Nutropin - Kit Pws(5mg) & Liq(10mL) IM SC Product Monograph

SUMMARY PRODUCT INFORMATION

DESCRIPTION

Somatropin is a single-chain protein of 191 amino acids, including four cysteine residues present as two intrachain disulfides. Somatropin is synthesized in a specific laboratory strain of E. coli bacteria (which has been modified by the addition of a plasmid coding for hGH) as a precursor consisting of the rhGH molecule preceded by the secretion signal from an E. coli protein. This precursor is then cleaved in the plasma membrane of the cell. The native protein is secreted into

the periplasm where it is folded appropriately. The primary and secondary structures of somatropin are identical with pituitary-derived human growth hormone.

INDICATIONS AND CLINICAL USE

Pediatric Patients

NUTROPIN (somatropin) is indicated for:

• the long-term treatment of children who have growth failure due to growth hormone inadequacy.
• the treatment of children who have growth failure associated with chronic renal insufficiency up to the time of renal transplantation. Therapy with NUTROPIN should be used in conjunction with optimal management of chronic renal insufficiency.
• the long-term treatment of short stature associated with Turner syndrome.

Adult Patients

NUTROPIN (somatropin) is indicated for:

• the replacement of endogenous growth hormone (GH) in patients with adult GH deficiency

  (GHD) who meet both of the following two criteria:

  1. 1. Biochemical diagnosis of adult GH deficiency by means of a subnormal response to a standard growth hormone stimulation test (peak GH ≤5µg/L), and
  2. 2. Adult-onset: Patients who have adult GH deficiency either alone or with multiple hormone deficiencies (hypopituartarism) as a result of pituitary disease, hypothalmic disease, surgery, radiation therapy, or trauma; or
  3. 3. Childhood-onset: Patients who were GH deficient during childhood, confirmed as an adult before replacement therapy with NUTROPIN is started.

CONTRAINDICATIONS

$ NUTROPIN (somatropin) is contraindicated in patients who are hypersensitive to somatropin or to any ingredient in the formulation. For a complete listing, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section of the product monograph.

$ Growth hormone should not be initiated to treat patients with acute critical illness due to the complications following open heart or abdominal surgery, multiple accidental trauma or to patients having acute respiratory failure. [See WARNINGS AND PRECAUTIONS].

• NUTROPIN should not be used in pediatric patients with closed epiphyses.
• NUTROPIN should not be used in patients with active neoplasia. Growth hormone therapy should be discontinued if evidence of neoplasia develops.

• NUTROPIN (somatropin for injection) 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 AND PRECAUTIONS]

• Growth hormone is contraindicated in patients with Prader-Willi syndrome who are severely obese or have severe respiratory impairment. [See WARNINGS AND PRECAUTIONS]
• Unless patients with Prader-Willi syndrome also have a diagnosis of growth hormone deficiency, NUTROPIN is not indicated for the long-term treatment of pediatric patients who have growth failure due to genetically confirmed Prader-Willi syndrome.

WARNINGS AND PRECAUTIONS

General

In two placebo controlled clinical trials in non-growth hormone deficient adult patients (n=522) a significant increase in mortality has been reported among somatropin treated patients with acute critical illnesses in intensive care units due to complications following open heart surgery or abdominal surgery, multiple accidental trauma, or to patients having acute respiratory failure (41.9%) compared to those receiving placebo (19.3%). Doses of 5.3-8 mg/day were given. 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 an acute critical illness should be weighed against the potential risk.

There have been reports of fatalities after initiating therapy with growth hormone in pediatric patients with Prader-Willi syndrome who had one or more of the following risk factors: severe obesity, history of upper airway obstruction or sleep apnea, or unidentified respiratory infection. Male patients with one or more of these factors may be at greater risk than females. Patients with Prader-Willi syndrome should be evaluated for signs of upper airway obstruction and sleep apnea before initiation of treatment with growth hormone. If during treatment with growth hormone, patients show signs of upper airway obstruction (including onset of or increased snoring) and/or new onset of sleep apnea, treatment should be interrupted. All patients with Prader-Willi syndrome treated with growth hormone should also have effective weight control and be monitored for signs of respiratory infection, which should be diagnosed as early as possible and treated aggressively. [See CONTRAINDICATIONS] Unless patients with Prader-Willi syndrome also have a diagnosis of growth hormone deficiency, NUTROPIN (somatropin)

is not indicated for the long-term treatment of pediatric patients who have growth failure due to genetically confirmed Prader-Willi syndrome.

NUTROPIN should be prescribed by physicians experienced in the diagnosis and management of patients with growth failure, Turner syndrome, or chronic renal insufficiency (CRI). No studies have been performed with NUTROPIN in children who have received renal transplants.

Benzyl alcohol as a preservative in Bacteriostatic Water for Injection, USP has been associated with toxicity in newborns. When administering NUTROPIN (somatropin for injection) 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 dose of NUTROPIN per vial and discard the unused portion. [See DOSAGE AND ADMINISTRATION, Administration]

Carcinogenesis and Mutagenesis

Carcinogenicity and mutagenicity studies have not been conducted with NUTROPIN. Patients developing neoplasia should be reported to the Health Products and Food Branch (HPFB) by the treating physician.

Endocrine and Metabolism

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

For patients with diabetes mellitus, the insulin dose may require adjustment when GH therapy is instituted. Because GH may reduce insulin sensitivity, particularly in obese individuals, patients should be observed for evidence of glucose intolerance. Patients with diabetes or glucose intolerance should be monitored closely during GH therapy.

Therapy with NUTROPIN in adults with GHD of adult onset was associated with an increase of median fasting insulin in the NUTROPIN 0.0125 mg/kg/day group from 9.0 µU/mL at baseline to 13.0 µU/mL at Month 12 with a return to the baseline median after a 3-week post-washout period off GH therapy. In the placebo group there was no change from 8.0 µU/mL at baseline to Month 12, and after the post-washout the median was 9.0 µU/mL. The between-treatment-groups difference in change from baseline to Month 12 was significant, p <0.0001. In childhood onset subjects there was a change of median fasting insulin in the NUTROPIN 0.025 mg/kg/day group from 11.0 µU/mL at baseline to 20.0 µU/mL at Month 12, in the NUTROPIN 0.0125 mg/kg/day group from 8.5 µU/mL to 11.0 µU/mL and in the placebo group from 7.0 µU/mL to 8.0 µU/mL. The between-treatment-groups difference for these changes was significant, p =0.0007.

