Description for Nutropin AQ
Nutropin AQ [somatropin (rDNA origin)] for Injection is a human growth hormone (hGH) produced by recombinant DNA technology. Nutropin AQ has 191 amino acid residues and a molecular weight of 22,125 daltons. The amino acid sequence of the product is identical to that of pituitary-derived hGH. Nutropin AQ may contain not more than fifteen percent deamidated GH at expiration. The deamidated form of GH has been extensively characterized and has been shown to be safe and fully active.
Nutropin AQ is a sterile liquid intended for subcutaneous administration. The product is nearly isotonic at a concentration of 5 mg of GH per mL and has a pH of approximately 6.0. Each pen cartridge or NuSpin contain either 5 mg, 10 mg or 20 mg of somatropin formulated in 17.4 mg sodium chloride, 5 mg phenol, 4 mg polysorbate 20, and 10 mM sodium citrate [See HOW SUPPLIED/Storage and Handling].
ADVERSE REACTIONS
The following important adverse reactions are also described elsewhere in the labeling:
- Increased mortality in patients with acute critical illness [see Warnings and Precautions (5.1)]
- Fatalities in children with Prader-Willi syndrome [see Warnings and Precautions (5.2)]
- Neoplasms in pediatric patients [see Warnings and Precautions (5.3)]
- Glucose intolerance and diabetes mellitus [see Warnings and Precautions (5.4)]
- Intracranial hypertension [see Warnings and Precautions (5.5)]
- Severe hypersensitivity [see Warnings and Precautions (5.6)]
- Fluid retention [see Warnings and Precautions (5.7)]
- Hypoadrenalism [see Warnings and Precautions (5.8)]
- Hypothyroidism [see Warnings and Precautions (5.9)]
- Slipped capital femoral epiphysis in pediatric patients [see Warnings and Precautions (5.10)]
- Progression of preexisting scoliosis in pediatric patients [see Warnings and Precautions (5.11)]
- Otitis media and cardiovascular disorders in patients with Turner syndrome [see Warnings and Precautions (5.12)]
- Osteodystrophy in pediatric patients with chronic kidney disease [see Warnings and Precautions (5.13)]
- Lipoatrophy [see Warnings and Precautions (5.14)]
- Pancreatitis [see Warnings and Precautions (5.16)]
Clinical Trials Experience
Because clinical trials are conducted under varying conditions, adverse reaction rates observed during the clinical trials performed with one somatropin formulation cannot always be directly compared to the rates observed during the clinical trials performed with a second somatropin formulation, and may not reflect the adverse reaction rates observed in practice.
Pediatric Patients
Growth Hormone Deficiency (GHD)
Injection site discomfort has been reported. This is more commonly observed in children switched from another somatropin product to Nutropin AQ.
Turner Syndrome
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 somatropin.
Idiopathic Short Stature (ISS)
In a post-marketing surveillance study, the National Cooperative Growth Study (NCGS), the pattern of adverse events in over 8,000 patients with ISS was consistent with the known safety profile of growth hormone (GH), and no new safety signals attributable to GH were identified. The frequency of protocol-defined targeted adverse events is described in the table, below.
Table 1
Protocol-Defined Targeted Adverse Events in the ISS NCGS Cohort
| Reported Events | NCGS (N = 8018) | ||
| Any Adverse Event | |||
| Overall | 103 (1.3%) | ||
| Targeted Adverse Event | |||
| Overall | 103 (1.3%) | ||
| Injection-site reaction | 28 (0.3%) | ||
| New onset or progression of scoliosis | 16 (0.2%) | ||
| Gynecomastia | 12 (0.1%) | ||
| Any new onset or recurring tumor (benign) | 12 (0.1%) | ||
| Arthralgia or arthritis | 10 (0.1%) | ||
| Diabetes mellitus | 5 (0.1%) | ||
| Edema | 5 (0.1%) | ||
| Cancer, neoplasm (new onset or recurrence) | 4 (0.0%) | ||
| Fracture | 4 (0.0%) | ||
| Intracranial hypertension | 4 (0.0%) | ||
| Abnormal bone or other growth | 3 (0.0%) | ||
| Central nervous system tumor | 2 (0.0%) | ||
| New or recurrent SCFE or AVN | 2 (0.0%) | ||
| Carpal tunnel syndrome | 1 (0.0%) | ||
|
AVN = avascular necrosis; SCFE = slipped capital femoral epiphysis. |
|||
In subjects treated in a long-term study of Nutropin for ISS, mean fasting and postprandial insulin levels increased, while mean fasting and postprandial glucose levels remained unchanged. Mean hemoglobin A1c (A1C) levels rose slightly from baseline as expected during adolescence; sporadic values outside normal limits occurred transiently.
