CADTH Health Technology Review

Drug Shortages and Patient Harms

Technology Review

What Is the Issue?

• Drug shortages are a global issue with complex dynamics. Shortages can occur because of disruption at any point along the drug supply chain. Several strategies are used in Canada to prevent or alleviate the effects of drug shortages, including mandatory reporting by drug manufacturers.

• An understanding of the amount and types of real or potential harms caused to patients can inform policy decisions around drug shortage management and prevention.

What Did We Do?

• We searched for literature providing evidence on patient outcomes associated with supply chain disruptions of pharmaceuticals and vaccines. An information specialist conducted a search of peer-reviewed literature sources published between January 1, 2003, and September 13, 2023.

• Documents were excluded if the objective was to investigate the potential effects of a drug shortage in the absence of an actual drug shortage or if the outcomes were not direct patient harms.

What Did We Find?

• One scoping review and 33 nonrandomized studies were identified that evaluated patient outcomes associated with supply chain disruptions of pharmaceuticals and vaccines.

• We identified a wide variety of drug classes experiencing shortages. The most frequently reported shortages were anesthetics, oncology drugs, vaccines, drugs for the treatment of COVID-19, antimicrobials, and small-volume parenteral solutions.

• Most of the included primary studies concluded that the replacement drug or protocol was a safe or acceptable alternative to the shortage drug. The subset of primary studies that concluded that the replacement drug or protocol was not a safe or acceptable alternative to the shortage drug reported worse outcomes in health system use (including length of hospital stay), adverse events, disease progression, and mortality.

What Does This Mean?

• Drug shortages have the potential to cause harm to patients and some drug shortages may have a greater impact on patients than others. The ability to predict which drugs could cause the greatest harm during a supply disruption would be a great benefit for future planning.

• The diversity of drugs experiencing shortages and their associated harms emphasizes that decision-makers may need to take a case-by-case approach when developing policies meant to lessen the impact of drug shortages.

Context and Policy Issues

What Is the Problem?

Drug shortages are a global issue with complex dynamics. Between 2022 and 2023, more than 2,700 drug shortages were reported to Health Canada, lasting an average of 98 days.¹ Of these, 34 were considered high impact — shortages with the greatest potential consequences to people and health care systems (e.g., no therapeutic alternatives available).^1,2

There are multiple steps along the drug supply chain, including:

• drug development and regulatory approval

• manufacturing

• purchase and distribution

• delivery to hospitals, pharmacies, and patients.³

Interruptions to any of these phases can cause a shortage. For example:

• good manufacturing practices noncompliance leading to recalls

• nonprofitable drugs leading to decisions to cease production

• stockpiling of medication

• external factors, such as a natural disaster.^3,4

In addition, weak points in the supply chain, such as relying on the supply of drugs from a single source or not having protocols in place to respond to increases in demand, can also cause or worsen existing drug shortages.^3,4

What Is the Current Practice?

Strategies currently used in Canada to attempt to prevent or alleviate drug shortages include:

• an expedited drug review process to accelerate Health Canada approval of substitute drugs in urgent circumstances

• drug manufacturing quality assurance protocols

• the development of ethical frameworks for resource allocation

• compounding drugs

• rationing protocols at the hospital and pharmacy level.³

Furthermore, mandated reporting of drug shortages went into effect in 2017,² Drug manufacturers are required to report anticipated shortages or discontinuations, ideally 6 months in advance, to allow time to put mitigation plans into place. Manufacturers are also required to report actual shortages as soon as they are aware of them.²

Why Is It Important to Do This Review?

People can experience clinical harm as a result of drug shortages. This can take several forms:

• inadequate treatment or management of health conditions

• withdrawal-related side effects

• adverse or safety events associated with replacement drugs

• medication errors.⁴

Some drugs have the potential for much greater patient harm if they become difficult to obtain. For example, shortages of drugs with life-saving benefits or strict dosing schedules might have more impact on patient outcomes, especially if there are no alternative options available.^2,4

This report is the first in a series of CADTH-published initiatives that aims to emphasize potential priority medications and to ultimately support decision-making during drug shortages.

