1.1 Pediatric Patients

ZOMACTON is indicated for the treatment of pediatric patients with:

• 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 (HSDS) ≤-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.

1.2 Adult Patients

ZOMACTON is indicated for the replacement of endogenous GH in adults with GH deficiency.

2.1 Administration and Use Instructions

• Therapy with ZOMACTON should be supervised by a physician who is experienced in the diagnosis and management of patients with the conditions for which ZOMACTON is indicated [see Indications and Usage (1)].
• Fundoscopic examination should be performed routinely before initiating treatment with ZOMACTON to exclude preexisting papilledema, and periodically thereafter [see Warnings and Precautions (5.5)].
• Administer ZOMACTON by subcutaneous injection to the back of the upper arm, abdomen, buttock, or thigh with regular rotation of injection sites to avoid lipoatrophy.
• ZOMACTON 5 mg and 10 mg can be administered using a standard sterile disposable syringe. For proper use, please refer to the Instructions for Use provided with the administration device. The volume of the syringe should be small enough so that the prescribed dose can be withdrawn from the vial with reasonable accuracy.

2.2 Pediatric Dosage

• Individualize dosage for each patient based on the growth response.
• Divide the calculated weekly ZOMACTON dosage into equal doses given either 3, 6, or 7 days per week.
• The recommended weekly dose in milligrams (mg) per kilogram (kg) of body weight for pediatric patients is:
  • Pediatric GH Deficiency: 0.18 mg/kg/week to 0.3 mg/kg/week (0.026 mg/kg/day to 0.043 mg/kg/day)
  • Turner syndrome: Up to 0.375 mg/kg/week (up to 0.054 mg/kg/day)
  • Idiopathic short stature: Up to 0.37 mg/kg/week (up to 0.053 mg/kg/day)
  • SHOX Deficiency: 0.35 mg/kg/week (0.05 mg/kg/day)
  • Small for Gestational Age (SGA): Up to 0.47 mg/kg/week (up to 0.067 mg/kg/day)
    • In very short pediatric patients, HSDS less than -3, and older pubertal pediatric patients consider initiating treatment with a larger dose of ZOMACTON (up to 0.067 mg/kg/day). Consider a gradual reduction in dosage if substantial catch-up growth is observed during the first few years of therapy. In pediatric patients less than 4 years of age with less severe short stature, baseline HSDS values between -2 and -3, consider initiating treatment at 0.033 mg/kg/day and titrate the dose as needed.
• Assess compliance and evaluate other causes of poor growth such as hypothyroidism, under-nutrition, advanced bone age and antibodies to recombinant human GH if patients experience failure to increase height velocity, particularly during the first year of treatment.
• Discontinue ZOMACTON for stimulation of linear growth once epiphyseal fusion has occurred [see Contraindications (4)].

2.3 Adult Dosage

• Patients who were treated with somatropin for GH deficiency in childhood and whose epiphyses are closed should be reevaluated before continuation of somatropin for GH deficient adults.
• Consider using a lower starting dose and smaller dose increment increases for geriatric patients as they may be at increased risk for adverse reactions with ZOMACTON than younger individuals [see Use in Specific Populations (8.5)].
• Estrogen-replete women and patients receiving oral estrogen may require higher doses [see Drug Interactions (7)].
• Administer the prescribed dose daily
• Either of two ZOMACTON dosing regimens may be used:
  • Non-weight based
    • Initiate ZOMACTON with a dose of approximately 0.2 mg/day (range, 0.15 mg/day to 0.3 mg/day) and increase the dose every 1 to 2 months by increments of approximately 0.1 mg/day to 0.2 mg/day, according to individual patient requirements based on the clinical response and serum insulin-like growth factor 1 (IGF-1) concentrations.
    • Decrease the dose as necessary on the basis of adverse reactions and/or serum IGF-1 concentrations above the age- and gender-specific normal range.
    • Maintenance dosages will vary considerably from person to person, and between male and female patients.
  • Weight-based
    • Initiate ZOMACTON at 0.006 mg/kg daily and increase the dose according to individual patient requirements to a maximum of 0.0125 mg/kg daily.
    • Use the patient's clinical response, adverse reactions, and determination of age- and gender-adjusted serum IGF-1 concentrations as guidance in dose titration.
    • Not recommended for obese patients as they are more likely to experience adverse reactions with this regimen.

