A PRACTICAL REVIEW OF INSULIN PEN DEVICES
`*Teresa L. Pearson
`
`Director; Clinical Services at Innovative Health Care Designs, LLC, Minneapolis, Minnesota, USA
`*Correspondence to tpearson9@comcast.net
`
`Disclosure: No potential conflict of interest.
`Received: 06.05.14 Accepted: 21.07.14
`Citation: EMJ Diabet. 2014;2:58-64.
`
`ABSTRACT
`
`Since the advent of insulin pens in 1985, there have been ongoing improvements providing several
`advantages over the traditional vial and syringe method of insulin delivery. In recent years, pens have
`become increasingly user-friendly, and some models are highly intuitive to use, requiring little or no
`instruction. Despite this progress, there remains to be disparity in access to insulin pens to people with
`diabetes in various countries . There is a need for improved awareness of the benefits of insulin pens among
`healthcare professionals. Continual advances have been made to address patient needs such as improved
`technology to make them easier to use; less painful; more discreet and convenient; and more accuracy for
`small doses of insulin, as well as the incorporation of a memory function , all contribute to an insulin delivery
`device that allows the patient to better manage their diabetes anytime and anyplace, without the bulk
`and challenge of carrying a v ial and syringe. These advances have resulted in increased patient satisfaction
`with insulin pens and most importantly, all of these benefits improve adherence and result in improved
`clinical outcomes . This review highlights these benefits of insulin pen use and presents the issues to be
`considered when helping patients decide on the insulin pen that will best suit their needs.
`
`Keywords: Type 2 diabetes, insulin, insulin pen, practical use.
`
`INTRODUCTION
`
`For over 50 years, vial and syringe was the only
`method of delivering insulin. While life-saving, it
`was crude at best, and ever since its discovery
`much effort has gone into improving the insulin.
`Initially, insulin was used primarily for people with
`Type 1 diabetes mellitus (TlDM), but research has
`shown that most people with Type 2 diabetes
`mellitus (T2DM) will also require insulin to maintain
`HbAlc at levels recommended by the American
`Diabetes Association/European Association for the
`Study of Diabetes.1•2 While insulins have improved,
`they still require an injection. Additional effort has
`gone into finding an adequate delivery method; in
`the 1970s insulin pumps became available, and
`in 1985, the first insulin pen was introduced. 3 This
`review will focus on insulin pens.
`
`Insulin pens have been shown to have several
`advantages over the traditional vial and syringe
`method of insulin delivery,
`including
`improved
`
`patient satisfaction and adherence, greater ease of
`use, and superior dosing accuracy. 4-10 About two(cid:173)
`thirds of insulin prescriptions in Europe and about
`three-quarters in Japan are for pen devices9 while
`only 15% of patients are thought to use insulin pens
`in the US.11 According to the recent report, Access
`to Quality Medicines and Medical Devices
`for
`Diabetes Care in Europe,12 there remains a great
`disparity in access to insulin pens across Europe.
`While insulin seems to be a covered benefit in
`most countries, use of insulin pens varies more
`widely and may, in some cases, be restricted to
`people with TlDM and/or to children under the age
`of 18 years.
`
`In spite of the convenience and greater ease of use,
`cost may be an issue. The greater cost of insulin
`cartridges and prefilled insulin pens, compared with
`insulin vials, can impact the acceptance of insulin
`pens as a viable option for people with T2DM.
`For some patients, the cost may be the same
`depending on coverage, and in fact, if they have
`
`58
`
`DIABETES • October 2014
`
`EUROPEAN MEDICAL JOURNAL
`
`Sanofi Exhibit 2114.001
`Mylan v. Sanofi
`IPR2018-01675
`
`

`

`preference for insulin pens versus vial and syringe
`was statistically significant 18 citing convenience,
`ease of use - including assembly - injection, and
`confidence in the dosage. The visual and auditory
`cues from the pen contribute to the increased
`level of confidence. Two open-label, randomised,
`crossover studies found that patients have greater
`dose confidence with a prefilled insulin pen over
`a vial and syringe. 6·20 In the first of these studies,
`73% of patients felt more confident in the accuracy
`of
`the
`insulin dose delivered with
`the pen,
`compared with 19% for the vial/syringe. 6
`In the
`other study, 88% of patients had greater
`confidence that they were taking the right dose
`with the pen than with the vial and syringe. 20
`The vial and syringe do not offer this level of
`confidence and, as eyesight and dexterity decrease
`with age, the vial and syringe become much more
`challenging to handle.