Objective

The purpose of this report is to summarize the evidence on patient outcomes associated with supply chain disruptions of pharmaceuticals and vaccines.

Research Question

What is the evidence on patient outcomes associated with supply chain disruptions of pharmaceuticals and vaccines?

Methods

Literature Search Methods

An information specialist conducted a literature search on key resources, including MEDLINE and the Cochrane Database of Systematic Reviews. The search approach was customized to retrieve a limited set of results, balancing comprehensiveness with relevancy. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. Search concepts were developed based on the elements of the research questions and selection criteria. The main search concept was drug shortages. CADTH-developed search filters were applied to limit retrieval to health technology assessments, systematic reviews, meta-analyses, or indirect treatment comparisons; any types of clinical trials or observational studies; real-world evidence using routinely collected data; or to the context in Canada. The search was completed on September 13, 2023, and limited to documents published since January 1, 2003.

Selection Criteria and Summary Methods

One reviewer screened citations and selected studies. In the first level of screening, titles and abstracts were reviewed and potentially relevant articles were retrieved and assessed for inclusion. The final selection of full-text articles was based on the inclusion criteria presented in Table 1. Information from the relevant studies was extracted into summary tables and organized into broad clinical indication categories by 1 reviewer. Data were extracted on the study characteristics; shortage drug and its substitute, if applicable; findings that related to direct patient harms; and overall conclusion. Outcome results and their direction of effect were briefly summarized as reported by the study’s authors and categorized into the following: no difference, worse, improved, or mixed between groups (e.g., in studies with multiple comparator groups, an outcome may improve in 1 group but worsen in another). No formal critical appraisal (e.g., risk of bias assessment) of the included studies was conducted.

Exclusion Criteria

Articles were excluded if they did not meet the selection criteria outlined in Table 1, they were duplicate publications, or were published before 2003.

Studies were excluded if:

• the natural effects of a drug shortage could not be observed because of the study design (e.g., randomized controlled trial)

• the shortage product was a multivitamin, supplement, homeopathic medication, or device

• the purpose of the study was to investigate the potential effects of a drug shortage in the absence of an actual drug shortage (e.g., anticipatory)

• the primary or secondary outcomes were not direct patient harms (e.g., studies that reported treatment delays without describing a direct measurable effect to patients were excluded).

Because of the large volume of potentially relevant articles identified for full-text review, those published before January 1, 2018, were excluded. A list of the articles published before 2018 that were identified for full-text review, but not screened for inclusion and exclusion criteria, can be found in Appendix 2.

Overall Summary

Quantity of Research Available

A total of 1,871 citations were identified in the literature search. Following screening of titles and abstracts, 1,742 citations were excluded and 129 potentially relevant reports from the electronic search were retrieved for full-text review. Of these potentially relevant articles, 95 publications were excluded for various reasons, and 34 publications met the inclusion criteria and were included in this report. These comprised 1 scoping review (SR) and 33 nonrandomized studies (NRSs).

Appendix 1 presents the PRISMA⁵ flow chart of the study selection. Additional references of potential interest are provided in Appendix 2.

Summary of Study Characteristics

The SR by Phuong et al. (2019)⁶ included 40 studies. Sixteen primary studies published between 2006 and 2017 met the inclusion criteria for this report. Of these, 3 were prospective cohort studies and 13 were retrospective cohort studies. The authors of the SR were from Australia.⁶

Of the 16 relevant primary studies in the SR, 4 were conducted in a surgical setting, 2 in a nonspecific hospital setting, 1 in the intensive care unit, 1 in an air medical setting, and 8 did not specify a setting.⁶

