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Adrenaline Auto-injectors:

A Review of Clinical and Quality Considerations

04 June 2014

Contents Abbreviations ....................................................................................................... 3

1 Lay Summary .................................................................................................. 4

2 Introduction .................................................................................................... 6

2.1 Background .............................................................................................. 6

2.1.1 The issues .......................................................................................... 6

2.1.2 History of auto-injectors ...................................................................... 6

2.2 Anaphylaxis .............................................................................................. 8

2.2.1 Incidence and treatment ...................................................................... 8

2.2.2 Pharmacokinetics of adrenaline ............................................................. 9

2.2.3 Doses needed to treat anaphylaxis ...................................................... 10

3 Quality Aspects ............................................................................................. 10

3.1 Drug Substance:- adrenaline .................................................................... 10

3.2 Design and Operating Principle of auto-injectors ......................................... 10

3.3 Finished product specification ................................................................... 12

4 Non-Clinical Evidence ..................................................................................... 14

4.1 Gelatine models ...................................................................................... 14

4.2 Pig models ............................................................................................. 16

4.3 Non-Clinical Conclusion ............................................................................ 16

5 Clinical Evidence ............................................................................................ 17

5.1 Intramuscular vs subcutaneous injection .................................................... 17

5.1.1 Intramuscular versus subcutaneous injection conclusions ...................... 19

5.2 Site of injection ...................................................................................... 19

5.2.1 Conclusion ....................................................................................... 21

5.3 Appropriate needle length ........................................................................ 22

5.3.1 Clinical Comment .............................................................................. 25

5.4 Post-marketing data ................................................................................ 26

5.4.1 Exposure data .................................................................................. 26

5.4.2 Clinical Comment: ............................................................................. 28

6 Discussion and recommendations .................................................................... 28

7 Independent Advice Received .......................................................................... 30

References ......................................................................................................... 32

Adrenaline Auto-injectors: A Review of Clinical and Quality Considerations

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Abbreviations

AAI Adrenaline Auto-injector

ADR Adverse Drug Reaction

BP British Pharmacopoeia

BMI Body mass index

Cmax Maximum plasma concentration

CT Computed tomography

DoH Department of Health

EVDAS EudraVigilance Data Analysis System

IM Intramuscular

ISO International Organization for Standardization

MAH Marketing Authorisation Holder

NHS National Health Service

Ph Eur European Pharmacopoeia

PIL Patient Information Leaflet

PK Pharmacokinetic

RMS Reference Member State

SC Subcutaneous

STMD Skin To Muscle Depth

Tmax Time to maximum plasma concentration


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1 Lay Summary

Adrenaline auto-injectors (AAIs) are intended for self-administration of adrenaline

solution as an emergency, on-the-spot treatment during the early onset of symptoms of

an anaphylactic reaction. As the progression of anaphylactic shock can be rapid,

individuals with known allergy profiles are prescribed AAIs to carry with them at all times

and they should be familiar with the operation of their specific auto-injector.

The Medicines and Healthcare products Regulatory Agency (MHRA) has undertaken a

review of all AAIs licensed in the UK on the recommendation of a coroner’s report into a

death of a patient who had used such a device to self-treat anaphylaxis.

This paper mainly discusses two of the issues raised by the coroner:

1. The most effective site for injection and the clarity of instructions

2. The most appropriate auto-injector needle length for injections into the muscle

(intramuscular or IM) rather than injections into the fatty layer under the skin

(subcutaneous or SC) administration

The review has also considered information supplied with these products and whether

clearer instructions and advice to prescribers, patients and carers could be provided in

order to improve outcome.

Anaphylaxis is a severe type of allergic response and is a life-threatening condition that

can escalate into something very serious extremely rapidly. It can be associated with

marked swelling of the face and neck causing constriction of the throat and upper

airway, tightness of the chest and difficulty in breathing, a raised skin rash and

sometimes a marked decline in blood pressure causing collapse of the patient. Known

factors affecting severity of an anaphylactic episode include the degree of exposure to

the substance responsible for the allergic reaction (the “allergen”) and other factors such

as associated poorly controlled asthma, recent illness or strenuous exercise after

exposure to the allergen. Fortunately, fatalities occurring as a result of anaphylaxis are

rare and even less common when AAIs have been used. It is vital however that these

devices are used correctly and an important part of the MHRA review has been to clarify

information provided with these products to ensure as far as possible their correct use.

Anaphylaxis can be fatal and in these unfortunate cases, death usually occurs very soon

after contact with the allergen. Some allergens act faster than others. Food allergens can

cause breathing to stop (respiratory arrest) after approximately 30–35 minutes; insect

stings can cause collapse from shock after 10–15 minutes; and allergic reactions to

medicines given by injection can cause death within 5 minutes. Therefore the speed of

treatment of an anaphylactic reaction is of great importance and can have a significant

impact on the patient’s recovery.

It is widely accepted that an injection into the muscle is the best way for treatment with

adrenaline to be administered. Even if the injection does not reach into the muscle, it will

still have some effect, but it may take longer to relieve the symptoms of anaphylaxis.

The best place for the injection is considered to be the side of the thigh in the middle

between the hip and the knee, as recommended in the Resuscitation Council Guidelines.

This review considered the data regarding all possible injection sites and concluded that

patients should continue to use the middle of the thigh, as this represented the best

location and minimised the risk of the needle going too deep and hitting bone or

accidentally injecting adrenaline into a blood vessel or tendon which could cause

additional problems.

As everyone has different body shapes, concerns were raised about the length of the

needle within the actual auto-injector devices and whether or not these were long

enough to inject adrenaline into the muscle of all patients needing treatment for

anaphylaxis. It is difficult to study how deep the needle goes into the thighs of patients

using these devices. Models using blocks of gelatine and pork tissue have been used to

represent the thigh and measure how far the adrenaline travels after being propelled

from an auto-injector device following injection. The pork tissue model is considered

more like the human thigh than the gelatine model but both models provide some data


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that shows that the spring-loaded auto-injectors can project the adrenaline beyond the

end of the needle to as much as twice the depth that the needle penetrates. However,

not all of the pork tissue studies confirm this. Furthermore, the models cannot fully

mirror the real-life situation where other factors exist including local tissue blood flow

and barriers such as fibrous tissue layers surrounding muscle, all of which may have an

impact on how efficiently the adrenaline can penetrate into the muscle tissue.

Two studies19,20 measured the skin to muscle distance in adults and in children and

showed that the skin to muscle depth is greater than the length of the needle (15mm) in

many people, particularly women due to a different distribution of fat from men. These

studies also showed that Body Mass Index (BMI) and skin to muscle depth are not

directly linked and people with low BMI may have still have thighs with a high skin to

muscle depth.

The AAI devices are spring loaded and the manufacturers claim that the adrenaline is

injected forcibly into the muscle tissue. This is supported by non-human studies which

provide some reassurance that the adrenaline does penetrate beyond the exposed

needle length. However, as outlined above, there are additional factors that may

influence how well the adrenaline penetrates.

The MHRA’s report was presented to and evaluated by independent panels of experts

(Commission on Human Medicines (CHM) and the Chemistry, Pharmacy and Standards

Expert Advisory Group) in January 2014 and a number of recommendations were made.

The experts advised on improvements to the information for healthcare professionals

and patients on the management of an anaphylaxis episode, they proposed that

manufacturers should conduct studies to evaluate injection delivery and should improve

the quality standards for AAIs. The full list of recommendations made is provided in this

report. The recommendations are currently being taken forward by the MHRA for

consideration at a European level. This will enable the different AAIs authorised across

Europe to benefit from this review.


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2 Introduction

2.1 Background

2.1.1 The issues Adrenaline auto-injectors (AAIs) are intended for self-administration of adrenaline

solution as an emergency, on-the-spot treatment during the early onset symptoms of

anaphylaxis. As the progression of anaphylactic shock can be rapid, individuals with

severe allergies are prescribed AAIs to carry with them at all times and they should be

familiar with the operation of their specific brand of auto-injector.

A coroner’s report raised four areas for consideration and investigation in relation to the

death of a patient following use of an AAI for emergency treatment of an anaphylactic

episode.

