drug or the sterility limits set by <797>. The stability of the CSP is dependent on the drug, diluent, and container/closure (eg, the syringe) in which it is placed. The sterility limits are based on the storage time between when the CSP is compounded and when administration begins. The maximum BUDs listed in <797> are different for low-risk (eg, preparing a single syringe for a single patient) or medium-risk (eg, batch preparation), and are much shorter if the CSP is mixed in a segregated compounding area (SCA) instead of a cleanroom (see TABLE 2). Note that SCAs cannot be used to prepare batches, as that practice is limited to preparation of low-risk CSPs.30
BUD limits are measured from the time the drug is compounded until administration begins; however, with continuous 24-hour infusions, the drug must be stable at diluted concentrations until the end of the infusion. For example, with a BUD of 7 days refrigerated, the piperacillin/tazobactam 24-hour infusion must be initiated 24 hours prior to expiration (ie, day 6).31
Looking to the Future
The FDA continues to work with drug manufacturers affected by Hurricane Maria to reduce the impact of shortages and to restore operations in Puerto Rico. The agency is allowing temporary importation of IV saline products from facilities outside of the US; however, these imported supplies are not expected to fully meet demand.32 In addition, the FDA is encouraging the expansion of production at existing facilities to meet shortfalls, as well as expediting the review of new product applications that will help address shortages. Current availability of affected products varies based on products and manufacturers, with most orders being fulfilled intermittently via allocation.7 Estimates for full recovery also vary among manufacturers, but most project these shortages to last for several additional months.
More recently, large-volume parenteral injection bags and empty IV fluid bags have also experienced shortages. This is likely due at least in part to increased demand for these alternative products during the SVP shortage. There are currently no estimated release dates for most of these other products; available products are also currently on allocation.
It is still unclear when Puerto Rico-based manufacturing facilities will return to full capacity.5 If conditions do not improve, more drug and medical device shortages can be expected.
As a result of the devastation to manufacturing facilities in Puerto Rico caused by Hurricane Maria, the US is currently experiencing significant, widespread drug shortages. Shortages of IV fluids, specifically SVPs used for compounding many drugs, require implementation of strategies such as conservation; inventory control; and operational, device (eg, infusion pumps), and informatics changes. Safe, effective alternative administration strategies, such as IV push and CI administration for certain drugs, have been shown to be reasonable alternatives during SVP shortages. When utilizing alternative administration strategies, USP <797> compliance, proper preparation, and adequate nursing staff education are critical to success.
- World Health Organization. WHO model lists of essential medicines. www.who.int/medicines/publications/essentialmedicines/en. Accessed January 2, 2018.
- Ventola CL. The drug shortage crisis in the united states: causes, impact, and management strategies. Pharmacy and Therapeutics. 2011;36(11):740-757.
- Bomey, N. Hurricane maria halts crucial drug manufacturing in Puerto Rico, may spur shortages. USA Today. www.usatoday.com/story/money/2017/09/22/hurricane-maria-pharmaceutical-industry-puerto-rico/692752001. Accessed January 2, 2018.
- Hurricane Maria Updates: In Puerto Rico, the Storm ‘Destroyed Us’. New York Times. www.nytimes.com/2017/09/21/us/hurricane-maria-puerto-rico.html. Accessed February 15, 2018.
- U.S. Hospitals Wrestle With Shortages of Drug Supplies Made in Puerto Rico.www.nytimes.com/2017/10/23/health/puerto-rico-hurricane-maria-drug-shortage.html. Accessed February 15, 2018.
- US Food & Drug Administration. Testimony of Scott Gottlieb, MD, commissioner of food and drugs, before the subcommittee on oversight and investigations committee on energy and commerce U.S. house of representatives. “Examining HHS’s public health preparedness for and response to the 2017 hurricane season” October 24, 2017. docs.house.gov/meetings/IF/IF02/20171024/106530/HHRG-115-IF02-Wstate-GottliebMDS-20171024.pdf. Accessed January 2, 2018.
- US Food & Drug Administration. Current and resolved drug shortages and discontinuations reported to FDA. www.accessdata.fda.gov/scripts/drugshortages/default.cfm. Accessed January 2, 2018.
- American Society of Health-System Pharmacists. Drug shortages list: current drug shortage bulletins. www.ashp.org/drug-shortages/current-shortages/drug-shortages-list?page=CurrentShortages. Accessed January 2, 2018.
- American Society of Health-System Pharmacists. Amino acid products with electrolytes in dextrose with calcium (Clinimix E). www.ashp.org/drug-shortages/current-shortages/Drug-Shortage-Detail.aspx?id=1024. Accessed January 2, 2018.
- Baxter. Baxter provides update on Puerto Rico recovery status post hurricane maria. www.baxter.com/news-media/newsroom/press-releases/2017/10-12-17-baxter-provides-puerto-rico-update.page. Accessed January 2, 2018.