Adult Patients
Growth Hormone Deficiency
In clinical studies with Nutropin AQ in GHD adults, edema or peripheral edema was reported in 41% of GH-treated patients and 25% of placebo-treated patients. In GHD adults, arthralgias and other joint disorders were reported in 27% of GH-treated patients and 15% of placebo-treated patients.
Nutropin therapy in adults with GHD of adult-onset was associated with an increase of median fasting insulin level in the Nutropin 0.0125 mg/kg/day group from 9.0 mU/mL at baseline to
13.0 mU/mL at Month 12 with a return to the baseline median level after a 3-week post-washout period of GH therapy. In the placebo group there was no change from 8.0 mU/mL at baseline to Month 12, and after the post-washout period, the median level was 9.0 mU/mL. The
between-treatment group difference on the change from baseline to Month 12 in median fasting insulin level was significant, p < 0.0001. In childhood-onset subjects, there was an increase of median fasting insulin level in the Nutropin 0.025 mg/kg/day group from 11.0 mU/mL at baseline to
20.0 mU/mL at Month 12, in the Nutropin 0.0125 mg/kg/day group from 8.5 mU/mL to 11.0 mU/mL, and in the placebo group from 7.0 mU/mL to 8.0 mU/mL. The between-treatment group differences for these changes were significant, p = 0.0007.
In subjects with adult-onset GHD, there were no between-treatment group differences on change from baseline to Month 12 in mean A1C level, p = 0.08. In childhood-onset GHD, the mean A1C level 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 group differences were significant, p = 0.009.
Immunogenicity
As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Nutropin with the incidence of antibodies to other products may be misleading. In the case of GH, antibodies with binding capacities lower than 2 mg/L have not been associated with growth attenuation. In a very small number of patients treated with somatropin, when binding capacity was greater than 2 mg/L, interference with the growth response was observed.
In clinical studies of pediatric patients that were treated with Nutropin for the first time,
0/107 GHD patients, 0/125 CKD patients, 0/112 TS, and 0/117 ISS patients screened for antibody production developed antibodies with binding capacities ³ 2 mg/L at six months. In a clinical study of patients that were treated with Nutropin AQ for the first time, 0/38 GHD patients screened for antibody production for up to 15 months developed antibodies with binding capacities ³ 2 mg/L.
Additional short-term immunologic and renal function studies were carried out in a group of pediatric patients with CKD after approximately one year of treatment to detect other potential adverse effects of antibodies to GH. Testing included measurements of C1q, C3, C4, rheumatoid factor, creatinine, creatinine clearance, and blood urea nitrogen (BUN). No adverse effects of GH antibodies were noted.
Post-Marketing Experience
The following adverse reactions have been identified during post approval use of somatropin or NUTROPIN AQ. Because these adverse events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The adverse events reported during post-marketing surveillance do not differ from those listed/discussed above in Sections 6.1 and 6.2 in children and adults.
Serious systemic hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with postmarketing use of somatropin products [see Warnings and Precautions (5.6)]. Leukemia has been reported in a small number of GHD children treated with somatropin, somatrem (methionylated rhGH) and GH of pituitary origin. It is uncertain whether these cases of leukemia are related to GH therapy, the pathology of GHD itself, or other associated treatments such as radiation therapy. On the basis of current evidence, experts have not been able to conclude that GH therapy per se was responsible for these cases of leukemia. The risk for children with GHD, CKD, or TS, if any, remains to be established [see Contraindications (4) and Warnings and Precautions (5.3)].
The following additional adverse reactions have been reported in GH-treated patients: gynecomastia (children), and pancreatitis [Children and adults, see Warnings and Precautions (5.16)].
The following adverse reactions have been observed during the use of somatropin, including NUTROPIN AQ: Slipped capital femoral epiphysis [children, see Warnings and Precautions (5.10)] and osteonecrosis (children).