The 33 included primary clinical studies comprised 1 registry study,⁷ 5 prospective cohort studies,^8-12 and 27 retrospective cohort studies.^13-39 Two studies were published as research letters.^8,30 The studies were published between 2018 and 2023. The primary clinical studies were conducted by authors from Australia,^11,12 Brazil,²³ Canada,^13,20,30,33 the Democratic Republic of the Congo,³⁸ France,^7,14,27 Japan,⁸ the Netherlands,³⁹ and the US.^{9,10,15-19,21,22,24-26,28,29,31,32,34-37}

Twenty of the included primary studies compared outcomes between the shortage drug and its substitute before and during a drug shortage period.^{13-22,24,26,27,31-35,37,39} Of these, 3 studies had at least 1 substitute drug group that had a supply disruption and was further compared to an additional substitute drug group.^14,34,39 In Cole et al. (2021), the intervention and comparator groups flipped partway through when supply of the shortage drug resumed, and the substitute drug went into shortage.¹⁰ In Li and Cimino (2020), the study occurred during the drug shortage period and compared patients who continued receiving the shortage drug to those who switched to a substitute drug.²⁸ In van Langenberg et al. (2020), for long-term outcomes, the intervention group was the substitute drug and was compared to patients who switched back to the shortage drug when supply resumed.¹¹ In this same study, there was no comparator group for short-term outcomes.¹¹ Nine studies did not have a comparator group.^{8,9,12,23,25,29,30,36,38} The registry study aimed to identify adverse drug reactions related to drug shortages and describe the types of drugs and harms involved.⁷

Nine of the included primary studies were conducted in a nonspecific hospital setting,^{13,18,22,24,25,29,35,36,39} 6 in the emergency department (ED),^{10,15,26,32-34} 5 in the intensive care unit,^{17,20,21,27,31} 5 in the community,^8,9,12,30,38 3 in a surgical setting,^16,19,37 3 in a hospital outpatient setting,^11,14,28 and 1 in dialysis clinics.²³

Summary of Findings

The 16 relevant primary studies from the SR are summarized in Table 2. The registry study and 32 NRSs are summarized in Table 3.

There was considerable variability in the types of drugs experiencing shortages. Broadly defined categories by clinical indication were identified as follows:

• anesthetic, analgesic, or sedative medications (SR: 3 studies; NRS: 7 studies)^{6,10,17-19,26,34,37}

• oncology drugs and drugs used in conjunction with oncology drugs (SR: 4 studies; NRS: 5 studies)^{6,13,14,28,35,36}

• vaccines (NRS: 4 studies)^8,9,12,38

• antimicrobials, including antibiotics and antivirals, and drugs used in conjunction with antimicrobials (SR: 3 studies; NRS: 3 studies)^6,22,31,33

• drugs specific to the treatment or management of COVID-19 (NRS: 3 studies)^20,27,39

• drugs that did not fit into the previously mentioned categories (SR: 6 studies; NRS: 6 studies)^{6,11,16,21,23,30,32}

• nondrug, specifically, small-volume parenteral solutions, which are used to administer IV drugs (NRS: 4 studies).^15,24,25,29

Strategies used to manage drug shortages:

• alternative drug (SR: 13 studies; NRS: 14 studies)^{6,8-14,16,26,30-32,34,37}

• dose-sparing strategies (e.g., fixed dose) (SR: 1 study; NRS: 3 studies)^6,20,22,38

• alternative route of administration (e.g., oral formulations) (NRS: 4 studies)^18,21,35,36

• alternative method of administration (e.g., infusion technique) (SR: 1 study; NRS: 4 studies)^{6,15,24,25,29}

• none (e.g., no suitable replacement available) (SR: 1 study; NRS: 2 studies)^6,23,33

• a combination of the previously mentioned categories, either at the same time or in sequence (NRS: 5 studies).^{17,19,27,28,39}

Outcomes related to patient harms and the direction of effect during a drug shortage period:

