US Pharm. 2021;46(2):25-28.
ABSTRACT: The uncertainty of coronavirus disease 2019 (COVID-19) caused anticipatory purchasing of medications around the world, driving demand to an unprecedented high. Meanwhile, drug factories shut down in order to prevent the spread of COVID-19, the drug-supply chain was disrupted, and drug shortages resulted. In the face of these drug shortages, pharmacy personnel responded by initiating local policy changes, implementing detailed antibiotic stewardship, and enacting quantity limits for in-demand medications. Pharmacists are indispensable during a drug shortage because of their unique skills and ability to bridge shortage gaps with effective action plans that will not imperil patient safety.
“‘There’s a shortage of everything’: Pharmacies in New York City struggle to keep key medications stocked amid coronavirus outbreak.”1 “Coronavirus pandemic is causing ‘unacceptable’ shortages in US drug supplies.”2 These headlines and many others have overwhelmed news outlets, social media, and general conversation among the American public for months. When pharmacy personnel hear about drug shortages, panic, fear, and frustration begin to set in. Pharmacy’s primary responsibility is to supply patients with life-saving medications. When drugs run out, pharmacy personnel may feel responsible for failing to supply the patient with a life-saving pharmaceutical. Accordingly, when pharmacy professionals encounter drug shortages, there is a call to action to be prepared. Pharmacies prepare by purchasing available product, looking for alternatives, implementing protocols to save stock, and finding creative solutions to conserve valuable resources. The uncertainty of coronavirus disease 2019 (COVID-19) has highlighted the difficulties inherent in having a global drug-supply chain and has caused an increase in global demand for certain medications. It is imperative for pharmacists to understand the causes of drug shortages during the COVID-19 pandemic, key medications affected at this time, and how to ensure patient safety during a shortage.
Causes of Drug Shortages
Drug shortages have been an ongoing problem for the medical community for decades; however, drug-shortage concerns have been exacerbated by this worldwide pandemic. Drug manufacturing follows standard business practices in order to make a profit. Excess stock in the warehouse is risky from a business standpoint. It costs money to store and maintain product in anticipation of sales and profit. Therefore, businesses may operate on a just-in-time model by manufacturing the product when it is needed in order to keep costs down and maintain efficiency. With no on-hand reserve, if anything alters supply or increases demand, a shortage can occur.3
The supply of goods to the market directly relates to the quantity of goods coming off the production lines over a given time. In order to produce a drug, raw materials must be acquired. The drug-manufacturing process is wholly dependent on the supplier of the raw materials. Often, there are multiple manufacturers for a drug, but there may be only one producer of the raw material. Therefore, any interruption in the supply of the raw material will affect all manufacturers of the drug.4 Currently, about 80% of the raw materials for drugs are imported from abroad, making the American drug supply highly dependent on other countries.4
Even when adequate raw materials are available, there is a maximum capacity or a limited number of units that can be manufactured at a given time. Because the FDA approves a specific manufacturing line to produce a specific drug at a specific facility, a manufacturer cannot set up additional production of a drug in short supply elsewhere in the facility.4 Further limitations to production include the good manufacturing practices, chemical reactions, and in-process controls that must be in place to turn out a quality product.5
The spread of COVID-19 to the level of a global pandemic impacted the acquisition of raw material and caused manufacturing shutdowns around the world. China is a major source of active pharmaceutical ingredients, finished dosage forms, and raw materials.6 In response to COVID-19, roughly 37 pharmaceutical factories in China that manufactured active ingredients for U.S. drug products were shut down.7 Consequently, manufacturers in other parts of the world were forced to depend on current stock or find alternative supply sources. India, which imports roughly 70% of its raw materials from China and is the world’s largest producer of generic drugs, began to experience delays in receiving ingredients and could not keep up with global demand under these conditions.7 In anticipation of drug shortages, the Indian government restricted the exportation of medications to other parts of the world in order to prevent a potential shortage in its own country.7 The limiting of drug exports from India amplified shortages in other areas of the world that depend on that supply.
With factory doors closed and COVID-19 a global threat, supplies start to run low. Not knowing when and where the next COVID-19 surge will occur, everyone is trying to be prepared. Pharmacies prepare by managing the inventory of critical drugs required for providers to adequately treat the virus. As soon as evidence surfaces to support a potential treatment, pharmacies begin procuring the drug, and global demand starts to increase. Some drugs that have been in high demand in association with COVID-19 include albuterol metered-dose inhalers (MDIs), azithromycin, hydroxychloroquine and chloroquine, and sedation medications.
