Evolution of Growth Hormone Devices: Matching Devices with Patients Dawn Raimer-Hall and Heidi Chamberlain Shea

G

rowth hormone deficiency (GHD) was initially treated in the 1950s with growth hormone (GH) extracted from human pituitary glands. Recombinant forms of GH became available in the 1980s, produced by either genetically engineered Escherichia coli (E. coli) or a mammalian cell-derived recombinant form using murine C127 cells (Flodh, 1986; Zeisel, von Petrykowski, & Wais, 1992). The unlimited availability of recombinant GH allowed the expansion of treatment for GH-related disorders. The etiology of GH-related disorders in children is varied, and FDA-approved pediatric GH treatment indications currently include GHD, small for gestational age (SGA) without catch-up growth, idiopathic short stature, Turner syndrome with short stature, Noonan syndrome with short stature, Prader-Willi syndrome (PWS) with short stature, short stature homeobox-containing gene (SHOX) deficiency, and poor growth due to chronic renal insufficiency (Franklin & Geffner, 2009). GH treatment becomes part of a child’s treatment plan when growth failure is recognized. For optimal outcomes, referral to a pediatric endocrinologist should occur early, and children may receive GH treatment from as young as infancy through teenage years. Patient adherence to the daily GH treatment regimen is needed for optimal treatment benefit, and GH delivery devices have evolved to support

Self-injection of growth hormone (GH) by children with GH deficiency can be problematic. They may have difficulty manipulating injection devices or preparing medication, and injections can be painful and create anxiety. Adherence to daily GH injections optimizes treatment benefit. Studies indicate that injection pens or needle-free devices enable easy self-injection by children, minimize medication reconstitution and storage requirements, and reduce injection pain. Newer GH delivery devices potentially encourage improved patient adherence. Reviewing features of GH devices will help nurses decide which GH device best fits the needs and abilities of pediatric patients. We searched recent medical literature about GH device development, about device-associated patient preferences and treatment adherence, and comparisons among GH devices. We concluded that improved awareness of the strengths and limitations of GH devices will enable nurses to guide families in selecting and using GH devices, improving adherence and outcomes, and helping children reach full growth potential.

improved patient adherence. GH delivery devices have progressed from conventional syringe/vials to include injector pens, an electronic injector, and needle-free injectors. Goals underlying GH device development include the simplification of drug delivery and reduction of injection anxiety and anticipated pain. Adherence is a central issue because lower adherence to GH injections has been associated with significantly lower height velocities (Desrosiers, O’Brien, & Blethen, 2005; Kapoor et al., 2008). Device characteristics that may contribute to low adherence include greater handling complexity, storage and preparation requirements that interfere with the patient’s daily routine, poor ease of use, low reliability and accuracy, and injection pain (Haverkamp et al., 2008; Kirk, 2010). GH devices are reviewed, focusing on features that

Dawn Raimer-Hall, BSN, RN-BC, CPN, is an Endocrine Nurse, Children’s Medical Center, Dallas, TX. Heidi Chamberlain Shea, MD, is a Medicine and Pediatrics Endocrinologist, Endocrine Associates of Dallas, P.A., Dallas, TX. Acknowledgment: The authors wish to thank Lynanne McGuire, PhD, of MedVal Scientific Information Services, LLC, for providing medical writing and editorial assistance. This article was prepared according to the International Society for Medical Publication Professionals’ “Good Publication Practice for Communicating Company-Sponsored Medical Research: the GPP2 Guidelines.” The article was reviewed for scientific accuracy by Novo Nordisk, Inc., and funding to support the preparation of this manuscript was provided by Novo Nordisk, Inc.

72

may optimize ease of use and patient adherence while providing device feature comparisons to assist nursing staff in the selection of the GH device best suited to their patients’ needs and abilities.

