Arch Dis Child 1998;79:59–62
`
`59
`
`Accuracy and reproducibility of low dose insulin
`administration using pen-injectors and syringes
`
`M G Gnanalingham, P Newland, C P Smith
`
`Abstract
`Many children with diabetes require small
`doses of insulin administered with sy-
`ringes or pen-injector devices (at
`the
`Booth Hall Paediatric Diabetic Clinic,
`20% of children aged 0–5 years receive
`1–2 U insulin doses). To determine how
`accurately and reproducibly small doses
`are delivered, 1, 2, 5, and 10 U doses of
`soluble insulin (100 U/ml) were dispensed
`in random order 15 times from five new
`NovoPens (1.5 ml), five BD-Pens (1.5 ml),
`and by five nurses using 30 U syringes.
`Each dose was weighed, and intended and
`actual doses compared. The two pen-
`injectors delivered less insulin than sy-
`ringes,
`diVerences
`being
`inversely
`proportional
`to dose. For 1 U (mean
`(SD)): 0.89 (0.04) U (NovoPen), 0.92
`(0.03) U (BD-Pen), 1.23 (0.09) U (sy-
`ringe); and for 10 U: 9.8 (0.1) U (Novo-
`Pen), 9.9 (0.1) U (BD-Pen), 10.1 (0.1) U
`(syringe). The accuracy (percentage er-
`rors) of the pen-injectors was similar and
`more accurate than syringes delivering 1,
`2, and 5 U of insulin. Errors for 1 U:
`11(4)% (NovoPen),
`8(3)% (BD-Pen),
`23(9)% (syringe). The reproducibility
`(coeYcient of variation) of actual doses
`was similar (< 7%) for all three devices,
`which were equally consistent at under-
`dosing (pen-injectors) or overdosing (sy-
`ringes)
`insulin. All
`three
`devices,
`especially syringes, are unacceptably in-
`accurate when delivering 1 U doses of
`insulin. Patients on low doses need to be
`educated that their dose may alter when
`they transfer from one device to another.
`(Arch Dis Child 1998;79:59–62)
`
`Keywords: pen-injector device; insulin syringes; insulin
`administration; low dose insulin
`
`In 1983, U100/ml insulin was introduced and
`the more dilute U40/ml and U80/ml insulins
`were withdrawn in the UK. This simplified
`treatment and reduced the potential for dosage
`errors, but it also resulted in small doses of
`insulin being dispensed in extremely small vol-
`umes (1 U = 0.01 ml). Many children require
`small doses and these may be administered
`using a variety of pen-injector devices or diVer-
`ent sized syringes. It is obviously important
`that small doses are administered accurately,
`and that the magnitude of potential dosage
`error is appreciated. Furthermore, because
`patients may change from using syringes to
`pen-injectors, any diVerences in dosage accu-
`
`racy and precision using these devices should
`be recognised.
`The limitations of professionals and patients
`attempting to draw up small doses of insulin
`into syringes are well recognised,1 2 inaccura-
`cies being inversely proportional to the pre-
`scribed dose of insulin.1 Casella et al concluded
`that insulin injections of less than 20 µl (2 U of
`U100) administered by syringe had an unac-
`ceptably large error.2 Similar
`information
`about pen-injector devices
`is not
`readily
`available, although one report found that the
`NovoPen 1 delivered 2 U very accurately.3
`To establish a policy for the administration
`of small doses of insulin, we compared the
`accuracy and reproducibility of administering
`small doses of insulin using two pen-injector
`devices and 30 U insulin syringes.
`
`Methods
`To determine how frequently children require
`insulin doses of < 5 U, the insulin regimen and
`individual doses used by children attending the
`Booth Hall Paediatric Diabetic Clinic were
`collected from their last outpatient visit. The
`children’s age, sex, and duration of disease
`were recorded, and the device used (pen-
`injector or syringe) for insulin injection was
`noted.
