Journal of Diabetes Science and Technology
` Volume 4, Issue 3, May 2010
` © Diabetes Technology Society
`
`SYMPOSIUM
`
`Practical Aspects of Insulin Pen Devices
`Teresa L. Pearson, M.S., R.N., CDE
`
`Abstract
`Insulin pen devices have several advantages over the traditional vial-and-syringe method of insulin delivery,
`including improved patient satisfaction and adherence, greater ease of use, superior accuracy for delivering
`small doses of insulin, greater social acceptability, and less reported injection pain. 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, uptake of these devices in the United States has not matched that in many
`other areas of the world. There is a need for improved awareness of the current characteristics of insulin
`pen devices among United States health care professionals. Knowledge of the design improvements that have
`been incorporated into pens, both to address patient needs and as a result of the improved technology behind the
`device mechanics, is essential to promoting the use of insulin pen devices. This review highlights some of the
`practical aspects of pen use and discusses the factors to be considered when selecting among different insulin pens.
`J Diabetes Sci Technol 2010;4(3):522-531
`
`Introduction
`
`Numerous studies have shown that insulin pen
`
`devices 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.1–7 Despite these
`advantages, the use of insulin pen devices in the United
`States remains low compared with other developed
`countries.8 About two-thirds of insulin prescriptions in
`Europe and about three-quarters in Japan are for pen
`devices.9 In contrast, in the United States, only 15% of
`patients are thought to use insulin pens.10
`
`Possible reasons for the low adoption rates in the United
`States include lack of awareness among health care
`providers of the advantages of pens compared with the
`vial and syringe.8,11 An additional issue is the greater
`
`prescription cost of insulin cartridges and prefilled insulin
`pens compared with insulin vials, although the cost to the
`patient may be the same depending on their coverage;
`in fact, if they have one copay per box of pens, the cost
`to the patient may actually be less per unit of insulin.
`It should be noted, however, 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.1,2,12 In addition, most pen devices have good
`formulary coverage. For example, the FlexPen® prefilled
`pen is covered on more than 90% of managed care plans.13
`Therefore, in theory, costs should not prevent the use of
`these devices.14 However, many smaller health maintenance
`organizations and state Medicaid plans may require prior
`authorization for insulin pens.
`
`Author Affiliation: Fairview Health Services, Minneapolis, Minnesota
`Keywords: diabetes, insulin, insulin pen, practical use
`Corresponding Author: Teresa L. Pearson, Director, Diabetes Care, Fairview Health Services, Minneapolis, MN 55436; email address
`tpearson9@comcast.net
`
`522
`
`Mylan Ex. 1045
`Mylan v. Sanofi - IPR2018-01676
`
`

`

`Practical Aspects of Insulin Pen Devices
`
`Pearson
`
`Given the clinical, practical, and potential health economic
`advantages of insulin pens, there is a need for improved
`awareness of insulin pen devices among U.S. health care
`professionals. A study of patients with type 2 diabetes
`in the United States found that the physician’s role in
`presenting the pen as an option and recommending
`pen use was a critical factor in patients’ use of pens.15
`Physicians, nurses, and diabetes educators should therefore
`become familiar with the various insulin delivery devices
`available so that they can discuss the potential benefits
`of these devices with patients and offer advice on
`which device best meets an individual patient’s needs.
`Nurses, diabetes educators, and pharmacists have a
`particularly important role in educating patients on how to
`use insulin pens because incorrect use can affect pen
`performance and thus the accuracy of the administered
`dose.16 This review describes the practical aspects of
`insulin pen devices,
`including considerations when
`selecting among different insulin pens.