2.4 Reconstitution

• Reconstitute ZOMACTON 5 mg with 1 mL to 5 mL of diluent, Bacteriostatic Sodium Chloride Injection, USP with 0.9% benzyl alcohol as a preservative. Do not use diluent if the patient has a known hypersensitivity to benzyl alcohol [see Contraindications (4)] or in neonates [see Warnings and Precautions (5.13)], or pregnant or lactating women [see Use in Specific Populations (8.1,8.2)] instead reconstitute with 0.9% Sodium Chloride Injection, USP, use only one dose per vial, and discard the unused portion.
• Reconstitute ZOMACTON 10 mg with 1 mL syringe of diluent, Bacteriostatic Water for Injection, USP with 0.33% metacresol as a preservative. Do not use diluent if the patient has a known hypersensitivity to metacresol [see Contraindications (4)].
• Aim the stream of diluent against the side of the vial to prevent foaming and gently swirl the vial with a rotary motion until the contents are completely dissolved and the solution is clear. Do not shake the vial since shaking or vigorous mixing will cause the solution to be cloudy.
• Inspect visually for particulate matter and discoloration. If the resulting solution is cloudy or contains particulate matter do not use.
• Occasionally, after refrigeration, some cloudiness may occur. Allow the product to warm to room temperature. If cloudiness persists or particulate matter is noted do not use.

5.1 Increased Mortality in Patients with Acute Critical Illness

Increased mortality in patients with acute critical illness due to complications following open heart surgery, abdominal surgery or multiple accidental trauma, or those with acute respiratory failure has been reported after treatment with pharmacologic doses of somatropin [see Contraindications (4)]. Two placebo-controlled clinical trials in non-GH deficient adult patients (n=522) with these conditions in intensive care units revealed a significant increase in mortality (42% vs. 19%) among somatropin-treated patients (doses 5.3 mg/day-8 mg/day) compared to those receiving placebo. The safety of continuing ZOMACTON treatment in patients receiving replacement doses for approved indications who concurrently develop these illnesses has not been established. ZOMACTON is not indicated for the treatment of non-GH deficient adults.

5.2 Sudden Death in Pediatric Patients with Prader-Willi Syndrome

There have been reports of sudden death after initiating therapy with somatropin in pediatric patients with Prader-Willi syndrome who had one or more of the following risk factors: severe obesity, history of upper airway obstruction or sleep apnea, or unidentified respiratory infection. Male patients with one or more of these factors may be at greater risk than females. Patients with Prader-Willi syndrome should be evaluated for signs of upper airway obstruction and sleep apnea before initiation of treatment with somatropin. If, during treatment with somatropin, patients show signs of upper airway obstruction (including onset of, or increased, snoring) and/or new onset sleep apnea, treatment should be interrupted. All patients with Prader-Willi syndrome treated with somatropin should also have effective weight control and be monitored for signs of respiratory infection, which should be diagnosed as early as possible and treated aggressively [see Contraindications (4)]. ZOMACTON is not indicated for the treatment of pediatric patients who have growth failure due to Prader-Willi syndrome.

5.3 Increased Risk of Neoplasms

5.4 Glucose Intolerance and Diabetes Mellitus

Treatment with somatropin may decrease insulin sensitivity, particularly at higher doses. New onset type 2 diabetes mellitus has been reported in patients taking somatropin. Previously undiagnosed impaired glucose tolerance and overt diabetes mellitus may be unmasked. Monitor glucose levels periodically in all patients receiving ZOMACTON, especially in those with risk factors for diabetes mellitus, such as obesity, Turner syndrome, or a family history of diabetes mellitus. Patients with preexisting type 1 or type 2 diabetes mellitus or impaired glucose tolerance should be monitored closely. The doses of antidiabetic agents may require adjustment when ZOMACTON is initiated.

5.5 Intracranial Hypertension

Intracranial hypertension (IH) with papilledema, visual changes, headache, nausea, and/or vomiting has been reported in a small number of patients treated with somatropin. Symptoms usually occurred within the first eight (8) weeks after the initiation of somatropin. In all reported cases, IH-associated signs and symptoms resolved rapidly after cessation of therapy or a reduction of the somatropin dose. Fundoscopic examination should be performed routinely before initiating treatment with ZOMACTON to exclude preexisting papilledema, and periodically thereafter. If papilledema is observed by fundoscopy, treatment should be stopped. If somatropin-induced IH is diagnosed, treatment with ZOMACTON can be restarted at a lower dose after IH-associated signs and symptoms have resolved. Patients with Turner syndrome may be at increased risk for the development of IH.

5.6 Severe Hypersensitivity

Serious systemic hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with postmarketing use of somatropins. Patients and caregivers should be informed that such reactions are possible and that prompt medical attention should be sought if an allergic reaction occurs [see Contraindications (4)].

