Prescription Drugs

CLINICAL PHARMACOLOGY General In vivo preclinical and clinical testing has demonstrated that growth hormone (GH) stimulates longitudinal bone growth and elevates insulin-like growth factor-I (IGF-I) levels. Actions that have been demonstrated for hGH include: Tissue Growth - 1) Skeletal Growth: GH stimulates skeletal growth in pediatric patients with growth failure due to a lack of adequate secretion of endogenous GH. 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 growth hormone deficient (GHD), but increase during treatment with GH. 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. 2) Cell Growth: Treatment with hGH results in an increase in both the number and the size of skeletal muscle cells. 3) Organ Growth: GH increases the size of internal organs, including kidneys, and increases red cell mass. Treatment of hypophysectomized or genetic dwarf rats with GH results in increases in organ and overall body growth. In normal rats subjected to nephrectomy-induced uremia, GH 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 during GH therapy. Carbohydrate Metabolism - GH is a modulator of carbohydrate metabolism. Patients with inadequate endogenous secretion of GH sometimes experience fasting hypoglycemia that is improved by treatment with GH. GH therapy may decrease insulin sensitivity. Administration of hGH formulated for daily dosing resulted in increased mean fasting and postprandial insulin levels, more commonly in overweight or obese individuals. Mean trough levels for fasting and postprandial insulin were unchanged after 3 or 6 months of Nutropin Depot (somatropin (rdna origin) for inj) therapy in GHD children. As with daily GH, mean trough levels for fasting glucose, postprandial glucose, and hemoglobin A1c remained unchanged after 3 or 6 months of Nutropin Depot (somatropin (rdna origin) for inj) therapy. Lipid Metabolism - In GHD patients, administration of GH formulated for daily dosing 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 GH administration apparently results from cellular growth. Serum levels of inorganic phosphorus may increase slightly in patients with inadequate secretion of endogenous GH 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. (See PRECAUTIONS: Laboratory Tests.) GH therapy results in increases in serum alkaline phosphatase. Connective Tissue Metabolism - GH stimulates the synthesis of chondroitin sulfate and collagen as well as the urinary excretion of hydroxyproline. Pharmacokinetics Nutropin Depot (somatropin (rdna origin) for inj) is a long-acting dosage form of somatropin designed to be administered by subcutaneous (SC) injection once or twice monthly. Following the injection, bioactive rhGH is released from the microspheres into the SC environment initially by diffusion, followed by both polymer degradation and diffusion. Although no studies have been performed that address the distribution, elimination, or metabolism of Nutropin Depot (somatropin (rdna origin) for inj) , once released and absorbed the rhGH is believed to be distributed and eliminated in a manner similar to somatropin formulated for daily administration. The serum hGH concentration-time profiles of single doses of 0.75 mg/kg and 1.5 mg/kg of Nutropin Depot (somatropin (rdna origin) for inj) have been characterized in pediatric GHD patients (refer to Figure 1). The in vivo profiles are characterized by an initial rapid release followed by a slow decline in GH concentration. Both the maximum concentrations achieved (Cmax) and total exposure (AUC0-28 days) appear to be proportional to dose. Serum hGH levels greater than 1 µg/L persist for approximately 11-14 days postdose for the two doses. Repeated dosing of Nutropin Depot (somatropin (rdna origin) for inj) over 6 months showed no progressive accumulation of GH. Absorption - In a study of Nutropin Depot (somatropin (rdna origin) for inj) in pediatric patients with GHD, an SC dose of 0.75 mg/kg (n = 12) or 1.5 mg/kg (n = 8) was administered. The mean ± SD hGH Cmax values were 48±26 µg/L and 90±23 µg/L, respectively, at 12-13 hours postdose. The corresponding AUC0-28 days values were 83±49 µg • day/L and 140±34 µg•day/L, respectively, for the two doses. For the 0.75 mg/kg and 1.5 mg/kg doses, the AUC0-2days accounted for approximately 52±16 percent and 61±10 percent of the total AUC0-28 days, respectively. Estimates of relative bioavailability in GHD children for a single dose of Nutropin Depot (somatropin (rdna origin) for inj) ranged from 33% to 38% when compared to a single dose of Nutropin AQ® [somatropin (rDNA origin) injection] in healthy adults, and from 48% to 55% when compared to chronically dosed Protropin® (somatrem for injection) in GHD children. Distribution - Animal studies with rhGH formulated for daily administration showed that GH localizes to highly perfused organs, particularly the liver and kidney. The volume of distribution at steady state for rhGH formulated for daily administration 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 using rhGH formulated for daily administration 