The four areas were:

1. The need to contact emergency services after first use of auto-injector even if

symptoms are abating

2. The most effective site for injection and clarity of instructions

3. The most appropriate auto-injector needle length for IM injection

rather than SC administration

4. The best position for transporting a patient following an anaphylactic event

The MHRA was asked to address the first three items. Item 1 was addressed by the

MHRA during 2012. All marketing authorisation holders (MAHs) were required to clearly

state in the Patient Information Leaflet (PIL) and/or labelling of all AAIs licensed in the

UK that the patient should call 999 even if symptoms appeared to be abating.

Although the review did not specifically address Item 4, it did consider whether

improvements could be made to the information supplied by the manufacturers of these

products, relating to instructions to be followed by the patient/carer and healthcare

professionals at the scene of the emergency, as well as advice for follow-up.

Therefore the scope of this paper is primarily to address items 2 and 3.

In order to help with this review the MAHs for EpiPen (Meda Pharmaceuticals Ltd), Jext

(Alk-Abello A/S) and Emerade (Namtall AB) were asked to provide:

(a) Evidence that a complete dose of adrenaline solution is delivered intra-

muscularly throughout the proposed shelf life of the product

(b) Evidence that the above can be delivered through clothing

(c) Any post-marketing clinical evidence that the product (adrenaline plus device)

is effective in the treatment of acute anaphylaxis

(d) A summary of out of specification (OOS) results from stability studies

conducted on all product strengths over the past three years

(e) Product complaints history (reported by either patients or healthcare

professionals).

2.1.2 History of auto-injectors Auto-injectors were developed in the 1960s for military use following research between

the American military and NASA. The original objective was to develop a self-injecting

device that would inject atropine, the antidote for nerve agents in biological weapons.

From this original design platform the AAI was developed and was introduced into the

medical field approximately 25 years ago in the United States of America.

The first marketing authorisation in Europe was for EpiPen® which was granted a

Marketing Authorisation in Germany in 1989 and in the UK in March 1996.

Subsequently other brands of AAIs were licensed: Anapen®, Jext® and most recently


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Emerade®. Anapen® is no longer marketed in the UK but is still available in other EU

countries.

Scope of review

Currently the following AAIs are licensed in the UK for use in adults and children and

were included in the review:

Table 1: Licensed AAIs

Product name Container

closure

detail

Product licence

number/Type

of licence

Marketing

Authorisation Holder’s

name and address

EpiPen®

Adrenaline

(Epinephrine)

Auto-Injector

0.3mg

Pre-filled

cartridge

encased in

an auto-

injector

PL 15142/0245

MEDA Pharmaceuticals

Limited, Skyway House

Parsonage Road

Takeley, Bishop’s

Stortford, CM22 6PU

United Kingdom

EpiPen® Jr.

Adrenaline

(Epinephrine)

Auto-Injector

0.15mg

PL 15142/0246

Jext 150

micrograms

solution for

injection in pre-

filled pen

Pre-filled

cartridge

enclosed in

an auto-

injector

PL 10085/0052

ALK-Abelló A/S

Bøge Allé 6-8

DK-2970 Hørsholm

Sweden Jext 300

micrograms

solution for

injection in pre-

filled pen

PL 10085/0053

Emerade 150

micrograms,

solution for

injection in pre-

filled pen

Pre-filled

syringe

encased in

an auto-

injector

PL 42457/0001

NAMTALL AB

Rapsgatan 7, SE-754 50

Uppsala, Sweden

Emerade 300

micrograms,

solution for

injection in pre-

filled pen

PL 42457/0002

European

Emerade 500

micrograms,

solution for

injection in pre-

filled pen

PL 42457/0003

European

No new clinical studies were required to be submitted in support of the original

applications.


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2.2 Anaphylaxis

2.2.1 Incidence and treatment Anaphylaxis is a severe, life-threatening systemic reaction that can affect all ages. The

clinical syndrome may involve multiple target organs, including skin, respiratory,

gastrointestinal and cardiovascular systems. The essential underlying mechanism is the

presence of biologically active chemical mediators such as histamine and tryptase

released from mast cells or basophils. The complex signalling cascades that regulate

mast cell activation have been extensively investigated and described in the literature1.

The true incidence of anaphylaxis is unknown. Epidemiological studies have shown

differing results owing to differences in both definitions of anaphylaxis and the

population groups studied; however the incidence is increasing in recent years.

Prescribing of adrenaline increased by 97% between the years 2001 and 2005. It has

been estimated that by the end of 2005 there were 37,800 people in England that had

experienced anaphylaxis at some point in their lives2.

There are very limited data on trends in anaphylaxis internationally, but data indicate a

dramatic increase in the rate of hospital admissions for anaphylaxis in England,

increasing from 0.5 to 3.6 admissions per 100,000 between 1990 and 2004: an increase

of 700% (Figure 1)5.

Most of the data for the incidence of anaphylaxis have been derived from hospital

databases, and it is widely believed that anaphylaxis is under-recognised and under-

reported3.

Anaphylaxis can be triggered by any of a very broad range of allergens, but those most

commonly identified include food, drugs and venom (including wasp and bee stings). The

relative importance of these varies very considerably with age; with food being


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particularly important in children and medicinal products being much more common

triggers in older people.

Anaphylaxis remains a significant cause of mortality. Of 164 fatal reactions identified

between 1992 and 1998 in the United Kingdom, around half were caused by drugs. Of

those not caused by drugs, half were related to venom and most of the remainder to

food3. With the increase in food allergies, the Office of National Statistics (ONS) started

recording deaths from anaphylaxis due to food allergies separately from anaphylaxis due

to other causes in 2002.

When anaphylaxis is fatal, death usually occurs very soon after contact with the trigger.

From a case-series, fatal food reactions cause respiratory arrest typically after 30–35

minutes; insect stings cause collapse from shock after 10–15 minutes; and deaths

caused by intravenous medication occur most commonly within five minutes. Death

never occurred more than six hours after contact with the trigger

Studies of fatal and near-fatal anaphylaxis in humans delineate risk factors for

anaphylaxis such as pre-existing asthma, a current asthma attack, food allergies

(particularly peanuts, tree nuts and shellfish), reaction to trace amounts of foods and

use of non-selective β-blockers4. Other factors include recent infection, intense exercise

after the exposure and concurrent exposure to other allergens such as pollen in pollen

allergic individuals.

Treatment

Early intramuscular adrenaline is the optimal treatment for patients suffering

anaphylaxis5. Most studies of fatal anaphylaxis show that a lack of, or delay in,

administration of adrenaline is a frequent factor in death, whereas early administration

of adrenaline even in severe attacks is associated with survival. The median time to

respiratory or cardiac arrest is reported to be 30 minutes for food- and 15 minutes for

venom-induced anaphylaxis, so adrenaline usually needs to be administered before

medical help is available. However, self-injectable adrenaline is underused even when it

is available4.

The recommended dose for auto-injectors is 300-500 µg for adults and 150-300µg for

children depending on body weight (10 µg/kg).

One injection from an auto-injector should be given immediately when symptoms are

recognised and a second injection can be given 5-15 minutes later if symptoms are not

improving. Therefore patients known to be at risk of anaphylaxis should have access to

at least two AAIs.

The Resuscitation Council guidelines advise that patients should always be observed

after treatment for anaphylaxis, for at least 6 hours and up to 24 hours in adults and for

12 to 24 hours in children, as symptoms can recur up to 24 hours after the initial

reaction (this is called a biphasic reaction). The incidence of biphasic reactions is

reported as 1-20% and unfortunately it is not possible to predict which patients will

experience a biphasic reaction.

2.2.2 Pharmacokinetics of adrenaline Adrenaline is a naturally occurring substance produced by the adrenal gland in the body

and secreted in response to exertion or stress. Endogenous plasma concentrations of

adrenaline in normal subjects are in the range 30–160 ng/L.

Adrenaline is rapidly destroyed in the gut if swallowed and therefore needs to be given

by injection. The effects of adrenaline after subcutaneous (SC) injection (injection into

the fatty tissue beneath the skin) are produced within 5 minutes but increase more

slowly, taking 30 minutes to reach optimal levels compared with a more rapid peak after

intramuscular (IM) injection (injection into the muscle)6.