`
`The vial and syringe has many disadvantages
`including fear of injections, poor dose accuracy,
`lack of social acceptance,
`lengthy
`training
`time, and difficulty of transportation. 21 These are
`potential barriers
`to
`insulin
`therapy,
`impacting
`flexibility, and affecting adherence to treatment,
`thus negatively
`impacting
`the achievement of
`euglycaemia. 22·23 Insulin pens were designed to help
`address these issues, with resulting improvements
`in portability, dosing accuracy, mealtime flexibility,
`and convenience of delivery.7-9·24 Increased patient
`preference,
`treatment satisfaction, and quality
`of
`life have been
`reported
`for pen devices
`compared with the vial and syringe.6
`26 Other
`10
`25
`·
`·
`·
`studies have shown that pen devices are associated
`with
`improved costs of care,
`less
`reported
`injection pain,
`and
`improved
`patient
`self(cid:173)
`management behaviours, including adherence to
`treatment, compared with the vial and syringe.4·27-29
`Many of these benefits make insulin pens especially
`beneficial to people with visual
`impairment or
`reduced dexterity.
`
`USING AN INSULIN PEN
`
`insulin analogue vials,
`use, most
`in
`Once
`cartridges, and prefilled pens must be discarded
`after 28 days. The exceptions to the 28-day discard
`date is insulin detemir (Levemir'')), which can be
`kept for up to 42 days once in use. Two types of
`insulin pens are available: prefilled disposable
`pens and refillable pens. 30-46 Most insulin pens are
`proprietary devices, and are designed
`to work
`with specific insulins from the same manufacturer.
`
`one co-payment per box of pens, the cost to the
`patient may actually be less per unit of insulin. If
`this seems to be an issue it is important to consider
`that despite the higher unit cost of insulin in pen
`devices versus vials, several studies have found that
`overall diabetes-related treatment costs are lower
`with pen devices than with vial and syringe.3A,,,
`Increased adherence with the use of insulin pens
`has been demonstrated and further emphasises the
`need to consider them as an option when initiating
`insulin. 5
`3 Therefore, in theory, costs should not
`11
`•
`prevent the use of these devices.
`
`•1
`
`PERSPECTIVES
`
`Healthcare Providers
`
`Despite the many advantages of insulin pens, there
`is a lack of awareness among healthcare providers
`of those advantages which have been cited as a
`possible reason for low adoption rates in some
`countries.14
`5 It has been shown that the physician
`plays a significant role in the patient's acceptance
`of the insulin pen as an option.16 In fact, the most
`powerful predictor of pen use was found to be
`physician recommendation. This emphasises the
`importance of the role of the physician in this
`self-care practice. It also emphasises the need to
`ensure that physicians are aware of insulin pens
`and how
`they can benefit patient adherence
`resulting in better outcomes. Nurses and diabetes
`educators should also become familiar with the
`various insulin pens available so they can discuss
`the potential benefits with
`their patients and
`offer advice on which device best meets their
`patients' needs. Nurses, diabetes educators, and
`pharmacists have particularly important roles in
`educating patients on how to use insulin pens.
