1. Drug Shortages in anesthesia
Bernadette Henrichs, PhD, CRNA, CCRN

2. Disclosure
Attended an Advisory Committee 6/2018 for Frezenius Kabi, a manufacturing company that makes neostigmine

3. Objectives Understand the causes of drug shortages in the U.S.
Explain and describe the impact on anesthesia providers.
Describe what anesthesia providers can do to manage care of the patient.
Describe actions taken to prevent drug shortages from affecting the clinical management of patients.
Describe a variety of roles that clinicians of all specialties may be asked to take in drug shortage management.
Explain what can be done at a national perspective as well as at a local level.

4. National Drug Shortages
Defined as periods when demand for a drug in the US exceeds its supply.
The number of drug shortages in the U.S. has increased by greater than 7- fold since 2007, increasing the risk of patient harm and cost of healthcare.
In a survey done in April 2018, 98% of hospitals reported moderate to severe shortages of key opioids: morphine, fentanyl, hydromorphone
Shortage of anti-cancer drugs for pediatrics has been reported which can lead to potential morbidity and mortality
: Ave 4633 drugs short in Belgium
: Ave 8020
Chen, SI, Fox, ER, Hall, MF, Ross, JS, Bucholz, EM et al: Despite federal legislation, shortages of drugs used in acute care settings remain persistent and prolonged. ProQuest 2016; 35(5): F; Reed, BN, Fox, ER, Konig, M, Jackevicius, CA, Masoudi JF, et al: The impact of drug shortages on patients with CVD. Am Heart J 2016; 175:

5. National Drug Shortages: Active Shortages by Quarter since 2013
This number is higher as it includes all drugs that are on the short, not just those that were added to the list. For example, a drug may be on the list for 6 months or more.

6. Most Common Drug shortages
Common classes of drugs affected by shortages:
Anesthesia medications (85%)
Antibiotics
Pain medications (81%)
Nutrition and electrolyte products
Chemotherapy agents
ER and anesthetic drugs are the most common drugs on the list
Fox, ER, Sweet, BV & Jensen, V: Drug shortages: A complex HC crisis. Mayo Clinic Proceedings; Mar 2014; 89(3):

7. The drug shortages -Examples
Examples of drug shortages affecting anesthesia providers (< 3 month period)
Benzocaine
Hydralazine IV-alternative medications suggested
Ipratropium/Atrovent oral inhaler
Magnesium IV
Ciprofloxacin
Diltiazem/Cardizem IV
Morphine IV
Hydromorphone IV
Potassium Chloride IV-Critical worsening shortage
Calcium IV
Ondansetron/Zofran IV – Critical shortage – alternate suggestions given
Ketamine IV – Critical shortage
IV opioids Critical shortage of fentanyl, hydromorphone, morphine
Propofol prior to this time
Lidocaine, bupivacaine
Lorazepam
Time period from 3/23 – 6/14/208`
Propofol shortage in 2010

8. Opioid shortages
Shortage of injected opioids occurred in summer 2017 after FDA uncovered serious problems at a Pfizer factory in Kansas that made 60% of the country’s opioids; may last until 2019.
Hospitals had to ration supplies or reserve them for patients with the most pain.
Survey of 2500 anesthesia providers conducted by ASA found that 98% of respondents “regularly experience drug shortages at their institutions”.
More than 95% noted the shortages affect the way they treat patients
Forces us to ask “What do we “have” and what do we “not have” each day?”
Goodwyn, W: Doctors raise alarm about shortages of pain medications. NPR Online (7/20/18)

9. Opioid shortages Reason: Pharmaceutical industry consolidation
FK Matt Kuhn: “The manufacturing process is complicated, and while they have increased production and added workers, “one company is not going to be able to completely fulfill all the needs for clinicians and their patients”.
The federal government, meanwhile, is trying to control supply due to the opioid addiction and overdose crisis.
Although the FDA is under pressure to address the injectable opioid shortage, the agency cannot order a manufacturer to make a specific drug.
For now, FDA is focusing on expanding the number of suppliers and searching for and expediting approval of additional sources.
Goodwyn, W: Doctors raise alarm about shortages of pain medications. NPR Online (7/20/18)

10. Drug Shortages: Scope of the Problem
Considerable attention in lay media
Big enough problem to draw action from the President, Congress and FDA
Appears to be a growing issue
Are shortages the “new norm”?

