Nutropin AQ (Somatropin)

NUTROPIN® NUTROPIN® AQ

Roche

Somatropin

Growth Hormone

Action And Clinical Pharmacology: General: Somatropin is a human growth hormone (hGH) produced by recombinant DNA technology. The amino acid sequence of the somatropin protein is identical to that of pituitary-derived human growth hormone. In vitro and in vivo preclinical testing, and clinical testing have demonstrated that somatropin is therapeutically equivalent to pituitary-derived human growth hormone in pharmacokinetics, in stimulation of linear growth and in other actions.

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

Somatropin treatment of children with chronic renal insufficiency results in improved growth rate and height standard deviation and an overall increase in cumulative growth, as compared to placebo-treated children with chronic renal insufficiency.

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

Tissue Growth: Skeletal Growth: Somatropin stimulates skeletal growth in children with growth failure due to a lack of adequate secretion of endogenous growth hormone and in children with growth failure secondary to chronic renal insufficiency. Skeletal growth is accomplished at the epiphyseal plates at the ends 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 somatropin. 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.

The clinical effect of the skeletal growth action of somatropin has been observed in well-controlled clinical trials with somatropin in the treatment of growth hormone inadequacy and chronic renal insufficency patients. Limited data regarding the clinical post-transplant growth effect of somatropin treatment administered prior to transplant is available.

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: 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. In normal rats subjected to nephrectomy-induced uremia, somatropin promoted skeletal and 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 (BUN) concentration during growth hormone therapy.

Carbohydrate Metabolism: Growth hormone is a modulator of carbohydrate metabolism. For example, 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 somatropin to normal adults, patients who lack adequate secretion of endogenous growth hormone and patients with chronic renal insufficiency resulted in increases in mean serum fasting and postprandial insulin levels. However, mean fasting and postprandial glucose levels and mean hemoglobin A1C levels remained within the normal range. There were no clinically significant persistent abnormalities in any of these measurements of glucose regulation that were related to growth hormone treatment.

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 growth hormone administration often decreases body fat. Mean cholesterol levels decreased in patients treated with somatropin.

Mineral Metabolism: The retention of total body potassium in response to growth hormone administration is thought to result from cellular growth. Serum levels of inorganic phosphorus may increase slightly in patients with inadequate secretion of endogenous growth hormone or chronic renal insufficiency after growth hormone therapy due to the 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).

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

Pharmacokinetics: The pharmacokinetics of Nutropin (somatropin lyophilized powder) have been investigated in healthy men after the s.c. administration of 0.1 mg/kg. A mean peak concentration (Cmax) of 56.1 ng/mL occurred at a mean time of 7.5 hours. The extent of absorption of somatropin, assessed by area under the concentration vs time curve (AUC), was 626 ng.hr/mL and compares with that of somatrem (590 ng.hr/mL). The AUC of somatropin is similar regardless of site of injection.

After s.c. injection of 0.1 mg/kg Nutropin AQ (somatropin injection), a mean peak concentration (Cmax) of 71.1 ng/mL occurred at a mean time of 3.9 hours. The extent of absorption of Nutropin AQ (AUC) was 673 ng.h/mL and was comparable with that of Nutropin lyophilized powder. Nutropin AQ was bioequivalent to Nutropin lyophilized powder after s.c. administration based on the statistical evaluation of the ratios of the geometric mean of log transformed AUC and Cmax.

In both normal and growth hormone deficient (GHD) adults and children, the i.m. and s.c. pharmacokinetic profiles of somatropin are similar regardless of growth hormone or dosing regimen used.

Distribution: Growth hormone 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, approximating the serum volume.

Metabolism: Both the liver and kidney have been shown to be important metabolizing organs for pituitary-derived human growth hormone.

Elimination: Clearance of rhGH after i.v. administration in healthy adults and children is reported to be in the range of 116 to 174 mL/h/kg.

Special Populations: Children: Available literature data suggests that rhGH clearances are similar in adults and children.

Gender: No data is available for rhGH. Available data for methionyl human growth hormone and pituitary-derived human growth hormone suggests that there are no consistent gender-based differences in rhGH clearance.

Race: No data is available.

Growth Hormone Insufficiency (GHI): Reported values for clearance of rhGH in adults and children with GHI range from 138 to 245 mL/h/kg and are similar to those observed in healthy adults and children. Mean terminal t1/2 values following i.v. and s.c. administration in GHI patients are also similar to those observed in healthy adult males.

Renal Insufficiency: Children and adults with chronic renal failure (CRF) tend to have decreased clearance as compared to normals. However, no rhGH accumulation has been reported in children with CRF or end-stage renal disease dosed with current regimens.