In subjects with adult onset GHD there was no between treatment group difference in changes from baseline to Month 12 in mean HbA1c, p =0.08. In childhood onset mean HbA1c increased in the NUTROPIN 0.025 mg/kg/day group from 5.2% at baseline to 5.5% at Month 12, and did not change in the NUTROPIN 0.0125 mg/kg/day group from 5.1% at baseline or in the placebo group from 5.3% at baseline. The between-treatment-groups difference was significant, p =0.009.

Immune

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.

Musculoskeletal

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. Children with chronic renal insufficiency receiving growth hormone should be serially monitored for avascular necrosis, slipped capital femoral epiphysis and renal osteodystrophy with serial radiographs and appropriate clinical chemistry tests.

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 NUTROPIN.

Patients with Turner syndrome should be evaluated carefully for otitis media and other ear disorders. In a randomized-controlled trial, there was a statistically significant increase, as compared to untreated controls, in otitis media (43% vs. 26%) and ear disorders (18% vs. 5%) in patients receiving GH. In addition, patients with Turner syndrome should be monitored closely for cardiovascular disorders (e.g. stroke, aortic aneurysm, hypertension) as these patients are also at risk for these conditions.

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.

Patients with epiphyseal closure who were treated with GH replacement therapy in childhood should be re-evaluated according to the criteria in the INDICATIONS AND CLINICAL USE section before continuation of GH therapy at the reduced dose level recommended for GH-deficient adults.

Neurologic

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 eight (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 Turner syndrome and CRI may be at increased risk for development of IH.

Special Populations

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

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

Pediatrics (6 months - 3 years of age): Prudence is indicated for children aged 6 months to 3 years, when administering NUTROPIN (somatropin for injection) 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 per day.

Geriatrics (> 65 years of age): Clinical studies of NUTROPIN did not include sufficient numbers of elderly subjects to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. Experience with prolonged rhGH treatment in adults is limited.

Monitoring and Laboratory Tests

Serum levels of inorganic phosphorous, alkaline phosphatase, and parathyroid hormone may increase with therapy with NUTROPIN. 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 NUTROPIN, patients should have periodic thyroid function tests and should be treated with thyroid hormone when indicated. Patients with Turner syndrome have an inherently increased risk of developing autoimmune thyroid disease.

Information for Patients

Patients 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 [See PART III: CONSUMER INFORMATION, PROPER USE OF THIS MEDICATION, INFORMATION FOR THE

PATIENT/PARENT]. 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 PART III: CONSUMER INFORMATION, PROPER USE OF THIS MEDICATION, INFORMATION FOR THE PARENT/PATIENT]

ADVERSE REACTIONS

Adverse Drug Reaction Overview

The adverse event data reflect the clinical trial and post-marketing experience of using NUTROPIN (somatropin).

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

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 for injection) lyophilized powder for the first time, 0/107 growth hormone inadequate (GHI) patients and 0/125 chronic renal insufficiency (CRI) patients screened for antibody production developed antibodies with binding capacities ≥ 2 mg/L at six 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 2mg/L.

Short-term immunologic and renal function studies were carried out in a group of patients with chronic renal insufficiency after approximately one 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 blood urea nitrogen (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 tumours. On the basis of current evidence, experts cannot conclude that growth hormone therapy is responsible for these occurrences. The risk to GHI, Turner syndrome, and CRI patients, if any, remains to be established.

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

Adverse drug reactions which have been reported infrequently (< 1%) in growth hormone-treated children include mild and transient peripheral edema. In GHD adults, edema or peripheral edema was reported in 41% of GH-treated patients and 25% of placebo-treated patients. In GHD adults, arthraligias and joint disorders were reported in 27% of GH-treated patients and 15% of placebo-treated patients.

Other rare (< 0.1%) adverse drug reactions reported in growth hormone-treated patients include the following: 1) Musculoskeletal: arthralgias; carpal tunnel syndrome, 2) Skin: increased growth of pre-existing nevi (malignant nevi transformation has not been reported), 3) Endocrine: gynecomastia and pancreatitis.

Post-Market Adverse Drug Reactions

Adverse events that have been observed during the post-marketing period are similar to those seen in clinical trials with NUTROPIN.

DRUG INTERACTIONS

Overview

Concomitant glucocorticoid therapy may inhibit the growth promoting effect of NUTROPIN (somatropin). If glucocorticoid replacement is required, the glucocorticoid dose should be carefully adjusted. The use of NUTROPIN in patients with chronic renal insufficiency (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.

DOSAGE AND ADMINISTRATION

Dosing Considerations

The dosage and administration schedule of NUTROPIN (somatropin) should be individualized for each patient.

Recommended Dose and Dosage Adjustment

Pediatric Growth Hormone Deficiency: A somatropin dose of up to 0.3 mg/kg/week (approximately 0.90 IU/kg/wk) administered in divided daily doses by subcutaneous or intramuscular injection is recommended.

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

Dose (mg) per injection = Patient weight (kg) x up to 0.043 (mg/kg)

In pubertal patients, a weekly dosage of up to 0.7 mg/kg divided daily may be used.

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

Dose (mg) per injection = Patient weight (kg) x up to 0.1 (mg/kg)

Therapy should not be continued if final desired height is achieved or epiphyseal fusion occurs. Patients who fail to respond adequately while on therapy with NUTROPIN should be evaluated to determine the cause of unresponsiveness.

Turner syndrome: A weekly dosage of up to 0.375 mg/kg/week divided into equal doses 3 to 7 times per week by subcutaneous injection is recommended.

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

Dose (mg) per injection = Patient weight (kg) x up to 0.054 (mg/kg)

For administration three times a week, the total number of milligrams (mg) per dose is calculated as follows:

Dose (mg) per injection = Patient weight (kg) x up to 0.125 (mg/kg)

Therapy should not be continued if final desired height is achieved or epiphyseal fusion occurs. Patients who fail to respond adequately while on therapy with NUTROPIN 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/wk) administered in divided daily doses by subcutaneous or intramuscular injection is recommended.

