Protropin^® (somatrem for injection) is a polypeptide hormone produced by recombinant DNA technology. Protropin has 192 amino acid residues and a molecular weight of about 22,000 daltons. The product contains the identical sequence of 191 amino acids constituting pituitary-derived human growth hormone plus an additional amino acid, methionine, on the N-terminus of the molecule. Protropin is synthesized in a special laboratory strain of E. coli bacteria which has been modified by the addition of the gene for human growth hormone production.

Protropin is a highly purified preparation. Biological potency is determined by measuring the increase in body weight induced in hypophysectomized rats.

Protropin is a sterile, white, lyophilized powder intended for intramuscular or subcutaneous administration after reconstitution with Bacteriostatic Water for Injection, USP (benzyl alcohol preserved).

Each 5 mg Protropin vial contains 5 mg (approximately 15 IU) somatrem, lyophilized with 40 mg mannitol, and 1.7 mg sodium phosphates (0.1 mg sodium phosphate monobasic and 1.6 mg sodium phosphate dibasic).

Each 10 mg Protropin vial contains 10 mg (approximately 30 IU) somatrem, lyophilized with 80 mg mannitol, and 3.4 mg sodium phosphates (0.2 mg sodium phosphate monobasic and 3.2 mg sodium phosphate dibasic).

Phosphoric acid may be used for pH adjustment.

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

Protropin^® (somatrem for injection) is indicated only for the long- term treatment of children who have growth failure due to a lack of adequate endogenous growth hormone secretion. Other etiologies of short stature should be excluded.

A weekly dosage of 0.30 mg/kg (approximately 0.90 IU/kg) of body weight administered by daily intramuscular or subcutaneous injection is recommended.

The Protropin^® (somatrem for injection) dosage and administration schedule should be individualized for each patient. Therapy should not be continued if final height is achieved or epiphyseal fusion occurs. Patients who fail to respond adequately while on Protropin therapy should be evaluated to determine the cause of unresponsiveness.

After the dose has been determined, reconstitute as follows: each 5 mg vial should be reconstituted with 1-5 mL of Bacteriostatic Water for Injection, USP (benzyl alcohol preserved); or each 10 mg vial should be reconstituted with 1-10 mL Bacteriostatic Water for Injection, USP (benzyl alcohol preserved) only. For use in newborns see WARNINGS. The pH of Protropin after reconstitution with Bacteriostatic Water for Injection, USP (benzyl alcohol preserved) is approximately 7.8.

To prepare the Protropin solution, inject the Bacteriostatic Water for Injection, USP (benzyl alcohol preserved) into the Protropin vial, aiming the stream of liquid against the glass wall. Then swirl the product vial with a GENTLE rotary motion until the contents are completely dissolved. DO NOT SHAKE. Because Protropin is a protein, shaking can result in a cloudy solution. The Protropin solution should be clear immediately after reconstitution. Occasionally, after refrigeration, you may notice that small colorless particles of protein are present in the Protropin solution. This is not unusual for solutions containing proteins. If the solution is cloudy immediately after reconstitution or refrigeration, the contents MUST NOT be injected.

Before needle insertion, wipe the septum of both the Protropin and diluent vials with rubbing alcohol or an antiseptic solution to prevent contamination of the contents by microorganisms that may be introduced by repeated needle insertions. It is recommended that Protropin be administered using sterile, disposable syringes and needles. The syringes should be of small enough volume that the prescribed dose can be drawn from the vial with reasonable accuracy.

Protropin^® (somatrem for injection) is supplied as 5 mg (approximately 15 IU) or 10 mg (approximately 30 IU) of lyophilized, sterile, somatrem per vial.

Each 5 mg carton contains two vials of Protropin^® (somatrem for injection) (5 mg per vial) and one 10 mL multiple dose vial of Bacteriostatic Water for Injection, USP (benzyl alcohol preserved). NDC 50242-015-02

Each 10 mg carton contains two vials of Protropin^® (somatrem for injection) (10 mg per vial) and two 10 mL multiple dose vials of Bacteriostatic Water for Injection, USP (benzyl alcohol preserved). NDC 50242-016-20

As with all protein pharmaceuticals, a small percentage of patients may develop antibodies to the protein. Growth hormone antibody binding capacities below 2 mg/L have not been associated with growth attenuation. In some cases when binding capacity exceeds 2 mg/L, growth attenuation has been observed. In clinical studies and postmarketing experience of patients treated with Protropin^® (somatrem for injection), approximately 0.4 percent of patients screened for antibody production developed antibodies with binding capacities > 2 mg/L at six months. Out of approximately 26,000 patients who have been treated with Protropin, 5 patients have had growth deceleration associated with binding capacities > 2 mg/L. If growth deceleration is observed that is not attributable to another cause, the patient should be tested for antibodies to growth hormone. Although no evidence exists to indicate that the methionine on the N-terminus of somatrem causes antibodies to growth hormone, the physician should consider transferring the patient to somatropin (rDNA origin) for injection, if a patient has antibody binding capacity > 2 mg/L, and has exhibited growth attenuation.