GH Treatment Goals The goals of GH treatment across pediatric treatment indications are to improve poor growth velocity in children with growth failure and to maximize patient height outcome. Additional benefits found with GH treatment of adolescents with GHD at completion of linear growth include increased bone mass, improved lipid profile, and improved body composition with increased muscle mass and decreased fat mass (Boot, van der Sluis, Kenning, & de Muinck KeizerSchama, 2009; Colao et al., 2002; Drake et al., 2003). Patients with growth failure should be referred to a pediatric endocrinologist early for evaluation and GH treatment. Evaluation of the need for GH treatment varies by diagnosis but typically includes clinical and biochemical examination, such as auxological data indicating poor growth velocity for age and sex, genetic (e.g., girls with short stature should have chromosomal analysis for Turner syndrome) and renal function testing, and GH

PEDIATRIC NURSING/March-April 2015/Vol. 41/No. 2

stimulation testing. In the United States, most third-party payers require positive results from two GH stimulation tests using different agents. These stimulation tests use insulin (insulin tolerance test [ITT]) or two of the following agents – GH-releasing hormone (GHRH), arginine, glucagon, clonidine, or carbadopa/levodopa – to evaluate GH response (Cook, Yuen, Biller, Kemp, & Vance, 2009). The gold standard test is the ITT; however, the ITT is rarely used in children due to risks associated with hypoglycemia (Nguyen & Misra, 2009). Although a recommended test, GHRH is not currently available in the United States. If the ITT is not used, then a combination of arginine with clonidine or of arginine with glucagon or carbidopa/ levodopa can be used (Cook et al., 2009). The choice of agents used is institution-dependent. GH treatment has been shown to be safe (Bell et al., 2010). Potential adverse effects include benign intracranial hypertension and skeletal disorders, including new onset and progression of pre-existing scoliosis, slipped capital femoral epiphysis, and avascular necrosis (Bell et al., 2010; Darendeliler, Karagiannis, & Wilson, 2007). Increased monitoring is necessary in patients with prior malignancy history or a malignancy-associated syndrome (Wilton, Mattsson, & Darendeliler, 2010). Patients at risk for abnormal glucose metabolism and insulin resistance, such as those with obesity or a family history of diabetes, require additional assessment of their glucose metabolism (Bell et al., 2010). Patients with PWS require sleep evaluations prior to and following the initiation of GH therapy due to the potential for sleep apnea (Bell et al., 2010). Because GH therapy may alter the metabolism of thyroid hormones and cortisol, patients receiving multiple hormone replacement therapy need laboratory tests to be followed for possible dosing adjustments (Bell et al., 2010). GH treatment is long-term, involving daily GH injections, and depending on the time of GH initiation, treatment may last for many years. Ideally, evaluation of the need for GH treatment is initiated as soon as poor growth velocity is identified. Unless the patient shows continued severe GHD, GH therapy is discontinued when most of the growth has been completed. Historically, GH treatment required intramuscular injec-

tions two to three times weekly (Kastrup, Christiansen, Andersen, & Orskov, 1983). Following studies showing greater growth response to daily subcutaneous (SC) injections, as opposed to intramuscular injections, GH treatment shifted to daily SC injections (Kastrup et al., 1983; Russo & Moore, 1982). Despite being more frequent, SC injection was preferred by patients due to shorter needles and reduced injection pain compared with intramuscular injections (Kastrup et al., 1983; Russo & Moore, 1982). The development of SC GH delivery devices continues to evolve, with a key target of optimization of treatment adherence to further improve treatment outcome. Nursing staff who are knowledgeable about the strengths and limitations of available devices are well-positioned to assist patients with GH device selection and training.

GH Delivery Devices Features of the most recent generation of devices among manufacturers authorized to sell GH brands by prescription in the United States are provided in Table 1. Patients prefer simple, convenient, and easy-to-use delivery devices, and report higher burden associated with devices requiring refrigeration or reconstitution (Ahmed, Smith, & Blamires, 2008; Dumas, Panayiotopoulos, Oarjerm & Pongpairochana, 2006; Kremidas et al., 2013; Wickramasuriya et al., 2006). In line with patient preferences, the newest generation of GH delivery devices improves upon the original devices that used conventional needle and syringe. The disadvantages of using needle and syringe for pediatric patients include greater difficulty in handling the syringe and in accurately reconstituting the GH dose, which could increase the likelihood of injection pain and dosing errors. A visible needle may make injections more psychologically difficult (Fidotti, 2001). Device developments simplified daily injections and increased the tolerability of treatment for patients. Reusable injector pen devices were introduced in the 1990s, and became the standard for GH injection. Additional device developments have included prefilled cartridges that do not require reconstitution, an electronic injector, and needle-free injectors (see Tables 1 and 2).

