NUTROPIN AQ NUSPIN 10

Nutropin AQ (somatropin) injection, for subcutaneous use 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 (16) ] .

Nutropin AQ is a recombinant human growth hormone indicated for: Pediatric Patients : Treatment of children with growth failure due to growth hormone deficiency (GHD), idiopathic short stature (ISS), Turner syndrome (TS), and chronic kidney disease (CKD) up to the time of renal transplantation ( 1.1 ). Adult Patients: Treatment of adults with either childhood-onset or adult-onset GHD ( 1.2 ). 1.1 Pediatric Patients Growth Hormone Deficiency (GHD) - Nutropin AQ ® is indicated for the treatment of pediatric patients who have growth failure due to inadequate secretion of endogenous growth hormone (GH). Growth Failure Secondary to Chronic Kidney Disease (CKD) - Nutropin AQ is indicated for the treatment of growth failure associated with CKD up to the time of renal transplantation. Nutropin AQ therapy should be used in conjunction with optimal management of CKD. Idiopathic Short Stature (ISS) - Nutropin AQ is indicated for the treatment of ISS, also called non-GHD short stature, defined by height SDS ≤ –2.25, and associated with growth rates unlikely to permit attainment of adult height in the normal range, in pediatric patients whose epiphyses are not closed and for whom diagnostic evaluation excludes other causes associated with short stature that should be observed or treated by other means. Short Stature Associated with Turner Syndrome (TS) - Nutropin AQ is indicated for the treatment of short stature associated with TS. 1.2 Adult Patients Nutropin AQ is indicated for the replacement of endogenous GH in adults with GHD who meet either of the following two criteria: Adult Onset : Patients who have GHD, either alone or associated with multiple hormone deficiencies (hypopituitarism), as a result of pituitary disease, hypothalamic disease, surgery, radiation therapy, or trauma; or Childhood Onset : Patients who were GH deficient during childhood as a result of congenital, genetic, acquired, or idiopathic causes. Patients who were treated with somatropin for GHD in childhood and whose epiphyses are closed should be reevaluated before continuation of somatropin therapy at the reduced dose level recommended for GH deficient adults. According to current standards, confirmation of the diagnosis of adult GHD in both groups involves an appropriate GH provocative test with two exceptions: (1) patients with multiple pituitary hormone deficiencies due to organic disease; and (2) patients with congenital/genetic GHD.

