US Pharm. 2014;39(4):44-46.
ABSTRACT: Anaphylaxis is a serious, potentially
fatal medical emergency that requires prompt treatment with epinephrine.
Patients at risk for anaphylaxis are commonly prescribed an epinephrine
auto-injector (EAI). The FDA has assigned BX ratings to EAIs,
indicating that sufficient data are not available to determine
therapeutic equivalence. It is important that pharmacists understand
that patients will have received training from their physician on the
proper use of the EAI they have been prescribed. As each of the marketed
EAIs differ in appearance, design, and administration, dispensing a
different EAI than prescribed could possibly lead to confusion by users
during an anaphylactic event.
Anaphylaxis is a severe, potentially fatal allergic reaction that can occur rapidly after exposure to a specific allergen.1
Typically affecting two or more organ systems (e.g., skin, respiratory,
gastro-intestinal), anaphylaxis is characterized clinically by symptoms
that may include flushing, itching, swelling, tightness of the throat
and chest, and abdominal pain.2
Triggers for anaphylaxis include exposure to specific
foods (e.g., peanuts, milk, shellfish), drugs (e.g., beta-lactam
antibiotics), biologicals (e.g., monoclonal antibodies), insect stings
(e.g., bees, wasps, ants), and latex.2 Exercise and other physical factors (e.g., cold air) have also been associated with anaphylaxis.2
The lifetime prevalence of anaphylaxis is estimated to be
between 0.05% and 2%, but it is thought to be greater because of the
level of underreporting that occurs.3 In the United States,
between 1.2% and 16.8% of the population may experience anaphylaxis
during their lifetime, resulting in death in 0.002% of patients.4
In children and adolescents, estimates for the incidence of anaphylaxis
range from 0.2 to 10.5 episodes per 100,000 person-years.5,6
However, these numbers may not reflect the current burden of
anaphylaxis, as rates of food allergy in children tripled between 1997
and 2007.7 Furthermore, prevalence of severe food allergy in children has been estimated at 3.1%.8
Guidelines recommend that patients experiencing anaphylaxis receive
prompt treatment with intramuscular (IM) epinephrine as the preferred
route of administration.1,9 Fatalities have occurred in
patients who either never received treatment with epinephrine or were
not treated in a timely fashion.10,11
Patients at risk for an acute episode of anaphylaxis are
commonly prescribed epinephrine auto-injectors (EAIs), which are used to
administer epinephrine by IM injection into the anterolateral thigh.2 There are currently four EAIs marketed in the U.S. (see TABLE 1):
EpiPen/EpiPen Jr (Mylan Specialty LP, Basking Ridge, NJ); Auvi-Q
(sanofi-aventis US LLC, Bridgewater, NJ); Adrenaclick (Amedra
Pharmaceuticals LLC, Horsham, PA); and Epinephrine injection, USP
auto-injector (Lineage Therapeutics, Horsham, PA), the authorized
generic to Adrenaclick.12-15 Each of the EAIs administers a
single dose of either 0.3 or 0.15 mg of epinephrine. The 0.3-mg dose is
intended for patients who weigh 30 kg or more, and the 0.15-mg dose is
intended for patients who weigh 15 to 30 kg.12-15
Some of the EAIs currently marketed in the U.S. are dispensed as a two-pack rather than as a single EAI.12,13
This is an important distinguishing feature, as 16% to 36% of patients
are estimated to require more than 1 dose of epinephrine during an
anaphylactic episode.16,17 The need for more than 1 dose of
epinephrine has been shown to be directly associated with the severity
of the anaphylactic reaction.17
Epinephrine does not have any absolute contraindications when used in a life-threatening situation.12-15
However, administration of a therapeutic dose of epinephrine may cause
transient, systemic adverse reactions in some patients. These include
moderate anxiety, apprehensiveness, difficulty breathing, restlessness,
dizziness, headache, nausea and vomiting, palpitations, pallor,
sweating, tremor, and weakness. Also, potentially fatal arrhythmias have
been reported in patients with underlying cardiac disorders. Finally,
rapid increases in blood pressure have produced cerebral hemorrhage, and
angina may occur in patients with coronary artery disease.12-15
BX Ratings as They Apply to EAIs
The FDA has assigned EAIs a BX rating, the Orange Book code