PEDIATRIC NURSING/March-April 2015/Vol. 41/No. 2

Injector Pens Injector pens, which offer greater ease of use and injection by pressing a button rather than depressing a syringe plunger, are preferred by patients over conventional needles and syringes (Kirk, 2010). Several features of the pen devices have increased the convenience of GH treatment and decreased the pain associated with injection compared with standard syringes and needles (Kirk, 2010). Some pens are prefilled with GH, and these pens provide greater ease of use by removing the reconstitution preparation step (see Table 2). A dial built into the pen casing to set the dose prior to injection increases convenience and dosing accuracy. Pens provide greater ease of use for patients with smaller hands, especially smaller pens with more easily reached buttons. This allows pediatric patients to self-inject.

Needle-Free Injector Two needle-free devices are currently available in the United States (see Table 1). Both devices use a small nozzle to expel GH at high pressure, forcing the medication through the skin where it disperses SC. Two studies have shown that patients like needle-free injection (Desrosiers et al., 2005; Plotnick, Rapaport, Desrosiers, & Fugua, 2009), and better treatment adherence occurs with a needle-free device compared with needle and syringe injection (P = 0.002) (Desrosiers et al., 2005). Needle-free injection administers GH bioequivalent in rate and extent of GH exposure relative to conventional needle and syringe injection (Brearley, Priestley, Leighton-Scott, & Christen, 2007). Side effects of needle-free injection include occasional pain, discomfort, and local reactions due to the high pressure of drug delivery, and greater bleeding, pain, soreness, and bruising have been observed compared with needles (Dorr et al., 2003). The device produces a noise or startle factor that some patients may not like, and some patients may not tolerate the pressure. Additionally, needlefree injectors should not be used in patients with known bleeding disorders, such as hemophilia (EMD Serono, Inc., 2012).

Electronic Injector The fully automated and programmable Easypod™ is the only available 73

Evolution of Growth Hormone Devices: Matching Devices with Patients

Table 1. GH Delivery Devices Available in the United States Device (Manufacturer)

GH Solution

Website

Storage

Injector Pens Genotropin Miniquick® (Pfizer) Genotropin®

http://www.genotropin.com

No refrigeration for up to 3 months.

Genotropin pen (Pfizer)

®

Genotropin

http://www.genotropin.com

Cartridge stored in pen; pen is refrigerated before and after reconstitution.

HumatroPenTM (Lilly)

Humatrope®

http://www.humatrope.com

Cartridge stored in pen between injections; pen refrigerated before and after reconstitution.

Norditropin FlexPro® (Novo Nordisk Inc.)a

Norditropin®

http://www.norditropin-us.com

Refrigerate prior to first use: After first use, all pens can be stored at room temperature (up to 77 degrees F) for three weeks or up to four weeks if refrigerated).

Nutropin AQ NuSpin® (Genentech)

Nutropin AQ®

http://www.nutropin.com

Refrigerated before and after use.

Omnitrope® pen (Sandoz)

Omnitrope®

http://www.omnitrope.com

Refrigerated before and after use.

Saizen®

http://www.saizenus.com

Click.easy® cartridge stored in device; Click.easy® cartridge is refrigerated post reconstitution.

Cool.click2TM (Merck Serono)

Saizen®

http://www.saizenus.com

Cartridge stored outside device, inserted at each use, is refrigerated post reconstitution.

Tjet® (Teva)

Tev-Tropin®

http://www.tev-tropin.com

Vial stored outside device, inserted at each use, is refrigerated.

