le2st9-aduate
`nneacine
`
`Mr Hard nve.11reNonal
`
`Postgraduate Medicine
`
`Taylor&Francis
`.."•
`
`ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: https://www.tandfonline.com/loi/ipgm20
`
`Insulin delivery using pen devices
`
`Nancy J. V. Bohannon
`
`To cite this article: Nancy J. V. Bohannon (1999) Insulin delivery using pen devices, Postgraduate
`Medicine, 106:5, 57-68, DOI: 10.3810/pgm.1999.10.15.751
`To link to this article: https://doi.org/10.3810/pgm.1999.10.15.751
`
`Published online: 30 Jun 2015.
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`

`Insulin delivery using pen devices
`Insulin delivery using pen devices
`Simple-to-use tools may help young and old alike
`Simple-to-use tools may help young and old alike
`
`Nancy J. V. Bohannon, MD
`Nancy J. V. Bohannon, MD
`
`PREVIEW
`PREVIEW
`Clinical trials have convincingly demonstrated that improved glycemic control
`Clinical trials have convincingly demonstrated that improved glycemic control
`significantly reduces the risk of diabetes-related complications. However,
`significantly reduces the risk of diabetes-related complications. However,
`tight control is not always easy for patients to achieve. To help overcome
`tight control is not always easy for patients to achieve. To help overcome
`some of the problems linked with tight control, insulin pen devices have been
`some of the problems linked with tight control, insulin pen devices have been
`developed to offer easier, safer, more accurate, and more discreet insulin
`developed to offer easier, safer, more accurate, and more discreet insulin
`injection. In this article, Dr Bohannon provides information about these in-
`injection. In this article, Dr Bohannon provides information about these in(cid:173)
`sulin pens and discusses which patients are most likely to benefit.
`sulin pens and discusses which patients are most likely to benefit.
`
`With the rapid pace of
`W ith the rapid pace of
`
`modern life, the time re-
`modern life, the time re(cid:173)
`quired to optimally man-
`quired to optimally man(cid:173)
`age diabetes may be hard to find.
`age diabetes may be hard to find.
`New insulin and insulin delivery
`New insulin and insulin delivery
`systems can make this easier while
`systems can make this easier while
`offering additional benefits of life-
`offering additional benefits of life(cid:173)
`style flexibility and improved gly-
`style flexibility and improved gly(cid:173)
`cemic control. Insulin analogues,
`cemic control. Insulin analogues,
`such as insulin lispro (Humalog),
`such as insulin lispro (Humalog),
`also improve convenience by
`also improve convenience by
`their rapid action; this allows in-
`their rapid action; this allows in(cid:173)
`sulin injection immediately be-
`sulin injection immediately be(cid:173)
`fore meals, rather than the 30- to
`fore meals, rather than the 30- to
`60-minute interval needed for
`60-minute interval needed for
`the best postprandial glucose
`the best postprandial glucose
`control with regular insulin.
`control with regular insulin.
`Insulin pens are another inno-
`Insulin pens are another inno(cid:173)
`vation designed to provide the
`vation designed to provide the
`patient with an easy-to-use, con-
`patient with an easy-to-use, con(cid:173)
`venient, and accurate method of
`venient, and accurate method of
`insulin delivery. The goal is to
`insulin delivery. The goal is to
`improve glycemic control by mak-
`improve glycemic control by mak(cid:173)
`ing it less difficult to follow the
`ing it less difficult to follow the
`current recommendations for in-
`current recommendations for in-
`
`tensive insulin regimens.
`tensive insulin regimens.
`Two types of insulin pens are
`Two types of insulin pens are
`available today: prefilled and
`available today: prefilled and
`reusable. Prefilled pens are simply
`reusable. Prefilled pens are simply
`discarded when the insulin car-
`discarded when the insulin car(cid:173)
`tridge is spent, whereas reusable
`tridge is spent, whereas reusable
`pens contain a replaceable in-
`pens contain a replaceable in(cid:173)
`sulin cartridge that is loaded into
`sulin cartridge that is loaded into
`and removed from the pen by the
`and removed from the pen by the
`patient. Most pens function on
`patient. Most pens function on
`simple mechanical principles and
`simple mechanical principles and
`are durable. The technique for
`are durable. The technique for
`insulin delivery is similar for both
`insulin delivery is similar for both
`prefilled and reusable pens.