5.7 Fluid Retention

Fluid retention during somatropin replacement therapy in adults may frequently occur. Clinical manifestations of fluid retention (e.g. edema, arthralgia, myalgia, nerve compression syndromes including carpal tunnel syndrome/paresthesias) are usually transient and dose dependent.

5.8 Hypoadrenalism

Patients receiving somatropin therapy who have or are at risk for pituitary hormone deficiency(s) may be at risk for reduced serum cortisol levels and/or unmasking of central (secondary) hypoadrenalism. In addition, patients treated with glucocorticoid replacement for previously diagnosed hypoadrenalism may require an increase in their maintenance or stress doses following initiation of ZOMACTON. Monitor patients for reduced serum cortisol levels and/or need for glucocorticoid dose increases in those with known hypoadrenalism [see Drug Interactions (7)].

5.9 Hypothyroidism

Undiagnosed or untreated hypothyroidism may prevent response to ZOMACTON, in particular, the growth response in pediatric patients. Patients with Turner syndrome have an increased risk of developing autoimmune thyroid disease and primary hypothyroidism. In patients with GH deficiency, central (secondary) hypothyroidism may first become evident or worsen during somatropin treatment. Therefore, patients should have periodic thyroid function tests performed, and thyroid hormone replacement therapy should be initiated or appropriately adjusted when indicated.

5.10 Slipped Capital Femoral Epiphysis in Pediatric Patients

Slipped capital femoral epiphysis may occur more frequently in patients undergoing rapid growth. Evaluate pediatric patients with the onset of a limp or complaints of hip or knee pain.

5.11 Progression of Preexisting Scoliosis in Pediatric Patients

Somatropin increases the growth rate and progression of existing scoliosis can occur in patients who experience rapid growth. Somatropin has not been shown to increase the occurrence of scoliosis. Monitor patients with a history of scoliosis for progression of scoliosis.

5.12 Pancreatitis

Cases of pancreatitis have been reported in pediatric patients and adults receiving somatropin. The risk may be greater in pediatric patients compared with adults. Published literature indicates that girls who have Turner syndrome may be at greater risk than other pediatric patients receiving somatropin. Pancreatitis should be considered in patients who develop abdominal pain.

5.13 Risk of Serious Adverse Reactions in Infants due to Benzyl Alcohol Preserved Solution

Serious and fatal adverse reactions including "gasping syndrome" can occur in neonates and infants treated with benzyl alcohol-preserved drugs, including the bacteriostatic 0.9% sodium chloride diluent provided with ZOMACTON 5 mg. The "gasping syndrome" is characterized by central nervous system depression, metabolic acidosis, and gasping respirations.

When administering ZOMACTON 5 mg to infants, reconstitute with 0.9% sodium chloride injection, not with the diluent provided. Use only one dose per vial and discard the unused portion [see Use in Specific Populations (8.4)].

5.14 Lipoatrophy

When somatropin is administered subcutaneously at the same site over a long period of time, tissue atrophy may result. Rotate injection sites when administering ZOMACTON to reduce this risk [see Dosage and Administration (2.2)].

5.15 Laboratory Tests

Serum levels of inorganic phosphorus, alkaline phosphatase, parathyroid hormone and IGF-1 may increase after ZOMACTON treatment.

6.1 Clinical Trials Experience

Because clinical trials are conducted under varying conditions, adverse reaction rates observed during the clinical trials performed with one somatropin formulation cannot always be directly compared to the rates observed during the clinical trials performed with a different approved somatropin formulation and may not reflect the adverse reaction rates observed in practice.

6.2 Postmarketing Experience

Because the following adverse events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Severe Hypersensitivity Reactions — Serious systemic hypersensitivity reactions including anaphylactic reactions and angioedema

Neurologic — Headaches (common in pediatric patients and occasional in adults)

Skin — Increase in size or number of cutaneous nevi

Endocrine — Gynecomastia.

Gastrointestinal — Pancreatitis

Metabolic — New-onset type 2 diabetes mellitus

Neoplasia — Leukemia has been reported in a small number of GH deficient pediatric patients treated with somatropin, somatrem (methionylated rhGH), and GH of pituitary origin.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

Safety and effectiveness of ZOMACTON in pediatric patients have been established in growth failure due to inadequate secretion of endogenous growth hormone, short stature associated with Turner syndrome, idiopathic short stature (ISS), short stature or growth failure in SHOX deficiency, and short stature in children born small for gestational age (SGA) with no catch-up growth by 2 years to 4 years of age.

