Toxicology

Shortages of agents used to treat antimuscarinic delirium

a b s t r a c t

Introduction: Antimuscarinic delirium (AD), a potentially life-threatening condition frequently encountered by emergency physicians, results from poisoning with antimuscarinic agents. Treatment with physostigmine and benzodiazepines is the mainstay of pharmacotherapy, and use of dexmedetomidine and non-physostigmine centrally-acting acetylcholinesterase inhibitors (cAChEi) such as rivastigmine has also been described. Unfortu- nately, these medications are subject to drug shortages which negatively impact the ability to provide appropri- ate pharmacologic treatment of patients with AD. Methods: Drug shortage data were retrieved from the University of Utah Drug Information Service (UUDIS) data- base from January 2001 through December 2021. Shortages of first-line agents used to treat AD (physostigmine and parenteral benzodiazepines) and second-line agents (dexmedetomidine and non-physostigmine cAChEi) were examined. Drug class, formulation, route of administration, reason for shortage, shortage duration, generic status, and whether the drug was a single-source product (made by only one manufacturer) were extracted. Shortage overlap and median shortage durations were calculated.

Results: Twenty-six shortages impacting drugs used to treat AD were reported to UUDIS from January 1, 2001 to December 31, 2021. Median shortage duration for all medication classes was 6.0 months. Four shortages were unresolved at the end of the study period. The single medication most often on shortage was dexmedetomidine, however benzodiazepines were the most common medication class on shortage. Twenty-five shortages involved parenteral formulations, and one shortage involved the transdermal patch formulation of rivastigmine. The majority (88.5%) of shortages involved generic medications, and 50% of products on shortage were single- source. The most common reported reason for shortage was a manufacturing issue (27%). Shortages were often prolonged and, in 92% of cases, overlapped temporally with other shortages. Shortage frequency and dura- tion increased during the second half of the study period.

Conclusion: Shortages of agents used in the treatment of AD were common during the study period and affected all agent classes. Shortages were often prolonged and multiple shortages were ongoing at study period end. Mul- tiple concurrent shortages involving different agents occurred, which could hamper substitution as a means of mitigating shortage. Healthcare stakeholders must develop innovative patient- and institution-specific solutions in times of shortage and work to build resilience into the medical product supply chain to minimize future short- ages of drugs used for treatment of AD.

(C) 2023

Abbreviations: Antimuscarinic delirium, AD; Centrally acting acetylcholinesterase inhibitor, cAChEi; University of Utah Drug Information Service, UUDIS; American Society of Health-System Pharmacists, ASHP.

? Data in this manuscript were previously presented at the American College of Medical

Toxicology Annual Scientific Meeting, virtual, 2021.

* Corresponding author at: MAILSTOP 3025, Boston Children’s Hospital, 300 Longwood Avenue, Boston, MA 02115, USA.

E-mail address: [email protected] (J.D. Whitledge).

  1. Introduction

Antimuscarinic delirium (AD) is a potentially life-threatening condi- tion caused by medications such as atropine, triCyclic antidepressants, antipsychotics, antihistamines, and plants such as Datura stramonium and Atropa belladonna [1]. AD results from competitive antagonism of acetylcholine at postsynaptic M1 muscarinic receptors of the central

https://doi.org/10.1016/j.ajem.2023.02.036

0735-6757/(C) 2023

nervous system [2]. Patients with AD present clinically with agitation, auditory and Visual hallucinations, mumbling or incoherent speech, and carphologia, and in cases of severe toxicity respiratory compromise, seizures, coma, and even death may occur, making timely and effective supportive and pharmacologic treatment critical [3]. Self-harm and un- intentional xenobiotic exposures resulting in AD are frequently encoun- tered in the emergency department (ED) and emergency physicians must be able to recognize and pharmacologically treat this condition [4]. Up to 15-20% of hospital admissions and 40% of intensive care unit admissions for poisoning are attributable to antimuscarinic toxicity [3]. Elderly patients are at particularly high risk for toxicity as they are more likely to be prescribed antimuscarinic medications and are also more susceptible to adverse effects; 39% of elderly delirium cases and up to 30% of elderly delirium hospital admissions are attribut- able to medication exposure, with a large proportion of these exposures being antimuscarinic in nature [5-7].