`prefilled and reusable pens.
`
`Technical advances
`Technical advances
`
`Medical therapy for diabetes mel-
`Medical therapy for diabetes mel(cid:173)
`litus has changed dramatically
`litus has changed dramatically
`since Banting and Best discovered
`since Banting and Best discovered
`insulin in 1921. Not only have
`insulin in 1921. Not only have
`therapies for diabetes advanced
`therapies for diabetes advanced
`significantly, but the technology
`significantly, but the technology
`for the delivery of insulin has also
`for the delivery of insulin has also
`changed. Nonetheless, syringes
`changed. Nonetheless, syringes
`
`were the sole method of insulin
`were the sole method of insulin
`delivery for decades. The original
`delivery for decades. The original
`glass syringes and their large,
`glass syringes and their large,
`reusable needles had to be boiled
`reusable needles had to be boiled
`for sterilization. The needles were
`for sterilization. The needles were
`sharpened with a pumice stone
`sharpened with a pumice stone
`for reuse. Syringes continue to
`for reuse. Syringes continue to
`play a prominent role in patient
`play a prominent role in patient
`care today, but they are now dis-
`care today, but they are now dis(cid:173)
`posable plastic devices that de-
`posable plastic devices that de(cid:173)
`liver as little as 0.5-unit dosing
`liver as little as 0.5-unit dosing
`increments through 30-gauge,
`increments through 30-gauge,
`short, attached needles.
`short, attached needles.
`Although advancements in
`Although advancements in
`technology have provided vari-
`technology have provided vari(cid:173)
`ous sizes of syringes and needle
`ous sizes of syringes and needle
`systems, the traditional insulin
`systems, the traditional insulin
`injection process remains time-
`injection process remains time(cid:173)
`consuming, cumbersome, incon-
`consuming, cumbersome, incon(cid:173)
`venient, and somewhat painful.
`venient, and somewhat painful.
`Furthermore, insulin dosing via
`Furthermore, insulin dosing via
`syringe is associated with a high
`syringe is associated with a high
`risk of dosage errors; as many as
`risk of dosage errors; as many as
`80% of patients carry out some
`80% of patients carry out some
`aspect of insulin administration
`aspect of insulin administration
`via syringe incorrectly.' Now, to
`via syringe incorrectly.' Now, to
`allow more flexibility and conve-
`allow more flexibility and conve(cid:173)
`nience, patients are seeking op-
`nience, patients are seeking op(cid:173)
`tions other than the traditional
`tions other than the traditional
`vial-and-syringe delivery method.
`vial-and-syringe delivery method.
`Insulin pens meet this need and
`Insulin pens meet this need and
`also address issues of patient and
`also address issues of patient and
`environmental safety, social con-
`environmental safety, social con(cid:173)
`cerns, and more accurate dosage
`cerns, and more accurate dosage
`control (table 1).
`control (table 1).
`Insulin pen devices are unique
`Insulin pen devices are unique
`continued
`continued
`
`VOL 106 / NO 5 / OCTOBER 15, 1999 / POSTGRADUATE MEDICINE / INSULIN DELIVERY
`VOL 106/ NO 5/ OCTOBER 15, 1999/ POSTGRADUATE MEDICINE /INSULIN DELIVERY
`
`57
`57
`
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`
`

`

`Insulin delivery, continued
`Insulin delivery, continued
`
`Table 1. Advantages of insulin
`Table 1. Advantages of insulin
`pen devices over conventional
`pen devices over conventional
`insulin syringes
`insulin syringes
`
`More convenient insulin delivery
`More convenient insulin delivery
`More accurate dosing
`More accurate dosing
`Less pain because smaller-gauge
`Less pain because smaller-gauge
`needles are used
`needles are used
`Better quality of life
`Better quality of life
`Easier compliance with insulin
`Easier compliance with insulin
`regimen
`regimen
`Simpler for specific populations to
`Simpler for specific populations to
`use (eg, older adults, children and
`use (eg, older adults, children and
`adolescents, pregnant women)
`adolescents, pregnant women)
`Improved social acceptability,
`Improved social acceptability,
`especially at school
`especially at school
`More flexibility because of
`More flexibility because of
`disposable or reusable options
`disposable or reusable options
`
`in that they combine the insulin
`in that they combine the insulin
`container and the syringe in a
`container and the syringe in a
`single unit. Their compact size
`single unit. Their compact size
`allows discreet insulin adminis-
`allows discreet insulin adminis(cid:173)
`tration but still provides ex-
`tration but still provides ex(cid:173)
`tremely accurate insulin delivery.