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 (IV) administration of rhGH formulated for daily administration in healthy adult males is estimated to be 19.5+3.1 minutes. Clearance of rhGH after IV administration in healthy adults and children is reported to be in the range of 116-174 mL/hr/kg. Figure 1: Single-Dose Mean (SD) GH Concentrations in Pediatric GHD Patients Special Populations Pediatric - Available literature data suggest that rhGH clearances are similar in adults and children. Gender - Following administration of either 0.75 mg/kg or 1.5 mg/kg Nutropin Depot (somatropin (rdna origin) for inj) , Day 1 GH levels were higher in females compared to males. No relationship was observed between gender and pharmacodynamic marker (IGF-I and IGFBP-3) levels. Race - The effect of race on Nutropin Depot (somatropin (rdna origin) for inj) disposition is unknown due to the limited number of non-Caucasian patients in the Nutropin Depot (somatropin (rdna origin) for inj) studies. Growth Hormone Deficiency - Nutropin Depot (somatropin (rdna origin) for inj) has not been studied in healthy adults or children. However, reported values for clearance of rhGH formulated for daily administration in adults and children with GHD range from 138-245 mL/hr/kg and are similar to those observed in healthy adults and children. Mean terminal t1/2 values following IV and SC administration in adult and pediatric patients with GHD are also similar to those observed in healthy adult males. Renal Insufficiency - Nutropin Depot (somatropin (rdna origin) for inj) has not been studied in patients with renal insufficiency. Children and adults with chronic renal failure (CRF) and end-stage renal disease (ESRD) tend to have decreased clearance of rhGH formulated for daily administration compared with normals. Endogenous GH production may also increase in some individuals with ESRD. However, no GH accumulation has been reported in children with CRF or ESRD dosed with daily regimens. Hepatic Insufficiency - Nutropin Depot (somatropin (rdna origin) for inj) has not been studied in patients with hepatic insufficiency. A reduction in clearance of rhGH formulated for daily administration has been noted in patients with severe liver dysfunction. The clinical significance of this decrease is unknown. Pharmacodynamics IGF-I levels peaked between 1.5 and 3.5 days postdose and remained above baseline for approximately 16 to 20 days, confirming GH activity for an extended period. Repeated dosing of Nutropin Depot (somatropin (rdna origin) for inj) over 6 months showed no progressive accumulation of IGF-I (as shown in Figure 2) or IGF-binding protein 3 (IGFBP-3). Figure 2: Repeated-Dose Mean (SD) IGF-I Concentrations in Pediatric GHD Patients Efficacy Studies Pediatric Growth Hormone Deficiency (GHD) In two multicenter, open-label clinical studies in prepubertal children (mean age (± SD) 7.4+2.8) with idiopathic or organic GHD previously untreated with rhGH, 91 patients were treated with Nutropin Depot (somatropin (rdna origin) for inj) at 1.5 mg/kg once monthly or 0.75 mg/kg twice monthly by subcutaneous injection for up to six months. (See DOSAGE AND ADMINISTRATION for the number of injections required per dose.) The mean prestudy growth rate was 4.8±2.4 cm/yr (n=89). The dose-pooled, mean 6-month annualized growth rate on Nutropin Depot therapy was 8.4±2.2 cm/yr (n=89). Seventy-six patients continued treatment in an extension study. For patients who completed 12 months the mean growth rate was 7.8±1.9 cm/yr for the two dose groups combined (n=69). Mean height SD score changed from -3.0±1.0 prestudy to -2.5±0.9 at Month 12 (n=69). The mean 0 to 12 month change in bone age was 1.0±0.4 years (n=63). During the long-term extension study, fourteen of seventy-five (19%) patients discontinued due to dissatisfaction with growth response. Historical studies of GHD children treated with daily Protropin® (somatrem for injection) or Nutropin® [somatropin (rDNA origin) for injection] injections for 12 months at 0.3 mg/kg weekly had the following mean values: baseline growth rate 3.6 to 4.8 cm/yr; first year growth rate 10.1 to 11.3 cm/yr; first year change in bone age 1.1 to 1.5 years. In a dose-ranging study, 24 patients previously treated with daily GH (mean age 9.6±2.2 years; mean duration of prior GH therapy 2.8±1.6 yr, range 0.9 to 6.1 yr) were switched to Nutropin Depot (somatropin (rdna origin) for inj) therapy at the above doses. The mean growth rate on previous treatment was 8.2±3.0 cm/yr (range 3.2 to 13.1 cm/yr) and on Nutropin Depot (somatropin (rdna origin) for inj) was 5.1±2.0 cm/yr (range 2.4 to 9.6 cm/yr). During a long-term extension study, four of ten previously treated patients discontinued due to dissatisfaction with growth response. Historical studies of GHD children (n=181) treated with daily Protropin or Nutropin at a dose of 0.3 mg/kg weekly had the following mean growth rates: first year growth rate 9.7 to 11.4 cm/yr; second year growth rate 8.1 to 8.9 cm/yr; third year growth rate 7.5 to 7.8 cm/yr; fourth year growth rate 6.6 to 7.1 cm/yr.