Acutely, in addition to airway protection and stabilization of cardio- pulmonary status, parenteral benzodiazepines and physostigmine are considered First-line treatments for AD [1,3]. Physostigmine, a tertiary amine carbamate reversible acetylcholinesterase inhibitor, crosses the blood-brain brain barrier and increases synaptic acetylcholine concen- trations, thereby reversing antimuscarinic toxicity, which can be thera- peutic and also diagnostic for AD in cases of diagnostic uncertainty [8]. Benzodiazepines are GABA-A receptor agonists that do not reverse antimuscarinic toxicity, instead acting as sedating agents that suppress delirium-related agitation [9]. Drug shortages are common in the United States, and unfortunately, despite frequent therapeutic necessity, physostigmine and benzodiazepines are often impacted by shortage [10]. Physostigmine shortages in particular have forced physi- cians to utilize second-line agents including dexmedetomidine, a centrally-acting alpha-2 agonist with sedative properties, and non- physostigmine centrally acting acetylcholinesterase inhibitors (cAChEi) such as rivastigmine, donepezil, and galantamine, which like physostig- mine increase synaptic acetylcholine concentrations, but are prescribed on-label for dementia [11-18]. While potentially useful, second-line agents have less efficacy data and physicians may be unfamiliar with their administration, resulting in Medication errors and adverse patient outcomes [10]. The objective of this study is to describe trends in drug shortages impacting drugs commonly used to treat AD, which may negatively affect care of patients in the emergency department and in the critical settings.

  1. Methods

Drug shortage data were retrieved from the University of Utah Drug Information Service (UUDIS) from January 2001 through December 2021. UUDIS began collecting national drug shortage data in January 2001, and they publish critical drug shortage information on a public website (https://www.ashp.org/Drug-Shortages/) hosted by the American Society of Health-System Pharmacists (ASHP). UUDIS and ASHP define a drug shortage as “a supply issue that affects how the pharmacy prepares or dispenses a drug product or influences patient care when prescribers must use an alternative agent.” UUDIS receives voluntary reports of drug shortages via the reporting feature on the ASHP website. clinical pharmacists at UUDIS conduct research on each reported shortage to verify if it actually exists. This research includes determining all potential manufacturers and all drug presentation National Drug Codes for the product in question. Then each manufac- turer is contacted to determine which National Drug Codes are in short- age (backorder, allocation, etc.) at the national level. If the majority of suppliers are having a national shortage, then UUDIS will post informa- tion at the ASHP drug shortage website noting which products are affected, which products are available and any specific methods for accessing the product, reasons for the drug shortage, estimated resupply dates, and if applicable, implications for patient care, Safety concerns, and alternatives and management strategies. UUDIS does not track

regional shortage trends and cannot reliably distinguish between lim- ited availability of a drug versus complete absence. UUDIS considers a shortage to be resolved when all suppliers have all presentations avail- able or have discontinued their products. UUDIS also follows FDA’s drug shortage website and will generally resolve shortages when the FDA considers the shortage resolved unless there are specific presentations that are clinically relevant that remain unavailable [19].

Using UUDIS, shortages of physostigmine and parenteral benzodiaz- epines, which are the first-line medications used to treat AD, were ex- amined. Shortages of dexmedetomidine and non-physostigmine cAChEi, which are second-line agents for AD therapy, were also evalu- ated. Oral and transdermal non-physostigmine cAChEi formulations were considered as there are case reports of using both formulations during times of physostigmine shortage. Peripherally-acting quaternary amine acetylcholinesterase inhibitors such as pyridostigmine were ex- cluded because they do not cross the blood-brain barrier and therefore would not be effective for the management of AD. Data were analyzed focusing on drug class, formulation, route of administration, reason for shortage, shortage duration, generic status, and whether the drug was a single-source product (made by only one manufacturer). Overlapping shortages were examined. Business decisions resulting in permanent product discontinuation were included in counting of overall shortage number but were not included in shortage duration calculations. Median shortage durations and associated interquartile ranges (IQR) were calculated, however ongoing shortages were excluded from these calculations, as this would underestimate true duration.

