686 Archives ofDisease in Childhood 1991; 66: 686-688

Evaluation of a pen injector system for growth Arch Dis Child: first published as 10.1136/adc.66.6.686 on 1 June 1991. Downloaded from hormone treatment

Peter D Gluckman, Wayne S Cutfield

Abstract the accuracy and economy of the injector pen The increasing use of human growth hormone relative to earlier formulations. (hGH) treatment has resulted in the introduc- tion of a number of alternative delivery sys- tems to conventional syringe and needle admi- Methods nistration. We examined patients' evaluation At the time of this survey, all patients received of a new delivery system, the Kabipen (Kabi- one of three formulations (Genotropin, Kabi- Vitrum). We also assessed the accuracy of Vitrum, Stockholm) of recombinant hGH: 4 hGH delivery by the Kabipen. Of the 77 sur- unit single dose vials, 12 unit multiple dose vey respondents 13 had used only the Kabi- vials, or the Kabipen (KabiVitrum) system. pen, 14 the syringe only, and 50 had used both The latter consists of an injector pen into which systems. Altogether 46 (92%) of those who is inserted a 16 unit cartridge of recombinant had used both systems preferred the Kabipen. hGH. The powdered hormone and diluent Children over 10 years were more likely to self within the cartridge are in separate compart- administer hGH with the Kabipen (64%) than ments. Automatic mixing occurs with insertion syringe (25%). Patient instructions, conveni- of the cartridge into the pen which is then avail- ence of use, and comfort of use were rated able for multiple and variable (0 5-4 units) dose better for the Kabipen than syringe. With a selection over several days without further pre- dose setting of 2 units the Kabipen delivered a paration. The pen was licenced in New Zealand mean (SD) of 1-997 (0.073) units with 102*5% in June 1989. recovery from a unit cartridge. In summary The survey evaluating modes of hGH treat- the Kabipen is an accurate device clearly pre- ment was conducted in April 1990. Of the 105 ferred by the majority of hGH recipients sur- children on the hGH treatment register, ques- veyed. tionnaires were sent to 96 with current ad- dresses. http://adc.bmj.com/ Anonymous questionnaires were completed Clinicians prescribing human growth hormone by the parent in conjunction with the subject (hGH) are aware of the problems that limit the receiving hGH. The questionnaire complied acceptance of this form of treatment by many with the guidelines of the human subjects families. Recent studies have unequivocally research ethical committee of the University of shown the value of daily rather than traditional Auckland. injections three times a week. 2 With the rapid The questionnaire evaluated the respondent's on September 26, 2021 by guest. Protected copyright. increase in utilisation of hGH as a result of its perception of: the benefits of the injector pen wider availability alternative delivery systems compared with conventional syringe based hGH have been developed to facilitate ease of ad- treatment, the adequacy of patient/family in- ministration. struction on use of hGH administration, satis- The traditional form of hGH formulation has faction regarding information provided on the been a single dose vial, which had to be recon- growth disorder, and on the response to treat- stituted with diluent for each injection. More ment. recently multiple dose vials have been develo- Subject preference with explanation was ped in which several doses can be drawn into requested of those who had used both systems. syringes from a single reconstituted vial. Most Subjects were asked to rate the quality of recently a device originally developed for instructions provided, the convenience of use, insulin administration, the pocket injector pen,3 and the comfort of use for each type of delivery has been applied to hGH treatment. Although system they had used. The subject was also some hGH injector pens still require reconsti- asked to comment on whether the system could tution of the powdered formulation in vials and be improved and to detail technical or practical transfer to the injector unit, others utilise speci- problems with the device. Qualitative scales Department of fic vials for the injector device and thus mini- were also used to rate satisfaction with the clini- Paediatrics, University of Auckland, mise patient involvement and error in preparing cal service provided. Private Bag, the formulation. New Zealand was the first Both of the authors randomly and indepen- Auckland, country to licence a pen for hGH treatment and dently evaluated the accuracy of the hormone New Zealand Peter D Gluckman the purpose of this paper is to review our experi- delivery systems. A random selection of pens Wayne S Cutfield ence. We report on the results of a blinded was used to deliver eight doses of 2 units each Correspondence to: questionnaire of patients and their families into preweighed vials. The needle was replaced Dr Cutfield. which compared the injector pen with conven- after each dose. The manufacturer's instruc- Accepted 5 February 1991 tional syringe administration. We also report on tions for priming and delivery were followed Evaluation ofa pen injector system for growth hormone treatment 687

exactly. By weighing the vial before and after Table 2 Comparison of both systems by respondents who priming and at the end of the delivery of the used both (mean score,* n=SO) eighth dose the actual delivery from a 16 unit Pen Syringe p Valuet Arch Dis Child: first published as 10.1136/adc.66.6.686 on 1 June 1991. Downloaded from vial was assessed. Similarly the accuracy and Quality of instructions 1-5 2-3 <0 01 recovery from 12 unit vials was carefully asses- Convenience of use 1-3 3-3 <0 01 sed by the authors using 1 ml B-D plastipak Comfort of use 2-2 3 5 <0 01 syringes (Becton-Dickinson) with microfme III *A 1-5 rating system was used with 1 indicating the most needles. The syringe and needle were replaced favourable response. tMann-Whitney test. after every second dose.