`Incorrect use can affect pen performance, and
`thus,
`the accuracy of the administered dose.17
`Healthcare professionals have been found to be
`strongly supportive of the use of insulin pens and
`they find them to be easier to handle, preferable
`to use, and more accurate in delivering insulin
`doses as compared to vial and syringe.18
`9
`
`•1
`
`•1
`
`Patients
`
`Patient perception has also been found to be an
`important predictor of pen use. A vial and syringe
`is clumsy to say the least but, over time, most
`people adapt to it quite well. The insulin pen, on
`the other hand, can easily fit into a pocket or purse,
`is durable, and much more discreet to use. In an
`open-label, randomised, multicentre study, patient
`
`DIABETES • October 2014
`
`EUROPEAN MEDICAL JOURNAL
`
`59
`
`Sanofi Exhibit 2114.002
`Mylan v. Sanofi
`IPR2018-01675
`
`

`

`Insulin cartridges or prefilled disposable pens are
`available
`for all
`insulin analogues (rapid-acting,
`long-acting, ultra-long-acting, and premixed) and
`for most human insulins. Most currently-available
`pens are either prefilled with 3 ml of insulin or are
`refillable pens that are designed for use with 3 ml
`insulin cartridges. Ul00 insulin is used
`in most
`devices providing 300 units of insulin per cartridge
`or prefilled device. However,
`insulin degludec
`(Tresiba@)
`is also available
`in U200 strength,
`providing 600 units of insulin per device. The dose
`counter window for degludec will show the number
`of units, irrespective of the strength, so no dose
`conversion is required. 47
`
`insulin pen devices, pen needles are
`For all
`purchased separately and may require a separate
`prescription. Pen needles are available from various
`manufacturers and come in gauges ranging from
`29 G to 32 G, and in lengths from 4 to 12.7 mm. 46
`More recent developments have resulted in the
`introduction of safety needles with protective
`shields that not only reduce needle-stick injuries
`but may also allay patient anxieties about needle
`use. 48 Health professionals are also being advised
`to use these safety needles in accordance with
`the safety recommendations of the EU Council
`Directive 2010/32/EU. 49 As shorter needles have
`become available, the question of how to select
`the appropriate needle length has come up. For
`the average adult, 4, 5, and 6 mm needles are
`appropriate and can be injected at a 90-degree
`angle. For
`the overweight or obese patient,
`research shows that needle length should not be
`a concern. 50-52 According
`to
`the First
`Injection
`Technique (FIT) Guidelines,52
`there really
`is no
`reason, even for very obese patients, to use a needle
`longer than 8 mm.
`
`For very lean patients, it is recommended to raise
`a fold of skin and inject at an angle to prevent a
`possible intramuscular (IM) injection, especially if
`using an 8 mm needle or greater.50
`53 For children,
`52
`·
`·
`6 mm or shorter needles are recommended. A
`4 mm needle may be injected at a 90-degree
`angle while a 5 or 6 mm needle will require a lifted
`skin-fold to avoid possible IM injection. If an 8 mm
`needle is all that is available for a child it is essential
`to do a lifted skin-fold. Therefore, needle length
`should not be a concern but proper injection
`technique should be a part of the training for both
`insulin pens and vial and syringe use.50
`54 The use
`·
`of the FIT Guidelines is an excellent resource if any
`questions remain.
`
`ASSISTING YOUR PATIENTS
`
`the
`Healthcare practitioners should work with
`patient to select the insulin pen that is most suited
`to their insulin regimen,
`lifestyle, and personal
`preferences. A
`regimen
`that causes
`the
`least
`disruption to the patient's lifestyle is much more
`likely to be used. Pens are more than just a matter
`of convenience, though; their ease of use allows
`patients to take better care of their own condition.16
`Patients across all age groups often have concerns
`regarding
`insulin
`therapy, and many of
`these
`concerns can be effectively addressed
`through
`choosing an insulin pen.55 In particular, adolescents
`and children may find insulin pens more socially
`acceptable because of the pens' greater portability
`and discreetness. The NovoPen'') Junior,
`the
`HumaPen'') Luxura™ HD, and the NovoPenEcho''>,
`have been developed specifically for use in children
`and others requiring
`the ability to adjust their
`insulin in half-unit increments.36
`
`For people with visual impairment there are some
`advantages to using an insulin pen over a vial and
`syringe. For example, the numbers on insulin pens
`are larger than those on syringes, making it easier
`to select the correct dose. The audible clicks notify
`the user of the number of units injected, as well
`as when the insulin has been fully injected. And
`patients with impaired manual dexterity may find
`insulin pens easier to use because it eliminates
`the process of drawing up the insulin from the vial
`with the syringe. There have also been advances
`to improve needle safety and potentially reduce
`any anxiety about needles. The use of safety
`needles has been shown to reduce the incidence
`of needle-stick injuries among nurses, a common
`occupational hazard. 48A9 While the safety needles
`are not readily available outside
`the hospital
`setting, they may be a consideration for secondary
`caregivers
`to avoid needle-stick
`injuries. The
`safety pen needles conceal the needle, so could
`potentially be used
`to reduce needle anxiety.