Drugs in Demand for COVID-19 Treatment
Albuterol MDIs: Treatment of COVID-19 often involves the use of bronchodilators owing to the specific lung cells targeted by the virus. Given that nebulizers increase the generation of aerosolized virus in COVID-19 patients and potentially escalate the spread of the virus, MDI use is preferred. Inhaler shortages are occurring because of increased demand by hospitals for treatment of COVID-19.8 To combat potential shortages, hospitals can conserve supply by creating local policies that would allow patients to bring their inhaler supply from home to use during their inpatient stay.9 Another way to conserve supply is when an inpatient pharmacy dispenses an inhaler for hospital use, then gives it to the patient upon discharge, eliminating the need for the patient to obtain a new prescription from the outpatient pharmacy.9 The possibility of using one MDI for multiple patients has been discussed. The Institute for Safe Medication Practices (ISMP) currently recommends against a common MDI-canister protocol.9 Common canister protocol involves using the same MDI for multiple patients by disinfecting the MDI mouthpiece with an alcohol pad before inserting it into a patient-specific spacer with a one-way valve, administering the medication, and disinfecting the MDI mouthpiece after use.9 Studies have found rates of bacterial contamination on the disinfected mouthpiece of up to 5%.9 The ISMP states that using a common canister for patients on isolation or those who are immunocompromised may not be appropriate and that the methods in previous studies have been aimed at preventing bacterial contamination, which would not be applicable to COVID-19.9 Given the elevated demand for MDIs because of COVID-19, it is imperative that pharmacists consider their current inventory and plan to conserve supplies if needed.
Azithromycin: Azithromycin has been used as adjunctive therapy to provide antibacterial coverage and potential immunomodulatory and anti-inflammatory effects in the treatment of some viral respiratory tract infections.10 Many trials are testing the effect of azithromycin in conjunction with hydroxychloroquine in COVID-19 patients.10 The increasing number of reports on azithromycin has led to an increased demand for the drug. On April 14, 2020, the FDA reported that there was currently a shortage of azithromycin owing to high demand.11 Although the intention to acquire supplies to keep on hand in case of a COVID-19 surge is laudable, it is important to remember that in 2018 the United States dispensed 38.5 million azithromycin prescriptions for conditions other than COVID-19.12 In order to reserve a supply of azithromycin, it is imperative that pharmacists practice good antibiotic stewardship and ensure that patients who receive azithromycin have an appropriate indication. In the U.S. alone, the CDC estimates that at least 30% of outpatient antibiotic prescriptions are unnecessary, commonly being written for viral respiratory infections when therapy is not indicated.13 Some other examples of inappropriate antibiotic prescribing include the use of non–first-line antibiotics and the use of an antibiotic with excessively broad-spectrum activity for which a narrow-spectrum drug could be substituted.13 Pharmacists should review all azithromycin prescriptions to ensure that there is a proper indication and, when appropriate, recommend other proven therapy alternatives in order to help conserve the azithromycin supply.