- US Food & Drug Administration. Small-volume parenteral solutions shortages: suggestions for management and conservation. www.fda.gov/downloads/Drugs/DrugSafety/DrugShortages/UCM582461.pdf. Accessed January 2, 2018.
- Poole SM, Nowobilski-Vasilios A, Free F. Intravenous push medications in the home. J Intraven Nurs. 1999;22:209-215.
- ISMP safe practice guidelines for adult IV push medications: a compilation of safe practices from the ISMP adult iv push medication safety summit. www.ismp.org/Tools/guidelines/ivsummitpush/ivpushmedguidelines.pdf. Accessed January 2, 2018.
- Nowobilski-Vasilios A, Poole SM. Development and preliminary outcomes of a program for administering antimicrobials by IV push in home care. Am J Health-Syst Pharm. 1999;56(1):76-79.
- Garrelts JC, Ast D, LaRocca J, et al. Postinfusion phlebitis after intravenous push versus intravenous piggyback administration of antimicrobial agents. Clin Pharm. 1988;7(10):760-765.
- Biggar C, Nichols C. Comparison of postinfusion phlebitis in intravenous push versus intravenous piggyback cefazolin. J Infus Nurs. 2012;35(6):384-388.
- Robinson DC, Cookson TL, Grisafe JA. Concentration guidelines for parenteral antibiotics in fluid-restricted patients. Drug Intell Clin Pharm. 1987;21(12):985-989.
- Ambrose PG, Bhavnani SM, Rubino CM, et al. Pharmacokinetics-pharmacodynamics of antimicrobial therapy: it’s not just for mice anymore. Clin Infect Dis. 2007;44(1):79-86.
- Ambrose PG, Bui KQ, Richerson MA, et al. Pharmacoeconomic analysis of intravenous push vs slow infusion of β-lactam antibiotics. Clin Drug Invest. 1999;17(5):407-410.
- Butterfield-Cowper JM, Burgner K. Effects of iv push administration on β-lactam pharmacodynamics. Am J Health-Syst Pharm. 2017;74(9):e170-e175.
- Kasiakou SK, Sermaides GJ, Michalopoulos A, et al. Continuous versus intermittent intravenous administration of antibiotics: a meta-analysis of randomised controlled trials. Lancet Infect Dis. 2005;5(9):581-589.
- Roberts JA, Abdul-Aziz MH, Davis JS, et al. Continuous versus intermittent β-lactam infusion in severe sepsis. a meta-analysis of individual patient data from randomized trials. Am J Respir Crit Care Med. 2016;194(6):681-691.
- Kim A, Sutherland C, Kuti JL, et al. Optimal dosing of piperacillin-tazobactam for the treatment of pseudomonas aeruginosa infections: prolonged or continuous infusion? Pharmacotherapy. 2007;27(11):1490-1497.
- Grant EM, Kuti JL, et al. Clinical efficacy and pharmacoeconomics of a continuous-infusion piperacillin-tazobactam program in a large community teaching hospital. Pharmacotherapy. 2002;22(4):471-483.
- Hughes DW, Frei CR, Maxwell PR, et al. Continuous versus intermittent infusion of oxacillin for treatment of infective endocarditis caused by methicillin-susceptible Staphylococcus aureus. Antimicrob Agents Chemother. 2009;53(5):2014-2019.
- Li J, Echevarria KL, Hughes DW, et al. Comparison of cefazolin versus oxacillin for treatment of complicated bacteremia caused by methicillin-susceptible Staphylococcus aureus. Antimicrob Agents Chemother. 2014;58(9):5117-5124.
- Schuster KM, Wilson D, Schulman CI, et al. Continuous-infusion oxacillin for the treatment of burn wound cellulitis. Surg Infect (Larchmt). 2009;10(1):41-45.
- Patel GW. Impact of a pharmacist-initiated conversion from intermittent dosing to continuous infusion of nafcillin, cefotaxime, and piperacillin/tazobactam at a community hospital. ASHP Midyear Clinical Meeting. 39 (December 2004): poster P340E.
- Knoderer CA, Kamire LC, Nichols KR. Clinical outcomes with continuous nafcillin infusions in children. J Pediatr Pharmacol Ther. 2017;22(4):261-265.
- The United States Pharmacopeial Convention (USP). USP <797>. www.usp.org. Accessed January 2, 2018.
- Pfizer Injectables. Piperacillin/tazobactam (package insert). www.pfizerinjectables.com/sites/default/files/prod/child/uspi/EN-4386.pdf. Accessed January 3, 2018.
- US Food & Drug Administration. Important prescribing information: temporary importation of intravenous drug products to address drug shortages. www.fda.gov/downloads/drugs/drugsafety/drugshortages/ucm579560.pdf. Accessed January 3, 2018.