`tremely accurate insulin delivery.
`Advances in the technology of
`Advances in the technology of
`needle manufacturing continue
`needle manufacturing continue
`to make needles more comfort-
`to make needles more comfort(cid:173)
`able to use.' With all these refine-
`able to use. 2 With all these refine(cid:173)
`ments combined, insulin pens
`ments combined, insulin pens
`improve the likelihood that pa-
`improve the likelihood that pa(cid:173)
`tients will adhere more closely to
`tients will adhere more closely to
`
`Nancy J. V. Bohannon, MD
`Nancy J. V. Bohannon, MD
`Dr Bohannon is in solo private practice in inter(cid:173)
`Dr Bohannon is in solo private practice in inter-
`nal medicine/endocrinology in San Francisco.
`nal medicine/endocrinology in San Francisco.
`Correspondence: Nancy J. V. Bohannon, MD,
`Correspondence: Nancy J. V. Bohannon, MD,
`1580 Valencia St, Suite 504, San Francisco, CA
`1580 Valencia St, Suite 504, San Francisco, CA
`94110-4415. E-mail: sugarnancy@pol.net.
`94110-4415. E-mail: sugarnancy@pol.net.
`
`recommended insulin dosing
`recommended insulin dosing
`schedules.
`schedules.
`
`Pen types and styles
`Pen types and styles
`
`Insulin pens have become ex-
`Insulin pens have become ex(cid:173)
`tremely popular throughout the
`tremely popular throughout the
`world; in some countries, 70% to
`world; in some countries, 70% to
`90% of all insulin is delivered by
`90% of all insulin is delivered by
`pen.' However, in the United
`pen. 3 However, in the United
`States only about 2% of insulin is
`States only about 2% of insulin is
`injected via pen. This is probably
`injected via pen. This is probably
`because of difficulties with reim-
`because of difficulties with reim(cid:173)
`bursement from insurance com-
`bursement from insurance com(cid:173)
`panies or a lack of knowledge on
`panies or a lack of knowledge on
`the part of patients and physicians
`the part of patients and physicians
`about pen availability. The fact is
`about pen availability. The fact is
`that insulin pens are available in
`that insulin pens are available in
`various types and styles (table 2)
`various types and styles (table 2)
`and can benefit a large number of
`and can benefit a large number of
`patients.
`patients.
`
`Prefilled pens
`Prefilled pens
`Prefilled pens contain a built-in,
`Prefilled pens contain a built-in,
`single-use insulin cartridge.
`single-use insulin cartridge.
`Because this device requires no
`Because this device requires no
`loading by the patient, it is espe-
`loading by the patient, it is espe(cid:173)
`cially convenient and easy to
`cially convenient and easy to
`use. These portable, durable, and
`use. These portable, durable, and
`lightweight delivery systems are
`lightweight delivery systems are
`particularly helpful for patients
`particularly helpful for patients
`who have difficulty handling the
`who have difficulty handling the
`cartridges in reusable pens or peo-
`cartridges in reusable pens or peo(cid:173)
`ple with busy schedules who pre-
`ple with busy schedules who pre(cid:173)
`fer not to have to stop to change
`fer not to have to stop to change
`cartridges. However, prefilled
`cartridges. However, prefilled
`pens may be slightly more expen-
`pens may be slightly more expen(cid:173)
`sive over time, compared with
`sive over time, compared with
`reusable pens. Also, both types of
`reusable pens. Also, both types of
`pens are more expensive than
`pens are more expensive than
`vial-and-syringe insulin therapy.
`vial-and-syringe insulin therapy.