CLINICAL PHARMACOLOGY 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). Pharmacodynamics In vitro and in vivo preclinical and clinical testing have demonstrated that Nutropin 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 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. 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 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 therapy results in increases in serum alkaline phosphatase [see WARNINGS AND PRECAUTIONS]. 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 t½ 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 t½ 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 has been determined to be bioequivalent to Nutropin AQ 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 t½ 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. The available literature indicates that the pharmacokinetics of somatropin are similar in men and women. Table 2: Summary of Nutropin Pharmacokinetic Parameters in Healthy Adult Males 0.1 mg (approximately 0.3 IUa)/kg SC Cmax (μg/L) Tmax (hr) t½(hr) AUC0-∞ (μg • hr/L) CL/Fsc (mL/[hr • kg]) MEANb 71.1 3.9 2.3 677 150 CY% 17 56 18 13 13 a Based on current International Standard of 3 IU = 1 mg. b n=36. Abbreviations: AUC0-m = area under the curve. Cmax=maximum concentration. CL/Fsc = systemic clearance. CY%=coefficient of variation in %; SC=subcutaneous. Fsc=subcutaneous bioavailability (not determined). t½=half-life. Figure 1: Single Dose Mean Growth Hormone Concentrations in Healthy Adult Males Clinical Studies Pubertal Patients with Growth Hormone Deficiency (GHD) One open label, multicenter, randomized clinical trial of two dosages of Nutropin was performed in pubertal patients with GHD. Ninety-seven patients (mean age 13.9 years, 83 male, 14 female) currently being treated with approximately 0.3 mg/kg/wk of GH were randomized to 0.3 mg/kg/wk or 0.7 mg/kg/wk Nutropin doses. All patients were already in puberty (Tanner stage ≥ 2) and had bone ages ≤14 years in males or ≤ 12 years in females. Mean baseline height standard deviation score (SDS) 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 3: Last Measured Height by Sex and Nutropin Dose for Pubertal Patients with GHD Age (yr) Last Measured Height* (cm) Height Difference Between Groups (cm) 0.3 mg/kg/wk 0.7 mg/kg/wk Mean ± SD (range) Mean ± SD Mean ± SD Mean ± SE Male 17.2 ± 1.3 (13.6 to 19.4) 170.9 ±7.9 (n=42) 174.5 ± 7.9 (n = 41) 3.6 ± 1.7 Female 15.8 ± 1.8 (11.9 to 19.3) 154.7 ± 6.3 (n=7) 157.6 ± 6.3 (n=7) 2.9 ± 3.4 *Adjusted for baseline height The mean height SDS at last measured height (n = 97) was -0.7 ± 1.0 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 Nutropin treatment (15/49 patients 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 cm 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 SDS above -1.0 were able to attain normal adult heights with the 0.3 mg/kg/wk dose of Nutropin (mean height SDS at near-adult height = -0.1, n = 15). Thirty-one patients had bone mineral density (BMD) determined by dual energy x-ray absorptiometry (DEXA) scans at study conclusion. The two dose groups did not differ significantly in mean SDS 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 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. Pediatric Patients with Growth Failure Secondary to Chronic Kidney Disease (CKD) Two multicenter, randomized, controlled clinical trials were conducted to determine whether treatment with Nutropin prior to renal transplantation in patients with CKD could improve their growth rates and height deficits. One study was a double-blind, 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 (0.35 mg/kg/week) administered daily by subcutaneous injection. Combining the data from those patients completing two years in the two controlled studies results in 62 patients treated with Nutropin and 28 patients in the control groups (either placebo-treated or untreated). The mean first year growth rate was 10.8 cm/yr for Nutropin-treated patients, compared with a mean growth rate of 6.5 cm/yr for placebo/untreated controls (p < 0.00005). The mean second year growth rate was 7.8 cm/yr for the Nutropin-treated group, compared with 5.5 cm/yr for controls (p < 0.00005). There was a significant increase in mean height SDS in the Nutropin group (-2.9 at baseline to -1.5 at Month 24, n = 62) but no significant change in the controls (-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 Nutropin-treated patients (n = 27) suggests that Nutropin stimulates growth beyond two years. However, there are no control data for the third year because control patients crossed over to Nutropin treatment after two years of participation. The gains in height were accompanied by appropriate advancement of skeletal age. These data demonstrate that Nutropin therapy improves growth rate and corrects the acquired height deficit associated with CKD. The North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) has reported data for growth post-transplant in children who did not receive GH prior to transplantation as well as children who did receive Nutropin during the clinical trials prior to transplantation. The average change in height SDS during the initial two years post-transplant was 0.15 for the 2,391 patients who did not receive GH pre-transplant and 0.28 for the 57 patients who did. For patients who were followed for 5 years post-transplant, the