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

Dose (mg) per injection = Patient weight (kg) x 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 therapy with NUTROPIN 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. 1. Hemodialysis patients should receive their injection at night just prior to going to sleep or at least 3-4 hours after their hemodialysis to prevent hematoma formation due to heparin.
2. 2. Chronic Cycling Peritoneal Dialysis patients should receive their injection in the morning after they have completed dialysis.
3. 3. Chronic Ambulatory Peritoneal Dialysis patients should receive their injection in the evening at the time of the overnight exchange.

Adult Growth Hormone Deficiency: The recommended dosage at the start of therapy is not more than 0.042 mg/kg/week given as a daily subcutaneous injection. The dose may be increased according to individual patient requirements to a maximum of 0.175 mg/kg /week in patients under 35 years and to a maximum of 0.0875 mg/kg/week in patients over 35 years.

Starting Dose: The total number of milligrams (mg) per daily dose for adult patients is calculated as follows:

Dose (mg) per injection = Patient weight (kg) x 0.006 (mg/kg)

Maximum Dose: For patients under 35 years, the total number of milligrams (mg) per daily dose is calculated as follows:

Dose (mg) per injection = Patient weight (kg) x up to 0.025 (mg/kg)

For patients over 35 years, the total number of milligrams (mg) per daily dose is calculated as follows:

Dose (mg) per injection = Patient weight (kg) x up to 0.0125 (mg/kg)

To minimize the occurrence of adverse events in older or overweight patients, lower doses may be necessary. During therapy, dosage should be decreased if required by the occurrence of side

effects or excessive insulin-like growth factor I [IGF-I] levels.

Missed Dose

Patients who miss a dose of NUTROPIN should contact their physician for instructions.

Administration

NUTROPIN (somatropin for injection) - Vials of 5 mg and 10 mg

Reconstitution:

NUTROPIN (somatropin for injection) lyophilized powder is dispensed in vials of 5 mg and 10 mg.

• 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). (For example, a 5 mg vial of NUTROPIN lyophilized powder reconstituted with 5 mL of Bacteriostatic Water will be reconstituted to a concentration of 1 mg somatropin/mL Bacteriostatic 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). (For example, a 10 mg vial of NUTROPIN lyophilized powder reconstituted with 10 mL of Bacteriostatic Water will be reconstituted to a concentration of 1 mg somatropin/mL Bacteriostatic Water).

When NUTROPIN lyophilized powder is reconstituted to 1 mg somatropin per mL, the recommended daily somatropin 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. The recommended daily somatropin dose of 0.1 mg/kg for treatment of growth hormone deficiency for pubertal patients contains 0.09 mg/kg benzyl alcohol. The recommended daily dose of 0.054 mg/kg for Turner’s syndrome contains 0.486 mg/kg benzyl alcohol, while the three dose a week regimen contains 1.134 mg/kg benzyl alcohol in each dose.

See WARNINGS AND PRECAUTIONS (General; Pediatrics) for use in newborns, persons sensitive to benzyl alcohol and for use in children aged 6 months to 3 years. When Sterile Water for Injection, USP is used use only one dose of NUTROPIN per vial and discard the unused portion.

To prepare the NUTROPIN solution, slowly inject the Bacteriostatic Water for Injection, USP into the NUTROPIN vial, aiming the stream of liquid against the glass wall of the vial. Then swirl the NUTROPIN vial with a gentle rotary motion until the contents are completely dissolved. Do not shake. Because NUTROPIN is a protein, shaking can result in a cloudy solution. After reconstitution, the NUTROPIN solution should be clear, ie. 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 colourless particles of protein may be present in the NUTROPIN 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 (somatropin injection) - Vials of 10 mg

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 NUTROPIN 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. NUTROPIN 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 intramuscular, the needle should be of sufficient length [usually 2.5 cm (1 inch) or more)] to ensure that the injection reaches the muscular layer. The site of injection should be rotated each time NUTROPIN is administered. Recommended injection sites include upper arm, abdomen, and thigh.

NUTROPIN AQ PEN Cartridge (somatropin injection) of 10 mg

The NUTROPIN AQ PEN Cartridge is intended for use only with the NUTROPIN AQ PEN. The pen cartridges contain a solution ready for injection. No reconstitution or preparation is required.

Injection:

Before needle insertion, wipe the septum of the cartridge with rubbing alcohol or an antiseptic solution to prevent contamination of the contents by microorganisms that may be introduced by repeated needle insertions. Load the pen cartridge into the NUTROPIN AQ PEN barrel and attach the needle. Push the button on the side of the pen opposite the digital display, which releases a spring-loaded “knob” at the top of the pen. The “knob” is then twisted in a clockwise direction that brings the desired dose into the dose selection window. Once the dose is selected, remove the needle cap, insert the needle into the injection site, and depress the “knob” located at the top of the pen. This advances the plunger to displace the selected dose. After the injection, the needle is removed from the pen and discarded. NUTROPIN AQ must be administered using sterile, disposable needles. The NUTROPIN AQ PEN allows for administration of a minimum dose of 0.1 mg to a maximum dose of 4.0 mg, in 0.1 mg increments. Detailed instructions on how to use the NUTROPIN AQ PEN are provided in the Information for the Parent/Patient Guide [See PART III: CONSUMER INFORMATION, PROPER USE OF THIS MEDICATION].

OVERDOSAGE

Theoretical risks of long-term human growth hormone treatment with doses exceeding the recommended dosage are signs and symptoms of gigantism and/or acromegaly. If any signs of overdosage occur, treatment should be discontinued.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

General

NUTROPIN (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 NUTROPIN 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 NUTROPIN results in an increase in growth rate and an increase in insulin-like growth factor-I [IGF-I], similar to that seen with pituitary-derived human growth hormone.

Treatment with NUTROPIN in children with Turner’s syndrome (a condition without a deficiency of GH) results in an increase in growth rate and an overall increase in cumulative growth, as compared with Historical Controls.

Treatment with NUTROPIN 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. Adults with growth hormone deficiency acquired during childhood or adulthood treated with NUTROPIN show an improvement in body fat mass and lean mass. Adults with growth hormone deficiency acquired during childhood treated with NUTROPIN also show an improvement in bone mineral density.

