Protropin (Somatrem)

PROTROPIN®

Roche

Somatrem

Growth Hormone

Action And Clinical Pharmacology: Somatrem is a polypeptide (methionyl human growth hormone) produced by recombinant DNA technology using the gene for human growth hormone.

Somatrem has the same amino acid sequence as pituitary-derived human growth hormone plus an additional amino acid, methionine, on the N-terminus of the molecule. The two molecules also have the same disulfide bond arrangement and the same secondary and tertiary structure.

In vitro and in vivo preclinical testing and clinical testing have demonstrated that somatrem is therapeutically equivalent to pituitary-derived human growth hormone in pharmacokinetics and in stimulation of linear growth as well as other actions.

Somatrem treatment of children who lack adequate secretion of endogenous growth hormone resulted in an increase in growth rate and an increase in levels of insulin-like growth factor-I, similar to that seen with pituitary-derived human growth hormone.

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

Tissue Growth: Skeletal Growth: Somatrem 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 end of a growing long 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.

Cell Growth: Treatment with pituitary-derived human growth hormone results in an increase in both the number and the size of skeletal muscle cells.

Organ Growth: Pituitary-derived human growth hormone influences the size of internal organs, including kidneys, and also increases red cell mass. Treatment of hypophysectomized or genetic dwarf rats with growth hormone results in organ growth that is proportional to the overall body growth.

Protein Metabolism: Linear growth is facilitated in part 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.

Carbohydrate Metabolism: Growth hormone is a modulator of carbohydrate metabolism. Children with inadequate secretion of growth hormone sometimes experience fasting hypoglycemia which is improved by treatment with growth hormone. Growth hormone therapy may decrease glucose tolerance. Administration of growth hormone to normal adults and patients who lack adequate secretion of endogenous growth hormone results in increases in mean serum fasting and postprandial insulin levels. However, mean fasting and postprandial glucose levels and mean hemoglobin A1C levels remain within the normal range.

Lipid Metabolism: Acute administration of pituitary-derived human growth hormone to humans results in lipid mobilization. Nonesterified fatty acids increase in plasma within 2 hours of pituitary-derived human growth hormone administration. In growth hormone-deficient patients, long-term administration of growth hormone often decreases body fat. Mean cholesterol levels decrease in patients treated with growth hormone.

Mineral Metabolism: The retention of total body potassium in response to growth hormone administration is thought to result from cellular growth. Sodium retention also occurs. 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 (see Precautions, Laboratory Tests).

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

Indications And Clinical Uses: For the long-term treatment of children who have growth failure due to growth hormone inadequacy.

Contra-Indications: Should not be used in patients with closed epiphyses.

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

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

Manufacturers’ Warnings In Clinical States: Benzyl alcohol as a preservative in Bacteriostatic Water for Injection, USP has been associated with toxicity in newborns. When administering somatrem in newborns or in patients sensitive to benzyl alcohol, reconstitute with Sterile Water for Injection, USP. When Sterile Water for Injection, USP is used, use only one somatrem dose per vial and discard the unused portion .

Precautions: General: Somatrem should be prescribed by physicians experienced in the diagnosis and management of patients with growth failure.

Because somatrem 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.

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 the 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.

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 somatrem-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.

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 may increase with somatrem therapy. Changes in thyroid hormone laboratory measurements may develop during human growth hormone treatment of children who lack adequate endogenous growth hormone secretion. As untreated hypothyroidism prevents optimal response to somatrem, 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 somatrem. If glucocorticoid replacement is required, the glucocorticoid dose should be carefully adjusted.

Children: Prudence is indicated for children aged 6 months to 3 years, when administering somatrem reconstituted in Bacteriostatic Water for Injection, USP (benzyl alcohol preserved); although there is no information on the toxicity of benzyl alcohol for this age group, the toxic dose for premature neonates is in the range of 100 to 250 mg/kg/day.

Pregnancy: Reproduction studies have not been conducted with somatrem. It is not known whether somatrem can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Somatrem should be given to a pregnant woman only if clearly needed.

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

Carcinogenicity and Mutagenicity: Carcinogenicity and mutagenicity studies have not been conducted with somatrem. Patients developing neoplasia should be reported to HPB by the treating physician.

Information for the Patient: 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 by the physician to be desirable, 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.

If home use is prescribed, a puncture-resistant container for the disposal of used syringes and needles should be recommended to the patient. Patients and/or parents should be thoroughly instructed in the importance of proper disposal and cautioned against any reuse of needles and syringes (see Blue Section – Information for the Patient “Protropin”).

Adverse Reactions: 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 somatrem, approximately 0.4 % of patients screened for antibody production developed antibodies with binding capacities >2 mg/L at 6 months. Reports of growth deceleration associated with binding capacities >2 mg/L in these patients are rare (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.

No other adverse effects of anti-growth hormone antibody formation were observed in additional short-term immunologic and renal function studies carried out in a group of patients after approximately 2 years of treatment. The antibodies to growth hormone were determined to be of the IgG class; no antibodies to growth hormone of the IgE class were detected.