Drug Interactions for Nutropin AQ
11 ß-Hydroxysteroid Dehydrogenase Type 1 (11βHSD-1)
The microsomal enzyme 11βHSD-1 is required for conversion of cortisone to its active metabolite, cortisol, in hepatic and adipose tissue. Growth hormone (GH) and somatropin inhibit 11βHSD-1. Consequently, individuals with untreated GH deficiency have relative increases in 11βHSD-1 and serum cortisol. Introduction of somatropin treatment may result in inhibition of 11βHSD-1 and reduced serum cortisol concentrations. As a consequence, previously undiagnosed central (secondary) hypoadrenalism may be unmasked and glucocorticoid replacement may be required in patients treated with somatropin. In addition, patients treated with glucocorticoid replacement for previously diagnosed hypoadrenalism may require an increase in their maintenance or stress doses following initiation of somatropin treatment; this may be especially true for patients treated with cortisone acetate and prednisone since conversion of these drugs to their biologically active metabolites is dependent on the activity of 11βHSD-1.
Pharmacologic Glucocorticoid Therapy and Supraphysiologic Glucocorticoid Treatment
Pharmacologic glucocorticoid therapy and supraphysiologic glucocorticoid treatment may attenuate the growth-promoting effects of somatropin in children. Therefore, glucocorticoid replacement therapy should be carefully adjusted in children with concomitant GH and glucocorticoid deficiency to avoid both hypoadrenalism and an inhibitory effect on growth.
The use of Nutropin AQ in patients with Chronic Kidney Disease (CKD) requiring glucocorticoid therapy has not been evaluated. Concomitant glucocorticoid therapy may inhibit the growth promoting effect of Nutropin AQ. Therefore, if glucocorticoid replacement is required for CKD, the glucocorticoid dose should be carefully adjusted to avoid an inhibitory effect on growth. In the clinical trials there was no evidence of drug interactions with Nutropin and commonly used drugs used in the management of CKD.
Cytochrome P450 (CYP450)-Metabolized Drugs
Limited published data indicate that somatropin treatment increases CYP450-mediated antipyrine clearance in man. These data suggest that somatropin administration may alter the clearance of compounds known to be metabolized by CYP450 liver enzymes (e.g., corticosteroids, sex steroids, anticonvulsants, cyclosporine). Careful monitoring is advisable when somatropin is administered in combination with other drugs known to be metabolized by CYP450 liver enzymes. However, formal drug interaction studies have not been conducted.
Oral Estrogen
Because oral estrogens may reduce insulin-like growth factor (IGF-1) response to somatropin treatment, girls and women receiving oral estrogen replacement may require greater somatropin dosages [see Dosage and Administration (2.2)].
Insulin and/or Oral/Injectable Hypoglycemic Agents
In patients with diabetes mellitus requiring drug therapy, the dose of insulin and/or oral/injectable hypoglycemic agents may require adjustment when somatropin therapy is initiated [see Warnings and Precautions (5.4)].
Warnings for Nutropin AQ
Included as part of the PRECAUTIONS section.
Precautions for Nutropin AQ
Acute Critical Illness
Increased mortality in patients with acute critical illnesses due to complications following open heart surgery, abdominal surgery or multiple accidental trauma, or those with acute respiratory failure has been reported after treatment with pharmacologic amounts of somatropin [see Contraindications (4)]. Two placebo-controlled clinical trials in non-GHD adult patients (n = 522) with these conditions in intensive care units revealed a significant increase in mortality (42% vs. 19%) among somatropin-treated patients (doses 5.3-8 mg/day) compared to those receiving placebo. The safety of continuing somatropin 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 somatropin in patients having acute critical illnesses should be weighed against the potential risk.
Prader-Willi Syndrome (PWS) in Children
There have been reports of fatalities after initiating therapy with somatropin in pediatric patients with PWS 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 PWS syndrome should be evaluated for signs of upper airway obstruction and sleep apnea before initiation of treatment with somatropin. If during treatment with somatropin, patients show signs of upper airway obstruction (including onset of or increased snoring) and/or new onset sleep apnea, treatment should be interrupted. All patients with PWS treated with somatropin 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 (4)]. Nutropin AQ is not indicated for the treatment of pediatric patients who have growth failure due to genetically confirmed PWS.