• Mortality: no difference (SR: 5 studies; NRS: 9 studies);^{6,11,15-17,21,22,24,27,31} worse (SR: 1 study; NRS: 1 study);^6,20 improved (NRS: 1 study);¹³ mixed results between groups (NRS: 1 study)³⁹

• Hospital admission: no difference (NRS: 1 study);³⁰ worse (NRS: 1 study);¹¹ mixed results between groups (NRS: 1 study)³⁴

• Intensive care unit (ICU) admission: no difference (SR: 1 study; NRS 1 study);^6,34 worse (NRS: 2 studies)^13,39

• ED visit: no difference (NRS: 2 studies);^18,37 worse (NRS: 1 study)³⁰

• Hospital readmission: no difference (NRS: 1 study);³³ improved (NRS: 2 studies)^18,24

• Hospital length of stay (LOS): no difference (SR: 3 studies; NRS: 7 studies);^{6,17,18,20,22,24,31,35} worse (NRS: 1 study);¹³ mixed results between groups (NRS: 2 studies)^34,39

• ICU LOS: no difference (NRS: 4 studies)^17,20,21,34

• ED LOS: mixed results between groups (NRS: 2 studies)^10,34

• Postanesthetic care unit LOS: worse (NRS: 1 study)³⁷

• Adverse events: no difference (SR: 8 studies; NRS: 17 studies);^{6,8,9,12,14-16,25-29,31,33-36,38} worse in at least 1 safety outcome (SR: 2 studies; NRS: 5 studies);^{6,11,13,19,24,37} improved in at least 1 safety outcome (SR: 2 studies; NRS: 1 study);^6,32 mixed results between groups (NRS: 1 study)¹⁰

• Disease progression: no difference (SR: 1 study; NRS: 2 studies);^6,27,28 worse (SR: 2 studies; NRS: 3 studies);^6,11,23,31 improved (NRS: 1 study)¹³

• Duration of mechanical ventilation: no difference (SR: 1 study; NRS: 2 studies);^6,17,20 worse (SR: 1 study);⁶ improved (NRS: 1 study)²¹

• Pain: no difference (NRS: 1 study)¹⁷

Primary study author’s conclusions:

• The replacement drug or protocol was a safe or acceptable alternative to the shortage drug (NRS: 26 studies).^{8-10,12-18,20-22,24-30,32-36,38}

• The replacement drug or protocol was considered not safe or at increased risk of harmful outcomes (NRS: 6 studies).^{11,19,23,31,37,39} The shortage drug class differed for all 6 studies^{11,19,23,31,37,39} and was compared to an alternative drug or protocol in 5 studies.^{11,19,31,37,39} There was no suitable replacement therapy available in 1 study.²³ For these 6 studies, worsening direct patient harms were reported for the following outcome categories: health system use (3 studies),^11,37,39 adverse events (3 studies),^11,19,37 and disease progression (3 studies).^11,23,31 Swets et al. (2023) reported lower survival in 2 of the 3 replacement drug groups compared to the shortage drug.³⁹

Context in Canada

Four primary studies investigated drug shortages occurring in Canada.^13,20,30,33 The shortage drugs were carmustine, tocilizumab, probenecid (in conjunction with an antibiotic), and generic valsartan.^13,20,30,33 Lachance et al. (2023) reported that the alternative drug, bendamustine, had worse outcomes in adverse events and ICU admissions and better outcomes in survival and disease progression.¹³ Stukas et al. (2022) reported that the decreased dose of tocilizumab had worse outcomes in mortality, but no difference in hospital LOS, ICU LOS, or duration of mechanical ventilation.²⁰ Landry et al. (2019) reported that using the antibiotic without addition of the shortage drug had no difference in readmissions or adverse events.³³ McAlister and Youngson (2020) reported worse outcomes for ED and outpatient visits, but no difference in hospital admissions.³⁰ Three studies concluded that the replacement drug or protocol was an acceptable alternative to the shortage drug.^13,20,33 The fourth study concluded that there were no long-term adverse effects because of the shortage.³⁰

Table 2: Summary of Included Scoping Review — Phuong et al. (2019)⁶

ICU = intensive care unit; LOS = length of stay; NR = not reported; NSS = not statistically significant.