corresponding changes in height SDS were also similar between groups. Pediatric Patients with Turner Syndrome (TS) Three US studies, two long-term, open-label, multicenter, historically controlled studies (Studies 1 and 2), and one long-term, randomized, dose-response study (Study 3) and one Canadian, long-term, randomized, open-label, multicenter, concurrently controlled study, were conducted to evaluate the efficacy of somatropin treatment of short stature due to TS. In the US Studies 1 and 2, the effect of long-term GH treatment (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 TS who received no growth-promoting therapy. In Study 1, estrogen treatment was delayed until patients were at least age 14. GH therapy resulted in a mean adult height gain of 7.4 cm (mean duration of GH therapy of 7.6 years) vs. matched historical controls by ANCOVA. In Study 2, patients treated with early Nutropin therapy (before 11 years of age) 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. Compared with matched historical controls, early Nutropin therapy (mean duration of 5.6 years) combined with estrogen replacement at age 12 years resulted in an adult height gain of 5.9 cm (n = 26), whereas girls who initiated estrogen at age 15 years (mean duration of Nutropin therapy 6.1 years) had a mean adult height gain of 8.3 cm (n = 29). Patients who initiated Nutropin after age 11 (mean age 12.7 years; mean duration of Nutropin therapy 3.8 years) had a mean adult height gain of 5.0 cm (n = 51). Thus, in Studies 1 and 2, the greatest improvement in adult height was observed in patients who received early GH treatment and estrogen after age 14 years. In Study 3, a randomized, blinded dose-response study, patients were treated from a mean age of 11.1 years for a mean duration of 5.3 years with a weekly GH dose of either 0.27 mg/kg or 0.36 mg/kg administered in divided doses 3 or 6 times weekly. The mean near-final height of GH-treated patients was 148.7 ± 6.5 cm (n=31). When compared to historical control data, the mean gain in adult height was approximately 5 cm. The Canadian randomized study compared near-adult height outcomes for GH-treated patients to those of a concurrent control group who received no injections. The somatropin-treated patients received a dosage of 0.3 mg/kg/week given in divided doses 6 times per week from a mean age of 11.7 years for a mean duration of 4.7 years. Puberty was induced with a standardized estrogen regimen initiated at 13 years of age for both treatment groups. The somatropin-treated group (n = 27) attained a mean (± SD) near final height of 146.0 ± 6.2 cm; the untreated control group (n = 19) attained a near final height of 142.1 ± 4.8 cm. By ANCOVA (with adjustments for baseline height and mid-parental height), the effect of GH-treatment was a mean height increase of 5.4 cm (p = 0.001). In summary, patients with TS (total n = 181 from the 4 studies above) treated to adult height achieved statistically significant average height gains ranging from 5.0-8.3 cm. Table 4 : Summary of Efficacy Results in Turner Syndromea Study Group Study Designb N at Adult Height GH Age (yr) Estrogen Age (yr) GH Duration (yr) Adult Height Gain (cm)c US 1 MHT 17 9.1 15.2 7.6 7.4 US 2 A* MHT 29 9.4 15.0 6.1 8.3 B* 26 9.6 12.3 5.6 5.9 C* 51 12.7 13.7 3.8 5.0 US 3 RDT 31 11.1 8-13.5 5.3 ~5d Canadian RCT 27 11.7 13 4.7 5.4 a Data shown are mean values. b RCT: randomized controlled trial; MHT: matched historical controlled trial; RDT: randomized dose-response trial. c Analysis of covariance vs. controls. d Compared with historical data. * A = GH age < 11 yr, estrogen age 15 yr. B = GH age < 11 yr, estrogen age 12 yr. C = GH age > 11 yr, estrogen at Month 12. Pediatric Patient with Idiopathic Short Stature (ISS) A long-term, open-label, multicenter study was conducted to examine the safety and efficacy of Nutropin in pediatric patients with ISS, also called non-growth hormone deficient short stature. For the first year, 122 pre-pubertal subjects over the age of 5 years with stimulated serum GH ≥10 ng/mL were randomized into two treatment groups of approximately equal size; one group was treated with Nutropin 0.3 mg/kg weekly divided into three doses per week and the other group served as untreated controls. For the second and subsequent years of the study, all subjects were re-randomized to receive the same total weekly dose of Nutropin (0.3 mg/kg weekly) administered either daily or three times weekly. Treatment with Nutropin was continued until a subject's bone age was > 15.0 years (boys) or > 14.0 years (girls) and the growth rate was < 2 cm/yr, after which subjects were followed until adult height was achieved. The mean baseline values were: height SDS-2.8, IGF-I SDS -0.9, age 9.4 years, bone age 7.8 years, growth rate 4.4 cm/yr, mid-parental target height SDS -0.7, and Bayley-Pinneau predicted adult height SDS -2.3. Nearly all subjects had predicted adult height that was less than mid-parental target height. During the one-year controlled phase of the study, the mean height velocity increased by 0.5 ± 1.8 cm (mean ± SD) in the no-treatment control group and by 3.1 ± 1.7 cm in the Nutropin group (p < 0.0001). For the same period of treatment the mean height SDS increased by 0.4 ± 0.2 and remained unchanged (0.0 ± 0.2) in the control group (p < 0.001). Of the 118 subjects who were treated with Nutropin (70%) reached near-adult