Neoplasms
In childhood cancer survivors who were treated with radiation to the brain/head for their first neoplasm and who developed subsequent GHD and were treated with somatropin, an increased risk of a second neoplasm has been reported. Intracranial tumors, in particular meningiomas, were the most common of these second neoplasms. In adults, it is unknown whether there is any relationship between somatropin replacement therapy and CNS tumor recurrence [see Contraindications (4)].
Monitor all patients with a history of GHD secondary to an intracranial neoplasm routinely while on somatropin therapy for progression or recurrence of the tumor.
Because children with certain rare genetic causes of short stature have an increased risk of developing malignancies, practitioners should thoroughly consider the risks and benefits of starting somatropin in these patients. If treatment with somatropin is initiated, these patients should be carefully monitored for development of neoplasms.
Monitor patients on somatropin therapy carefully for increased growth, or potential malignant changes, of preexisting nevi.
Glucose Intolerance and Diabetes Mellitus
Treatment with somatropin may decrease insulin sensitivity, particularly at higher doses in susceptible patients. As a result, previously undiagnosed impaired glucose tolerance (IGT) and overt diabetes mellitus may be unmasked during somatropin treatment, and new onset type 2 diabetes mellitus has been reported in patients taking somatropin. Therefore, glucose levels should be monitored periodically in all patients treated with somatropin, especially in those with risk factors for diabetes, such as obesity, Turner syndrome (TS), or a family history of diabetes mellitus.
Patients with preexisting type 1 or type 2 diabetes mellitus or IGT should be monitored closely during somatropin therapy. The doses of antihyperglycemic drugs (i.e. insulin or oral/injectable agents) may require adjustment when somatropin therapy is instituted in these patients.
Intracranial Hypertension
Intracranial Hypertension (IH) with papilledema, visual changes, headache, nausea, and/or vomiting has been reported in a small number of patients treated with somatropin products. Symptoms usually occurred within the first eight (8) weeks after the initiation of somatropin therapy. In all reported cases, IH-associated signs and symptoms rapidly resolved after cessation of therapy or a reduction of the somatropin dose. Funduscopic examination should be performed routinely before initiating treatment with somatropin to exclude preexisting papilledema, and periodically during the course of somatropin therapy. If papilledema is observed by funduscopy during somatropin treatment, treatment should be stopped. If somatropin-induced IH is diagnosed, treatment with somatropin can be restarted at a lower dose after IH-associated signs and symptoms have resolved. Patients with TS, chronic kidney disease (CKD), and PWS may be at increased risk for the development of IH.
Severe Hypersensitivity
Serious systemic hypersensitivity reactions including anaphylactic reaction and angioedema have been reported with postmarketing use of somatropin products. Patients and caregivers should be informed that such reactions are possible and that prompt medical attention should be sought if an allergic reaction occurs.
Fluid Retention
Fluid retention during somatropin replacement therapy in adults may occur. Clinical manifestations of fluid retention (e.g., edema, arthralgia, myalgia, nerve compression syndromes including carpal tunnel syndrome/paraesthesias) are usually transient and dose dependent.
Hypoadrenalism
Patients receiving somatropin therapy who have or are at risk for pituitary hormone deficiency(s) may be at risk for reduced serum cortisol levels and/or unmasking of central (secondary) hypoadrenalism. In addition, patients treated with glucocorticoid replacement for previously diagnosed hypoadrenalism may require an increase in their maintenance or stress doses following initiation of somatropin treatment [see Section 7.1, 11-β Hydroxysteroid Dehydrogenase Type 1].
Hypothyroidism
Undiagnosed/untreated hypothyroidism may prevent an optimal response to somatropin, in particular, the growth response in children. Patients with TS have an inherently increased risk of developing autoimmune thyroid disease and primary hypothyroidism. In patients with GHD, central (secondary) hypothyroidism may first become evident or worsen during somatropin treatment.
Therefore, patients treated with somatropin should have periodic thyroid function tests and thyroid hormone replacement therapy should be initiated or appropriately adjusted when indicated.