`There are injection aids for insulin pens that also
`conceal
`the needle: NeedleAid™ and NovoPen@
`3 PenMate''). Concealing
`the needle using
`the
`NovoPen 3 PenMate has been shown to reduce
`pain perception.53 The NeedleAid is an attachment
`designed to help visually impaired patients self(cid:173)
`administer insulin.
`
`Limitations of Insulin Pens
`
`Insulin pens are not without their limitations and it
`is important that patients and healthcare workers
`
`60
`
`DIABETES • October 2014
`
`EUROPEAN MEDICAL JOURNAL
`
`Sanofi Exhibit 2114.003
`Mylan v. Sanofi
`IPR2018-01675
`
`

`

`are aware of these to ensure the best outcomes.
`The maximum dose with most insulin pens is 60-
`80 units, but with a syringe it is 100 units. Patients
`cannot mix their own insulin formulations for use
`in a single injection given by insulin pen. Despite
`their ease of use, there have been some cases of
`malfunction reported in the literature.57 Therefore,
`patients using an insulin pen should have a backup
`pen with them at all times.
`
`Choosing Between Insulin Pens
`
`The choice of insulin pen will be, to a large extent,
`determined by the choice of insulin, as particular
`insulins are specific to certain makes of insulin
`pen. Anecdotally, many patients prefer prefilled
`disposable pens
`to
`refillable pens, because
`disposable pens are typically lighter and smaller,
`and are also simpler
`to use, as
`there
`is no
`requirement
`to
`load new
`insulin cartridges.
`However, some refillable pens have features, such
`as a memory function or the ability to dial in half(cid:173)
`unit increments that are not available with prefilled
`pens. This may be
`important in children or in
`those sensitive to insulin. Some insulin pens have
`a larger maximum dose (80 units) than the other
`insulin pens, and
`therefore, may be preferable
`in patients who take large doses of insulin.58
`
`the push(cid:173)
`improved
`technologies have
`Newer
`button mechanisms to reduce injection force while
`
`60 and still retaining
`maintaining dose accuracy59
`•
`the ability to dial back. This may be particularly
`suitable for patients with impaired manual dexterity
`or conditions such as arthritis. Colour coding has
`also been incorporated into several of the pens to
`distinguish between insulin types. Some pens now
`supply auditory feedback to assist patients with
`T2DM who may suffer from visual impairments and/
`or manual dexterity.61 Several insulin pens provide a
`confirmatory click when the correct dose has been
`delivered. Memory is an added feature that is now
`available. In a study comparing an insulin pen with
`memory function to a pen without memory function
`it was
`found
`that significantly more patients
`preferred the memory function, indicating that it
`gave them more confidence about when they last
`injected, how much insulin they injected, and in
`improving their diabetes management.62
`
`How to Use an Insulin Pen
`
`the patient and physician
`In a study assessing
`acceptability of a prefilled insulin pen device, 88%
`of the 33 physicians who completed questionnaires
`at the end of the study said it took less time to
`teach patients to use a pen, and 73% thought that
`it took less time to initiate insulin therapy with the
`pen, compared with a vial and syringe. 63 The basic
`steps in teaching patients how to use an insulin
`pen are shown in Figure 1.
`
`1. Ensure insulin is at room temperature.
`2. If using a pre-mixed insulin, first gently roll the insulin pen ten times and then
`gently invert ten times (not shaken) to resuspend the insulin. The solution should be a
`milky white.
`3. Attach the needle to the pen.
`4. Prime the insulin pen (also referred to as 'doing a safety test' or 'doing an air shot'a).
`5. Select the dose by dialling.
`6. Hold the pen gently against the skin.
`7. Inject the dose by depressing the button, holding it in position in the skin for at least
`10 seconds.b
`8. After the injection, remove the needle from the pen and replace the cover on the pen.
`
`Figure 1: The eight steps of insulin pen use.
`a This is performed by instructing the patient to dial up 2 units and to inject these units into the air.