Oscar E. Guzman, PharmD, BCCCP, BCPS, is the clinical director for infectious diseases and critical care for Cardinal Health—Innovative Delivery Solutions. He received his Doctor of Pharmacy degree from the University of Florida and then pursued a pharmacy practice and specialty residency in critical care at Indiana University Health. In his current role, Oscar provides clinical strategies, support activities, and educational programs to optimize antimicrobial stewardship, as well as drug safety, efficacy, and cost-effectiveness related to infectious diseases and critical care.
Katherine Shea, PharmD, BCPS-AQ-ID, AAHIVE, is the clinical director for infectious diseases for Cardinal Health—Clinical Quality Services. She received her PharmD from the University of Connecticut and then completed 2 years of post-graduate residency training, specializing in infectious diseases and antimicrobial stewardship. Katherine provides strategies, support activities, education, and programs to optimize antimicrobial stewardship, as well as drug safety, efficacy, and cost-effectiveness related to infectious diseases.
Dustin D. Spencer, PharmD, MBA, BCPS, is a clinical director of cardiopulmonary diseases for Cardinal Health Innovative Delivery Solutions and affiliate assistant professor of pharmacy practice at Purdue University College of Pharmacy. He received his PharmD from Purdue University and a Master of Business Administration from the University of Indianapolis.
Jeffrey Bariteau, BS, PharmD, BCPS, DPLA, is a clinical director for Cardinal Health Innovative Delivery Solutions, providing clinical, quality, and operational support, as well as education and consulting services, to hospitals and health systems. He is a graduate of the Massachusetts College of Pharmacy and Allied Health Sciences in Boston and the Philadelphia College of Pharmacy, where he received a BS in pharmacy and his Doctor of Pharmacy degree, respectively.
Patricia C. Kienle, RPh, MPA, FASHP, an employee of Cardinal Health since 1999, currently serves as the director of accreditation and medication safety. She is the recipient of an MPA in health service administration from Marywood College in Scranton, Pennsylvania, a BSc in pharmacy from Philadelphia College of Pharmacy and Science, and has completed an executive fellowship in patient safety from Virginia Commonwealth University. She is a member of the USP Compounding Expert Committee, though her comments here are her own and not endorsed by or affiliated with USP. Patti is also an adjunct associate professor at Wilkes University in Wilkes-Barre, Pennsylvania.
Drug Shortage Management Resources
The FDA monitors at-risk products, reports active drug shortages, and takes steps to mitigate the potential for new shortages. Hospitals should actively monitor the FDA’s drug shortage website (www.accessdata.fda.gov/scripts/drugshortages/) for new and updated alerts and resources. Key information available on the site includes affected presentations and remaining availability, reasons for the shortage, estimated duration of the shortage, and other shortage-related information (eg, manufacturer letters to clinicians).
ASHP provides drug shortage resources at the ASHP Drug Shortages Online Center (www.ashp.org/Drug-Shortages), including a wealth of information and resources on drug products and availability to both members and non-members. The website includes information on current and resolved drug shortages, discontinued products, and preparations that are no longer available. Additional ASHP resources include drug shortage publications, guidelines, surveys, and online tools. The ASHP Guideline on Managing Drug Product Shortages in Hospitals and Health Systems provides a comprehensive process for decision-making in drug shortages management. Key steps outlined in this guideline include shortage identification, operational and therapeutic assessments, shortage impact analyses, how to develop a shortage plan, and how to implement a communication and shortage-management procedure.1
On October 18, 2017, ASHP released a formal guidance document, Small-Volume Parenteral (SVP) Solutions Shortages Suggestions for Management and Conservation (www.ashp.org/Drug-Shortages/Shortage-Resources/Publications/Small-Volume-Parenteral-Solutions-Shortages), which outlines several conservation, inventory control, and operational strategies for pharmacies, in addition to recommendations for device optimization (eg, infusion pumps) and informatics (see FIGURE below). The guidance also highlights important caveats and safety information related to SVP shortage management. Specifically, ASHP cites the importance of open communication during the shortage period; access to new or amended policies, protocols, and guidelines; education and training for new administration techniques and technology (eg, IV push, CIs, syringe pumps); and using caution when compounding sodium chloride solutions from sterile water for injection or concentrated sodium chloride.2
*Adapted from ASHP: Small-Volume Parenteral Solutions Shortages Suggestions for Management and Conservation.
DSCSA=Drug Supply Chain Security Act; EHR=electronic health record; IM=intramuscular; IT=information technology; PCA=patient-controlled analgesia; SubQ=subcutaneous; SVP=small volume parenteral.
1. ASHP Expert Panel on Drug Product Shortages, Fox ER, Birt A, et al. ASHP guidelines on managing drug product shortages in hospitals and health systems. Am J Health-Syst Pharm. 2009;66:1399-1406.
2. American Society of Health-System Pharmacists. Small-Volume Parenteral Solutions Shortages. www.ashp.org/Drug-Shortages/Shortage-Resources/Publications/Small-Volume-Parenteral-Solutions-Shortages. Accessed January 2, 2018
Part 1 of a 2-Part Series: Elements of a USP <800> Compliant Cleaning Program
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