Table 3: Summary of Included Nonrandomized Studies by Clinical Indication

5-ASA = 5-aminosalicylate; ADR = adverse drug reaction; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BCG = Bacillus Calmette-Guérin; DRC = Democratic Republic of the Congo; ECMO = extracorporeal membrane oxygenation; ED = emergency department; GI = gastrointestinal; H1A = histamine-1 antagonist; H2A = histamine-2 antagonists; HDTMX = high-dose methotrexate; ICU = intensive care unit; LOS = length of stay; NSS = not statistically significant; PACU = post-anesthetic care unit; RRT = renal replacement therapy; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; TIA = transient ischemic attack.

Conclusions

The development of a preventive approach could possibly help mitigate the impacts of drug shortages. To achieve this, first, drugs that are potentially the highest impact need to be identified. Anticipating which drugs are likely to be most impactful during a shortage involves identifying those most at risk of supply chain disruptions and those most likely to cause patient harm. Ranking drugs based on their risk of shortage and their risk of harm during a shortage can help decision-makers put into place pre-emptive strategies. This report supports this objective by summarizing types of harms that may occur during drug shortages, and, although not the primary intent of this report, by identifying the types of drugs experiencing shortages studied in the literature. Most of the published trials examined the effectiveness and safety of alternative drugs during drug shortages. The harms outcomes that were most frequently reported were adverse events or safety-related outcomes and health system use, including length of stay, mortality, and disease progression. Similarly, a French registry study described the types of adverse drug reactions related to drug shortages as reported to a pharmacovigilance database.⁷ The authors described harms from adverse drug reactions; serious adverse drug reactions, including hospitalization, life-threatening events, or death; and disease progression.⁷ The primary studies that concluded that the examined drug shortage had negative consequences reported health system use, adverse events, disease progression, and mortality as harms outcomes.^{11,19,23,31,37,39}

This report summarizes the available evidence on the effect of drug shortages on patient outcomes and will be used in combination with other CADTH work to support future decision-making regarding drug shortages, including:

• an environmental scan of existing clinical tools or scoring systems available for drug shortage or supply chain disruptions

• facilitation of a Delphi panel to support the identification of high-priority drugs based on their supply chain risk and clinical risk.

References

1.Drug Shortages in Canada. Ottawa (ON): Health Canada; 2023: https://www.canada.ca/content/dam/hc-sc/documents/services/drugs-health-products/drug-products/drug-shortages/2022-2023-review/2022-2023-review-en.pdf. Accessed 2023 Nov 9.

2.Protocol for the Notification and Communication of Drug Shortages. Drug Shortages Canada; 2017: https://www.drugshortagescanada.ca/files/MSSC_Protocol_2017.pdf. Accessed 2023 Nov 9.

3.A Toolkit for Improved Understanding and Transparency of Drug Shortage Response in Canada. Drug Shortages Canada; 2017: https://www.drugshortagescanada.ca/files/MSSC_Toolkit_2017.pdf. Accessed 2023 Nov 9.

4.Aronson JK, Heneghan C, Ferner RE. Drug shortages. Part 1. Definitions and harms. Br J Clin Pharmacol. 2023;16:16. PubMed

5.Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Syst. 2021;10(1):89. PubMed

6.Phuong JM, Penm J, Chaar B, Oldfield LD, Moles R. The impacts of medication shortages on patient outcomes: A scoping review. PLoS ONE. 2019;14(5):e0215837. PubMed

7.Bourneau-Martin D, Babin M, Grandvuillemin A, et al. Adverse drug reaction related to drug shortage: A retrospective study on the French National Pharmacovigilance Database. Br J Clin Pharmacol. 2023;89(3):1080-1088. PubMed

8.Miyazato Y, Terada M, Ujiie M, et al. A nationwide prospective cohort study on safety of the 17D-204 yellow fever vaccine during a vaccine shortage in Japan. J Travel Med. 2023;30(2):05.

