General Information

Humatrope is a recombinant human growth hormone.

Humatrope is specifically indicated for:

• Pediatric Patients: growth failure due to inadequate secretion of endogenous growth hormone (GH); short stature associated with Turner syndrome; Idiopathic Short Stature (ISS), height standard deviation score (SDS) <-2.25, and associated with growth rates unlikely to permit attainment of adult height in the normal range; short stature or growth failure in short stature homeobox-containing gene (SHOX) deficiency; short stature born small for gestational age (SGA) with no catch-up growth by 2 years to 4 years of age.(1.1)
• Adult Patients: replacement of endogenous GH in adults with GH deficiency.

The recommended dosing is as follows:

• Administer by subcutaneous injection to the back of upper arm, abdomen, buttock, or thigh with regular rotation of injection sites. (2.1)
• Pediatric Dosage - divide the calculated weekly dosage into equal doses given either 6, or 7 days per week.
  • GHD: 0.18 mg/kg/week to 0.3 mg/kg/week.
  • Turner Syndrome: Up to 0.375 mg/kg/week. 
  • ISS: Up to 0.37 mg/kg/week. 
  • SHOX Deficiency: 0.35 mg/kg/week. 
  • SGA: Up to 0.47 mg/kg/week. 
• Adult Dosage - Either of the following two dosing regimens may be used:
  • Non-weight based dosing: Initiate with a dose of approximately 0.2 mg/day (range, 0.15 mg/day-0.3 mg/day) and increase the dose every 1-2 months by increments of approximately 0.1 mg/day-0.2 mg/day, according to individual patient requirements 
  • Weight-based dosing (Not recommended for obese patients): Initiate at 0.006 mg/kg daily and increase the dose according to individual patient requirements to a maximum of 0.0125 mg/kg daily 

Mechanism of Action

Somatropin binds to dimeric GH receptors located within the cell membranes of target tissue cells. This interaction results in intracellular signal transduction and subsequent induction of transcription and translation of GH-dependent proteins including IGF-1, IGF BP-3 and acid-labile subunit. Somatropin has direct tissue and metabolic effects or mediated indirectly by IGF-1, including stimulation of chondrocyte differentiation, and proliferation, stimulation of hepatic glucose output, protein synthesis and lipolysis.

Somatropin stimulates skeletal growth in pediatric patients with GHD as a result of effects on the growth plates (epiphyses) of long bones. The stimulation of skeletal growth increases linear growth rate (height velocity) in most somatropin-treated pediatric patients. Linear growth is facilitated in part by increased cellular protein synthesis.

Side Effects

Adverse effects associated with the use of Humatrope may include, but are not limited to, the following:

• upper respiratory infection
• fever
• pharyngitis
• headache
• otitis media
• edema
• arthralgia
• paresthesia
• myalgia
• carpal tunnel syndrome
• peripheral edema
• flu syndrome
• hypothyroidism
• hyperglycemia
• impaired glucose tolerance

Clinical Trial Results

Pediatric Patients with Growth Failure Due to Inadequate Secretion of Endogenous Growth Hormone

An open-label, uncontrolled, multicenter study with Humatrope was conducted in, 314 treatment-naive children aged >2 years who had GH deficiency. Patients were treated with HUMATROPE (0.06 mg/kg 3 times per week) for up to 8 years. The efficacy of HUMTROPE was assessed by evaluating height velocity. Mean increase in height velocity from baseline of 3.6 ± 1.9 cm/year to 8.8 ± 2.3 cm/year was achieved by 1 year of treatment. Height velocity remained increased above baseline for a small subset of patients (n=12) who remained on-study up to 8 years during the long-term extension phase (6.3 ± 2.5 cm/year at year 8 of treatment).

Pediatric Patients with Short Stature Associated with Turner Syndrome

One long-term, randomized, open-label, Canadian multicenter, concurrently controlled study, two long-term, open-label multicenter, historically controlled US studies and one long-term, randomized, US dose-response study were conducted to evaluate the efficacy of HUMATROPE for treatment of short stature due to Turner syndrome.

The randomized, open-label, Canadian study compared near-adult height outcomes for HUMATROPE-treated patients to those of a concurrent control group who received no injections. The HUMATROPE-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.