For subcutaneous injection . Therapy with Nutropin AQ should be supervised by a physician who is experienced in the diagnosis and management of pediatric patients with short stature associated with growth hormone deficiency (GHD), chronic kidney disease, Turner syndrome, idiopathic short stature, or adult patients with either childhood-onset or adult-onset GHD. Nutropin AQ should be administered subcutaneously ( 2 ). Injection sites should always be rotated to avoid lipoatrophy ( 2.3 ). Pediatric GHD: Up to 0.3 mg/kg/week ( 2.1 ) Pubertal Patients: Up to 0.7 mg/kg/week ( 2.1 ) Idiopathic Short Stature: Up to 0.3 mg/kg/week ( 2.1 ) Chronic Kidney Disease: Up to 0.35 mg/kg/week ( 2.1 ) Turner Syndrome: Up to 0.375 mg/kg/week ( 2.1 ) Adult GHD: Either a non-weight based or weight-based dosing regimen may be followed, with doses adjusted based on treatment response and IGF-I concentrations ( 2.2 ). Non-weight-based: A starting dose of approximately 0.2 mg/day (range 0.15–0.3 mg/day) increased gradually every 1–2 months by increments of approximately 0.1–0.2 mg/day. Weight-based : Initiate from not more than 0.006 mg/kg/day; the dose may be increased up to a maximum of 0.025 mg/kg/day in patients ≤ 35 years old or 0.0125 mg/kg/day in patients > 35 years old. 2.1 Dosing for Pediatric Patients Nutropin AQ dosage and administration schedule should be individualized for each patient. Response to growth hormone (GH) therapy in pediatric patients tends to decrease with time. However, in pediatric patients failure to increase growth rate, particularly during the first year of therapy, suggests the need for close assessment of compliance and evaluation of other causes of growth failure, such as hypothyroidism, under-nutrition, advanced bone age and antibodies to recombinant human GH (rhGH). Treatment with Nutropin AQ for short stature should be discontinued when the epiphyses are fused. Pediatric Growth Hormone Deficiency (GHD ) A weekly dosage of up to 0.3 mg/kg of body weight divided into daily subcutaneous injection is recommended. In pubertal patients, a weekly dosage of up to 0.7 mg/kg divided daily may be used. Growth Failure Secondary to Chronic Kidney Disease (CKD) A weekly dosage of up to 0.35 mg/kg of body weight divided into daily subcutaneous injection is recommended. Nutropin AQ therapy may be continued up to the time of renal transplantation. In order to optimize therapy for patients who require dialysis, the following guidelines for injection schedule are recommended: Hemodialysis patients should receive their injection at night just prior to going to sleep or at least 3 to 4 hours after their hemodialysis to prevent hematoma formation due to the heparin. Chronic Cycling Peritoneal Dialysis (CCPD) patients should receive their injection in the morning after they have completed dialysis. Chronic Ambulatory Peritoneal Dialysis (CAPD) patients should receive their injection in the evening at the time of the overnight exchange. Idiopathic Short Stature (ISS) A weekly dosage of up to 0.3 mg/kg of body weight divided into daily subcutaneous injections is recommended. Short Stature Associated with Turner Syndrome (TS) A weekly dosage of up to 0.375 mg/kg of body weight divided into equal doses 3 to 7 times per week by subcutaneous injection is recommended. 2.2 Dosing for Adult Patients Adult Growth Hormone Deficiency (GHD) Either of two approaches to Nutropin AQ dosing may be followed: a weight-based regimen or a non-weight-based regimen. Weight based – Based on the dosing regimen used in the original adult GHD registration trials, the recommended dosage at the start of treatment is not more than 0.006 mg/kg daily. The dose may be increased according to individual patient requirements to a maximum of 0.025 mg/kg daily in patients ≤ 35 years and to a maximum of 0.0125 mg/kg daily in patients over 35 years old. Clinical response, side effects, and determination of age- and gender-adjusted serum insulin-like growth factor (IGF-1) concentrations should be used as guidance in dose titration. Non-weight based – Alternatively, taking into account the published literature, a starting dose of approximately 0.2 mg/day (range, 0.15 to 0.30 mg/day) may be used without consideration of body weight. This dose can be increased gradually every 1 to 2 months by increments of approximately 0.1 to 0.2 mg/day, according to individual patient requirements based on the clinical response and serum IGF-1 concentrations. The dose should be decreased as necessary on the basis of adverse events and/or serum IGF-1 concentrations above the age- and gender-specific normal range. Maintenance dosages vary considerably from person to person, and between male and female patients. A lower starting dose and smaller dose increments should be considered for older patients, who are more prone to the adverse effects of somatropin than younger individuals. In addition, obese individuals are more likely to manifest adverse effects, when treated with a weight-based regimen. In order to reach the defined treatment goal, estrogen-replete women may need higher doses than men. Oral estrogen administration may increase the dose requirements in women. 2.3 Preparation and Administration The solution should be clear immediately after removal from the refrigerator. Occasionally, after refrigeration, you may notice that small colorless particles of protein are present in the solution. This is not unusual for solutions containing proteins. Allow the pen cartridge or NuSpin ® to come to room temperature and gently swirl. If the solution is cloudy, the contents MUST NOT be injected. Parenteral drug products should always be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Injection sites, which may be located on the thigh, upper arm, abdomen or buttock, should always be rotated to avoid lipoatrophy. Nutropin AQ Pen Cartridge The Nutropin AQ Pen 10 and 20 mg Cartridges are color-banded to help ensure appropriate use with the Nutropin AQ Pen delivery device. Each cartridge must be used with its corresponding color-coded Nutropin AQ Pen [See Dosage Forms and Strengths (3) ] . Wipe the septum of the Nutropin AQ Pen Cartridge with rubbing alcohol or an antiseptic solution to prevent contamination of the contents by microorganisms that may be introduced by repeated needle insertions. It is recommended that Nutropin AQ be administered using sterile, disposable needles. Follow the directions provided in the Nutropin AQ Pen Instructions for Use. The Nutropin AQ Pen 10 allows for administration of a minimum dose of 0.1 mg to a maximum dose of 4.0 mg, in 0.1 mg increments. The Nutropin AQ Pen 20 allows for administration of a minimum dose of 0.2 mg to a maximum dose of 8.0 mg, in 0.2 mg increments. Nutropin AQ NuSpin The Nutropin AQ NuSpin 5, 10 and 20 are multi-dose, dial-a-dose injection devices prefilled with Nutropin AQ in a 5 mg/2 mL, 10 mg/2 mL or 20 mg/2 mL cartridge, respectively, for subcutaneous use. It is recommended that Nutropin AQ be administered using sterile, disposable needles. Follow the directions provided in the Nutropin AQ NuSpin 5, 10 or 20 Instructions for Use. The Nutropin AQ NuSpin 5 allows for administration of a minimum dose of 0.05 mg to a maximum dose of 1.75 mg, in increments of 0.05 mg. The Nutropin AQ NuSpin 10 allows for administration of a minimum dose of 0.1 mg to a maximum dose of 3.5 mg, in increments of 0.1 mg. The Nutropin AQ NuSpin 20 allows for administration of a minimum dose of 0.2 mg to a maximum dose of 7.0 mg, in increments of 0.2 mg.