`Advantages of Pen Devices Compared
`with Vial and Syringes
`The traditional route of subcutaneous insulin adminis-
`tration has been the vial and syringe. However, this
`method of administration has many disadvantages,
`including fear of injections, poor dose accuracy, lack of
`social acceptance, lengthy training time, and difficulty of
`transportation. These factors can all act as barriers to
`insulin therapy, impacting on lifestyle flexibility and
`negatively influencing treatment adherence, patient self-
`management behavior, and achievement of euglycemia.17,18
`Insulin pens have been developed to help address
`these issues, with resulting improvements in portability,
`dosing accuracy, mealtime flexibility, and convenience
`of delivery.4–6,19 Increased patient preference, treatment
`satisfaction, and quality of life have been reported for
`pen devices compared with the vial and syringe;3,7,20,21
`these benefits may be particularly important due to their
`demonstrated impact on patient adherence. Other studies
`have shown that pen devices are associated with improved
`costs of care, less reported injection pain, and improved
`patient self-management behaviors, including adherence
`to treatment, compared with the vial and syringe.1,22–24
`Because of the greater ease of use of insulin pens,
`people with visual impairment or reduced dexterity may
`especially benefit from using an insulin pen rather than
`a vial and syringe.
`insulin analog vials, cartridges,
`Once
`in use, most
`and prefilled pens must be discarded after 28 days.
`This means that many patients who use a 10-ml vial end
`up either wasting insulin or using insulin beyond its
`
`recommended discard date. This is rarely a problem for
`patients using either a 3-ml prefilled pen or a reusable
`pen containing a 3-ml insulin cartridge. Exceptions to
`the 28-day discard date are insulin detemir (vials and
`pens), which can be kept for up to 42 days once in use;
`biphasic insulin aspart 70/30 prefilled pens, which must
`be discarded after 14 days; and cartridges and prefilled
`pens containing biphasic insulin lispro premixes, which
`must be discarded after 10 days.
`
`Two open-label, randomized, crossover studies have
`examined whether patients have greater dose confidence
`with a prefilled insulin pen or with a vial and syringe;
`both studies found that patients preferred the pen
`over the vial and syringe in this regard.3,25 In the first
`of these studies, 73% of patients felt more confident in
`the accuracy of the insulin dose delivered with the pen
`(original FlexPen) compared with 19% for the vial/syringe.3
`In the other study, 88% of patients had greater confidence
`that they were taking the right dose with the pen
`(KwikPen®) than with the vial and syringe.25 A more
`detailed discussion on the benefits of pen devices over
`vial and syringe can be found in the article by Selam26
`in this issue of Journal of Diabetes Science and Technology.
`Available Insulin Pen Devices
`Two types of insulin pen are available: prefilled disposable
`(Table 1).27–44 Most
`pens and refillable pens
`insulin
`pens are proprietary devices, manufactured by Eli Lilly,
`Novo Nordisk, and sanofi-aventis, and are designed to
`work with specific insulins from the same manufacturer.
`All currently available pens either are prefilled with 3 ml
`(300 units) of insulin or are refillable pens designed for use
`with 3-ml insulin cartridges (pens taking 1.5 ml insulin
`were formerly available). Insulin cartridges or prefilled
`disposable pens are available for all insulin analogs
`(rapid-acting, long-acting, and premixed) and for most
`human insulins (Table 1).
`
`For all insulin pen devices, a separate prescription for
`pen needles is required. Pen needles are available from
`various manufacturers (Allison Medical, BD, Can-Am Care,
`Delta Hi-Tech, Medical Plastic Devices, Novo Nordisk,
`Owen Mumford, UltiMed) and come in gauges ranging
`from 29 to 32 gauge and in lengths from 5 to 12.7 mm.45
`More recent developments have resulted in the intro-
`duction of safety needles with protective shields that
`not only reduce needle-stick injuries but may also allay
`patient anxieties about needle use.46 These are discussed
`in more detail in the section entitled “Individualizing
`Insulin Treatment with Pen Devices.”
`
`J Diabetes Sci Technol Vol 4, Issue 3, May 2010
`
`523
`
`www.journalofdst.org
`
`Mylan Ex. 1045
`Mylan v. Sanofi - IPR2018-01676
`
`

`

`Practical Aspects of Insulin Pen Devices
`
`Pearson
`
`Table 1.