In two of the US studies, the effect of long-term treatment with Humatrope (0.375 mg/kg/week given in divided doses 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 Turner syndrome who received no growth-promoting therapy. Puberty was induced with a standardized estrogen regimen initiated after 14 years of age in one study; in the second study patients treated early (before 11 years of age) were randomized to begin pubertal induction at either age 12 (n=26) or 15 (n=29) years (conjugated estrogens, 0.3 mg escalating to 0.625 mg daily); those whose treatment was initiated after 11 years of age began estrogen replacement after 1 year of treatment with HUMATROPE.

In the third US study, a randomized, blinded dose-response study, patients were treated from a mean age of 10.9 years for a mean duration of 5.5 years with a weekly HUMATROPE dosage of either 0.27 mg/kg or 0.36 mg/kg administered in divided doses 3 or 6 times weekly.

In summary, patients with Turner syndrome (total n=249 from the 4 studies above) treated to adult height achieved average height gains ranging from 5.0 to 8.3 cm.

Pediatric Patients with Idiopathic Short Stature (ISS)

Two randomized, multicenter studies, one placebo-controlled and one dose-response, were conducted in pediatric patients with idiopathic short stature. The diagnosis of idiopathic short stature was made after excluding other known causes of short stature, as well as GH deficiency. The placebo-controlled study enrolled 71 pediatric patients (55 males, 16 females) 9 to 15 years old (mean age 12.4 ± 1.5 years), with short stature, 68 of whom received placebo (n=31) or HUMATROPE (n=37). Patients were predominately prepubertal (Tanner I, 45%) or in early puberty (Tanner II, 47%) at baseline. In this double-blind study, patients received subcutaneous injections of either HUMATROPE 0.222 mg/kg/week, or placebo given in divided doses 3 times per week until height velocity decreased to ≤1.5 cm/year (“final height”). Final height measurements were available for 33 subjects (22 treated with HUMATROPE, 11 treated with placebo) after a mean treatment duration of 4.4 years (range 0.1-9.1 years).

The number of patients whose final height was above the 5th percentile of the general population height standard for age and sex was significantly greater in the HUMATROPE group than the placebo group (41% vs. 0%), as was the number of patients who gained at least 1 SDS unit in height across the duration of the study (50% vs. 0%).

Pediatric Patients with Short Stature or Growth Failure in SHOX Deficiency

A randomized, controlled, two-year, three-arm, open-label study was conducted to evaluate the efficacy of HUMATROPE for treatment of short stature in pediatric patients with SHOX deficiency who were not GH–deficient. A total of 52 patients (24 male, 28 female) with SHOX deficiency, 3 to 12.3 years of age, were randomized to either a HUMATROPE-treated arm (27 patients; mean age 7.3 ± 2.1 years) or an untreated control arm (25 patients; mean age 7.5 ± 2.7 years). To determine the comparability of treatment effect between patients with SHOX deficiency and patients with Turner syndrome, the third study arm enrolled 26 patients with Turner syndrome, 4.5 to 11.8 years of age (mean age 7.5 ± 1.9 years) who received HUMATROPE treatment. All patients were prepubertal at study entry. Patients in the HUMATROPE-treated group(s) received daily subcutaneous injections of 0.05 mg/kg of HUMATROPE, equivalent to 0.35 mg/kg/week. Patients in the untreated group received no injections. One untreated patient discontinued the study during the first year. The mean first-year height velocity of treated patients with SHOX deficiency was significantly greater than that of the untreated patients (mean between-group difference = 3.5 [95% CI: 2.8 – 4.2] cm/year, p<0.001).

Pediatric Patients with Short Stature Born Small for Gestational Age (SGA) Who Fail to Demonstrate Catch-up Growth by Age 2 - 4 Years

The height increases would be considered similar if the lower bound of the 95% confidence interval (CI) for the mean difference between the groups (IAD – FHD) was greater than -0.5 height SDS. A 2-year, open-label, multicenter, European study enrolled 193 prepubertal, non-GH deficient children with mean chronological age 6.8 ± 2.4 years (range: 3 to 12.3). Study entry criteria included birth weight <10th percentile and/or birth length SDS <-2 for gestational age, and height SDS for chronological age ≤-3. Exclusion criteria included syndromal conditions (e.g., Turner syndrome), chronic disease (e.g., diabetes mellitus), and active tumors. The primary objective was to compare the increase from baseline in height SDS after 1 year of treatment when HUMATROPE is administered according to an individually adjusted dose (IAD) regimen with a fixed high dose (FHD) regimen. Patients were randomized to either a FHD (0.067 mg/kg/day [0.47 mg/kg/week]; n=99) or an IAD treatment group (n=94). The initial HUMATROPE dosage in the IAD treatment group was 0.035 mg/kg/day (0.25 mg/kg/week). The dosage was increased to 0.067 mg/kg/day in those patients in the IAD group whose 1-year height gain predicted at Month 3 was <0.75 height SDS (n=40) or whose actual height gain measured at Year 1 was <0.75 height SDS (n=11).