In addition to an evaluation of compliance with the prescribed treatment program and thyroid status, testing for antibodies to human growth hormone should be carried out in any patient who fails to respond to therapy.

Additional short-term immunologic and renal function studies were carried out in a group of patients after approximately two years of treatment to detect other potential adverse effects of antibodies to growth hormone. The antibody was determined to be of the IgG class; no antibodies to growth hormone of the IgE class were detected. Testing included immune complex determination, measurement of total hemolytic complement and specific complement components, and immunochemical analyses. No adverse effects of growth hormone antibody formation were observed.

These findings are supported by a toxicity study conducted in a primate model in which a similar antibody response to growth hormone was observed. Protropin, administered to monkeys by intramuscular injection at doses of 125 and 625 ug/kg TIW, was compared to pituitary-human growth hormone at the same doses and with placebo over a period of 90 days. Most monkeys treated with high-dose Protropin developed persistent antibodies at week four. There were no biologically significant drug related changes in standard laboratory variables. Histopathologic examination of the kidney and other selected organs (pituitary, lungs, liver and pancreas) showed no treatment related toxicity. There was no evidence of immune complexes or immune complex toxicity when the kidney was also examined for the presence of immune complexes and possible toxic effects of immune complexes by immunohistochemistry and electron microscopy.

In studies in children treated with Protropin, injection site pain was reported infrequently.

Leukemia has been reported in a small number of growth hormone deficient patients treated with growth hormone. It is uncertain whether this increased risk is related to the pathology of growth hormone deficiency itself, growth hormone therapy, or other associated treatments such as radiation therapy for intracranial tumors. On the basis of current evidence, experts cannot conclude that growth hormone therapy is responsible for these occurrences. The risk to an individual patient, if any, remains to be established.

Other adverse drug reactions that have been reported in growth hormone-treated patients include the following: 1) Metabolic: Infrequent, mild and transient peripheral edema. 2) Musculoskeletal: Rare carpal tunnel syndrome. 3) Skin: Rare increased growth of pre-existing nevi. Malignant nevi transformation has not been reported. 4) Endocrine: Rare gynecomastia. Rare pancreatitis.

Concomitant glucocorticoid therapy may inhibit the growth promoting effect of Protropin. If glucocorticoid replacement is required, the dose should be carefully adjusted.

Benzyl alcohol as a preservative in Bacteriostatic Water for Injection, USP has been associated with toxicity in newborns. When administering Protropin^® (somatrem for injection) to newborns, reconstitute with Sterile Water for Injection, USP. USE ONLY ONE DOSE PER PROTROPIN VIAL AND DISCARD THE UNUSED PORTION.

General

Protropin^® (somatrem for injection) should be prescribed by physicians experienced in the diagnosis and management of patients with growth failure.

Because Protropin may induce a state of insulin resistance, patients should be observed for evidence of glucose intolerance.

Patients with a history of an intracranial lesion should be examined frequently for progression or recurrence of the lesion.

Slipped capital femoral epiphysis may occur more frequently in patients with endocrine disorders or in patients undergoing rapid growth. Physicians and parents should be alert to the development of a limp or complaints of hip or knee pain in Protropin-treated patients.

Progression of scoliosis can occur in children 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. 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 eight (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.

See WARNINGS for use of Bacteriostatic Water for Injection, USP (benzyl alcohol preserved) in newborns.

As with any protein, local or systemic allergic reactions may occur. Parents/Patient should be informed that such reactions are possible and that prompt medical attention should be sought if allergic reactions occur.

Laboratory Tests

Serum levels of inorganic phosphorus, alkaline phosphatase, and parathyroid hormone (PTH) may increase with Protropin therapy. Changes in thyroid hormone laboratory measurements may develop during Protropin treatment of children who lack adequate endogenous growth hormone secretion. Untreated hypothyroidism prevents optimal response to Protropin. Therefore, patients should have periodic thyroid function tests and should be treated with thyroid hormone when indicated.

Drug Interactions

Concomitant glucocorticoid therapy may inhibit the growth promoting effect of Protropin. If glucocorticoid replacement is required, the dose should be carefully adjusted.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity, mutagenicity and reproduction studies have not been conducted with Protropin.