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

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

Somatropin is also indicated for the treatment of children who have growth failure associated with chronic renal insufficiency up to the time of renal transplantation. Somatropin therapy should be used in conjunction with optimal management of chronic renal insufficiency.

Contra-Indications: Somatropin should not be used in subjects with closed epiphyses.

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

Nutropin (somatropin lyophilized powder), 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 Nutropin (somatropin lyophilized powder) 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 Nutropin dose per vial and discard the unused portion.

Precautions: General: Somatropin should be prescribed by physicians experienced in the diagnosis and management of patients with growth failure or chronic renal insufficiency (CRI). No studies have been performed with somatropin in children who have received renal transplants.

Because somatropin 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.

Patients with growth failure secondary to chronic renal insufficiency should be examined periodically for evidence of progression of renal osteodystrophy. Slipped capital femoral epiphysis or avascular necrosis of the femoral head may be seen in children with advanced renal osteodystrophy, and it is uncertain whether these problems are affected by growth hormone therapy. X-rays of the hips should be obtained prior to initiating therapy for CRI patients.

Slipped capital femoral epiphysis may also occur more frequently in patients with endocrine disorders or in patients undergoing rapid growth. Therefore, physicians and parents should be alert to the development of a limp or complaints of hip or knee pain in both GHI and CRI patients treated with somatropin.

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/patients 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 phosphorous, alkaline phosphatase, and parathyroid hormone may increase with somatropin therapy. Changes in thyroid hormone laboratory measurements may develop during growth hormone treatment of children who lack adequate endogenous growth hormone secretion. As untreated hypothyroidism prevents optimal response to somatropin, 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 somatropin. If glucocorticoid replacement is required, the glucocorticoid dose should be carefully adjusted. The use of somatropin in patients with CRI receiving glucocorticoid therapy has not been evaluated.

There was no evidence in the controlled studies of somatropin’s interaction with drugs commonly used in patients. However, formal drug interaction studies have not been conducted.

Children: Prudence is indicated for children aged 6 months to 3 years, when administering Nutropin (somatropin lyophilized powder) 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 somatropin. It is also not known whether somatropin can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Somatropin should be given to a pregnant woman only if clearly needed.

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

Carcinogenicity and Mutagenicity: Carcinogenicity and mutagenicity studies have not been conducted with somatropin. Patients developing neoplasia should be reported to the Health Protection Branch (HPB) by the treating physician.

Information for the Patient/Parent: Patients who are being treated with growth hormone and/or their parents should be informed regarding 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 “Information for the Patient/Parent” 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 unintended 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 Information for the Patient in Blue Section).

Adverse Reactions: A small percentage of patients may develop antibodies to the growth hormone 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 during growth hormone treatment, growth attenuation has been observed.

In clinical studies of patients treated with Nutropin (somatropin lyophilized powder) for the first time, 0/107 GHI patients and 0/125 CRI patients screened for antibody production developed antibodies with binding capacities ³2 mg/L at 6 months.

In a clinical study of naive patients who were treated with Nutropin AQ (somatropin injection), 0/60 GHD patients who were screened for development of antibodies throughout 15 months of treatment, developed antibodies with binding capacities above 2 mg/L.

Short-term immunologic and renal function studies were carried out in a group of patients with chronic renal insufficiency after approximately 1 year of growth hormone treatment to detect potential adverse effects of antibodies to growth hormone. Testing included measurements of Clq, C3, C4, rheumatoid factor, creatinine, creatinine clearance and BUN. No adverse effects of growth hormone antibodies were noted.

In addition to an evaluation of compliance with the 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.

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 GHI and CRI patients, if any, remains to be established.

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

Adverse drug reactions which have been reported infrequently:

Musculoskeletal: carpal tunnel syndrome.

Skin: increased growth of pre-existing nevi (malignant nevi transformation has not been reported).

Endocrine: gynecomastia and pancreatitis.

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

Dosage And Administration: Somatropin dosage and administration schedule should be individualized for each patient.

Growth Hormone Inadequacy: A somatropin dose of up to 0.3 mg/kg/week (approximately 0.9 IU/kg/week) administered in divided daily doses by s.c. or i.m. injection is recommended.

The total number of mg per daily dose is calculated as follows: Dose (mg) per 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 somatropin therapy should be evaluated to determine the cause of unresponsiveness.

Chronic Renal Insufficiency: A somatropin dose of up to 0.35 mg/kg/week (approximately 1.05 IU/kg/week) administered in divided daily doses by s.c. or i.m. injection is recommended.

