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CLINICAL STUDY
Year : 2017  |  Volume : 6  |  Issue : 1  |  Page : 40-43

Growth hormone utilization review in a pediatric primary care setting


1 Growth and Development Research Center, Children's Excellence Medical Center, Tehran University of Medical Sciences, Tehran, Iran
2 Department of Clinical Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
3 Department of Clinical Pharmacy and Pharmacy Practice, Isfahan University of Medical Sciences, Isfahan, Iran
4 Noncommunicable Diseases Research Center, Alborz University of Medical Sciences, karaj, Iran
5 Department of Clinical Pharmacy; Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran

Date of Web Publication27-Feb-2017

Correspondence Address:
Mania Radfar
Department of Clinical Pharmacy; Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran
Iran
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2279-042X.200989

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  Abstract 

Objective: One of the main problems facing public health providers and administrators in many countries is ensuring the rational use of high-cost drugs. In this regard, on-going process of medication use evaluation can be considered as a useful tool. In this study, we evaluated certain usage aspects of a highly-cost medication, that is, recombinant growth hormone (GH).
Methods: This cross-sectional study conducted from August 2012 to August 2014. Children receiving GH ± gonadotropin releasing hormone (GnRH) analogs were included in the study. A researcher-designed checklist was developed to evaluate the GH utilization in these patients. Baseline demographic characteristics and background clinical and growth data, as well as any aspects of drug therapy including indications, dosing, monitoring, and discontinuation were collected from the patients' medical records.
Findings: Seventy children receiving GH entered the study, of which 23 patients (32.85%) received GH and GnRH analogs simultaneously. At the baseline, 67 children (95.7%) had GH stimulation test, whereas serum insulin-like growth factor-1 (IGF-1) levels were measured in 63 (90%) patients. Sixty-seven patients (95.71%) had thyroid function test, whereas bone age was determined in 68 children (97.14%). The mean ± standard deviation of GH dose for idiopathic short stature, GH deficiency, Turner's syndrome and born small for gestational age in our study was 0.22 ± 0.025 mg/kg/week, 0.23 ± 0.04 mg/kg/week, 0.22 ± 0.015 mg/kg/week, and 0.23 ± 0.02 mg/kg/week, respectively. Height and weight of all patients were followed every 3–6 months, regularly. Thirty patients were treated with GH for at least 1 year, of which thyroid hormones and IGF-1 levels were measured annually in 25 (83.33%) and 26 (86.66%) patients, respectively; while bone age was evaluated in 13 (43.33%) children, annually. GH treatment was discontinued in 15 patients (21.42%), while financial problem was the major reason.
Conclusion: Diagnostic tests and monitoring of height, weight, IGF-1 level and thyroid function was properly performed in this setting. However, a number of patients with ISS and Turner's syndrome were under-dosed.

Keywords: Growth hormone, medication use evaluation, monitoring, pediatrics


How to cite this article:
Sayarifard F, Imcheh FB, Badri S, Faghihi T, Qorbani M, Radfar M. Growth hormone utilization review in a pediatric primary care setting. J Res Pharm Pract 2017;6:40-3

How to cite this URL:
Sayarifard F, Imcheh FB, Badri S, Faghihi T, Qorbani M, Radfar M. Growth hormone utilization review in a pediatric primary care setting. J Res Pharm Pract [serial online] 2017 [cited 2020 May 29];6:40-3. Available from: http://www.jrpp.net/text.asp?2017/6/1/40/200989


  Introduction Top


Growth hormone (GH) is a necessary factor for normal constitutional and pubertal growth in children. Growth is increased by direct effect of GH on the growth plates and by its stimulating effect on the production of insulin-like growth factor (IGF). GH deficiency, Turner's syndrome, chronic renal insufficiency, born small for gestational age (SGA), idiopathic short stature (ISS), and Prader–Willi syndrome are among the Food and Drug Administration (FDA) approved indications for recombinant human GH (somatropin).[1] However, treatment with the recombinant human GH has not immediate therapeutic advantages,[2] and to achieve therapeutic benefits, the medication should be given 6–7 injections per week for several years.[3]