Table 3 Accuracy of 2 unit delivery DATA ANALYSIS was tech- Kabipen Genotropin* Statistical analysis by non-parametric (n=35)t 12 unit vial niques as the ratings used a ordinal not interval (n= 18)t scale. The Mann-Whitney test was used for two Mean (SD) (units) 1-997 (0-073) 2 000(0 067) sample comparison, the Kruskal-Wallis test for Coefficient of variation (%) 335 3-33 oneway analysis of variance, and the Wilcoxon Experimental range (units) 1-87-2-08 1-82-2-06 matched pair signed rank test for paired data; x2 *Delivered by B-D plastipak 1 ml syringe and microfme III analysis was used for frequency distribution needle. analysis. tNumber of doses weighed. number of respondents who had used only the Results pen (n= 13) or syringe (n= 14) were compared, Of 80 returned questionnaires three were exclu- there were no differences in patient evaluation. ded from the analysis: one had discontinued Of the 63 injector pen users, 13 had minor treatment, one had yet to start, and one return problems in the initial month of use solved by was incomplete. The analysis is based on a 83% further training. Eleven pens were replaced response rate. because of mechanical problems; however of Fifty respondents had used both the syringe these nine were from the first production batch and injector pen system. Fourteen had used and occurred in the first months after licensing. only a syringe system and of these nine were Subsequently mechanical problems have not currently using a multiple dose vial and five been encountered. Only two subjects had were using the 4 unit vial. Thirteen had used switched back to a syringe system, both because only the injector pen-the latter were those most they found the pen heavy to use and had been recently placed on hGH treatment. on a syringe system for some years previously. The hormone was self administered in 35 The injector pen and syringe systems are of subjects and by a parent for the remaining sub- comparable accuracy with the coefficient of http://adc.bmj.com/ jects except for one infant where the hormone variation for the delivery of a 2 unit dose being was administered by a visiting nurse. When the 3 5% and 3-3% respectively (table 3). The reco- analysis was restricted to children 10 years or vered hormone from a vial averaged 102-5% in older, self administration was far more likely the pen system and 100% for the 12 unit vial using the injector pen (64%) than the syringe system. (25%, p<0 04) (table 1). The most useful sources of patient education with regard to hGH administration were clearly Discussion on September 26, 2021 by guest. Protected copyright. the clinic nurse and/or videotaped administra- Relatively little consideration has been given to tion demonstration (67% of respondents). Other the patient perspective for hGH treatment. His- health professionals (9%), pharmaceutical rep- torically this reflects the fact that until recently resentatives (8%), doctors (7%), and written restrictions on hGH supply and the generally material (4%) played only a minor role. non-commercial origin of the hormone meant There were appreciable differences when that there was little motivation to consider these patient evaluation of the injector pen and apsects. However the use of hGH has increased syringe delivery systems were compared (table considerably after the introduction in 1985 of 2). Of the 50 respondents who had used both commercially produced recombinant hGH.A delivery systems, 92% indicated a preference for The range of indications continues to broaden the injector pen. The quality of instructions and it is now generally accepted that daily injec- (p<0-01), the convenience of use (p<001), and tions are the minimum frequency for an optimal the comfort of use (p<0-01) were rated signifi- growth response.9 It is now evident that hGH cantly better for the injector pen than for the should be prescribed in relation to body size syringe systems (table 2). When the small rather than as the traditional fixed dose regimen of 4 units three times a week.'0 11 Conse- quently, the need for administration systems Table I Administration of hGH that allow for individualised daily dose sched- Total study (n= 77) Subjects ¢10 years ules has become important to avoid wastage (n=55)* from either excessive hormone administration Pen users Syringe Pen users Syringe or incomplete vial usage. The multiple dose vial users users systems achieve that purpose, but do not greatly Subject 31 4 30 2 alter the convenience for the patient or care Care giver 32 10 17 6 giver, except for the reduced frequency of vial *p<0 05 by x2 test. preparation. 688 Gluckman, Cutfield