Slipped Capital Femoral Epiphysis (SCFE) in Pediatric Patients
SCFE may occur more frequently in patients with endocrine disorders (including GHD and TS) or in patients undergoing rapid growth. SCFE may lead to osteonecrosis. Cases of SCFE with or without osteonecrosis have been reported in pediatric patients with short stature receiving somatropin, including NUTROPIN AQ. Any pediatric patient with the onset of a limp or complaints of hip or knee pain during NUTROPIN AQ therapy should be evaluated for SCFE and osteonecrosis and managed accordingly.
Progression of Preexisting Scoliosis in Pediatric Patients
Progression of scoliosis can occur in patients who experience rapid growth. Because somatropin increases growth rate, patients with a history of scoliosis who are treated with somatropin should be monitored for progression of scoliosis. However, somatropin has not been shown to increase the occurrence of scoliosis. Skeletal abnormalities including scoliosis are commonly seen in untreated TS patients. Scoliosis is also commonly seen in untreated patients with PWS. Physicians should be alert to these abnormalities, which may manifest during somatropin therapy.
Otitis Media and Cardiovascular Disorders in Patients with Turner Syndrome
Patients with TS should be evaluated carefully for otitis media and other ear disorders, as these patients have an increased risk of ear and hearing disorders. Somatropin treatment may increase the occurrence of otitis media in patients with TS. In addition, patients with TS should be monitored closely for cardiovascular disorders (e.g., hypertension, aortic aneurysm or dissection, stroke) as these patients are also at increased risk for these conditions.
Osteodystrophy in Pediatric Patients with Chronic Kidney Disease
Children with growth failure secondary to CKD should be examined periodically for evidence of progression of renal osteodystrophy. SCFE 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 somatropin therapy. X-rays of the hip should be obtained prior to initiating somatropin therapy in CKD patients and physicians and parents should be alert to the development of a limp or complaints of hip or knee pain in these patients treated with Nutropin AQ. No studies have been completed evaluating Nutropin AQ therapy in patients who have received renal transplants. Currently, treatment of patients with functioning renal allografts is not indicated.
Lipoatrophy
When somatropin is administered subcutaneously at the same site over a long period of time, tissue atrophy may result. This can be avoided by rotating the injection site [see Dosage and Administration (2.3)].
Laboratory Tests
Serum levels of inorganic phosphorus, alkaline phosphatase, and parathyroid hormone (PTH), and IGF-1 may increase during somatropin therapy.
Pancreatitis
Cases of pancreatitis have been reported rarely in children and adults receiving somatropin treatment, with some evidence supporting a greater risk in children compared with adults. Published literature indicates that girls who have TS may be at greater risk than other somatropin-treated children. Pancreatitis should be considered in any somatropin–treated patient, especially a child, who develops persistent severe abdominal pain.
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity, mutagenicity, and reproduction studies have not been conducted with Nutropin AQ.
OVERDOSAGE
Short Term
Short-term overdosage could lead initially to hypoglycemia and subsequently to hyperglycemia.
Furthermore, overdose with somatropin is likely to cause fluid retention.
Long Term
Long-term overdosage could result in signs and symptoms of gigantism and/or acromegaly consistent with the known effects of excess growth hormone (GH) [see Dosage and Administration (2.2)].
Contraindications for Nutropin AQ
· Acute Critical Illness
Treatment with pharmacologic amounts of somatropin is contraindicated in patients with acute critical illness due to complications following open heart surgery, abdominal surgery or multiple accidental trauma, or those with acute respiratory failure [see Warnings and Precautions (5.1)].
· Prader-Willi Syndrome (PWS) in Children
Somatropin is contraindicated in patients with PWS who are severely obese, have a history of upper airway obstruction or sleep apnea, or have severe respiratory impairment. There have been reports of sudden death when somatropin was used in such patients. Nutropin AQ is not indicated for the treatment of pediatric patients who have growth failure due to genetically confirmed PWS [see Warnings and Precautions (5.2)].
· Active Malignancy
In general, somatropin is contraindicated in the presence of active malignancy. Any pre-existing malignancy should be inactive and its treatment complete prior to instituting therapy with somatropin. Somatropin should be discontinued if there is evidence of recurrent activity. Since growth hormone deficiency (GHD) may be an early sign of the presence of a pituitary tumor (or, rarely, other brain tumors), the presence of such tumors should be ruled out prior to initiation of treatment. Somatropin should not be used in patients with any evidence of progression or recurrence of an underlying intracranial tumor [see Warnings and Precautions (5.3)].