Hydroxychloroquine and Chloroquine: Hydroxychloroquine and chloroquine are indicated for a very small population of patients with uncommon conditions such as lupus, rheumatoid arthritis, and malaria. Therefore, typical purchasing quantities are minimal. However, COVID-19 research involving hydroxychloroquine and chloroquine has heightened the demand for these drugs. Many small trials began testing the use of these drugs in COVID-19 patients because their mechanisms of action include targeting of lysosome, which can control graft-versus-host disease; inhibition of entry of the virus; prevention of virus cell fusion; anti-inflammatory effects; and reduction of cytokine storm.10 On March 20, 2020, the FDA issued an Emergency Use Authorization (EUA) for hydroxychloroquine and chloroquine from the Strategic National Stockpile to be used by licensed healthcare providers to treat patients hospitalized with COVID-19.14 An analysis of outpatient retail pharmacy transaction data found that the prescribing of these drugs increased from 383,435 prescriptions in February 2020 to 759,186 prescriptions in March 2020.14 With demand doubling over 1 month, shortages followed, and the FDA published information on the shortages on March 31, 2020.15 In response, certain state boards of pharmacy established new rules to control use by requiring a diagnosis for the indicated disease to be written on the prescription, placing quantity limits for COVID-19 prescriptions, and restricting refills.16 On June 15, 2020, the FDA rescinded its EUA because the federal COVID-19 Treatment Guidelines Panel issued recommendations against the use of hydroxychloroquine and chloroquine to treat COVID-19 and noted that, at the time, no medication could be recommended for COVID-19 preexposure or postexposure prophylaxis outside the clinical-trial setting.14 Following the release of this information, dispensing trends began to return to prepandemic levels, and the shortage resolved in late June 2020.14
Sedation Medications: COVID-19 can result in acute respiratory distress, and in extreme cases it requires the use of mechanical ventilation. Anticipation of an increase in mechanically ventilated patients and heightened demand for analgesics, sedatives, and paralytics created the perfect conditions for drug shortages. One way to save drug product is to minimize waste. Inpatient pharmacies should consider purchasing or compounding smaller drug volumes, when applicable, in order to minimize waste. Pharmacists should also review current hospital protocols and work with key stakeholders to make contingency plans for shortages of sedation medications. Traditionally, IV administration of opioids is preferred in mechanically ventilated patients; however, to conserve resources and keep opioid use to a minimum, hospitals can establish protocols for intermittent bolus analgesia, enteral administration of opioids, or implementation of adjuvant therapies.17 In ventilated patients, light sedation—which helps conserve drug supply—is preferred over deep sedation.17 Nonbenzodiazepine sedatives such as propofol and dexmedetomidine are preferred, but contingencies should be put in place to use other agents, such as ketamine, benzodiazepines, and pentobarbital.17 Awakening trials with reassessment of sedation needs should be performed daily. This practice may result in a reduction in sedation requirements while effectively conserving drug supply.17 In addition to analgesics and sedatives, some patients with COVID-19 will require paralytics. In order to conserve resources, hospital guidelines should be established for the use of continuous infusion versus intermittent bolus use of paralytic agents.17 In general, when a drug shortage arises, it is imperative that pharmacists familiarize themselves with all alternative products and assist in creating contingency plans.
Patient Safety During a Drug Shortage
A drug shortage commonly requires the substitution of an item that is ordered, prepared, or dispensed differently than the standard product. When prescribing practices switch to less-familiar alternative agents—especially those that are less efficacious, have a worse adverse-effect profile, or require an unusual or difficult dosing regimen—medication errors are more likely to occur.18 To minimize medication errors and maximize patient safety, the American Society of Health-System Pharmacists (ASHP) guidelines on managing drug-product shortages recommend implementing a drug-product shortage team, creating a resource-allocation committee, and establishing a process for approving alternative therapies and addressing ethical considerations.18 The product-shortage team would have multiple responsibilities, including the purchasing of alternative agents, decisions on conserving or rationing supplies, implementation of technology updates, and communication of changes.18 The resource-allocation committee would create a framework for rationing drug resources in advance, thereby eliminating the need for bedside decisions during a shortage.18 The final ASHP recommendation is to have a process in place for approving alternative therapies and addressing ethical considerations. A multidisciplinary team would be responsible for establishing ethical procedures and protocols before they are needed in order to ensure that the rationing of life-saving drugs reflects the fundamental healthcare principles of justice, beneficence, and nonmaleficence.18
The overarching recommendation for preventing medication errors and ensuring patient safety is to focus on communicating information about the drug shortage. Communication updates should include all pertinent information about the shortage, such as the drug affected and the substitution or rationing plan.18 If a new drug is being selected, educational references about prescribing differences should be distributed, and pharmacists should be prepared to answer questions about the new agent. When information is being disseminated, it is important to include all potential stakeholders across all shifts. With drug shortages on the rise during the COVID-19 pandemic, it is imperative that the pharmacy profession take a proactive leadership role in developing and implementing processes to address drug shortages and ensure patient safety.
The pharmacy profession has been dealing with drug shortages for years. However, no past experience could have adequately prepared pharmacists for the drug shortages and unprecedented high demand resulting from the extensive disruptions caused by COVID-19. The pandemic crippled the global drug-supply chain by leading to factory closings, limited access to raw materials, and altered import and export rates of final dosage forms. With an inadequate supply chain and high demand worldwide, prescription drug shortages became a common topic in the pharmacy realm. Fear of not having enough supplies to battle the virus motivated pharmacy personnel to change current practices by initiating local policy changes, focusing on antibiotic stewardship, and implementing quantity limits in order to conserve drug stock. Overall, the need to combat historic drug shortages during the COVID-19 pandemic has led to innovation and critical thinking in an effort to conserve valuable supplies without sacrificing patient safety under less-than-ideal circumstances. Pharmacists are indispensable during a drug shortage because of their unique skills and ability to bridge shortage gaps with effective action plans that will not imperil patient safety.
