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From: Paul Lee10/22/2015 11:09:06 AM
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The Neostigmine Shortage: A Clinical Conundrum with Few Drug Alternatives

by Steven Greenberg, MD, FCCP; Sorin J. Brull, MD, FCARCSI (Hon); Pavan Rao, MD, MBA; Robert L. Barkin, MBA, PharmD, FCP, DAAPM, DACFM; Jeff Thiel, MS, PharmD; Joseph Szokol, MD, MBA, JD; and Richard C. Prielipp, MD, MBA, FCCM



Nationwide drug shortages affect anesthesia professionals every day.1 In 2012, a survey generated by the American Society of Anesthesiologists (ASA), and accessible on the ASA website, suggested that 97.6% of anesthesiologists experienced a drug shortage in their practices. There have been several documented reasons for drug shortages, which include raw material shortages, manufacturing quality control issues, industry consolidation, and manufacturer discontinuation. Despite governmental and provider organization support to reduce drug shortages, they appear to be on the rise.1 At the present time, no governmental agency or other entity has the accountability, authority, or responsibility to mandate a corporation or manufacturer to continue production, maintain levels of inventory and/or set prices of any drug. Drug manufacturing is a market-driven process, and pharmaceutical companies­—like all corporations­­­—must balance the needs of customers (physicians and patients), the marketplace, and shareholders. When drugs are in short supply, suspended, prohibitively expensive, or eliminated, anesthesia providers respond by searching for alternative options. However, when a drug with few alternatives becomes the focus of a drug shortage, it may significantly alter practice patterns and ultimately, patient safety.

In the previously cited ASA survey, as well as in a 2013 Survey conducted by the AANA, and accessible on the AANA website, neostigmine was one of the drugs most commonly associated with drug shortages. This shortage was in part, and interestingly, due to new U.S. Food and Drug Administration (FDA) rules. In 2011, the FDA issued revised guidance on marketed, unapproved drugs: “Compliance Policy Guide Sec 440.100, Marketed New Drugs Without Approved NDAs or ANDAs (CPG440.100).”a The FDA guidance established “an orderly approach for removing unapproved drugs from the market.” In 2013, Eclat Pharmaceuticals, the only makers of “FDA-approved” neostigmine (Bloxiverz)b sent a letter calling on the FDA to stop all 5 of its competitors (Cardinal Health, West-Ward Pharmaceuticals, Fresenius Kabi USA, American Regent and General Injectables & Vaccines) from selling the “FDA-unapproved” generic neostigmine.c In this letter to the FDA, Eclat Pharmaceuticals also claimed that the manufacturers of unapproved neostigmine “lack complete labeling and pose a potential safety hazard.” Flamel Technologies, which acquired Eclat Pharmaceuticals in 2012, significantly raised the price of Bloxiverz, the only available neostigmine preparation.d In the current marketplace in 2015, neostigmine is only manufactured by 2 companies (Fresenius Kabi and Eclat Pharmaceuticals),e which significantly increased the cost of the drug. More importantly, the shortage created a clinical conundrum for anesthesia providers because alternatives to neostigmine are quite limited. Institutions and providers across the United States may need to decide between the following choices to provide effective perioperative clinical care:

  1. Continue using neostigmine at a much higher cost
  2. Minimize "waste" of neostigmine by using prefilled syringes with fixed volumes/doses
  3. Consider an alternative like edrophonium (with premixed atropine), called “Enlon Plus”.
  4. Minimize or eliminate use of NMB drugs, and thus nullify the need for reversal agents altogether.
These choices, however, may be associated with substantial unintended consequences. The unexpected increase in neostigmine pricing may create considerable financial pressure on the OR pharmacy and anesthesiology budgets. Perhaps a better alternative is to minimize the waste of neostigmine by placing it in prefilled syringes, which facilitates a more cost conscious utilization of the drug. The high cost of the reversal agent may also promote more conservative use of neuromuscular blocking agents (NMBAs) in the perioperative period. However, it may also raise the danger of an increase in residual neuromuscular blockade in the PACU because providers might inadvertently under-dose patients during the reversal process in an attempt to save on the cost of neostigmine.

Changing to the only available alternative product, edrophonium plus atropine (“Enlon Plus” in its premixed fashion) also may have unintended consequences. Many anesthesia providers may be unfamiliar with the dosing, pharmacokinetics ,and side effects of this combination reversal alternative. For instance, there may be an increase in the incidence of central anticholinergic syndrome with the addition of atropine to edrophonium. Moreover, patients with comorbidities (specifically cardiac) may be more susceptible to the drug-induced effects of secondary tachycardia or bradycardia sometimes observed with this pre-mixed product. Additional education is certainly required to avoid drug errors and enhance clinician awareness of the potential adverse effects of this combination drug.

The difference in onset and offset of edrophonium (peak effect of 2–4 minutes) vs. neostigmine (peak effect of 6–10 minutes) must also be reviewed by anesthesia providers, and the administration should be timed appropriately. The recommended dose of Enlon Plus is 0.5–1 mg/kg edrophonium and 0.007–0.014 mg/kg atropine given intravenously over a minimum of 45–60 seconds.2 The anticholinesterase effect of edrophonium lasts approximately 70 minutes (assuming normal renal function), and therefore, it is unlikely to result in reappearance of neuromuscular block (“re-curarization”) with the intermediate acting modern muscle relaxants.2 To make it easier for clinicians, the solution is 10 mg/mL of edrophonium, and the dose range is from 0.05–0.1 mL/kg. Therefore, a 70-kg patient would typically receive 3.5–7 mL of the Enlon-Plus mixture. Lastly, the long-term availability of edrophonium is not entirely clear, particularly if the prices of “FDA-approved” neostigmine preparations start decreasing.