11. Reasons for Shortages
Often, it is a quality concern issue at the factory.
From a study done in Utah in 2017Normally, the main reason for drug shortages is a quality concern at the factory.

12. Quality and Manufacturing Issues
Manufacturing equipment breakdown
Natural disasters causing loss of manufacturing time or loss of inventory
Fire at raw material/finished product manufacturing site
Japan earthquake led to several shortages
Icelandic volcano caused transportation delays
Hurricane Maria
Strategic Plan for Preventing and Mitigating Drug Shortages, FDA, October 2103; odcock J, Wosinska J. Clin Pharm Ther. Feb (2)

13. Recent Quality and Manufacturing Issues
Sterility problems—including bacterial and mold contamination
Particles of foreign matter (glass, metal and fibers) in vials
Crystallization of the active ingredient
Precipitate formation (due to reaction with raw materials or container or stopper with the drug)
Newly identified impurities or degradants

15. Other causes of drug shortages
Lack of competition
Pfizer produces almost ALL of the world’s sterile injectable drugs, including 60% of injectable opioids
Pfizer bought Hospira in February 2015 which had aging facilities (received 8 FDA letters and multiple recalls for poor testing and training; 239 recalls from )
Rocky Mountain and McPherson facilities manufactured the bulk of injectable drugs
June 2016: FDA issued 483 post-inspection citations against Rocky Mountain
Pfizer closed McPherson Jan-Mar 2017 for upgrades
Decreasing prices; driving generics out of the market; Collapse of competition

16. Natural disasters 90 products related to the hurricane affected
Hurricane Maria hit Puerto Rico, September 2017
80 manufacturing facilities, including 7 of the top 10 drugs globally manufactured were affected
Employees could not get to work
Fuel to run the plants became short
Plants were operating without power or phones
Plants still trying to return to a normal schedule
90 products related to the hurricane affected
IV normal saline affected
More than 40 drugs affected

17. Drug shortages are a cause of significant patient concerns.

18. impact on patient care

19. impact on patient care
Study looking at propofol shortage demonstrated abrupt change in clinical practice
Before propofol shortage: 80% of surgical patients received propofol (n = 2830)
During propofol shortage: 81% received etomidate (n = 3066)
Etomidate use increased by 600%
Methohexital use increased (rarely used prior to shortage)
Study did not detect increased mortality.
However, unsure if it led to adrenal insufficiency or death due to suppression of adrenal steroidogenesis
Romito, B, Stone, J, Ning, N, Yin, C, Liano, EM, et al: How drug shortages affect clinical care: The case of the surgical anesthetic propofol. Hosp Pharm 2015; 50(9):

20. impact on patient care
Another study examined using inhaled agents instead of propofol during propofol shortage
Found higher incidence of PONV by 2-fold, greater need for rescue antiemetics, and longer duration of stay.
More patients reported PONV at home (14% vs 7%)
2 required unplanned admission or return to hospital.
Findings suggest that despite mitigation efforts, inability to use propofol was associated with worse PONV outcomes.
Neff MP et al: Propofol drug shortage associated with worse PONV despite mitigation strategy. AANAJ 2018; 86(2): 1-8.

21. Impact on patient care
Shortage of norepinephrine led to increased in-hospital mortality by 3.7%.
Phenylephrine was most commonly used as a replacement vasopressor.
Shortages and increases in the Epi-Pen by Mylan led to patients using expired drug.
Increases in anaphylaxis-related diagnoses & hospitalizations
“Increased demand” and lack of competition with other companies led Mylan to raise the price, ”gouging” customers, the government and insurers
2011 shortage of norepi: study showed a 3.7% absolute increase leads to thousands more deaths per year from sepsis
Vail, E, Gershengorn, HB, Hua, M, Walkey, AJ, Rubenfeld, G & Wunsch, H: Association between US norepinephrine shortage and mortality among patients with septic shock. JAMA 2017; 317(14): ; Gabrielli, A, Layon, NT, Bones, HL & Layon, AJ: The tragedy of the commons-drug shortages and our patients’ health. AJM 2016; 129(2):