`Insulin Pen Devices Currently Available in the United States.a, 27–44
`Dose range
`Increment
`Recommended
`needle typeb
`(unit)
`(unit)
`
`Product name
`
`Insulin type
`
`Dialing feature
`
`Other features
`
`Prefilled disposable insulin pens
`
`Humalog®
`KwikPen®
`
`Original
`Humalog® pen
`
`Humalog®
`Mix75/25™ pen
`Humalog®
`Mix50/50™ pen
`
`Humulin® N pen
`
`Humulin® 70/30 pen
`
`Maximum
`dose
`60 units
`
`Maximum
`dose
`60 units
`
`Insulin lispro
`and insulin
`lispro protamine
`suspension
`
`Insulin lispro
`
`Insulin lispro
`protamine
`suspension/insulin
`lispro injection
`
`Human insulin
`isophane
`suspension
`
`Maximum
`dose
`60 units
`
`Human insulin
`isophane
`suspension/human
`insulin injection
`
`Lantus® SoloSTAR®
`
`Insulin glargine
`
`Apidra® SoloSTAR®
`
`Insulin glulisine
`
`Levemir®FlexPen®c
`
`Insulin levemir
`Insulin aspart
`
`Novolog® FlexPen®c
`Novolog® Mix 70/30
`FlexPen®c
`
`Insulin aspart
`protamine
`suspension/insulin
`aspart
`
`Maximum
`dose
`80 units
`
`Maximum
`dose
`60 units
`
`1
`
`1
`
`1
`
`1
`
`1
`
`BD Ultra-
`Fine™ needles
`
`BD Ultra-Fine
`needles
`
`BD Ultra-Fine
`needles
`
`BD Ultra-Fine
`needles
`
`Dial-back feature
`Cannot dial more than
`the amount of insulin
`remaining
`
`Dial-back feature
`After full dose is
`delivered, an arrow or
`diamond is centered
`in dose window
`Cannot dial more than
`the amount of insulin
`remaining
`
`Dial-back feature
`After full dose is
`delivered an arrow or
`diamond is centered
`in the dose window
`Cannot dial more than
`the amount of insulin
`remaining
`
`Dial-back feature
`Cannot dial more than
`the amount of insulin
`remaining
`
`NovoFine or
`NovoTwist
`needles
`
`Dial-back feature
`Cannot dial more than
`the amount of insulin
`remaining
`
`Refillable pens
`
`Autopen® classic
`
`Insulin lispro
`protamine
`suspension/insulin
`lispro injection
`
`Maximum
`dose
`21 or 42
`units
`
`1 or
`2 unit
`models
`available
`
`Compatible
`with all pen
`needles
`
`Dial back not possible
`
`Autopen 24®
`
`Insulin glargine
`Insulin glulisine
`
`HumaPen®
`LUXURA™ and
`LUXURA™ HDd
`
`Insulin lispro
`Insulin lispro
`protamine
`suspension/insulin
`lispro injection
`
`Maximum
`dose
`21 or 42
`units
`
`Maximum
`dose
`60 units
`or 30 units
`(HD)
`
`1 or
`2 unit
`models
`available
`
`1 or 0.5
`(HD)
`(minimum
`dose 1
`unit)
`
`Compatible
`with all pen
`needles
`
`Dial back not possible
`
`BD Ultra-Fine
`needles
`
`Dial-back feature
`
`Light and portable
`
`The two pens are
`distinguished by
`color, and the Apidra
`SoloSTAR has a raised
`dot on the push button
`
`Little force required,
`dose delivery is
`confirmed by audible
`click, different insulins
`color coded, only pen
`with all three types of
`insulin analogs
`Raised dot on push
`button
`
`Side-mounted release
`button that is pushed
`the same minimal
`distance to inject,
`regardless of the dose
`size and the needle
`gauge
`
`The two dosing models
`are distinguished by
`color
`
`Relatively heavy; long
`reach needed for large
`doses
`
`4
`Continued
`
`J Diabetes Sci Technol Vol 4, Issue 3, May 2010
`
`524
`
`www.journalofdst.org
`
`Mylan Ex. 1045
`Mylan v. Sanofi - IPR2018-01676
`
`

`

`Practical Aspects of Insulin Pen Devices
`
`Pearson
`
`Table 1. Continued
`
`I
`
`1
`
`Dose range
`(unit)
`
`Insulin type
`
`1
`
`Increment
`(unit)
`
`1
`
`1
`
`I
`
`Other features
`
`Dialing feature
`
`Recommended
`needle typeb
`
`Product name
`
`Refillable pens
`
`HumaPen® Memoir™
`
`NovoPen® 3
`
`As HumaPen
`LUXURA
`
`Maximum
`dose
`60 units
`
`Insulin aspart
`Insulin levemir
`Insulin aspart
`protamine
`suspension/insulin
`aspart
`Human insulin
`isophane suspension
`
`1
`
`1
`
`1
`
