Benzodiazepine Shortages: A Recurrent Challenge in Need of a Solution

Since the approval of chlordiazepoxide in 1960 by the United States Food and Drug Administration (FDA), benzodiazepines have been widely utilized, including in the practice of toxicology [1]. Alcohol and sedative-hypnotic withdrawal, agitation associated with sympathomimetic and anticholinergic toxidromes, serotonin syndrome, neuroleptic malignant syndrome, and drug-induced seizures represent just some of the toxicologic conditions treated with benzodiazepines [2–6]. Because benzodiazepines occupy such a vital place within the toxicology formulary, perhaps unmatched by other medication classes in frequency and breadth of use, shortages of these agents are a challenge to toxicologists and other healthcare providers caring for poisoned patients.

Unfortunately, benzodiazepine shortages have become more frequent and protracted in recent years. Since the University of Utah Drug Information Service (UUDIS) began tracking benzodiazepine shortages in 2001, 35 in total have occurred. UUDIS defines 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 tracks shortages at the national level, but does not track regional trends and cannot always differentiate between a limited supply of drug versus a complete absence [7]. In the first decade of the twenty-first century, 11 shortages occurred with a median duration of 230 days, but in the second decade, this number increased to 20 shortages with a median duration of 244 days, and four of these shortages are still ongoing; the longest involves parenteral lorazepam which has been on shortage since February 2016. Since 2020, four more shortages have occurred, three of which are ongoing in 2022 and include parenteral diazepam and midazolam. While the increasing frequency and duration of these shortages alone are troubling, shortages of parenteral formulations of diazepam, lorazepam, and midazolam are particularly concerning because they are regularly utilized in the care of critically ill patients. Fifteen parenteral benzodiazepine shortages have occurred since 2001 (Table 1). Parenteral benzodiazepine shortages also tend to be much longer in duration, with a median duration of 576 days compared to 216 days for oral formulations.

Table 1.

Characteristics of parenteral benzodiazepines on shortage 2001–2022 (UUDIS data).

Benzodiazepine	Total number of shortages	Median shortage duration (days)a	Current shortage
Diazepam	7	505	Yes
Lorazepam	3	1436	Yes
Midazolam	4	967	Yes
Chlordiazepoxide	1	1594	No

^aIncludes resolved shortages only.

Multiple concurrent shortages make substitution between agents more difficult. When substitution does occur, differences in agent characteristics may negatively impact patient care, particularly when healthcare providers use medications with which they are less familiar or that are not ideal agents for a particular patient or scenario [8–10]. For example, diazepam, which has slow and erratic intramuscular absorption, might be given instead of intramuscular midazolam, which displays reliably rapid absorption, with resultant decreased antiepileptic effect in the case of a drug-induced seizure when the patient does not have intravenous access [11]. Healthcare providers may also need to substitute non-benzodiazepine alternatives such as phenobarbital, ketamine, or antipsychotics, which carry their own unique risk profiles. These alternative agents may increase resource utilization; for example, some hospitals’ guidelines mandate intensive care unit (ICU) admission in the case of phenobarbital use for alcohol withdrawal. In the specific case of the commonly encountered anticholinergic toxidrome, for which benzodiazepines are a treatment mainstay, pharmacotherapy is further complicated by prolonged and recurrent physostigmine shortages [12]. Even if substitution occurs, patients may experience undertreatment of their disease process during benzodiazepine shortage, leading to increased morbidity and mortality [8]. In an effort to decrease waste of scarce drug, using medication vials multiple times may inadvertently compromise sterility [10, 13]. Outright medication errors such as dosing mistakes may even occur because of lack of provider familiarity with a substitute agent or stocking of a different concentration than usual [7–9]. In addition to direct patient harm, benzodiazepine shortages may inflict heavy labor burdens on healthcare institutions, which are particularly concerning in light of current hospital staff shortages [8, 14].

Despite the safety concerns posed by benzodiazepine shortages and drug shortages in general, healthcare institutions, the pharmaceutical industry, and policymakers have struggled to devise effective solutions. Shortages tend to involve generic, parenteral medications with a single or few suppliers, which describe most benzodiazepines used to treat toxicologic conditions [15, 16]. Most shortages of sterile injectable medications are due to quality or manufacturing problems which can be time-consuming to remediate, and a lack of mandated manufacturing redundancy makes it difficult for suppliers to compensate by increasing production at a different location [17]. Of the 15 parenteral benzodiazepine shortages since 2001, seven involve products that are “single-source,” meaning that there is only a single supplier, and even if a product is not single-source, one company often occupies the majority of the market share and if it experiences a shortfall, other suppliers may be unable to sufficiently increase production to compensate [18].

Fixing the intractable problem of benzodiazepine shortages will require a multi-pronged approach enlisting multiple stakeholders, including toxicologists and other healthcare providers. At an institutional level toxicologists, who have a unique clinical and pharmacologic skillset, should be included as members of Pharmacy and Therapeutics and Drug Shortage committees to aid in providing guidance regarding conservation of limited drug supply and appropriate therapeutic alternatives [8]. Compounding of scarce drug can be considered, though this carries risks of contamination and dosing miscalculation which toxicologists must be aware of [10, 19, 20]. Drug manufacturer identity and location should be disclosed to healthcare institutions to facilitate purchasing transparency, and a quality rating system for manufacturers should be implemented [8, 21]. When possible, healthcare systems should purchase from suppliers with proven track records of high quality and availability [8, 18]. Benzodiazepine manufacturers must develop business continuity plans to implement in case of unexpected manufacturing problems [8, 21]. Incentives to encourage market entry of new manufacturers in the form of tax credits, rebates for factory upkeep, temporary market exclusivity, accelerated approval of another product, and removal of Medicare generic injectable price caps could be considered [21, 22]. Legislation imposing appropriate financial penalties on suppliers who fail to report shortages must be passed [23]. While many of these solutions are outside the scope of traditional toxicology practice, some toxicologists may assume leadership, regulatory, and legislative roles during their careers that afford the opportunity for implementation. Additionally, toxicologists can advocate for these changes through their elected representatives and professional organizations. Finally, outcome data from shortages are limited and yet crucial to effecting legislative change, without which suppliers motivated primarily by financial incentives will not implement changes necessary to prevent future shortages [8, 24]. We recommend documenting patient harm and potential patient harm related to shortages, as well as patient- and institution-specific solutions, through a database such as the ToxIC Registry or MedWatch. Toxicologists should act as reporting advocates within their institutions, emphasizing the importance of recording these findings, which must be assiduously conveyed to the scientific community, legislative and regulatory bodies, and the public.

The problem of benzodiazepine shortages is not easily solved; however, it is crucial that all stakeholders make a concerted, collaborative effort to do so through implementation of the aforementioned strategies. Suppliers are ultimately responsible for addressing manufacturing issues, but regulatory and legislative action on transparency and quality metrics can facilitate this process. Toxicologists can make a difference in multiple ways, including at the bedside, institutionally, as outcome reporters and advocates for change, and we must embrace these opportunities, for the implications of ongoing shortages for patients and those who provide their care are unacceptable.

Funding

This work has no source of funding.

Declarations

Conflicts of Interest

James Whitledge and Maryann Mazer-Amirshahi report no conflicts of interest. 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 shortages from the Drug Information Association.