`To determine how accurately and reproduc-
`ibly two pen-injector devices deliver small
`doses of insulin, five new NovoPens (1.5 ml)
`(NovoNordisk Pharmaceuticals) and five new
`BD-Pens (1.5 ml) (Becton Dickinson, Oxford,
`UK) with 29 G needles (BD microfine) were
`used to deliver Humulin S (Eli Lilly, Basing-
`stoke, Hants, UK) and Human Actrapid
`(NovoNordisk Pharmaceuticals, Crawley, West
`Sussex, UK) insulin, respectively. The 1.5 ml
`insulin cartridges (100 U/ml) were left at room
`temperature for two hours before use. Before
`the sequence of measurements was made from
`each cartridge, an “air shot” was performed
`and 5 U insulin was wasted. From each pen, 1,
`2, 5, and 10 U doses were expelled in random
`order 15 times, and the mean was used in sub-
`sequent analyses. All measurements were
`performed by a single investigator (MG) who
`waited 10 seconds after depressing the plunger
`each time to ensure that all the dialled dose was
`expelled. Each dose of insulin was deposited
`onto a polystyrene weighing container and was
`weighed immediately using an analytical bal-
`ance (Avery Berkel FA214 balance; Avery Ber-
`kel Ltd, Shirley Institute, Manchester, UK)
`which has an accuracy of 0.0001 g and a
`reproducibility of < – 0.0001 g. The balance
`has an autocalibration facility, and was zeroed
`before the next dose of insulin was deposited
`and weighed.
`
`Department of
`Paediatrics, Booth
`Hall Children’s
`Hospital, Charlestown
`Road, Blackley,
`Manchester M9 2AA,
`UK
`M G Gnanalingham
`C P Smith
`
`Department of Clinical
`Biochemistry, Booth
`Hall Children’s
`Hospital
`P Newland
`
`Correspondence to:
`Dr Smith.
`
`Accepted 3 February 1998
`
`MYLAN INST. EXHIBIT 1071 PAGE 1
`
`MYLAN INST. EXHIBIT 1071 PAGE 1
`
`

`

`60
`
`Gnanalingham, Newland, Smith
`
`For comparison, five paediatric nurses who
`regularly administered insulin, used 30 U
`insulin syringes with 29 G needles (BD micro-
`fine) to draw up the same doses (1, 2, 5, and
`10 U) of soluble insulin (100 U/ml) in random
`order 15 times. The vials of insulin were left at
`room temperature for two hours before use.
`Individual doses were expelled and weighed as
`previously described and the nurses were
`unable to view the results.
`To study the pen-injector devices further, we
`considered whether the device or the insulin
`cartridge was the main source of any error. The
`BD-Pen and the NovoPen that had the lowest
`percentage error during the initial experiment
`were selected for further study. Following
`appropriate air shots, 5 U of soluble insulin
`were dispensed and measured repeatedly until
`each insulin cartridge was emptied. Measure-
`ments were made using five cartridges of
`Humulin S and Human Actrapid insulin in the
`BD-Pen and NovoPen, respectively. For the
`purposes of analysis, each cartridge was
`divided into first, second, third, and fourth
`quarters, and there was an average of seven
`measurements from each of the quarters.
`To validate the methodology that formed the
`basis of this study, 10 µl of distilled water or
`10 µl of soluble insulin was dispensed 15 times
`using a laboratory pipette (10 µl Gilson Micro-
`man Bio-pipette; Villiers-le-bel, France) and
`was weighed as described previously. Aliquots
`of water had a mean (SD) weight of 0.01001
`(0.00027) g and insulin samples weighed
`0.00963 (0.00021) g. The coeYcient of varia-
`tion for the method was < 3%, and for the pur-
`poses of this study it was assumed that 10 U of
`insulin (10 µl) weighed 0.01 g.
