Karolina Cieslak And Varanya Chaiyaperm MEDICATION ...

Authors: Karolina Cieslak And Varanya Chaiyaperm Published on IVT Network (www.ivtnetwork.com) GXP Volume 24, Issue 2 – March 2020

MEDICATION SAFETY: EPINEPHRINE/ADRENALINE PROBLEMS,

CORRECTIONS, AND APPLICATIONS

ABSTRACT

Medication errors associated with the use of epinephrine products and medical devices are a significant healthcare problem.

Epinephrine is a high-alert medication; erroneous use of epinephrine bears a high risk of causing significant patient harm.

Medication safety problems associated with the design and use of epinephrine products are described. Problems addressed

include drug content ratio-strength expressions such as 1:1,000 and 1:10,000; leading and trailing zeros when writing decimal

dosage expressions; look-alike and sound-alike (LASA) drug errors with ephedrine; route of administration errors such as

administering IM dosage via an IV route; and auto-injector use problems. Errors involving dosage calculations and incorrect

routes of administration to patients are the most significant epinephrine errors. Corrective and preventive actions addressing

problems are discussed; activities for drug industry and for healthcare practitioners are proposed. Awareness of epinephrine

problems provides information useful for epinephrine. Concepts described can also be applied to design and use of other

pharmaceutical products.

INTRODUCTION

Medication errors associated with pharmaceutical drug products are a significant problem in healthcare practice (1). Design

aspects of marketed pharmaceutical products may contribute to these errors through confusion with drug names, dosage

strengths, labeling, packaging, device use, and other factors. Practitioner use of products may also contribute to medication

errors; human factors coupled with communication problems (written, verbal, electronic), emergency use situations, and other

concerns may contribute to drug errors. These general considerations – product design and practitioner use – must be examined

when evaluating the potential for medication safety problems with any pharmaceutical product or medical device.

This discussion addresses medication safety problems associated with the design and use of epinephrine products. Epinephrine

is also known as adrenaline around the world. Problems discussed are the most frequently reported problems associated with

epinephrine products and routes of administration. Epinephrine is a critical drug that has been used in life-saving situations for

many years. Numerous medication safety problems including drug concentration calculations, drug name confusion,

administration route errors, device operation, and other problems have been reported with epinephrine. Awareness of these

problems and approaches for error correction and prevention are useful for epinephrine as well as for application to other

products.

Topics discussed supplement and expand content presented in “Medication Safety: Industry Considerations - Part 1, Problem

Overview (1), and Medication Safety: Industry Considerations -- Part 2, Drug Names (2).

Epinephrine/Adrenaline Overview

Epinephrine is a hormone produced in the adrenal medulla. It is a sympathetic system neurotransmitter with a catecholamine

molecular structure (Figure 1) similar to norepinephrine and dopamine. Epinephrine activity in the body is associated with the

“fight or flight” response when the body reacts to danger, fear, stress, or other high-anxiety situations. Epinephrine is an alpha-

receptor and beta-receptor agonist. Epinephrine stimulation of alpha receptors in the arteries causes constriction and increases

the blood pressure. Epinephrine stimulation of the beta receptors in the heart and lungs causes an increase in heart rate and

dilation of lung bronchioles. These effects are most relevant to the drug use of epinephrine in treatment of patients. Other

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epinephrine effects on human physiology include contraction of some muscles to increase circulation, relaxation of other

muscles, glycogen breakdown for energy, increased gastric motility, increased mental alertness, pupil dilation, and other effects.

Figure 1. Epinephrine Molecular Structure

Therapeutic Use. Epinephrine is indicated for use in several clinical applications utilizing its sympathomimetic pharmacology.

Primary epinephrine therapeutic indications include cardiac arrest, bradyarrhythmia, hypotension, anaphylaxis, asthma, croup,

minor bleeding, and prolonging local anesthesia. Epinephrine is administered by several injection routes depending on the

indication.

Cardiac indications such as cardiac arrest, bradycardia, and hypotension use intravenous (IV) injection or other cardiac routes

(intracardiac, intraosseous) of administration to increase circulation. Serious heart conditions may require intracardiac injection

into the left ventricle. IV dosages are relatively high (1-3 mg) to provide rapid response. Cardiac indications may require

repeated injections or continuous infusion to maintain acceptable blood pressure. The rate of administration is also critical in

IV cardiac dosage.

Respiratory indications such as allergy, anaphylaxis, asthma, and croup use primarily intramuscular (IM) or subcutaneous (SC)

administration to improve breathing. Therapeutic dosages are lower and usually require a limited number of doses for

treatment.

Topical indications are used to control superficial bleeding and prolong local anesthesia to prevent pain in minor surgical and

dental procedures. Epinephrine constricts local circulation extending the effect of the anesthetic drug. Relative dosages are

lowest for topical indications.

Medication Safety Problems. Epinephrine is a potent drug with therapeutic doses in the milligram/microgram range;

exceedingly small doses result in a significant clinical effect. Epinephrine has been designated a high alert medication by the

Institute for Safe Medication Practices (ISMP). High-alert medications are drugs that bear a heightened risk of causing

significant patient harm when they are erroneously administered. Mistakes with high-alert drugs may be less common, but

when they occur, their pharmacologic consequences are devastating to patients. Mistakes with epinephrine may be fatal.

The broad pharmacologic activity of epinephrine, high potency, and multiple methods of administration create the potential for

significant medication errors. The dose and route of administration will determine which receptors are impacted and the drug

onset of action. Epinephrine has a greater affinity for beta-adrenergic receptors in small doses and greater alpha-adrenergic

activity in larger doses. For example, a patient being treated for an anaphylactic reaction who is mistakenly given IV

epinephrine instead of IM dosage will quickly exhibit significant adverse cardiac effects. Correct dosages administered via

correct routes and proper rates of administration are critical with epinephrine.



Commercial Products. Epinephrine commercial products are low-concentration solution products. Depending on the country,

products are labeled as Epinephrine USP or as adrenaline. Multiple dosage strength products are available. Products are

available in ampoules, multiple sizes of vials, syringes, proprietary syringe systems, auto-injection devices, ophthalmic drops,

and aerosols for inhalation. This discussion focuses on sterile epinephrine products for injection. Commercial names listed

below describe product names available in the USA.

Primary epinephrine solution products addressed in this discussion are the following.

• 1 mg/mL (1:1,000)

• 0.1 mg/mL (1:10,000).

Products are available as generic products from multiple suppliers. Adrenalin® is a proprietary name for

epinephrine/adrenaline products.

Auto Injector unit dose solution devices:

• 0.3 mg. (contains 0.3 mL of 1 mg/mL solution [1:1,000 solution])

• 0.15 mg. (contains 0.3 mL of 0.5 mg/mL solution [1:2,000 solution]).

