Mechanism of Action
Somatropin (as well as endogenous growth hormone) binds to
dimeric growth hormone receptors located within the cell membranes of target
tissue cells resulting in intracellular signal transduction and a host of
pharmacodynamic effects. Some of these pharmacodynamic effects are primarily
mediated by insulin-like growth factor (IGF-1) produced in the liver and also
locally (e.g., skeletal growth, protein synthesis), while others are primarily
a consequence of the direct effects of somatropin (e.g., lipolysis).
In vitro and in vivo preclinical and clinical testing have
demonstrated that Nutropin is therapeutically equivalent to pituitary-derived
hGH. Pediatric patients who lack adequate endogenous growth hormone (GH)
secretion, patients with chronic kidney disease (CKD), and patients with Turner
syndrome (TS) that were treated with Nutropin AQ or Nutropin resulted in an
increase in growth rate and an increase in IGF-1 levels similar to that seen
with pituitary-derived hGH.
Nutropin stimulates skeletal growth in pediatric patients
with growth failure due to a lack of adequate secretion of endogenous GH or
secondary to CKD and in patients with TS. Skeletal growth is accomplished at
the epiphyseal plates at the ends of a growing bone. Growth and metabolism of
epiphyseal plate cells are directly stimulated by GH and one of its mediators,
IGF-I. Serum levels of IGF-I are low in children and adolescents who are GHD,
but increase during treatment with somatropin. In pediatric patients, new bone
is formed at the epiphyses in response to GH and IGF-I. This results in linear
growth until these growth plates fuse at the end of puberty.
Treatment with somatropin results in an increase in both the
number and the size of skeletal muscle cells.
GH influences the size of internal organs, including
kidneys, and increases red cell mass. Treatment of hypophysectomized or genetic
dwarf rats with somatropin results in organ growth that is proportional to the overall
body growth. In normal rats subjected to nephrectomy-induced uremia, somatropin
promoted skeletal and body growth.
Linear growth is facilitated in part by GH-stimulated
protein synthesis. This is reflected by nitrogen retention as demonstrated by a
decline in urinary nitrogen excretion and blood urea nitrogen (BUN) during
GH is a modulator of carbohydrate metabolism. For example,
patients with inadequate secretion of GH sometimes experience fasting
hypoglycemia that is improved by treatment with Nutropin. Somatropin therapy
may decrease insulin sensitivity. Untreated patients with CKD and TS have an
increased incidence of glucose intolerance. Administration of somatropin to
adults or children resulted in increases in serum fasting and postprandial
insulin levels, more commonly in overweight or obese individuals. In addition,
mean fasting and postprandial glucose and hemoglobin A1C levels remained in the
In GHD patients, administration of somatropin resulted in
lipid mobilization, reduction in body fat stores, increased plasma fatty acids,
and decreased plasma cholesterol levels.
The retention of total body potassium in response to
somatropin administration apparently results from cellular growth. Serum levels
of inorganic phosphorus may increase slightly in patients with inadequate
secretion of endogenous GH, CKD, or TS during Nutropin therapy due to metabolic
activity associated with bone growth as well as increased tubular reabsorption
of phosphate by the kidney. Serum calcium is not significantly altered in these
patients. Sodium retention also occurs. Adults with childhood-onset GHD show
low bone mineral density (BMD). Nutropin therapy results in increases in serum alkaline phosphatase [see WARNINGS AND PRECAUTIONS].
Connective Tissue Metabolism
GH stimulates the synthesis of chondroitin sulfate and
collagen as well as the urinary excretion of hydroxyproline.
The absolute bioavailability of somatropin after
subcutaneous administration in healthy adult males has been determined to be 81
± 20%. The mean terminal t½ after subcutaneous administration is
significantly longer than that seen after intravenous administration (2.1 ±
0.43 hours vs. 19.5 ± 3.1 minutes) indicating that the subcutaneous absorption
of the compound is slow and rate-limiting.
Animal studies with somatropin showed that GH localizes 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 body weight, approximating the serum volume.
Both the liver and kidney have been shown to be important
metabolizing organs for GH. Animal studies suggest that the kidney is the
dominant organ of clearance. GH 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.
