Should You Really Have Epinephrine Autoinjectors in Your Emergency Kit?

Home , Dosage form

Published with permission of the Academy of General Dentistry. © Copyright 2016 by the Academy of General Dentistry. All rights reserved. For printed and electronic reprints of this article for distribution, please contact [email protected].

PHARMACOLOGY Challenging historical dogma: should you really have epinephrine autoinjectors in your emergency kit?

Jason H. Goodchild, DMD ¢ Mark Donaldson, BSP, RPH, ACPR, PHARMD, FASHP, FACHE

hat should the price for What should really be in A good example of an emergency medi- convenience be? Back your medical emergency kit? cation that some oral healthcare practi- Win 2010, most of us were There is general agreement among oral tioners currently may be required to have comfortable paying just over $100 for healthcare practitioners as to the essential available is smelling salts (ammonia inhal- the EpiPen 2-Pak (Mylan Specialty, LP) medications in emergency medical kits: ants). Despite their clear lack of safety to stock our emergency kit. This was the epinephrine, diphenhydramine, nitro- and efficacy in addressing the underlying most expensive drug and dosage form glycerin, albuterol, glucose, aspirin, and pathophysiology of syncope, ammonia 4,5 in our kit, but it gave us peace of mind oxygen. Furthermore, it is incumbent on inhalants remain part of medical emer- 6 that in an emergency situation we had all oral healthcare providers to keep up to gency kits for some dental offices. This access to the right lifesaving medication date with the regulations of their licensing is just one example of historical dogma in an easy-to-administer formulation, board regarding the specific emergency that is slowly changing in clinical and even if the typical shelf life required us medications needed to remain compliant regulatory practice; indeed, there is a to purchase a replacement every 12-18 with the rules of the state or province in strong safety argument to be made for months. In 2015, when the price tripled which they are licensed to practice. If the not exposing patients to this nonspecific to $300 for the EpiPen 2-Pak—partly board states that practitioners must have respiratory irritant, because it can worsen due to the American Heart Association’s a particular medicine available, then that the condition of a patient with airway “endorsement” of autoinjectors in their medication must be available—and in edema or infection, can trigger acute updated cardiopulmonary resuscitation date—if a medical emergency in which asthma, and will increase intracranial 7 guidelines, the first time the guidelines that medication may be appropriate arises. pressure. According to the material safety referenced a particular dosage form (autoinjector) and not just an active drug (epinephrine)—many practitioners began to question the value of these single-use applicators, as did social media, journals, 1,2 and other publications. When the price for the EpiPen 2-Pak doubled to $600 in 2016, and parents with at-risk children now had to decide between this dosage formulation and food on their tables, 3 enough was enough. Hospitals, clinics, emergency respond- ers, and even dental offices are beginning to question the historical dogma: Are epinephrine autoinjectors truly essential in emergency kits? Is the price for convenience really worth the value? Should it all be about price? Fig 1. Typical epinephrine autoinjector after removal from its plastic carrying case (training unit).

10 GENERAL DENTISTRY November/December 2016 Fig 2. Safety cap removal from a typical epinephrine autoinjector (training unit).