Administration of gonadotropin releasing hormone (GnRH) analog is the treatment of choice for central precocious puberty, which can improve adult height by suppressing pubertal development and reducing bone maturation. Monotherapy with GnRH analogs in both sexes has small and variable effect on adult height and is usually not recommended, while combination therapy with a GnRH analog and GH may have potential effect on final adult height.[4],[5] Although, it should be noted that GH treatment can have variable treatment efficacies in different patients.[6],[7]

Patients should be evaluated every 3–6 months. Increases in height and height velocity are the most important markers of response to GH treatment. Monitoring of serum IGF-1 levels is recommended for assurance of compliance, dosing, and safety considerations. Hypothyroidism may occur during the GH treatment; hence, thyroid function assessment should be considered periodically.[8],[9]

Postmarketing studies have shown the efficacy and safety of GH when used in FDA-approved indications.[10] Although not prevalent, headache, visual problems, nausea and vomiting, peripheral edema, arthralgia, myalgia, paresthesia, antibody formation, hypothyroidism, and injection site reactions are the reported side effects of GH therapy.[11]

One of the problems facing public health providers and administrators in many countries is ensuring the rational use of drugs.[12] One strategy to ascertain the appropriate use of drugs is the ongoing process of medication use evaluation (MUE). MUE is a tool for monitoring the prescribing patterns of health-care providers to ensure appropriate pharmacotherapy.[13] MUE findings may help health-care systems to improve prescribing patterns and optimize use of scarce resources. Appropriate prescribing can be recognized at three levels: (a) indication for drug therapy, (b) choice of the drug, and (c) duration of treatment, route of administration, frequency of monitoring, and drug interactions.[14] MUE can recognize inappropriate and/or unnecessary high-cost drug therapies by comparing the actual status of medication use with predetermined standards or guidelines.[15]

There are approved protocols for the appropriate use of recombinant GH in different indications;[16] however in Iran because of high treatment expenses and limitations in drug availability, they may not be followed thoroughly. While any incorrect use of the drug (including dosage and duration of treatment) involve the wastage of such highly-cost medication. Since there are sparse data in this regard in our population, the current study was designed to investigate the certain aspects of GH utilization such as indication, dosing, monitoring and discontinuation, in Iranian pediatric population.


  Methods Top


This cross-sectional study conducted from August 2012 to August 2014 at Endocrine clinic, Children's Medical Center, affiliated to Tehran University of Medical Sciences (TUMS). The study protocol was approved by TUMS Ethics Committee. Children receiving GH (somatropin) ± GnRH analog (Triptorelin) were included. A researcher-designed checklist was developed to evaluate the usage pattern of GH and GnRH analogs in these patients. The checklist had four sections: (a) demographic, clinical and laboratory data; (b) GH and GnRH analog indications and dosing schedule; (c) follow-up data such as patient's height, weight, pubertal stage, laboratory tests, drug compliance and side effects; (d) reasons for discontinuation of GH treatment. Data were collected from the patients' medical records.

The baseline variables included: patient's sex, age, birth weight, gestational age and delivery status, current height, weight, bone age, puberty stage, and parents' height.

To measure drug compliance, parents of study subjects were interviewed and asked about the number of missing injections during the last month. Patients were categorized as high compliance if they received more than 80% of injections, moderate compliance if they received 60%–80% of injections and low compliance if they received <60% of injections.

The collected data were analyzed using SPSS software (IBM company, Chicago, IL, USA), version 16.0. Distribution of continuous variables was determined using Kolmogorov–Smirnov test. Continuous variables are shown as mean ± standard deviation (SD), whereas categorical data are shown as number (percentage).


