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LETTERS

Annals of Internal Medicine
OBSERVATION

Table. Total Amount of Epinephrine Remaining in
Expired EpiPens
Identification

Epinephrine Concentrations in EpiPens After the
Expiration Date

T

Background: Interest and outrage have been mounting
over dramatic price increases for the emergency-use epinephrine autoinjection device EpiPen (Mylan). Since 2007,
the price of this potentially lifesaving medication has risen
more than 400%. This sharp increase has caused patients
to ask health care practitioners whether they can use expired
EpiPens because they cannot afford to replace them.
Objective: To determine whether EpiPens expired up to
50 months retain their stated potency.
Methods: Over 2 weeks, patients and practitioners at a
community clinic were asked to provide unused, expired
EpiPens. All pens were examined for color changes and expiration date. Two separate aliquots of each EpiPen's content
were quantitatively analyzed for epinephrine concentrations
by liquid chromatography (Agilent 1260 Infinity II LC, Agilent
Technologies)–tandem mass spectrometry (Triple Quad 5500,
AB SCIEX). Epinephrine was monitored using 2 transitions
(mass– charge ratio, 184.1 to 107.0 and 184.1 to 166.0) and
quantified by isotope dilution using epinephrine-d6 as an internal standard.
Results: We collected and analyzed 31 expired EpiPens
(epinephrine, 1 mg/mL) and 9 EpiPen Jrs (epinephrine, 0.5
mg/mL) (Table). None was discolored. All were 1 to 50
months past their expiration dates. Nineteen of the EpiPens
(65%) and 5 of the EpiPen Jrs (56%) contained at least 90% of
their stated amount of epinephrine.
Discussion: Studies have shown that many medications
retain full potency up to 40 years beyond their expiration
dates (1). However, these studies rarely involve biological
agents like epinephrine, which may not maintain their activity as long as other medications. Although medications in
the United States are typically assigned expiration dates up
to 3 years after manufacture, EpiPens are typically labeled
with an expiration date of 18 months or less. One study
found that expired EpiPens retained at least 50% of their
stated amount of epinephrine up to 90 months past
expiration (2), and another found that those less than 25
months past expiration contained at least 90% of the labeled amount (3).
The U.S. Food and Drug Administration permits most
medications marketed in the United States to contain 90%
to 110% of the labeled concentration of the active ingredients (4). In this study, approximately two thirds of the expired EpiPens and more than half of the expired EpiPen Jrs
met this standard and all contained at least of 80% of their
labeled concentrations. These findings are important because dosing recommendations for out-of-hospital treatment of anaphylaxis, which are based on anecdotal experience, specify a maximum initial dose of 0.2 to 0.5 mg in
adults and 0.01 mg/kg of body weight (with a maximum

Dose,
mg/mL

Time Beyond
Expiration, mo

Epinephrine
Remaining, %

EpiPens
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31

1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1

50
50
49
49
49
49
44
44
36
36
35
35
29
25
25
25
25
23
23
23
23
20
20
13
13
13
13
5
5
5
5

84
88
84
86
87
87
88
90
88
87
86
88
90
91
94
90
90
92
90
92
93
91
92
94
90
95
90
94
89
92
100

EpiPen Jrs
1
2
3
4
5
6
7
8
9

0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5

30
30
30
7
7
2
2
1
1

82
81
86
91
88
97
98
92
99

total dose of 0.3 mg/kg) in children (5). Given that each
EpiPen and EpiPen Jr delivers a dose of 3 mL, all of the products tested should deliver a dose within the recommended
initial range.
In summary, our data show that EpiPen products can retain substantial amounts of epinephrine well beyond their expiration dates. Although we observed declining concentrations of epinephrine over time, we expect that the dose
available 50 months after expiration would still provide a beneficial pharmacologic response. Thus, we conclude that the
process for establishing expiration dates for EpiPens should
be revised and that, in the setting of outpatient anaphylaxis
without other therapeutic alternatives, patients and caregivers
should consider the potential benefits of using an expired
EpiPen.

This article was published at Annals.org on 9 May 2017.
© 2017 American College of Physicians 1

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LETTERS
F. Lee Cantrell, PharmD
California Poison Control System
San Diego, California

References
1. Cantrell L, Suchard JR, Wu A, Gerona RR. Stability of active ingredients in
long-expired prescription medications [Letter]. Arch Intern Med. 2012;172:
1685-7. [PMID: 23045150]
2. Simons FE, Gu X, Simons KJ. Outdated EpiPen and EpiPen Jr autoinjectors:

Patricia Cantrell, MD
Kaiser Permanente
San Diego, California

past their prime? J Allergy Clin Immunol. 2000;105:1025-30. [PMID:
10808186]
3. Rachid O, Simons FE, Wein MB, Rawas-Qalaji M, Simons KJ. Epinephrine

Anita Wen, BS
Roy Gerona, PhD
University of California, San Francisco
San Francisco, California
Disclosures: Authors have disclosed no conflicts of interest. Forms
can be viewed at www.acponline.org/authors/icmje/ConflictOfInterest
Forms.do?msNum=L16-0612.

doses contained in outdated epinephrine auto-injectors collected in a Florida
allergy practice [Letter]. Ann Allergy Asthma Immunol. 2015;114:354-6. [PMID:
25707326] doi:10.1016/j.anai.2015.01.015
4. U.S. Food and Drug Administration. Questions and answers on levothyroxine sodium products. 3 October 2007. Accessed at www.fda.gov/Drugs
/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders
/ucm161266.htm?utm_source=fdaSearch&utm_medium=website&utm
_term= on 21 October 2016.
5. Simons FE. First-aid treatment of anaphylaxis to food: focus on epinephrine.
J Allergy Clin Immunol. 2004;113:837-44. [PMID: 15131564]

doi:10.7326/L16-0612

2 Annals of Internal Medicine • Vol. 166 No. 12 • 20 June 2017

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