height (hereafter called adult height) after 2-10 years of Nutropin therapy. Their last measured height, including post-treatment follow-up, was obtained at a mean age of 18.3 years in males and 17.3 years in females. The mean duration of therapy was 6.2 and 5.5 years, respectively. Adult height was greater than pretreatment predicted adult height in 49 of 60 males (82%) and 19 of 23 females (83%). The mean difference between adult height and pretreatment predicted adult height was 5.2 cm (2.0 inches) in males and 6.0 cm (2.4 inches) in females (p < 0.0001 for both). The table (below) summarizes the efficacy data. Table 5: Long-Term Efficacy in ISS (Mean ± SD) Characteristic Males (n = 60) Females (n=23) Adult height (cm) 166.3 ± 5.8 153.1± 4.8 Pretreatment predicted adult height (cm) 161.1 ±5.5 147.1 ±5.1 Adult height minus pretreatment predicted adult height (cm) + 5.2 ± 5.0a +6.0 ± 5.0a Adult height SDS -1.5 ± 0.8 -1.6±0.7 Pretreatment predicted adult height SDS -2.2±0.8 -2.5 ± 0.8 Adult height minus pretreatment predicted adult height SDS + 0.7 ± 0.7a + 0.9±0.8a a p < 0.0001 versus zero. Nutropin therapy resulted in an increase in mean IGF-I SDS from -0.9 ± 1.0 to -0.2 ± 0.9 in Treatment Year 1. During continued treatment, mean IGF-I levels remained close to the normal mean. IGF-I SDS above + 2 occurred sporadically in 14 subjects. Adult Growth Hormone Deficiency Two multicenter, double-blind, placebo-controlled clinical trials were conducted in growth hormone-deficient adults. Study 1 was conducted in subjects with adult-onset GHD (n = 166), mean age 48.3 years, at doses of 0.0125 or 0.00625 mg/kg/day; doses of 0.025 mg/kg/day were not tolerated in these subjects. Study 2 was conducted in previously treated subjects with childhood-onset GHD (n = 64), mean age 23.8 years, at randomly assigned doses of 0.025 or 0.0125 mg/kg/day. The studies were designed to assess the effects of replacement therapy with Nutropin on body composition. Significant changes from baseline to Month 12 of treatment in body composition (i.e., total body % fat mass, trunk % fat mass, and total body % 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 % 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 6: Mean Changes from Baseline to Month 12 in Proportion of Fat and Lean by DEXA for Adult- and Childhood- Onset GHD Studies Proportion Adult Onset (Study 1) Childhood Onset (Study 2) Placebo (n=62) Nutropin (n=63) Between- Groups 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 Total body percent fat Baseline 36.8 35.0 0.38 35.0 37.1 38.4 0.45 Month 12 36.8 31.5 — 35.2 31.3 32.1 — Baseline to Month 12 change -0.1 -3.6 < 0.0001 + 0.2 -5.8 -6.3 <0.0001 Post-washout 36.4 32.2 — NA NA NA — Baseline to postwashout change -0.4 -2.8 <0.0001 NA NA NA — Trunk percent fat Baseline 35.3 33.9 0.50 32.5 37.9 36.7 0.23 Month 12 35.4 29.5 — 33.1 30.6 29.0 — Baseline to Month 12 change 0.0 -4.3 <0.0001 + 0.6 -7.3 -7.6 <0.0001 Post-washout 34.9 30.5 — NA NA NA — Baseline to postwashout change -0.3 -3.4 — NA NA NA — Total body percent lean Baseline 60.4 62.2 0.37 62.0 60.0 59.1 0.48 Month 12 60.5 65.7 — 61.8 66.0 65.5 — Baseline to Month 12 change + 0.2 + 3.6 <0.0001 -0.2 + 6.0 + 6.4 <0.0001 Post-washout 60.9 65.0 — NA NA NA — Baseline to postwashout change + 0.4 + 2.8 < 0.0001 NA NA NA — NA=not available In the adult-onset study, significant decreases from baseline to Month 12 in low-density lipoprotein (LDL) cholesterol and LDL:high-density lipoprotein (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 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 Nutropin-treated patients. 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 Nutropin therapy were observed in the two studies. A subsequent 32-week, multicenter, open-label, controlled clinical trial was conducted using Nutropin AQ, Nutropin Depot, or no treatment in adults with both adult-onset and childhood-onset GHD. Subjects were randomized into the three groups to evaluate effects on body composition, including change in visceral adipose tissue (VAT) as determined by computed tomography (CT) scan. For subjects evaluable for change in VAT in the Nutropin AQ (n = 44) and untreated (n = 19) groups, the mean age was 46.2 years and 78% had adult-onset GHD. Subjects in the Nutropin AQ group were treated at doses up to 0.012 mg/kg per day in women (all of whom received estrogen replacement therapy) and men under age 35 years, and up to 0.006 mg/kg per day in men over age 35 years. The mean absolute change in VAT from baseline to Week 32 was -10.7 cm² in the Nutropin AQ group and + 8.4 cm² in the untreated group (p = 0.013 between groups). There was a 6.7% VAT loss in the Nutropin AQ group (mean percent change from baseline to Week 32) compared with a 7.5% increase in the untreated group (p = 0.012 between groups). The effect of reducing VAT in adult GHD patients with Nutropin AQ on long-term cardiovascular morbidity and mortality has not been determined. Table 7: Visceral Adipose Tissue by Computed Tomography Scan: Percent Change and Absolute Change from Baseline to Week 32 in Study 3 Nutropin AQ (n = 44) Untreated (n = 19) Treatment Difference (adjusted mean) p-value Baseline VAT (cm²) (mean) 126.2 123.3 Change in VAT (cm²) (adjusted mean) - 10.7 + 8.4 - 19.1 0.013a Percent change in VAT (adjusted mean) - 6.7 +7.5 - 14.2 0.012a a ANCOVA using baseline VAT as a covariate VAT=visceral adipose tissue.