The mean terminal t½ after intravenous administration of
somatropin in healthy adult males is estimated to be 19.5 ± 3.1 minutes.
Clearance of rhGH after intravenous administration in healthy adults and
children is reported to be in the range of 116-174 mL/hr/kg.
Bioequivalence of Formulations
Nutropin has been determined to be bioequivalent to Nutropin
AQ based on the statistical evaluation of area under the curve (AUC) and
maximum concentration (Cmax).
Pediatric: Available literature data suggests that
somatropin clearances are similar in adults and children.
Geriatrics: 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.
Race: 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.
Growth Hormone Deficiency: Reported values for
clearance of somatropin in adults and children with GHD range 138-245 mL/hr/kg
and are similar to those observed in healthy adults and children. Mean terminal
t½ values following intravenous and subcutaneous administration in adult and
pediatric GHD patients are also similar to those observed in healthy adult
Chronic Kidney Disease: Children and adults with CKD
and end-stage renal disease (ESRD) tend to have decreased clearance compared to
normals. In a study with six pediatric patients 7 to 11 years of age, the
clearance of Nutropin was reduced by 21.5% and 22.6% after the intravenous
infusion and subcutaneous injection, respectively, of 0.05 mg/kg of Nutropin
compared to normal healthy adults. Endogenous GH production may also increase
in some individuals with ESRD. However, no somatropin accumulation has been
reported in children with CKD or ESRD dosed with current regimens.
Turner Syndrome: No pharmacokinetic data are
available for exogenously administered somatropin. However, reported
half-lives, absorption, and elimination rates for endogenous GH in this
population are similar to the ranges observed for normal subjects and GHD
Hepatic Insufficiency: A reduction in somatropin
clearance has been noted in patients with severe liver dysfunction. The
clinical significance of this decrease is unknown.
Gender: No gender-specific pharmacokinetic studies
have been done with Nutropin. The available literature indicates that the
pharmacokinetics of somatropin are similar in men and women.
Table 2: Summary of Nutropin Pharmacokinetic Parameters
in Healthy Adult Males 0.1 mg (approximately 0.3 IUa)/kg SC
||AUC0-∞ (μg • hr/L)
||CL/Fsc (mL/[hr • kg])
|a Based on current International Standard of 3 IU
= 1 mg.
Abbreviations: AUC0-m = area under the curve. Cmax=maximum concentration.
CL/Fsc = systemic clearance. CY%=coefficient of variation in %;
SC=subcutaneous. Fsc=subcutaneous bioavailability (not determined).
Figure 1: Single Dose Mean Growth Hormone Concentrations
in Healthy Adult Males
Pubertal Patients with Growth Hormone Deficiency (GHD)
One open label, multicenter, randomized clinical trial of
two dosages of Nutropin was performed in pubertal patients with GHD.
Ninety-seven patients (mean age 13.9 years, 83 male, 14 female) currently being
treated with approximately 0.3 mg/kg/wk of GH were randomized to 0.3 mg/kg/wk
or 0.7 mg/kg/wk Nutropin doses. All patients were already in puberty (Tanner stage ≥ 2) and had bone ages ≤14 years in males or ≤ 12 years in
females. Mean baseline height standard deviation score (SDS) was -1.3.
The mean last measured height in all 97 patients after a
mean duration of 2.7 ± 1.2 years, by analysis of covariance (ANCOVA) adjusting
for baseline height, is shown below.
Table 3: Last Measured Height by Sex and Nutropin Dose
for Pubertal Patients with GHD
||Last Measured Height* (cm)
||Height Difference Between Groups (cm)
|Mean ± SD (range)
||Mean ± SD
||Mean ± SD
||Mean ± SE
||17.2 ± 1.3 (13.6 to 19.4)
||170.9 ±7.9 (n=42)
||174.5 ± 7.9 (n = 41)
||3.6 ± 1.7
||15.8 ± 1.8 (11.9 to 19.3)
||154.7 ± 6.3 (n=7)
||157.6 ± 6.3 (n=7)
||2.9 ± 3.4
|*Adjusted for baseline height
The mean height SDS at last measured height (n = 97) was
-0.7 ± 1.0 in the 0.3 mg/kg/wk group and - 0.1 ± 1.2 in the 0.7 mg/kg/wk group.