1. Kimball S. ‘There’s a shortage of everything’: pharmacies in New York City struggle to keep key medications stocked amid coronavirus outbreak. www.cnbc.com/2020/04/04/coronavirus-pharmacies-struggle-to-meet-demand-amid-supply-shortages.html. Accessed November 12, 2020.
2. Erdman SL. Coronavirus pandemic is causing ‘unacceptable’ shortages in US drug supplies, report says. www.cnn.com/2020/10/22/health/drug-shortages-coronavirus/index.html. Accessed November 12, 2020.
3. Mullins TD, Cook AM. Drug shortages: causes and cautions. Orthopedics. 2011;34(9):712-714.
4. Ventola CL. The drug shortage crisis in the United States: causes, impact, and management strategies. P T. 2011;36(11):740-757.
5. Wichrowski NJ, Fisher AC, Arden NS, Yang X. An overview of drug substance manufacturing processes. AAPS PharmSciTech. 2020;21(7):271.
6. Van Arnum P. API sourcing: the supply side for US-marketed drugs. www.dcatvci.org/6213-global-api-sourcing-which-countries-lead. Accessed January 8, 2021.
7. Center for Infectious Disease Research and Policy (CIDRAP). COVID-19: The CIDRAP Viewpoint. Part 6: ensuing a resilient US prescription drug supply. Minneapolis, MN: University of Minnesota; 2020.
8. American College of Allergy, Asthma and Immunology. A message to asthma sufferers about a shortage of albuterol metered dose inhalers. https://acaai.org/news/message-asthma-sufferers-about-shortage-albuterol-metered-dose-inhalers. Accessed November 12, 2020.
9. Institute for Safe Medication Practices. Revisiting the need for MDI common canister protocols during the COVID-19 pandemic. https://ismp.org/resources/revisiting-need-mdi-common-canister-protocols-during-covid-19-pandemic. Accessed November 12, 2020.
10. Wu R, Wang L, Kuo HC, et al. An update on current therapeutic drugs treating COVID-19. Curr Pharmacol Rep. 2020:1-15.
11. FDA. FDA drug shortages. Azithromycin tablets. www.accessdata.fda.gov/scripts/drugshortages/dsp_ActiveIngredientDetails.cfm?AI=Azithromycin&Tablets&st=c#. Accessed November 12, 2020.
12. CDC. Outpatient antibiotic prescriptions—United States, 2018. www.cdc.gov/antibiotic-use/community/programs-measurement/state-local-activities/outpatient-antibiotic-prescriptions-US-2018.html. Accessed November 12, 2020.
13. CIDRAP. Overuse and overprescribing of antibiotics. www.cidrap.umn.edu/asp/overuse-overprescribing-of-antibiotics. Accessed November 12, 2020.
14. Bull-Otterson L, Gray EB, Budnitz DS, et al. Hydroxychloroquine and chloroquine prescribing patterns by provider specialty following initial reports of potential benefit for COVID-19 treatment—United States, January–June 2020. MMWR Morb Mortal Wkly Rep. 2020;69(35):1210-1215.
15. FDA. FDA drug shortages. Hydroxychloroquine sulfate tablets. www.accessdata.fda.gov/scripts/drugshortages/dsp_ActiveIngredientDetails.cfm?AI=Hydroxychloroquine&Sulfate&Tablets&st=r. Accessed November 12, 2020.
16. Arthritis Foundation. Hydroxychloroquine (Plaquenil) shortage causing concern. www.arthritis.org/drug-guide/medication-topics/plaquenil-shortage. Accessed November 12, 2020.
17. Ammar MA, Sacha GL, Welch SC, et al. Sedation, analgesia, and paralysis in COVID-19 patients in the setting of drug shortages. J Intensive Care Med. 2021;36(2):157-174.
18. Fox ER, McLaughlin MM. ASHP guidelines on managing drug product shortages. Am J Health Syst Pharm. 2018;75(21):1742-1750.
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