given to drug products for which data reviewed are insufficient to make
a determination of therapeutic equivalence to other pharmaceutically
equivalent products.18 Drug products are considered to be
therapeutically equivalent when there are no known or suspected problems
with bioequivalence or when potential problems have been resolved by in
vivo and/or in vitro evidence supporting bioequivalence.18
Only products that have been assigned an “A” code are considered
therapeutically equivalent and, therefore, are the only products
expected to produce the same clinical effect and safety profile as the
Under specific conditions, pharmacists in 21 states can substitute a drug product despite a BX rating.19
These conditions include meeting the state’s definition of an
equivalent drug product; substituting a therapeutically equivalent drug
product in the economic interest of the patient; deeming a product to be
therapeutically equivalent on the basis of the pharmacist’s
professional judgment; having a drug listed in the state’s or community
pharmacy’s formulary of generic and brand name products; substituting a
drug product when requested by a prescriber or purchaser; and
substituting a drug product that does not meet adequate standards on the
basis of the pharmacist’s professional judgment.19
Epinephrine auto-injectors differ not only in appearance but also in design and method of administration (TABLE 1).
In addition, each EAI has different design features that are
continually examined (e.g., change in color of safety cap, addition of
yellow arrow pointing to black injection tip) in order to evaluate which
minor alterations may enhance correct usage during an emergency.20 Patients experiencing anaphylaxis require immediate administration of epinephrine,1,9
so proper training and education on the use of the specific EAI
prescribed to a patient by his or her physician is critical to enable
immediate use during an anaphylactic episode.
Patients and caregivers who are familiar with a given EAI
are at increased risk for confusion during an anaphylactic episode if
they are switched to another EAI without receiving appropriate training
on how to administer the product.21 For example, some EAIs
require the patient or caregiver to remove two caps before use, while
other EAIs require the removal of only one cap. These differences may
lead patients who are familiar with a one-cap EAI and are then switched
to a two-cap EAI to potentially be confused regarding proper injection
during an anaphylactic episode.21 Additionally, patients and caregivers may be exposed to accidental needle sticks if the caps are removed out of order.21
Similarly, patients and caregivers familiar with EAIs that provide
needle protection after use may be exposed to accidental needle sticks
when switched to an EAI that requires recapping.
Different EAIs have specific techniques for
administration; for example, some EAIs use a “swing and firmly push”
method, while others employ a “press and hold” method.22,23
Considering emergency use, BX ratings, differences between EAIs, and the
potential for confusion between marketed products, it is important that
pharmacists not exchange a prescribed EAI for another marketed EAI
without discussing this with the patient’s physician first. Patients
would also require training on the new device.
EAIs are the current recommended first-line treatment for
patients at risk for anaphylaxis, and it is critical that patients be
properly trained and familiar with the device on which they may need to
rely during an emergency. Pharmacists should have an understanding of BX
ratings in the context of the products they may dispense to patients
and be aware of the potential consequences of sending patients or
caregivers home with an EAI for which they have not received adequate
1. Sampson HA, Muñoz-Furlong A, Campbell RL, et al. Second
symposium on the definition and management of anaphylaxis: summary
report—second National Institute of Allergy and Infectious Disease/Food
Allergy and Anaphylaxis Network symposium. Ann Emerg Med. 2006;47:373-380.
2. Simons FE, Sheikh A. Anaphylaxis: the acute episode and beyond. BMJ. 2013;346:f602.
3. Lieberman P, Camargo CA Jr, Bohlke K, et al.
Epidemiology of anaphylaxis: findings of the American College of
Allergy, Asthma and Immunology Epidemiology of Anaphylaxis Working
Group. Ann Allergy Asthma Immunol. 2006;97:596-602.