Products are available as generic products from multiple suppliers. Proprietary names for device products include EpiPen®,

Adrenaclick®, Twinject®, and Auvi-Q®, and Symjepi®.

Combination products containing anesthetics and epinephrine include the following:

• Lidocaine HCl 2% and Epinephrine Injection 1:100,000


• Lidocaine HCl 1.5% and Epinephrine Injection 1:200,000


• Lidocaine HCl 0.5% and Epinephrine Injection 1:200,000.

Products are available as generic products from multiple suppliers. Proprietary names for lidocaine/epinephrine products

include Xylocaine®, Alphacaine®, Lignospan®, and Lignospan Forte®.

• Bupivicaine HCl 0.75% and Epinephrine Injection 1:200,000

• Bupivicaine HCl 0.5% and Epinephrine Injection 1:200,000

• Bupivicaine HCl 0.25% and Epinephrine Injection 1:200,000.

Products are available as generic products from multiple suppliers. Proprietary names for bupivacaine/epinephrine products

include Marcaine® and Sensorcaine®.

• Articaine HCl 4% (40 mg/mL) and Epinephrine Injection 1:200,000

• Articaine HCl 4% (40 mg/mL) and Epinephrine Injection 1:100,000.

Products are available as generic products from multiple suppliers. Proprietary names for articaine/epinephrine products

include Septocaine®, Orabloc®, Ultracaine D-S®, and Ultracaine D-S Forte®.

• Prilocaine HCl 4% and Epinephrine Injection 1:200,000.

Products are available as generic products from multiple suppliers. Citanest Forte® is a proprietary name for

prilocaine/epinephrine.



Discussion Topics

This discussion addresses specific medication safety problems associated with epinephrine products. The following are

addressed:

• Drug content ratio strength expressions

• Leading and trailing zeros

• Look-alike and sound-alike (LASA) errors

• Routes of administration. IV, IM, SC, and other routes

• Auto-injector device problems

• Additional topics – Compounding under non-ideal conditions and drug shortages

• Corrective and preventive actions (CAPA) -- drug industry and healthcare practitioners.

DRUG CONTENT RATIO-STRENGTH EXPRESSIONS

Epinephrine dosage errors involving ratio-strength expressions have been a significant medication safety problem for many

years. Drug content in epinephrine products has been labeled using a ratio-strength expression. Examples of these expressions

are 1:1,000 and 1:10,000. Problems occurred, for example, when epinephrine was prescribed in milligrams and health

professionals would calculate the volume of drug solution to provide the prescribed drug amount. The following illustrates: A

physician orders 0.5 mg epinephrine for IV administration treatment of cardiac arrest. Two solution products are available –

1:1,000 and 1:10,000. Which should be used? How many mL of the selected solution should be injected IV to provide 0.3 mg

epinephrine? This calculation would likely be needed under emergency conditions when timing is critical for patient treatment.

USP eliminated the use of ratio-strength expressions in labeling of epinephrine and other single-entity drug products in 2016.

Epinephrine drug content must now be labeled using mg/mL format. In the mg/mL format:

• Epinephrine 1:1,000 = Epinephrine 1 mg/mL

• Epinephrine 1:10,000 = Epinephrine 0.1 mg/mL.

Global Products. The ratio-strength change is specific for USA products and global countries compliant with USP standards.

Non-USP products used globally and countries not utilizing USP standards may still employ ratio-strength labeling of

epinephrine products. Some products are labeled with both ratio strength and mg/mL to be acceptable to all countries.

Ratio-Strength Solution Definition

Ratio-strength expressions for drug content for pharmaceutical products apply to dilute mixtures of drug in liquids. For

example, 1:100 is a ratio-strength concentration. Ratio-strength expressions describe “parts” of a mixture and are expressed as

A:B. The A term before the colon is usually 1; the B term after the colon is the total volume of the mixture. Grams and

milliliters are assumed units of measure in ratio strength notation. A 1:100 solution thus contains 1 gram of drug in 100 mL of

solution.

History of Ratio-Strength Expression Change

Epinephrine dosage by ratio-strength expression has been used for more than 100 years. The Institute for Safe Medication

Practice (ISMP) petitioned USP in 2004 (3) to consider the following changes to epinephrine labeling:

1) Label epinephrine and ephedrine with enhanced letter characters (tall man lettering)

2) If above not acceptable, change the name of ephedrine injection to efedrine injection

3) Label epinephrine injections in mg per ml (e.g., 1 mg/mL) and to discontinue ratio strength labeling (e.g., 1:1,000

and 1:10,00



The Pennsylvania Patient Safety Reporting System (PA-PSRS) identified ratio-strength labeling problems with epinephrine in

2006 (4). Their report included examples of numerous situations of epinephrine administration errors that resulted in harm and

even deaths to further highlight the problem of epinephrine labeling.

USP officially eliminated ratio-strength labeling for single-entity drug products in 2016 (5) . USP <7> Labeling stated that as

of May 1, 2016, USP-NF is eliminating ratios and deeming them an unacceptable method for expressing single-entity injectable

product strength. Epinephrine 1:1,000 must now be labeled epinephrine 1 mg/mL. FDA is supportive of the USP change (6).

USP has recently (2019) issued a new summary of ratio-strength changes and additional changes to USP <7> Labeling.

Comments were requested from interested parties. The comment period ended November 2019 (5).

USP <7> Labeling

Pharmaceutical product standards in the USA are specified in USP General Chapter <7> Labeling. The term “labeling” is an

inclusive term. Labeling includes all labels and other written, printed, or graphic matter on the immediate container or on any

package or wrapper in which product is enclosed. The package insert and other enclosed materials supplied with the product

are included in the “umbrella” term of labeling. Outer shipping containers are not included in labeling requirements. The term

“label” is more specific, that is, USP <7> defines the label as that part of the labeling on the immediate drug container (7).

USP <7> requires single-entity injectable drug products to be labeled in terms of quantity per milliliter (quantity/mL) and not

as a ratio expression. For epinephrine products:

● Epinephrine Injection, 1:1000 must be expressed as 1 mg/mL

● Epinephrine Injection, 1:10,000 must be expressed as 0.1 mg/mL.

Isoproterenol injection products and neostigmine injection products are also affected by USP <7> requirements. These

products must be labeled as follows:

● Isoproterenol HCl Injection, 1:5,000 must be labeled 0.2 mg/mL

● Isoproterenol HCl Injection, 1:50,000 must be labeled 0.02 mg/mL

● Neostigmine Methylsulfate Injection, 1:400 must be labeled 2.5 mg/mL

● Neostigmine Methylsulfate Injection, 1:1000 must be labeled 1 mg/mL

● Neostigmine Methylsulfate Injection, 1:2000 must be labeled 0.5 mg/mL.

Epinephrine, isoproterenol, and neostigmine have been labeled used with ratio-strength labeling for many years. Changing the

dosage strength labeling for these products is a significant change to long-established practice.