Pregnancy

Pregnancy (Category C). Animal reproduction studies have not been conducted with Protropin . It is also not known whether Protropin can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Protropin should be given to a pregnant woman only if clearly needed.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Protropin is administered to a nursing mother.

Information for Patients

See PATIENT INFORMATION section.

The recommended dosage of up to 0.30 mg/kg (approximately 0.90 IU/kg) of body weight weekly should not be exceeded due to the potential risk of known effects of excess human growth hormone.

Protropin^® (somatrem for injection) should not be used in subjects with closed epiphyses.

Protropin should not be used in patients with active neoplasia. Growth hormone therapy should be discontinued if evidence of neoplasia develops.

Protropin, when reconstituted with Bacteriostatic Water for Injection, USP (benzyl alcohol preserved) should not be used in patients with a known sensitivity to benzyl alcohol.

General

In vitro and in vivo preclinical, and clinical testing have demonstrated that Protropin^® (somatrem for injection), is therapeutically equivalent to pituitary-derived human growth hormone. Treatment of children who lack adequate endogenous growth hormone secretion with Protropin resulted in an increase in growth rate and an increase in insulin-like growth factor-I levels similar to that seen with pituitary-derived human growth hormone.

Actions that have been demonstrated for Protropin, somatropin and/or pituitary-derived human growth hormone include:

A. Tissue Growth--1) Skeletal Growth: Protropin stimulates skeletal growth in children with growth failure due to a lack of adequate secretion of endogenous growth hormone. 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 growth hormone and one of its mediators, insulin-like growth factor-I. Serum levels of insulin-like growth factor-I are low in children and adolescents who are growth hormone deficient, but increase during treatment with Protropin. New bone is formed at the epiphyses in response to growth hormone. This results in linear growth until these growth plates fuse at the end of puberty. 2) Cell Growth: Treatment with pituitary-derived human growth hormone results in an increase in both the number and the size of skeletal muscle cells. 3) Organ Growth: Growth hormone of human pituitary origin influences the size of internal organs, including kidneys, and increases red cell mass. Treatment of hypophysectomized or genetic dwarf rats with somatropin results in organ growth that is proportional to the overall body growth.

B. Protein Metabolism--Linear growth is facilitated in proof by growth hormone- stimulated protein synthesis. This is reflected by nitrogen retention as demonstrated by a decline in urinary nitrogen excretion and blood urea nitrogen during growth hormone therapy.

C. Carbohydrate Metabolism--Growth hormone is a modulator of carbohydrate metabolism. For example, children with inadequate secretion of growth hormone sometimes experience fasting hypoglycemia that is improved by treatment with growth hormone. Protropin therapy may decrease glucose tolerance. Administration of Protropin to normal adults and patients who lacked adequate secretion of endogenous growth hormone resulted in increases in mean serum fasting and postprandial insulin levels. However, mean glucose and hemoglobin A_1C levels remained in the normal range.

D. Lipid Metabolism--Acute administration of pituitary-derived human growth hormone to humans resulted in lipid mobilization. Nonesterified fatty acids increased in plasma within two hours of pituitary-derived human growth hormone administration. In growth hormone deficient patients, long-term growth hormone administration often decreases body fat. Mean cholesterol levels decreased in patients treated with growth hormone.

E. Mineral Metabolism--The retention of total body potassium in response to growth hormone administration apparently results from cellular growth. Serum levels of inorganic phosphorus may increase slightly in patients with inadequate secretion of endogenous growth hormone after growth hormone 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. (See PRECAUTIONS: Laboratory Tests.)

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

Patients being treated with growth hormone and/or their parents should be informed of the potential benefits and risks associated with treatment. If home use is determined to be desirable by the physician, instructions on appropriate use should be given, including a review of the contents of the Patient Information Insert. This information is intended to aid in the safe and effective administration of the medication. It is not a disclosure of all possible adverse or intended effects.

STABILITY AND STORAGE

Before Reconstitution--Protropin^® (somatrem for injection), and Bacteriostatic Water for Injection, USP (benzyl alcohol preserved), must be stored at 2-8°C/36-46°F (under refrigeration). Avoid freezing the vials of Protropin and Bacteriostatic Water for Injection, USP (benzyl alcohol preserved). Expiration dates are stated on the labels.

After Reconstitution--Vial contents are stable for 14 days when reconstituted with Bacteriostatic Water for Injection, USP (benzyl alcohol preserved) at 2-8°C/36-46°F (under refrigeration). Store the unused portion of Bacteriostatic Water for Injection, USP (benzyl alcohol preserved) at 2-8°C/36-46°F (under refrigeration). Avoid freezing the vials of Protropin and Bacteriostatic Water for Injection, USP (benzyl alcohol preserved).