The total number of mg per daily dose is calculated as follows: Dose (mg) per injection=Patient weight (kg)´up to 0.05 (mg/kg).

Therapy may be continued up to the time of renal transplantation. Therapy should not be continued if final height is achieved or epiphyseal fusion occurs. Patients who fail to respond adequately while on somatropin therapy should be evaluated to determine the cause of unresponsiveness.

In order to optimize therapy for CRI patients who require dialysis, the following guidelines for selecting the injection schedule are recommended: 1. Hemodialysis patients should receive their injection at night just prior to going to sleep or at least 3 to 4 hours after their hemodialysis to prevent hematoma formation due to the heparin. 2. Chronic Cycling Peritoneal Dialysis patients should receive their injection in the morning after they have completed dialysis. 3. Chronic Ambulatory Peritoneal Dialysis patients should receive their injection in the evening at the time of the overnight exchange.

Reconstitution of Lyophilized Powder: A 5 mg vial of Nutropin lyophilized powder 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 somatropin/mL with 5 mL of the water.)

A 10 mg vial of Nutropin lyophilized powder 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 somatropin/mL with 10 mL of the water.)

When Nutropin lyophilized powder is reconstituted to 1 mg somatropin/mL, the recommended daily dose of 0.05 mg/kg for treatment of chronic renal insufficiency contains 0.45 mg/kg benzyl alcohol while the recommended daily somatropin dose of 0.043 mg/kg for treatment of growth hormone deficiency contains 0.387 mg/kg benzyl alcohol.

See Warnings for reconstitution of Nutropin lyophilized powder for use in newborns and persons sensitive to benzyl alcohol, and see Precautions for use in children aged 6 months to 3 years.

To prepare the Nutropin solution, slowly inject the Bacteriostatic Water for Injection, USP into the vial, aiming the stream of liquid against the glass wall of the vial. Then swirl the vial with a gentle rotary motion until the contents are completely dissolved. Do not shake. Because somatropin is a protein, shaking can result in a cloudy solution. After reconstitution, the 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 solution. This is not unusual for solutions containing proteins. Allow the vial to come to room temperature and gently swirl until the solution is clear. If the solution remains cloudy or hazy, do not inject it.

Nutropin AQ: The vials contain a solution ready for injection. No reconstitution or preparation is required.

Injection: Before needle insertion, wipe the septum of all vials to be used, both the somatropin 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. Somatropin 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 2.5 cm or more) to ensure that the injection reaches the muscular layer. The site of injection should be rotated each time somatropin is administered.

Stability and Storage: Before Reconstitution: Nutropin lyophilized powder and Bacteriostatic Water for Injection, USP (benzyl alcohol preserved) must be refrigerated at 2 to 8°C. Avoid freezing the vials of Nutropin 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. Discard the unused portion after 14 days. Do not freeze the reconstituted vial of Nutropin.

The remaining Bacteriostatic Water for Injection, USP in the multiple use vial must be refrigerated at 2 to 8°C, and may be used for 14 days after first entry. Avoid freezing the Bacteriostatic Water for Injection, USP (benzyl alcohol preserved).

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

Nutropin AQ: Store under refrigeration at 2 to 8°C. Do not freeze.

Availability And Storage: Nutropin: 5 mg: Each vial of sterile, white, lyophilized powder contains: somatropin 5 mg (approximately 15 IU). Nonmedicinal ingredients: glycine, mannitol, sodium phosphate dibasic and sodium phosphate monobasic; diluent contains: bacteriostatic water for injection and benzyl alcohol. After reconstitution, the resultant solution is nearly isotonic at a concentration of 5 mg growth hormone/mL and has a pH of approximately 7.4. Cartons of 6 Nutropin vials and one 10 mL multiple use diluent vial.

10 mg: Each vial of sterile, white, lyophilized powder contains: somatropin 10 mg (approximately 30 IU). Nonmedicinal ingredients: glycine, mannitol, sodium phosphate dibasic and sodium phosphate monobasic; diluent contains: bacteriostatic water for injection and benzyl alcohol. After reconstitution, the resultant solution is nearly isotonic at a concentration of 5 mg growth hormone/mL and has a pH of approximately 7.4. Cartons of 2 Nutropin vials and two 10 mL multiple use diluent vials.

Nutropin AQ: Each mL of clear, sterile, nearly isotonic solution contains: somatropin 5 mg. Nonmedicinal ingredients: phenol, polysorbate 20, sodium chloride and sodium citrate. The solution has a pH of approximately 6. Vials of 2 mL (10 mg, approximately 30 IU).

NUTROPIN® NUTROPIN® AQ Roche Somatropin Growth Hormone

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