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The amount of adrenaline in the blood is halved in about 2.5 minutes. However, by

subcutaneous or intramuscular routes, local constriction of the blood supply slows the

absorption, so that the effects build up and last much longer than the half-life of

2.5 minutes would predict7.

Adrenaline does have side effects, mainly on the heart (fast or irregular heartbeat, or

angina).

2.2.3 Doses needed to treat anaphylaxis Even though adrenaline is considered to be the optimal drug for use in connection with

anaphylactic or threatening anaphylactic reactions, very little is known about what doses

or plasma concentrations are required in this context.

The recommended dose of adrenaline is usually within the range 5-10 µg/kg bodyweight

but higher doses may be necessary in some cases. When adrenaline is delivered by an

auto-injector device the following are recommended doses: in children between 15 kg

and 30 kg in weight the usual dose is 150 µg and in adolescents and adults the

recommended dose is 300 to 500 µg.

There is a risk of overdosing small children with a body weight of under 15kg with an

auto-injector so these are not generally recommended for such small children.

The following intramuscular doses are recommended in the Resuscitation Council

Guidelines which are specified as being in the context of administration by a healthcare

professional:

> 12 years: 500 µg IM i.e. same as adult dose 300 µg if child is small or

prepubertal

> 6 – 12 years: 300 µg IM

> 6 months – 6 years: 150 µg IM

< 6 months: 150 µg IM

Most patients only require one dose but the dose can be repeated after 5-15 minutes if

symptoms do not improve or recur.

The scientific basis for the recommended doses is weak. The recommended doses are

based on what is considered to be safe and practical to draw up and inject in an

emergency.

3 Quality Aspects

3.1 Drug Substance: adrenaline

The European Pharmacopeia (Ph Eur) is a publication detailing the official European

quality standards for ingredients of medicinal products. The quality of the drug

substance adrenaline is controlled according to the Ph Eur. specification in all of the

licenced AAIs.

3.2 Design and Operating Principle of auto-injectors

All AAIs comprise a sterile adrenaline solution filled into a container consisting of either a

glass cartridge (also known as a carpoule) or pre-filled glass syringe with a fixed needle.

In all cases they are made from glass suitable for injections. There are two fundamental

designs for AAIs licensed in the UK:


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- the cartridge type injector for example EpiPen® and Jext®

- the syringe type injector for example Emerade®

Each auto-injector brand has a different delivery/administration system. Likewise the

firing mechanism which provides the force behind the actual injection process which

pierces the skin and enters the outer (antero-lateral) thigh is unique to each brand. The

assembled auto-injectors are enclosed in a “carry case” to protect them from mechanical

shock and damage.

In the cartridge type injectors the volume of adrenaline solution that the auto-injector

contains (the fill volume) is significantly larger than the actual volume of adrenaline

solution intended to be injected (the delivered volume) so unused solution remains in

the activated auto-injector after use. In the case of EpiPen the volume of adrenaline

delivered is the same in both the adult and the paediatric injectors: the concentration of

adrenaline in the solution is adjusted to give the different doses (150 µg for paediatric

use and 300 µg for adult). Conversely the paediatric and adult versions of JEXT and

Emerade auto-injectors contain the same concentration of adrenaline solution but the

delivered volume is adjusted to achieve the correct paediatric dose.

As delivered volume relates to the quantity of adrenaline actually injected it is a critical

test for all AAIs to ensure delivery of the intended dose throughout the shelf life of the

product.

During a conventional manual injection i.e. one given by a healthcare professional to an

individual in a medical setting, the force to move the solution in a pre-filled syringe is

provided by the thumb pushing the plunger. An auto-injector is generally intended for

self-administration by an individual or by a family member or friend. Prior to use the

plunger and needle are concealed within a plastic shell. The injector is activated by

pulling off a cap or pressing a button and either swinging the AAI towards the thigh or

placing it against the thigh. A coiled spring is then released inside the auto-injector

which pushes the plunger to inject the solution into the patient. The adrenaline solution

is pressurised to varying degrees depending on the design of the AAI. When the auto-

injector is used the needle is propelled forward to pierce the skin and deliver the

solution.

Discussion on the design of AAIs

There has been considerable discussion in the medical community and in patient groups

regarding the suitability of the needle length used with AAIs with respect to the ability of

the injectors to deliver the adrenaline solution to the optimal body compartment i.e. into

the thigh muscle tissue. All UK licensed products claim to deliver an intra-muscular

injection of adrenaline. The way the AAI is used (its method of operation), the force

behind the adrenaline solution and how these factors contribute to the dose delivery

have also been debated. Evidence of how these factors influence the site of deposition in

the tissue is based on limited studies using non-clinical models. These three issues (a)

needle length (b) method of operation and (c) applied mechanical force are discussed in

greater detail below.

(a) Needle length

As there are differences in AAI design and method of operation, the total needle length

cannot be considered on its own, as a portion of the needle remains within the device

once fired - unlike a manual injection. The extended needle length measurement


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provides an indication of the effective needle length available to deliver the adrenaline

solution into the body and should be controlled.

Schwirtz and Seeger11 reported “the mean exposed needle length was 15.36 mm

(standard deviation [SD] 0.22) for Jext and 15.02 mm (SD 0.25) for EpiPen”. Non-

clinical evidence exists -using both ballistic gelatine and porcine models - to support that

adrenaline solution from both EpiPen and JEXT auto-injectors penetrate some distance

into body tissues beyond the needle tip (Refer to section 4. Non-Clinical Evidence, for

study detail and discussion). This suggests that there are additional factors to take into

consideration when determining where the adrenaline solution is actually deposited in

the body:-

1. the method of operation of the respective auto-injectors, and

2. the force applied to the plunger by the firing mechanism.

(b) Method of operation

In all AAIs a safety cap is removed immediately prior to the actual injection sequence.

The safety cap is at the opposite end of the device from the needle and once removed

the device is considered to be “armed” for use. There are two principal methods used for

the self-injection of adrenaline using auto-injectors. These are the “swing and jab”

method or “place and press” method. EpiPen® utilises the swing and jab method of

administration while JEXT® and Emerade® utilise the place and press method. The

method employed is related to the activation force required for each delivery system.

It is possible that there is some degree of tissue compression during both the “swing and

jab” technique and the “place and press method”. This may result in a net decrease in

the skin to muscle distance (STMD), enabling the solution to penetrate deeper into the

tissues.

(c) Force applied to the plunger by firing mechanism/power pack

As liquids cannot be compressed, the adrenaline solution is pressurised to varying

degrees depending on the individual device design and construction. This phenomenon

theoretically causes the solution to be expelled beyond the needle tip to varying degrees

and is device dependent. This is confirmed by studies where ballistic gelatine has been

used as a substitute for human tissue (Refer to section 4. Non-Clinical Evidence).

However, it is not known how this correlates to administration into live human tissue.

3.3 Finished product specification

AAIs comprise a drug product i.e. the adrenaline solution, which is sealed in a glass

container, with a device component (the injector) for delivering the solution. These

elements form the finished product. The finished product specification is a set of

characteristics and acceptance limits that each batch of finished product must comply

with before it can be released for sale.

As a part of this review the finished product specifications were examined for all licensed

AAIs. The tests applied to auto-injectors can be sub divided into the following:

a. Tests to meet the Ph Eur general requirements for injections

b. Tests to monitor adrenaline content, degradation substances and other

impurities and levels of important ingredients such as sodium

metabisulphite (an antioxidant used to stabilise the adrenaline solution)


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c. Functional tests to monitor the performance of the delivery mechanism

d. The British Pharmacopeia (BP) monograph controls the quality of the

adrenaline solution to a minimum standard in respect of the content of the

active pharmaceutical ingredient, pH and degradation products.

The above quality standards are reviewed for each individual product in an application

for a marketing authorisation in the European Union.

Functional tests related to the delivery mechanism

Although these quality characteristics are controlled in the design of the products, they

should be brought together in the finished product specification:

1. Delivered volume

The delivered volume (the volume of adrenaline solution released when the auto-

injector is deployed) requires tight control.

2. Delivery time

The time taken to eject the adrenaline solution from the needle (the delivery time) is

critical. As anaphylaxis progresses very rapidly, delivery time should be measured for all

AAIs and should reflect a rapid delivery time in the order of seconds.

