OmniTrope®

OMNITROPE™ 5.8 mg is dispensed in a vial containing 5.8 mg of somatropin (approximately 17.4 IU), glycine (27.6 mg), disodium hydrogen phosphate heptahydrate (2.09 mg), and sodium dihydrogen phosphate dihydrate (0.56 mg). The product is supplied with a vial containing 1.14 mL diluent (Bacteriostatic Water for Injection containing 1.5% benzyl alcohol as a preservative). After reconstitution of the lyophilized powder, the solution has a concentration of 5 mg/mL (approx. 15 IU/mL).

OMNITROPE™ 1.5 mg is dispensed in a vial containing 1.5 mg of somatropin (approximately 4.5 IU), glycine (27.6 mg), disodium hydrogen phosphate heptahydrate (0.88 mg), and sodium dihydrogen phosphate dihydrate (0.21 mg). The product is provided with a vial containing 1.13 mL of diluent (Sterile Water for Injection). After reconstitution of the lyophilized powder, the solution has a concentration of 1.33 mg/mL (approx. 4 IU/mL).

The reconstituted somatropin solution has an osmolality of approximately 300 mOsm/kg, and a pH of approximately 7.0. The concentration of the reconstituted solution varies by strength and presentation (see HOW SUPPLIED section).

Clinical Pharmacology
TIn vitro, preclinical, and clinical tests have demonstrated that somatropins are therapeutically equivalent to human growth hormone of pituitary origin and achieve similar pharmacokinetic profiles in normal adults. In pediatric patients who have growth hormone deficiency (GHD), treatment with somatropin stimulates linear growth and normalizes concentrations of Insulin-like Growth Factor -I (IGF-I).

In adults with GHD, treatment with somatropin results in reduced fat mass, increased lean body mass, metabolic alterations that include beneficial changes in lipid metabolism, and normalization of IGF-I concentrations.

In addition, the following actions have been demonstrated for OMNITROPE™ and/or somatropin.

1. Tissue Growth

A. Skeletal Growth: Somatropin stimulates skeletal growth in pediatric patients with GHD. The measurable increase in body length after administration of somatropin results from an effect on the epiphyseal plates of long bones. Concentrations of IGF-I, which may play a role in skeletal growth, are generally low in the serum of pediatric patients with GHD, but tend to increase during treatment with OMNITROPE™. Elevations in mean serum alkaline phosphatase concentration are also seen.

B. Cell Growth: It has been shown that there are fewer skeletal muscle cells in short-statured pediatric patients who lack endogenous growth hormone as compared with the normal pediatric population. Treatment with somatropin results in an increase in both the number and size of muscle cells.

2. Protein Metabolism
Linear growth is facilitated in part by increased cellular protein synthesis. Nitrogen retention, as demonstrated by decreased urinary nitrogen excretion and serum urea nitrogen, follows the initiation of therapy with somatropin.

3. Carbohydrate Metabolism
Pediatric patients with hypopituitarism sometimes experience fasting hypoglycemia that is improved by treatment with somatropin. Large doses of growth hormone may impair glucose tolerance.

4. Lipid Metabolism
In GHD patients, administration of somatropin has resulted in lipid mobilization, reduction in body fat stores, and increased plasma fatty acids.

5. Mineral Metabolism
Somatropin induces retention of sodium, potassium, and phosphorus. Serum concentrations of inorganic phosphate are increased in patients with GHD after therapy with somatropin. Serum calcium is not significantly altered by somatropin. Growth hormone could increase calciuria.

6. Body Composition
Adult GHD patients treated with somatropin at the recommended adult dose (see DOSAGE AND ADMINISTRATION) demonstrate a decrease in fat mass and an increase in lean body mass. When these alterations are coupled with the increase in total body water, the overall effect of somatropin is to modify body composition, an effect that is maintained with continued treatment.

Adult Growth Hormone Deficiency (GHD)
Randomized, placebo-controlled clinical trials with somatropin have been conducted in adult GHD patients.

In these trials, beneficial changes in body composition were observed at the end of a 6-month treatment period for patients receiving somatropin as compared with the placebo patients. Lean body mass, total body water, and lean/fat ratio increased, while total body fat mass and waist circumference decreased. These effects on body composition were maintained when treatment was continued beyond 6 months. Bone mineral density declined after 6 months of treatment but returned to baseline values after 12 months of treatment.

INDICATIONS AND USAGE
OMNITROPE™ is indicated for: Long-term treatment of pediatric patients who have growth failure due to an inadequate secretion of endogenous growth hormone.

Long-term replacement therapy in adults with growth hormone deficiency (GHD) of either childhood- or adult- onset etiology. GHD should be confirmed by an appropriate growth hormone stimulation test.

CONTRAINDICATIONS
OMNITROPE™ should not be used when there is any evidence of neoplastic activity. Intracranial lesions must be inactive and antitumor therapy complete prior to the institution of therapy. OMNITROPE™ should be discontinued if there is evidence of tumor growth.