For patients completing 3.5 or more years (mean 4.1 years) of Nutropin
treatment (15/49 patients in the 0.3 mg/kg/wk group and 16/48 patients in the
0.7 mg/kg/wk group), the mean last measured height was 166.1 ± 8.0 cm in the
0.3 mg/kg/wk group and 171.8 ± 7.1 cm in the 0.7 mg/kg/wk group, adjusting for
baseline height and sex.
The mean change in bone age was approximately one year for
each year in the study in both dose groups. Patients with baseline height SDS
above -1.0 were able to attain normal adult heights with the 0.3 mg/kg/wk dose
of Nutropin (mean height SDS at near-adult height = -0.1, n = 15).
Thirty-one patients had bone mineral density (BMD)
determined by dual energy x-ray absorptiometry (DEXA) scans at study
conclusion. The two dose groups did not differ significantly in mean SDS for
total body BMD (-0.9 ± 1.9 in the 0.3 mg/kg/wk group vs. -0.8 ± 1.2 in the 0.7
mg/kg/wk group, n = 20) or lumbar spine BMD (-1.0 ± 1.0 in the 0.3 mg/kg/wk
group vs.-0.2 ± 1.7 in the 0.7 mg/kg/wk group, n = 21).
Over a mean duration of 2.7 years, patients in the 0.7
mg/kg/wk group were more likely to have IGF-I values above the normal range
than patients in the 0.3 mg/kg/wk group (27.7% vs. 9.0% of IGF-I measurements
for individual patients). The clinical significance of elevated IGF-I values is
Pediatric Patients with Growth Failure Secondary to Chronic
Kidney Disease (CKD)
Two multicenter, randomized, controlled clinical trials were
conducted to determine whether treatment with Nutropin prior to renal
transplantation in patients with CKD could improve their growth rates and
height deficits. One study was a double-blind, placebo-controlled trial and the
other was an open-label, randomized trial. The dose of Nutropin in both
controlled studies was 0.05 mg/kg/day (0.35 mg/kg/week) administered daily by
subcutaneous injection. Combining the data from those patients completing two
years in the two controlled studies results in 62 patients treated with
Nutropin and 28 patients in the control groups (either placebo-treated or
untreated). The mean first year growth rate was 10.8 cm/yr for Nutropin-treated
patients, compared with a mean growth rate of 6.5 cm/yr for placebo/untreated
controls (p < 0.00005). The mean second year growth rate was 7.8 cm/yr for
the Nutropin-treated group, compared with 5.5 cm/yr for controls (p <
0.00005). There was a significant increase in mean height SDS in the Nutropin
group (-2.9 at baseline to -1.5 at Month 24, n = 62) but no significant change
in the controls (-2.8 at baseline to -2.9 at Month 24, n = 28). The mean third
year growth rate of 7.6 cm/yr in the Nutropin-treated patients (n = 27)
suggests that Nutropin stimulates growth beyond two years. However, there are
no control data for the third year because control patients crossed over to
Nutropin treatment after two years of participation. The gains in height were
accompanied by appropriate advancement of skeletal age. These data demonstrate
that Nutropin therapy improves growth rate and corrects the acquired height
deficit associated with CKD.
The North American Pediatric Renal Transplant Cooperative
Study (NAPRTCS) has reported data for growth post-transplant in children who
did not receive GH prior to transplantation as well as children who did receive
Nutropin during the clinical trials prior to transplantation. The average
change in height SDS during the initial two years post-transplant was 0.15 for
the 2,391 patients who did not receive GH pre-transplant and 0.28 for the 57
patients who did. For patients who were followed for 5 years post-transplant,
the corresponding changes in height SDS were also similar between groups.
Pediatric Patients with Turner Syndrome (TS)
Three US studies, two long-term, open-label, multicenter,
historically controlled studies (Studies 1 and 2), and one long-term,
randomized, dose-response study (Study 3) and one Canadian, long-term,
randomized, open-label, multicenter, concurrently controlled study, were
conducted to evaluate the efficacy of somatropin treatment of short stature due
In the US Studies 1 and 2, the effect of long-term GH
treatment (0.375 mg/kg/week given either 3 times per week or daily) on adult
height was determined by comparing adult heights in the treated patients with
those of age-matched historical controls with TS who received no
growth-promoting therapy. In Study 1, estrogen treatment was delayed until
patients were at least age 14. GH therapy resulted in a mean adult height gain
of 7.4 cm (mean duration of GH therapy of 7.6 years) vs. matched historical
controls by ANCOVA.