`Dose accuracy and reproducibility were
`defined as follows:
`
`intended dose−
`Accuracy (% error) = actual dose dispensed
`intended dose
`
`·100%
`
`·100%
`
`Reproducibilty
`(coeYcient of
`variation)
`
`standard
`= deviation of mean
`mean of actual dose
`dispensed
`All results were presented as means (SD)
`unless otherwise stated. Data were analysed by
`two factor ANOVA to determine population dif-
`ferences and by post hoc Duncan’s multiple
`range test to detect intergroup variation. The
`interaction term states the relation between the
`device used and the intended dose of insulin. A
`probability of < 0.05 was considered signifi-
`cant.
`
`Results
`One hundred and twelve children (64 boys and
`48 girls) attended the clinic. Their mean (SD)
`age was 11.51 (4.21) years and duration of dis-
`ease 4.48 (3.52) years. Insulin was adminis-
`tered twice daily (101 children), once daily
`(seven children) or four times daily (three chil-
`dren). One girl who had autoimmune entero-
`pathy received subcutaneous insulin once daily
`and insulin by intravenous infusion overnight
`while she received total parenteral nutrition.
`Twenty six of the 112 children were adminis-
`
`Table 1 Doses of insulin delivered by two pen-injector
`devices and 30 U insulin syringes
`
`Intended
`dose
`
`1 U
`
`2 U
`
`5 U
`
`10 U
`
`Mean (SD) delivered dose (U) (range)
`
`NovoPen
`
`BD-Pen
`
`30 U syringe
`
`0.89 (0.04)
`(0.85–0.95)
`1.90 (0.03)
`(1.85–1.93)
`4.87 (0.03)
`(4.84–4.91)
`9.80 (0.09)
`(9.72–9.94)
`
`0.92 (0.03)
`(0.87–0.95)
`1.90 (0.05)
`(1.82–1.94)
`4.87 (0.07)
`(4.77–4.94)
`9.86 (0.09)
`(9.73–9.96)
`
`1.23 (0.09)*
`(1.16–1.37)
`2.24 (0.09)*
`(2.15–2.35)
`5.18 (0.06)*
`(5.10–5.26)
`10.07 (0.07)*
`(9.97–10.14)
`
`*At all intended doses, 30 U syringes delivered significantly
`higher doses than the pen-injector devices (p < 0.01).
`
`tered one or more doses of 1–5 U insulin and
`the other five received one or more doses of
`only 1–2 U. Of 15 children aged 0–5 years,
`three were receiving doses of only 1–2 U. Pen-
`injector devices were used by 101 children and
`appropriately sized insulin syringes by the
`other 11 children. Only one child was receiving
`self mixed insulin.
`Table 1 shows the intended and actual doses
`of insulin delivered by the pen-injectors and
`syringes. The two pen-injector devices deliv-
`ered significantly less insulin than did experi-
`enced nurses using 30 U insulin syringes at all
`doses
`studied (pen-injectors
`syringes,
`v
`F = 151,
`p < 0.0001;
`units
`of
`insulin,
`F = 58160, p < 0.0001;
`interaction term,
`F = 1, p = 0.4). There were no diVerences in
`the mean insulin dose delivered by NovoPens
`and BD-Pens, and both tended to underdose.
`Nurses using 30 U syringes tended to over-
`dose, particularly when attempting to deliver
`1 U (+34% and +38% compared with Novo-
`Pens and BD-Pens, respectively) and 2 U
`(+18% compared with both pen-injectors).
`Figure 1 shows the percentage error (accu-
`racy)
`and
`coeYcient
`of
`variation
`(reproducibility) with which the pen-injector
`devices and 30 U syringes delivered small
`doses of insulin. Over the dose range studied,
`both pen-injector devices performed similarly
`and had lower percentage errors overall than
`nurses using 30 U syringes (pen-injectors v
`syringes, F = 130, p < 0.0001). For 1, 2, and
`5 U insulin doses, the percentage error using
`syringes was greater than with the NovoPen
`and BD-Pen (p < 0.01). With all three devices,
`the percentage error diminished with increas-
`ing doses of insulin: 1 > 2 > 5 ~10 U (units of
`insulin, F = 1.6, p < 0.2;
`interaction term,
`F = 29, p < 0.0001).