Figure 2. Epinephrine Injection, 1 mg/mL

Note absence of ratio-strength labeling.



Concentration Equivalence Calculations. The amount/volume concentrations listed above are equivalent to the original ratio-

strength concentration. See stepwise calculations below.

● 1:1,000 = 1 gram/1,000 mL = 1000 mg/1,000 mL = 1 mg/mL

● 1:10,000 = 1 gram/10,000 mL = 1000 mg/10,000 mL = 1 mg/10 mL = 0.1 mg/mL



● 1:400 = 1 gram/400 mL = 1000 mg/400 mL = 1 mg/0.4 mL = 2.5 mg/mL

● 1:2,000 = 1 gram/2,000 mL = 1000 mg/2,000 mL = 1 mg/2 mL = 0.5 mg/mL.

Products with >1 mL Volume. USP <7> Labeling directs that single-entity injectable drug products greater than 1 mL should

be formatted as quantity per total volume on the principle display panel of the label followed in close proximity by the quantity

per milliliter (quantity/mL) enclosed by parentheses.

Figure 3. Isuprel (Isoproterenol HCl) Injection, 1 mg/5 mL (0.2 mg/mL)

Note quantity per total volume and quantity/mL labeling.

Ratio Expression Exceptions. The USP elimination of ratio-strength expressions has exceptions. When combined with a local

anesthetic, the concentration of epinephrine continues to be expressed as a ratio. Examples with optional drug name formats are

described. Note ratio-strength labeling of epinephrine concentration.

Lidocaine and epinephrine products may be expressed as:

● Lidocaine Hydrochloride and Epinephrine Injection 1%/1:100,000 or

● Lidocaine Hydrochloride 1% and Epinephrine Injection 1:100,000.

Bupivicaine and epinephrine products may be expressed as:

● Bupivicaine Hydrochloride and Epinephrine Injection 0.25%/1:200,000 or

● Bupivicaine Hydrochloride 0.25% and Epinephrine Injection 1:200,000.

● Bupivicaine Hydrochloride and Epinephrine Injection 0.5%/1:200,000 or

● Bupivicaine Hydrochloride 0.5% and Epinephrine Injection 1:200,000.



Figure 4. Lidocaine HCl 1% and Epinephrine Injection 1:100,000

Note respective lidocaine percent and epinephrine ratio strength labeling.

LEADING AND TRAILING ZEROS

Leading and training zeros are problems with careless printed or written communication of dosage strengths, especially dosages

involving decimals. A leading zero is the zero placed to the left of the decimal point. A trailing zero is placed after other

numbers to the right of the decimal point. While basic mathematics rules dictate the leading or trailing zeros do not change the

value of the actual number, use of these zeros may lead to medication errors.

Epinephrine doses often involve decimal amounts of drugs. Drug amounts in auto-injector products are 0.3 mg and 0.15 mg.

The epinephrine dosage for pediatric cardiac patients is 0.01 mg/kg. Careful notation with zeros and decimal points is critical in

these calculations. Incorrect use of leading zeros and training zeros may contribute to erroneous epinephrine use as well as use

with other drugs dosed in milligram or microgram amounts.

Leading Zeros

Leading zeros should always be used when writing a number (8). For example, 0.45 contains a leading zero, while .45 does not.

The decimal point can be missed when the leading zero is omitted. In other words, if .45 is printed or written (no leading zero),

then the number may be misread as 45 -- a 100-fold dosage error.

Trailing Zeros

On the other hand, a trailing zero after the decimal point should never be used (8). For example, a dose of 1 mg should be

written as 1 mg and not be written as 1.0 mg or 1.00 mg. The use of a trailing zero in the number increases the chances that the

decimal point will be overlooked – again a potentially significant overdose (8).

LOOK-ALIKE AND SOUND-ALIKE (LASA) ERRORS

Look-alike and sound-alike (LASA) problems are exactly as may be inferred from terminology -- pairs of drug names that look

alike when reading printed or written words, or that sound alike when spoken. LASA errors may occur with epinephrine in

several ways.



Epinephrine and Ephedrine

Epinephrine and ephedrine are LASA problems. These words are similar in appearance and may be easily misread, especially

when reading written handwriting with incorrect spelling. Epinephrine and ephedrine have some of the same pharmacologic

properties. However, epinephrine is 100-1000 times more potent than ephedrine. Erroneous administration of epinephrine

instead of prescribed ephedrine may have significant adverse effects (9,10). If epinephrine is ordered and ephedrine is

administered, dosage will be subtherapeutic. Tall man lettering is recommended to help distinguish between epinephrine and

ephedrine. As mentioned above, ISMP also proposed improved labeling of epinephrine and ephedrine in their petition to USP

in 2004 (3).

Tall Man Lettering. The Institute for Safe Medication Practice (ISMP) is the leading global organization addressing the topic

of medication safety. ISMP has compiled extensive lists of LASA medication names and related information that have been

involved in medication errors to identify safeguards to reduce error and minimize harm. Most notable among these are lists

including tall man lettering (11). Tall man lettering is the practice of writing part of a drug's name in upper case letters to help

distinguish LASA drug names from one another. This technique draws the viewer’s eye to the capital letters which emphasize

dissimilarities between drug names to avoid medication errors. Capitalized letters in tall man lettering are bolded for enhanced

readability. ISMP has proposed application of tall man lettering for epinephrine and ephedrine as follows:

• Epinephrine should be written as EPINEPHrine

• Ephedrine should be written as ePHEDrine.

Several studies have been performed to test the impact of tall man lettering on medication safety (12,13,14,15). There is

sufficient evidence to conclude that tall man lettering is worth implementing. The use of tall man lettering is endorsed by

ISMP, The Joint Commission, FDA, WHO, and the International Medication Safety Network (IMSN) (16,17).

Other Look-Alike Problems

Other look-alike considerations combined with epinephrine-ephedrine LASA confusion may contribute to medication errors.

Epinephrine mg/mL and Ephedrine mg/mL. USP conversion from ratio-strength notation to mg/mL notation may actually

increase the likelihood of epinephrine-ephedrine LASA problems. Since both epinephrine and ephedrine labels use mg/mL

format, LASA errors may be more likely -- epinephrine mg/mL and ephedrine mg/mL are more similar than the former

epinephrine 1:1,000 and ephedrine 50 mg/mL. FDA has acknowledged an increased potential for LASA errors with this change

(6).

Ratio-Strength Notation Without Commas – 1:1000 and 1:10000. Countries continuing to use ratio-strength notation must

use commas when writing the solution term. Epinephrine 1:1,000 and epinephrine 1:10,000 are tenfold different in drug

potency – a significant difference with clinical effects. Epinephrine 1:1000 (no comma) and epinephrine 1:10000 (no commas)

may be easily misread if commas are not used. Some products are labeled 1:1000 (no comma) and 1:10,000 (with comma).