  1. Results

There were a total of 26 shortages impacting drugs used to treat AD reported to UUDIS from January 1, 2001 to December 31, 2021 (Table 1). Median shortage duration for resolved shortages of all medication classes was 6.0 months (range: 0.4 to 89.5 months, IQR 14.2 months). The single longest shortage, now resolved, was 89.5 months and in- volved lorazepam. Four shortages were unresolved at the end of the study period. The single medication most often on shortage was dexmedetomidine, however benzodiazepines (diazepam, lorazepam, midazolam) were the most common medication class on shortage, with 12 occurrences in total. Median duration of the ten resolved benzo- diazepine shortages was 16.8 months (IQR 26.6 months). Benzodiaze- pines were on shortage for 185.4 months (72%) of the study period. 25 shortages involved parenteral formulations, and one shortage in- volved the transdermal patch formulation of rivastigmine. There were no shortages of oral non-physostigmine cAChEi. Three of 26 products (11.5%) were brand-name products, and 23 of 26 (88.5%) were generics. 50% of products on shortage were single-source. Suppliers reported

multiple reasons for shortage (Table 2).

For 46% of shortages, suppliers did not provide a reason for shortage. When a reason was provided, the most common reported cause was a manufacturing issue (27%). Shortages were often prolonged, overlap- ping, and simultaneously involved multiple agent classes (Fig. 1).

Twenty-four of 26 shortages (92%) temporally overlapped with other concurrent shortages. Benzodiazepines were particularly

Table 1

Medications for Antimuscarinic Delirium Affected by Shortage 2001-2021.

Medication

Number of shortages (n = 26)

Total shortage months

Percent of study period on shortage

Median duration in months of resolved shortages (IQR)

Physostigmine

6 (1 active)

37.6

14.7%

4.9 (0.9)

Rivastigmine

1

2.6

1.0%

2.6?

Dexmedetomidine

7 (1 active)

64.0

25.0%

7.2 (10.1)

Diazepam

6

96.3

37.7%

16.8 (18.9)

Lorazepam

3 (1 active)

167.4

65.5%

47.9 (41.7)

Midazolam

3 (1 active)

104.8

41.0%

32.2 (28.7)

* Only one resolved shortage occurred therefore no interquartile range (IQR) calculated.

Table 2

Reported Reasons for Shortage.

This study’s findings demonstrate numerous prolonged and overlap- ping shortages of agents used to treat AD over the 21-year study period,

Shortage Reason

Number of shortages (n = 26)

Total shortage months

Percent of study period on shortage

Median duration in months of resolved shortages (IQR)

and these shortages affected every drug class employed for this indica- tion. This trend accelerated over time, with shortage frequency and duration both increasing in the second half of the study period.

Manufacturing 7 (1 active) 109.0 42.6% 12.4 (18.9)

Supply/demand 4 39.2 15.3% 9.4 (11.2)

Short-dated 2 (1 active) 44.6 17.4% 4.2?

Benzodiazepines as a class experienced both the greatest number of shortage occurrences and spent the greatest proportion of the study pe-

riod on shortage. Lorazepam, which for many clinicians is the preferred

Business

decision

1 14.5 5.6% 14.5?

benzodiazepine for treatment of agitation due to lower risk of respira-

Not reported 12 (2 active) 156.4 61.2% 5.3 (6.0)

* Only one resolved shortage occurred therefore no IQR calculated.

susceptible to overlapping shortage: 81.8 months of the study period (32%) had multiple concurrent benzodiazepine shortages. In 2019, con- temporaneous shortages of every AD therapeutic agent occurred, except for non-physostigmine cAChEi. The majority (61.5%) of shortages oc- curred after June 30, 2011, during the second half of the study period. Median duration of resolved shortages increased from 5.3 months in the first half of the study period to 7.2 months in the second half.