8.5 Geriatric Use

The safety and effectiveness of somatropin in patients aged 65 years and over has not been evaluated in clinical studies. Elderly patients may be more sensitive to the action of somatropin, and therefore may be more prone to development of adverse reactions. A lower starting dose and smaller dose increments should be considered for geriatric patients [see Dosage and Administration (2.3)].

9.1 Controlled Substance

ZOMACTON contains somatropin, which is not a controlled substance.

9.2 Abuse

Inappropriate use of somatropin may result in significant negative health consequences.

9.3 Dependence

Somatropin is not associated with drug related withdrawal adverse reactions.

12.1 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 effects 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.

12.2 Pharmacodynamics

Subcutaneous administration of a single dose of 4 mg ZOMACTON in healthy subjects (n=54) with suppressed endogenous growth hormone results in an increased mean (SD) IGF-1 level from 233 (95) ng/mL predose to maximal level of 414 (120) ng/mL after approx. 24 hours. After 96 hours, the subjects displayed a mean (SD) IGF-1 concentration of 228 (74) ng/mL, comparable to the predose value.

12.3 Pharmacokinetics

12.6 Immunogenicity

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of ZOMACTON or other somatropins.

In a clinical trial with another recombinant growth hormone during the first 6 months of somatropin therapy in 314 naive patients, 1.6% developed specific antibodies to somatropin (binding capacity ≥0.02 mg/L). None had antibody concentrations which exceeded 2 mg/L. Throughout 8 years of this same study, two patients (0.6%) had binding capacity >2 mg/L. Neither patient demonstrated a decrease in growth velocity at or near the time of increased antibody production. It has been reported that growth attenuation from pituitary-derived GH may occur when antibody concentrations are >1.5 mg/L.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

ZOMACTON has shown no potential for mutagenicity in the Ames Test. Carcinogenesis and fertility studies have not been conducted with ZOMACTON.

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

A 2-year open-label, multi-center study with ZOMACTON was conducted in the United States and in Israel in 164 pediatric patients with short stature due to GHD. The subjects ranged in age from 2.1 to 17.7 years with a mean of 10.8 years. One hundred twenty (73%) of the subjects were male and 44 (27%) were female. Two subjects were Asian, 12 were Black, 130 were Caucasian, and 20 were categorized as 'other'.

The primary efficacy of the product was assessed by calculating height velocity. Mean cumulative increases in height velocity from baseline of 6.6, 4.6, and 6.3 cm/year were attained by 24 weeks of treatment (p < 0.01) in Naïve Type I (serum GH < 10 ng/mL in response to at least two provocative pharmacological tests), Naïve Type II (integrated GH level < 3.5 ng/mL with or without at least one serum GH ≥ 10 ng/mL), and Non-Naïve (treated with GH up to study Day 1, or previously treated and discontinued GH treatment at least 6 months prior to study Day 1) subjects, respectively. After 12 months of treatment, the mean cumulative increases in height velocity from baseline were 5.7, 4.4 and 5.3 cm/year (p= 0.01) in Naïve Type I, Naïve Type II, and Non-Naïve subjects, respectively.

14.2 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 another somatropin product for treatment of short stature due to Turner syndrome.

The Canadian randomized study compared near-adult height outcomes for patients treated with another somatropin product to those of a concurrent control group who received no injections. Patients received a dosage of 0.3 mg/kg/week given in divided doses 6 times per week from a mean age of 12 years for a mean duration of 5 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 another somatropin product (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 another somatropin product.

In a dose-response study in the US, patients were treated from a mean age of 11 years for a mean duration of 5 years with a weekly dosage of either 0.27 mg/kg or 0.36 mg/kg of another somatropin product administered in divided doses 3 or 6 times weekly.

In summary, patients with Turner syndrome (total n=181 from the 4 studies above) treated to adult height achieved statistically significant average height gains ranging from 5.0 to 8.3 cm (see Table 8).

14.3 Pediatric Patients with Idiopathic Short Stature

Two randomized, multicenter studies, 1 placebo-controlled and 1 dose-response, were conducted with another somatropin product 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 ± 1.5 years), with short stature, 68 of whom received another somatropin product. 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 another somatropin product 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, 11 placebo) after a mean treatment duration of 4.4 years (range 0.1-9.1 years).

Results are presented in Table 9. 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 treated 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%).