`BD Ultra-Fine
`needles
`
`Dial-back feature
`
`NovoFine
`needles
`
`NovoPen 3 dial
`back requires partial
`disassembly
`
`Digital display and
`memory of last
`16 doses, including
`priming doses
`(i.e., eight injections)
`Relatively heavy; long
`reach needed for large
`doses
`
`NovoFine
`needles
`
`NovoPen 4 has easy
`dial back and cannot
`dial more than the
`amount of insulin
`remaining
`
`Large easier-to-read
`numbers, reduced dose
`force, dose delivery
`confirmed by audible
`click
`
`0.5
`(minimum
`dose 1
`unit)
`
`1
`
`NovoFine
`needles
`
`Dial back requires
`partial disassembly
`
`Ypsomed
`Clickfine™
`needles or
`BD Ultra-Fine
`needles
`
`Dial-back feature
`Cannot dial more than
`the amount of insulin
`remaining
`
`Distinguished from
`NovoPen 3 by raised
`circle on push button
`
`Dose displayed for
`2 minutes
`
`Maximum
`dose
`70 units
`
`Maximum
`dose 60
`units
`
`Maximum
`dose 35
`units
`
`Maximum
`dose, 80
`units
`
`NovoPen® 4
`
`As NovoPen 3
`
`NovoPen® Junior
`
`As NovoPen 3
`
`OptiClik®
`
`Insulin glargine
`Insulin glulisine
`
`a Cartridge delivery capacity is 300 units, unless otherwise stated.
`b Needle types shown are recommended by the insulin pen device manufacturer. BD Ultra-Fine and Ypsomed Clickfine needles also fit all
`current insulin pens.
`c Also known as the improved FlexPen.
`d Half dose.
`
`How to Use an Insulin Pen
`In a study assessing patient and physician acceptability
`of the prefilled Humulin®/Humalog® insulin pen device,
`88% of the 33 physicians who completed questionnaires
`at the end of the study thought that it took less time
`to teach patients to use the pen and 73% thought that
`it took less time to initiate insulin therapy with the pen
`compared with a vial and syringe.47 Teaching patients
`how to use an insulin pen can be summarized in the
`five main steps shown in Figure 1. It should be noted
`that because of the mechanics of pen devices, insulin can
`still be flowing out of the pen for several seconds after
`the button is fully depressed.11 Patients must therefore
`keep the device in place with the button pressed in
`for 5–10 seconds (the stipulated time varies between
`
`package inserts of the various insulin pens). For example,
`SoloSTAR® recommends a longer in situ time (10 seconds)
`compared with the FlexPen (6 seconds).37,38,41,42 The easiest
`way to ensure this is to instruct the patient to count to 5
`(or 10, if using the SoloSTAR) before removing the needle.
`If the patient is using more than 50 units of insulin per
`dose, a good rule of thumb might be to instruct them to
`count to 10 regardless of the pen they are using to ensure
`complete absorption of the insulin.
`
`If patients are using a pen that contains an insulin
`suspension (neutral protamine Hagedorn insulin or an
`insulin premix), they must carefully roll or tip the pen
`for the recommended number of times according to the
`
`J Diabetes Sci Technol Vol 4, Issue 3, May 2010
`
`525
`
`www.journalofdst.org
`
`Mylan Ex. 1045
`Mylan v. Sanofi - IPR2018-01676
`
`

`

`Practical Aspects of Insulin Pen Devices
`
`Pearson
`
`1. Attach the needle to the pen
`
`1
`
`2. Prime the pen (also referred to as "doing a safety test"
`or "performing an air shot")a
`
`3. Select the dose by dialing
`
`4. Inject the dose by depressing the buttonb
`
`5. After the injection, remove the needle from the pen
`
`Figure 1. The five steps of insulin pen use. aThis is performed by
`instructing the patient to dial up 2 units and to inject these units into
`the air. bThe button needs to be pressed and the needle held in the
`skin for 5–10 seconds to ensure complete delivery of insulin dose.