  1. Discussion

Antimuscarinic delirium from xenobiotic exposure is commonly en- countered by emergency physicians, medical toxicologists, critical care physicians, and other clinicians. Treatment requires specific pharmaco- therapies, traditionally physostigmine and benzodiazepines as first-line agents, and more recently in cases of shortage, dexmedetomidine and non-physostigmine cAChEi have been utilized as well as second-line agents. If clinicians are unable to access medications in a timely manner when treating patients with AD, undertreatment from rationing or com- plete lack of treatment may adversely affect patient outcomes [20,21].

tory depression and lack of active metabolites, was most affected, spending almost two thirds of the 21-year study period on shortage [22]. Physostigmine, the other first-line pharmacotherapy besides ben- zodiazepines, also experienced multiple shortages, the latest of which is currently ongoing without a projected end date [23]. Physostigmine shortages were only present for 14.7% of the study period, less than any of the benzodiazepines or dexmedetomidine, yet its recurrent ab- sence is particularly well-publicized within the field of toxicology, reflecting physostigmine’s unique diagnostic and therapeutic value as the only therapy capable of rapid central antimuscarinic toxicity rever- sal within minutes [3].

Use of the non-physostigmine cAChEi rivastigmine, donepezil, and gal- antamine has been reported as a therapeutic alternative or adjunct to phy- sostigmine [11-14,16,18]. This is mechanistically appealing because these medications, like physostigmine, are uncharged tertiary amine acetylcho- linesterase inhibitors that cross the blood-brain barrier and boost synaptic acetylcholine levels, thereby reversing the pathophysiology of AD in a long-lasting manner as opposed to merely suppressing associated agitation like benzodiazepines and dexmedetomidine until residual antimuscarinic toxin is metabolized [3,9,17]. An additional appeal is that these medications were well-insulated from shortage during the study pe- riod, experiencing only a single 2.6 month shortage of the transdermal for- mulation of rivastigmine. Some drawbacks do exist however. Onsets of action for oral rivastigmine (time to peak serum drug concentration,

Fig. 1. Overlapping Shortages 2001-2021.

Tmax, 1 h), transdermal rivastigmine (Tmax, 8-16 h), oral galantamine (Tmax, 1 h), and oral donepezil (Tmax, 3-8 h) are slower than physostig- mine (Tmax, 3 min), precluding rapid dose titration; Oral formulations carry an aspiration risk in Delirious patients unless administered via nasogastric tube and absorption may be unreliable due to gastrointestinal tract dysmotility from muscarinic antagonism; and a longer Duration of action than physostigmine, while offering extended delirium control, also means that iatrogenic muscarinic toxicity from ill-defined dosing may require prolonged treatment, though therapeutic dementia dosing has been well-tolerated in published cases [11-14,18].

In the authors’ experience and in case reports, dexmedetomidine, a centrally-acting alpha-2 agonist with sedative properties, is an effective adjunct or substitute for benzodiazepines for suppression of AD- associated agitation, yet was itself on shortage for one quarter of the study period, sometimes with multiple concurrent shortages [15,17].

Medication substitution in general carries the potential for Patient harm due to lack of clinician familiarity with substitute agent character- istics including appropriate dosage, pharmacokinetics, adverse effects, and concentration, yet remains an important solution in times of pri- mary drug shortage [10,24-27]. In the case of AD therapeutics how- ever, providers’ ability to substitute one drug for another, both within the benzodiazepine class and across drug classes, may have been hampered by temporally overlapping shortages. Contempora- neous shortages of different benzodiazepines were present for 32% of the study period, and shortages of agents from different classes overlapped for 92% of the study period. The year 2019 is a particu- larly striking example: shortages of diazepam, lorazepam, midazo- lam, physostigmine, and two formulations of dexmedetomidine occurred simultaneously.