The dose-response study included 239 pediatric patients (158 males, 81 females), 5 to 15 years old, (mean age 10 ± 2 years). Mean ± SD baseline characteristics included: height SDS -3.21 ± 0.70, predicted adult height SDS -2.63 ± 1.08, and height velocity

SDS -1.09 ± 1.15. All but 3 patients were prepubertal. Patients were randomized to one of three treatment groups:

0.24 mg/kg/week; 0.24 mg/kg/week for 1 year, followed by 0.37 mg/kg/week; and 0.37 mg/kg/week. Height velocity was assessed by dose during the first 2 years of therapy. After completing the initial 2-year dose-response phase of the study, 50 patients were followed to final height.

Patients who received the dosage of 0.37 mg/kg/week had a significantly greater increase in mean height velocity after 2 years of treatment than patients who received 0.24 mg/kg/week (4.04 vs. 3.27 cm/year, p=0.003). The results are presented in Table 10. While no patient had height above the 5th percentile in any dosage group at baseline, 82% of the patients who received 0.37 mg/kg/week and 47% of the patients who received 0.24 mg/kg/week achieved final heights above the 5th percentile of the general population height standards (p=NS).

14.4 Pediatric Patients with Short Stature or Growth Failure with SHOX Deficiency

A randomized, controlled, two-year, three-arm, open-label study was conducted to evaluate the efficacy of another somatropin product 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 years of age, were randomized to either a treated arm (27 patients; mean age 7 ± 2 years) or an untreated control arm (25 patients; mean age 8 ± 3 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, 5 to 12 years of age (mean age 8 ± 2 years), to treatment. All patients were prepubertal at study entry. Patients in the treated group(s) received daily subcutaneous injections of 0.05 mg/kg of another somatropin product, equivalent to 0.35 mg/kg/week. Patients in the untreated group received no injections. The results are presented in Table 11.

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

A 2-year, open-label, multicenter, European study enrolled 193 prepubertal, non-GH deficient children with mean chronological age 7 ± 2 years (range: 3 to 12). 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 tumor activity. The primary objective was to demonstrate that the increase from baseline in height SDS after 1 year of treatment with another somatropin product would be similar when treatment is administered according to an individually adjusted dose (IAD) regimen or a fixed high dose (FHD) regimen. 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. Pediatric patients were randomized to either a FHD (0.067 mg/kg/day; n=99) or an IAD treatment group (n=94). The initial dosage in the IAD treatment group was 0.035 mg/kg/day. 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). Approximately 85% of the randomized patients completed 2 years of therapy.

The results are presented in Table 12. The results were similar when children who entered puberty during the study were removed from the analysis.

An open-label, multicenter, single arm study conducted in France, during which 35 prepubertal, non-GH deficient children were treated for 2 years with another somatropin product 0.067 mg/kg/day. Mean chronological age at baseline was 9 ± 0.9 years (range: 7 to 11). Additional study entry criteria included birth length SDS <-2 or <3rd percentile for gestational age, and height SDS for chronological age <-2. Exclusion criteria included syndromal conditions (e.g., Turner syndrome), chronic disease (e.g., diabetes mellitus), and any active disease. All 35 patients completed the study. Mean height SDS increased from a baseline value of -2.7 (SD 0.5) to -1.5 (SD 0.6) after 2 years of treatment.

14.6 Adult Patients with Growth Hormone Deficiency

Two studies in patients with adult-onset GH deficiency (total n=98) and two studies in adult patients with childhood-onset GH deficiency (total n=67) were designed to assess the effects of replacement therapy with another somatropin product. Adult-onset patients and childhood-onset patients differed by diagnosis (organic vs. idiopathic pituitary disease), body size (average vs. small [mean height and weight]), and age (mean 44 vs. 29 years). These four studies each included a 6-month randomized, blinded, placebo-controlled phase, during which approximately half of the patients received placebo injections, while the other half received injections with another somatropin product. The 6-month, double-blind phase was followed by 12 months of open-label somatropin treatment for all patients. The dosages of this other somatropin product 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 primary efficacy measures were body composition (lean body mass and fat mass) and lipid parameters. 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, treatment with another somatropin product (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. 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 high-density lipoprotein (HDL) cholesterol which were low at baseline (mean, 30.1 mg/mL and 33.9 mg/mL in adult-onset and childhood-onset patients, respectively) had normalized by the end of 18 months of treatment with this other somatropin product (mean change of 13.7 mg/dL and 11.1 mg/dL for the adult-onset and childhood-onset groups, respectively p<0.001).

16.1 How Supplied

ZOMACTON (somatropin) for injection is a white, lyophilized powder available as:

16.2 Storage and Handling