Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2021 Publisher: Ipsen Pharma, 65 quai Georges Gorse, 92100 Boulogne-Billancourt, France
Pharmacotherapeutic group: Pituitary and hypothalamic hormones and analogues, Somatropin and analogues
ATC Code: H01AC01
Somatropin stimulates growth rate and increases adult height in children who lack endogenous growth hormone and in children who have growth failure due to Turner Syndrome or CRI. Treatment of growth hormone deficient adults with somatropin results in reduced fat mass, increased lean body mass and increased spine bone mineral density. Metabolic alterations in these patients include normalisation of IGF-I serum levels.
In vitro and in vivo preclinical and clinical tests have demonstrated that somatropin is therapeutically equivalent to human growth hormone of pituitary origin.
Actions that have been demonstrated for human growth hormone include:
Tissue Growth:
Protein metabolism:
Linear growth is facilitated in part by growth hormone-stimulated protein synthesis. This is reflected by nitrogen retention as demonstrated by a decline in urinary nitrogen excretion and blood urea nitrogen during growth hormone therapy.
Carbohydrate metabolism:
Patients with inadequate growth hormone secretion sometimes experience fasting hypoglycaemia that is improved by treatment with somatropin. Growth hormone therapy may decrease insulin sensitivity and impair glucose tolerance.
Mineral metabolism:
Somatropin induces retention of sodium, potassium and phosphorus. Serum concentration of inorganic phosphorus are increased in patients with growth hormone deficiency after NutropinAq therapy due to metabolic activity associated with bone growth and increased tubular reabsorption in the kidney. Serum calcium is not significantly altered by somatropin. Adults with growth hormone deficiency show low bone mineral density and in the childhood-onset patient, NutropinAq has been shown to increase spine bone mineral density in a dose-dependent manner.
Connective tissue metabolism:
Somatropin stimulates the synthesis of chondroitin sulphate and collagen as well as the urinary excretion of hydroxyproline.
Body composition:
Adult growth hormone deficient patients treated with somatropin at a mean dosage of 0.014 mg/kg bodyweight daily demonstrate a decrease in fat mass and increase in lean body mass. When these alterations are coupled with the increase in total body water and bone mass, the overall effect of somatropin therapy is to modify body composition, an effect that is maintained with continued treatment.
Two pivotal, open label, uncontrolled, multicentre studies have been conducted, one exclusively in previously untreated patients (n=67), and the other in previously untreated patients (n=63) and in children previously treated with somatropin (n=9). The dose in both studies was 0.043 mg/kg/day, administered subcutaneously (s.c.). Doses used in these US based studies are consistent with the US approved dose regimen. Of the 139 patients included, 128 completed the first 12 months of therapy, with an average treatment time of 3.2 and 4.6 years and a total exposure of 542 patient years. In both studies there was a significant improvement in growth rate in the naïve patients, increasing from 4.2 to 10.9 cm/year in one study and from 4.8 to 11.2 cm/year in the other at 12 months. The growth rate decreased after the first year in both studies, but continued to be greater than pretreatment levels for up to 48 months treatment (7.1 cm/year). The height standard deviation score (SDS) improved each year, increasing from -3.0 to -2.7 at baseline to -1.0 to -0.8 at Month 36. The improvements in growth were not accompanied by undue advancement of bone age, which would jeopardise future growth potential. Predicted adult height (PAH) increased from 157.7-161.0 cm at baseline to 161.4-167.4 cm at Month 12 and 166.2-171.1 cm at Month 36.
Supportive data are provided by two other studies, in which patients were given a dose of 0.3 or 0.6 mg/kg/week either as a daily injection or three times per week, or 0.029 mg/kg/day. The data on growth rate and height SDS were broadly similar to those observed in the pivotal studies.
For 51 patients who achieved near-adult height after an average duration of treatment of 6 years in males and 5 years in females, the mean near-adult height SDS was -0.7 in males and -1.2 in females.
IGF-I levels increased from a baseline of 43 ng/ml to 252 ng/ml at 36 months, which approximate to the normal levels expected in children of this age.
The most common adverse events (AEs) observed in the pivotal studies were infection, headache, otitis media, fever, pharyngitis, rhinitis and gastroenteritis and vomiting.