`b The button needs to be pressed and the needle held in the skin for 5-70 seconds to ensure complete
`delivery of insulin dose. The easiest way to ensure this is to instruct the patient to count to five (or ten if
`using the SoloSTAR"') before removing the needle.
`
`DIABETES • October 2014
`
`EUROPEAN MEDICAL JOURNAL
`
`61
`
`Sanofi Exhibit 2114.004
`Mylan v. Sanofi
`IPR2018-01675
`
`

`

`Because it is possible for insulin to still be flowing
`out of the pen for several seconds after the button
`has been fully depressed,15 to prevent any leakage
`of insulin, it is important to instruct patients to hold
`the pen in place with the button pressed in for 5-10
`seconds (the exact time varies between the various
`insulin pens and is described in their respective
`package inserts).38·39A1A3 The easiest way to ensure
`this is to instruct the patient to count to five (or
`ten, if using the SoloSTAR'')) before removing the
`needle. If the patient is using >50 units of insulin
`per dose, a good rule of thumb might be to instruct
`them to count to ten regardless of the pen they are
`using to ensure complete absorption of the insulin.
`
`If patients are using a pen that contains neutral
`protamine Hagedorn insulin, or an insulin premix,
`it is
`important that they gently mix the insulin
`by carefully rolling or tipping the pen
`for the
`recommended number of times according to the
`package insert to ensure even mixing of the insulin
`suspension before attaching the needle. Emphasise
`this even for patients who have used the vial and
`syringe method, as vials have a greater diameter
`than cartridges and so need to be tipped less
`often.64 Pens must be primed before each injection,
`and the needle removed immediately after each
`use.15 This is performed by instructing the patient
`to dial up 2 units and inject these units into the air
`(also called an 'airshot'). This will displace any air in
`the needle and ensure an accurate injection.
`
`Insulin pens should never be used by more than
`one individual, even if the pen needle is changed,
`because sharing of insulin pens can
`result
`in
`transmission of hepatitis viruses, HIV, or other
`blood-borne pathogens. Prior
`to first use,
`the
`insulin cartridge or pen should be stored in the
`refrigerator. The pen should be warmed to room
`temperature (30 °C) for most insulin analogues
`before use. After the first use, the pen should remain
`at room temperature ( <30 °C) in order to avoid
`producing air bubbles, which can form when the
`pen mechanism and the insulin expand/contract
`during a temperature change. As with all types of
`insulin, pens in use should be kept from extremes
`in temperature; keep them as close as possible
`to room temperature (<30 °C) at all times. Insulin
`glulisine (Apidra'')) has a narrower temperature
`range for storage than the other insulin analogues;
`
`once in use, insulin glulisine must be stored <25 °c.
`In some buildings,
`for example schools, air
`conditioning is turned off at night, which may result
`in the room temperature rising above 25 °c or 30
`0 c.
`If a change
`in
`temperature
`is anticipated,
`insulated storage packs are recommended. If a
`patient is switching from one type of insulin pen
`to another, it is important to check whether the
`procedure used for the previous pen also applies to
`the new pen.
`
`Clinical Studies Comparing Insulin Pens
`
`Several studies have investigated dosing accuracy
`between pens. Generally, dosing accuracy
`is
`good.56·65-70
`Insulin pens also differ in the force
`required to inject an insulin dose, and this feature
`has been investigated in severa I studies.56·68•71-73 In
`general, differences in the injection force between
`insulin pens are relatively small.59
`72 Data on ease of
`•
`use and patient preference for different types of
`pen have been assessed in a number of clinical
`studies and in clinical practice. Many open-label
`studies have obtained
`information on patient
`preference, and the results show that newer designs
`of pens are
`increasingly user-friendly, and are
`intuitive to use, requiring little or no instruction.51,74-ao
`
`CONCLUSIONS
`
`In conclusion, insulin pens offer many benefits to
`people with diabetes who use insulin. They provide
`an opportunity to select a delivery device that will
`meet the specific needs of the patient. Insulin pens
`are increasingly more user-friendly requiring little
`or no instruction. For the healthcare professional,
`this means that teaching a patient how to use an
`insulin pen, along with the importance of accurate
`dosing, can be done quickly and efficiently in a
`busy clinical setting. In spite of the ease of use
`with insulin pens, educating patients about the
`practical aspects and purpose of insulin in general
`remains important. It is important that healthcare
`providers are aware of the benefits of insulin pens
`and the role they play in increasing adherence.