`In the United States, the first
`In the United States, the first
`
`prefilled pen was the Novolin
`prefilled pen was the Novolin
`70/30, introduced in 1993; the
`70/30, introduced in 1993; the
`newest prefilled pens are the in-
`newest prefilled pens are the in(cid:173)
`sulin lispro (Humalog) and hu-
`sulin lispro (Humalog) and hu(cid:173)
`man insulin (Humulin) devices
`man insulin (Humulin) devices
`manufactured by Eli Lilly & Com-
`manufactured by Eli Lilly & Com(cid:173)
`pany. These pens have single-
`pany. These pens have single(cid:173)
`unit dosing increments, audible
`unit dosing increments, audible
`clicks when dialing the dose, a
`clicks when dialing the dose, a
`large magnifying window that
`large magnifying window that
`shows unit dose, two-way dose
`shows unit dose, two-way dose
`setting that allows the user to
`setting that allows the user to
`decrease the dose without taking
`decrease the dose without taking
`the pen apart or discharging in-
`the pen apart or discharging in(cid:173)
`sulin from the pen, and an end-
`sulin from the pen, and an end(cid:173)
`of-dose click that indicates that
`of-dose click that indicates that
`the full dose has been delivered.
`the full dose has been delivered.
`
`Reusable pens
`Reusable pens
`With the reusable pen, the pa-
`With the reusable pen, the pa(cid:173)
`tient inserts an insulin cartridge
`tient inserts an insulin cartridge
`into the pen's delivery chamber.
`into the pen's delivery chamber.
`For some patients, this allows
`For some patients, this allows
`greater flexibility (ie, changing
`greater flexibility ( ie, changing
`types of insulin without needing
`types of insulin without needing
`to buy another pen if prescription
`to buy another pen if prescription
`changes), and it may be more
`changes), and it may be more
`economical than using prefilled
`economical than using prefilled
`pens. In addition to being durable
`pens. In addition to being durable
`and easy to use, the reusable pens
`and easy to use, the reusable pens
`are designed for longer duration
`are designed for longer duration
`of use. Disadvantages of the
`of use. Disadvantages of the
`reusable pens are the potential
`reusable pens are the potential
`loss of sterility with use' and the
`5 and the
`loss of sterility with use4
`·
`possible damage that may occur
`possible damage that may occur
`to the pen over time.
`to the pen over time.
`With individual use of the pen
`With individual use of the pen
`device, the risk of infection is
`device, the risk of infection is
`minimized.' Among the reusable
`minimized. 5 Among the reusable
`pens currently on the US market
`pens currently on the US market
`are: Autopen AN 3000 and AN
`are: Autopen AN 3000 and AN
`3100 (Owen Mumford, Inc.),
`3100 (Owen Mumford, Inc.),
`continued
`continued
`
`58
`58
`
`INSULIN DELIVERY / VOL 106 / NO 5 / OCTOBER 15, 1999 / POSTGRADUATE MEDICINE
`INSULIN DELIVERY I VOL 106 I NO 5 I OCTOBER 15. 1999 I POSTGRADUATE MEDICINE
`
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`Mylan v. Sanofi - IPR2018-01675
`
`

`

`Insulin delivery, continued
`Insulin delivery, continued
`
`B-D Pen Classic and B-D Pen
`B-D Pen Classic and B-D Pen
`Mini (Becton Dickinson), Novo-
`Mini (Becton Dickinson), Novo(cid:173)
`Pen 1.5 and NovoPen 3.0
`Pen 1.5 and NovoPen 3.0
`(Novo Nordisk), and Humalog
`(Novo Nordisk), and Humalog
`and Humulin pens (Lilly).
`and Humulin pens (Lilly).
`
`Device preparation
`Device preparation
`
`Regardless of whether a patient
`Regardless of whether a patient
`chooses the prefilled or the reus-
`chooses the prefilled or the reus(cid:173)
`able pen design, the techniques
`able pen design, the techniques
`for dose preparation and insulin
`for dose preparation and insulin
`delivery are generally similar.
`delivery are generally similar.
`Once a disposable needle is
`Once a disposable needle is
`screwed on to the pen and the
`screwed on to the pen and the
`pen is primed, the patient simply
`pen is primed, the patient simply
`dials to the appropriate dose,
`dials to the appropriate dose,
`which can be seen in the device's
`which can be seen in the device's
`display window and can be heard
`display window and can be heard
`as audible clicks in many pen de-
`as audible clicks in many pen de(cid:173)
`vices. The needle is inserted sub-
`vices. The needle is inserted sub(cid:173)
`cutaneously, and the plunger in-
`cutaneously, and the plunger in(cid:173)
`jection button is depressed to
`jection button is depressed to
`deliver the dose. One disadvan-
`deliver the dose. One disadvan(cid:173)
`tage of pen devices is that the in-
`tage of pen devices is that the in(cid:173)
`jection itself takes slightly longer
`jection itself takes slightly longer
`than does the traditional syringe
`than does the traditional syringe
`injection. The pen needle should
`injection. The pen needle should
`remain in the subcutaneous tissue
`remain in the subcutaneous tissue
`for 5 seconds after complete de-
`for 5 seconds after complete de(cid:173)
`pression of the plunger.
