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Somatropin (Genotropin) for Subcutaneous Injection: Long-term Treatment of Children who have Growth Failure Due to an Inadequate Secretion of Endogenous Growth Hormone [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2014 Jan.

EXECUTIVE SUMMARY

Introduction

Growth hormone deficiency (GHD) is the most common endocrine cause of short stature, although growth failure is also associated with other causes, such as Turner syndrome, Prader-Willi syndrome, and chronic renal insufficiencies. Diagnosis of GHD is usually based on a combination of auxologic assessment, biochemical tests (growth hormone stimulation tests) and neuroimaging of the hypothalamic-pituitary region. The prevalence of GHD is estimated to be between 1 in 3,500 and 1 in 4,000 children. Once the diagnosis of GHD is established in children, recombinant human growth hormone (also called somatropin) therapy is recommended as soon as possible in order to enhance growth velocity and normalize final adult height.

Genotropin is one of several somatropin products available in Canada and is indicated for treatment of pediatric GHD at a dose of 0.16 mg/kg to 0.24 mg/kg body weight per week divided into six to seven doses and administered by subcutaneous injection. According to the product monograph, the dose of Genotropin should be adjusted based on the concentration of insulin-like growth factor-1 and adverse effects.

The objective of this systematic review is to compare the benefits and harms of Genotropin with other available somatropin products in children with GHD.

Indication under review
Long-term treatment of children who have growth failure due to an inadequate secretion of endogenous growth hormone
Listing criteria requested by sponsor
List in a similar manner to other growth hormone products

Results and Interpretation

Included Studies

Two parallel randomized controlled trials of children with GHD were included in this review. One phase 3 open-label trial (Romer et al., n = 89, nine months’ duration) was conducted in Europe and compared Genotropin 0.03 mg/kg per day (subcutaneously) with Omnitrope 0.03 mg/kg per day (subcutaneously). Shih et al. (n = 15, 12 months’ duration) was conducted in Taiwan and compared Genotropin 0.1 IU/kg per day with Humatrope 0.1 IU/kg per day and Saizen 0.2 IU/kg three times a week. Romer et al. was designed as an equivalence study and had a pre-set equivalence margin of 2 cm per year for height velocity. The primary outcomes in the two trials were all height-related (Romer et al.: height, height standard deviation score [HtSDS], height velocity [HV], and height velocity standard deviation score [HVSDS]; Shih et al.: height, HV, and HtSDS) at study end.

Efficacy

In the two included trials, the mean increase in height from baseline to the study end (ninth month or twelfth month) in children with GHD ranged from 8 cm to 11 cm across the somatropin products (Genotropin, Omnitrope, Humatrope, and Saizen). In the Romer et al. study, the baseline-adjusted difference between Omnitrope and Genotropin for the change in HV was not statistically significant after nine months of treatment: −0.20 cm per year (95% confidence interval [CI], −1.34 to 0.94). Thus, the effect on HV of Genotropin and Omnitrope may be considered equivalent, given that the 95% CI did not exceed ± 2 cm per year. In addition, the Romer et al. study reported no statistically significant differences between Genotropin and Omnitrope for the outcomes of change in height and HtSDS over nine months: 0.23 cm (95% CI, −0.59 to 1.06) and 0.12 (95% CI, −0.06 to 0.30) respectively.

In the Shih et al. study, patients receiving Humatrope consistently underperformed those receiving Saizen or Genotropin in three linear growth measures (height, HtSDS, and HV). However, the study did not report the statistical significance of between-treatment differences and, given the small sample size, any such analyses are unlikely to provide meaningful results. Thus, the most credible results of comparative efficacy come from the Romer et al. study, which is restricted to the comparison of Genotropin and Omnitrope.

Additional limitations of the available data include the short duration of the trials and the uncertain relationship between short-term increases in growth and final adult height. In addition, the reviewed trials did not examine the impact of somatropin treatment on quality of life.

Harms

Harms appeared to be insufficiently reported in the Shih et al. trial. The assertion by Shih et al. that no adverse events were observed in the year-long trial appears to be suspect; it appears more likely that the incidence of adverse events was just not captured adequately. In the Romer et al. study, there were few notable differences in adverse events between Genotropin and Omnitrope except for hypothyroidism (none in the Genotropin group versus five in the Omnitrope group); however, the small sample size precludes definitive conclusions regarding the comparative safety. The increase in insulin-like growth factor-1 from baseline in the Genotropin group was slightly higher (between-group difference: 18.3 ng/mL versus Omnitrope) in the Romer et al. study; the observed between-treatment difference was not considered clinically meaningful.

