DESCRIPTION:

Nutropin® [somatropin (rDNA origin) for injection] is a human growth hormone (hGH) produced by recombinant DNA technology. Nutropin has 191 amino acid residues and a molecular weight of 22,125 daltons. The amino acid sequence of the product is identical to that of pituitary-derived human growth hormone. The protein is synthesized by a specific laboratory strain of E. coli as a precursor consisting of the rhGH molecule preceded by the secretion signal from an E. coli protein. This precursor is directed to the plasma membrane of the cell. The signal sequence is removed and the native protein is secreted into the periplasm so that the protein is folded appropriately as it is synthesized.

Nutropin is a highly purified preparation. Biological potency is determined using a cell proliferation bioassay.

Nutropin is a sterile, white, lyophilized powder intended for subcutaneous administration after reconstitution with Bacteriostatic Water for Injection, USP (benzyl alcohol preserved). The reconstituted product is nearly isotonic at a concentration of 5 mg/mL growth hormone (GH) and has a pH of approximately 7.4.

Each 5 mg Nutropin vial contains 5 mg (approximately 15 IU) somatropin, lyophilized with 45 mg mannitol, 1.7 mg sodium phosphates (0.4 mg sodium phosphate monobasic and 1.3 mg sodium phosphate dibasic), and 1.7 mg glycine.

Each 10 mg Nutropin vial contains 10 mg (approximately 30 IU) somatropin, lyophilized with 90 mg mannitol, 3.4 mg sodium phosphates (0.8 mg sodium phosphate monobasic and 2.6 mg sodium phosphate dibasic), and 3.4 mg glycine.

Bacteriostatic Water for Injection, USP, is sterile water containing 0.9 percent benzyl alcohol per mL as an antimicrobial preservative packaged in a multidose vial. The diluent pH is 4.5-7.0.

CLINICAL PHARMACOLOGY

General

In vitro and in vivo preclinical and clinical testing have demonstrated that Nutropin is therapeutically equivalent to pituitary-derived human GH (hGH). Pediatric patients who lack adequate endogenous GH secretion, patients with chronic renal insufficiency, and patients with Turner syndrome that were treated with Nutropin resulted in an increase in growth rate and an increase in insulin-like growth factor-I (IGF-I) levels similar to that seen with pituitary-derived hGH.

Actions that have been demonstrated for Nutropin, somatrem, and/or pituitary-derived hGH include:

Tissue Growth

1) Skeletal Growth: GH stimulates skeletal growth in pediatric patients with growth failure due to a lack of adequate secretion of endogenous GH or secondary to chronic renal insufficiency and in patients with Turner syndrome. 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 GH deficient, but increase during treatment with GH. 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.

2) Cell Growth: Treatment with hGH results in an increase in both the number and the size of skeletal muscle cells.

3) Organ Growth: GH influences the size of internal organs, including kidneys, and increases red cell mass. Treatment of hypophysectomized or genetic dwarf rats with GH results in organ growth that is proportional to the overall body growth. In normal rats subjected to nephrectomy-induced uremia, GH promoted skeletal and body growth.

Protein Metabolism-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 during GH therapy.

Carbohydrate Metabolism-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 GH. GH therapy may decrease insulin sensitivity. Untreated patients with chronic renal insufficiency and Turner syndrome have an increased incidence of glucose intolerance. Administration of hGH 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 A 1c levels remained in the normal range.

Lipid Metabolism-In GH-deficient patients, administration of GH resulted in lipid mobilization, reduction in body fat stores, increased plasma fatty acids, and decreased plasma cholesterol levels.

Mineral Metabolism-The retention of total body potassium in response to GH administration apparently results from cellular growth. Serum levels of inorganic phosphorus may increase slightly in patients with inadequate secretion of endogenous GH, chronic renal insufficiency, or patients with Turner syndrome during GH 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 GH deficiency show low bone mineral density (BMD). (See PRECAUTIONS: Laboratory Tests .)

Connective Tissue Metabolism-GH stimulates the synthesis of chondroitin sulfate and collagen as well as the urinary excretion of hydroxyproline.

Pharmacokinetics

Subcutaneous Absorption-The absolute bioavailability of recombinant human growth hormone (rhGH) after subcutaneous administration in healthy adult males has been determined to be 81±20%. The mean terminal t 1/2 after subcutaneous administration is significantly longer than that seen after intravenous administration (2.1±0.43 hr vs. 19.5±3.1 min) indicating that the subcutaneous absorption of the compound is slow and rate-limiting.

Distribution-Animal studies with rhGH showed that GH localizes to highly perfused organs, particularly the liver and kidney. The volume of distribution at steady state for rhGH in healthy adult males is about 50 mL/kg body weight, approximating the serum volume.

Metabolism-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.

Elimination-The mean terminal t 1/2 after intravenous administration of rhGH 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® [somatropin (rDNA origin) injection] based on the statistical evaluation of AUC and C max .

Special Populations

Pediatric-Available literature data suggest that rhGH clearances are similar in adults and children.

Gender-No data are available for exogenously administered rhGH. Available data for methionyl recombinant GH, pituitary-derived GH, and endogenous GH suggest no consistent gender-based differences in GH clearance.

Geriatrics-Limited published data suggest that the plasma clearance and average steady-state plasma concentration of rhGH 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 (GHD)-Reported values for clearance of rhGH 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 t 1/2 values following intravenous and subcutaneous administration in adult and pediatric GHD patients are also similar to those observed in healthy adult males.

Renal Insufficiency-Children and adults with chronic renal failure (CRF) and end-stage renal disease (ESRD) tend to have decreased clearance compared to normals. Endogenous GH production may also increase in some individuals with ESRD. However, no rhGH accumulation has been reported in children with CRF or ESRD dosed with current regimens.

Turner Syndrome-No pharmacokinetic data are available for exogenously administered rhGH. 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 populations.

Hepatic Insufficiency-A reduction in rhGH clearance has been noted in patients with severe liver dysfunction. The clinical significance of this decrease is unknown.

Summary of Nutropin Pharmacokinetic Parameters in Healthy Adult Males

0.1 mg (approximately 0.3 IU a )/kg SC C max

(µg/L) T max

(hr) t 1/2

(hr) (AUC 0-(infinity)

µg·hr/L) CL/F SC

(mL/[hr·kg])

MEAN b

67.2 6.2 2.1 643 158

CV%

29 37 20 12 12

Abbreviations: C max =maximum concentration; t 1/2 =half life; AUC 0-(infinity) =area under the curve; CL/F SC =systemic clearance; F SC =subcutaneous bioavailability (not determined); CV%=coefficient of variation in %; SC=subcutaneous

a Based on current International Standard of 3 IU=1 mg

b n=36

Efficacy Studies

Effects of Nutropin on Growth Failure Due to Chronic Renal Insufficiency (CRI)

Two multicenter, randomized, controlled clinical trials were conducted to determine whether treatment with Nutropin prior to renal transplantation in patients with chronic renal insufficiency 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/wk) 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.