CLINICAL PHARMACOLOGY Mechanism Of Action SEROSTIM is an anabolic and anticatabolic agent which exerts its influence by interacting with specific receptors on a variety of cell types including myocytes, hepatocytes, adipocytes, lymphocytes, and hematopoietic cells. Some, but not all of its effects, are mediated by insulin-like growth factor-1 (IGF-1). Pharmacodynamics Effects On Protein, Lipid And Carbohydrate Metabolism A one-week study in 6 patients with HIV-associated wasting has shown that treatment with SEROSTIM 0.1 mg/kg/day improved nitrogen balance, increased protein-sparing lipid oxidation, and had little effect on overall carbohydrate metabolism. Decreases in trunk fat and total body fat, and increases in lean body mass were observed during two double-blind, placebo-controlled studies wherein SEROSTIM vs. placebo were administered daily for 12 weeks to patients with HIV Lipodystrophy [see Clinical Studies]. Effects On Nitrogen And Mineral Retention In the one-week study in 6 patients with HIV-associated wasting, treatment with SEROSTIM resulted in the retention of phosphorous, potassium, nitrogen, and sodium. The ratio of retained potassium and nitrogen during SEROSTIM therapy was consistent with retention of these elements in lean tissue. Physical Performance Cycle ergometry work output and treadmill performance were examined in separate 12-week, placebo-controlled trials [see Clinical Studies]. In both studies, work output improved significantly in the group receiving SEROSTIM 0.1 mg/kg/day subcutaneously vs placebo. Isometric muscle performance, as measured by grip strength dynamometry, declined, probably as a result of a transient increase in tissue turgor known to occur with SEROSTIM therapy. Pharmacokinetics Absorption The absolute bioavailability after subcutaneous administration was determined to be 70 to 90%. The mean t½ after subcutaneous administration is significantly longer than that seen after intravenous administration in normal male volunteers down-regulated with somatostatin (approximately 4.0 hrs. vs. 0.6 hrs.), indicating that the subcutaneous absorption of somatropin is a rate-limiting process. Distribution The steady-state volume of distribution (Mean ± SD) following intravenous administration of somatropin in normal male volunteers is 12.0 ± 1.08 L. Metabolism Although the liver plays a role in the metabolism of GH, GH is primarily cleaved in the kidney. GH undergoes glomerular filtration and, after cleavage within the renal cells, the peptides and amino acids are returned to the systemic circulation. Elimination The t½ in nine patients with HIV-associated wasting with an average weight of 56.7 ± 6.8 kg, given a fixed dose of 6.0 mg somatropin subcutaneously was 4.28 ± 2.15 hrs, similar to that observed in normal male volunteers. The renal clearance of r-hGH after subcutaneous administration in nine patients with HIV-associated wasting was 0.0015 ± 0.0037 L/h. No significant accumulation of r-hGH appears to occur after 6 weeks of daily dosing as indicated. Specific Populations Pediatric: Available evidence suggests that r-hGH clearances are similar in adults and children, but no pharmacokinetic studies have been conducted in children with HIV. Gender: Biomedical literature indicates that a gender-related difference in the mean clearance of r-hGH could exist (clearance of r-hGH in males > clearance of r-hGH in females). However, no gender-based analysis is available in normal volunteers or patients infected with HIV. Race: No studies have been conducted to determine the effect of race on the pharmacokinetics of SEROSTIM. Renal Impairment: Subjects with chronic renal failure tend to have decreased somatropin clearance compared to those with normal renal function. However, no studies have been conducted to determine the effect of renal impairment on the pharmacokinetics of SEROSTIM. Hepatic Impairment: No studies have been conducted to determine the effect of hepatic impairment on the pharmacokinetic of SEROSTIM. Clinical Studies HIV-Associated Wasting Or Cachexia The clinical efficacy of SEROSTIM in HIV-associated wasting or cachexia was assessed in two placebo-controlled trials. All study subjects received concomitant antiretroviral therapy. There was no increase in the incidence of Kaposi's sarcoma (KS), lymphoma, or in the progression of cutaneous Kaposi's sarcoma in clinical studies of SEROSTIM. Patients with internal KS lesions were excluded from the studies. Potential effects on other malignancies are unknown. Clinical Trial 1 A 12-week, randomized, double-blind, placebo-controlled study followed by an open-label extension phase enrolled 178 patients with severe HIV wasting taking nucleoside analogue therapy (pre-HAART era). The primary endpoint was body weight. Body composition was assessed using dual energy X-ray absorptiometry (DXA) and physical function was assessed by treadmill exercise testing. Patients meeting the inclusion/exclusion criteria were treated with either placebo or SEROSTIM 0.1 mg/kg daily. Ninety-six percent (96%) were male. The average baseline CD4 count/microliter was 85. The results from one hundred forty (140) evaluable patients were analyzed (those completing the 12-week course of treatment and who were at least 80% compliant with study drug). After 12 weeks of therapy, the mean difference in weight increase between the SEROSTIM-treated group and the placebo-treated group was 1.6 kg (3.5 lb). Mean difference in lean body mass (LBM) change between the SEROSTIM-treated group and the placebo-treated group was 3.1 kg (6.8 lbs) as measured by DXA. Mean increase in weight and LBM, and mean decrease in body fat, were significantly greater in the SEROSTIM-treated group than in the placebo group (p=0.011, p < 0.001, p < 0.001, respectively) after 12 weeks of treatment (Figure 1). There were no significant changes with continued treatment beyond 12 weeks suggesting that the original gains of weight and LBM were maintained (Figure 1). Treatment with SEROSTIM resulted in a significant increase in physical function as assessed by treadmill exercise testing. The median treadmill work output increased by 13% (p=0.039) at 12 weeks in the group receiving SEROSTIM (Figure 2). There was no improvement in the placebo-treated group at 12 weeks. Changes in treadmill performance were significantly correlated with changes in LBM. Figure 1: Mean Changes in Body Composition Figure 2: Median Treadmill Work Output Clinical Trial 2 A 12-week, randomized, double-blind, placebo-controlled study enrolled 757 patients with HIV-associated wasting, or cachexia. The primary efficacy endpoint was physical function as measured by cycle ergometry work output. Body composition was assessed using bioelectrical impedance spectroscopy (BIS) and also by dual energy X-ray absorptiometry (DXA) at a subset of centers. Patients meeting the inclusion/exclusion criteria were treated with either placebo, approximately 0.1 mg/kg every other day (qod) of SEROSTIM, or approximately 0.1 mg/kg daily at bedtime of SEROSTIM. All results were analyzed in intent-to-treat populations (for cycle ergometry work output, n=670). Ninety-one percent (91%) were male and 88% were on HAART anti-retroviral therapy. The average baseline CD4 count/μL was 446. Six hundred forty-six patients (646) completed the 12-week study and continued in the SEROSTIM treatment extension phase of the trial. Clinical Trial 2 results are summarized in Tables 4 and 5: Table 4: Mean (Median) of Cycle Work Output (kJ) Response after 12 weeks of Treatment ITT Population Placebo Half-Dose SEROSTIMb Full-Dose SEROSTIMa Cycle work output (kJ) n=222 n=230 n=218 Baseline 25.92 (25.05) 27.79 (26.65) 27.57 (26.30) Change from baseline -0.05 (-0.25) 2.48 (2.30) 2.52 (2.40) Percent change from baseline 0.2% 8.9% 9.1% Difference from Placebo Mean (2-sided 95% C.I.) - 2.53c (0.81, 4.25) 2.57c (0.83, 4.31) Median - 2.55 2.65 a approximately 0.1 mg/kg daily b approximately 0.1 mg/kg every other day c p < 0.01 Table 5: Mean (Median) Change from Baseline for Lean Body Mass, Fat Mass and Body Weight Placebo Half-Dose SEROSTIMb Full-Dose SEROSTIMa N Mean (Median) n Mean (Median) n Mean (Median) Lean body mass (kg) (by BIS) 222 0.97 (0.67) 223 3.89 (3.65) 205 5.84 (5.47) Fat mass (kg) (by DXA) 94 0.03 (0.01) 100 -1.25 (-1.23) 85 -1.72 (-1.51) Body weight (kg) 247 0.69 (0.68) 257 2.18 (2.15) 253 2.79 (2.65) a approximately 0.1 mg/kg daily b approximately 0.1 mg/kg every other day The mean maximum cycle work output until exhaustion increased after 12 weeks by 2.57 kilojoules (kJ) in the SEROSTIM 0.1 mg/kg daily group (p < 0.01) and by 2.53 kJ in the SEROSTIM 0.1 mg/kg every other day group (p < 0.01) compared with placebo (Table 4). Cycle work output improved approximately 9% in both active treatment arms and decreased < 1% in the placebo group. Lean body mass (LBM) and body weight (BW) increased, and fat mass decreased, in a dose-related fashion after treatment with SEROSTIM and placebo (Table 5). The LBM results obtained by BIS were confirmed with DXA. Patients' perceptions of the impact of 12 weeks of treatment on their wasting symptoms as assessed by the Bristol-Meyers Anorexia/Cachexia Recovery Instrument improved with both doses of SEROSTIM in Clinical Trial 2. Extension Phase: All patients (n=646) completing the 12-week placebo-controlled phase of Clinical Trial 2 continued SEROSTIM treatment into an extension phase. Five hundred and forty eight of these patients completed an additional 12 weeks of active treatment. In these patients, changes in cycle ergometry work output, LBM, BW, and fat mass either improved further or were maintained with continued SEROSTIM treatment.