  Results Top


Seventy children receiving GH entered the study, of which 23 patients (32.85%) received GH and GnRH analogue simultaneously. Baseline characteristics and background data of children are shown in [Table 1]. Duration of GH treatment was 9.27 ± 6.02 months. Twenty-two patients (31.42%) had family history of constitutional delay of growth and puberty, whereas there were no reports of family history of GH deficiency among all patients. One patient was receiving letrozole, 2 were receiving hydrocortisone, 6 were receiving levothyroxine and as mentioned previously, 23 patients were on triptoreline. Among patients who were receiving combination of GH and GnRH analog, 21 (91.3%) were female.
Table 1: Baseline demographic characteristics and background clinical and growth data of the study patients (n=70)

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At baseline, GH stimulation test was carried out in 67 children (95.71%) and serum IGF-1 levels were measured in 63 patients (90%). Sixty-seven patients (95.71%) had thyroid function tests, whereas 22 patients (31.42%) had luteinizing hormone (LH) and follicle-stimulating hormone (FSH) measurements. Blood glucose was measured in 11 patients and bone age was determined by X-ray in 68 children (97.14%) at the beginning of treatment.

GH was administrated as nightly subcutaneous injection once a day in almost all children except for seven, which had 6 days a week injections. In four patients with ISS, after 6 months of therapy, GH dose was reduced to 6 days a week, due to increased IGF-1 levels. GH dosing was initiated based on body weight for all patients at the beginning of the treatment and was adjusted according to serum IGF-1 levels after 6 months.

The mean dose of somatropin for children with ISS, GH deficiency, Turner's syndrome and SGA in our study was 0.22 ± 0.03 mg/kg/week, 0.23 ± 0.04 mg/kg/week, 0.22 ± 0.02 mg/kg/week and 0.23 ± 0.02 mg/kg/week, respectively. All patients used pen devices for GH injection. Dosing regimen for triptorelin was 3.75 mg every 28 days and 11.25 mg every 90 days for 17 and 6 patients, respectively.

Height and weight of all patients were followed every 3–6 months. There were thirty patients who were treated with GH for at least 1 year. Thyroid function tests and IGF-1 levels were measured every 6 months in 25 (83.33%) and 26 (86.66%) patients, respectively. Bone age was evaluated in 13 (43.33%) children at least annually. During GH treatment, IGF-1 levels met the therapeutic goal (slightly higher than average) except in four patients in whom IGF-1 increased to higher than normal range and GH dose was adjusted accordingly.

Sixteen patients were treated with the combination of GH and triptorelin for more than 6 months, of which ten patients (62.50%) had measurements of LH and FSH levels, every 6 months during their follow-up. The mean height increment was 4.21 ± 1.91 cm in children who were treated with GH alone, and 3.55 ± 1.61 cm in those who were treated with GH in combination with GnRH analog (P = 0.16).

In the current study, three children had leg pain, one had headache and one had experienced injection site reaction. GH treatment was discontinued in 15 patients (21.42%) because of financial problems (n = 11), fears of side effects (n = 2), orthopedic problems (n = 1), and achievement of the final height (n = 1).

After 6 months of therapy, height development was 4.59 ± 1.78 cm and 4.82 ± 2.03 cm in girls and boys, respectively. Fifty-three patients (75.71%) had high compliance, while 5 (7.14%) had moderate and 12 (17.14%) had poor compliance to GH injections.


  Discussion Top


GH has been used in various growth disorders for more than five decades. It is usually administered as daily subcutaneous injections. Diagnosis and body weight of the patient are determinants of GH dose.[16] GnRH agonists and GH combination therapy have been used to improve adult height in precocious puberty.[17] GH treatment is costly, and stopping the treatment at a “normal” rather than “maximum” height is a strategy to limit costs. Justifying the cost of treatment by considering the morbidity of short stature and benefits of GH treatment is an issue that those who prescribe and pay for GH treatment are encountered.[18]

Evaluation of GH utilization in our study demonstrated that initiating GH therapy was according to the literature. More than 95% of our patients had GH stimulation test and in 90% of subjects, IGF-1 level was measured. Majority of our patients had ISS and more than half of the patients (n = 44) were girls.