`The easiest way to ensure this is to instruct the patient to count to 5
`(or 10, if using the SoloSTAR®) before removing the needle.
`
`package insert to ensure even mixing of the insulin
`suspension before attaching the needle. This issue may
`be especially important 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.48
`
`Pens must be primed before each injection, and the needle
`removed immediately after each use.11 This is performed
`by instructing the patient to dial up 2 units and inject these
`units into the air (also called an “air shot”). This will
`displace any air in the needle and ensure an accurate
`injection. This air shot may need to be repeated when
`using a new pen or cartridge until a steady stream of
`insulin is observed. Insulin pens are manufactured
`with enough extra insulin to account for this air shot.
`An insulin pen must never be used by more than one
`individual, even if the pen needle is changed, because
`sharing of insulin pens can result in the transmission
`of hepatitis viruses, human immunodeficiency virus, or
`other blood-borne pathogens.49
`
`Patients and health care workers also need to be aware
`of the different procedures associated with insulin pens
`in case of accidentally dialing a dose larger than required.
`In the case of the Autopen®, the side push-button design
`makes it impossible to dial back, and care should be
`taken not to dial past the required dose. With older
`versions of NovoPen® and NovoPen® Junior, the dose
`can be adjusted back down by partial disassembly of
`
`the pen. This involves pulling the mechanical section
`and the cartridge holder apart and pressing the dial-
`up button back to zero. With other pens, namely the
`SoloSTAR, the improved FlexPen, Humalog KwikPen,
`original Humalog/Humulin pens, HumaPen® LUXURA™,
`HumaPen® LUXURA™ HD, HumaPen® Memoir™,
`OptiClik®, and NovoPen 4, easy dial back is possible by
`simply reversing the dial-up action.
`
`Prior to first use, the insulin cartridge or pen should be
`stored in the refrigerator. The pen should be warmed to
`room temperature [below 86°F (30°C) for most insulin
`analogs] before use. After use, the pen should remain
`at room temperature below 86°F (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,
`keeping them as close as possible to room temperature
`below 86°F (30°C) at all times. Insulin glulisine has a
`narrower temperature range for storage than the other
`insulin analogs: Once in use, insulin glulisine must be
`stored below 77°F (25°C). In some buildings, for example,
`schools, the air conditioning is turned off at night,
`which may result in the room temperature rising above
`77°F (25°C) or 86°F (30°C). Insulated storage packs are
`recommended in such conditions.
`
`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.50
`Individualizing Insulin Treatment with
`Pen Devices
`Health care practitioners should work with the patient to
`select insulin delivery devices that are compatible with
`their insulin regimen, lifestyle, and personal preferences.
`A regimen that causes the least disruption to the patient’s
`day-to-day life 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.15 As discussed by Selam26 and summarized
`earlier, insulin pens can provide many potential benefits
`over vial-and-syringe delivery.
`
`Patients across all age groups often have concerns regarding
`insulin therapy, and many of these concerns can be
`addressed effectively through choosing an insulin pen
`device rather than a vial and syringe.51 In particular,
`adolescents and children may find insulin pens more
`socially acceptable because of the pens’ greater portability
`
`J Diabetes Sci Technol Vol 4, Issue 3, May 2010
`
`526
`
`www.journalofdst.org
`
`Mylan Ex. 1045
`Mylan v. Sanofi - IPR2018-01676
`
`

`

`Practical Aspects of Insulin Pen Devices
`
`Pearson
`
`and discreetness. The NovoPen Junior, for example, has
`been developed specifically for use by children and
`teenagers or others requiring the ability to adjust their
`insulin in half-unit increments.33 The HumaPen LUXURA
`HD can also deliver insulin in half-unit increments.
`However, both these pens administer a minimum dose
`of 1 unit, meaning that no pen is yet available that can
`deliver a dose of one-half unit. This can be problematic
`for young children, especially at school. With proper
`training, loading insulin and attaching the needle should
`be simple enough for grade school-aged kids.