A B C

Fig 3. Counterintuitive delivery design (training unit). A. User’s thumb incorrectly positioned Fig 4. Deceptive “button” end, where the over the “button” at the end opposite to the end where the safety cap was removed. needle actually comes out (training unit). B. Incorrect positioning of the autoinjector. C. Correct positioning of the autoinjector. data sheet, inhaled ammonia can cause a validate whether autoinjectors are really in the literature, enough to enable “[b]urning pain in the mouth and throat, the safest dosage form to administer life- a meta-analysis (the highest level of constriction of the throat and coughing saving epinephrine. medical evidence) on this topic, rais- followed by nausea, vomiting or diarrhea While autoinjector formulations have ing questions about the safety of this 8 15-17 when ingested or inhaled.” been designed for both the public and dosage formulation. the trained healthcare worker to inject, Another significant concern about the The argument for putting this delivery mechanism is not entirely safety of autoinjectors is that they are patient safety first intuitive and has led to inadvertent lac- all equipped with a 28-gauge, 0.5-inch 10-14 Epinephrine is the most important medi- erations and self-injections. Once the needle. Several studies have shown that cation in the minimal dental emergency device is removed from the plastic case, this needle length may be inadequate kit. It is a true, lifesaving, α1-adrenergic the instructions are to first remove the to deposit epinephrine into the rich vasoconstrictor that reverses an immedi- cap (Fig 1). Removal of the cap exposes capillary bed beneath the vastus late- ate type 1, immunoglobulin E–mediated a hole that the cap had covered; one’s ralis (thigh) muscle so that systemic anaphylactic reaction by relieving upper instinct might suggest that this hole epinephrine levels rise fast enough and 18-20 airway obstruction, increasing blood should be where the needle comes out high enough to save the patient’s life. pressure, and decreasing mucosal edema, (Fig 2). The opposite end of the auto- It would appear that some manufactur- thereby relieving and preventing shock. injector is a distinctly different color ers of epinephrine autoinjectors are There are no absolute contraindications and has the appearance of a button over aware of this design flaw, since, rather to epinephrine use in patients experienc- which the user would naturally place than change their production to include ing anaphylaxis, and most dental offices the thumb to administer the injection a needle of appropriate length, they ask have 1:1000 epinephrine available in a (Fig 3). Unfortunately, because of this patients to continue to press and hold very convenient autoinjector formulation poor design, and especially during a the autoinjector in place for an additional that facilitates fast and easy adminis- stressful event such as a life-threatening 3-10 seconds, depending on the prod- 9 21-25 tration. Since patient safety is always medical emergency, autoinjector self- uct. This is something that is difficult the primary concern, and the oaths of injections occur because the “button” to do for anyone suffering an immediate beneficence and non-maleficence that all end is actually where the needle comes and accelerated anaphylactic reaction dentists took upon graduation included out (Fig 4). Every year there are multiple and certainly not an appropriate response “First, do no harm,” it is necessary to reports of inadvertent self-injections to overcome a potential design flaw.

www.agd.org/generaldentistry 11 Challenging historical dogma: should you really have epinephrine autoinjectors in your emergency kit?