`It
`is
`important
`for healthcare professionals
`to
`keep up-to-date on the latest developments in
`pen devices and
`teaching approaches in order
`to assist
`their patients
`in making
`informed,
`individualised decisions.
`
`62
`
`DIABETES • October 2014
`
`EUROPEAN MEDICAL JOURNAL
`
`Sanofi Exhibit 2114.005
`Mylan v. Sanofi
`IPR2018-01675
`
`

`

`REFERENCES
`
`lnzucchi SE et al. Management of
`1.
`hyperglycemia
`in
`type 2 diabetes: a
`patient-centered
`approach:
`position
`statement of
`the American Diabetes
`Association (ADA) and
`the European
`Association for the Study of Diabetes
`(EASD). Diabetes Care.
`2012;35(6):
`1364-79.
`2. UK Prospective Diabetes Study
`(UKPDS) Group. Intensive blood-glucose
`control with sulphonylureas or insulin
`compared with conventional treatment
`and risk of complications in patients with
`type 2 diabetes (UKPDS 33). Lancet.
`1998;352(9131):837-53.
`3. Rex J et al. A review of 20 years'
`experience with
`the NovoPen
`family
`of insulin
`injection devices. Clin Drug
`lnvestig. 2006;26(7):367-401.
`4. Cobden D et al. Health outcomes and
`economic impact of therapy conversion
`to a biphasic insulin analog pen among
`privately insured patients with type 2
`diabetes mellitus.
`Pharmacotherapy.
`2007;27(7):948-62.
`5. Lee WC et al. Medication adherence and
`the associated health-economic impact
`among patients with type 2 diabetes
`mellitus converting to insulin pen therapy:
`an analysis of third-party managed care
`claims data. Clin Ther. 2006;28(10):
`1712-25.
`6. Korytkowski M et al. A multicenter,
`randomized, open-label, comparative,
`two-period crossover trial of preference,
`efficacy, and safety profiles of a prefilled,
`disposable pen and conventional vial/
`syringe for insulin injection in patients
`with type 1 or 2 diabetes mellitus. Clin
`Ther. 2003;25(11):2836-48.
`7. Keith K et al. Accuracy and precision
`of low-dose insulin administration using
`syringes, pen injectors, and a pump. Clin
`Pediatr (Phila). 2004;43(1):69-74.
`8. Lteif AN, Schwenk WF. Accuracy of
`pen injectors versus insulin syringes in
`children with type 1 diabetes. Diabetes
`Care. 1999;22(1):137-40.
`9. Graff MR, Mcclanahan MA. Assessment
`by patients with diabetes mellitus of two
`insulin pen delivery systems versus a vial
`and syringe. Clin Ther. 1998;20(3):486-96.
`10. Kadiri A et al. Comparison of NovoPen
`3 and syringes/vials in the acceptance of
`insulin therapy in NIDDM patients with
`secondary failure to oral hypoglycaemic
`agents. Diabetes Res Clin Pract.
`1998;41(1):15-23.
`11. Pawaskar MD et al. Health care costs
`and medication adherence associated
`with initiation of insulin pen therapy in
`medicaid-enrolled patients with
`type
`2 diabetes: a retrospective database
`
`analysis. Clin Ther. 2007;29 Spec No:
`1294-305.
`to quality medicines and
`12. Access
`medical devices
`for diabetes care
`in
`Europe. International Diabetes Federation
`Europe. August 2013.
`13. Shelmet J et al. Preference and
`resource utilization in elderly patients:
`lnnoLet versus vial/syringe. Diabetes Res
`Clin Pract. 2004;63(1):27-35.
`14. Da Costa S et al. A comparison of
`insulin pen use in the United States and
`the United Kingdom. Diabetes Educ.
`2002;28(1):52-6, 59-60.
`15. Magnotti MA, Rayfield EJ. An update
`on
`insulin
`injection devices.
`Insulin.
`2007;2( 4 ):173-81.