9.Rojas A, Hachey W, Kaur G, Korejwo J, Muhammad R. Enhanced safety surveillance of STAMARIL R yellow fever vaccine provided under the expanded access investigational new drug program in the United States. J Travel Med. 2023;31:31. PubMed

10.Cole JB, Stang JL, DeVries PA, Martel ML, Miner JR, Driver BE. A Prospective Study of Intramuscular Droperidol or Olanzapine for Acute Agitation in the Emergency Department: A Natural Experiment Owing to Drug Shortages. Ann Emerg Med. 2021;78(2):274-286. PubMed

11.van Langenberg DR, Cheng RK, Garg M. Outcomes of a drug shortage requiring switching in patients with ulcerative colitis. World J Gastrointest Pathophysiol. 2020;11(2):32-42. PubMed

12.Wong NX, Buttery J, McMinn A, Azhar Z, Crawford NW. Safety of the Polish BCG-10 Vaccine During a Period of BCG Vaccine Shortage: An Australian Experience. Pediatr Infect Dis J. 2020;39(6):e66-e68. PubMed

13.Lachance S, Bourguignon A, Boisjoly JA, et al. Impact of Implementing a Bendamustine-Based Conditioning Regimen on Outcomes of Autologous Stem Cell Transplantation in Lymphoma while Novel Cellular Therapies Emerge. Transplant Cell Ther. 2023;29(1):34.e31-34.e37. PubMed

14.Strobbe G, Gaboriau L, Abele M, et al. Impact of histamine-2 antagonist shortage on the incidence of hypersensitivity reactions to paclitaxel: a reconsideration of premedication protocols in France (PACLIREACT Study). Eur J Clin Pharmacol. 2023;79(9):1229-1238. PubMed

15.Academia EC, Jenrette JE, Mueller SW, McLaughlin JM. Evaluation of First-Dose, Intravenous Push Penicillins and Carbapenems in the Emergency Department. J Pharm Pract. 2022;35(3):369-376. PubMed

16.Dannemiller RE, Knowles DM, Cook BM, Goodberlet MZ, Kelly JM, Malloy R. Comparison of trauma-dosed tranexamic acid versus aminocaproic acid in cardiac surgery in the setting of drug shortage. J Card Surg. 2022;37(10):3243-3249. PubMed

17.John K, Cape K, Goodman L, Elefritz J. Impact of the Injectable Opioid Drug Shortage on Analgesia and Sedation Management in the Medical Intensive Care Unit: A Retrospective Cohort Study. Hosp Pharm. 2022;57(1):160-166. PubMed

18.Katsivalis KV, Kosacz J, Austin Szwak J. Opioid Use in Vaso-Occlusive Crisis During Intravenous Opioid Drug Shortage. Hosp Pharm. 2022;57(6):721-726. PubMed

19.Rodriguez-Monguio R, Lun Z, Bongiovanni T, Chen CL, Seoane-Vazquez E. Postoperative Respiratory Events in Surgical Patients Exposed to Opioid Analgesic Shortages Compared to Fully Matched Patients Non-exposed to Shortages. Drug Saf. 2022;45(4):359-367. PubMed

20.Stukas S, Goshua G, Kinkade A, et al. Reduced fixed dose tocilizumab 400 mg IV compared to weight-based dosing in critically ill patients with COVID-19: A before-after cohort study. Lancet Reg Health Am. 2022;11:100228. PubMed

21.Freeman L, Newsome AS, Huang E, Rowe E, Waller J, Forehand CC. Assessment of Electrolyte Replacement in Critically Ill Patients During a Drug Shortage. Hosp Pharm. 2021;56(4):296-301. PubMed