In this study, shortages predominantly affected generic, parenteral agents, which is consistent with national shortage trends of other med- ications [20,28]. Perhaps in part because failure to report shortage does not result in financial penalty for manufacturers, 46% of shortages in this study did not have a reported reason, however the most common re- ported reason was a problem with manufacturing, followed by Supply and demand mismatch [29]. Generic, parenteral drugs often have a small number of suppliers with a single manufacturer occupying most of the market, or all of it in the case of single-source products. When a manufacturing or quality issue arises in a sterile drug production facility, it may require significant time to rectify prior to resuming production, resulting in prolonged supply and demand mismatch due to the inabil- ity of other suppliers to fully compensate for the scarcity. The shortage may be particularly severe if a single-source agent is involved, as was the case for one half of medication shortages in this study [30,31]. Nu- merous shortage solutions beyond the scope of this paper have been proposed, including thoughtful medication rationing and substitution at the hospital level, drug compounding, increased purchasing transpar- ency, a manufacturer quality rating system, incentives encouraging new supplier entry into the market, mandated manufacturing redundancy, and timely shortage reporting enforced by financial penalties [24].

This study has multiple limitations due to the characteristics of the UUDIS database. The first is an inability to assess shortage effects on in- dividual patients and institutions, both in terms of patient outcomes and Hospital resources expended. Likewise, institutional responses to short- ages which may be informative, such as substituting rivastigmine for physostigmine, and the resultant outcomes, could not be assessed. Shortage severity, for example whether a drug’s supply was limited or completely depleted, could not be ascertained. Institutional and re- gional variation in severity is also not captured by UUDIS; for example, an academic tertiary care hospital in the midwestern United States may through supplier purchasing relationships maintain adequate stockpiles of lorazepam and substitute agents and be relatively unaf- fected by a lorazepam shortage, whereas a rural community hospital in the northeastern United States may have no access to lorazepam and minimal substitute agents stockpiled during a shortage and there- fore be adversely affected to a greater extent.

  1. Conclusions

Shortages of critical and life-saving medications in the U.S. are com- mon. Shortages of agents needed to treat antimuscarinic delirium have negative implications for patient care and are particularly challenging due to prolonged and overlapping shortages, limited data for second- line alternatives when first-line agents are unavailable, as well as the emergent need for these medications. The National Academies of Science, Engineering, and Medicine (NASEM) recently published a consensus report providing a framework to build resilience into the medical product supply chain. Stakeholders including physicians and pharmacists, health systems, drug suppliers, lawmakers, and govern- ment agencies should work to implement the recommendations provided in this framework [32]. In addition, further investigation of efficacy of second-line therapies for AD is needed.

CRediT authorship contribution statement

James D. Whitledge: Data curation, Formal analysis, Methodology, Project administration, Supervision, Writing – original draft. Pelayia Soto: Conceptualization, Data curation, Formal analysis, Methodology, Project administration, Writing – original draft. Kieran M. Glowacki: Data curation, Formal analysis, Writing – original draft. Erin R. Fox: Conceptualization, Data curation, Methodology, Writing – original draft. Maryann Mazer-Amirshahi: Conceptualization, Data curation, Formal analysis, Methodology, Project administration, Supervision, Writing – original draft.

Declaration of Competing Interest

This work has no source of funding.

Maryann Mazer-Amirshahi, Kieran Glowacki, Pelayia Soto, and James Whitledge have no Financial benefits or conflicts of interest to dis- close. Erin Fox leads the University of Utah Drug Information Service (UUDIS). The UUDIS has a contract with Vizient (a GPO) to provide drug shortage information. The total amount represents less than 5% of the UUDIS budget. No funds are paid directly to Erin Fox. Erin Fox receives partial travel support for providing continuing education on drug short- ages from the Drug Information Association. We certify that our submis- sion is original and not under review by any other journal. All authors meet the criteria for authorship stated in the Uniform Requirements for Manuscripts Submitted to Biomedical journals, and all listed authors have read and approve this submission.