In our study, there was no significant difference between males and females growth response. While in a study by Cohen et al., prepubertal males had a linear GH dose-response curve for growth which differed from prepubertal females.[19]

Pasquino et al. concluded in their study that the growth response obtained with the combination therapy of GH and GnRH analogs is more significant. However, they also recommended that the cost-effectiveness of such invasive treatment must be considered.[17]

In our study, there was no significant difference in growth response between patients treated with GH alone and children treated with combination of GH and GnRH analog. In line with our study, van Gool et al. showed that there was no significant difference in height gain among patients who used GH and GnRH agonist combination or GH alone.[20]

In the current study, 48 subjects were treated with lower than recommended GH dose, including 2 patients with Turner's syndrome and 45 patients with ISS. However, despite the insufficient dose, all patients had appropriate growth response to GH treatment. All children with GH deficiency were receiving the adequate dose which can be due to the fact that doses tend to be lower in GH deficiency.[16]

Cohen et al. study on prepubertal GH-deficient children showed that individual sensitivity to GH treatment, as manifested by achieved serum IGF-I levels, plays a key role in growth response.[19] In our study, most of the patients' IGF-1 levels met the therapeutic goal during follow up. Based on the data presented here, IGF-1 and thyroid function monitoring were done properly in the studied clinic.

While according to Kaufman and Sy study it seems that bone age monitoring is useful in evaluation of growth response to GH treatment, bone age was only evaluated in 43.33% of our patients.[21] It seems that bone age is a better predictor of response compared with chronological age, because of the relationship between growth potential and bone maturity.[22]

General safety of recombinant human GH for treatment of various pediatric growth disorders has been demonstrated. It has been demonstrated that adverse effects of GH therapy is less frequent in children (3%) than adults (10%).[9] There were few reported adverse effects in our study.

Implementing strategies to improve compliance with GH injection might be of particular clinical benefit.[6] Despite the availability of GH vials in our country, all patients used pen devices in our study which can be related to ease of administration.

The main factors which influenced compliance in this study were financial problems and fear of GH adverse effects. Although insurance companies cover 90% of GH costs in Iran, financial problems is still the major barrier to patient compliance and needs to be considered by policymakers. Furthermore, patients should be assured about overall safety of GH therapy by health care professionals.

Diagnostic tests and monitoring of height, weight, IGF-1 level, and thyroid function were properly conducted in the study setting. But GH dosing was not within the recommended dosage range for patients with ISS and Turner's syndrome. Drug compliance was acceptable, although it can be improved by addressing the barriers.


  Authors' Contribution Top


Fatemeh Sayarifard designed the study and interpreted the data, Fereshteh Bakhshi Imcheh selected the patients, obtained and interpreted the data and drafted the manuscript, Toktam Faghihi designed the study, Shirinsadat Badri designed the study and revised the manuscript, Mostfa Qorbani carried out statistical analysis and interpreted the data, Mania Radfar designed and supervised the study, interpreted the data and revised the manuscript.

Acknowledgments

This study was a part of PharmD thesis supported by Tehran University of Medical Sciences.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Christensen T, Buckland A, Bentley A, Djurhuus C, Baker-Searle R. Cost-effectiveness of somatropin for the treatment of short children born small for gestational age. Clin Ther 2010;32:1068-82.  Back to cited text no. 1
    
2.
Fuchs GS, Mikkelsen S, Knudsen TK, Kappelgaard AM. 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. Clin Ther 2009;31:2906-14.  Back to cited text no. 2
    
3.
Ferguson LA. Growth hormone use in children: Necessary or designer therapy? J Pediatr Health Care 2011;25:24-30.  Back to cited text no. 3
    
4.
Lee PA. Use of GnRH agonists in GH-deficient patients: Arguments for and against. The case for GnRH agonists in GH-deficient patients. Pediatr Endocrinol Rev 2008;5 Suppl 2:744-9.  Back to cited text no. 4
    
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Reiter EO. A brief review of the addition of gonadotropin-releasing hormone agonists (GnRH-Ag) to growth hormone (GH) treatment of children with idiopathic growth hormone deficiency: Previously published studies from America. Mol Cell Endocrinol 2006;254:221-5.  Back to cited text no. 5
    
6.
Haverkamp F, Johansson L, Dumas H, Langham S, Tauber M, Veimo D, et al. Observations of nonadherence to recombinant human growth hormone therapy in clinical practice. Clin Ther 2008;30:307-16.  Back to cited text no. 6
    
7.
Cutfield WS, Derraik JG, Gunn AJ, Reid K, Delany T, Robinson E, et al. Non-compliance with growth hormone treatment in children is common and impairs linear growth. PLoS One 2011;6:e16223.  Back to cited text no. 7
    