`Figure 1B shows how reproducibly small
`doses of insulin can be delivered using the three
`devices, regardless of their accuracy. The coef-
`ficient of variation was
`similar
`for both
`pen-injector devices and for the 30 U insulin
`syringes (F = 0.5, p = 0.6) —that is, they were
`equally consistent at under or overadminister-
`ing insulin. With all three devices, the coef-
`ficient of variation diminished with increasing
`insulin: 1 > 2 > 5 ~10 U (F = 52,
`doses of
`p < 0.0001;
`interaction
`term,
`F = 0.4,
`p = 0.9).
`There were no diVerences in the 5 U doses
`of insulin delivered from the four quarters of
`
`MYLAN INST. EXHIBIT 1071 PAGE 2
`
`MYLAN INST. EXHIBIT 1071 PAGE 2
`
`

`

`Accuracy and reproducibility 11low dose insulin adminirmtum
`
`61
`
`|:| NovoPen
`- BD Pen
`
`Key messages
`0 Insulin doses of < 2 U are administered
`inaccurately by syringe and pen-injector
`devices
`
`The reproducibility (coefficient of varia-
`tion) of actual doses was similar (< 7%)
`using two pen-injector devices (NovoPen
`and BD-Pen), and 30 U syringes
`
`and nurses
`Pen-injectors underdose
`using 30 U syringes overdose insulin
`
`Transferring patients on low insulin
`doses from syringe to pen—injector may
`result in a significant dose change
`
`than the nurses could} Bell et al reported much
`higher percentage errors (45% for 2 U, 20% for
`5 U) probably because their study involved self
`mixing regular and isophane insulins, which
`were shown to be far less accurate, and the par-
`ticipants were not allowed to overdraw the
`syringe and evacuate the excess.‘ Disappoint-
`ingly, use of the narrower bore 30 U syringe
`instead of 50 U and 100 U syringes did not
`improve
`the
`accuracy
`or
`precision of
`professionals,‘ 2 but in patients there was a
`small but significant
`improvement at
`low
`doses} Because 30 U syringes were better or
`certainly no worse at delivering small doses, we
`confined ourselves to the 30 U syringe in this
`study.
`Information about the accuracy and preci-
`sion of pen-injector devices delivering small
`doses is not readily available, although Gordon
`and colleagues’ reported that the accuracy of
`NovoPen l delivering 2 U was good, having a
`percentage error of 2.8%. This compares with
`percentage errors of 5.1% for 2 U doses
`administered using the NovoPen 1.5 or the
`BD-Pen 1.5 in our study. Our results demon—
`strated that the accuracy and reproducibility of
`the NovoPens and BD—Pens were similar and
`
`both improved as the dose increased. Both
`pen-injectors were signifimntly more accurate
`than 30 Uinsulin syringes atdoses of 1,2,and
`5 U but, perhaps surprisingly, the variability of
`actual doses administered was very similar
`between the pen devices and syringes. Our
`results demonstrated that when using syringes
`there was a human bias towards overdosage
`while pen—injector devices tended to under—
`dose. This is important if one is considering
`transferring patients fiom syringe to pen or vice
`versa. An intended dose of l U may be an
`actual dose of 0.89 U by pen or 1.23 U by
`syringe, so changing fi'om one device to the
`other would amount to a change in dose of
`38%.
`
`favourably on pen—
`This study reflects
`injector devices in terms of their accuracy, and
`the BD—Pen and NovoPen were equally good.