3. Exposed needle length

The design of an auto-injector should ensure that consistent extended needle length

occurs when the device is activated by a patient.

4. Activation Force

All auto-injectors need to be activated by the patient before use. This is achieved by

removing the safety cap and either swinging or pressing the needle end of the device to

the thigh. These operations should be possible for both adults and children; however the

safety cap should not come away too readily either, to prevent accidental removal.

The force required to initiate the injection cycle should be consistent during storage to

ensure that AAIs are usable throughout the shelf-life period.

Discussion on functional testing

The approach to functional testing varies between manufacturers. Our recommendation

is that the acceptance criteria for functional tests should be based on a critical evaluation

of historical long-term stability data with consideration of the impact on the delivered

dose. Critical quality attributes which ensure the correct dose is delivered within defined

time limits should be included in the release and shelf-life specification requirements.

AAI product defect reporting and product recalls

In the past two years quality defects have been reported regarding Anapen® and JEXT.

A recall was issued by the MHRA Defective Medicines Report Centre (DMRC) for all

strengths of Anapen in 2012, based on finished product testing failures to deliver the

correct volume and/or delivery time failure. The JEXT quality defect was announced by

the Reference Member State (RMS) Sweden and a Class II recall notification was issued

by the DMRC in early December 2013. In January 2014 Sweden (RMS) issued a Class II

recall notification for Emerade due to suspected technical defects, at this point the


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product had not been launched within the UK. In addition there was a recall in October

2013 concerning another auto-injector product (which does not contain adrenaline) as a

small number of syringes potentially had needles protruding through the needle shield.

Assembly of “ready to use” injectable drug products is complex and these incidents

suggest that additional controls might be necessary.

AAIs are intended for single use and are classified as medicinal products with an integral

delivery system (device). The device aspects of AAIs should be designed and qualified by

the manufacturers to be fit for purpose with relevant supporting data on the

development and manufacture of the device submitted in the marketing authorisation

application reviewed by the Licensing Authority.

Although the AAIs do not require a CE mark, they should be compliant with the relevant

sections of standards published by the International Organization for Standardization

(ISO), for example BS EN ISO 11608 Needle-based injection systems for medical use.

They should meet the essential requirements of Annex 1 of the Medical Device Directive.

The marketing authorisations for AAIs should be reviewed with respect to ensuring the

finished product specifications and in-process controls (IPCs) for the device assembly

process are adequately described and that a summary of the following is provided.

1. The design and qualification of the delivery system i.e. the device development

history.

2. A summary of identified critical failure modes for the delivery system.

3. Updated finished product specifications including appropriate functional tests with

sample size tested per batch and the acceptable quality level (AQL) for each test.

4. An overview of how the essential requirements of Annex 1 of the Medical Device

Directive are met.

Product Stability Update

At the request of the MHRA, the manufacturers of the licensed AAIs provided updated

stability data for their products to the MHRA for review.

4 Non-Clinical Evidence

Two main non-clinical models have been cited in the MAH’s response to the MHRA’s

request to provide further information on their products; gelatine and porcine tissue.

Both have been used in the study of ballistics and weapons research. A brief discussion

is presented below of both models in the context of their usefulness for assessing the

performance of injector pens in delivering adrenaline to the muscle layer.

4.1 Gelatine models

Ballistic gelatine is reported as being designed to simulate living soft tissue (Nicholas and

Welsch, 2004)8. It is regarded by the US military as the standard for evaluating the

effectiveness of firearms against humans because of its convenience and acceptability

over animal or cadaver testing. Use by the military would appear to have resulted in the

acceptance of the use of gelatine in ballistic and other research and it has been referred

to in some publications (including those cited by the MAH) as a ‘validated tissue

simulant’. However, its use appears to be based more on custom and practice than

inherent suitability. It was first used in 1960 and various techniques were used to

measure the kinetic energy of a projectile travelling through a block of gelatine. Early

models were not compared to living tissue in a quantitative or reproducible way.


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In the first of many papers in the mid to late 1980s, researchers at the Letterman Army

Institute of Research (LAIR) used both live swine (50-70 kg) and gelatine blocks to test

bullets and subsequently compared the results9. Although the paper did not include

specific comparisons between gelatine and animal tissue, the LAIR team and many other

researchers afterward cited this published paper as the foundation for using Fackler’s

gelatine model as an approximate or equivalent substitute for animal tissue. A paper by

Fackler and Malinowski (1985)10 states that the depth of penetration measured in living

swine leg muscle was reproduced in the gelatine within 3%. These findings and the

convenience of using non-animal or non-cadaveric tissue appear to have led to the use

of gelatine on its own.

While the conditions and preparation of the gelatine have been standardised to some

extent, and can be used to compare the behaviour of projectiles within that limited

context, the model cannot be regarded as fully representative of living tissue, primarily

because it is homogeneous rather than heterogeneous. The different types and textures

of animal tissue, particularly bones, cannot be regarded as being adequately simulated

in a gelatine alone system. Also, differences in the gelatine such as method of

preparation, concentration and temperature mean that consistency between laboratories

cannot be guaranteed.

The acceptance of the model for ballistics has led to its use in investigating the track of

injections from auto-injectors. In this context, it could be suitable for investigating the

depth to which a drug might be injected, as the only tissues to be penetrated are skin

and fat, unlike in ballistics research, where the full range of tissues could be

encountered. It might be acceptable, for example, to use gelatine models to rank

devices against one another for depth of penetration, but it would not simulate clinical

conditions as closely as live animal or human tissue.

A study comparing three injector pens was reported by Schwirtz and Seeger (2012)11.

Three AAIs (Jext, EpiPen® and Anapen) were tested for, amongst other features, the

injection depth and estimated volume of black ink delivered into ballistic gelatine. The

mean maximum injection depths in gelatine within 10 seconds were 28.87 mm (SD

0.73) for Jext, 29.68 mm (SD 2.08) for EpiPen® and 18.74 mm (SD 1.25) for Anapen

(Figure 2). The length of the EpiPen® and Jext needles is 14.3 mm and the Anapen

needle is 8.9 mm to 9.9 mm.

Figure 2: Photographs showing the total injection depth into gelatine 10

seconds after activation of Jext (A), EpiPen (B), and Anapen (C), measured as

the vertical distance from the surface of the gelatine to the lowest part of the

ink area using digital image processing.

(Photographs copyright of Schwirtz and Seeger, 201212)

A previous pilot study reported by the same authors (Schwirtz and Seeger, 2010)12

included a simulation of firing two AAIs through clothes, EpiPen® Junior and Anapen®

Junior. Each auto-injector was fired into ballistic gelatine in the presence or absence of a


16

piece of denim (a double seam of Levi’s blue jeans). The activation force was recorded,

and the effective (exposed) needle length was measured by a calliper after the device

was removed from the ballistic gelatine. The presence of denim did not alter the

activation force or effective needle length of either of the AAIs.

4.2 Pig models

Based on current knowledge, the pig as an animal model for human skin is generally

accepted as being the most representative of human skin13 and it is commonly used in

pharmaceutical development for local tolerance and skin penetration studies. Given the

difficulty in generating clinical data on injector pens, the use of the pig for this purpose is

considered appropriate and the most valid model currently available.

The MAH for Epipen® has cited a study conducted by the US military on the depth of

penetration into porcine thighs achieved by the EpiPen® to address the question of its

performance in obese patients14. Adrenaline from 21 EpiPen® devices was mixed with

methylene blue as a colour tracer and triggered into the lateral aspect of 21 cadaver pig-

thighs. The results show that with an exposed needle length of 14.3 mm, the mean ± SD

delivery depth from the skin to the muscle was 26.9 ± 5.4 mm (p<0.0001), consistent

with approximately twice the needle length. All injections delivered adrenaline beyond

the needle length and into muscle. However in these pigs the depth of the fat layer was

only 7mm according to a further communication from one of the authors (T Ted Song).