®

Electronic injector EasypodTM (Merck Serono)

Needle-free injectors

a

The 30-mg pen is available as a NordiFlex® pen.

electronic injector. A key feature is the ability for health care providers to download device use data and review patient adherence to the injection schedule (Dahlgren, 2008). An additional unique feature is the ability to program the device in 27 languages. This can help decrease language barriers, which can adversely affect adherence. Studies are needed to elucidate whether this capability translates into improved GH treatment adherence in the pediatric population. Additional features include GH dose presetting by a physician or nurse; the ability to customize injection depth, speed, and duration; and the device allows for splitting a dose over two cartridges, avoiding waste or inaccurate dosing (Dahlgren, 2008). The device can be set to notify the user when a split dose is needed or can be set to average the dose administration over several cartridges to most efficiently use the medication. This feature may require additional parent and/or patient training to reduce potential confusion about correct dosing of medication. Positive 74

patient feedback has been received in open-label, uncontrolled user trials of the Easypod (Dahlgren, Veimo, Johansson. & Bech, 2007; Tauber et al., 2008). Potential limitations of the Easypod include difficulty for smaller hands in handling the device and difficulty in the mixing and reconstitution of GH. A longer period of device training is also needed.

Comparisons of Product Features among Devices GH injection devices differ in key features that may influence adherence through ease of use (see Table 2). Important device features include one- versus two-step injection; the size of the device; the ease of preparation of the GH dose, which ranges from GH requiring reconstitution to prefilled, ready-to-use devices; and the GH solution associated with the device because differences in preservatives and buffers among GH products may influence injection pain. Oneversus two-step injection refers only to

needle insertion and dose delivery, and does not include differences among devices in preparation of the device or reconstitution of GH. Onestep injection, in which needle insertion and dose delivery occur with onebutton push, is currently available with the electronic and needle-free injectors. One-step injection may be easier for children to complete once familiar with the device. Two-step delivery, which involves needle insertion and a button for dose delivery, is provided by injector pens. The Genotropin® pen, HumatroPen™ and Omnitrope® pen are reusable and use replacement cartridges. The multidose Norditropin® FlexPro® and Nutropin AQ NuSpin® are prefilled and disposable. The disposable Genotropin Miniquick® contains a single GH dose, and reconstitution is completed by turning the plunger knob to mix the prefilled powder and liquid, providing added convenience for patients who are traveling or visually impaired. Other device improvements have included reducing the size of the

PEDIATRIC NURSING/March-April 2015/Vol. 41/No. 2

X X X X

X

X X

X

X X

a

One- versus two-step injection refers to needle insertion and dose delivery, and does not include differences among devices in preparation of the device or reconstitution of GH. b HumatroPen 6-mg pen. c Genotropin Miniquick® is a daily disposable prefilled syringe that requires reconstitution by turning the plunger rod clockwise until it stops to mix the GH powder and liquid.

X X X Xc

X

X

X

X

X X X Xc

X X X X X

X X

Needles Automatic needle insertion Needle-free Hidden needle GH dosing 1-step injectiona 2-step injection Minimal dosing increments ≤ 0.05 mg Ease of preparation/reconstitution Prefilled ready-to-use Reconstitution required Disposability Daily disposable Multiuse disposable pen Durable (reusable) cartridge-based device Small size/easy for small hands

X

X

X

X

X

X

X Xb

X X X

X X

X

X

X

Tjet® Nutropin AQ Omnitrope® NuSpin® Pen Humatro® Pen Genotropin® Pen Genotropin MiniQuick® EasypodTM FlexPro® Cool.click2TM Features