Two pivotal, multicentre, controlled studies have been conducted in patients with growth failure associated with chronic renal insufficiency (CRI). Each study had a two year treatment period which included a placebo arm, followed by an open label uncontrolled extension in which all patients received somatropin. The dose was 0.05 mg/kg/day s.c. in both studies. The results of both studies were similar.
In total, 128 patients received somatropin over the 24 month controlled phase of the 2 studies, and 139 patients were treated with somatropin in the open extension phases. Overall, 171 patients were exposed to somatropin for an average of 3.5 or 2.8 years.
Both studies demonstrated a statistically significant increase in growth rate compared to placebo over the first year (9.1-10.9 cm/year vs 6.2-6.6 cm/year), which decreased slightly in the second year (7.4-7.9 cm/year vs 5.5-6.6 cm/year). There was also a significant increase in height SDS in somatropin-treated patients, from -2.9 to -2.7 at baseline to -1.6 to -1.4 at 24 months. Height gains were maintained in the patients treated for 36 or 48 months. A total of 58% and 65% of somatropin-treated patients, who were below normal range at baseline, had reached heights within the normal range by Month 24.
The results to Month 60 show continued improvement, and more patients reached height SDS in the normal range. The average change in height SDS after 5 years of treatment was close to 2 standard deviations (SDs). A statistically significant increase in mean PAH SDS was observed, from -1.6 or -1.7 at baseline to -0.7 or -0.9 at Month 24. This continued to increase in those patients treated for 36 and 48 months.
IGF-I levels, which were low at study entry, were restored to within the normal range with somatropin therapy.
The most frequently reported AEs were associated with both NutropinAq and placebo and were fever, infection, vomiting, cough increased, pharyngitis, rhinitis and otitis media. There was a high incidence of urinary tract infections.
One pivotal, multicentre, open label, controlled study has been conducted in Turner Syndrome. Patients received an s.c. dose of 0.125 mg/kg three times a week or 0.054 mg/kg/day, both regimens giving a cumulative weekly dose of approximately 0.375 mg/kg. Patients under 11 years of age were also randomised to receive oestrogen therapy, either in late (aged 15 years) or early (aged 12 years) adolescence.
A total of 117 patients were treated with somatropin; 36 received somatropin 0.125 mg/kg three times a week and 81 patients received 0.054 mg/kg somatropin daily. The average treatment time was 4.7 years in the somatropin three times a week group and 4.6 years in the somatropin daily group.
Growth rate increased significantly from 3.6-4.1 cm/year at baseline to 6.7-8.1 cm/year at Month 12, 6.7-6.8 cm/year at Month 24 and 4.5-5.1 cm/year at Month 48. This was accompanied by a significant increase in height SDS from -0.1 to 0.5 at baseline to 0.0 to 0.7 at Month 12 and 1.6 to 1.7 at Month 48. Compared with matched historical controls, early somatropin therapy (mean duration of 5.6 years) combined with oestrogen replacement at age 12 years resulted in an adult height gain of 5.9 cm (n=26), whereas girls who initiated oestrogen at age 15 years (mean duration of somatropin therapy 6.1 years) had a mean adult height gain of 8.3 cm (n=29). Thus, the greatest improvement in adult height was observed in patients who received early GH treatment and oestrogen after age 14 years.
The most commonly reported AEs were flu syndrome, infection, headache, pharyngitis, rhinitis and otitis media. These events are expected in children and were mild/moderate AEs.
Two pivotal, multicentre, placebo-controlled, double-blind studies have been conducted in patients diagnosed with adult growth hormone deficiency (AGHD), one in adult-onset AGHD (n=166) and the other in childhood-onset AGHD (n=64). The dose of somatropin was 0.0125 mg/kg/day sc in adult-onset AGHD and 0.0125 or 0.025 mg/kg/day in childhood-onset AGHD.
In both studies, somatropin treatment resulted in significant changes compared to placebo in total body % fat (-6.3 to -3.6 vs +0.2 to-0.1), trunk % fat (-7.6 to -4.3 vs +0.6 to 0.0) and total body % lean (+3.6 to +6.4 vs -0.2 to +0.2). These changes were highly significant at the 12-month time point in both studies, and at the 24-month time point in the childhood-onset study. At the 12-month time point, the percentage change was higher in the childhood-onset study than in the adult-onset study. No significant changes in bone mineral density (BMD) were observed in adult-onset AGHD patients, however in the childhood-onset study, all groups had an increase in BMD at 24 months, although there was no statistically significant dose response for total body BMD. Lumbar spine BMD had statistically significant increases in both treated groups, and the increase was dose dependent.