The child on hGH treatment is faced with trast the handling of any syringe system will daily injections for a number of years. Given the involve greater risk of error and of hormone need to maintain sterility and for appropriate loss or contamination. However, it should be Arch Dis Child: first published as 10.1136/adc.66.6.686 on 1 June 1991. Downloaded from storage of the hormone and diluent vials, there noted that not all injector pen systems are are a number of practical inconveniences as- equivalent. At least two other systems are sociated with classical formulations of hGH. marketed which require extensive handling of These are perceived by many families as intru- the hormone by the patient as the vial is not pre- sive on their life styles. In addition the problems loaded. As accuracy of dose delivery, hormone arising from the use of syringes and needles recovery, and cost are all equivalent in the sys- appear somewhat complex to families-this is tems we evaluated then the major consideration seen in the present study among children 10 in the choice of a delivery system must be years or older who are far more likely to self patient comfort. The present study clearly administer hGH by Kabipen than syringe demonstrates patient preference for the injector (table 1). pen delivery system. Little consideration has been previously The survey also clearly shows that the most given to the patient's attitudes in the choice of successful way to educate patients and their hGH delivery systems. We assessed in blind families is to use a clinic nurse educator and/or a fashion the responses of 50 families who had videotape. experienced a syringe system before use of the In summary the Kabipen is an injector injector pen. Most (92%) preferred the injector device that accurately delivers the dose set with- pen primarily because of the greater conveni- out any wastage from a 16 unit cartridge. When ence. This included the considerably less time compared with syringe administration the needed each day for hormone administration, Kabipen was clearly preferred by the majority the less complex preparation, the greater free- of patients and was more likely to result in self dom to travel with less equipment, and a greater administration in older children. 'sense of independence'. These advantages were reflected in the increased frequency of self This work was funded in part by the Medical Research Council of New Zealand. We thank Ms Karen Tailuga and Vanessa Cox for administration among pen users. Such auto- their assistance. nomy facilitates the adaptation of the child to his/her treatment programme. Several families 1 Albertsson-Wikland K, Westphat 0, Westgren U. Daily also expressed the concern that syringes and subcutaneous administration of human growth hormone in needles stored in the house could be taken and growth hormone deficient children. Acta Paediatr Scand 1986;75:89-97. used for illicit drug use. The pen was also consi- 2 Kastrup KW, Sandahl Christiansen J, Koch Anderson J, dered to be significantly more comfortable to Orskov H. Increased growth rate following transfer to daily s.c. administration from three weekly i.m. injections of use, although only a few (8%) gave this hGH in growth hormone deficient children. Acta Endo- increased comfort as the primary reason for pre- crinol (Copenh) 1983;104:148-52. 3 Saubrey N, Arnold-Larsen S, Moller-Jensen B, Kuhl C. ferring the pen. Comparison of continuous subcutaneous insulin infusion http://adc.bmj.com/ The reasons given by the small subgroup with multiple insulin injections using the novopen. Diabetic Medicine 1988;5:150-3. (8%) of subjects who preferred the syringe sys- 4 Rosenfeld RG, Hintz RL, Johanson AJ, et al. Three year tem principally included dissatisfaction regard- results of a randomised prospective trial of methionyl human growth hormone and oxandrolone in Turner syn- ing pen administration instruction and lack of drome. J Pediatr 1988;113:393-400. information on and/or disappointment with 5 Takano K, Shizume K, Hibi I. Turner syndrome: treatment of 203 patients with recombinant human growth hormone growth progress. These concerns appear to be a for one year. Acta Endocrinol (Copenh) 1989;120:559-68. reflection of inadequate information rather than 6 Wit JM, Fokker MH, de Muinck Keizer Schrama SM, et al. Effects of two years of methionyl growth hormone therapy on September 26, 2021 by guest. Protected copyright. any technical benefits that the syringe system in two dosage regimens in prepubertal children with short had to the injector pen. stature, subnormal growth rate and normal growth hormone response to secretagogues. J7 Pediatr 1989;115: Very similar scores were given for the injector 720-5. pen by those who had only used the injector pen 7 Koch VH, Lippe BM, Nelson PA, Boechat MI, Sherman BM, Fine RN. Accelerated growth after recombinant and those who had used both systems. How- human growth hormone treatment ot children with chronic ever, those who had used only the syringe sys- renal failure. J Pediatr 1989;115:365-71. 8 Stanhope R, Ackland F, Hamill G, Clayton J. Physiological tems tended to rate the syringe based systems growth hormone secretion and response to growth hormone better than those who had experience of both, treatment in children with short stature and intrauterine growth retardation. Acta Paediatr Scand [Suppl] 1989;349: reflecting that this was a group of older and 47-52. longer treated patients, who had generally been 9 Smith PJ, Hindmarsh PC, Brook CG. Contribution of dose and frequency of administration to the therapeutic effect of reluctant to change systems and were generally growth hormone. Arch Dis Child 1988;63:491-4. satisfied with their management. 10 Preece MA, Tanner JM, Whitehouse RH, Cameron N. Dose dependence of growth response to human growth hormone No difference in accuracy or recovery was in growth hormone deficiency. J Clin Endocrinol Metab observed between the two systems. However, 1975;42:477-83. the of the vial is minimal for the injec- 11 Frasier SD, Costin G, Lippe BM, Aceto T, Bunger PF. Dose handling response curve for human growth hormone. J Clin Endo- tor pen system assessed in this study. In con- crinol Metab 1981;53:1213-7.