`It must be remembered, however, that there are
`numerous opportunities to introduce error
`when using such devices in clinical practice—
`for example, when patients do not remove the
`needle between injections or do not do an air
`shot before iniecting.‘ Also, insufin is delivered
`
`MYLAN INST. EXHIBIT 1071 PAGE 3
`
`- Syringes
`
`Coefficientofvariation(96)
`
`
`
`Error(56)
`
`2
`
`5
`
`10
`
`Insulin (units)
`
`(A) Meanpercentageenvrand (B) meficiens afvariaa'on (SD) when
`Figure I
`delivering],2, 5,and10 UafinsulinusingfiveNmPensHfiwBD-Pens andfive30U
`wliiremhdevtce,amnof15mndommeasmmmnafeachdouqfinsulhm
`calculated‘p<0.,05fp<0.,011Udiflasfivm 2,5,0r10Uddiveredbythesame
`device, ‘“p<0.,01 30UsyringesdiflersfiumNovoHemandBD—Pensforthesamedoseof
`insulin. (TwofactorANom andposthocDuncansmultiple rung test.)
`
`the cartridges in the NovoPens and BD-Pens
`(F = 0.42, p = 0.7) (results not shown).
`
`Discussion
`This is the first study to compare the accuracy
`and reproducibility of pen—injectors and sy—
`ringes delivering small doses of insulin. Previ-
`ous studies have shown that delivering small
`doses of insulin using 30, 50, and 100 U
`syringes is extremely inaccurate and imprecise
`with
`a
`human
`bias
`towards
`over-
`
`administration.‘ 2 Casella et al reported that
`paediatric nurses attempting to deliver 0.5, l .0,
`and 2.0 U insulin resulted in delivered doses of
`0.975 (0.315), 1.638 (0.376), and 2.153
`(0.435) U, respectivelyl; an overdose of 95%,
`64%, and 7.5%, respectively. They concluded
`that insulin injections of less than 20 ul (2 U of
`UlOO/ml) had an unacceptably large error
`when administered by syringe. Our results
`concurred with this, the percentage errors of
`paediatric nurses drawing up 1U and 2 U
`doses using 30 U insulin syringes being 23%
`and l 2%, respectively. It is interesting that par-
`ents could draw up insulin more accurately
`
`MYLAN INST. EXHIBIT 1071 PAGE 3
`
`MYLAN INST. EXHIBIT 1071 PAGE 3
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`

`

`62
`
`Gnanalingham, Newland, Smith
`
`more slowly from cartridges than syringes
`because of the compressible elements of the
`cartridge.4 If patients fail to leave the needle in
`place for the recommended five or 10 seconds
`after pushing down the plunger (when using
`12.7 mm 29 G or 8 mm 30 G needles, respec-
`tively), they may administer less insulin than
`intended.
`We tried to determine whether the devices or
`the insulin cartridges were the most important
`source of error
`for
`the pen-injectors. By
`comparing the doses delivered from the four
`quarters of the cartridge, we attempted to
`detect errors created by defects in the glass cyl-
`inders
`that make up the cartridges. No
`diVerences were found between the doses
`delivered from the diVerent parts of
`the
`cartridge, but we acknowledge that we used
`fairly crude methodology. Becton Dickinson
`informed us that the glass cartridges were
`probably the most important source of dosage
`variability (personal communication).