Edrophonium is not as effective as a reversal agent as neostigmine, because the bonds it forms to acetylcholinesterases are mostly ionic, rather than the more resistant covalent bonding of neostigmine. Thus, if edrophonium is used for reversal of neuromuscular block, the clinician should wait for sufficient spontaneous recovery (Train-Of-Four (TOF) count of 2–3) prior to reversal. Once this level of recovery is attained, the full dose of 1 mg/kg edrophonium should be administered over at least 3–5 minutes. It should be recognized that the faster the administration, the greater the peak plasma concentration of edrophonium/atropine, so the greater the potential for side effects. In patients at risk of bradycardia (elderly, pediatrics, patients on beta-blockers, etc.), the clinician should consider giving some additional atropine upfront. If TOF count is 4, and there appears to be no fade to TOF stimulation assessed subjectively, only 25%–50% of the full dose should be administered again, over at least 3–5 min.3

A final strategy to avoid the high cost of neostigmine is to refrain from using reversal agents altogether—the obvious concern with this choice is the high likelihood of residual neuromuscular blockade and its associated negative effects.4 A preferred alternative would be to monitor neuromuscular function objectively (by using an accelerograph or the integrated kinetomyograph) or at least with the use of a nerve stimulator in the TOF mode. Then, choose an appropriate reversal dose based on the degree of neuromuscular recovery.

While the dilemma of neostigmine shortage and high pricing highlights the impact of drug shortages on practice patterns, it will not be the last one. In the 2015 February issue of the APSF Newsletter, Orlovich and Kelly wrote a concise review on the drug shortage issue as it relates to anesthesia providers. They offered several factors and potential solutions to proactively prevent the ever-increasing anesthesia drug shortage epidemic.5 It is up to anesthesia organizations, business leaders, hospital administrators, and government officials to rethink viable solutions to this ever growing problem, so that our patients do not assume unnecessary perioperative risk. Lastly, but perhaps most importantly, Hsia et al. recently suggested that a clear majority of patients (60.9%) want to be informed of a drug shortage even if it made little difference to patient outcomes.6 On the other hand, informing patients of the shortages may increase their fear and anxiety unnecessarily, just prior to surgery, and therefore this disclosure needs to be reviewed carefully and critically. However, it may allow us, as providers, to stop and appreciate that our patients are becoming more concerned and knowledgeable about their care and the ever-escalating problem of drug shortages. This may be the right time to enhance our alliance with our patients and help lobby for effective changes to curb this recurring problem. Meanwhile, we must continue to prioritize patient safety and value-based care.

_______

a. http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/EnforcementActivitiesbyFDA/SelectedEnforcementActionsonUnapprovedDrugs/ucm270834.htm. Accessed Aug 7, 2015.
b. http://bloxiverz.com. Accessed August 8, 2015.
c. http://www.fdanews.com/ext/resources/newsletters/Sample-PDFs/WDL091613web.pdf
d. http://www.bloomberg.com/article/2015-01-15/aRDS4F8u8pEs.html
e. http://www.ashp.org/menu/DrugShortages/CurrentShortages/Bulletin.aspx?id=1150



Dr. Greenberg is Assistant Editor of the APSF Newsletter, Clinical Associate Professor in the Department of Anesthesiology/Critical Care at the University of Chicago Pritzker School of Medicine, and Director of Critical Care Services at Evanston Hospital, NorthShore University HealthSystems

Dr. Brull is the Patient Safety Section Editor, Anesthesia & Analgesia, Executive Committee Member of the APSF, and Professor of Anesthesiology at the Mayo Clinic, Jacksonville, FL.
Dr. Rao is an Anesthesiology Resident at the University of Chicago, Pritzker School of Medicine


Dr. Barkin is Professor of Anesthesiology, Pharmacology and Family Medicine at Rush Medical College in Chicago, IL. He is also a Clinical Pharmacologist at North Shore University Health System at Skokie and Evanston Pain Centers.

Dr. Thiel is Assistant Vice President, Pharmacy Services at NorthShore University HealthSystem.

Dr. Szokol is Vice Chairperson, Department of Anesthesiology, NorthShore University HealthSystem and Clinical Professor in the Department of Anesthesiology/Critical Care at the University of Chicago Pritzker School of Medicine

Dr. Prielipp is Chairperson of the APSF Committee on Education and Training, Executive Committee Member of the APSF, and Professor of Anesthesiology at the University of Minnesota.

Editorial Note: In a 2013 survey conducted by the AANA, 48.6% of respondents reported a neostigmine shortage as well.



References

  1. De Oliveira GS, Jr, Theilken LS, McCarthy RJ. Shortage of perioperative drugs: implications for anesthesia practice and patient safety. Anesth Analg 2011;113: 1429-35.
  2. Cronnelly R, Morris RB, Miller RD: Edrophonium: Duration of action and atropine requirement in humans during halothane anesthesia. Anesthesiology 1982; 57: 261-6.
  3. Thilen SR, Hansen BE, Ramaiah R, Kent CD, Treggiari MM, Bhanaker SM. Intraoperative neuromuscular monitoring site and residual paralysis. Anesthesiology 2012;117: 964-72.
  4. Murphy GS, Brull S. Residual neuromuscular block: Lessons unlearned. Part I: definitions, incidence, and adverse physiologic effects of residual neuromuscular block. Anesth Analg 2011;111: 120-8.
  5. Orlovich DS, Kelly RJ. Drug shortages in the US - A balanced perspective. APSF Newsletter 2015;29: 49-50.
  6. Hsia IKH, Dexter F, Logvinov I, et al. Survey of national drug shortage effect on anesthesia and patient safety: A patient perspective. Anesth Analg 2015;121: 502-6.









©Copyright 2015 Anesthesia Patient Safety Foundation


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