Table 2. Growth Hormone (GH) Delivery Device Features

device or changing the location of dosing buttons to allow easier use by children or those with limited manual dexterity. Injector pens that may be more cumbersome for children with small hands due to larger size and location of dosing buttons include the Genotropin pen and HumatroPen (Fidotti, 2001). FlexPro has improved on its previous design, Nordiflex®, by reducing the size of the device and the force of injection. Patients have reported a preference for FlexPro over their current device (Kappelgaard, Mikkelsen, Bagger, & Fuchs, 2010; Kappelgaard, Mikkelsen, Bagger, Knudsen, & Fuchs, 2010). FlexPro is 11 mm shorter, making it easier for small hands to handle, and allows for a 4-fold-reduced dose force for injection (Yuen & Amin, 2011). GH delivery occurs through continuous depression of the dose button with negligible force, and the easy-to-push dosing button does not extend out, reducing the length the thumb must stretch to complete the injection (Fuchs, Mikkelsen, Knudsen, & Kappelgaard, 2009; Yuen & Amin, 2011). Another important ease-of-use feature is whether reconstitution of GH is needed prior to injection. Patients prefer liquid GH that does not require reconstitution to devices using GH powders that do require reconstitution (Stanhope et al., 2001). Nutropin AQ and Omnitrope provide liquid GH in prefilled cartridges, and Norditropin NordiFlex (30 mg formulation), Norditropin FlexPro (5, 10, and 15 mg formulation), and Nutropin AQ Nuspin provide prefilled, readyto-use pens (see Table 2). Mixing and reconstitution are required for Humatrope, Genotropin, Easypod, and the needle-free injectors. Appropriate adherence to storage and reconstitution requirements is necessary to maintain a stable GH product with optimal efficacy. The easier the storage requirements are, the greater patient adherence is likely to be, and the more likely the product will retain optimal efficacy. Storage is simplified with Norditropin 5 mg/1.5 mL or 10 mg/1.5 mL injector pens. These pens have room temperature stability, and they may be stored unrefrigerated after the first use for up to 3 weeks at not more than 77°F. However, the pens must be refrigerated prior to first use. Alternatively, Genotropin Miniquick, a single-use device, can be stored unrefrigerated for up to three months at

PEDIATRIC NURSING/March-April 2015/Vol. 41/No. 2

75

Evolution of Growth Hormone Devices: Matching Devices with Patients not more than 77°F before reconstitution. Additionally, Saizen does not have to be shipped cold and can be stored at room temperature (59° to 86°F) prior to reconstitution. Following reconstitution, Saizen requires refrigeration (36° to 46°F). Minimizing injection pain is important because it may improve adherence to daily injections, and thus, affect treatment outcome. Variations among GH products in their solutions (preservatives and buffers) have been shown to influence injection pain perception and local tissue reactions (Kappelgaard et al., 2004). Specifically, significantly more participants reported that injections using a citrate-buffered GH solution (e.g., Nutropin AQ NuSpin) caused more pain than a histidinebuffered GH solution (e.g., FlexPro) immediately after injection (P = 0.002) (Laursen, Hansen, & Fisker, 2006). Additionally, injections using solutions containing the preservative m-cresol (e.g., Genotropin pen, HumatroPen, Click.easy for the EasyPod and Cool.click2) have been associated with more pain compared with benzyl alcohol solutions (e.g., Tjet, Omnitrope 5-mg pen), and benzyl alcohol-containing solutions have been associated with greater injection pain compared with phenol–containing solutions (e.g., FlexPro, Nutropin AQ NuSpin, Omnitrope 10 mg pen) (Kappelgaard, Bojesen, Skydsgaard, Sjogren, & Laursen, 2004). The Genotropin Miniquick syringe does not contain a preservative and must be used within 24 hours of reconstitution. Although studies directly comparing devices are limited, such studies have demonstrated patient device preferences based on ease of preparation, ease of measuring doses, and ease of administration (Shine et al., 2003). A time-and-motion simulation study found Norditropin pen devices took less total time weekly to use than the comparator Genotropin and Humatrope pen devices, due to differences in time to prepare the device and learn to use (Nickman, Haak, & Kim, 2010). The ability to select finer dosing increments with Norditropin NordiFlex resulted in less product waste compared with Humatrope pen or vial, Genotropin pen or Nutropin AQ pen in a theoretical statistical model (Bazalo, Joshi, & Germak, 2007). Though not included in the Bazalo et al. (2007) study, the Easypod 76

and needle-free injectors also allow fine dosing increments. In a study comparing Norditropin FlexPro with Easypod and Genotropin pen in children with GHD, short children born SGA, and Turner girls who were 10 years of age and older and younger than 18 years of age, FlexPro was associated with shorter injection times and higher dose accuracy and was rated as easier to learn (Pfutzner et al., 2010). Easypod’s GH dose delivery feedback feature was preferred by more patients compared with FlexPro or Genotropin devices, and the Genotropin pen was preferred for appearance (Pfutzner et al., 2010).