4. Neugut AI, Ghatak AT, Miller RL. Anaphylaxis in the United States: an investigation into its epidemiology. Arch Intern Med. 2001;161:15-21.
5. Bohlke K, Davis RL, DeStefano F, et al. Epidemiology of
anaphylaxis among children and adolescents enrolled in a health
maintenance organization. J Allergy Clin Immunol. 2004;113:536-542.
6. Macdougall CF, Cant AJ, Colver AF. How dangerous is
food allergy in childhood? The incidence of severe and fatal allergic
reactions across the UK and Ireland. Arch Dis Child. 2002;86:236-239.
7. Branum AM, Lukacs SL. Food allergy among children in the United States. Pediatrics. 2009;124:1549-1555.
8. Gupta RS, Springston EE, Warrier MR, et al. The
prevalence, severity, and distribution of childhood food allergy in the
United States. Pediatrics. 2011;128:e9-e17.
9. Simons FE, Ardusso LR, Bilò MB, et al. 2012 update:
World Allergy Organization guidelines for the assessment and management
of anaphylaxis. Curr Opin Allergy Clin Immunol. 2012;12:389-399.
10. Bock SA, Muñoz-Furlong A, Sampson HA. Fatalities due to anaphylactic reactions to foods. J Allergy Clin Immunol. 2001;107:191-193.
11. Bock SA, Muñoz-Furlong A, Sampson HA. Further fatalities caused by anaphylactic reactions to food, 2001-2006. J Allergy Clin Immunol. 2007;119:1016-1018.
12. EpiPen/EpiPen Jr (epinephrine auto-injectors 0.3/0.15 mg) package insert. Basking Ridge, NJ: Mylan Specialty LP; 2012.
13. Auvi-Q (epinephrine injection, USP) package insert. Bridgewater, NJ: sanofi-aventis US LLC; 2012.
14. Adrenaclick (epinephrine injection, USP auto-injector) package insert. Horsham, PA: Amedra Pharmaceuticals LLC; 2013.
15. Epinephrine injection, USP auto-injector package insert. Horsham, PA: Lineage Therapeutics Inc; 2013.
16. Kelso JM. A second dose of epinephrine for anaphylaxis: how often needed and how to carry. J Allergy Clin Immunol. 2006;117:464-465.
17. Korenblat P, Lundie MJ, Dankner RE, Day JH. A
retrospective study of epinephrine administration for anaphylaxis: how
many doses are needed? Allergy Asthma Proc. 1999;20:383-386.
18. FDA Center for Drug Evaluation and Research. Approved Drug Products With Therapeutic Equivalence Evaluations. 33rd ed. Silver Spring, MD: US Department of Health and Human Services; 2013.
19. State regulations on generic substitution. Pharm/Prescrib Lett. 2006;22:220901.
20. Bakirtas A, Arga M, Catal F, et al. Make-up of the epinephrine autoinjector: the effect on its use by untrained users. Pediatr Allergy Immunol. 2011;22:729-733.
21. Ram FSF, Hoare K, Arroll B, Hoare S. Epinephrine
self-administration in anaphylactic emergencies: comparison of commonly
available autoinjectors. J Asthma Allergy Educators. 2012;3:178-181
22. EpiPen/EpiPen Jr (epinephrine auto-injectors 0.3/0.15 mg) patient information. Basking Ridge, NJ: Mylan Specialty LP; 2012.
23. Auvi-Q (epinephrine injection, USP) trainer instructions. Bridgewater, NJ: sanofi-aventis US LLC; 2012.
24. Adrenaclick (epinephrine injection, USP auto-injector) patient information. Horsham, PA: Amedra Pharmaceuticals LLC; 2013.
25. Epinephrine injection, USP auto-injector patient information. Horsham, PA: Lineage Therapeutics Inc; 2013.
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