Pharmaceutical manufacturers and healthcare practitioners should consistently use commas on all dosage strengths with these

numbers. Anesthetic/epinephrine products use commas in their labeling (1:100,000). ISMP and FDA have both recognized the

problem of writing ratio-strength expressions without commas (3,6).



Global Products

Countries using adrenaline as the drug generic name instead of epinephrine do not have the epinephrine-ephedrine LASA

problem; adrenaline does not look similar to ephedrine. Countries continuing to use ratio-strength notation must use commas

(or periods) when writing the solution term in ratio notation.

ROUTES OF ADMINISTRATION

Epinephrine is administered by multiple routes of administration. These may include IV, intraosseous (IO), intracardiac, IM,

SC, endotracheal, intraocular routes, topical, and other routes. Routes of administration as well as dosages and rates of

administration depend on clinical indications. Epinephrine has a narrow therapeutic index, i.e., there is a small range of dosage

that provides the intended therapeutic effect without causing toxic effects. As mentioned above, epinephrine is also categorized

as a high alert drug that may cause significant patient harm when erroneously used. The following discussion addresses

epinephrine routes of administration and reported medication errors.

Cardiac Indications (IV)

Epinephrine is used for various cardiac indications including cardiac arrest. Dosage is primarily via IV routes. Serious cases

may require intracardiac administration. Reported medication errors exemplify safety problems with cardiac use of

epinephrine. For example, a typical cardiac dosage is epinephrine 0.5 mg IV; dosage of 5 mL of 0.1 mg/mL solution is

administered. Erroneous dosage using 5 mL of 1 mg/mL solution (higher strength product) would provide a tenfold epinephrine

overdose (5 mg) causing toxic cardiac and hypertensive effects. Another error report described a missing crash cart syringe that

would be compatible with a needleless administration set. Only intracardiac syringes (with needle) were available in the cart.

Commercial package appearance of the intracardiac device was the same as other epinephrine packages causing limited

awareness of differences. Ready availability of drug product is especially critical in emergency situations (18).

Respiratory Indications (IM/SC)

Epinephrine doses for respiratory indications such as allergy, anaphylaxis, asthma, and related conditions may be administered

IM, SC, or through endotracheal tubing. A typical IM or SC dosage would be 0.3 mg epinephrine. Auto-injector devices are

available that provide unit doses. When auto-injector devices are not available, drug is provided as 0.3 mL of 1 mg/mL solution

for IM administration. Reported medication safety problems for respiratory indications have involved erroneous IV

administration of epinephrine (instead of IM administration) causing cardiac effects (x). Anaphylaxis events may require

administration of steroids and antihistamines IV – epinephrine is administered IM. Another reported medication error involved

epinephrine dosage through an endotracheal tube. Endotracheal epinephrine dosage is typically two-to-three times the IV dose;

the required dose was erroneously administered IV causing significant cardiac effects (19).

Even when correct routes of administration are chosen, incorrect locations of injection have also been reported. To receive the

best absorption associated with IM dosage, drug must be administered correctly to receive the most reliable absorption. The

recommended IM injection site is the anterolateral aspect of the thigh (vastus lateralis muscle) due to its location, size, and

available blood flow. Epinephrine should not be injected into buttock, digits, hands, or feet (20).

Respiratory indications requiring epinephrine dosage should be dosed IM. IV dosage should only be used if IM is ineffective.



Topical Indications

Vasoconstrictor properties of epinephrine are utilized to minimize bleeding in minor surgical procedures and to support

anesthetic dosage in dental procedures. Two medication errors involving topical epinephrine dosages have been reported (21).

In both cases, topical epinephrine 1:100,000 was ordered for topical use, but epinephrine 1:1,000 was administered – a 100 fold

overdose. Both patients died. Drug solutions were not labeled in both events – a unlabeled solution was administered. In one

of these cases, epinephrine was used to irrigate the ear in a tynpanomastoidectomy of a 7-year old child resulting in the child’s

death.

AUTO-INJECTOR DEVICES

Significant epinephrine auto-injector device problems emerged in the early 2000’s. Users complaints focused on operational

issues including difficult activation, premature activation, leakage, and bent needles. FDA reported the most common

complications between 1993 and 2017 including accidental exposure (806 cases), device failure (645), drug ineffective (462),

and expired product administered (320). Medical device malfunctions led to hundreds of people reporting serious life-

threatening complications resulting in hospitalizations and several deaths. Manufactures recalled more than 80,000 devices in

the Unites States, Europe, Asia, and South America. Redesign of devices has resulted in several improvements helpful to

device safety. These included device mechanism improvements including an improved spring, new needle cover, different

colors for each dosage strength, “needle end” labeling, ergonomic structure, and a training device without drug for user training

(22). See Figure 5 below.

Device Problems

The following are current problems with epinephrine auto-injectors and are common challenges with all auto-injector products.

• Device Defects. Despite redesign efforts described above, problems with device defects continue. Complaints are

much reduced, but still significant (23).

• Dosage Outside of Product Content. Epinephrine auto-injector products are available in the following dosage

strengths:

o 0.3 mg. This product contains 0.3 mL of 1 mg/mL solution intended for patients weighing more than 30 kg

(66 pounds)

o 0.15 mg. This product contains 0.3 mL of 0.5 mg/mL solution intended for patient weighing 15-30 kg (33-66

pounds).

Repeat dosages. Approximately 30% of patients require repeat dosing with auto-injector devices. Health professionals

must also use judgment when determining dosages. Adults weighing 150 pounds receive dosage for a 66 lb person. A

child weighing 29 kg should receive a 0.3 mg dose rather than the 0.15 mg dose. Maximum dosages for anaphylaxis is

0.5 to 1 mg.

Patients weighing less than 15 kg require calculation to determine dosage followed by dose preparation. Dosages are

calculated based on 0.01 mg/kg. ISMP reported a 6.5 kg infant who received a dose of 0.65 mg instead of 0.065 mg, a

tenfold overdose (19,24).



• Multiple Auto-Injector Device Designs. Drug shortages have resulted in hospitals receiving devices from different

drug companies.. Drug dosage is the same in all products; however, products have different delivery designs requiring

different techniques for activation and administration. Health workers do not receive training on all available devices.

Instances of health professionals inadvertantly injecting drug into their fingers due to unfamiliarity with device

operation have been reported, some of whom required drug treatment.

• Training Devices. Some drug auto-injector devices packages contain two activie drug syringes and one device without

drug for training purposes. See second figure below. Training devices have been mixed with active drug devices in

hospital crash carts and inadvertantly used for treatment. There is no drug in the training device.

• Syringe Cost. Product cost is another consideration with epinephrine auto-injector syringes. Auto-injector products

are costly (>$100/syringe). Preparation of an equivalent dosage from solution in ampoules or vials is much less

expensive (~$20/ampoule). Preparing equivalent dosage from ampoules or vials requires calculations, dose

preparation, and associated activities, again increasing the potential for medication errors. Hospitals may prefer

preparation of injection products from ampoules or vials for cost reduction purposes (25).