treatment, and likely suboptimal outcomes associated with decreased adherence (Rosenfeld & Bakker, 2008; Smith, Hindmarsh, & Brook, 1993). To improve treatment adherence, user-friendly injection pens or needlefree devices (see Table 2) should be selected to prioritize ease of use for self-injection by children. Additionally, it is the experience of the authors that minimal reconstitution and storage requirements, reduced injection pain, and small dosing increments are necessary attributes to improve adherence. References

Assisting Patients with GH Device Selection and Use Allowing patients to choose a delivery device has been associated with better treatment adherence (Kapoor et al., 2008). Ideally, nursing staff familiar with GH devices can assist patients with selection of the GH device best matched to the patient’s preferences and needs to maximize treatment tolerability and adherence. Through discussion with the patient and his or her caregivers, nursing staff can learn what device characteristics may make taking daily GH most acceptable and maximize adherence. For example, if the patient fears needles, use of a needle cover or a needle-free device is recommended. Or, if anyone in the patient’s household is an intravenous drug user, a needle-free device is recommended. Although selection of the GH device may be determined by the patient’s health insurance company formulary guidelines, nursing staff with experience with GH devices can play an essential role in patient education and training in the use of the selected device. Education and training may include device demonstrations, instructional DVDs, product literature, and discussion of the strengths and limitations of the device. Coaching and support, as well as guidance to parents, provided by nursing staff following device selection are critical to achieve optimal treatment adherence. The patienthealth care provider relationship is key to maximizing adherence (Haverkamp et al., 2008). Possible contributing factors for low adherence that should be addressed with education include the patient’s lack of understanding of the disease, optimal

Ahmed, S.F., Smith, W.A., & Blamires, C. (2008). Facilitating and understanding the family’s choice of injection device for growth hormone therapy by using conjoint analysis. Archives of Diseases in Childhood, 93, 110-114. Bazalo, G.R., Joshi, A.V., & Germak, J. (2007). Comparison of human growth hormone products’ cost in pediatric and adult patients. A budgetary impact model. Managed Care, 16, 45-51. Bell, J., Parker, K.L., Swinford, R.D., Hoffman, A.R., Maneatis, T., & Lippe, B. (2010). Long-term safety of recombinant human growth hormone in children. Journal of Clinical Endocrinology and Metabolism, 95, 167-177. Boot, A.M., van der Sluis, I.M., Krenning, E.P., & de Muinck Keizer-Schrama, S.M. (2009). Bone mineral density and body composition in adolescents with childhood-onset growth hormone deficiency. Hormone Research, 71, 364371. Brearley, C., Priestley, A., Leighton-Scott, J., & Christen, M. (2007). Pharmacokinetics of recombinant human growth hormone administered by Cool.click 2, a new needle-free device, compared with subcutaneous administration using a conventional syringe and needle. BMC Clinical Pharmacology, 7, 10. Colao, A., Di Somma, C., Salerno, M., Spinelli, L., Orio, F., & Lombardi, G. (2002). The cardiovascular risk of GHdeficient adolescents. Journal of Clinical Endocrinology and Metabolism, 87, 3650-3655. Cook, D.M., Yuen, K.C., Biller, B.M., Kemp, S.F., & Vance, M.L. (2009). American Association of Clinical Endocrinologists medical guidelines for clinical practice for growth hormone use in growth hormone-deficient adults and transition patients – 2009 update. Endocrine Practice, 15(Suppl. 2), 1-29. Dahlgren, J. (2008). Easypod: A new electronic injection device for growth hormone. Expert Review of Medical Devices, 5, 297-304. Dahlgren, J., Veimo, D., Johansson, L., & Bech, I. (2007). Patient acceptance of a novel electronic auto-injector device to administer recombinant human growth hormone: Results from an open-label,