The argument for efficacy price of $730.33 for the 2-pack at the time Irving, Texas; a clinical professor, Skaggs Given the design challenges of all cur- of writing. Recently, the manufacturer School of Pharmacy, University of rently available epinephrine autoinjectors, has decided to introduce an “autho- Montana, Missoula; and a clinical assistant the efficacy of these products is also rized generic” version of EpiPen for professor, School of Dentistry, Oregon 29 being called into question. Needle length approximately $300. Meanwhile, the Health & Science University, Portland. inadequacy was the primary reasons for Adrenaclick epinephrine autoinjector the recent removal of one epinephrine (Amedra Pharmaceuticals, LLC) is sold in Disclaimer 30 autoinjector (Auvi-Q, Sanofi US) from a 2-pack for approximately $500. The authors have no financial, economic, the market, as the company had received Perhaps a better alternative from a commercial, or professional interests 26 reports of device malfunctions from safety, efficacy, and cost perspective related to topics presented in this article. patients in the United States and Canada would be for dental practitioners to make as of October 26, 2015. No one died as a their own anaphylaxis kits: a 1-mL vial References 1. Neumar RW, Shuster M, Callaway CW, et al. Part 1: Execu- result, but patients continued to experience or ampule of 1:1000 epinephrine; a 1-mL 26 tive Summary: 2015 American Heart Association Guide- symptoms of hypersensitivity reaction. syringe; a 25-gauge, 1.0- to 1.5-inch needle; lines Update for Cardiopulmonary Resuscitation and Another challenge related to efficacy any other needed supplies (eg, alcohol Emergency Cardiovascular Care. Circulation. 2015;132(18 has to do with the shelf life of all autoin- wipe, labels); and step-by-step instructions Suppl 2):S315-S367. 2. Miller M. There’s absolutely no reason why an EpiPen jectors, which is consistently between 12 with pictures. This would certainly offer should cost $300. Slate. July 8, 2016. Available at: http:// and 18 months. This contrasts with the a better alternative than the historical www.slate.com/articles/health_and_science/moneybox/ more than 2 years of best-use dating for dogma and at a price point that allows for 2016/07/epipen_costs_have_soared_450_percent_in_ the_past_12_years_for_no_good_reason.html. Accessed most ampules and vials of 1:1000 epineph- frequent practice to demonstrate compe- September 1, 2016. rine. This shorter shelf life can sometimes tency. While oral healthcare providers may 3. Elsevier. The rising cost of epinephrine autoinjectors. Clini- mean that expired medication, which may be reluctant to access medication in vials cal Solutions. Gold Standard Drug Database. 2016. https:// not be as potent or efficacious and could or ampules, given the increased complex- www.elsevier.com/solutions/drug-database. Accessed Au- gust 31, 2016. lead to poor patient outcomes, is being ity inherent to these dosage forms com- 4. Rosenberg M. Preparing for medical emergencies: the es- administered in an emergency situation. pared to the more convenient autoinjector sential drugs and equipment for the dental office. J Am In addition, because epinephrine has formulations, this lack of understanding Dent Assoc. 2010;141(Suppl 1):14S-19S. a half-life of around 2 minutes, many or training can be overcome with regular 5. Malamed SF. Medical emergencies in the dental surgery, 1: preparation of the office and basic management. J Ir Dent patients may require a second dose of this practice to ensure competency. Assoc. 2015;61(6):302-308. lifesaving medication if emergency medi- Alternatively, clinicians could consider 6. Bledsoe BE. This procedure stinks: the hazards of ammonia cal personnel cannot reach the patient a similar, commercially available kit that inhalant use. JEMS. 2003;28(3):52-53. 31 7. McCrory P. Smelling salts. Br J Sports Med. 2006;40(8): within 10 to 15 minutes of the initial dose. retails for just over $100. 659-660. To be best prepared, most dental offices 8. X-Gen Pharmaceuticals, Inc. Ammonia Inhalant Solution should carry at least 2 adult and 2 pedi- Conclusion (Non-Rx) [safety data sheet]. Last updated March 27, 2015. atric epinephrine autoinjectors, in date, There are many longstanding dogmas http://www.safety.vanderbilt.edu/msds/products/ammonia-inhalant-solution.pdf. Accessed August 29, 2016. at all times. This is the reason that most in medicine that deserve review as new 9. Simons FER. Anaphylaxis. J Allergy Clin Immunol. 2010; autoinjectors are available for purchase data, techniques, devices, and evidence 125(2 Suppl 2):S161–S181 [erratum: 2010;126(4):885]. 27 in a twin pack. Since up to 16% of the come to light. Epinephrine autoinjectors 10. Brown JC, Tuuri RE, Akhter S, et al. Lacerations and em- bedded needles caused by epinephrine autoinjector use in general population are considered to be have undergone such significant price children. Ann Emerg Med. 2016;67(3):307-315. hyporesponders, it may even be prudent increases over the last few years that an 11. Umasunthar T, Procktor A, Hodes M, et al. Patients’ ability for more remote locales to have 3 adult investigation into their relative value com- to treat anaphylaxis using adrenaline autoinjectors: a ran- and 3 pediatric autoinjectors at all times, pared to the convenience they provide is domized controlled trial. Allergy. 2015;70(7):855-863. 28 12. Dennerlein JT. Anaphylaxis treatment: ergonomics of epi- should the patient require a third dose. warranted. Based on current evidence, nephrine autoinjector design. Am J Med. 2014;127(1 Suppl): additional safety and efficacy concerns S12-S16. What about the price? with this dosage form indicate that pre- 13. Peyko V, Cohen V, Jellinek-Cohen SP, Pearl-Davis M. Evalu- Since safety and efficacy concerns do not paring your own anaphylaxis kit may be a ation and treatment of accidental autoinjection of epinephrine. Am J Health Syst Pharm. 2013;70(9):778-781. always make as eye-catching headlines better approach to keeping patients safe. 14. Arga M, Bakirtas A, Topal E, et al. Effect of epinephrine au- as monumental price hikes, publicity has toinjector design on unintentional injection injury. Allergy focused more on the geometric increase Author information Asthma Proc. 2012;33(6):488-492. 15. Bakirtas A, Arga M, Catal F, Derinoz O, Demirsoy MS, Turk- in price of these autoinjectors. The price Dr Goodchild is an associate professor and tas I. Make-up of the epinephrine autoinjector: the effect of a 1-mL ampule of 1:1000 epinephrine chair, Department of Diagnostic Sciences, on its use by untrained users. Pediatr Allergy Immunol. has remained stable at around $1, and a Creighton University School of Dentistry, 2011;22(7):729-733. 1-mL vial of the same drug costs about Omaha, Nebraska; a clinical associate 16. Guerlain S, Hugine A, Wang L. A comparison of 4 epinephrine autoinjector delivery systems: usability and patient twice as much. Each of these dosage professor, Department of Oral Medicine, preference. Ann Allergy Asthma Immunol. 2010;104(2): forms contains enough medicine for 3 University of Pennsylvania, School of 172-177. adult doses, whereas the adult single-dose Dental Medicine, Philadelphia; and in pri- 17. Simons FE, Lieberman PL, Read EJ Jr, Edwards ES. Hazards of unintentional injection of epinephrine from autoinjec- EpiPen autoinjector—with its shorter vate practice in Havertown, Pennsylvania. tors: a systematic review. Ann Allergy Asthma Immunol. shelf life, poor design, and inadequate Dr Donaldson is a senior executive direc- 2009;102(4):282-287. needle length—has an average wholesale tor, Vizient Pharmacy Advisory Solutions,