`pression of the plunger.
`Insulin cartridges are available
`Insulin cartridges are available
`in either a 1.5-mL or 3.0-mL
`in either a 1.5-mL or 3.0-mL
`volume (150 U or 300 U, respec-
`volume (150 U or 300 U, respec(cid:173)
`tively) and are specific for the
`tively) and are specific for the
`pen size (ie, a 150-U cartridge
`pen size (ie, a 150-U cartridge
`will not fit in a 300-U pen, and
`will not fit in a 300-U pen, and
`vice versa).
`vice versa).
`The following insulins are cur-
`The following insulins are cur(cid:173)
`rently available in 1.5 mL car-
`rently available in 1.5 mL car(cid:173)
`tridges: regular human insulin
`tridges: regular human insulin
`(Humulin R, Novolin R), human
`(Humulin R, Novolin R), human
`
`Insulin pen devices are
`Insulin pen devices are
`unique in that they combine
`unique in that they combine
`the insulin container and
`the insulin container and
`the syringe in a single unit.
`the syringe in a single unit.
`
`isophane insulin suspension
`isophane insulin suspension
`(Humulin N, Novolin N), 70%
`(Humulin N, Novolin N), 70%
`human isophane insulin suspen-
`human isophane insulin suspen(cid:173)
`sion with 30% regular human
`sion with 30% regular human
`insulin (Humulin 70/30, Novo-
`insulin (Humulin 70/30, Novo(cid:173)
`lin 70/30), and insulin lispro
`lin 70/30), and insulin lispro
`(Humalog).
`(Humalog).
`The cartridges should be stored
`The cartridges should be stored
`in the refrigerator before use. How-
`in the refrigerator before use. How(cid:173)
`ever, once a cartridge is placed in
`ever, once a cartridge is placed in
`a reusable pen, the pen can be
`a reusable pen, the pen can be
`kept at room temperature (<86°F)
`kept at room temperature ( <86°F)
`for a month, as long as it is away
`for a month, as long as it is away
`from direct heat and light.
`from direct heat and light.
`The pen and cartridge config-
`The pen and cartridge config(cid:173)
`urations vary, so that only Lilly
`urations vary, so that only Lilly
`3.0-mL cartridges fit Lilly, Becton
`3.0-mL cartridges fit Lilly, Becton
`Dickinson, and Owen Mumford
`Dickinson, and Owen Mumford
`3.0-mL pens. Novo Nordisk
`3.0-mL pens. Novo Nordisk
`3.0-mL cartridges fit only 3.0-mL
`3.0-mL cartridges fit only 3.0-mL
`NovoPens. The Disetronic pens
`NovoPens. The Disetronic pens
`accept any insulin but require use
`accept any insulin but require use
`of Disetronic cartridges.
`of Disetronic cartridges.
`The disposable needles that
`The disposable needles that
`are attached to insulin pens have
`are attached to insulin pens have
`some advantages over standard
`some advantages over standard
`syringe needles. Manufacturers
`syringe needles. Manufacturers
`offer pen needles that are one
`offer pen needles that are one
`third shorter (12.7 mm) than
`third shorter (12.7 mm) than
`standard-length needles and are
`standard-length needles and are
`a larger gauge (thus a smaller
`a larger gauge (thus a smaller
`bore diameter) for greater patient
`bore diameter) for greater patient
`comfort. Because the pen needle
`comfort. Because the pen needle
`
`does not puncture the stopper of
`does not puncture the stopper of
`an insulin vial before injection,
`an insulin vial before injection,
`the needle maintains its sharpness
`the needle maintains its sharpness
`and beveled angle, thereby po-
`and beveled angle, thereby po(cid:173)
`tentially reducing the pain of in-
`tentially reducing the pain of in(cid:173)
`jection, compared with the tradi-
`jection, compared with the tradi(cid:173)
`tional vial-and-syringe technique.
`tional vial-and-syringe technique.
`
`Clinical studies
`Clinical studies
`
`Although insulin pens have been
`Although insulin pens have been
`available for more than a decade,
`available for more than a decade,
`few clinical studies in the United
`few clinical studies in the United
`States have evaluated their use.