`
`Numbers on insulin pen dials are also larger than those
`on syringes, making it easier for those with visual
`impairment to select the correct dose. Some devices also
`incorporate audible clicks that notify the user of the
`number of units injected. Patients with impaired manual
`dexterity may find an insulin pen easier to use because
`it eliminates a step in the injection procedure, i.e., filling
`the syringe with insulin from the vial.
`
`Advances in pen devices have also been made to improve
`needle safety and potentially reduce any needle anxiety.
`Needle-stick injuries are a common occupational hazard
`for health care professionals, particularly nurses. Use of
`the NovoFine® Autocover® safety pen needle has been
`shown to reduce the incidence of needle-stick injuries
`among nurses.46 Although safety needles are not readily
`available outside the hospital setting, they may be a
`consideration for secondary caregivers to avoid needle-
`stick injuries. The other currently available safety pen
`needle is the BD AutoShield™. Both the NovoFine
`Autocover and the BD AutoShield conceal the needle, thus
`also potentially reducing needle anxiety. Two injection
`aids for insulin pens are available that also conceal
`the needle: NeedleAid™ and NovoPen 3 PenMate®.45
`Concealing the needle using the NovoPen 3 PenMate has
`been shown to reduce pain perception.52 The NeedleAid
`is an attachment designed to help visually impaired
`patients self-administer insulin.
`
`Insulin pens are not without their limitations, and it is
`important that patients and health care workers are
`aware of these to ensure maximal outcomes. The maximum
`dose with most insulin pens is 60 to 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 an insulin pen. Despite their ease of use, pens are
`mechanically more complex than syringes, and some cases
`of malfunction have been reported in the literature.53,54
`Therefore, patients using an insulin pen should have a
`backup pen available if traveling.
`
`In terms of costs, there should be few reimbursement
`issues with most private health plans,9 although coverage
`by third-party payers may be under a tier that does
`not pay out in full.11 However, costs to the patient for
`prefilled pens are minimized, as the pack dispensed by
`the pharmacy under one copayment contains five pens.11
`Most pens are now covered by Medicare.9,14 Some pens
`are associated with specific reimbursement issues.11
`Considerations When Choosing among
`Insulin Pens
`In U.S. medical practice, 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. Anecdotal reports suggest that 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.55 However, certain refillable pens
`have features, such as a memory function or the ability
`to dial in half-unit increments, that are not available
`with prefilled pens (Table 1). For example, the HumaPen
`LUXURA HD and NovoPen Junior are the only pens
`that allow the dose to be selected in half-unit increments.
`This may be important in children or in those sensitive
`to insulin. The OptiClik and SoloSTAR 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.
`
`The recently introduced improved FlexPen has a push-
`button mechanism that has been modified to reduce
`injection force while maintaining dose accuracy56,57 and
`retaining the ability to dial back. It therefore provides
`significantly less discomfort when injecting, which may
`be particularly suitable for patients with impaired manual
`dexterity or conditions such as arthritis. The improved
`FlexPen also has color-coded cartridges and packaging that
`clearly differentiate among insulin types.19 Color coding
`has also been incorporated into the SoloSTAR Lantus
`and Apidra pens to distinguish among insulin types.
`
`Another initiative is for pens to supply auditory feedback,
`particularly since patients with type 2 diabetes often suffer
`from impairments in vision as well as manual dexterity.58
`The OptiClik, NovoPen 4, and improved FlexPen provide a
`confirmatory click when the correct dose has been delivered.
`In addition, the recently introduced NovoTwist® needle,
`for use with the improved FlexPen, has an easy twist-on
`action with an audible click when the needle is in place.
`
`J Diabetes Sci Technol Vol 4, Issue 3, May 2010
`
`527
`
`www.journalofdst.org
`
`Mylan Ex. 1045
`Mylan v. Sanofi - IPR2018-01676
`
`

`

`Practical Aspects of Insulin Pen Devices
`
`Pearson
`
`Both the OptiClik and the HumaPen Memoir devices
`have liquid crystal display screens powered by non-
`replaceable batteries. Therefore, when the battery runs
`out, patients have no visual confirmation of the dose
`selected, and the pen must be replaced. However, the
`OptiClik pen can be obtained only through a physician’s
`office, making replacement more difficult. According to
`the manufacturers, the expected battery life for each of
`these pens is 3 years.