· Hypersensitivity
Nutropin AQ is contraindicated in patients with a known hypersensitivity to somatropin or any of its excipients. Systemic hypersensitivity reactions have been reported with postmarketing use of somatropin products [see Warnings and Precautions (5.6)].
· Diabetic Retinopathy
Somatropin is contraindicated in patients with active proliferative or severe non-proliferative diabetic retinopathy.
· Closed Epiphysis
Somatropin should not be used for growth promotion in pediatric patients with closed epiphysis.
Clinical Pharmacology for Nutropin AQ
Mechanism of Action
Somatropin (as well as endogenous growth hormone) binds to dimeric growth hormone receptors located within the cell membranes of target tissue cells resulting in intracellular signal transduction and a host of pharmacodynamic effects. Some of these pharmacodynamic effects are primarily mediated by insulin-like growth factor (IGF-1) produced in the liver and also locally (e.g., skeletal growth, protein synthesis), while others are primarily a consequence of the direct effects of somatropin (e.g., lipolysis) [see Clinical Pharmacology (12.2)].
Pharmacodynamics
In vitro and in vivo preclinical and clinical testing have demonstrated that Nutropin AQ is therapeutically equivalent to pituitary-derived hGH. Pediatric patients who lack adequate endogenous growth hormone (GH) secretion, patients with chronic kidney disease (CKD), and patients with Turner syndrome (TS) that were treated with Nutropin AQ or Nutropin resulted in an increase in growth rate and an increase in IGF-1 levels similar to that seen with pituitary-derived hGH.
Tissue Growth
- Skeletal Growth: Nutropin AQ stimulates skeletal growth in pediatric patients with growth failure due to a lack of adequate secretion of endogenous GH or secondary to CKD and in patients with TS. Skeletal growth is accomplished at the epiphyseal plates at the ends of a growing bone. Growth and metabolism of epiphyseal plate cells are directly stimulated by GH and one of its mediators, IGF-I. Serum levels of IGF-I are low in children and adolescents who are GHD, but increase during treatment with somatropin. In pediatric patients, new bone is formed at the epiphyses in response to GH and IGF-I. This results in linear growth until these growth plates fuse at the end of puberty.
- Cell Growth: Treatment with somatropin results in an increase in both the number and the size of skeletal muscle cells.
- Organ Growth: GH 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 GH-stimulated protein synthesis. This is reflected by nitrogen retention as demonstrated by a decline in urinary nitrogen excretion and blood urea nitrogen (BUN) during somatropin therapy.
Carbohydrate Metabolism
GH is a modulator of carbohydrate metabolism. For example, patients with inadequate secretion of GH sometimes experience fasting hypoglycemia that is improved by treatment with Nutropin AQ. Somatropin therapy may decrease insulin sensitivity. Untreated patients with CKD and TS have an increased incidence of glucose intolerance. Administration of somatropin to adults or children resulted in increases in serum fasting and postprandial insulin levels, more commonly in overweight or obese individuals. In addition, mean fasting and postprandial glucose and hemoglobin A1C levels remained in the normal range.
Lipid Metabolism
In GHD patients, administration of somatropin resulted in lipid mobilization, reduction in body fat stores, increased plasma fatty acids, and decreased plasma cholesterol levels.
Mineral Metabolism
The retention of total body potassium in response to somatropin administration apparently results from cellular growth. Serum levels of inorganic phosphorus may increase slightly in patients with inadequate secretion of endogenous GH, CKD, or TS during Nutropin AQ therapy due to metabolic activity associated with bone growth as well as increased tubular reabsorption of phosphate by the kidney. Serum calcium is not significantly altered in these patients. Sodium retention also occurs. Adults with childhood-onset GHD show low bone mineral density (BMD). Nutropin AQ therapy results in increases in serum alkaline phosphatase [see Warnings and Precautions (5.14)].
Connective Tissue Metabolism
GH stimulates the synthesis of chondroitin sulfate and collagen as well as the urinary excretion of hydroxyproline.