22. Impact on patient care
Shortages in anesthetic medications have led us to practice in a non-usual manner.
Different drugs have different potencies, increasing the chance of a medication error.
Ex: Sufentanil:1,000 times more potent than morphine; patient went apneic after receiving sufentanil
Two patient deaths were reported from accidental overdoses.
Shortages in opioids have led to cancer patients receiving less potent drugs.
2011 shortage of norepi: study showed a 3.7% absolute increase leads to thousands more deaths per year from sepsis
Vail, E, Gershengorn, HB, Hua, M, Walkey, AJ, Rubenfeld, G & Wunsch, H: Association between US norepinephrine shortage and mortality among patients with septic shock. JAMA 2017; 317(14): ; Gabrielli, A, Layon, NT, Bones, HL & Layon, AJ: The tragedy of the commons-drug shortages and our patients’ health. AJM 2016; 129(2):

23. impact on patient care Medication errors
More likely to occur when a pharmacy alters how a product is ordered, prepared or dispensed
More likely to occur when prescribing practices change to less- familiar alternative agents
Substitutions may lead to a drug that is less efficacious or requires an unusual or difficulty dosing regimen
Substitution drugs may have ↑ side effects, worsening complications
Ex: Substituting hydromorphone with morphine
Hydromorphone commonly used due to fast onset and less side effects
Morphine: Increased histamine release, N & V, etc
Morphine now short, so we are going to even older drugs (meperidine)
Types of medication errors: Omission, Wrong dose dispensed/administered, Wrong frequency, Wrong route, Wrong indication
Romito, B, Stone, J, Ning, N, Yin, C, Liano, EM, et al: How drug shortages affect clinical care: The case of the surgical anesthetic propofol. Hosp Pharm 2015; 50(9): ; Reed, BN, Fox, ER, Konig, M, Jackevicius, CA, Masoudi JF, et al: The impact of drug shortages on patients with CVD. Am Heart J 2016; 175:

24. impact on patient care
Acute and critical care areas (Ex: OR) have had the most impact; described as a “crisis”
May lead to:
Increased morbidity and mortality
Delays or cancellations in care
Ex: CVD patient - NTG critically short due to shortages of raw material
Rationing a specific medication, preventing a patient who needs it to have it available.
Reserving IV opioids for patients suffering most; giving slower-acting or less effective PO pills
Romito, B, Stone, J, Ning, N, Yin, C, Liano, EM, et al: How drug shortages affect clinical care: The case of the surgical anesthetic propofol. Hosp Pharm 2015; 50(9): ; Reed, BN, Fox, ER, Konig, M, Jackevicius, CA, Masoudi JF, et al: The impact of drug shortages on patients with CVD. Am Heart J 2016; 175:

25. Effects on patient outcomes
Alternative medication may not be as effective; suboptimal
Delay of treatment/therapy
Treatment failure; readmission due to treatment failure
Increased monitoring needed due to alternative drug given
Need for transfer of patient to institution that has drug available
Increased length of hospitalization

26. What can anesthesia providers do?
Work with pharmacy; substitute other medications, hoping they won’t become short.
Ex: Sufentanil and remifentanil are less commonly used opioids, but they are also falling into shortage as hospitals rely on them more.
Do not hoard medications if a shortage is predicted.
Stockpiling can cause artificial shortages, is costly and may not be absorbed by normal usage if shortages do not occur as anticipated.
Plan ahead to use alternative therapies with information on how to appropriately use and dose the medication.
Use the stocked medication for those most in need
Ex: Prioritize who will receive limited ondansetron; save for those with severe PONV or those with highest risk
Fox, ER, Sweet, BV & Jensen, V: Drug shortages: A complex HC crisis. Mayo Clinic Proceedings; Mar 2014; 89(3): ; ASHP Guidelines on Managing Drug Product Shortages 2018

27. What can anesthesia providers do?
Use a multimodal approach to combat the shortage of IV fentanyl, hydromorphone and morphine, including regional anesthesia.
Considered “best practice”.
Utilize regional blocks when possible
Local anesthetics, such as bupivacaine, lidocaine and ropivacaine, are also in short supply.
Use other agents such as NSAIDS, acetaminophen, gabapentin, antidepressants to avoid using opioids that are in short supply
Consider meditation, physical therapy, occupational therapy
Fox, ER, Sweet, BV & Jensen, V: Drug shortages: A complex HC crisis. Mayo Clinic Proceedings; Mar 2014; 89(3): ; ASHP Guidelines on Managing Drug Product Shortages 2018

28. What are manufacturers doing?
Compounding companies like Pharmedium do not have to follow the rules like manufacturers do. They can decide to stop a drug for no reason at all (low profit). All they have to do is inform the government. Manufacturers do follow the rules and meet Joint Commission requirements such as expiration date on the vial. Their drugs are good for 24 months.