12 GENERAL DENTISTRY November/December 2016 18. Bhalla MC, Gable BD, Frey JA, Reichenbach MR, Wilber ST. 25. Pfizer Canada, Inc. Prescribing Information: EpiPen and Predictors of epinephrine autoinjector needle length inad- EpiPen Jr. Revised March 12, 2012. http://www.pfizer.ca/ equacy. Am J Emerg Med. 2013;31(12):1671-1676. sites/g/files/g10017036/f/201410/EpiPen_PM_E_153460_ 19. Song TT, Nelson MR, Chang JH, Engler RJ, Chowdhury BA. 13Mar2012.pdf. Accessed September 26, 2016. Adequacy of the epinephrine autoinjector needle length in 26. Lowes R. Sanofi US recalls all Auvi-Q epinephrine injection. delivering epinephrine to the intramuscular tissues. Ann Medscape. October 29, 2015. http://www.medscape.com/ Allergy Asthma Immunol. 2005;94(5):539-542. viewarticle/853445. Accessed August 30, 2016. 20. Stecher D, Bulloch B, Sales J, Schaefer C, Keahey L. Epi- 27. Mylan Specialty, LP. EpiPen and EpiPen Jr [instructions for nephrine auto-injectors: is needle length adequate for use]. Revised May 2016. http://www.accessdata.fda.gov/ delivery of epinephrine intramuscularly? Pediatrics. 2009; drugsatfda_docs/label/2016/019430s061lbl.pdf. Accessed 124(1);65-70. August 31, 2016. 21. Mylan Specialty, LP. How to Use Your EpiPen (Epinephrine 28. Ramsey L. Mylan’s decision to make a cheaper, generic Injection, USP) Auto-Injector. 2016. https://www.epipen. EpiPen “baffles” experts. Business Insider. August 31, com/en/about-epipen/how-to-use-epipen. Accessed Au- 2016. http://www.businessinsider.com/mylans-decision- gust 30, 2016. to-make-an-authorized-generic-epipen-is-confusing- 22. Amedra Pharmaceuticals, LLC. How to Use Adrenaclick people-2016-8. Accessed September 1, 2016. (Epinephrine Injection, USP Auto-injector). May 2013. 29. Ingle JI, Bakland LK. Endodontics. 5th ed. Hamilton, Cana- http://adrenaclick.com/how_to_use_adrenaclick_ da: BC Decker; 2002:383. epinephrine_injection_USP_auto_injector.php. Accessed 30. Amedra Pharmaceuticals, LLC. Adrenaclick. Convenient September 26, 2016. Packaging Options. May 2013. http://adrenaclick.com/ 23. Pfizer Canada, Inc. How to Use EpiPen [videos]. 2015. convenient_packaging_options.php. Accessed Septem- http://www.epipen.ca/en/epipen-resources/epipen- ber 1, 2016. videos. Accessed September 26, 2016. 31. Snap Medical Industries, LLC. Epinephrinesnap Epineph- 24. How to Use Your EpiPen [video]. Uploaded August 27, rine Convenience Kit. 2016. http://epinephrinesnap.com/. 2008. https://youtu.be/pgvnt8YA7r8. Accessed Septem- Accessed August 31, 2016. ber 26, 2016.