References

  1. Boley SP, Olives TD, Bangh SA, Fahrner S, Cole JB. Physostigmine is superior to non- antidote therapy in the management of antimuscarinic delirium: a prospective study from a regional poison center. Clin Toxicol. 2019 Jan 2;57(1):50-5.
  2. Pratico C, Quattrone D, Lucanto T, Amato A, Penna O, Roscitano C, et al. Drugs of an- esthesia acting on central cholinergic system may cause post-operative cognitive dysfunction and delirium. Med Hypotheses. 2005 Jan;65(5):972-82.
  3. Dawson AH, Buckley NA. Pharmacological management of anticholinergic delirium – theory, evidence and practice: anticholinergic delirium. Br J Clin Pharmacol. 2016 Mar;81(3):516-24.
  4. Mowry JB, Spyker DA, Brooks DE, Zimmerman A, Schauben JL. 2015 annual report of the American Association of Poison control centers‘ National Poison Data System (NPDS): 33rd annual report. Clin Toxicol. 2016 Nov 25;54(10):924-1109.
  5. Nishtala PS, Chyou T. Risk of delirium associated with antimuscarinics in older adults: a case-time-control study. Pharmacoepidemiol Drug Saf. 2022 Aug;31(8): 883-91.
  6. Catic AG. Identification and management of in-hospital drug-induced delirium in older patients. Drugs Aging. 2011 Sep;28(9):737-48.
  7. Moore AR, ST O Keeffe. Drug-induced cognitive impairment in the elderly. Drugs Aging. 1999;15(1):15-28.
  8. Arens AM, Kearney T. Adverse effects of physostigmine. J Med Toxicol. 2019 Jul;15 (3):184-91.
  9. Iii CEG, Kaye AM, Kaye AD. Benzodiazepine pharmacology and central nervous system-mediated effects. 2013;13(2):10.
  10. Mazer-Amirshahi M, Hawley KL, Zocchi M, Fox E, Pines JM, Nelson LS. Drug short- ages: Implications for medical toxicology; 2015; 6.
  11. Van Kernebeek MW, Ghesquiere M, Vanderbruggen N, Verhoeven E, Hubloue I, Crunelle CL. Rivastigmine for the treatment of anticholinergic delirium following se- vere procyclidine intoxication. Clin Toxicol. 2021 May 4;59(5):447-8.
  12. Hughes AR, Moore KK, Mah ND, Birmingham AR, Clark RK, Thompson JA, et al. Letter in response to Rivastigmine for the treatment of anticholinergic delirium following severe procyclidine intoxication. Clin Toxicol. 2021 Sep 2;59(9):855-6.
  13. Ahmad J, Hasan MJ, Anam AM, Barua DK. Donepezil: an unusual therapy for acute diphenhydramine overdose. BMJ Case Rep. 2019 Mar;12(3):e226836.
  14. Sandia SI, Ramirez VJ, Pinero AJ, Baptista TT. Treating ‘Devil’s Breath’ intoxication: use of rivastigmine in six patients with toxic psychoses due to non pharmaceutical scopolamine. Eur Neuropsychopharmacol. 2017 Aug;27(8):833-4.
  15. Cowan K, Landman RA, Saini A. Dexmedetomidine as an adjunct to treat anticholin- ergic toxidrome in children. Glob Pediatr Health. 2017 Jan 1.;4 2333794X1770476.
  16. Cozanitis DA. Galanthamine hydrobromide, a longer acting anticholinesterase drug, in the treatment of the central effects of scopolamine (hyoscine); 2023; 3.
  17. Gee SW, Lin A, Tobias JD. Dexmedetomidine infusion to control agitation due to an- ticholinergic toxidromes in adolescents, a case series. J Pediatr Pharmacol Ther. 2015 Aug 1;20(4):329-34.