In the publication by Schwirtz and Seeger (2012) cited above, a separate study to

simulate the clinical conditions more closely was reported. A model was used in which

the contents of AAIs were replaced with a contrast agent, the AAI was activated into

fresh cadaver pork shoulder, and computed tomography (CT) scanning was used to

examine the injection pathway. The maximum exposed needle lengths ranged from 14.5

mm to 15.2 mm for Jext and EpiPen® compared with 8.9mm to 9.9mm for Anapen. The

maximum injection depths ranged from 22.45 mm to 35.05 mm for Jext and EpiPen®

and from 10.00 mm to 14.80 mm for Anapen. The maximum injection depth for Jext and

EpiPen® always reached the muscle, even when the skin-to-muscle distance was greater

than the exposed needle length. The depth of fat ranged from 3.90 mm (‘lean’) to 19.40

mm (‘fat’). The delivery depths reported for EpiPen® are in broadly the same range as

those published by Ferguson et al14 (mean of 26.9 mm), and confirm that the contents

of the AAI can be delivered to a depth greater than the exposed length of the needle.

However, although the adrenaline solution appears to reach the surface of the muscle

even when the skin to muscle distance exceeds the length of the needle, it is not clear

whether the adrenaline actually penetrates the body of the muscle tissue – which would

be required for optimal clinical effect – or whether it merely reaches the surface of the

muscle and surrounding connective tissue.

4.3 Non-Clinical Conclusion

There are difficulties with attempting to generate clinical data on AAIs because of the

nature of the clinical indication and the conditions surrounding the occurrence of

anaphylaxis. A valid model would, therefore, be very useful. The similarity between

porcine and human tissues indicates that the pig model is suitable for testing injector

pens and the use of the model is acceptable as it is the best substitute for clinical data

currently available. The MAH’s approach in the response in using porcine data is

considered reasonable and the results are considered to be acceptably robust and

biologically meaningful. The MAH’s conclusion that the EpiPen® can be reliable for use

in patients with a fat thickness of up to twice the length of the needle is supported by

the data from the papers by Ferguson and Schwirtz. However, it is unknown what the

limitations of cadaveric material might be and how representative it is of live tissue with

a functioning blood supply.


17

The data from ballistic gelatine are consistent with those obtained using porcine tissue.

Consistent results were obtained in the study reported by Schwirtz and for the purposes

of comparison of the three devices, the model is considered acceptable. While the results

in a gelatine system show that the degree of penetration was not affected by the

presence of denim, the results are not considered as robust as if porcine tissues covered

with denim had been used. Nonetheless, the data are considered to be reasonably

reliable and the conclusion that the performance of the AAI is not affected by the

presence of clothing, including denim, is considered acceptable.

5 Clinical Evidence

The following section contains evidence from published literature and evidence provided

by the Marketing Authorisation Holders (MAH) at the request of the MHRA.

5.1 Intramuscular vs subcutaneous injection

There is some debate over the most appropriate route of administration of adrenaline in

the treatment of acute anaphylaxis. Many different authoritative recommendations have

been made but these are largely based on descriptive studies, clinical experience and

tradition rather than on prospective clinical studies, tailored for these products.

Adrenaline is most effective when given immediately after the onset of anaphylaxis

symptoms. The initial recommended adult dose is 300 - 500 µg, injected intramuscularly

in the anterolateral aspect of the mid-thigh. When injected by other routes, adrenaline

appears to have a less satisfactory therapeutic window; for example, onset of action is

potentially delayed when it is injected subcutaneously, and the risk of adverse effects

potentially increases when it is injected intravenously. An intravenous injection should

only be given under medical supervision when continuous monitoring is available.

Pharmacokinetics

Simons et al15 conducted a prospective, randomized, blinded, placebo-controlled, 6-way

crossover study of intramuscular versus subcutaneous injection of adrenaline in healthy

allergic men aged 18-35 years. The objective of the study was to provide information

regarding the optimal route and site of adrenaline injection in adults.

During the course of the study, each participant received 4 injections of adrenaline 0.3

mg (0.3 mL) and 2 injections of saline solution (0.9% NaCl, 0.3 mL) through use of a

variety of injection routes and sites. Adrenaline USP I: 1000, 0.3 mg (0.3 mL) was

injected either IM into the thigh (vastus lateralis) muscle or the upper arm (deltoid)

muscle or SC in the upper arm.

To ensure blinding, all injections were given by a nurse not otherwise involved in the

study, and at each visit both the thigh and upper arm sites were covered after the

injection.


18

Figure 3: Mean plasma adrenaline concentrations versus time are shown after administration of an identical 0.3 mg (0.3mL) dose of adrenaline by IM or SC injection in 2 different sites. T; Thigh; A upper arm. Mean endogenous plasma adrenaline concentrations are shown after IM or SC injection of 0.9% saline solution (0.3 mL) in the upper arm. The plasma adrenaline concentrations

shown were calculated by averaging (mean ±SEM) the adrenaline concentrations at each sampling time for each route and each site of injection.

The results showed a swift increase in plasma levels of adrenaline following IM injection

into the thigh, which was greater than levels achieved from an IM or SC injection into

the arm. Unfortunately the study did not investigate SC injection into the thigh. The time

to maximum concentration in the blood (Tmax) for the IM injection was around 10

minutes

Using the EpiPen a second peak in plasma concentration was seen at 40 minutes which

the authors suggest may be due to further absorption of exogenous adrenaline at the

injection site after a period of initial vasoconstriction at the site, or due to rebound

endogenous adrenaline release. The latter seems unlikely as it is not seen with the other

routes of administration. Another explanation could be that part of the dose from the

EpiPen was delivered subcutaneously and was therefore absorbed more slowly giving a

delayed onset of action.

A further study by Simons et al16 in children measured the pharmacokinetics (PK) of

adrenaline following subcutaneous injection (9 children) and intramuscular injection (8

children). The study was a prospective, randomised, blinded parallel group study in

children with a history of anaphylaxis. The subcutaneous injection was administered via

needle and syringe while the intramuscular injection was administered using an EpiPen

Auto-injector.

Results

In the nine children who received a SC injection the mean maximum plasma

concentration of adrenaline was 1802 ±214 pg/mL, achieved at a mean time of 34 ±14

minutes (range 5 to 120 minutes). Only two of the children achieved a maximum

concentration of adrenaline by 5 minutes. In the eight children who received


19

intramuscular injection via EpiPen the mean maximum concentration of adrenaline was

2136 ±351 pg/mL achieved at a mean time of 8 ±2 minutes, which was significantly

faster than the mean time at which maximum plasma concentrations of adrenaline were

achieved using the SC route.

Figure 4: Mean plasma adrenaline concentration versus time after injection of

adrenaline subcutaneously or intramuscularly

The results of this study, despite its limitations, support the intramuscular route as the

optimal route of injection of adrenaline in the treatment of anaphylaxis.

5.1.1 Intramuscular versus subcutaneous injection conclusions The data regarding subcutaneous versus intramuscular injections are sparse and the

recommendation for intramuscular injection of adrenaline in the treatment of

anaphylaxis appears to be mainly based on theoretical grounds. It is imperative that the

adrenaline is absorbed quickly in order to minimise the risk of a fatal outcome in

anaphylaxis and therefore the intramuscular route is the logical choice. The study by

Simons et al in children with a history of anaphylaxis supports the assumption that the

intramuscular route gives a faster time to maximum plasma concentration of adrenaline,

although the data are limited by the small number of children included in the study. It

also lends some support to the supposition that EpiPen delivers its dose intramuscularly

at least in the children studied; but it should be borne in mind that children, in general,

have less subcutaneous fat than adults. Owing to the nature of anaphylaxis no clinical

studies to compare the relative effectiveness of the two routes during an actual

anaphylactic reaction have been conducted, nor would they be ethical. It may be that

the auto-injectors actually deliver some of the dose intramuscularly and some

subcutaneously. As the subcutaneous portion would be absorbed more slowly this may

be beneficial in some cases where the anaphylactic reaction is prolonged, but it is

imperative that the adrenaline is delivered quickly to halt the allergic cascade and

therefore the major part of the dose should be delivered intramuscularly.

5.2 Site of injection

The Resuscitation Council Guidelines state that the best site for IM injection is the

anterolateral aspect of the middle third of the thigh and that the subcutaneous or inhaled

routes for adrenaline are not recommended for the treatment of an anaphylactic reaction

because they are less effective. Injection in the anterolateral aspect of the middle third


20

of the thigh is emphasised in the auto-injector Patient Information Leaflet (PIL) for

EpiPen and in the DVD given to patients.