`16. Rubin RR, Peyrot M. Factors affecting
`use of insulin pens by patients with type
`2 diabetes. Diabetes Care. 2008;31(3):
`430-2.
`injection
`Insulin pen
`17. Thurman JE.
`devices for management of patients with
`type 2 diabetes: considerations based on
`an endocrinologist's practical experience
`in
`the United States. Endocr Pract.
`2007;13(6):672-8.
`18. Ahmann A et al. Comparing patient
`preferences and healthcare provider
`recommendations with the pen versus
`vial-and-syringe
`insulin
`delivery
`in
`patients with type 2 diabetes. Diabetes
`Technol Ther. 2014;16(2):76-83.
`19. Asakura T. Comparison of clinically
`relevant technical attributes of five insulin
`injection pens. J Diabetes Sci Technol.
`2011;5(5):1203-9.
`20.
`lgnaut DA et al. Comparative
`device assessments: Humalog KwikPen
`compared with vial and syringe and
`FlexPen. Diabetes Educ. 2009;35(5):
`789-98.
`21. Pearson TL. Practical aspects of insulin
`pen devices. J Diabetes Sci Technol.
`2010;4(3):522-31.
`22. Peyrot M et al. Resistance to insulin
`therapy among patients and providers:
`results of the cross-national Diabetes
`Attitudes, Wishes, and Needs (DAWN)
`study. Diabetes Care. 2005;28(11):2673-9.
`23. Summers KH et al. Preference for
`insulin delivery systems among current
`insulin users and nonusers. Clin Ther.
`2004;26(9):1498-505.
`24. Sommavilla B et al. Safety, simplicity
`and convenience of a modified prefilled
`insulin pen. Expert Opin Pharmacother.
`2008;9(13):2223-32.
`25. Lee IT et al. Improvement in health(cid:173)
`related quality of life,
`independent of
`fasting glucose concentration, via insulin
`pen device in diabetic patients. J Eval Clin
`
`DIABETES • October 2014
`
`Pract. 2009;15( 4 ):699-703.
`Insulin-pen
`26. Hbrnquist JO et al.
`treatment, quality of life and metabolic
`control:
`retrospective
`intra-group
`evaluations. Diabetes Res Clin Pract.
`1990;10(3):221-30.
`27. Davis EM et al. Nurse satisfaction
`using insulin pens in hospitalized patients.
`Diabetes Educ. 2009;35(5):799-809.
`28. McKay M et al. A comparison of insulin
`injection needles on patients' perceptions
`of pain, handling, and acceptability: a
`randomized, open-label, crossover study
`in subjects with diabetes. Diabetes
`Technol Ther. 2009;11(3):195-201.
`29. Davis EM et al. Patient satisfaction
`and
`costs
`associated with
`insulin
`administered by pen device or syringe
`during hospitalization. Am J Health Syst
`Pharm. 2008;65(14):1347-57.
`30. Eli Lilly. HumaPen® LUXURA™ HD
`insulin delivery device user manual (11
`November, 2006).
`31. Eli Lilly. HumaPen® MEMOIR™ user
`manual (revised 20 November, 2006).
`32. Eli Lilly. KwikPen™ disposable insulin
`delivery device user manual.
`33. Eli Lilly. Humalog insulin lispro injection:
`insulin
`pens.
`http://www.humalog.
`com/Pag es/Results.aspx?k= I nsu Ii n%20
`pens&s=Humalog. Accessed:
`31
`July,
`2009.
`34. Eli Lilly. Prefilled insulin delivery device
`user manual. Revised 17 April, 2009.
`35. Novo Nordisk. NovoPen® 3 PenMate:
`instruction manual. 1999.
`36. Novo Nordisk. NovoPen® Junior
`instructions for use. 2001.
`37. Novo Nordisk. FlexPen®:
`delivery that goes with you. 2014.
`38. Novo Nordisk. Insulin pens. http://
`www.novonordisk.com/d i a betes_ca re/
`insu I in_pens_a nd_need I es/d efau It. asp.
`2014.
`39. Novo Nordisk. NovoLog® FlexPen®.
`http ://www. n ovol og .com/devices(cid:173)
`flexpen.asp?s=ds&h=150. 2014.
`40. Novo Nordisk. Levemir® FlexPen®.