Given the short duration and relatively small sample size, neither study provided meaningful data related to long-term harms, including mortality or malignancy outcomes. Observational data have suggested that persons treated with somatropin in childhood have a higher incidence of all-cause mortality compared with the general population; however, the role of somatropin in the higher incidence of mortality is unclear.

Other Considerations

A number of somatropin products available in Canada are indicated for the treatment of GHD in children, and they show similar pharmacokinetic/pharmacodynamic characteristics. The available products differ in terms of their dose formulation, injection devices, and cost. Choice of product is generally based upon patient and/or parent preference, in consultation with the clinician.

Pharmacoeconomic Summary

Somatropin (Genotropin) is available as an injection with multiple strengths (0.6 mg, 0.8 mg, 1.0 mg, 1.2 mg, 1.4 mg, 1.6 mg, 1.8 mg, and 2.0 mg syringes, and 5.3 mg and 12 mg pens). The manufacturer used a cost-minimization analysis to support its request for reimbursement of Genotropin for use in pediatric patients with GHD.1 Similar clinical effectiveness for Genotropin and comparators was assumed based on the results of one trial comparing Genotropin to Omnitrope in children with GHD.2 There were no published indirect comparisons of these agents. Based on Common Drug Review calculations using a confidential price of $▬ per milligram, the daily cost of the maximum dose of Genotropin ($▬; 0.16 mg/kg to 0.24 mg/kg per week) is less than that of Humatrope ($77; 0.18 mg/kg to 0.30 mg/kg per week), Nutropin ($64; up to 0.3 mg/kg per week), Saizen ($59; 0.20 mg/kg to 0.24 mg/kg per week), and Omnitrope ($42; 0.025 mg/kg to 0.035 mg/kg per day).

Conclusions

The Common Drug Review identified two randomized controlled trials in children with GHD that compared Genotropin with other somatropin products available in Canada. The Shih et al. study was considered underpowered to provide meaningful results. Results of the Romer et al. study suggest Genotropin has similar effects on linear growth compared with Omnitrope over a period of nine months. There are insufficient data from the reviewed trials regarding the comparative efficacy and safety of Genotropin versus other somatropin products available in Canada, particularly in relation to final height, health-related quality of life, and infrequent or long-latency adverse events.

TABLE 1Summary of Results

OutcomeRomer et al.Shih et al.
Genotropin
N = 45
Omnitrope
N = 44
Genotropin
N = 5
Humatrope
N = 5
Saizen
N = 5
Height, cm
  Mean change from baseline8.48.611.39.411.1
  Difference in change between groups (95% CI)0.23 (−0.59 to 1.06)NR
HV, cm per year
  Mean change from baseline6.86.97.95.47.4
  Difference in change between groups (95% CI)−0.20 (−1.34 to 0.94)NR
HtSDS
  Mean change from baseline0.670.731.330.661.06
  Difference in change between groups (95% CI)0.12 (−0.06 to 0.30)NR
HVSDS
  Mean change from baseline7.288.14NR
  Difference in change between groups (95% CI)0.76 (−0.57 to 2.10)
WDAEs, N (%)00
Subjects with SAEs, N (%)NR0
IGF-1
  Mean change from baseline172.6 ng/mL154.3 ng/mL0.74 U/mL1.19 U/mL1.47 U/mL
  Difference in change between groupsa18.3Genotropin: −0.45 versus Humatrope; −0.73 versus Saizen

CI = confidence interval; HV = height velocity; HtSDS = height standard deviation score; HVSDS = height velocity standard deviation score; IGF-1 = insulin-like growth factor-1; NR = not reported; SAE = serious adverse event; WDAE = withdrawal due to adverse event.

a

Calculated by the Common Drug Review (CDR).

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Cover of Somatropin (Genotropin) for Subcutaneous Injection
Somatropin (Genotropin) for Subcutaneous Injection: Long-term Treatment of Children who have Growth Failure Due to an Inadequate Secretion of Endogenous Growth Hormone [Internet].

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