A prospective study by Bewick et al17 recruited 93 children (age range, 1-16 years) with

food allergies who attended the authors’ regional paediatric allergy outpatient clinics

over a 6-month period in mid-2012. Using a MicroMaxx portable ultrasound machine

with a linear HFL38/13.6 MHz probe the authors measured the distance from the skin

surface to the vastus lateralis muscle interface at 3 distances along the outer thigh (one-

fourth [proximal thigh], one-half [mid-thigh], and three-fourths [distal thigh] the

distance from the greater trochanter to the lateral epicondyle of the femur) as

determined with a tape measure. Weight, height and waist circumference were also

measured, and BMI as well as age- and sex-appropriate BMI centiles were calculated

(Table 2).

Table 2: Anthropometric measures of 93 children referred to the local paediatric

allergy service

Parameter* Children <30 kg weight

Children >30 kg weight

All children

No. (%) 62 (67) 31 (33) 93 (100)

Age (y), median (IQR) 4 (2-6) 12 (8-14) 6 (3-10) Boys, no. (%) 35 (57) 19 (61) 54 (58) Weight (kg), median (IQR) 16.6 (12.2 –

20.8) 43.8 (38.4-53.3) 20.8 (14.5-38.6)

Height (cm), median (IQR) 102 (88-114) 150 (140-159) 114 (96-141) BMI (kg/m2), median (IQR) 16.1 (15.5-17.1) 19.9 (18.2-22.4) 16.8 (15.7-19.1)

Waist circumference (cm), median (IQR)

52 (49-56) 75 (68-80) 56 (51-68)

Skin surface to muscle depth (mm), median (IQR)

Proximal thigh 10.0 (8.3-13.2) 19.2 (12.8-25.7) 12.0 (8.6-16.9) Mid-thigh 8.4 (7.0-10.2) 12.2 (7.8-16.5) 8.8 (7.0-12.9) Distal thigh 6.8 (5.8-8.5) 9.7 (7.2-12.2) 7.9 (5.9-9.6) Mid-calf 7.0 (6.2-7.2) 9.5 (8.6-10.5) 8.5 (7.0-9.8)

Skin surface to muscle depth greater than needle length

(mm)

>12.7 >15.9

Proximal thigh, no. (%) 17 (27) 19 (61) 36 (39) Mid-thigh, no. (%) 10 (16) 9 (29) 19 (0) Distal thigh, no. (%) 1 (2) 4 (13) 5 (5) Mid-calf, no. (%) 0 (0) 0 (0) 0 (0)

IQR, Interquartile range *The median (IQR) is based on triplicate measurements


21

Figure 5 Percentage of children whose skin surface-to-muscle depth was greater than

the Epipen (children > 30kg) or Epipen Junior (children <30kg) auto-injector exposed

needle length, based on level of obesity defined by age-corrected BMI. Healthy weight

(BMI <85th percentile) n = 67 (72%), overweight (BMI 85th-94th percentile) n = 9

(10%), obese (BMI ≥95th percentile) n = 17 (18%). Differences within all groups were

statistically significant, with a P <.001 (2 test).

A possible concern of injections into the distal thigh is the risk of the needle going into

the bone. Skin surface-to-bone depth, therefore, was measured at the distal thigh in 11

children ages 1 to 15 years, with BMI units (kg/m2) that ranged from 14 to 27 (median,

17). The median depth was 29.5 mm (interquartile range, 21-36 mm). The thinnest

skin-to-bone depth was 16.2 mm in a 5-year-old child with a BMI of only 14 and a

weight of 15 kg.

5.2.1 Conclusion The site of injection as the anterolateral aspect of the mid-thigh has been accepted since

the AAIs were developed and provides the best balance between safety and efficacy. It

is also the area most readily accessible to the patient when self-administering the

adrenaline.

The study reported by Bewick et al in children demonstrated that over 50%, even in the

obese category, would have a skin to muscle depth within the exposed needle length of

the respective Epipen injectors (junior versus adult, prescribed according to body

weight) at the mid-thigh. Furthermore, this study has not made any allowance for

compression during the activation of the device or for the adrenaline being expelled

beyond the needle length as demonstrated in the ballistic gel and porcine models, which

would also increase the possibility of penetration into muscle. The proviso is that the

data are circumstantial and do not directly demonstrate evidence for penetration of

adrenaline into the body of the muscle tissue.


22

5.3 Appropriate needle length

There are concerns that, owing to the increasing obesity (BMI ≥30) of the population in

the UK, the needle lengths in the currently licensed AAIs are not adequate to deliver the

dose of adrenaline to the muscle tissue of the thigh.

A survey published in 2012 found that just over a quarter of all adults (26%) in England

are obese.

The report compiled by the Health and Social Care Information Centre, relates to

information gathered during 2011. There has been a marked increase in obesity rates

over the past eighteen years – in 1993 13% of men and 16% of women were obese; in

2011 this rose to 24% for men and 26% for women. For children attending reception

class (aged 4-5 years) during 2011-12, 9.5% were obese18.

A study by Song et al19 investigated whether EpiPen auto-injector, with a needle length

of 14.3 mm, is sufficient for intramuscular delivery of adrenaline in men and women.

The distance from skin to muscle in the anterolateral aspect of the thigh was measured

in 50 men and 50 women who had undergone computed tomography (CT) of the thighs

for other medical reasons. For each individual, body mass index (BMI; a measure of

weight in kilograms divided by the square of height in meters) was also calculated, and

the individuals were classified as underweight (BMI, 18.5), normal (BMI, 18.5–24.9),

overweight (BMI, 25.0 –29.9), and obese (BMI, 30.0) using standard definition.

The CTs were analysed for measurement of the distance from the skin surface to the

muscle. This is the path the needle traverses before reaching the fascia of the vastus

lateralis muscle.

Results

The 50 men included 39 white individuals (78%), 4 African American individuals (8%), 1

Asian individual (2%), and 6 individuals of other races (12%). The 50 women included

35 white individuals (70%), 12 African American individuals (24%), 2 Asian individuals

(4%), and 1 individual of another race (2%).

In the study participants the mean ±SD distance from skin to muscle was 6.6 ±4.7 mm

for men and 14.8 ±7.2 mm for women (P <.001). One man (obese at a BMI of 42.2) and


23

21 women (11 obese with a mean BMI of 35.2, 6 overweight with a mean BMI of 30.1,

and 4 normal with a mean BMI of 24.5) had a greater distance from skin to muscle than

the EpiPen extended needle length of 14.3 mm.

As a certain pressure is required to activate the EpiPen device, in order to investigate the

role of any subsequent compression, the distance to muscle was measured with an

ultrasound machine in 1 representative man and 1 representative woman with and

without 8 lb. of weight applied. The 8 lb. of weight decreased the distance to muscle by

25% in the woman and 19% in the man. Assuming a liberal estimate of 25%

compression of distance to muscle in both sexes, the authors recalculated the distance

to muscle for all study participants. The single man with a distance to muscle of 34.7

mm would not be affected, whereas the number of women with a distance to muscle

greater than 14.3 mm was calculated to still be 14 (28%).

These results demonstrate that the EpiPen needle length is adequate to reach the muscle

and therefore deliver adrenaline intramuscularly in most men but not in a number of

women. Even when allowance was made for BMI the gender difference remained as seen

in the figure above. Applying the pressure needed to trigger an EpiPen device decreased

the skin to muscle distance in a representative man and woman but not sufficiently to

ensure that an intramuscular injection of the dose would be delivered in all women or in

very obese men. From this study it would seem that even the longer needle length of the

Emerade auto-injector would not be adequate for all subjects.

Another study conducted by Stecher et al20 in children demonstrated that the needle on

AAIs is not long enough to ensure delivery of the medication intramuscularly in a

significant number of children.

Patients between the ages of 1 and 12 years who presented to a children’s hospital were

enrolled in the study. Ultrasound was used to determine the depth from the skin to the

vastus lateralis muscle. The patient’s body mass index was also recorded. The data were

analysed using simple descriptive statistics, and logistic regression was used to identify

variables that might predict whether or not the needle length was exceeded.