Growth hormone should not be used for growth promotion in pediatric patients with fused epiphyses. Growth hormone should not be initiated to treat patients with acute critical illness due to complications following open heart or abdominal surgery, multiple accidental traumas, or to patients having acute respiratory failure. Two placebo-controlled clinical trials in non-growth hormone deficient adult patients with these conditions revealed a significant increase in mortality among somatropin-treated patients compared to those receiving placebo (see WARNINGS).

Growth hormone is contraindicated in patients with Prader-Willi syndrome who are severely obese or have severe respiratory impairment.

Treatment with OMNITROPE™ is contraindicated in case of hypersensitivity to somatropin or to any of the excipients.

WARNINGS
The OMNITROPE™ 5.8 mg presentation contains benzyl alcohol as a preservative. It should not be used in newborns.

See CONTRAINDICATIONS for information on increased mortality in patients with acute critical illnesses in intensive care units due to complications following open heart or abdominal surgery, multiple accidental traumas, or with acute respiratory failure. The safety of continuing growth hormone treatment in patients receiving replacement doses for approved indications who concurrently develop these illnesses has not been established. Therefore, the potential benefit of treatment continuation with growth hormone in patients having acute critical illnesses should be weighed against the potential risk.

PRECAUTIONS

General
Treatment with OMNITROPE™, as with other growth hormone preparations, should be directed by physicians who are experienced in the diagnosis and management of patients with GHD.

Patients and caregivers who will administer OMNITROPE™ in medically unsupervised situations should receive appropriate training and instruction on the proper use of OMNITROPE™ from the physician or other suitably qualified health professional.

Patients with GHD secondary to an intracranial lesion should be examined frequently for progression or recurrence of the underlying disease process. Review of literature reports of pediatric use of somatropin replacement therapy reveals no relationship between this therapy and recurrence of central nervous system (CNS) tumors. In adults, it is unknown whether there is any relationship between somatropin treatment and CNS tumor recurrence.

Patients should be monitored carefully for any malignant transformation of skin lesions.
Caution should be used if growth hormone is administered to patients with diabetes mellitus, and insulin dosage may need to be adjusted. Patients with diabetes or glucose intolerance should be monitored closely during treatment with OMNITROPE™. Patients with risk factors for glucose intolerance, such as obesity or a family history of Type II diabetes, should be monitored closely as well. Because growth hormone may induce a state of insulin resistance, patients should be observed for evidence of glucose intolerance.
In patients with hypopituitarism (multiple hormonal deficiencies) standard hormonal replacement therapy should be monitored closely when treatment with OMNITROPE™ is instituted. Hypothyroidism may develop during treatment with OMNITROPE™, and inadequate treatment of hypothyroidism may prevent medical response to OMNITROPE™. Therefore, patients should have periodic thyroid function tests and be treated with thyroid hormone when indicated.

Pediatric patients with endocrine disorders, including GHD, have a higher incidence of slipped capital femoral epiphyses. Any pediatric patient with the onset of a limp or complaints of hip or knee pain during growth hormone therapy should be evaluated. Progression of scoliosis can occur in patients who experience rapid growth. Because growth hormone increases growth rate, patients with a history of scoliosis who are treated with growth hormone should be monitored for progression of scoliosis. However, growth hormone has not been shown to increase the incidence of scoliosis.

Intracranial hypertension (IH) with papilledema, visual changes, headache, nausea and/or vomiting has been reported in a small number of patients treated with growth hormone products. Symptoms usually occurred within the first 8 weeks of the initiation of growth hormone therapy. In all reported cases, IH-associated signs and symptoms resolved after termination of therapy or a reduction of the growth hormone dose.

Funduscopic examination of patients is recommended at the initiation, and periodically during the course of growth hormone therapy. Before continuing treatment as an adult, a post-pubertal GHD patient who received growth hormone replacement therapy in childhood should be reevaluated with proper testing as described in INDICATIONS AND USAGE. If continued treatment is appropriate, OMNITROPE™ should be administered at the reduced dose level recommended for adult GHD patients.

Drug Interactions
Concomitant glucocorticoid treatment may inhibit the growth-promoting effect of growth hormone. Pediatric GHD patients with coexisting ACTH deficiency should have their glucocorticoid replacement dose carefully adjusted to avoid an inhibitory effect on growth (see also PRECAUTIONS - General). Limited published data indicate that growth hormone treatment increases cytochrome P450 (CP450) mediated antipyrine clearance in man. These data suggest that growth hormone administration may alter the clearance of compounds known to be metabolized by CP450 liver enzymes (e.g. corticosteroids, sex steroids, anticonvulsants, cyclosporine). Careful monitoring is advisable when growth hormone is administered in combination with other drugs known to be metabolized by CP450 liver enzymes.