  18. Whitledge JD, Watson CJ, Simpson M, Bakkar A, Boussi L, Scott M, et al. Diphenhydramine-induced antimuscarinic delirium treated with physostigmine and transdermal rivastigmine. J Med Toxicol [Internet]. 2022 Dec 27. Available from. https://doi.org/10.1007/s13181-022-00925-z. [cited 2022 Dec 28].
  19. Fox ER, McLaughlin MM. ASHP guidelines on managing drug product shortages. Am J Health Syst Pharm. 2018 Nov 1;75(21):1742-50.
  20. ACMT practice statement: Antidote shortages: Impact and response [internet]. American College of Medical Toxicology; 2012. [cited 2022 Sep 15]. Available from. https://www.acmt.net/_Library/Position_Drafts/AntidoteShortages111512. pdf.
  21. ACMT position statement on prescription drug shortages [internet]. American Col- lege of Medical Toxicology; 2020. Available from. https://www.acmt.net/cgi/ getdata.cgi/ACMT_Position_Statement_Prescription_Drugs_Shortages.pdf?tab= article&id=5975&col=picture.
  22. Riss J, Cloyd J, Gates J, Collins S. Benzodiazepines in epilepsy: pharmacology and pharmacokinetics. Acta Neurol Scand. 2008 Aug;118(2):69-86.
  23. Physostigmine salicylate injection [internet]. American Society of Health-System Pharmacists; 2022. [cited 2023 Jan 5]. Available from. https://www.ashp.org/ drug-shortages/current-shortages/drug-shortage-detail.aspx?id=721 &loginreturnUrl=SSOCheckOnly.
  24. J D Whitledge, Fox ER, Mazer-Amirshahi M. Benzodiazepine shortages: a recurrent challenge in need of a solution. J Med Toxicol. 2023 Jan;19(1):4-6.
  25. Mazer-Amirshahi M, Fox ER, Nelson LS, Smith SW, Stolbach AI. ACMT position state- ment on prescription drug shortages. J Med Toxicol. 2020 Jul;16(3):349-51.
  26. Farmer BM, Cole JB, Olives TD, Farrell NM, Rao R, Nelson LS, et al. ACMT position statement: medication administration and safety during the response to COVID-19 pandemic. J Med Toxicol. 2020 Oct;16(4):481-3.
  27. Mazer-Amirshahi M, Fox ER, Farmer BM, Stolbach AI. ACMT position statement: medication shortages during coronavirus disease pandemic. J Med Toxicol. 2020 Jul;16(3):346-8.
  28. Woodcock J, Wosinska M. Economic and technological drivers of generic sterile injectable drug shortages. Clin Pharmacol Ther [Internet]. 2012 Nov 7. Available from. https://doi.org/10.1038/clpt.2012.220. [cited 2022 Sep 4].
  29. S.2595 – Drug shortages prevention and quality improvement act [internet]. United States Congress; 2021. Available from. https://www.congress.gov/bill/117th- congress/senate-bill/2595.
  30. Drug shortages infographic [internet]. U.S. Food & Drug Administration; 2019. [cited

2022 Sep 15]. Available from. https://www.fda.gov/drugs/drug-shortages/drug- shortages-infographic.

  1. Mazer-Amirshahi M, Fox ER. Saline shortages — many causes, no simple solution. N Engl J Med. 2018 Apr 19;378(16):1472-4.
  2. Committee on Security of America’s Medical Product Supply Chain, Board on Health Sciences Policy, Health and Medicine Division, National Academies of Sciences, Engi- neering, and Medicine. In: Hopp WJ, Brown L, Shore C, editors. Building resilience into the nation’s medical product supply chains [internet]. Washington, D.C.: Na- tional Academies Press; 2022 [cited 2022 Aug 10]. Available from. https://www. nap.edu/catalog/26420.