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

Tissue Growth

Skeletal Growth: NUTROPIN 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, IGF-I. Serum levels of IGF-I are low in children and adolescents who are growth hormone deficient, but increase during treatment with NUTROPIN. 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 NUTROPIN in the treatment of growth hormone inadequacy, chronic renal insufficiency patients, and patients with Turner syndrome [See DETAILED PHARMACOLOGY]. Limited data regarding the clinical post-transplant growth effect of treatment with NUTROPIN administered prior to transplant is available [See DETAILED PHARMACOLOGY].

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 concentration during growth hormone therapy.

Carbohydrate Metabolism

Growth hormone is a modulator of carbohydrate metabolism. For example, patients 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. Untreated patients with chronic renal insufficiency and Turner syndrome have an increased incidence of glucose intolerance. Administration of NUTROPIN 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 A_1C 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 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 NUTROPIN.

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, chronic renal insufficiency, or patients with Turner syndrome, 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. Adults with childhood-onset GH deficiency show low bone mineral density (BMD). GH therapy results in increases in serum alkaline phosphatase. [See WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests]

Connective Tissue Metabolism

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

Pharmacokinetics

Table 1 Summary of Pharmacokinetic Parameters of NUTROPIN in Healthy Adult Males 0.1 mg (approximately 0.3 IU ^a )/kg SC

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

^b n=36

^c Compares with that of somatrem (590 ng•hr/mL); the AUC of NUTROPIN somatropin is similar regardless of site of injection. ^d In healthy adults and children.

Table 2 Summary of Pharmacokinetic Parameters of NUTROPIN AQ in Healthy Adult Males

0.1 mg (approximately 0.3 IU ^a )/kg SC

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

^b n=36

^c Comparable with that of NUTROPIN lyophilized powder. NUTROPIN AQ was bioequivalent to NUTROPIN lyophilized powder after subcutaneous administration based on the statistical evaluation of the ratios of the geometric mean of log transformed AUC and C_max.

^d In healthy adults and children.

In both normal and growth hormone deficient adults and children, the intramuscular and subcutaneous pharmacokinetic profiles of somatropin are similar regardless of growth hormone or dosing regimen used. Growth hormone localizes to highly perfused organs, particularly the liver and kidney. Both the liver and kidney have been shown to be important metabolizing organs for pituitary-derived human growth hormone.

Special Populations and Conditions

Pediatrics: 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.

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

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.

Turner Syndrome: No pharmacokinetic data are available for exogenously administered rhGH. However, reported half-lives, and elimination rates of endogenous GH in this population are similar to the ranges observed for normal subjects and GHD populations.

Growth Hormone Insufficiency (GHI): Reported values for clearance of rhGH in adults and children with GHI range from 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 GHI patients are also similar to those observed in healthy adult males.

STORAGE AND STABILITY

NUTROPIN (somatropin for injection)

Before Reconstitution: NUTROPIN (somatropin for injection) 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 seven days. Vials of reconstituted NUTROPIN lyophilized powder should not be exposed to temperatures greater than 25 °C for more than 24 hours in total.

NUTROPIN AQ (somatropin injection)

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

NUTROPIN AQ PEN Cartridge

Do not freeze. Protect from light. When not in use, store under refrigeration at 2 to 8°C.

NUTROPIN AQ PEN Cartridges should be discarded after 28 days of the first use.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Availability of Dosage Forms

NUTROPIN (somatropin for injection) lyophilized powder is supplied as:

• 5 mg (approximately 15 IU) of lyophilized, sterile somatropin per vial—There are six 5 mg vials of NUTROPIN and six 10 mL multiple use vials of Bacteriostatic Water for Injection, USP (benzyl alcohol preserved) per carton.
• 10 mg (approximately 30 IU) of lyophilized, sterile somatropin per vial— There is one 10 mg vial of NUTROPIN and one 10 mL multiple use vials of Bacteriostatic Water for Injection, USP (benzyl alcohol preserved) per carton.

NUTROPIN AQ (somatropin injection) is supplied as:

• 10 mg (approximately 30 IU) vials containing 2 mL of somatropin solution - There are six

  10 mg vials of NUTROPIN AQ per carton.

NUTROPIN AQ PEN Cartridge is supplied as:

• 10 mg (approximately 30 IU) pen cartridges containing 2 mL of somatropin solution - There is one 10 mg cartridge of NUTROPIN AQ per carton.

Composition

NUTROPIN Lyophilized Powder

5 mg NUTROPIN Vial

somatropin 5.0 mg (approx. 15 IU)

mannitol 45.0 mg

glycine 1.7 mg

sodium phosphate monobasic 0.4 mg

sodium phosphate dibasic 1.3 mg

10 mg NUTROPIN Vial

somatropin 10 mg (approx. 30 IU)

mannitol 90.0 mg

glycine 3.4 mg

sodium phosphate monobasic 0.8 mg

sodium phosphate dibasic 2.6 mg

Diluent Vial

The diluent vial contains Bacteriostatic Water for Injection, USP (benzyl alcohol preserved), packaged in a sterile 10 mL multiple use vial. Each mL contains 0.9% benzyl alcohol as an antimicrobial preservative. The diluent pH is 4.5-7.0. After reconstitution of NUTROPIN lyophilized powder with Bacteriostatic Water for Injection, USP, the resultant solution is nearly isotonic at a concentration of 5 mg growth hormone per mL and has a pH of approximately 7.4.

NUTROPIN AQ

2mL/10 mg Vial (5 mg/mL)

somatropin 10.0 mg (approx. 30 IU) (5 mg/mL)

sodium chloride 17.4 mg (8.7 mg/mL)

Phenol 5 mg (2.5 mg/mL)

Polysorbate 20 4 mg (2 mg/mL)

Sodium Citrate 10 mM (5 mM/mL)

The solution is nearly isotonic at a concentration of 5 mg/mL somatropin and has a pH of approximately 6.0.