22.Haiduc M, Patel M, Walsh TL, Moffa MA, Bremmer DN. Impact of a cefepime shortage on dosing regimens and outcomes in hospitalized adults with febrile neutropenia. J Oncol Pharm Pract. 2021;27(2):297-304. PubMed

23.Neto ME, de Moraes Soler L, Vasconcelos HVG, et al. Eculizumab interruption in atypical hemolytic uremic syndrome due to shortage: analysis of a Brazilian cohort. J Nephrol. 2021;34(4):1373-1380. PubMed

24.Tschumper E, Dupuis K, McCrory K, Pitts W. Evaluation of Prolonged Versus Continuous Infusions of Piperacillin/Tazobactam During Shortages of Small Volume Parenteral Solutions. J Pharm Technol. 2021;37(6):271-277. PubMed

25.Blair K, Covington EW. Incidence and Risk Factors of Acute Kidney Injury in Patients Receiving Concomitant Vancomycin and Continuous-Infusion Piperacillin/Tazobactam: A Retrospective Cohort Study. Ann Pharmacother. 2020;54(11):1096-1101. PubMed

26.Farrell NM, Killius K, Kue R, Langlois BK, Nelson KP, Golenia P. A Comparison of Etomidate, Ketamine, and Methohexital in Emergency Department Rapid Sequence Intubation. J Emerg Med. 2020;59(4):508-514. PubMed

27.Lecronier M, Beurton A, Burrel S, et al. Comparison of hydroxychloroquine, lopinavir/ritonavir, and standard of care in critically ill patients with SARS-CoV-2 pneumonia: an opportunistic retrospective analysis. Crit Care. 2020;24(1):418. PubMed

28.Li H, Cimino SK. Clinical impact of the etoposide injection shortage. J Oncol Pharm Pract. 2020;26(1):187-192. PubMed

29.Marsh K, Ahmed N, Decano A, et al. Safety of intravenous push administration of beta-lactams within a healthcare system. Am J Health-Syst Pharm. 2020;77(9):701-708. PubMed

30.McAlister FA, Youngson E. Impact of the Generic Valsartan Recall in Alberta, Canada. J Am Coll Cardiol. 2020;75(15):1860-1862. PubMed

31.Patel PD, Bhagat P, Bartlett AH, Bondi DS. Comparison of Neonatal Outcomes With the Use Cefotaxime Versus Ceftazidime in a Neonatal Intensive Care Unit. The Journal of Pediatric Pharmacology & Therapeutics. 2020;25(2):117-123. PubMed

32.Yang I, Smalley S, Ahuja T, Merchan C, Smith SW, Papadopoulos J. Assessment of dextrose 50 bolus versus dextrose 10 infusion in the management of hyperkalemia in the ED. Am J Emerg Med. 2020;38(3):598-602. PubMed

33.Landry DL, Eltonsy S, Jalbert LP, Girouard G, Couture J, Belanger M. Continuous cefazolin infusion versus cefazolin plus probenecid for the ambulatory treatment of uncomplicated cellulitis: A retrospective cohort study. J Assoc Med Microbiol Infect Dis Can. 2019;4(2):108-112. PubMed

34.Nelson AC, Kehoe J, Sankoff J, Mintzer D, Taub J, Kaucher KA. Benzodiazepines vs barbiturates for alcohol withdrawal: Analysis of 3 different treatment protocols. Am J Emerg Med. 2019;37(4):733-736. PubMed

35.Roy AM, Lei M, Lou U. Safety and efficacy of a urine alkalinization protocol developed for high-dose methotrexate patients during intravenous bicarbonate shortage. J Oncol Pharm Pract. 2019;25(8):1860-1866. PubMed

36.Visage R, Kaiser N, Williams M, Kim A. Oral Methods of Urinary Alkalinization for High-dose Methotrexate Administration: Alternatives to Intravenous Sodium Bicarbonate During a Critical Drug Shortage. J Pediatr Hematol Oncol. 2019;41(5):371-375. PubMed