Figure 5. Epinephrine Auto Injector Re-Design



Figure 6. Epinephrine Auto-Injector Products

Note training device in each package.

ADDITIONAL TOPICS

Several additional topics related to epinephrine as well as other drugs warrant mention at this time.

Drug Shortages

Shortages of drug products are significant problems for hospitals and healthcare practitioners. Epinephrine dosage forms have

been listed on the FDA drug shortage list for many years. When desired products are not available, other actions to prepare

required dosages must be performed. For example, when dosages utilizing epinephrine 0.1 mg/mL solution are ordered but

product is not available, preparation using 1 mg/mL solution is required. Calculations, aseptic dilutions, labeling, and

documentation are needed, all of which may contribute to potential medication errors. Epinephrine auto-injector products are

often not available requiring preparation from ampoules or vial solution products.

Drug Preparation Under Non-Ideal Conditions

The wide range of dosages described, and emergency circumstances involved often necessitate extemporaneous preparation of

epinephrine solutions. Drug shortages may also cause these situations. Healthcare workers who use auto-injector devices may

need to prepare equivalent dosages from ampoules when auto injectors are not available. Activities involved include drug

dosage calculations based on patient weight followed by actual preparation of the calculated dose. Commercial products are

diluted with normal saline using “clean” procedures to provide the desired drug concentration. Health professionals must know

fundamental techniques to accomplish these preparations. The following are critical:

• Cleanliness. Conditions to prepare the drug solution must be as clean as possible. Often these activities must be

conducted in the patient’s home, in an ambulance, or other non-aseptic conditions. Compounding personnel must have

clean hands, wear a face mask and sterile gloves, and a clean work area. Open exposure of sterile vials, needles, and

syringes must be minimized; surfaces must be wiped with sterile alcohol swabs. Activities must be completed as

quickly as possible not only for patient treatment, but also to minimize risk of contamination.

• Accuracy. Syringes used for dilutions must be appropriately chosen to minimize error. Ideally syringes should utilize

approximately 50% of syringe capacity. For example, to prepare a 1:10 dilution, 1 mL of drug is withdrawn using a 3

mL syringe (not a 10 mL syringe); 9 mL of saline is withdrawn using a 20 mL syringe (not a 10 mL syringe); the two

components are then mixed in the 20 mL syringe. Using appropriate syringes will minimize measurement error and

reduce risk of contamination during preparation.



• Labeling. Diluted preparations must always be completely labeled -- drug name and the prepared drug dosage

strength. Medication errors occurred when syringes containing epinephrine solution were not labeled.

• Documentation. Dilutions including starting materials, dilution solutions, and amounts of each used must also be

documented in the appropriate record system. Information provided must enable the procedure for preparation to be

completely understood and repeated if necessary.

CORRECTIVE ACTIONS AND PREVENTIVE ACTIONS (CAPA)

It is recommended that both the pharma industry (Quality, marketing, regulatory, others) and product users (hospitals,

emergency departments, fire departments, others) have ongoing programs and activities addressing medication safety issues.

The pharmaceutical industry can play a significant role in reducing the potential for medication errors by establishing

comprehensive practices in drug name design, labeling, packaging, and user-support activities related to medication safety.

Products containing epinephrine and other high-alert drugs need to be a focus of these programs. It should be a universal goal

for all pharmaceutical companies to balance marketing needs and uphold practices that improve medication safety.

Healthcare practitioners who use products for patient care must likewise be vigilant in addressing issues related to medication

safety. Product access, storage locations, storage containers, auxiliary labeling, training, and other activities to increase

awareness of potential medication problems should be implemented and maintained on an ongoing basis. Medication errors are

obvious negatives in patient care. If erroneous medications are selected by healthcare workers and administered to patients, the

benefits of intended prescribed drugs will not be realized and patients may even be seriously harmed.

Drug Industry – Product Design, Labeling, Packaging, and Supporting Activities

The following are considerations associated with epinephrine and other high alert drug safety issues applicable to

pharmaceutical industry.

1. USP <7> Labeling requirements. Pharmaceutical manufacturers must comply with comply with USP labeling

requirements for epinephrine products that became official in 2016. USP requirements are legal standards for drug

products.

• Use mg/mL format for single entity products; do not use ratio-strength format (1 mg/mL – not 1:1,000).

• Use both formats for product intended for global distribution.

• Continue to use ratio-strength format for combination products.

USP <7> deletion of ratio-strength expressions is a significant accomplishment with the potential to greatly reduce medication

errors. Labeling epinephrine products using mg/mL format will greatly simplify dosage calculations. Global countries still

using ratio-strength notation will still experience associated problems.

2. Product design. All aspects of product design – product appearance, labeling, and packaging -- must consider potential

medication errors in use. Non-sterile products may be designed to have unique distinguishing appearance. Sterile products

such as epinephrine are usually clear solutions, i.e., all products look the same. Sterile products must thus rely on unique

labeling and packaging to provide distinguishing products characteristics.



To preclude errors especially in medical emergency situations, labeling must clearly differentiates between the different

types of prefilled epinephrine syringes such as syringes for needleless IV connectors, syringes with needles, and syringes

for intracardiac use (18).

3. Commercial product names. If new products are developed containing epinephrine and requiring a commercial product

name, comply with FDA guidance for proprietary names (26). This guidance describes FDA expectations for proposed

names and supporting development work. Confusing drug names and drug names similar to other commercial products

must be avoided.

4. Bolded tall man lettering. Pharmaceutical manufacturers should use bolded tall man lettering for labeling, package

inserts, and other documents describing epinephrine, ephedrine, and other confused drug and product names.

• Epinephrine should be written as EPINEPHrine.

• Ephedrine should be written as ePHEDrine.

Countries using adrenaline as their generic name will not have the EPINEPHrine -ePHEDrine LASA name problem.

Figure 7. Tall Man Lettering

5. Leading and trailing zeros. Labeling and supporting product information must follow accepted notation rules for leading

and training zeros.

• Leading zeros should always be used when writing a number with a decimal point (0.1 – not .1).

• Trailing zeroes after the decimal point should never be used (1 mg – not 1.0 mg).

6. Ratio-strength numbers with commas. Labels and packaging using ratio-strength notation must use commas. Product

labels with 1:1000, 1:10000, and 1:100000 may look alike. Recognition of differences is critical for calculations. Labels

should be consistent in format – not 1:1000 (no comma) and 1:10,000 (with comma).

7. Medical Device Quality. Drug/device combination products must be designed, developed, manufactured, and monitored

against high quality standards. FDA has issued a draft guidance for epinephrine products proposing formulation

requirements, multiple comparative in vitro tests including delivery volume, trigger force, multiple needle tests, and other

considerations, and device requirements for human factors studies (27,28).