Leukemia has been reported in a small number of growth hormone deficient patients who were treated with growth hormone. It is uncertain whether this increased risk is related to the pathology of growth hormone deficiency, growth hormone therapy, or other associated treatments such as radiation therapy for intracranial tumors. The risk to an individual patient, if any, remains to be established.

In studies of children treated with somatrem, injection site pain was reported infrequently.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Theoretical risks of long-term human growth hormone treatment with doses exceeding the recommended dose levels could be signs and symptoms of gigantism and/or acromegaly.

Dosage And Administration: Dosage and administration schedule should be individualized for each patient. A dose of up to 0.3 mg/kg/week (approximately 0.9 IU/kg/week) administered daily in divided doses by s.c. or i.m. injection is recommended.

The total number of mg per daily dose is calculated as follows:

dose (mg)/injection= patient weight (kg)´up to 0.043 (mg/kg). Therapy should not be continued if final height is achieved or epiphyseal fusion occurs. Patients who fail to respond adequately while on somatrem therapy should be evaluated to determine the cause of unresponsiveness.

Reconstitution: Protropin is dispensed in vials of 5 mg (15 IU) and 10 mg (30 IU). Each 5 mg vial of Protropin should be reconstituted with 1 to 5 mL of Bacteriostatic Water for Injection, USP (benzyl alcohol preserved). (Vials are reconstituted to a concentration of 1 mg somatrem/mL with 5 mL of the water.)

Each 10 mg vial of Protropin should be reconstituted with 1 to 10 mL of Bacteriostatic Water for Injection, USP (benzyl alcohol preserved). (Vials are reconstituted to a concentration of 1 mg somatrem/mL with 10 mL of the water.)

When Protropin is reconstituted to 1 mg somatrem/mL, the recommended daily somatrem dose of 0.043 mg/kg contains 0.387 mg/kg benzyl alcohol.

See Warnings for reconstitution of Protropin for use in newborns and persons sensitive to benzyl alcohol and see Precautions for use in children age 6 months to 3 years.

To prepare the solution, slowly inject the Bacteriostatic Water for Injection, USP (benzyl alcohol preserved) into the Protropin vial, aiming the stream of liquid against the glass wall of the vial. Then swirl the somatrem vial with a gentle rotary motion until the contents are completely dissolved. Do not shake. Because somatrem is a protein, shaking can result in a cloudy solution. The somatrem solution should be clear , i.e., it should not have any solid particles floating on the surface. If you notice lumps or solid particles of powder, continue to gently swirl the solution until all of the powder has dissolved. If the solution does not become clear, do not inject it. Note also that occasionally, after refrigeration, small colorless particles of protein may be present in the Protropin solution. This is not unusual for solutions containing proteins. Allow the vial to come to room temperature and gently swirl until solution is clear. If the solution remains cloudy or hazy, do not inject it.

Injection: Before needle insertion, the septum of both the Protropin and diluent vials should be wiped with alcohol or an antiseptic solution to prevent contamination of the contents by microorganisms that may be introduced by repeated needle insertions. Protropin must 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. If the route of injection selected is i.m., the needle should be of sufficient length (usually 1 inch or more [2.5 cm]) to ensure that the injection reaches the muscular layer. The site of injection should be rotated each time Protropin is administered.

Stability and Storage: Before Reconstitution: Protropin and Bacteriostatic Water for Injection, USP (benzyl alcohol preserved), must be refrigerated at 2 to 8°C. 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) and refrigerated at 2 to 8°C. Avoid freezing the reconstituted vials of Protropin. See Warnings for storage information regarding reconstituted somatrem for use in newborns and persons sensitive to benzyl alcohol.

Unusual Handling Conditions: Vials of unreconstituted somatrem may be held at ambient temperature (not to exceed 37°C) for a total time not to exceed 7 days. Vials of reconstituted somatrem should not be exposed to temperatures greater than 25°C (controlled room temperature) for more than 24 hours in total.

Availability And Storage: 5 mg: Each vial of sterile, lyophilized powder contains: somatrem 5 mg (approx. 15 IU). Nonmedicinal ingredients: mannitol, sodium phosphate dibasic and sodium phosphate monobasic. May also contain phosphoric acid (used for pH adjustment). Cartons of two 5 mg vials and one multiple use vial with diluent [10 mL Bacteriostatic Water for Injection, USP (benzyl alcohol preserved)].

10 mg: Each vial of sterile, lyophilized powder contains: somatrem 10 mg (approx. 30 IU). Nonmedicinal ingredients: mannitol, sodium phosphate dibasic and sodium phosphate monobasic. May also contain phosphoric acid (use for pH adjustment). Cartons of two 10 mg vials and two multiple use vials with diluent [10 mL Bacteriostatic Water for Injection, USP (benzyl alcohol preserved)].

PROTROPIN® Roche Somatrem Growth Hormone

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