NUTROPIN AQ PEN Cartridge

2 mL/10 mg (5 mg/mL) pen cartridge

Somatropin 10.0 mg (approx. 30 IU) (5 mg/mL)

Sodium chloride 17.4 mg (8.7 mg/mL)

Phenol 5 mg (2.5 mg/mL)

Polysorbate 20 4 mg (2 mg/mL)

Sodium Citrate 10 mM (5 mM/mL)

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper or Common name: somatropin

Biological name: recombinant human growth hormone (rhGH)

Molecular weight: 22 125 daltons

Structure: Somatropin is a single-chain protein of 191 amino acids, including four cysteine residues present as two intrachain disulfides. The primary and secondary structures of somatropin are identical with pituitary-derived human growth hormone. [See DESCRIPTION]

Product Characteristics

Lyophilized Powder

NUTROPIN (somatropin for injection) lyophilized powder is a sterile white lyophilized powder of highly purified rhGH, intended for subcutaneous administration or intramuscular administration after reconstitution with Bacteriostatic Water for Injection, USP (benzyl alcohol preserved).

Solution

NUTROPIN AQ (somatropin injection) is a clear, sterile solution of highly purified rhGH, intended for subcutaneous administration.

CLINICAL TRIALS

Clinical Effect of NUTROPIN on Growth Failure in Pubertal Patients due to Growth Hormone Inadequacy (GHI)

Study demographics and trial design

Table 3 Summary of patient demographics for clinical trial M0380g in growth failure in pubertal patients due to GHI

Study #

Gender

M0380g

42 M, 7 F

41 M, 7 F

Study results

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

All patients were already in puberty (Tanner stage 2) and had bone ages ≤14 yr in males or ≤12 yr in females. Mean baseline height standard deviation (SD) score was - 1.3. The mean last measured height in all 97 patients after a mean duration of 2.7± 1.2 years, by analysis of covariance (ANCOVA) adjusting for baseline height, is shown below.

Table 4 Results of study FR M0380g in growth failure in pubertal patients due to GHI

Height Differences Between Groups (cm) Mean ± SE

Male

3.6 ± 1.7

Female

2.9 ± 3.4

*Adjusted for baseline height

The mean height SD score at last measured height (n=97) was -0.7±1.00 in the 0.3 mg/kg/wk group and -0.1 ± 1.2 in the 0.7 mg/kg/wk group. For patients completing 3.5 or more years (mean 4.1 years) of treatment with NUTROPIN (15/49 in the 0.3 mg/kg/wk group and 16/48 patients in the 0.7 mg/kg/wk group), the mean last measured height was 166.1±8.0 in the 0.3 mg/kg/wk group and 171.8 ± 7.1 cm in the 0.7 mg/kg/wk group, adjusting for baseline height and sex.

The mean change in bone age was approximately one year for each year in the study in both dose groups. Patients with baseline height SD scores above -1.0 were able to attain normal adult heights with 0.3 mg/kg/wk dose of NUTROPIN (mean height SD score at near adult height = -0.1, n=15).

Thirty-one patients had bone mineral density (BMD) determined by dual energy x-ray absorpitometry (DEXA) scans at study conclusion. The two dose groups did not differ significantly in mean SD score for total body BMD (- 0.9± 1.9 in the 0.3 mg/kg/wk group vs. -0.8 ± 1.2 in the 0.7 mg/kg/wk group, n=20) or lumbar spine BMD (-1.0± 1.0 in the 0.3 mg/kg/wk group vs. -0.2 ± 1.7 in the 0.7 mg/kg/wk group, n=21).

Over a mean duration of 2.7 years, patients in the 0.7 mg/kg/wk group were more likely to have IGF-I values above the normal range than the patients in the 0.3 mg/kg/wk group (27.7% vs. 9.0% of IGF-I measurements for individual patients). The clinical significance of elevated IGF-I values is unknown.

There was 1 incident of each of the following adverse events reported in the 0.7 mg/kg/wk group: broadening of the nasal bridge, large feet reported as “large shoe size”, ankle swelling and hip pain.

Three cases of eosinophilia were reported in the 0.7 mg/kg/wk group, which were of unknown significance. Mean changes in overall eosinophil counts in the 0.7 mg/kg/wk group were not clinically significant compared to the 0.3 mg/kg/wk group.

Clinical Effect of NUTROPIN on Growth Failure due to Chronic Renal Insufficiency (CRI)

Study demographics and trial design

Two multicenter, randomized, controlled clinical trials were conducted to determine whether treatment with NUTROPIN prior to renal transplantation in children with chronic renal insufficiency could improve their growth rates and height deficits. One study was a double-blinded, 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 administered daily by subcutaneous injection. Combining the data from all patients completing two years in the two controlled studies provides data from 62 children treated with NUTROPIN and 28 children as control subjects (either placebo-treated or untreated).

Study results

The mean first year growth rate was 10.8 cm/yr for patients treated with NUTROPIN, compared with a mean growth rate of 6.5 cm/yr for control subjects (p<0.00005). The mean second year growth rate was 7.8 cm/yr for patients treated with NUTROPIN, compared with a mean growth rate of 5.5 cm/yr for control subjects (p<0.00005). There was a significant improvement in the standard deviation score for mean height in the NUTROPIN group (-2.9 at baseline to -1.5 at month 24, n=62) but no significant change in the control subjects (-2.8 at baseline to -2.9 at month 24, n=28). The mean third year growth rate of 7.6 cm/yr in the patients treated with NUTROPIN (n=27) suggests that NUTROPIN stimulates growth rate beyond two years. However, there are no control data for the third year because control patients crossed over to growth hormone treatment after two years of participation in the placebo-controlled study. The gains in height were accompanied by appropriate advancement of skeletal age. These data demonstrate that therapy with NUTROPIN improves growth rate and corrects the acquired height deficit associated with CRI. Currently there are insufficient data regarding the benefit of treatment beyond three years. Although predicted final height was improved during therapy with NUTROPIN, the effect of NUTROPIN on final adult height remains to be determined.