`Clinical Studies Comparing Insulin Pens
`Several studies have investigated dosing accuracy among
`pens. Generally, dosing accuracy is good, but the OptiClik
`pen can be subject to underdosing.59,60 One study found
`that, because of underdosing, 6.8% of 10-unit doses and
`13.9% of 30-unit doses with the OptiClik pen were outside
`the International Organization for Standardization limits
`(±1 unit for a 10-unit dose, and ±1.5 units for a 30-unit
`dose).59 Another separate study found that OptiClik
`underdosed for 17.1% of doses at 10 units and for 28.9%
`of doses at 30 units.60 To avoid this, it may be necessary
`to carry out multiple priming before injecting with the
`OptiClik pen. Other studies have examined the dosing
`accuracy of SoloSTAR compared with FlexPen (improved
`and original), Humulin/Humalog pen, and OptiClik
`pen59,61–64 (Table 2). The largest of these comparative studies
`investigated 2280 doses of the SoloSTAR and the original
`FlexPen devices and showed that pens had comparable
`accuracy over the standard doses of 5, 10, and 30 units.53
`
`Another study also found that SoloSTAR and the
`original FlexPen were similarly accurate when used
`by device-naive individuals to deliver 20-unit doses of
`insulin.65 One study compared the improved FlexPen
`with SoloSTAR: both pens showed very good accuracy,
`and the improved FlexPen was even more accurate than
`the SoloSTAR (p < 0.05)64(Table 2).
`
`Insulin pens also differ in the force required to inject
`an insulin dose, and this feature has been investigated
`in several studies,56,63,66–68 with results summarized in
`Table 3. In general, differences in the injection force
`among insulin pens are relatively small; however, the
`improved FlexPen does seem to show benefits when
`compared with SoloSTAR and OptiClik pens.56,67
`
`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
`results show that newer designs of pens are increasingly
`user-friendly and intuitive to use, requiring little or no
`instruction.54,69–71 For example, an open-label, crossover
`study showed that the improved FlexPen was faster to
`teach, simpler to use, and more trusted by patients
`compared with OptiClik.69 Similarly, in an open-label,
`crossover study, the Novolog® Mix 70/30 FlexPen was
`associated with significantly greater intuitiveness and a
`shorter injection time compared with the HumaPen
`LUXURA device.70 A separate study also showed a
`
`Table 2.
`Studies of Dose Accuracy of Insulin Pens with Comparable End Points
`Improved
`HumaPen
`FlexPen
`LUXURA
`
`Original FlexPena
`
`SoloSTAR
`
`OptiClik
`
`Reference
`
`Deviation from
`10-IU dose (mean)
`
`Deviation from
`30-IU dose (mean)
`
`Mean delivered dose
`of 5 IU
`
`Mean delivered dose
`of 10 IU
`
`Mean delivered dose
`of 30 IU
`
`1.64 ± 0.84%
`
`NAb
`
`1.10 ± 0.20%
`
`2.61 ± 0.92%
`
`4.78 ± 3.31%
`
`NA
`
`1.63 ± 0.84%c
`
`NA
`
`2.11 ± 0.92%
`
`NA
`
`0.83 ± 0.26%
`
`NA
`
`0.62 ± 0.19%
`
`1.70 ± 0.84%
`
`2.97 ± 2.48%
`
`NA
`
`1.23 ± 0.76%d
`
`5.07 ± 0.15
`
`4.95 ± 0.19
`
`9.87 ± 0.16
`
`9.61 ± 0.27
`
`29.70 ± 0.38
`
`29.70 ± 0.34
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`1.54 ± 0.84%
`
`5.03 ± 0.21
`
`4.86 ± 0.39
`
`9.83 ± 0.14
`
`9.27 ± 0.52
`
`29.45 ± 0.25
`
`28.73 ± 0.47
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`59
`
`64
`
`59
`
`64
`
`61
`
`62
`
`61
`
`62
`
`61
`
`62
`
`a No longer available commercially.
`b Not assessed.
`c p < 0.001
`d p < 0.05 for improved FlexPen vs SoloSTAR.