The increase from baseline in height SDS in the IAD group was non-inferior to that in the FHD group at Year 1 (mean between-group difference = -0.3 SDS [95% CI: -0.4, -0.2 SDS]). The results were similar when children who entered puberty during the study were removed from the analysis. Data is shown for the efficacy analysis population that included all patients who received at least 1 dose of HUMATROPE and had at least 1 post randomization height measurement. Approximately 85% of the randomized patients completed 2 years of therapy.

 Adult Patients with Growth Hormone Deficiency

Two multicenter studies in patients with adult-onset GH deficiency (n=98) and two studies in patients with childhood-onset GH deficiency (n=67) were designed to assess the effects of replacement therapy with HUMATROPE. Adult-onset patients and childhood-onset patients differed by diagnosis (organic vs. idiopathic pituitary disease), body size (average vs. small [mean height (171 cm vs 161 cm) and weight (85 kg vs 64 kg)]), and age (mean 44 vs. 29 years).Each study included a 6-month randomized, blinded, placebo-controlled phase, during which approximately half of the patients received placebo injections, while the other half received HUMATROPE injections. The HUMATROPE dosages for all studies were identical: 1 month of treatment at 0.00625 mg/kg/day followed by 0.0125 mg/kg/day for the next 5 months. The 6-month, double-blind phase was followed by 12 months of open-label HUMATROPE treatment for all patients. The primary efficacy measures were body composition (lean body mass and fat mass) and lipid parameters [Total cholesterol, high-density lipoprotein (HDL) and low-density lipoprotein (LDL)]. Lean body mass was determined by bioelectrical impedance analysis (BIA), validated with potassium 40. Body fat was assessed by BIA and sum of skinfold thickness. Lipid subfractions were analyzed by standard assay methods in a central laboratory.

In patients with adult-onset GH deficiency, HUMATROPE treatment (vs. placebo) resulted in an increase in mean lean body mass (2.59 vs. -0.22 kg, p<0.001) and a decrease in body fat (-3.27 vs. 0.56 kg, p<0.001). Similar changes were seen in childhood-onset GH deficient patients. These changes in lean body mass persisted throughout the 18-month period for both the adult-onset and childhood-onset groups; the changes in fat mass persisted in the childhood-onset group. Serum concentrations of HDL cholesterol which were low at baseline (mean, 31.0 mg/dL and 33.9 mg/dL in adult-onset (n=46) and childhood-onset (n=30) patients, respectively) had increased by the end of 18 months of HUMATROPE treatment (mean change of 13.7 and 11.1 mg/dL for the adult-onset (n=40) and childhood-onset (n=21) groups, respectively p<0.001; there was no adjustment for missing data). Total cholesterol and LDL did not show significant difference from baseline results by the end of 18 months of HUMATROPE treatment.

In an additional 2-year, open-label, randomized study, 149 patients with childhood-onset GH deficiency who had completed pediatric somatropin therapy, had attained final height (height velocity <1 cm/yr) and were confirmed to be GH-deficient as young adults, were randomized to receive HUMATROPE 0.0125 mg/kg/day (n=59), HUMATROPE 0.025 mg/kg/day (n=58), or no treatment (control) (n=32). Total bone mineral content (BMC) increased by 5.2% ± 3.9% in the control group (n=28 for those with BMC measurements), 7.0% ± 7.2% in the HUMATROPE 0.025 mg/kg/day group (n=51) and 8.0% ± 8.9% in the HUMATROPE 0.0125 mg/kg/day group (n=51). For the treatment effect versus control group, p=0.012 (ANOVA); there was no statistically significant difference between the 2 HUMATROPE dose groups. A significant overall treatment effect (ANOVA, p=0.037) was seen for the percentage change in lumbar spine BMC, but not for femoral neck or hip.