`States have evaluated their use.
`After the pen's introduction in
`After the pen's introduction in
`1985, J efferson and associates6
`1985, Jefferson and associates'
`evaluated patient preferences and
`evaluated patient preferences and
`blood-glucose control indexes in
`blood-glucose control indexes in
`10 adolescents with diabetes, aged
`10 adolescents with diabetes, aged
`12 to 17 years. Over a 3-month
`12 to 17 years. Over a 3-month
`period, mean glycosylated hemo-
`period, mean glycosylated hemo(cid:173)
`globin (HbA1 ) levels decreased
`globin (HbA1c) levels decreased
`from 13.7 ± 2.7% to 11.7 ± 3.4%.
`from 13.7 ± 2.7% to 11.7 ± 3.4%.
`Most patients, including those
`Most patients, including those
`who had increased their injections
`who had increased their injections
`from once daily to four times a
`from once daily to four times a
`day, reported the pen's advan-
`day, reported the pen's advan(cid:173)
`tages outweighed the inconve-
`tages outweighed the inconve(cid:173)
`nience of multiple injections.
`nience of multiple injections.
`One of the first pen devices on
`One of the first pen devices on
`the market was used in this study.
`the market was used in this study.
`Since that time, pens have un-
`Since that time, pens have un(cid:173)
`dergone many significant im-
`dergone many significant im(cid:173)
`provements.
`provements.
`In 1993, Plevin and Sadur7
`In 1993, Plevin and Sadur1
`assessed the acceptance of pen
`assessed the acceptance of pen
`injections among 64 adult
`injections among 64 adult
`patients-19 with type 1 and 45
`patients-19 with type 1 and 45
`with type 2 diabetes. Most of the
`with type 2 diabetes. Most of the
`patients had been treated with
`patients had been treated with
`insulin for 6 months to 43 years
`insulin for 6 months to 4 3 years
`before the study; 22 of the 64
`before the study; 22 of the 64
`continued
`continued
`
`VOL 106/ NO 5/ OCTOBER 15, 1999/ POSTGRADUATE MEDICINE /INSULIN DELIVERY
`VOL 106 / NO 5 / OCTOBER 15, 1999 / POSTGRADUATE MEDICINE / INSULIN DELIVERY
`
`61
`61
`
`Mylan Ex.1046
`Mylan v. Sanofi - IPR2018-01675
`
`

`

`Insulin delivery, continued
`Insulin delivery, continued
`
`Table 2. Features of commercially available insulin pen devices
`Table 2. Features of commercially available insulin pen devices
`
`B-D Pen Classic
`B-D Pen Classic
`1.5 ml
`1.5 mL
`(Becton Dickinson)
`(Becton Dickinson)
`
`B·D Pen Mini
`B-D Pen Mini
`(Becton Dickinson)
`(Becton Dickinson)
`
`Physical characteristics
`Physical characteristics
`Prefilled
`Prefilled
`Reusable
`Reusable
`1.5 ml, 150 units
`1.5 mL, 150 units
`3.0 mL, 300 units
`3.0 mL, 300 units
`3.15 ml, 315 units
`3.15 mL, 315 units
`Pediatric "POP" pens
`Pediatric "POP" pens
`Special color graphics
`Special color graphics
`Viewed size of dose numbers
`Viewed size of dose numbers
`greater than or equal to 0.1 in.
`greater than or equal to 0.1 in.
`{or clip-on magnifier)
`(or clip-on magnifier)
`
`Dosing features
`Dosing features
`Manufacturer's stated dosing
`Manufacturer's stated dosing
`increment {units)
`increment (units)
`Minimum/maximum
`Minimum/maximum
`dose {units)
`dose (units)
`Dark dosing number on
`Dark dosing number on
`light background
`light background
`Dial and dose using same knob
`Dial and dose using same knob
`Two-way dose dialing
`Two-way dose dialing
`Audible click when dialing
`Audible click when dialing
`Audible click when injecting
`Audible click when injecting
`End of injection stroke indication
`End of injection stroke indication
`Insufficient remaining dose
`Insufficient remaining dose
`{predose indication)
`(predose indication)
`Indicator returns to zero at
`Indicator returns to zero at
`dose completion
`dose completion
`
`N
`N
`y
`y
`N
`N
`N
`N
`y
`y
`N
`N
`
`1
`
`1/30
`1/30
`
`y
`
`y
`N
`N
`y
`y
`y
`N
`N
`
`y
`
`N, no; NPH, isophane insulin suspension; R, regular insulin; Y, yes.