In Study 2, patients treated with early Nutropin therapy
(before 11 years of age) were randomized to receive estrogen-replacement
therapy (conjugated estrogens, 0.3 mg escalating to 0.625 mg daily) at either
age 12 or 15 years. Compared with matched historical controls, early Nutropin
therapy (mean duration of 5.6 years) combined with estrogen replacement at age
12 years resulted in an adult height gain of 5.9 cm (n = 26), whereas girls who
initiated estrogen at age 15 years (mean duration of Nutropin therapy 6.1
years) had a mean adult height gain of 8.3 cm (n = 29). Patients who initiated
Nutropin after age 11 (mean age 12.7 years; mean duration of Nutropin therapy
3.8 years) had a mean adult height gain of 5.0 cm (n = 51).
Thus, in Studies 1 and 2, the greatest improvement in adult
height was observed in patients who received early GH treatment and estrogen
after age 14 years.
In Study 3, a randomized, blinded dose-response study,
patients were treated from a mean age of 11.1 years for a mean duration of 5.3
years with a weekly GH dose of either 0.27 mg/kg or 0.36 mg/kg administered in
divided doses 3 or 6 times weekly. The mean near-final height of GH-treated
patients was 148.7 ± 6.5 cm (n=31). When compared to historical control data,
the mean gain in adult height was approximately 5 cm.
The Canadian randomized study compared near-adult height
outcomes for GH-treated patients to those of a concurrent control group who
received no injections. The somatropin-treated patients received a dosage of
0.3 mg/kg/week given in divided doses 6 times per week from a mean age of 11.7
years for a mean duration of 4.7 years. Puberty was induced with a standardized
estrogen regimen initiated at 13 years of age for both treatment groups. The
somatropin-treated group (n = 27) attained a mean (± SD) near final height of
146.0 ± 6.2 cm; the untreated control group (n = 19) attained a near final
height of 142.1 ± 4.8 cm. By ANCOVA (with adjustments for baseline height and
mid-parental height), the effect of GH-treatment was a mean height increase of
5.4 cm (p = 0.001).
In summary, patients with TS (total n = 181 from the 4
studies above) treated to adult height achieved statistically significant
average height gains ranging from 5.0-8.3 cm.
Table 4 : Summary of Efficacy Results in Turner Syndromea
||N at Adult Height
||GH Age (yr)
||Estrogen Age (yr)
||GH Duration (yr)
||Adult Height Gain (cm)c
|a Data shown are mean values.
b RCT: randomized controlled trial; MHT: matched historical
controlled trial; RDT: randomized dose-response trial.
c Analysis of covariance vs. controls.
d Compared with historical data.
* A = GH age < 11 yr, estrogen age 15 yr.
B = GH age < 11 yr, estrogen age 12 yr.
C = GH age > 11 yr, estrogen at Month 12.
Pediatric Patient with Idiopathic Short Stature (ISS)
A long-term, open-label, multicenter study was conducted to
examine the safety and efficacy of Nutropin in pediatric patients with ISS,
also called non-growth hormone deficient short stature. For the first year, 122
pre-pubertal subjects over the age of 5 years with stimulated serum GH ≥10
ng/mL were randomized into two treatment groups of approximately equal size;
one group was treated with Nutropin 0.3 mg/kg weekly divided into three doses
per week and the other group served as untreated controls. For the second and
subsequent years of the study, all subjects were re-randomized to receive the
same total weekly dose of Nutropin (0.3 mg/kg weekly) administered either daily
or three times weekly. Treatment with Nutropin was continued until a subject's
bone age was > 15.0 years (boys) or > 14.0 years (girls) and the growth rate
was < 2 cm/yr, after which subjects were followed until adult height was
achieved. The mean baseline values were: height SDS-2.8, IGF-I SDS -0.9, age
9.4 years, bone age 7.8 years, growth rate 4.4 cm/yr, mid-parental target
height SDS -0.7, and Bayley-Pinneau predicted adult height SDS -2.3. Nearly all
subjects had predicted adult height that was less than mid-parental target
During the one-year controlled phase of the study, the mean
height velocity increased by 0.5 ± 1.8 cm (mean ± SD) in the no-treatment
control group and by 3.1 ± 1.7 cm in the Nutropin group (p < 0.0001). For
the same period of treatment the mean height SDS increased by 0.4 ± 0.2 and
remained unchanged (0.0 ± 0.2) in the control group (p < 0.001).