Acute critical illness ( 4 ). Children with Prader-Willi syndrome (PWS) who are severely obese or have severe respiratory impairment – reports of sudden death ( 4 ). Active malignancy ( 4 ). Hypersensitivity to somatropin or excipients ( 4 ). Active proliferative or severe non-proliferative diabetic retinopathy ( 4 ). Children with closed epiphysis ( 4 ). 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.

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) ] Common somatropin-related adverse reactions include injection site reactions. Additional common adverse reactions in adults include edema, arthralgias, and carpal tunnel syndrome ( 6.1 , 6.2 ). To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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) AVN = avascular necrosis; SCFE = slipped capital femoral epiphysis. Data obtained with several rhGH products (Nutropin, Nutropin AQ, Nutropin Depot and Protropin). Any Adverse Even t 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%) 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 A 1c (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 µU/mL at baseline to 13.0 µU/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 µU/mL at baseline to Month 12, and after the post-washout period, the median level was 9.0 µU/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 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 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. 6.2 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 ≥ 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 ≥ 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 . 6.3 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).

Inhibition of 11 β-Hydroxysteroid Dehydrogenase Type 1: May require the initiation of glucocorticoid replacement therapy. Patients treated with glucocorticoid replacement for previously diagnosed hypoadrenalism may require an increase in their maintenance doses ( 7.1 , 7.2 ). Glucocorticoid replacement: Should be carefully adjusted ( 7.2 ). Cytochrome P450- Metabolized Drugs: Monitor carefully if used with somatropin ( 7.3 ). Oral estrogen: Larger doses of somatropin may be required in women ( 7.4 ). Insulin and/or other hypoglycemic agents: May require adjustment ( 7.5 ). 7.1 11 β-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. 7.2 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. 7.3 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. 7.4 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) ] . 7.5 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) ] .

Storage and Handling Nutropin AQ cartridge and NuSpin injection device contents are stable for 28 days after initial use when stored at 2–8°C/36–46°F (under refrigeration). Avoid freezing Nutropin AQ in the cartridge or NuSpin injection device. Nutropin AQ is light sensitive and the cartridges and Nutropin AQ NuSpin should be protected from light. Store the cartridge and Nutropin AQ NuSpin injection device refrigerated in a dark place when they are not in use.