Human Factors Engineering/Usability Engineering considerations and approaches should be incorporated into the device

design, development, and risk management processes. Testing conducted at or near the end of the device development

processes should be conducted to assess user interactions with the device to identify errors that may result in serious harm

to the patient or user. Human factors validation testing can also be used to assess the effectiveness of risk management

measures. Human factors validation testing would represent one portion of the device design validation (29,30).

FDA recommends that a risk analysis be performed that considers the overall use of the product. More specifically, the

risk of use of the drug delivered with the injectors as related to the human factors should be assessed. The purpose is to

identify the critical tasks, if performed incorrectly or not performed at all, that may cause serious harm -- these are the

critical device operational tasks. The final list of critical tasks is used to structure the human factors validation test to

ensure it focuses on the tasks that relate to the device use safety and effectiveness. Risk analysis such as failure modes

effects analysis (FMEA) and fault tree analysis (FTA) can be helpful tools (29,30).

8. Packaging. Epinephrine and as other high-alert drugs should include supportive identification such as distinctive label

colors, printing on ferrules or overseals, neck bands, and other supportive measures for enhanced user awareness.

Corporate desire for packaging uniformity must be compromised increase user awareness of potential safety problems.

USP requirements are specified in USP General Chapter <1>. For example:

• Neuromuscular blocking and paralyzing agents are packaged with a cautionary statement printed on the ferrules and

cap overseals. Wording such as “Warning: Paralyzing Agent” or “Paralyzing Agent” may be used.

• Potassium Chloride Concentrate Injection requires a black ferrule/overseal per USP <7>.

Figure 9. High Alert Drug Neckband

Photo courtesy of Health Care Logistics® Inc. www.gohcl.com.



Figure 9. High Alert Drug Shrink Film Overseal

Photo courtesy of Medi-Dose®/EPS®. www.medidose.com

Figure 10. Ferrule Printing on Neuromuscular Blocking Agent.

Figure 11. Potassium Chloride Concentrate Injection

Note black ferrule/overseals.

● Supportive Communication. Companies marketing epinephrine and other high-alert drugs may supply supporting

materials to help alert users to potential problems with drug use. FDA has published “Important Labeling Changes to

Critical Care Medications” communicating the ratio-strength labeling change (31). This poster is recommended as a

visual aid in healthcare facilities. The poster indicates which drugs are impacted and contains the conversions of the

ratio strength to the amount per unit of volume to reduce calculation errors.



Product Users – Hospitals, Emergency Departments, and Healthcare Professionals

The following are considerations associated with epinephrine medication safety issues applicable to healthcare providers who

use epinephrine and other high alert drugs. These include hospitals, emergency departments, healthcare professionals, police

and fire emergency personnel, ambulance services, first responders, and related functions.

1. Auxiliary Identification. Epinephrine and other high alert drugs may be identified with additional labeling to increase

awareness in products. Labels using tall man lettering may be affixed to products, storage areas, and compounded

preparations to increase personnel awareness of drug content.

Labels affixed to compounded preparation

containing high-alert drugs.

Figure 12. High Alert Drug Auxiliary Identification

Photos courtesy of Medi-Dose®/EPS®. www.medidose.com


https://www.medidose.com/LineTracingLabel-EPINEPHrine-TL-HA1601000Labels.aspx


2. Access and Storage. Epinephrine and other high alert drugs should have restricted access, specialized storage, or storage

apart from non-high alert drugs. Medication errors occur because drug names have the same first letter and are stored

alphabetically next to each other. Epinephrine and other high-alert drugs should be stored apart from general drug storage

and electronic dispensing systems. Re-evaluate the need to have epinephrine and ephedrine both stored in patient care areas

(10). Storage bins for identified drugs may be appropriately labeled, i.e., red for high-alert drugs, yellow for chemotherapy

drugs, for better awareness in selection and handling.

Photo courtesy of Health Care Logistics® Inc. www.gohcl.com.

Photo courtesy of Medi-Dose®/EPS®. www.medidose.com

Figure 13. High Alert Drug Access and Storage

3. Training. Product users should provide training to healthcare professionals and related personnel addressing epinephrine

and other high alert drugs. Training should be repeated at some reasonable frequency consistent with the risk to patients.

High alert drug training must not be a once-in-a-lifetime event. Displays, posters, and other illustrations related to high

alert drug training should be displayed in relevant areas. Training to police, fire, and other associated personnel should be

made available. ISMP offers numerous medication safety tools applicable to site training programs (32).



• Epinephrine training. Specific epinephrine training should be provided for personnel in emergency situations.

Training must comprise dosages, epinephrine-ephedrine LASA errors, and routes of administration – the primary

sources of medication errors with epinephrine.

• High Alert Drug Training. High alert drug training should be customized to the healthcare practice site. ISMP has

identified high alert drugs in acute care settings, ambulatory/community settings, and long-term care settings.

• Ratio-Strength Format. Countries using ratio-strength format for drug products must train healthcare practitioners on

calculations. The importance of using commas in ratio-strength notation must be emphasized.

• Other Numeric Formatting. Proper use of leading and trailing zeros must be taught. The potential for medication

errors must be demonstrated in printed and written documents should be demonstrated.

• Unit Dose Medical Device Training. If hospitals use multiple sources for auto-injector devices, training on use of

devices must be conducted when suppliers change. Each commercial product has a different mode of operation.

• “Clean” Technique Training. Healthcare workers who prepare drug dilutions outside of a clean room (laminar flow

hood) environment must be trained on minimizing potential contamination and on preparing accurate dosages of drugs.

4. Internal Audits. Training of healthcare workers is not enough to ensure correct practice. Internal audits that test the

ongoing efficacy of training must be conducted. These audits should not be announced to the workforce. Results of

internal audits should be evaluated. Training programs should be continually improved based on the results of internal

audits. ISMP offers medication safety self-assessments applicable to internal audits.

SUMMARY

This discussion has addressed topics associated with epinephrine pharmaceutical and medical device products. Many of these

topics are applicable to other high alert drugs, LASA problem drugs, and other medication safety situations. Pharmaceutical

industry personnel involved in the design of dosage forms, labeling, and supporting materials must be cognizant of potential

product confusion and the potential for medication errors. Healthcare practitioners must design practices and procedures to

minimize risk of errors in product use. Ongoing training of workers to maintain awareness of high-risk situations and develop a

medication safety culture within the work environment – industry groups and user groups -- is key. Primary points of this

discussion include the following:

1. Epinephrine is a potent high alert drug that has been used in life-saving applications for many years. Its use has been

associated with multiple medication safety problems -- product design problems and healthcare practitioner use

problems. Awareness of epinephrine problems provides information applicable to design and use of other

pharmaceutical products.