`N, no; NPH, isophane insulin suspension; R, regular insulin; Y, yes.
`
`N
`N
`y
`y
`N
`N
`N
`N
`y
`N
`N
`N
`N
`
`0.5
`0.5
`
`0.5/15
`0.5/15
`
`y
`
`y
`N
`N
`y
`y
`y
`N
`N
`
`y
`
`patients were new insulin users.
`patients were new insulin users.
`During the 4-week study, mean
`During the 4,week study, mean
`fasting blood glucose concentra-
`fasting blood glucose concentra,
`tion decreased from 197 mg/dL to
`tion decreased from 197 mg/dL to
`171 mg/dL (P<.05), and none of
`171 mg/dL (P<.05), and none of
`the patients reported an episode
`the patients reported an episode
`of moderate or severe hypoglyce-
`of moderate or severe hypoglyce,
`mia. Patient comments regarding
`mia. Patient comments regarding
`the pen were extremely positive:
`the pen were extremely positive:
`98% reported the pen was conve-
`98% reported the pen was conve,
`nient and easy to use, and 91%
`nient and easy to use, and 91%
`wanted to continue its use.
`wanted to continue its use.
`In an Italian study,' the safety,
`In an Italian study, 1 the safety,
`efficacy, and acceptability of a
`efficacy, and acceptability of a
`prefilled insulin injection pen de-
`prefilled insulin injection pen de,
`vice was assessed in 60 patients
`vice was assessed in 60 patients
`with diabetes who were over 50
`with diabetes who were over 50
`years of age and were using con-
`years of age and were using con,
`ventional insulin syringes. Hypo-
`ventional insulin syringes. Hypo,
`glycemic episodes did not differ
`glycemic episodes did not differ
`significantly among patients us-
`significantly among patients us,
`ing syringes compared with those
`ing syringes compared with those
`using pens, and no marked hypo-
`using pens, and no marked hypo,
`glycemia was noted. Blood glu-
`glycemia was noted. Blood glu,
`cose profiles were similar for both
`cose profiles were similar for both
`types of insulin administration,
`types of insulin administration,
`except for prelunch blood glucose
`except for prelunch blood glucose
`values, which were lower with
`values, which were lower with
`pen use (157 ± 52 mg/dL versus
`pen use (157 ± 52 mg/dL versus
`166 ± 49 mg/dL [P<.01]). About
`166 ± 49 mg/dL [P<.01)). About
`90% of patients administered in-
`90% of patients administered in,
`sulin more quickly and easily with
`sulin more quickly and easily with
`the pen than with the conven-
`the pen than with the conven,
`tional syringe.
`tional syringe.
`The investigators concluded
`The investigators concluded
`that the prefilled insulin pen was
`that the prefilled insulin pen was
`safe, efficacious, and highly ac-
`safe, efficacious, and highly ac,
`cepted in patients with diabetes
`cepted in patients with diabetes
`over age 50.' Ease of accurate
`over age 50. 1 Ease of accurate
`dosing is particularly important
`dosing is particularly important
`for older patients, who may have
`for older patients, who may have
`impaired vision, arthritis, or
`impaired vision, arthritis, or
`continued
`continued
`
`62
`62
`
`INSULIN DELIVERY I VOL 106/ NO 5/ OCTOBER 15, 1999/ POSTGRADUATE MEDICINE
`INSULIN DELIVERY / VOL 106 / NO 5 / OCTOBER 15, 1999 / POSTGRADUATE MEDICINE
`
`Mylan Ex.1046
`Mylan v. Sanofi - IPR2018-01675
`
`

`

`Insulin delivery, continued
`
`Autopen AN 3000,
`AN 3100
`(Owen Mumford)
`
`Humalog, Humulin
`pens (R, NPH, 70/30)
`3.0 ml (Lilly)
`
`NovoPen 1.5 mL
`(Novo Nordisk)
`
`NovoPen 3.0 mL
`(Novo Nordisk)
`
`Novolin Prefilled
`pen (R, NPH, 70/30)
`1.5 mL (Novo Nordisk)
`
`Disetronic pen
`3.15 ml
`(Disetronic)
`
`N
`Y
`Y
`N
`N
`N
`N
`Y
`
`3000,1
`3100, 2
`3000, 1/16
`3100, 2/32
`N
`
`N
`N
`Y
`N
`N
`Y
`
`Y
`
`Y
`N
`N
`Y
`N
`N
`N
`Y
`