PEDIATRIC NURSING/March-April 2015/Vol. 41/No. 2

user survey of everyday use. Current Medical Research and Opinion, 23, 1649-1655. Darendeliler, F., Karagiannis, G., & Wilton, P. (2007). Headache, idiopathic intracranial hypertension and slipped capital femoral epiphysis during growth hormone treatment: A safety update from the KIGS database. Hormone Research, 68(Suppl. 5), 41-47. Desrosiers, P., O’Brien, F., & Blethen, S. (2005). Patient outcomes in the GHMonitor: The effect of delivery device on compliance and growth. Pediatric Endocrinology Reviews, 2(Suppl. 3), 327-331. Dorr, H.G., Zabransky, S., Keller, E., Otten, B.J., Partsch, C.J., Nyman, L., … Schoenfeld, S.L. (2003). Are needlefree injections a useful alternative for growth hormone therapy in children? Safety and pharmacokinetics of growth hormone delivered by a new needlefree injection device compared to a fine gauge needle. Journal of Clinical Endocrinology and Metabolism, 16, 383-392. Drake, W.M., Carroll, P.V., Maher, K.T., Metcalfe, K.A., Camacho-Hubner, C., Shaw, N.J., … Monson, J.P. (2003). The effect of cessation of growth hormone (GH) therapy on bone mineral accretion in GH-deficient adolescents at the completion of linear growth. Journal of Clinical Endocrinology and Metabolism, 88, 1658-1663. Dumas, H., Panayiotopoulos, P., Parker, D., & Pongpairochana, V. (2006). Understanding and meeting the needs of those using growth hormone injection devices. BMC Endocrine Disorders, 6, 1-6. EMD Serono, Inc. (2012). Cool.click 2 [instructions for use]. Rockland, MD: Author. Fidotti, E. (2001). A history of growth hormone injection devices. Journal of Clinical Endocrinology and Metabolism, 14, 497-501. Flodh, H. (1986). Human growth hormone produced with recombinant DNA technology: Development and production. Acta Paediatrica Scandinavica. Supplement, 325, 1-9. Franklin, S.L., & Geffner, M.E. (2009). Growth hormone: The expansion of available products and indications. Endocrinology Metabolism Clinics of North America, 38, 587-611. Fuchs, G.S., Mikkelsen, S., Knudsen, T.K., & Kappelgaard, A.M. (2009). Ease of use and acceptability of a new pen device for the administration of growth hormone therapy in pediatric patients: An open-label, uncontrolled usability test. Clinical Therapeutics, 31, 2906-2914. Haverkamp, F., Johansson, L., Dumas, H., Langham, S., Tauber, M., Veimo, D., & Chiarelli, F. (2008). Observations of nonadherence to recombinant human

growth hormone therapy in clinical practice. Clinical Therapeutics, 30, 307-316. Kapoor, R.R., Burke, S.A., Sparrow, S.E., Hughes, I.A., Dunger, D.B., Ong, K.K., & Acerini, D.L. (2008). Monitoring of concordance in growth hormone therapy. Archives of Disease in Childhood, 93, 147-148. Kappelgaard, A.M., Bojesen, A., Skydsgaard, K., Sjogren, I., & Laursen, T. (2004). Liquid growth hormone: Preservatives and buffers. Hormone Research, 62(Suppl. 3), 98-103. Kappelgaard, A.M., Mikkelsen, S., Bagger, C., & Fuchs, G.S. (2010). Patient acceptability of a new injection device system to administer human growth hormone: Results from a multinational handling and questionnaire survey [abstract]. Endocrine Reviews, 31(Suppl. 1), S1217. Kappelgaard, A.M., Mikkelsen, S., Bagger, C., Knudsen, T.K., & Fuchs, G.S. (2010). Usability testing of a new pen injector and a combination of the new pen injector and a new PenMate® system to administer human growth hormone in three open-label user surveys [abstract]. Endocrine Reviews, 31(Suppl. 1), S1221. Kastrup, K.W., Christiansen, J.S., Andersen, J.K., & Orskov, H. (1983). Increased growth rate following transfer to daily sc administration from three weekly im injections of hGH in growth hormone deficient children. Acta Endocrinologica (Copenhagen), 104, 148-152. Kirk, J. (2010). Developments in growth hormone delivery. Current Drug Therapy, 5, 43-47. Kremidas, D., Wisniewski, T., Divino, V.M., Bala, K., Olsen, M., Germak, J., … Lee, W.C. (2013). Administration burden associated with recombinant human growth hormone treatment: Perspectives of patients and caregivers. Journal of Pediatric Nursing, 28(1), 5563. Laursen, T., Hansen, B., & Fisker, S. (2006). Pain perception after subcutaneous injections of media containing different buffers. Basic & Clinical Pharmacology & Toxicology, 98, 218-221. Nguyen, V.T., & Misra, M. (2009). Transitioning of children with GH deficiency to adult dosing: Changes in body composition. Pituitary, 12, 125-135. Nickman, N.A., Haak, S.W., & Kim, J. (2010). Cost minimization analysis of different growth hormone pen devices based on time-and-motion simulations. BMC Nursing, 9, 6. Pfutzner, A., Hartmann, K., Winter, F., Fuchs, G.S., Kappelgaard, A.M., & Rohrer, T.R. (2010). Intuitiveness, ease of use, and preference of a prefilled growth hormone injection pen: A noninterventional, randomized, open-label, crossover, comparative usability study of three