Note on post transplant growth: The North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) has reported data for growth after transplant in children who did not receive growth hormone (n=300). The average change in height SD score during the initial two years post-transplant was 0.18. Controlled studies of growth hormone treatment for short stature associated with CRI were not designed to compare the growth between treated and untreated patients after they received renal transplants, however, growth data is available from 7 patients who were not treated with growth hormone prior to undergoing transplant (control subjects) and 13 patients who were treated with NUTROPIN up to the time of transplant (treatment with NUTROPIN was discontinued at time of transplant). These 20 patients have been followed for at least 11 months post-transplant. Of the control patients, 4 showed improvement in their height SD score and 3 had either no significant change or a decrease in height SD score. Of the patients treated with NUTROPIN, all 13 had either no significant change or an increase in height SD score after transplantation, indicating that the individual gains achieved with growth hormone therapy prior to transplant were maintained after transplantation. The differences in the height deficit narrowed between the treated (prior to transplant) and untreated groups in the post-transplant period.

Clinical Effect of NUTROPIN on Growth Failure due to Turner Syndrome

Study demographics and trial design

A long-term, open-label multicenter, historically controlled study was conducted to evaluate the efficacy of GH for the treatment of girls with short stature due to Turner syndrome (85-044).

In the study, the effect of long-term treatment with NUTROPIN (0.375 mg/kg/week given either 3 times per week or daily) on adult height was determined by comparing adult heights in the treated patients with those of age-matched historical controls with Turner syndrome (TS) who never received any growth-promoting therapy. In Study 85-044, patients treated with NUTROPIN early were randomized to receive estrogen replacement therapy (conjugated estrogens, 0.3 mg escalating to 0.625 mg daily) at either age 12 or 15 years.

Study results

Table 5 Results of Study 85-044 in patients with Turner Syndrome Study Group

Adult Height Gain (cm)^a

A^b B^b C^b

8.3 5.9 5.0 ^aAnalysis of covariance vs. controls

^bA: GH age <11yr, estrogen age 15 yr

B: GH age <11 yr, estrogen age 12 yr

C: GH age >11 yr, estrogen at Month 12

In Study 85-044, early treatment with NUTROPIN (mean duration of GH therapy 5.6 years) combined with estrogen replacement at age 12 years resulted in an adult height gain of 5.9 cm (n=26) compared with matched historical controls. In patients who initiated estrogen at age 15 years (mean duration of GH therapy was 6.1 years), had a mean adult height gain of 8.3 cm (n=29). Patients who initiated treatment with NUTROPIN after age 11 (mean age 12.7 years; mean duration of GH therapy 3.8 years) had a mean adult height gain of 5.0 cm (n=51).

The greatest improvement in adult height was observed in patients who received early treatment with NUTROPIN and estrogen after age 14 years.

The National Cooperative Growth Study (NCGS) is an observational registry of children treated with recombinant growth hormone (GH) products manufactured by Genentech, Inc (South San Francisco, CA). As of December 2003, there were 4749 patients with Turner’s Syndrome in the NCGS database; 3938 had not previously received GH, were prepubertal at the onset of GH therapy, and were treated for at least 6 months with GH. Near adult height (NAH) was achieved

by 685 of these patients. Of these patients, 68 patients received NUTROPIN exclusively throughout therapy in NCGS, Of the 68 patients, 40 reported estrogen therapy (2 patients also reported androgen therapy), while 28 (or 41%) of the 68 patients had some degree of spontaneous pubertal development and no reported exogenous estrogen therapy. The use of estrogen was defined in the patients by the documentation of administration of any estrogen on the NCGS data sheets. The age at onset of estrogen exposure was determined as the last age that Tanner stage 1 breast development was noted on the NCGS report data sheet.

Results

There were no significant differences in baseline characteristics between the patients reporting estrogen therapy with or without androgen therapy and the patients not reporting estrogen therapy. At NAH the only significant differences, p<0.0001, between these groups were for years of estrogen-free NUTROPIN therapy and years of NUTROPIN and estrogen therapy. In all of these groups including the pooled data of all 68 patients, gain over Lyon PAH (cm) was significantly different from zero, p ≤ 0.001, as well as, gain over Lyon PAH SDS, p <0.0001. The average dose of NUTROPIN used in the total cohort (n=68) over the years of treatment (adjustments being made for weight changes at variable time points and for responsiveness) was 0.279 mg/kg/week (+/- 0.106).

Table 6 Turner Syndrome patients from NCGS treated with NUTROPIN achieving near adult height^*

Baseline

Minimum

Age (yr)

9.57 Height (cm)

103.40 Lyon Height SDS

-2.50 Lyon PAH^a (cm)

126.20 Bone Age^b (yr)

5.00 Bone Age Delay ^b (yr)

-1.06 Near Adult Height

Estrogen-Free NUTROPIN Rx (yr)

0.0

NUTROPIN Rx + Estrogen (yr)

0.0

Total NUTROPIN Rx (yr)

2.40 Age at onset of Estrogen Exposure (yr)

9.86

Age at Near Adult Height (yr)

14.01 Height (cm)

143.0 Gain over L.yon PAH^a (cm)

-11.20 Gain over Lyon PAH^a SDS

-0.79 ^*n=68

^aPAH is predicted adult height

^bn=53, which requires a baseline bone age >6 yr; 15 girls were missing baseline bone age and 2 bone ages were <6 yr.

^cp<0.0001

Adult Growth Hormone Deficiency (GHD)

Study demographics and trial design

Table 7 Summary of patient demographics for clinical trials M0431g (adult-onset)

and M0381g (childhood-onset) in adult GHD^a

Study #

Gender

M0431g

86 M, 80 F

M0381g

39 M, 25 F ^a The studies were designed to assess the effects of replacement therapy with GH on body composition. ^b Doses of 0.025 mg/kg/day were not tolerated in these subjects.

Study results

Significant changes from baseline to Month 12 of treatment in body composition (i.e., total body percent fat mass, trunk percent fat mass and total body percent lean mass by DEXA scan) were seen in all NUTROPIN groups in both studies (p <0.0001 for change from baseline and vs. placebo), whereas no statistically significant changes were seen in either of the placebo groups. In the adult-onset study, the NUTROPIN group improved mean total body fat from 35.0% to 31.5%, mean trunk fat from 33.9% to 29.5%, and mean lean body mass from 62.2% to 65.7%, whereas the placebo group had mean changes of 0.2% or less (p=not significant). Due to the possible effect of GH-induced fluid retention on DEXA measurements of lean body mass, DEXA scans were repeated approximately 3 weeks after completion of therapy; mean percent lean body mass in the NUTROPIN group was 65.0%, a change of 2.8% from baseline, compared with a change of 0.4% in the placebo group (p<0.0001) between groups).