Pharmacokinetics
Absorption
The absolute bioavailability of somatropin after subcutaneous administration in healthy adult males has been determined to be 81 ± 20%. The mean terminal t1/2 after subcutaneous administration is significantly longer than that seen after intravenous
administration(2.1 ± 0.43 hours vs. 19.5 ± 3.1 minutes) indicating that the subcutaneous absorption of the compound is slow and rate-limiting.
Distribution
Animal studies with somatropin showed that GH localizes to highly perfused organs, particularly the liver and kidney. The volume of distribution at steady state for somatropin in healthy adult males is about 50 mL/kg body weight, approximating the serum volume.
Metabolism
Both the liver and kidney have been shown to be important metabolizing organs for GH. Animal studies suggest that the kidney is the dominant organ of clearance. GH is filtered at 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.
Elimination
The mean terminal t1/2 after intravenous administration of somatropin in healthy adult males is estimated to be 19.5 ± 3.1 minutes. Clearance of rhGH after intravenous administration in healthy adults and children is reported to be in the range of 116-174 mL/hr/kg.
Bioequivalence of Formulations
Nutropin AQ has been determined to be bioequivalent to Nutropin based on the statistical evaluation of area under the curve (AUC) and maximum concentration (Cmax).
Special Populations
Pediatric: Available literature data suggests that somatropin clearances are similar in adults and children.
Geriatrics: Limited published data suggest that the plasma clearance and average steady-state plasma concentration of somatropin may not be different between young and elderly patients.
Race: Reported values for half-lives for endogenous GH in normal adult black males are not different from observed values for normal adult white males. No data for other races are available.
Growth Hormone Deficiency: Reported values for clearance of somatropin in adults and children with GHD range 138-245 mL/hr/kg and are similar to those observed in healthy adults and children. Mean terminal t1/2 values following intravenous and subcutaneous administration in adult and pediatric GHD patients are also similar to those observed in healthy adult males.
Chronic Kidney Disease: Children and adults with CKD and end-stage renal disease (ESRD) tend to have decreased clearance compared to normals. In a study with six pediatric patients 7 to 11 years of age, the clearance of Nutropin was reduced by 21.5% and 22.6% after the intravenous infusion and subcutaneous injection, respectively, of 0.05 mg/kg of Nutropin compared to normal healthy adults. Endogenous GH production may also increase in some individuals with ESRD. However, no somatropin accumulation has been reported in children with CKD or ESRD dosed with current regimens.
Turner Syndrome: No pharmacokinetic data are available for exogenously administered somatropin. However, reported half-lives, absorption, and elimination rates for endogenous GH in this population are similar to the ranges observed for normal subjects and GHD populations.
Hepatic Insufficiency: A reduction in somatropin clearance has been noted in patients with severe liver dysfunction. The clinical significance of this decrease is unknown.
Gender: No gender-specific pharmacokinetic studies have been done with Nutropin AQ. The available literature indicates that the pharmacokinetics of somatropin are similar in men and women.
Table 2
Summary of Nutropin AQ Pharmacokinetic Parameters in Healthy Adult Males
0.1 mg (approximately 0.3 IUa)/kg SC
|
Cmax |
Tmax |
t1/2 |
AUC0-∞ |
CL/Fsc |
|
|
MEANb |
71.1 |
3.9 |
2.3 |
677 |
150 |
|
CV% |
17 |
56 |
18 |
13 |
13 |
|
a Based on current International Standard of 3 IU = 1 mg. |
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Figure 1
Single Dose Mean Growth Hormone Concentrations in Healthy Adult Males
 |
PATIENT COUNSELING INFORMATION
Patients being treated with Nutropin AQ (and/or their parents) should be informed about the potential benefits and risks associated with Nutropin AQ treatment, including a review of the contents of the INSTRUCTIONS FOR USE. This information is intended to better educate patients (and caregivers); it is not a disclosure of all possible adverse or intended effects.
Patients and caregivers who will administer Nutropin AQ should receive appropriate training and instruction on the proper use of Nutropin AQ from the physician or other suitably qualified health care professional. A puncture-resistant container for the disposal of used syringes and needles should be strongly recommended. Patients and/or parents should be thoroughly instructed in the importance of proper disposal, and cautioned against any reuse of needles and syringes. This information is intended to aid in the safe and effective administration of the medication.
Please see the accompanying directions for use of the delivery device.
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