Of the 118 subjects who were treated with Nutropin (70%)
reached near-adult height (hereafter called adult height) after 2-10 years of
Nutropin therapy. Their last measured height, including post-treatment
follow-up, was obtained at a mean age of 18.3 years in males and 17.3 years in
females. The mean duration of therapy was 6.2 and 5.5 years, respectively.
Adult height was greater than pretreatment predicted adult height in 49 of 60
males (82%) and 19 of 23 females (83%). The mean difference between adult
height and pretreatment predicted adult height was 5.2 cm (2.0 inches) in males
and 6.0 cm (2.4 inches) in females (p < 0.0001 for both). The table (below)
summarizes the efficacy data.
Table 5: Long-Term Efficacy in ISS (Mean ± SD)
(n = 60)
|Adult height (cm)
||166.3 ± 5.8
|Pretreatment predicted adult height (cm)
|Adult height minus pretreatment predicted adult height (cm)
||+ 5.2 ± 5.0a
||+6.0 ± 5.0a
|Adult height SDS
||-1.5 ± 0.8
|Pretreatment predicted adult height SDS
||-2.5 ± 0.8
|Adult height minus pretreatment predicted adult height SDS
||+ 0.7 ± 0.7a
|a p < 0.0001 versus zero.
Nutropin therapy resulted in an increase in mean IGF-I SDS
from -0.9 ± 1.0 to -0.2 ± 0.9 in Treatment Year 1. During continued treatment,
mean IGF-I levels remained close to the normal mean. IGF-I SDS above + 2
occurred sporadically in 14 subjects.
Adult Growth Hormone Deficiency
Two multicenter, double-blind, placebo-controlled clinical
trials were conducted in growth hormone-deficient adults. Study 1 was conducted
in subjects with adult-onset GHD (n = 166), mean age 48.3 years, at doses of
0.0125 or 0.00625 mg/kg/day; doses of 0.025 mg/kg/day were not tolerated in
these subjects. Study 2 was conducted in previously treated subjects with
childhood-onset GHD (n = 64), mean age 23.8 years, at randomly assigned doses
of 0.025 or 0.0125 mg/kg/day. The studies were designed to assess the effects
of replacement therapy with Nutropin on body composition.
Significant changes from baseline to Month 12 of treatment
in body composition (i.e., total body % fat mass, trunk % fat mass, and total
body % lean mass by DEXA scan) were seen in all Nutropin groups in both studies
(p < 0.0001 for change from baseline and vs. placebo), whereas no
statistically significant changes were seen in either of the placebo groups. In
the adult-onset study, the Nutropin group improved mean total body fat from
35.0% to 31.5%, mean trunk fat from 33.9% to 29.5%, and mean lean body mass
from 62.2% to 65.7%, whereas the placebo group had mean changes of 0.2% or less
(p = not significant). Due to the possible effect of GH-induced fluid retention
on DEXA measurements of lean body mass, DEXA scans were repeated approximately
3 weeks after completion of therapy; mean % lean body mass in the Nutropin
group was 65.0%, a change of 2.8% from baseline, compared with a change of 0.4%
in the placebo group (p < 0.0001 between groups).
In the childhood-onset study, the high-dose Nutropin group
improved mean total body fat from 38.4% to 32.1%, mean trunk fat from 36.7% to
29.0%, and mean lean body mass from 59.1% to 65.5%; the low-dose Nutropin group
improved mean total body fat from 37.1% to 31.3%, mean trunk fat from 37.9% to
30.6%, and mean lean body mass from 60.0% to 66.0%; the placebo group had mean
changes of 0.6% or less (p = not significant).