In the childhood-onset study, the high-dose NUTROPIN group improved mean total body fat from 38.4% to 32.1%, mean trunk fat from 36.7% to 29.0% and mean lean body mass from 59.1% to 65.5%; the low-dose NUTROPIN group improved mean total body fat from 37.1% to

31.3%, mean trunk fat from 37.9% to 30.6% and mean lean body mass from 60.0% to 66.0%; the placebo group had mean changes of 0.6% or less (p=not significant).

Table 8 Results of studies M0431g and M0381g in adult GHD: Changes from baseline to month 12 in proportion of fat and lean by DEXA (Adult-onset and Childhood-onset, respectively)

M0431g M0381g

Primary

Endpoints Placebo

(n=62)

NUTROPIN (n=63)

Between-group

t-test

p-value

Placebo (n=13)

NUTROPIN 0.0125

mg/kg/day (n=15)

NUTROPIN 0.025

mg/kg/day (n=15)

Placebo vs. pooled

NUTROPIN t-test-p-value

Proportion Mean ± SD Number of subjects

Total body percent fat

Baseline 36.8 ± 11.3 35.0 ± 11.2 0.38 35.0 ± 7.4 37.1 ± 13.2 38.4 ± 11.8 0.45

Month 12 36.8 ± 1.5 31.5 ± 12.5 35.2 ± 8.2 31.3 ± 13.6 32.1 ± 13.4

Baseline to

month 12 change

-0.1 ± 3.0 -3.6 ± 3.6 < 0.0001 +0.2 ± 2.9 -5.8 ± 4.3 -6.3 ± 4.3 < 0.0001

Post-washout 36.4 ± 11.5 32.2 ± 12.5 N/A N/A N/A

Baseline to post-

washout change

-0.4 ± 3.1 -2.8 ± 3.5 < 0.0001 N/A N/A N/A

Trunk percent fat

Baseline 35.3 ± 11.6 33.9 ± 10.4 0.50 32.5 ± 8.3 37.9 ± 13.4 36.7 ± 12.8 0.23

Month 12 35.4 ± 11.6 29.5 ± 11.8 33.1 ± 9.4 30.6 ± 13.8 29.0 ± 13.6

Baseline to

month 12 change

0.0 ± 3.7 -4.3 ± 4.3 < 0.0001 +0.6 ± 3.9 -7.3 ± 4.8 -7.6 ± 5.3 <0.0001

Post-washout 34.9 ± 11.5 30.5 ± 11.6 N/A N/A N/A

Baseline to post-

washout change

-0.3 ± 3.5 -3.4 ± 4.1 N/A N/A N/A

Total body percent lean

Baseline 60.4 ± 11.0 62.2 ± 11.0 0.37 62.0 ±7.2 60.0 ± 12.7 59.1 ± 11.3 0.48

Month 12 60.5 ± 11.1 65.7 ± 12.3 61.8 ± 7.8 66.0 ± 13.4 65.5 ± 12.9

Baseline to

month 12 change

+ 0.2 ± 2.9 +3.6 ± 3.6 < 0.0001 -0.2 ± 2.8 +6.0 ± 4.2 +6.4 ± 4.2 <0.0001

Post-washout 60.9 ± 11.1 65.0 ± 12.2 N/A N/A N/A

Baseline to post-

washout change

+ 0.4 ± 3.0 +2.8 ± 3.4 < 0.0001 N/A N/A N/A

In the adult-onset study, significant decreases from baseline to Month 12 in LDL cholesterol and LDL:HDL ratio were seen in the NUTROPIN group compared to the placebo group, p <0.02; there were no statistically significant between-group differences in change from baseline to Month 12 in total cholesterol, HDL cholesterol or triglycerides. In the childhood-onset study, significant decreases from baseline to Month 12 in total cholesterol, LDL cholesterol and LDL:HDL ratio were seen in the high-dose NUTROPIN group only, compared to the placebo group, p <0.05. There were no statistically significant between-group differences in HDL cholesterol or triglycerides from baseline to Month 12.

In the childhood-onset study, 55% of the patients had decreased spine bone mineral density (BMD) (z-score <-1) at baseline. The administration of NUTROPIN (n=16) (0.025 mg/kg/day) for two years resulted in increased spine BMD from baseline when compared to placebo (n=13) (4.6% vs. 1.0%, respectively, p <0.03); a transient decrease in spine BMD was seen at six months in the patients treated with NUTROPIN. Thirty-five percent of subjects treated with this dose had supraphysiological levels of IGF-I at some point during the study, which may carry unknown risks. No significant improvement in total body BMD was found when compared to placebo. A lower GH dose (0.0125 mg/kg/day) did not show significant increments in either of these bone parameters when compared to placebo. No statistically significant effects on BMD were seen in the adult-onset study where patients received GH (0.0125 mg/kg/day) for one year.

Muscle strength, physical endurance, and quality of life measurements were not markedly abnormal at baseline, and no statistically significant effects of therapy with NUTROPIN were observed in the two studies.

DETAILED PHARMACOLOGY

NUTROPIN (somatropin) is identical in amino acid sequence to native human pituitary hormone.

Pharmacological studies were conducted in vivo in rodents, rabbits, primates and in vitro using human donor cells or isolated organ preparations to demonstrate the efficacy, pharmacokinetics, bioavailability and tissue distribution of rhGH. In addition, in vitro, preclinical and clinical testing have demonstrated that NUTROPIN is therapeutically equivalent to pituitary-derived human growth hormone.

Efficacy

The primary indication of clinical efficacy is increased stature following growth hormone supplementation in children with insufficient endogenous growth hormone, i.e. hypopituitary dwarfism, and chronic renal insufficiency. Recombinant human growth hormone was evaluated at five doses (up to five fold the clinical dose) in weight gain bioassays. NUTROPIN was shown to be bioequivalent in stimulating weight gain in growth hormone deficient (hypophysectomized)

rats. NUTROPIN exhibited equivalent effects on both overall bone growth, as measured by absolute length of the femur, and increased width of the proliferative zones of the growth plate.