In addition, the data were analysed using an estimate of 25% for displacement of tissue

with applied pressure from the adult study cited above.


24

Results

A total of 256 children were enrolled. Of these, 158 children weighed less than 30 kg and

would be prescribed the 0.15 mg AAI (extended needle length of 10.16 to 15.24 mm).

Nineteen of these children (12%) had a skin to muscle surface distance of >12.5 mm

and would not receive adrenaline intramuscularly from current auto-injectors. There

were 98 children weighing ≥30 kg who would receive the 0.3 mg AAI. Of these 98

children, a total of 29 (30%) had a skin to muscle surface distance of >16 mm and

would not receive adrenaline intramuscularly.

Figure 6: Scatter plot of depth to muscle from skin surface vs BMI (<30 kg

group). The vertical line represents the length of the needle (12.7 mm).

Figure 7: Scatter plot of depth to muscle from skin surface vs BMI (>30 kg

group). The vertical line represents the length of the needle (15.8 mm).


25

From these data there is no clear correlation between the muscle depth and the BMI in

this population of children. Also, not surprisingly, unlike the adult population, there is no

marked difference between the genders.

A further study was conducted by Bhalla et al21 in order to measure muscle depth and

evaluate predictors of auto-injector needle length inadequacy. This was a prospective

cross-sectional study of a sample of low acuity emergency department patients aged 18

to 55 years. Demographic data and thigh circumference were recorded and body mass

index (BMI) was calculated. Depth-to-muscle measurements of the vastus lateralus in a

standing position, with and without gentle pressure to simulate muscle compression that

occurs with correct auto-injector use were made using ultrasound.

Results

One hundred and twenty (120) subjects were enrolled with a mean BMI of 29.2 kg/m2.

Thirty-one percent (31%) of the sample were found to be failure risks (36/116;

confidence interval, 22.6%-39.5%) because these ED patients had compressed muscle

depths exceeding 15.9 mm.

Women were 6.4 times more likely than men to be a failure risk (54.4% vs 5% for men

failure rate; P <.001). Failures were more likely to be shorter, have a higher BMI, and

have larger thigh circumference (P <.001).

Unlike the study conducted by Song et al19, Bhalla et al found significant associations

between compressed muscle depth and BMI (r = 0.48; P b .001) as well as between

compressed muscle depth and thigh circumference (r =0.62; P b .001; Figs. 2 and 3

below).

5.3.1 Clinical Comment These three studies demonstrate that in adults and in many children a needle length of

14.3 mm and even the longer needle at 23 mm is not adequate to consistently ensure

delivery of an intramuscular injection. Only the study reported by Bhalla et al

demonstrated a correlation between BMI and skin to muscle distance. However, it may

be difficult to recommend the appropriate prescription for the individual patient should

devices with varying needle lengths be available.

Although the conclusion from these studies is that the currently available needle lengths

in AAIs are not adequate to ensure intramuscular injections in most patients this does


26

not take into account any projection of the adrenaline solution beyond the end of the

needle by the firing mechanism of the device.

5.4 Post-marketing data

The following relates to post-marketing data for the EpiPen® and Jext® AAIs. There are

no post-marketing data for Emerade AAI as it is only recently marketed.

5.4.1 Exposure data Since AAIs are used in case of emergency only, it is difficult to estimate the number of

doses actually administered as an unknown number of packages expire without having

been used. Of over 2.3 million devices sold each year it is estimated by one of the

manufacturers that only approximately 2% are actually used.

Currently, an EpiPen Patient Register Survey is on-going in Belgium initiated by the

manufacturer Meda Pharmaceuticals Ltd. One of the objectives is to evaluate how

EpiPen® is used by the patients in terms of purchase, therapeutic administration and

disposal. The survey started in March 2012 and about 400 patients are to be included.

End of the survey was planned for November 2013. Final results are expected for end of

the first quarter of 2014.

Auto-injector not working in a critical situation

Based on information provided in post marketing data, it has been estimated that ~40

units/million sold fail to activate. However it is often not possible to distinguish between

device failures and handling error. The auto-injectors are used by any age group and by

patients, caregivers or health care professionals in life threatening and high-stress

emergency situations.

Accidental injection

During a two-year period 128 cases (medically confirmed and consumer cases) of

accidental injections were reported. Of these 128 cases, 5 cases were additionally

classified as “auto-injector not working in a critical situation”.

This could have occurred due to people putting pressure on the wrong end of the device

leading in many cases to accidental injection into a finger. Designs and labelling of

devices have now improved to minimise this risk.

When the injection is not administered in the correct way, this misadministration puts

the patient suffering from anaphylaxis at significant risk. However backup measures – a

second auto-injector or emergency treatment in an ambulance or in the hospital – are

available and the overall number of these incidents is low.

Recently the design of the EpiPen auto-injector has been improved to make handling

easier and safer. The product information has also been updated to provide clearer

advice and there are additional training materials available from the MAH.

No or reduced effect from injection

Over a two-year period, for one AAI nineteen (19) cases (medically confirmed and

consumer cases) of “no or reduced effect from injection” were reported. Of these 19

cases, 5 cases were additionally classified as “auto-injector not working in a critical

situation”. Of the 14 that were classified as “no or reduced effect from injection” only, 12

were considered serious and 5 were associated with a fatal outcome.

The MAH for another AAI received 3 reports of lack of efficacy


27

Lack of efficacy reported to the MHRA

Figure 8: Reports from the UK Yellow Card system

Figure 9: The EudraVigilance Data Analysis System (EVDAS) data are shown

below. This database contains reports of adverse drug reactions (ADRs) from round the

world.


28

The rise in the number of cases in 2013 in the EVDAS data can be attributed to new

legislation being actioned which now requires companies to submit details of any reports

of lack of efficacy in addition to any reports of suspected side effects.

There is an apparent peak of reports around 2007 for which there is no explanation.

5.4.2 Clinical Comment: Lack of efficacy of the treatment of anaphylaxis with adrenaline may be due to several

factors such as delayed administration at the point when circulatory collapse is already

severe, the patient’s overall health, co-existing poorly controlled asthma, the amount of

allergen exposure, poor or slow adrenaline absorption (perhaps due to a subcutaneous

injection), and potentially, adrenaline resistance (for example due to concomitant beta-

blocker medication). Lack of an initial response may require a second injection

administered 5 to 15 minutes after the first. From the narratives of the cases reported

to the MHRA the majority report difficulty in activating the device or failure of the device

to activate. Many of the reports in the EVDAS database also relate to ‘device failure’.

However the failure may not be a quality issue but more one of lack of training of the

patient and/or carer who needs to be able to administer the adrenaline in an emergency

situation.

Although the percentage of devices reported to the MAH as possibly failing to deliver an

effective dose is small, in a life threatening situation such as acute anaphylaxis even one

failure may have fatal consequences. Of the 22 cases of ‘no or reduced effect’ from the

auto-injector that were reported, 5 were associated with a fatal outcome. The possibility

of providing two auto-injectors in a single pack has been proposed in order to facilitate

the recommendation that the patient should always carry two auto-injectors with them.

It is acknowledged that in some cases, a single injection is not sufficient to achieve a

response for a number of reasons, including severity of attack as well as the possibility

that a dose has not been effectively administered; a second injection may therefore be

needed. If the patient routinely carries two auto-injectors this will provide a safeguard.

6 Discussion and recommendations

The EpiPen® AAI was first licensed in the UK in 1996 for use in the treatment of acute

anaphylaxis by non-medically trained staff or patients.

The accepted optimal route of administration is by intramuscular injection into the

anterolateral aspect of the mid-thigh and this is supported by limited pharmacokinetic

data demonstrating that adrenaline by the intramuscular route is absorbed more quickly

(shorter Tmax) and gives a higher maximum plasma concentration (Cmax) than by the

subcutaneous route. This is important for a life-threatening condition such as

anaphylaxis where swift treatment decreases the risk of a fatal outcome. However the

data are sparse and mainly in healthy volunteers; no clinical trials have been conducted

in anaphylaxis because of practical and ethical considerations.

The recommendation that adrenaline is ideally administered by the intramuscular route

in the community setting is accepted.