37.Neff MP, Wagner D, Phillips BJ, et al. Propofol Drug Shortage Associated With Worse Postoperative Nausea and Vomiting Outcomes Despite a Mitigation Strategy. Aana J. 2018;86(2):147-154. PubMed

38.Nzolo D, Engo Biongo A, Kuemmerle A, et al. Safety profile of fractional dosing of the 17DD Yellow Fever Vaccine among males and females: Experience of a community-based pharmacovigilance in Kinshasa, DR Congo. Vaccine. 2018;36(41):6170-6182. PubMed

39.Swets MC, Moss RJ, Kor F, et al. A comparison of the effectiveness of different doses of tocilizumab and sarilumab in the treatment of severe COVID-19: a natural experiment due to drug shortages. Int J Infect Dis. 2023;129:57-62. PubMed

Appendix 1: Selection of Included Studies

Figure 1: Selection of Included Studies

Appendix 2: References of Potential Interest

Scoping Reviews

Unclear Outcomes

Tucker EL, Cao Y, Fox ER, Sweet BV. The Drug Shortage Era: A Scoping Review of the Literature 2001-2019. Clin Pharmacol Ther. 2020;108(6):1150-1155. PubMed

Nonrandomized Studies

Not Direct Patient Harm Outcomes

Chun B, He M, Jones C, et al. Variation in Statewide Intravesical Treatment Rates for Non-Muscle Invasive Bladder Cancer During the Bacillus Calmette-Guerin Drug Shortage. Urology. 2023;177():74-80.

N'Kaoua E, Attarian S, Delmont E, et al. Immunoglobulin shortage: Practice modifications and clinical outcomes in a reference centre. Rev Neurol (Paris). 2022;178(6):616-623. PubMed

Zhang B, Yeh DD, Ortiz-Reyes LA, Chang Y, Quraishi SA. Impact of nationwide essential trace element shortages: A before-after, single-center analysis of hospitalized adults receiving home parenteral nutrition therapy. Nutr Clin Pract. 2022;37(2):442-450. PubMed

Martei YM, Grover S, Bilker WB, et al. Impact of Essential Medicine Stock Outs on Cancer Therapy Delivery in a Resource-Limited Setting. J Global Oncol. 2019;5():1-11.

Hedlund NG, Isgor Z, Zwanziger J, et al. Drug Shortage Impacts Patient Receipt of Induction Treatment. Health Serv Res. 2018;53(6):5078-5105. PubMed

Additional References

Potentially Relevant Studies Published Before January 1, 2018

Alhogbani MM, Picard JA, Fassi-Fehri MH, Badet JL, Colombel CM. Prognostic impact of Bacillus Calmette-Guerin interruption at the time of induction and consolidation. Urol Ann. 2017;9(4):315-320. PubMed

Gross AE, Johannes RS, Gupta V, Tabak YP, Srinivasan A, Bleasdale SC. The Effect of a Piperacillin/Tazobactam Shortage on Antimicrobial Prescribing and Clostridium difficile Risk in 88 US Medical Centers. Clin Infect Dis. 2017;65(4):613-618. PubMed

Howard J, Wigley J, Rosen G, D'Mello J. Glycopyrrolate: It's time to review. J Clin Anesth. 2017;36():51-53.

Hsueh K, Reyes M, Krekel T, et al. Effective Antibiotic Conservation by Emergency Antimicrobial Stewardship During a Drug Shortage. Infect Control Hosp Epidemiol. 2017;38(3):356-359. PubMed

McLaughlin MM, Sutton SH, Jensen AO, Esterly JS. Use of High-Dose Oral Valacyclovir During an Intravenous Acyclovir Shortage: A Retrospective Analysis of Tolerability and Drug Shortage Management. Infect. 2017;6(2):259-264. PubMed

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