2. USP <7> has eliminated drug ratio-concentration expressions such as epinephrine 1:1,000. USP requires mg/mL

dosage strength labeling for single-entity products. Other products affected by this requirement include isoproterenol

and neostigmine products. Multi-component drug products such as anesthetics with epinephrine still utilize ratio-

strength labeling. Non-USP products outside of USA may not follow USP label requirements and may continue to be

labeled with a ratio-strength concentration format. Many products are now labeled with both mg/mL and ratio-strength

formats to accommodate USP requirements, historic use, and global commerce.



3. Numerical problems in use. Healthcare practitioners may introduce errors into drug name communications by careless

use of zeros when writing the drug name. Incorrect use of leading zeros and training zeros may contribute to erroneous

epinephrine use as well as use with other drugs dosed in milligram or microgram amounts. Global countries using

ratio-strength expressions must require use of commas; omitting commas, i.e., 1:1000 and 1:10000, is problematic.

4. Epinephrine and ephedrine are LASA problem drug names that should be written using bolded tall man lettering, i.e.,

EPINEPHrine and ePHEDrine. Many global countries use adrenaline as the preferred generic names for epinephrine;

use of adrenaline instead of epinephrine would eliminate the epinephrine-ephedrine LASA problem. The use of

mg/mL format for epinephrine potentially increases the opportunity for LASA errors with ephedrine; epinephrine

mg/mL and ephedrine mg/mL are similar in appearance.

5. Drug route of administration errors are another epinephrine problem having serious patient consequences. Some

medical conditions require IV epinephrine administration; other conditions require SC or IM administration. Injecting

an IM epinephrine dose by an IV route may be fatal.

6. Numerous problems have been reported with auto-injector products. The major problems with these devices are

mechanical operation problems. Other problems include dosage calculations outside of commercial product content,

multiple auto-injector device desngns, training devices confused with actual product, and syringe costs encouraging

compounding of equivalent dosages.

7. Drug shortages and preparation of dosages under non-ideal conditions create conditions for potential medication errors.

Drug shortages cause extemporaneous preparation of required dosages, such as when auto-injector devices are not

available. Extemporaneous preparation of dosages requires attention to cleanliness, accuracy, labeling, and

documentation.

8. Industry and user CAPA considerations addressing medication safety problems with epinephrine products are

described. Industry considerations involve design and development of the product appearance, name, labeling,

packaging, and associated information – all of which are concerned with the final product and associated information

supplied to the marketplace. User considerations involve auxiliary labeling, drug access and storage, training, and

internal audits in the user facility and working environment – all of which are associated with product selection, use,

and administration to the patient.

REFERENCES

1. Mancini, Alan M. Medication Safety: Industry Considerations Part 1 – Problem Overview. Journal of GXP Compliance,

Volume 23, #3, May 2019.

2. Pluta, Paul L., Jenna Crosby, Michaela Murphy, Alan M. Mancini. Medication Safety: Industry Considerations Part 2 –

Drug Names. Journal of GXP Compliance, Volume 23, #6, November 2019.

3. Cohen MR. Petition for Epinephrine labeling.pdf. https://www.ismp.org/sites/default/files/attachments/2018-04/USP.

Accessed January 26, 2020.

4. Pennsylvania Patient Safety Reporting System (PA-PSRS). Patient Safety Advisory. Let’s Stop this “Epi-demic” –

Preventing Errors with Epinephrine. Vol3, #3, September 2006.

http://patientsafety.pa.gov/ADVISORIES/Documents/200609_16.pdf. Accessed 3-24-20.


https://www.ismp.org/sites/default/files/attachments/2018-04/USP

http://patientsafety.pa.gov/ADVISORIES/Documents/200609_16.pdf


5. USP <7> Labeling. https://www.usp.org/health-quality-safety/medication-safety-labeling/elimination-ratio-expression-

single-entity-drug-labels. Accessed 3-22-20.

6. FDA. Single-Entity Injectable Drug Products. https://www.fda.gov/drugs/information-drug-class/single-entity-injectable-

drug-products. Accessed 3-24-20.

7. USP <7> Labeling. https://www.uspnf.com/notices/general-chapter-labeling. Accessed 3-24-20.

8. Grissinger, Mathew. Let’s Get to the Point. U.S. Pharmacist, 1-24-2008. https://www.uspharmacist.com/article/lets-get-to-

the-point. Accessed 3-24-20.

9. ISMP. Looks Like a Problem: Ephedrine-Epinephrine. https://www.ismp.org/resources/looks-problem-ephedrine-

epinephrine. Accessed 3-24-20.

10. ISMP Canada. Risk of Mix-ups Between Ephedrine and Epinephrine. Vol 7, #2, May 18, 2007. https://www.ismp-

canada.org/download/safetyBulletins/ISMPCSB2007-02Ephedrine.pdf. Accesses 3-24-20.

11. ISMP. FDA and ISMP Lists of Look Alike Drug Names with Recommended Tall Man Lettering.

https://www.intmedsafe.net/https://www.ismp.org/sites/default/files/attachments/2017-11/tallmanletters.pdf. Accessed 3-24-

20.

12. Grasha A. Cognitive systems perspective on human performance in the pharmacy: implications for accuracy, effectiveness,

and job satisfaction (Report No. 062100). Alexandria (VA): NACDS. 2000. https://www.medscape.org/viewarticle/418538.

Accessed 3-24-20.

13. Filik R, Purdy K, Gale A, Gerrett D. Labeling of medicines and patient safety: evaluating methods of reducing drug name

confusion. Human Factors. 2006;48(1):39-47. https://www.ncbi.nlm.nih.gov/pubmed/16696255. Accessed 3-24-20.

14. Gabriele S. The role of typography in differentiating look-alike/sound-alike drug names. Healthc Q. 2006; 9(Spec No):88-95.

https://www.ncbi.nlm.nih.gov/pubmed/17087175. Accessed 3-24-20.

15. Zhong W, Feinstein JA, Patel NS, Dai D, Feudtner C. Tall man lettering and potential prescription errors: a time series

analysis of 42 children’s hospitals in the USA over 9 years. BMJ Qual Saf. Published Online First: November 3, 2015.

https://www.ncbi.nlm.nih.gov/pubmed/26534995. Accessed 3-24-20.

16. ISMP Canada. Principles for the Application of Tall Man Lettering in Canada. October 2015. https://www.ismp-

canada.org/TALLman/. Accessed 3-24-20.

17. Position statement on improving the safety of international non-proprietary names of medicines (INNs). Horsham (PA):

International Medication Safety Network; November 2011. International Medication Safety Network; November 2011.

https://intmedsafe,net. Accessed 3-24-20,

18. ISMP Canada. Prefilled syringes of epinephrine and compatibility with intravenous tubing. Safety Bulletin. Vol. 8, No. 4.

Jun 30, 2008. Available at: https://www.ismp-canada.org/download/safetyBulletins/ISMPC2008-

04EpinephrinePrefilledSyringe.pdf Accessed Mar 19 2020.