The site of injection is accepted as the anterolateral aspect of the mid-thigh. The study

by Stecher et al20 in children suggested that the distal thigh would provide a shorter

distance to the muscle tissue but the risk of the needle hitting bone in this area is

greater. This could lead to the needle not deploying correctly or breaking in the tissue

or, theoretically, osteitis. It could be suggested that the distal thigh be recommended for

more overweight and obese patients but recommending different sites in different

situations could cause confusion. On balance it is accepted that the anterolateral aspect

of the mid-thigh continues to be the recommended site of injection.


29

The clinical data describing the skin to muscle distances in adult and child populations

support the concern that the needle length on AAIs is too short to be sure that the dose

of adrenaline is consistently delivered intramuscularly in all patients. This is a particular

problem in females in whom the skin to muscle distance is more frequently longer than

the exposed length of the needles of the currently available AAIs. Even the most recently

licensed auto-injector (Emerade) with an exposed needle length of 23 mm cannot ensure

an intramuscular injection in all patients.

The AAIs were originally developed for the military where the population would have

been mainly male and with less variability in weight and distribution of adipose (fatty)

tissue than in the current civilian population.

Unfortunately there appears to be no consistent correlation between BMI and skin to

muscle distance in males or females, adults or children so if a range of needle lengths

were available it would be difficult to provide any practical recommendations for the

prescription of the different devices.

It is not known how closely the studies measuring skin to muscle depth mimic the real

life use of an auto-injector. These devices are spring loaded and the manufacturers of

EpiPen and JEXT auto-injectors claim that the adrenaline is injected forcibly into the

muscle tissue. The only evidence to support this theory is non-clinical with the use of

porcine or ballistic gel models and these studies do provide some reassurance that the

adrenaline does penetrate beyond the exposed needle length of 14.3 mm and can

penetrate tissue up to depths of 15 mm to 26 mm. This however would still not be

sufficient to reach the muscle tissue in a substantial number of adults and children

according to the studies reported by Song and Stecher19,20.

A pressurised liquid will follow the path of least resistance. The resistance offered by a

uniform block of ballistic gelatine is useful to provide a qualitative comparison tool to

estimate the performance characteristics of different auto-injector products. However

mammalian limb tissue is a composite of different strata from the skin surface to sub

cutaneous adipose tissue to the muscle layer and other less permeable structures are

present within and between each discrete layer, such as blood vessels and connective

tissue forming a sheath-like covering over the muscle surface. The relative resistance of

each physiological layer to needle penetration and solution penetration/diffusion is not

known but is likely determined by multiple tissue architectural properties and

vascularity.

The Emerade auto-injector range has only recently been marketed (December 2013) in

some EU markets but there are no comparative studies in the public domain involving

this product versus JEXT and EpiPen auto-injectors. The selection of a 25 mm needle

length (23 mm exposed needle length) in this product was based on recommendations

(UK Resuscitation Guidelines 2008) for manual intramuscular injections. However even

this length of needle will not deliver an intramuscular injection to all patients and it is not

known if a 25 mm needle length is the optimum for an auto-injector.

From the post-marketing data it is demonstrated that in a small number of instances the

current AAIs are either failing to activate or failing to deliver an effective dose. The

reasons for this are uncertain. In a 2-year period between 2011 and 2013, five (5) such

cases were associated with a fatal outcome. It is also possible that in some cases even

when delivered appropriately that the severity of the anaphylactic reaction is such that

adrenaline will not be effective. Research is required to understand the factors that affect

severity but is beyond the remit of this review.

In order to ensure that all patients receive an intramuscular dose of adrenaline in the

case of an acute anaphylactic reaction it is recommended that the needle length of all

AAIs should be reviewed and the licence holders (MAHs) requested to provide data to

demonstrate that an intramuscular injection is delivered consistently.


30

7 Independent Advice Received

This review was presented to the Chemistry, Pharmacy and Standards Expert Advisory

Group and the Commission on Human Medicines; panels of independent experts who

advise the Licensing Authority.

They advised on improvements to the information for healthcare professionals and for

patients on the management of an anaphylaxis episode, they proposed that

manufacturers should conduct studies to evaluate injection delivery and should improve

the quality standards for AAIs. The full advice is summarised below:

1. In view of information that indicates that AAIs will not deliver an intramuscular

injection in all patients the needle length for all AAIs should be reviewed by the

manufacturers and increased, if necessary, to ensure that an intramuscular

injection is delivered to a greater proportion of patients. This is of particular

importance in patients with a high BMI or those with increased skin to muscle

distance.

2. MAHs should include penetration and absorption studies using stable isotopes or

other traceable markers and suitable imaging techniques and a range of patients

to demonstrate the characteristics of patients that limit the likelihood of

intramuscular injection. Currently approved AAI MAHs should submit such

studies to the relevant competent authority. The design of such studies should

reflect the technique for administration with an exact replica of the commercial

product including any features deployed automatically after solution injection in

order to prevent needle stick injuries. Pharmacokinetic measurements should be

included if feasible. The resulting data should be reflected in the SmPC.

3. Although intramuscular injection cannot be guaranteed for all patients, the

recommended site of injection should remain unchanged as the anterolateral

aspect of the mid-thigh until evidence is presented from penetration and

absorption studies that an alternative injection route is superior and does not

present additional risks.

4. In the absence of evidence that the devices can deliver adrenaline

intramuscularly to all patients, that the SmPC for all AAIs should be amended to

state that “Successful intramuscular (IM) administration is dependent on the skin

to muscle distance (SMTD) and in certain cases the administration may be

subcutaneous. Care should be taken to ensure IM administration as far as

possible”.

5. The outcome of this review on AAIs should be communicated to practitioners via

a DHCP letter and an article in Drug Safety Update (DSU). Consideration should

be given to the possibility of including on the MHRA website links to other

websites that give helpful information on the use of AAIs (e.g videos).

Consideration should also be given to informing the Ambulance Service of the

outcome of this review.

6. Advice to the patient and carers and healthcare professionals in the PIL should be

amended to:

a. Ensure the instructions for use are clear and clearly illustrated. Reference

to websites with video instruction on device use should be included.

b. Reinforce the instruction to dial 999 immediately after use of an AAI

c. Advise that the patient should not be left unattended and if alone should

seek assistance immediately after using the AAI.


31

d. Advise that the optimum position for the patient while waiting for medical

assistance is lying in a head down position to maintain effective circulation

7. Those food allergy sufferers with co-existent allergic asthma should be informed

that exposure to other allergens could result in increased susceptibility to an

anaphylactic reaction. This should be reflected in the SmPC.

8. Patient education with respect to their condition and training in the use of their

prescribed devices should be reviewed to ensure that MAHs provide such

information to all users of AAIs.

Other points for consideration

9. The finished product specifications for all AAIs should be reviewed with a view to

including or updating tests and their respective limits for functional performance.

10. The marketing authorisations for auto-injectors should be critically reviewed with

a view to updating the in-process controls (IPCs) in place to ensure they are

suitable for the delivery device assembly phase.

11. MAH’s should submit a summary of:

(a) The design and qualification of the delivery system i.e. device

development history

(b) A summary of identified critical failure modes for the delivery system

(c) Updated finished product specifications including appropriate functional

tests with sample size tested per batch and the acceptable quality level

AQL for each test

(d) An account of how the essential requirements of Annex 1 of the Directive

93/42/EC on Medical Devices are met.

12. An appropriate ISO standard should be developed specifically for AAIs.

13. The excipients guideline regarding drug product labelling and patient leaflet

information should be reviewed and amended to include related allergens to

peanuts/tree nuts. Patients may be unaware of the importance of potential cross-

reactivity to related legumes for example fenugreek, chick pea and lupin flour.

14. MAHs should be encouraged to develop a 500 µg strength AAI.

AAI products are available in the UK and throughout Europe and have been authorised

by either an independent national procedure or a European regulatory procedure.

Consequently, the recommendations arising from this review are currently being taken

forward for consideration at a European level by consulting the appropriate European

scientific committees. This will enable the different AAIs authorised throughout the

European Community to benefit from this review.


32

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http://www.nhs.uk/news/2013/02February/Pages/Latest-obesity-stats-for-England-are-alarming-reading.aspx

http://www.nhs.uk/news/2013/02February/Pages/Latest-obesity-stats-for-England-are-alarming-reading.aspx

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