General Information

Nutropin AQ (somatropin) is a recombinant human growth hormone.

Nutropin AQ is specifically indicated for the following:

Pediatric Patients

• Growth Hormone Deficiency (GHD): pediatric patients who have growth failure due to inadequate secretion of endogenous growth hormone (GH)
• Growth Failure Secondary to Chronic Kidney Disease (CKD): growth failure associated with CKD up to the time of renal transplantation 
• Idiopathic Short Stature (ISS) - also called non-GHD short stature, defined by height SDS ≤ −2.25, and associated with growth rates unlikely to permit attainment of adult height in the normal range, in pediatric patients whose epiphyses are not closed and for whom diagnostic evaluation excludes other causes associated with short stature that should be observed or treated by other means
• Short Stature Associated with Turner Syndrome (TS)

Adult Patients

Nutropin AQ is indicated for the replacement of endogenous GH in adults with GHD who meet either of the following two criteria:

• Adult Onset: Patients who have GHD, either alone or associated with multiple hormone deficiencies (hypopituitarism), as a result of pituitary disease, hypothalamic disease, surgery, radiation therapy, or trauma
• Childhood Onset: Patients who were GH deficient during childhood as a result of congenital, genetic, acquired, or idiopathic causes

Patients who were treated with somatropin for GHD in childhood and whose epiphyses are closed should be reevaluated before continuation of somatropin therapy at the reduced dose level recommended for GH deficient adults. According to current standards, confirmation of the diagnosis of adult GHD in both groups involves an appropriate GH provocative test with two exceptions: (1) patients with multiple pituitary hormone deficiencies due to organic disease; and (2) patients with congenital/genetic GHD.

Nutropin AQ is supplied as an injection for subcutaneous administration.  The recommended dosing schedule is as follows:

Pediatric Patients

Nutropin AQ dosage and administration schedule should be individualized for each patient. Response to growth hormone (GH) therapy in pediatric patients tends to decrease with time. However, in pediatric patients failure to increase growth rate, particularly during the first year of therapy, suggests the need for close assessment of compliance and evaluation of other causes of growth failure, such as hypothyroidism, under-nutrition, advanced bone age and antibodies to recombinant human GH (rhGH). Treatment with Nutropin AQ for short stature should be discontinued when the epiphyses are fused.

Pediatric Growth Hormone Deficiency (GHD)

• A weekly dosage of up to 0.3 mg/kg of body weight divided into daily subcutaneous injection is recommended. In pubertal patients, a weekly dosage of up to 0.7 mg/kg divided daily may be used.

Growth Failure Secondary to Chronic Kidney Disease (CKD)

• A weekly dosage of up to 0.35 mg/kg of body weight divided into daily subcutaneous injection is recommended. Nutropin AQ therapy may be continued up to the time of renal transplantation. In order to optimize therapy for patients who require dialysis, the following guidelines for injection schedule are recommended: • Hemodialysis patients should receive their injection at night just prior to going to sleep or at least 3 to 4 hours after their hemodialysis to prevent hematoma formation due to the heparin. • Chronic Cycling Peritoneal Dialysis (CCPD) patients should receive their injection in the morning after they have completed dialysis. • Chronic Ambulatory Peritoneal Dialysis (CAPD) patients should receive their injection in the evening at the time of the overnight exchange.

Idiopathic Short Stature (ISS)

• A weekly dosage of up to 0.3 mg/kg of body weight divided into daily subcutaneous injections is recommended.

Short Stature Associated with Turner Syndrome (TS)

• A weekly dosage of up to 0.375 mg/kg of body weight divided into equal doses 3 to 7 times per week by subcutaneous injection is recommended.

Adult Patients

Adult Growth Hormone Deficiency (GHD) Either of two approaches to Nutropin AQ dosing may be followed: a weight-based regimen or a non-weight-based regimen.

• Weight based – Based on the dosing regimen used in the original adult GHD registration trials, the recommended dosage at the start of treatment is not more than 0.006 mg/kg daily. The dose may be increased according to individual patient requirements to a maximum of 0.025 mg/kg daily in patients ≤ 35 years and to a maximum of 0.0125 mg/kg daily in patients over 35 years old. Clinical response, side effects, and determination of age- and gender-adjusted serum insulin-like growth factor (IGF-1) concentrations should be used as guidance in dose titration.
• Non-weight based – Alternatively, taking into account the published literature, a starting dose of approximately 0.2 mg/day (range, 0.15 to 0.30 mg/day) may be used without consideration of body weight. This dose can be increased gradually every 1 to 2 months by increments of approximately 0.1 to 0.2 mg/day, according to individual patient requirements based on the clinical response and serum IGF-1 concentrations. The dose should be decreased as necessary on the basis of adverse events and/or serum IGF-1 concentrations above the age- and gender-specific normal range.

Mechanism of Action

Nutropin AQ (somatropin) 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).

Side Effects

Adverse effects associated with the use of Nutropin may include, or not limited to, the following:

• injection site reactions
• edema
• arthralgias
• carpal tunnel syndrome

Clinical Trial Results

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 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 unknown.

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. The mean second year growth rate was 7.8 cm/yr for the Nutropin-treated group, compared with 5.5 cm/yr for controls. 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.

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 to TS. 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). 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.

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. 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. 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. 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.

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, 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. 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. 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.