`Added to the considerable inaccuracies and
`variability involved in administering small vol-
`umes of insulin, there are many other factors
`that aVect the absorption and hence the activ-
`ity profile of insulin. The reported intraindi-
`vidual and interindividual variation of absorp-
`tion is about 25% and 50%, respectively,5 6 and
`children are at high risk of receiving inadvert-
`ent intramuscular injections,7 8 which leads to
`faster absorption.9 10
`In conclusion, administering small volumes
`of insulin is fraught with problems, and yet in
`this study 20% of children aged 0–5 years were
`receiving doses of 1–2 U (10–20 µl of U100/
`ml). The incidence of diabetes in children aged
`0–4 years is increasing by 11% per year11 at a
`time when we know we should strive for
`normoglycaemia.12 However, tight control re-
`sults
`in
`a
`significant
`risk
`of
`severe
`hypoglycaemia,12 which is potentially more
`harmful in this age group.13 Any dosing error
`will increase this risk and so perhaps we should
`
`consider requesting the reinstatement of the
`more dilute U40 insulin, which is still available
`in some countries. This would enable parents
`to deliver small doses more accurately and pre-
`cisely. Alternatively, we should consider giving
`once rather than twice daily injections to
`children whose evening dose is less than 2 U,
`and possibly to those receiving 2 U doses.
`
`We are grateful to Sue Bennett (diabetes specialist nurse) and
`Franscine Radivan (senior pharmacist) for their help; as well as
`to Eli Lilly and Co and Novo Nordisk Pharmaceuticals Ltd for
`supplying the insulin.
`
`1 Bell DSH, Clements RS, Perentesis G, Roddam R,
`Wagenknecht L. Dosage accuracy of
`self-mixed vs
`premixed insulin. Arch Intern Med 1991;151:2265–9.
`2 Casella SJ, Mongilio RN, Plotnick LP, Hesterberg P, Long
`CA. Accuracy and precision of low-dose insulin adminis-
`tration. Pediatrics 1993;91:1155–7.
`3 Gordon D, Wilson M, Paterson KR, Semple CG. An assess-
`ment of the accuracy of NovoPen 1 delivery after prolonged
`use. Diabetic Medicine 1990;7:364–6.
`4 Ginsberg BH, Parkes JL, Sparacino C. The kinetics of insu-
`lin administration by insulin pens. Horm Metab Res
`1994;26:584–7.
`5 Galloway JA, Spradlin CT, Nelson RL, Wentworth SM,
`Davidson JA, Swarner JL. Factors influencing the absorp-
`tion, serum insulin concentration, and blood glucose
`responses after injections of regular insulin and various
`insulin mixtures. Diabetes Care 1981;4:366–76.
`6 Kolendorf K, Aaby P, Westergaard S, Deckert T. Absorption
`eVectiveness and side-eVects of highly purified porcine
`NPH-insulin preparations. Eur J Clin Pharmacol 1978;14:
`117–24.
`7 Smith CP, Sargent MA, Wilson BPM, Price DA. Subcuta-
`neous or intramuscular insulin injections. Arch Dis Child
`1991;66:879–82.
`8 Polak M, Beregszaszi M, Belarbi N, Benali K, Hassan M,
`Czernichow P, et al. Subcutaneous or intramuscular injec-
`tions of insulin in children. Diabetes Care 1996;19:1434–6.
`9 Frid A, Gunnarsson R, Guntner P, Linde B. EVects of acci-
`dental
`intramuscular injection on insulin absorption in
`IDDM. Diabetes Care 1988;11:41–5.
`10 Spraul M, Chantelau E, Koumoulidou J, Berger M. Subcu-
`taneous or nonsubcutaneous injection of insulin. Diabetes
`Care 1988;11:733–6.
`11 Gardner SG, Bingley PJ, Sawtell PA, Weeks S, Gale EAM,
`the Bart’s-Oxford Study Group. Rising incidence of insulin
`dependent diabetes in children aged under 5 years in the
`Oxford region: time trend analysis. BMJ 1997;315:713–17.
`12 The Diabetes Control and Complications Trial Research
`Group. The eVect of intensive treatment of diabetes on the
`development and progression of long-term complications
`in insulin-dependent diabetes mellitus. N Engl J Med 1993;
`329:977–86.
`13 Gold AE, Frier BM. Hypoglycaemia—practical and clinical
`implications. In: Kelnar CJH, ed. Childhood and adolescent
`diabetes. London: Chapman & Hall Medical, 1995:351–66.
`
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