Supporting data from a study on adult-onset GHD patients were generally consistent with those of the pivotal studies, with some improvements in BMD.
The most frequently reported AEs in the two pivotal studies were headache, oedema, arthralgia/arthrosis, tenosynovitis, paraesthesia and allergic reaction/rash. The incidence of these AEs was also high in the placebo groups.
The pharmacokinetic properties of NutropinAq have only been investigated in healthy adult males.
The absolute bioavailability of recombinant human growth hormone after subcutaneous administration is about 80%.
Animal studies with somatropin showed that growth hormone localises to highly perfused organs, particularly the liver and kidney. The volume of distribution at steady state for somatropin in healthy adult males is about 50 ml/kg bodyweight, approximating the serum volume.
Both the liver and the kidney have been shown to be important protein catabolising organs for growth hormone. Animal studies suggest that the kidney is the dominant organ of clearance. Growth hormone is filtered at the glomerulus and reabsorbed in the proximal tubules. It is then cleaved within renal cells into its constituent amino acids, which return to the systemic circulation.
After subcutaneous bolus administration, the mean terminal half-life t½ of somatropin is about 2.3 hours. After intravenous bolus administration of somatropin, the mean terminal half-life t½β or t½γ is about 20 minutes and the mean clearance is reported to be in the range of 116 – 174 ml/h/kg. Available literature data suggest that somatropin clearance is similar in adults and children.
Information about the pharmacokinetics of somatropin in elderly and paediatric populations, in different races or genders and in patients with renal or hepatic impairment is incomplete.
Available literature data suggests that somatropin clearances are similar in adults and children.
Limited published data suggest that the plasma clearance and average steady-state plasma concentration of somatropin may not be different between young and elderly patients.
Reported values for half-lives for endogenous GH in normal adult black males are not different from observed values for normal adult white males. No data for other races are available.
Clearance and mean terminal half-life t½ of somatropin in adult and paediatric growth hormone deficient patients are similar to those observed in healthy subjects.
Children and adults with chronic renal failure and end-stage renal disease tend to have decreased clearance compared to normal subjects. Endogenous growth hormone production may also increase in some individuals with end-stage renal disease. However, no somatropin accumulation has been reported in children with chronic renal failure or end-stage renal disease dosed with current regimens.
Limited published data for exogenously-administered somatropin suggest absorption and elimination half-lives and time of maximum concentration tmax in Turner patients are similar to those observed in both normal and growth hormone deficient populations.
In patients with severe liver dysfunction a reduction in somatropin clearance has been noted. The clinical significance of this decrease is unknown.
No gender-specific pharmacokinetic studies have been done with NutropinAq. The available literature indicates that the pharmacokinetics of somatropin are similar in men and women.
Non-clinical data reveal no special hazard for human based on conventional acute and repeated-dose toxicity studies.
Carcinogenicity and genotoxicity studies have not been conducted with Nutropin Aq. In genotoxicity studies with other recombinant growth hormone preparations, there was no evidence of gene mutation in bacterial reverse mutation assays, chromosomal damage in human lymphocyte and mouse bone marrow cells, gene conversion in yeast or unscheduled DNA synthesis in human carcinoma cells. In carcinogenicity studies testing biologically recombinant active growth hormone in rats and mice, no increase in the incidence of tumours was shown.
No conventional reproduction studies were performed. Somatropin is known to be associated with inhibition of the reproduction in male and female rats at doses of 3 IU/kg/day (1 mg/kg/day) or more, with reduced copulation and conception rates, lengthened or absent oestrous cycles, and at 10 IU/kg/day (3.3 mg/kg/day). Long-term treatment of monkeys during pregnancy and lactation and of newborn animals until adolescence, sexual maturity and reproduction did not indicate substantial disturbances of fertility, pregnancy, delivery, nursing or development of progeny.
Under the proposed indications, the use of somatropin is not expected to result in an unacceptable risk to the environment.
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