The efficacy of rhGH was further demonstrated in peripubertal rhesus monkeys with functional pituitary glands. These animals exhibited an increased circulating level of insulin-like growth factor I [IGF-I] and an increase in sitting height after the administration of the rhGH three times weekly, compared with untreated controls.

A Phase 1, double-blind, parallel study was conducted in 20 normal adult males to determine the safety and acute pharmacologic action of rhGH. There were no serious adverse effects associated with administration of rhGH to healthy volunteers at a dose of 0.125 mg/kg/day for 4 days. All subjects experienced an increase in weight. This change was significant 24 hours after the first dose and averaged 2-3 kg at the end of the study. An increase in intravascular volume and hemodilution probably account for the systemic decrease in hemoglobin. Myalgias were experienced by several of the subjects, possibly related to tissue swelling as a result of fluid retention. These observations are not common among children who are generally given smaller doses of growth hormone suggesting that fluid retention is related to the large doses given to these adult males.

The clinical growth effect of treatment with NUTROPIN in growth hormone inadequate and chronic renal insufficiency patients has been observed in well-controlled Phase III clinical trials.

Pharmacokinetics

Recombinant human growth hormone distributes to highly perfused tissues. Distribution studies of radio iodinated growth hormone injected into rats demonstrate that the liver and kidneys are the primary sites of localization. Animal studies suggest that the kidney is the dominant organ of clearance. Growth hormone is filtered by 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.

The pharmacokinetics of NUTROPIN (somatropin for injection) lyophilized powder have been investigated in healthy men after the subcutaneous administration of 0.1 mg/kg of body weight. A mean peak concentration (C_max) of 56.1 ng/mL occurred at a mean time of 7.5 hrs. The extent of absorption of NUTROPIN, assessed by area under the concentration versus time curve [AUC], was 626 ng•hr/mL. The AUC of NUTROPIN is similar regardless of site of injection.

After subcutaneous injection of 0.1 mg/kg NUTROPIN AQ, (somatropin injection) a mean peak concentration (C_max) of 71.1 ng/mL occurred at a mean time of 3.9h. 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 subcutaneous administration based on the statistical evaluation of the ratios of the geometric mean of log transformed AUC and C_max.

In both normal and growth hormone deficient (GHD) adults and children, the intramuscular and subcutaneous pharmacokinetic profiles of somatropin are similar regardless of the type of growth hormone or dosing regimen used. The subcutaneous pharmacokinetic profile of NUTROPIN is comparable to estimates in the published literature. A small number of dose-ranging studies suggest that clearance and AUC of somatropin is proportional to dose in the therapeutic dose range. The reduction in clearance rates seen in severe liver or kidney dysfunction are consistent with the role of the liver and kidney as major elimination organs for exogenously administered human growth hormone. Pharmacokinetic studies in children with chronic renal insufficiency, Turner syndrome, and growth failure have not been done.

TOXICOLOGY

Safety

No toxic effects were observed in rat or monkey after fourteen days of rhGH administration. In one study, rhGH was administered in doses ranging from 0.125 to 0.625 mg/kg to 36 rhesus monkeys for 2 weeks (6 injections). No clinical toxicity was seen. In another study 40 male and 40 female rats were assigned to one of the following dose groups (20/group with 5M,5F treated and 5M,5F as controls): 0, 0.125, 0.625 or 3.125 mg/kg per day. No treatment related effects were seen in the 0.125 mg/kg group, nor in females at 0.625 mg/kg. At 0.625 mg and 3.125 mg/kg/day, males showed elevated adrenal weights while females receiving 3.125 mg/kg/day showed elevated total body weight. These changes were most likely related to physiological effects and not to toxic effects. There was no local toxicity and local injection effects were comparable to the control group.

After 13 weeks of rhGH at up to six times the clinical dose of 0.1 mg/kg, there were no significant toxicological effects seen in monkeys treated three times weekly.

Intramuscular or subcutaneous administration of rhGH at two times the clinical dose in rabbits failed to show significantly greater local inflammation or degenerative changes at the sites of injection in these animals compared with placebo-treated animals whereas carageenan, a recognized irritant, caused markedly increased myodegeneration and necrosis at the injection site.

Immunogenicity

In studies in rhesus monkeys designed to predict possible immunogenicity of rhGH during therapeutic use, a positive antibody titer was observed in 2 out of 23 animals receiving rhGH at doses of 125 or 625 µg/kg body weight three times weekly for more than 12 weeks. These were two of the five animals treated with rhGH and estradiol; no monkeys dosed with rhGH alone had a positive antibody titer.

A study in transgenic mice (which express human growth hormone), to screen for the immunogenicity of somatropin NUTROPIN AQ (somatropin injection), indicated that NUTROPIN AQ does not have greater immunogenic potential than somatropin NUTROPIN (somatropin for injection) lyophilized powder.

Drug Interactions

The effects of thyroxine (0.02 mg/kg) and prednisone (10 mg/kg) co-administered with growth hormone (1.6 mg/kg) on rat hepatic drug metabolizing enzymes was also evaluated. Three days of prednisone therapy decreased cytochrome P-450 concentration, increased monoxygenase and UDP-glucuronosyltransferase activities, and slightly decreased glutathione S-transferase activity. After five days of prednisone therapy, all Phase II conjugation reactions were decreased. Thyroxine (0.1 and 0.2 mg/kg) administration caused a concentration-dependent decrease in cytochrome P-450 concentration and monooxygenase activities and no apparent effects on Phase II conjugation enzyme activities. Doses of 1 mg/kg thyroxine caused a decrease in glutathione S-transferase activity after five days. The results from this study suggest that prednisone and thyroxine do not statistically alter the hepatic microsomal mixed function oxidase system.

Earlier work by Wilson demonstrated that exogenously administered pituitary-derived growth hormone reduced the activity of the hepatic mixed function oxidase enzymes. Other investigators have documented a reduction in Phase I biotransformation reactions as well as Phase II enzymatic reactions. These results suggest that exogenously administered growth hormone alters the disposition of other drugs given concurrently with growth hormone as well as altering its own disposition. Additional studies are necessary to demonstrate the clinical significance of these alterations.

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