PEDIATRIC NURSING/March-April 2015/Vol. 41/No. 2

delivery devices in growth hormonetreated pediatric patients. Clinical Therapeutics, 32, 1918-1934. Plotnick, L., Rapaport, R., Desrosiers, P., & Fuqua, J.S. (2009). Update from the GHMonitors observational registry in children treated with recombinant human growth hormone (Saizen). Pediatric Endocrinology Reviews, 6(Suppl. 2), 278-282. Rosenfeld, R.G., & Bakker, B. (2008). Compliance and persistence in pediatric and adult patients receiving growth hormone therapy. Endocrine Practice, 14, 143-154. Russo, L., & Moore, W.V. (1982). A comparison of subcutaneous and intramuscular administration of human growth hormone in the therapy of growth hormone deficiency. Journal of Clinical Endocrinology and Metabolism, 55, 1003-1006. Shine, B., Musial, W., Owens, L., Deeb, L., Luetjen, T., & Howard, C. (2003). Patient and parent preference for growth hormone products. American Journal of Health System Pharmacy, 60, 89-90. Smith, S.L., Hindmarsh, P.C., & Brook, C.G. (1993). Compliance with growth hormone treatment – Are they getting it? Archives of Disease in Childhood, 68, 91-93. Stanhope, R., Buchanan, C., Butler, G., Costigan, C., Dunger, D., Greene, S., … Warner, J. (2001). An open-label acceptability study of Norditropin SimpleXx – A new liquid growth hormone formulation. Journal of Clinical Endocrinology and Metabolism, 14, 735-740. Tauber, M., Payen, C., Cartault, A., Jouret, B., Edouard, T., & Roger, D. (2008). User trial of Easypod, an electronic autoinjector for growth hormone. Annales d Endocrinoogiel (Paris), 69, 511-516. Wickramasuriya, B.P., Casey, A., Akhtar, S., Zia, R., Ehtisham, S., Barrett, T.G., … Kirk, J.M. (2006). Factors determining patient choice of device for GH therapy. Hormone Research, 65, 18-22. Wilton, P., Mattsson, A.F., & Darendeliler, F. (2010). Growth hormone treatment in children is not associated with an increase in the incidence of cancer: Experience from KIGS (Pfizer International Growth Database). Journal of Pediatrics, 157, 265-270. Yuen, K.C., & Amin, R. (2011). Developments in administration of growth hormone treatment: Focus on Norditropin® Flexpro®. Patient Preference and Adherence, 5, 117-124. Zeisel, H.J., von Petrykowski, W., & Wais, U. (1992). Pharmacokinetics and shortterm metabolic effects of mammalian cell-derived biosynthetic human growth hormone in man. Hormone Research, 37(Suppl. 2), 5-13.

77