Why 5 Injectable Drugs Have Been in Shortage for More Than a Decade

Atropine sulfate, cefotaxime, fentanyl citrate, epinephrine bitartrate, and lidocaine hydrochloride have each been in shortage for more than 10 years. In an interview with Pharmacy Times, Marissa Reigelman, manager of senior policy, content, and government affairs at United States Pharmacopeia (USP), discussed USP data showing that all 5 depend on at least 1 key starting material (KSM) manufactured in a single country, a vulnerability that active pharmaceutical ingredient (API) and finished-dose manufacturing data alone may not reveal. Reigelman also addressed how low prices compound this upstream concentration, how prolonged shortages reshape medication use practices in hospitals and health systems, and what manufacturers, providers, and policymakers can do to build a more resilient supply chain.

Pharmacy Times: Why have 5 injectable drugs—atropine sulfate, cefotaxime, fentanyl citrate, epinephrine bitartrate, and lidocaine hydrochloride—been in shortage for more than a decade? What do these drugs have in common?

Marissa Reigelman: These drugs are all injectable medicines that are important to patient care, yet their shortages have persisted for more than a decade. They span different therapeutic areas, but they share overlapping vulnerabilities. More specifically, all 5 depend on at least 1 KSM manufactured in a single country, creating potential single points of dependence far upstream in the supply chain. Three of the 5 also cost less than $3 per unit, showing how upstream concentration can coexist with challenging market economics.

The data USP has collected on drug shortages reinforces that they rarely stem from just one issue. More frequently, the root cause of a drug shortage reflects multiple structural vulnerabilities across the supply chain.

Pharmacy Times: Do these decade-long shortages span different therapeutic categories? Does the diversity reflect a broader pattern or learning?

Reigelman: Although the 5 drugs span 6 therapeutic categories, there is some overlap in their clinical uses. All five medicines can be used in pediatric care, and three are also used in anesthesia. This overlap illustrates a pattern around the effects of a prolonged shortage.

Shortages do not necessarily stay confined to a single medicine or therapeutic area. When clinicians are forced to ration available supply or turn to therapeutic substitutions, often disrupting patients’ care, this shift in demand can contribute to additional pressure on other products, which may result in shortages elsewhere. Increased reliance on alternatives can strain supply across the therapeutic area, creating a cycle of continuous shortages that is difficult to stop when vulnerabilities persist at the earliest stages of the supply chain.

Pharmacy Times: When USP mapped these medicines beyond finished dose and API manufacturing to KSMs, what vulnerabilities were identified?

Reigelman: Looking further upstream, data from USP’s Medicine Supply Map revealed vulnerabilities that are not evident from API or finished-dose manufacturing locations alone. All 5 of these medicines depend on at least 1 KSM manufactured exclusively in a single country. Four rely on China as their primary KSM supplier, with more than half of KSM volume sourced there, while the fifth, atropine sulfate, depends primarily on KSMs from India. Cefotaxime is particularly concentrated, with all KSMs sourced from China. Therefore, a single disruption in 1 of these KSM-producing countries could affect a wide range of medicines at 1 time.

API manufacturing for some of these medicines is more geographically diversified, but that diversity can mask significant concentration risk further upstream. Concentration at the KSM level can create single points of failure that are not apparent from API or finished-dose manufacturing alone. Without visibility into those upstream dependencies, providers may have limited warning of potential supply challenges and less time to prepare alternatives before medicine availability is affected.

Pharmacy Times: As you mentioned, 3 of these 5 medicines cost less than $3 per unit. How do low prices interact with upstream concentration to make an already vulnerable supply chain more challenging to stabilize?

Reigelman: Low price margins and upstream concentration of KSMs and APIs can negatively impact supply chain resilience by turning a single point of failure into a prolonged supply challenge that becomes difficult to resolve or stabilize.

Three of the 5 medicines USP has identified as being in long-term shortage – fentanyl citrate, lidocaine hydrochloride, and epinephrine bitartrate – are all priced below $3 per unit, which reflects a broader pattern that we identified in USP’s Annual Drug Shortages Report published earlier this year. Generic injectables in shortage have significantly lower average prices than those not in shortage, which has been a trend we have observed for years. When prices are low, manufacturers have less economic incentive to enter or remain in a market or invest in additional manufacturing capacity.

Addressing vulnerabilities driven by low price margins and limited manufacturers in the market will require procurement and policy approaches that reward reliability and quality, rather than the lowest unit price. For patients, a more resilient supply chain ultimately means reliable access to the medicines they need.

Pharmacy Times: What impact can a shortage lasting 10 years or more have on medication use practices across hospitals and health systems?

Reigelman: When a shortage lasts for a decade, what begins as a temporary workaround can become part of routine clinical practice. Hospitals and health systems may need to ration available supply, identify alternative therapies, alter dosing protocols, or reserve medicine for patients with the greatest need, impacting treatment plans and potentially patient health outcomes.

Increased reliance on alternatives can also shift demand and potentially contribute to shortages of those medicines. These changes can require updates to electronic health records, treatment guidelines, and staff training, adding new layers of administrative burden, complexity, and responsibilities for pharmacists and care teams.

Pharmacy Times: What should pharmaceutical manufacturers and health care providers take away from these findings?

Reigelman: Pharmaceutical manufacturers and providers should look at shortages as more than isolated, 1-time disruptions. The 5 medicines that have been in shortage for a decade show how vulnerabilities that exist throughout different parts of the supply chain can lead to serious disruptions that persist for years.

USP’s Medicine Supply Map provides visibility across the supply chain, while the USP Vulnerable Medicines List (VML) identifies medicines that may be structurally at risk even when supply has not yet been disrupted. The most recent iteration of the VML incorporates key starting material data, revealing upstream dependencies that may not be visible when looking at API or finished-dose manufacturing alone.

These insights can help manufacturers identify high-risk drug products and prioritize contingency planning. Providers can use the same information to anticipate which medicines may face persistent supply challenges, maintain appropriate inventory, and prepare alternatives in advance. By acting earlier, manufacturers, providers, and other industry members can help reduce treatment disruptions and limit the impact of shortages on patients.

Pharmacy Times: How does the industry need to think differently about supply chain diversification, particularly beyond API and finished-dose manufacturing?

Reigelman: A diversified supply chain requires looking beyond where an API or finished-dose product is manufactured and pursuing solutions that address dependencies across the product lifecycle. Strategies may include identifying additional suppliers for KSMs, developing alternative synthesis pathways, and investing in advanced manufacturing technologies, such as continuous manufacturing, that could improve production flexibility, efficiency, and resilience.

Advancing these solutions will require sustained investment and targeted policy support. USP has recommended establishing a federal drug supply chain resilience program that directs resources toward vulnerable medicines, incentivizes advanced manufacturing and alternative production methods, and encourages purchasing practices that recognize quality and supply reliability. Together, these efforts can help build a more resilient pharmaceutical supply chain that is better equipped to withstand disruptions and ensure patients have reliable access to the medicines they depend on.