`1
`
`1/60
`
`Y
`
`Y
`Y
`Y
`N
`Y
`Y
`
`N
`
`N
`Y
`Y
`N
`N
`N
`Y
`N
`
`1
`
`1/40
`
`N
`
`Y
`N
`Y
`Y
`Y
`N
`
`Y
`
`N
`Y
`N
`Y
`N
`N
`Y
`N
`CO
`
`1
`
`2/70
`
`N
`
`Y
`N
`Y
`Y
`Y
`N
`
`Y
`
`Y
`N
`Y
`N
`N
`N
`N
`N
`
`2
`
`2/58
`
`Y
`
`N
`Y
`Y
`N
`N
`Y
`
`Y
`
`N
`Y
`N
`N
`Y
`N
`N
`Y
`
`1
`
`1/80
`
`Y
`
`Y
`Y
`Y
`Y
`Y
`Y
`
`N
`
`VOL 106 / NO 5 / OCTOBER 15, 1999 / POSTGRADUATE MEDICINE / INSULIN DELIVERY
`
`63
`
`

`

`Insulin delivery, continued
`Insulin delivery, continued
`
`may especially benefit. However,
`may especially benefit. However,
`people who take regular or lispro
`people who take regular or lispro
`insulin before meals or snacks
`insulin before meals or snacks
`and NPH insulin at bedtime usu-
`and NPH insulin at bedtime usu(cid:173)
`ally need two pens, one for each
`ally need two pens, one for each
`type of insulin. Also, patients
`type of insulin. Also, patients
`who take mixtures of two kinds
`who take mixtures of two kinds
`of insulin in one syringe (eg, reg-
`of insulin in one syringe ( eg, reg(cid:173)
`ular or lispro and NPH or lente
`ular or lispro and NPH or lente
`other than the 70/30 premixed
`other than the 70/30 premixed
`insulin) would need to use two
`insulin) would need to use two
`pens and two injections for each
`pens and two injections for each
`dose. This often is less desirable
`dose. This often is less desirable
`than the single-syringe injection
`than the single-syringe injection
`of mixed insulin.
`of mixed insulin.
`
`Children, adolescents, and young
`Children, adolescents, and young
`adults
`adults
`Children, whose perceptions of
`Children, whose perceptions of
`syringe injections include pain
`syringe injections include pain
`and rejection by peers, often have
`and rejection by peers, often have
`more positive feelings about the
`more positive feelings about the
`pens. The pens are particularly
`pens. The pens are particularly
`convenient for administering an
`convenient for administering an
`accurate dose of insulin in a
`accurate dose of insulin in a
`timely fashion for children with
`timely fashion for children with
`busy sports or activities schedules.
`busy sports or activities schedules.
`In addition, the lower insulin
`In addition, the lower insulin
`doses typically used in children
`doses typically used in children
`are easier to measure with the
`are easier to measure with the
`pen device. For young children,
`pen device. For young children,
`pediatric "POP" pens are avail-
`pediatric "POP" pens are avail(cid:173)
`able in various bright colors or
`able in various bright colors or
`patterns that easily differentiate
`patterns that easily differentiate
`rapid-acting insulin devices from
`rapid-acting insulin devices from
`those containing intermediate-
`those containing intermediate(cid:173)
`acting insulin.
`acting insulin.
`Because of the stereotypical
`Because of the stereotypical
`association of syringes with illicit
`association of syringes with illicit
`drug use, insulin administration
`drug use, insulin administration
`is a special concern for young
`is a special concern for young
`people with diabetes. In many
`people with diabetes. In many
`elementary schools, the vial-and-
`elementary schools, the vial-and-
`
`syringe method of injecting in-
`syringe method of injecting in(cid:173)
`sulin often is relegated to the
`sulin often is relegated to the
`principal's office, which carries
`principal's office, which carries
`negative connotations. By com-
`negative connotations. By com(cid:173)
`parison, the pen device generally
`parison, the pen device generally
`can be used right in the classroom.
`can be used right in t