`http://www.levemir.com/. 2014.
`insulin
`41. Owen Mumford. Autopen:
`delivery pens (revised April 2006).
`42. Owen Mumford. Autopen®: simplifying
`insulin injections. 2009.
`to know
`43. Sanofi-Aventis. Get
`Lantus® SoloSTAR® pen. 2009.
`44. Sanofi-Aventis. Your guide to the
`Lantus® SoloStar® insulin pen. 2009.
`45. Sanofi-Aventis. OptiClik®. http://www.
`opticl ik.com/. 2009.
`46. BD. BD
`pen
`
`insulin
`
`the
`
`needles. http://
`
`EUROPEAN MEDICAL JOURNAL
`
`63
`
`Sanofi Exhibit 2114.006
`Mylan v. Sanofi
`IPR2018-01675
`
`

`

`www. b d. com/us/diabetes/page.
`aspx?cat=7002&id=10257. 2009.
`47. National Institute for Health and Care
`Excellence. ESNM24: Type 1 diabetes:
`insulin degludec [http://publications.nice.
`org.uk/esn m24-type-1-d iabetes-insul in(cid:173)
`degludec-esnm24. 2013. Accessed: 18
`July, 2014.
`48. American Diabetes Association. 2013
`Resource Guide. Diabetes Forecast.
`49. European Agency for Safety and
`Health at Work. Directive 2010/32/EU
`- prevention from sharp injuries in the
`hospital and healthcare sector. 2010.
`Accessed: 17 July, 2014.
`50. The Forum for Injection Technique.
`Diabetes care in the UK: the first UK
`injection
`technique
`recommendations
`2nd edition. 2011. Accessed: 18 July, 2014.
`51. Gibney MA et
`al. Skin
`and
`subcutaneous adipose
`layer
`thickness
`in adults with diabetes at sites used for
`insulin injections: implications for needle
`length recommendations. Curr Med Res
`Opin. 2010;26(6):1519-30.
`52. Hirsch LJ et al. Comparative glycemic
`control, safety and patient ratings for
`a new 4mm x 32G insulin pen needle in
`adults with diabetes. Curr Med Res Opin.
`2010;26(6):1531-41.
`53. Hofman PL et al. Defining the ideal
`injection techniques when using 5-mm
`needles in children and adults. Diabetes
`Care. 2010;33(9):1940-4.
`54. Siminerio L et al. Strategies
`for
`insulin
`injection
`therapy
`in diabetes
`self-management. A White Paper of
`the American Association of Diabetes
`Educators (AADE). 2011.
`55. Funnell MM. Overcoming barriers to
`the initiation of insulin therapy. Clin Diab.
`2007;25(1):36-8.
`56. Dig las Jet al. Reduced pain perception
`with Pen Mate™ an automatic needle
`insertion device for use with an insulin
`pen. Prac Diabetes Int. 1999;16(2):39-41.
`57. Boronat Met al. Severe deterioration of
`metabolic control caused by malfunction
`of a disposable insulin pen device. J Am
`Board Fam Med. 2008;21(6):575-6.
`58. Venekamp WJ et al. Functionality and
`
`acceptability of a new electronic insulin
`injection pen with a memory feature. Curr
`Med Res Opin. 2006;22(2):315-25.
`59. Shaefer CF. The pen is mightier than
`the sword. Insulin. 2009;4(3):132-5.
`60. Asakura T et al. Evaluation of injection
`force of three insulin delivery pens. Expert
`Opin Pharmacother. 2009;10(9):1389-93.
`61. Pfutzner A et al. Prefilled insulin device
`with
`reduced
`injection
`force: patient
`perception and accuracy. Curr Med Res
`Opin. 2008;24(9):2545-9.
`62. Klausmann G et al. Evaluation of
`preference for a novel durable insulin
`pen with memory
`function among
`patients with diabetes and health care
`professionals. Patient Prefer Adherence.
`2013;7:285-92.
`63. Lautier O et al. Risk of needlestick
`injuries among nurses using NovoFine®
`Autocover® safety needles and nurses'
`satisfaction with the needles: the NOVAC
`study. Insulin. 2008;3(4):232-7.
`64. Bohannon NJ et al. Patient a