`
`J Diabetes Sci Technol Vol 4, Issue 3, May 2010
`
`528
`
`www.journalofdst.org
`
`Mylan Ex. 1045
`Mylan v. Sanofi - IPR2018-01676
`
`

`

`Practical Aspects of Insulin Pen Devices
`
`Pearson
`
`Reference
`
`KwikPen
`
`Table 3.
`Studies of Injection Force of Insulin Pen Devices: FlexPen, Lilly Pen, SoloSTAR, and KwikPen
`Injection speed
`Original
`Improved
`FlexPena
`mm/s and insulin
`FlexPen
`
`Lilly Pen
`
`SoloSTAR
`
`Injection force using BD
`Micro-Fine 31-gauge
`needle (N)
`
`Injection force using
`NovoFine 32-gauge tip
`
`3.3
`
`5
`
`8.3
`
`4
`
`6
`
`8
`
`3.3
`
`5
`
`8.3
`
`4
`
`6
`
`8
`
`40 units rapid-acting
`insulin analog
`in 4 seconds
`
`40 units basal insulin
`analog in 4 seconds
`
`40 units NPHb insulin
`in 4 seconds
`
`30 units
`
`60 units
`
`17.2
`
`16.3
`
`17.7
`
`5.36
`
`5.62
`
`Maximum glide force (lb)
`
`a No longer available commercially.
`b Neutral protamine Hagedorn.
`c p < 0.05 for the improved FlexPen versus SoloSTAR or KwikPen.
`d p < 0.0001 for KwikPen versus original FlexPen.
`
`8.1 ± 0.7c
`
`10.7 ± 1.4c
`
`15.6 ± 0.9c
`
`5.7 ± 0.4c
`
`8.2 ± 0.7c
`
`12.7 ± 0.5c
`
`8.3 ± 0.6
`
`12.0 ± 0.9
`
`16.2 ± 1.3
`
`9.2 ± 0.5
`
`12.5 ± 1.6
`
`13.3 ± 0.8
`
`16.9 ± 1.2
`
`56
`
`20.7 ± 2.4
`
`24.5 ± 2.6
`
`12.9 ± 0.8
`
`20.5 ± 1.3
`
`29.6 ± 1.9
`
`67
`
`6.7 ± 0.3
`
`9.1 ± 1.3
`
`10.4 ± 2.1
`
`13.1 ± 0.8
`
`56
`
`16.3 ± 1.1
`
`21.6 ± 2.0
`
`10.2 ± 1.1
`
`15.7 ±1.5
`
`22.3 ± 1.1
`
`10.3
`
`11.3
`
`25.3
`
`24.2
`
`67
`
`63
`
`66
`
`3.42d
`
`3.61d
`
`greater patient preference with fewer problems for the
`Novolog Mix 70/30 FlexPen compared with the Humalog
`Mix75/25 Pen.71 Results of other studies have shown an
`overall preference for SoloSTAR (53%) rather than for the
`original FlexPen (31%) or Humulin/Humalog pen (15%),72
`with the SoloSTAR and original FlexPen found to be
`more user-friendly than the Eli Lilly disposable pen.73
`To date, there are no studies comparing patient preference
`for the improved FlexPen compared with the SoloSTAR
`or Humulin/Humalog Pen.
`
`Yakushiji and colleagues74 assessed the preferences of
`22 Japanese men and women for various insulin pens
`when self-injecting and when administering an injection
`to another person. Insulin injections were administered
`into prosthetic skin attached either to the participant
`or to a mock patient. The FlexPen was rated as the best
`
`device for self-injection, whereas the OptiClik, perhaps
`because of its larger size, was rated as the best device for
`administration of an injection to another person.
`Conclusions
`In conclusion, the use of insulin pens offers many options
`to allow insulin delivery to be tailored to the individual
`patient. Newer designs of pens are increasingly user-
`friendly and are intuitive to use, requiring little or no
`instruction. This means that patients can quickly be
`taught how to use an insulin pen, which should go hand
`in hand with educating the patient on the importance
`of achieving accurate dosing. Thorough training of patients
`in the practical aspects and aims of insulin injection
`remains important, as errors in insulin delivery can result
`in incorrect dose administration and thus affect