8.
Growth Hormone Research Society. Consensus guidelines for the diagnosis and treatment of growth hormone (GH) deficiency in childhood and adolescence: Summary statement of the GH Research Society. GH Research Society. J Clin Endocrinol Metab 2000;85:3990-3.  Back to cited text no. 8
    
9.
Wilson TA, Rose SR, Cohen P, Rogol AD, Backeljauw P, Brown R, et al. Update of guidelines for the use of growth hormone in children: The Lawson Wilkins Pediatric Endocrinology Society Drug and Therapeutics Committee. J Pediatr 2003;143:415-21.  Back to cited text no. 9
    
10.
Bell J, Parker KL, Swinford RD, Hoffman AR, Maneatis T, Lippe B. Long-term safety of recombinant human growth hormone in children. J Clin Endocrinol Metab 2010;95:167-77.  Back to cited text no. 10
    
11.
Quigley CA, Gill AM, Crowe BJ, Robling K, Chipman JJ, Rose SR, et al. Safety of growth hormone treatment in pediatric patients with idiopathic short stature. J Clin Endocrinol Metab 2005;90:5188-96.  Back to cited text no. 11
    
12.
le Grand A, Hogerzeil HV, Haaijer-Ruskamp FM. Intervention research in rational use of drugs: A review. Health Policy Plan 1999;14:89-102.  Back to cited text no. 12
    
13.
Holloway K, Green T. Tools to Investigate the Use of Medicines. Drug and Therapeutics Committees: A Practical Guide. World Health Organization (WHO); 2003. Available from: http://www.apps.who.int/medicinedocs/pdf/s4882e/s4882e.pdf. [Last accessed on 2016 Oct 10].  Back to cited text no. 13
    
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Schneeweiss S, Avorn J. A review of uses of health care utilization databases for epidemiologic research on therapeutics. J Clin Epidemiol 2005;58:323-37.  Back to cited text no. 14
    
15.
Moore T, Bykov A, Savelli T, Zagorski A. Guidelines for Implementing Drug Utilization Review Programs in Hospitals. Available from: http://www.apps.who.int/medicinedocs/documents/s22114en/s22114en.pdf. [Last accessed on 2016 Oct 10].  Back to cited text no. 15
    
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Kirk J. Indications for growth hormone therapy in children. Arch Dis Child 2012;97:63-8.  Back to cited text no. 16
    
17.
Pasquino AM, Pucarelli I, Roggini M, Segni M. Adult height in short normal girls treated with gonadotropin-releasing hormone analogs and growth hormone. J Clin Endocrinol Metab 2000;85:619-22.  Back to cited text no. 17
    
18.
Allen DB. Growth hormone therapy for short stature: Is the benefit worth the burden? Pediatrics 2006;118:343-8.  Back to cited text no. 18
    
19.
Cohen P, Bright GM, Rogol AD, Kappelgaard AM, Rosenfeld RG; American Norditropin Clinical Trials Group. Effects of dose and gender on the growth and growth factor response to GH in GH-deficient children: Implications for efficacy and safety. J Clin Endocrinol Metab 2002;87:90-8.  Back to cited text no. 19
    
20.
van Gool SA, Kamp GA, Visser-van Balen H, Mul D, Waelkens JJ, Jansen M, et al. Final height outcome after three years of growth hormone and gonadotropin-releasing hormone agonist treatment in short adolescents with relatively early puberty. J Clin Endocrinol Metab 2007;92:1402-8.  Back to cited text no. 20
    
21.
Kaufman FR, Sy JP. Regular monitoring of bone age is useful in children treated with growth hormone. Pediatrics 1999;104:1039-42.  Back to cited text no. 21
    
22.
Ranke MB, Lindberg A, Martin DD, Bakker B, Wilton P, Albertsson-Wikland K, et al. The mathematical model for total pubertal growth in idiopathic growth hormone (GH) deficiency suggests a moderate role of GH dose. J Clin Endocrinol Metab 2003;88:4748-53.  Back to cited text no. 22
    



 
 
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