29. What is the government doing?
FDA Safety and Innovation Act (FDASIA) was enacted in 2012, giving the FDA new and expanded regulatory powers to respond to national shortages.
Requires pharmaceutical manufacturers to report shortages early so production issues can be resolved.
Will expedite inspections and reviews of alternative products or manufacturing facilities
Will enable discretion in allowing distribution of products that may have quality issues but that do not confer undue risk to patients
The FDA cannot require a company to make more of a drug or tell them to whom they can sell or distribute, but can ask them to be more transparent.
What we can require: Notification by manufacturers (new FDASIA requirement) of supply disruptions, delays, discontinuations; no penalty for not reporting the notification of manufacturing changes; compounding facilities should be monitored more closely for quality
What we can’t require: A company to make a drug or make more; how much and to whom drug is sold or distributed
Chen, SI, Fox, ER, Hall, MF, Ross, JS, Bucholz, EM et al: Despite federal legislation, shortages of drugs used in acute care settings remain persistent and prolonged. ProQuest 2016; 35(5): F.

30. What Else is being done?
FDA allowed a shift in allocation of opioid products to other manufacturers in Feb/March 2018.
Cleveland Clinic is building a 503B-compliant facility.
Intermountain Health Care, Ascension, SSM and Trinity Health are working with the Veterans Association to form their own generic pharmaceutical company.
Pharmaceutical Companies are ramping up production
Frensenius Kabi
Westward
Akorn

31. What is being done locally?
SSM Health in St. Louis announced a mission-driven, nonprofit generic drug company, Civica Rx, to tackle chronic drug shortages and high prices.
Backed by seven large health systems and three philanthropic groups, the new venture will be based in Salt Lake City area.
It will initially focus on stable supplies for 14 generic drugs used in hospitals.
Mission: To make sure essential generic medicines are affordable and available to everyone.

32. What is being done at the aana level?
Society for Obstetric Anesthesia
and Perinatology, 2018
AANA Journal. August 2018;
online content
AANA Anesthesia E-ssential, May 3, 2018

33. ASHP Guidelines on Managing Drug Product Shortages 2018.
Summary
Drug shortages are a frequent problem impacting the anesthesia provider, pharmacy, and patients. Proper planning can reduce adverse effects on patient care and HC organization costs and can prevent problems from escalating into crises. AANA, ASA, ASHP, FDA, the pharmaceutical industry, and other organizations need to work together to prevent drug shortages in the future. The key to success, according to ASHP, is to gather information, assess options, use teamwork, make changes rapidly in information systems, and communicate with providers, patients and administrators.
Drug shortages are here to stay and resolution is will take years.
ASHP Guidelines on Managing Drug Product Shortages 2018.

34. Thank you!

35. References-Henrichs
ASHP Guidelines on Managing Drug Product Shortages 2018.
s from Barnes-Jewish Hospital OR Pharmacist, 2018.
Chen, SI, Fox, ER, Hall, MF, Ross, JS, Bucholz, EM et al: Despite federal legislation, shortages of drugs used in acute care settings remain persistent and prolonged. ProQuest 2016; 35(5): F
Claus, B, Bauters, T & Laureys G: Drug shortages in a pediatric stem cell transplantation ward. J of Oncol Pharm Practice 2018; 0(0): 1-6. DOI: /
Fox, ER, Sweet, BV & Jensen, V: Drug shortages: A complex HC crisis. Mayo Clinic Proceedings; Mar 2014; 89(3):
Gabrielli, A, Layon, NT, Bones, HL & Layon, AJ: The tragedy of the commons-drug shortages and our patients’ health. AJM 2016; 129(2):
Reed, BN, Fox, ER, Konig, M, Jackevicius, CA, Masoudi JF, et al: The impact of drug shortages on patients with CVD. Am Heart J 2016; 175:
Romito, B, Stone, J, Ning, N, Yin, C, Liano, EM, et al: How drug shortages affect clinical care: The case of the surgical anesthetic propofol. Hosp Pharm 2015; 50(9):
Vail, E, Gershengorn, HB, Hua, M, Walkey, AJ, Rubenfeld, G & Wunsch, H: Association between US norepinephrine shortage and mortality among patients with septic shock. JAMA 2017; 317(14):
Vlessides M: Opioid shortages force improvisation-and cancellations. Anesthesiology News May 7,