19. ISMP Canada. Epinephrine Use for Anaphylaxis – A Multi-Incident Analysis. Vol 17, #6, Ju file:///I:/ISMPCSB2017-06-

EpinephrineAnaphylaxis.pdfne 29, 2017. Accessed 3-24-20.

20. EpiPen Package Insert. Xxx https://druginserts.com/lib/rx/meds/epipen/. Accessed 3-24-20.

21. ISMP. Fatal Outcome After Topical Administration of Epinephrine. 3-26-2009. https://www.ismp.org/resources/fatal-

outcome-after-inadvertent-injection-topical-epinephrine. Accessed 3-24-20.

22. Popken, Ben. NBC News. Mylan’s Upgraded EpiPen Torn Apart by Experts. 9-30-2016.

https://www.nbcnews.com/business/consumer/mylan-says-it-upgraded-epipen-2009-so-experts-looked-inside-n652651

https://www.nbcnews.com/business/consumer/mylan-says-it-upgraded-epipen-2009-so-experts-looked-inside-n652651.

Accessed 3-24-20.

23. Mangan, Dan and Meg Tirrell. CNBC. FDA says there have been ‘hundreds of complaints’ about EpiPen misfires, some

followed by patient deaths. 9-7-17. https://www.cnbc.com/2017/09/07/fda-says-there-have-been-hundreds-of-complaints-

about-epipen-misfires.html. Accessed 3-24-20.


https://www.usp.org/health-quality-safety/medication-safety-labeling/elimination-ratio-expression-single-entity-drug-labels

https://www.usp.org/health-quality-safety/medication-safety-labeling/elimination-ratio-expression-single-entity-drug-labels

https://www.fda.gov/drugs/information-drug-class/single-entity-injectable-drug-products

https://www.fda.gov/drugs/information-drug-class/single-entity-injectable-drug-products

https://www.uspnf.com/notices/general-chapter-labeling

https://www.ismp.org/resources/looks-problem-ephedrine-epinephrine

https://www.ismp.org/resources/looks-problem-ephedrine-epinephrine

https://www.ismp-canada.org/download/safetyBulletins/ISMPCSB2007-02Ephedrine.pdf

https://www.ismp-canada.org/download/safetyBulletins/ISMPCSB2007-02Ephedrine.pdf

https://www.ismp.org/sites/default/files/attachments/2017-11/tallmanletters.pdf

https://www.medscape.org/viewarticle/418538

https://www.ncbi.nlm.nih.gov/pubmed/16696255



https://www.ismp-canada.org/TALLman/

https://www.ismp-canada.org/TALLman/

https://intmedsafe,net/

https://www.ismp-canada.org/download/safetyBulletins/ISMPC2008-04EpinephrinePrefilledSyringe.pdf

https://www.ismp-canada.org/download/safetyBulletins/ISMPC2008-04EpinephrinePrefilledSyringe.pdf

https://druginserts.com/lib/rx/meds/epipen/

https://www.ismp.org/resources/fatal-outcome-after-inadvertent-injection-topical-epinephrine

https://www.ismp.org/resources/fatal-outcome-after-inadvertent-injection-topical-epinephrine



https://www.cnbc.com/2017/09/07/fda-says-there-have-been-hundreds-of-complaints-about-epipen-misfires.html

https://www.cnbc.com/2017/09/07/fda-says-there-have-been-hundreds-of-complaints-about-epipen-misfires.html


24. Paperella, Susan F. EPINEPHrine: A Potpourri of Potential Medication Safety Risks. Journal of Emergency Nursing, Vol

39, #2, March 2013. file:///I:/Paparella%20Epi%20potpourri%20errors.pdf. Accessed 3-24-20.

25. ISMP. EPINEPHrine for Anaphylaxis: Autoinjector or 1 mL Vial or Ampule. https://www.ismp.org/resources/epinephrine-

anaphylaxis-autoinjector-or-1-mg-vial-or-ampul. Accessed 3-24-20.

26. FDA. Guidance for Industry. Best Practices in Developing Proprietary Names for Drugs.

https://www.fda.gov/media/88496/download. Accessed 3-24-20.

27. FDA. Draft Guidance on Epinephrine. October 2017.

https://www.accessdata.fda.gov/drugsatfda_docs/psg/Epinephrine_intramuscular%20and%20subcutaneous%20injectable_N

DA%20020800_RC08-17.pdf. Accessed 3-24-20.

28. FDA. Technical Considerations for Pen, Jet, and Related Injector Intended for Use with Drugs and Biological Products.

June 2013. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/technical-considerations-pen-jet-

and-related-injectors-intended-use-drugs-and-biological-products. Accessed 3-24-20.

29. FDA. Guidance for industry and food and drug administration staff. Applying human factors and usability engineering to

medical devices. Feb 3, 2016. Available at: https://www.fda.gov/media/80481/download. Accessed 3-29-20.

30. FDA. Guidance for industry and FDA staff. Technical considerations for pen, jet, and related injectors intended for use with

drugs and biological products. Jun 2013. https://www.fda.gov/media/76403/download Accessed 3-19-20.

31. FDA. Important Labeling Changes to Critical Care Medications. https://www.fda.gov/media/105663/download. Accessed

3-24-20.

32. ISMP. www.ismp.org.

ACKNOWLEDGMENTS

Helpful discussions with Alan M. Mancini, Richard Poska, and Paul L. Pluta are gratefully acknowledged.

Photos provided by Medi-Dose®/EPS® (www.medidose.com, 800-523-8966 are gratefully acknowledged.

Photos provided by Health Care Logistics® Inc. ( www.gohcl.com. 1-800-848-1633 are gratefully acknowledged.

AUTHORS

Karolina Cieslak is a 2021 PharmD candidate at the University of Illinois at Chicago College of Pharmacy., Chicago, IL

60612. Ms. Cieslak may be contacted at [email protected].

Varanya Chaiyaperm, PharmD, RPh, is Clinical Laboratory Instructor, University of Illinois College of Pharmacy,

Chicago, IL 60612. Dr. Chaiyaperm may be contacted at [email protected].


file:///I:/Paparella%20Epi%20potpourri%20errors.pdf

https://www.fda.gov/media/88496/download

https://www.accessdata.fda.gov/drugsatfda_docs/psg/Epinephrine_intramuscular%20and%20subcutaneous%20injectable_NDA%20020800_RC08-17.pdf

https://www.accessdata.fda.gov/drugsatfda_docs/psg/Epinephrine_intramuscular%20and%20subcutaneous%20injectable_NDA%20020800_RC08-17.pdf

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/technical-considerations-pen-jet-and-related-injectors-intended-use-drugs-and-biological-products

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/technical-considerations-pen-jet-and-related-injectors-intended-use-drugs-and-biological-products

https://www.fda.gov/media/80481/download.



http://www.medidose.com/

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