Table 6: Mean Changes from Baseline to Month 12 in
Proportion of Fat and Lean by DEXA for Adult- and Childhood- Onset GHD Studies
||Adult Onset (Study 1)
||Childhood Onset (Study 2)
||Between- Groups t-test p-value
||Placebo (n = 13)
||Nutropin 0.0125 mg/ kg/day (n = 15)
||Nutropin 0.025 mg/ kg/day (n = 15)
||Placebo vs. Pooled Nutropin t-test p-value
|Total body percent fat
|Baseline to Month 12 change
|Baseline to postwashout change
|Trunk percent fat
|Baseline to Month 12 change
|Baseline to postwashout change
|Total body percent lean
|Baseline to Month 12 change
|Baseline to postwashout change
In the adult-onset study, significant decreases from
baseline to Month 12 in low-density lipoprotein (LDL) cholesterol and
LDL:high-density lipoprotein (HDL) ratio were seen in the Nutropin group
compared to the placebo group, p < 0.02; there were no statistically
significant between-group differences in change from baseline to Month 12 in
total cholesterol, HDL cholesterol, or triglycerides. In the childhood-onset
study significant decreases from baseline to Month 12 in total cholesterol, LDL
cholesterol, and LDL:HDL ratio were seen in the high-dose Nutropin group only,
compared to the placebo group, p < 0.05. There were no statistically
significant between-group differences in HDL cholesterol or triglycerides from
baseline to Month 12.
In the childhood-onset study, 55% of the patients had
decreased spine BMD (z-score <-1) at baseline. The administration of
Nutropin (n = 16) (0.025 mg/kg/day) for two years resulted in increased spine
BMD from baseline when compared to placebo (n = 13) (4.6% vs. 1.0%,
respectively, p < 0.03); a transient decrease in spine BMD was seen at six
months in the Nutropin-treated patients. Thirty-five percent of subjects
treated with this dose had supraphysiological levels of IGF-I at some point
during the study, which may carry unknown risks. No significant improvement in
total body BMD was found when compared to placebo. A lower GH dose (0.0125
mg/kg/day) did not show significant increments in either of these bone
parameters when compared to placebo. No statistically significant effects on
BMD were seen in the adult-onset study where patients received GH (0.0125
mg/kg/day) for one year.
Muscle strength, physical endurance, and quality of life
measurements were not markedly abnormal at baseline, and no statistically
significant effects of Nutropin therapy were observed in the two studies.
A subsequent 32-week, multicenter, open-label, controlled
clinical trial was conducted using Nutropin AQ, Nutropin Depot, or no treatment
in adults with both adult-onset and childhood-onset GHD. Subjects were
randomized into the three groups to evaluate effects on body composition,
including change in visceral adipose tissue (VAT) as determined by computed
tomography (CT) scan.
For subjects evaluable for change in VAT in the Nutropin AQ
(n = 44) and untreated (n = 19) groups, the mean age was 46.2 years and 78% had
adult-onset GHD. Subjects in the Nutropin AQ group were treated at doses up to
0.012 mg/kg per day in women (all of whom received estrogen replacement
therapy) and men under age 35 years, and up to 0.006 mg/kg per day in men over
age 35 years.
The mean absolute change in VAT from baseline to Week 32 was
-10.7 cm² in the Nutropin AQ group and + 8.4 cm² in the untreated group (p =
0.013 between groups). There was a 6.7% VAT loss in the Nutropin AQ group (mean
percent change from baseline to Week 32) compared with a 7.5% increase in the
untreated group (p = 0.012 between groups). The effect of reducing VAT in adult
GHD patients with Nutropin AQ on long-term cardiovascular morbidity and
mortality has not been determined.
Table 7: Visceral Adipose Tissue by Computed Tomography
Scan: Percent Change and Absolute Change from Baseline to Week 32 in Study 3
(n = 44)
(n = 19)
|Treatment Difference (adjusted mean)
|Baseline VAT (cm²) (mean)
|Change in VAT (cm²) (adjusted mean)
|Percent change in VAT (adjusted mean)
|a ANCOVA using baseline VAT as a covariate
VAT=visceral adipose tissue.