CLINICAL PHARMACOLOGY 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 Pharmacodynamics]. 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]. 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 t½ 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 t½ 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 t½ 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 (μg/L) Tmax (hr) t½ (hr) AUC 0-∞ (μg•hr/L) CL/F sc (mL/[hr• kg]) MEANb 71.1 3.9 2.3 677 150 CV% 17 56 18 13 13 aBased on current International Standard of 3 IU = 1 mg. bn = 36. Abbreviations: AUC 0-∞ = area under the curve, C max =maximum concentration, CL/F sc = systemic clearance, CV% = coefficient of variation in %; SC = subcutaneous, F sc = subcutaneous bioavailability (not determined), t ½= half-life. Figure 1 : Single Dose Mean Growth Hormone Concentrations in Healthy Adult Males Clinical Studies Pubertal Patients With Growth Hormone Deficiency (GHD) One open label, multicenter, randomized clinical trial of two dosages of Nutropin was performed in pubertal patients with GHD. Ninety-seven patients (mean age 13.9 years, 83 male, 14 female) currently being treated with approximately 0.3 mg/kg/wk of GH were randomized to 0.3 mg/kg/wk or 0.7 mg/kg/wk Nutropin doses. All patients were already in puberty (Tanner stage ≥ 2) and had bone ages ≤ 14 years in males or ≤ 12 years in females. Mean baseline height standard deviation score (SDS) 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 3 :Last Measured Height* by Sex and Nutropin Dose for Pubertal Patients with GHD Age (yr) Last Measured Height* (cm) Height Difference Between Groups (cm) 0.3 mg/kg/wk 0.7 mg/kg/wk Mean ± SD (range) Mean ± SD Mean ± SD Mean ± SE Male 17.2 ± 1.3 170.9 ± 7.9 174.5 ± 7.9 3.6 ± 1.7 (13.6 to 19.4) (n=42) (n= 41) Female 15.8 ± 1.8 154.7 ± 6.3 157.6 ± 6.3 2.9 ± 3.4 (11.9 to 19.3) (n=7) (n = 7) *Adjusted for baseline height The mean height SDS at last measured height (n = 97) was -0.7 ± 1.0 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 Nutropin treatment (15/49 patients 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 cm 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 SDS above -1.0 were able to attain normal adult heights with the 0.3 mg/kg/wk dose of Nutropin (mean height SDS at near-adult height = -0.1, n = 15). Thirty-one patients had bone mineral density (BMD) determined by dual energy x-ray absorptiometry (DEXA) scans at study conclusion. The two dose groups did not differ significantly in mean SDS 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 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. Pediatric Patients With Growth Failure Secondary To Chronic Kidney Disease (CKD) Two multicenter, randomized, controlled clinical trials were conducted to determine whether treatment with Nutropin prior to renal transplantation in patients with CKD could improve their growth rates and height deficits. One study was a double-blind, 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 (0.35 mg/kg/week) administered daily by subcutaneous injection. Combining the data from those patients completing two years in the two controlled studies results in 62 patients treated with Nutropin and 28 patients in the control groups (either placebo-treated or untreated). The mean first year growth rate was 10.8 cm/yr for Nutropin-treated patients, compared with a mean growth rate of 6.5 cm/yr for placebo/untreated controls (p < 0.00005). The mean second year growth rate was 7.8 cm/yr for the Nutropin-treated group, compared with 5.5 cm/yr for controls (p < 0.00005). There was a significant increase in mean height SDS in the Nutropin group (-2.9 at baseline to -1.5 at Month 24, n = 62) but no significant change in the controls (-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 Nutropin-treated patients (n = 27) suggests that Nutropin stimulates growth beyond two years. However, there are no control data for the third year because control patients crossed over to Nutropin treatment after two years of participation. The gains in height were accompanied by appropriate advancement of skeletal age. These data demonstrate that Nutropin therapy improves growth rate and corrects the acquired height deficit associated with CKD. The North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) has reported data for growth post-transplant in children who did not receive GH prior to transplantation as well as children who did receive Nutropin during the clinical trials prior to transplantation. The average change in height SDS during the initial two years post-transplant was 0.15 for the 2,391 patients who did not receive GH pre-transplant and 0.28 for the 57 patients who did1. For patients who were followed for 5 years post-transplant, the corresponding changes in height SDS were also similar between groups. Pediatric Patients With Turner Syndrome (TS) Three US studies, two long-term, open-label, multicenter, historically controlled studies (Studies 1 and 2), and one long-term, randomized, dose-response study (Study 3) and one Canadian, long-term, randomized, open-label, multicenter, concurrently controlled study, were conducted to evaluate the efficacy of somatropin treatment of short stature due to TS. In the US Studies 1 and 2, the effect of long-term GH treatment (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 TS who received no growth-promoting therapy. In Study 1, estrogen treatment was delayed until patients were at least age 14. GH therapy resulted in a mean adult height gain of 7.4 cm (mean duration of GH therapy of 7.6 years) vs. matched historical controls by ANCOVA. In Study 2, patients treated with early Nutropin therapy (before 11 years of age) 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. Compared with matched historical controls, early Nutropin therapy (mean duration of 5.6 years) combined with estrogen replacement at age 12 years resulted in an adult height gain of 5.9 cm (n = 26), whereas girls who initiated estrogen at age 15 years (mean duration of Nutropin therapy 6.1 years) had a mean adult height gain of 8.3 cm (n = 29). Patients who initiated Nutropin after age 11 (mean age 12.7 years; mean duration of Nutropin therapy 3.8 years) had a mean adult height gain of 5.0 cm (n = 51). Thus, in Studies 1 and 2, the greatest improvement in adult height was observed in patients who received early GH treatment and estrogen after age 14 years. In Study 3, a randomized, blinded dose-response study, patients were treated from a mean age of 11.1 years for a mean duration of 5.3 years with a weekly GH dose of either 0.27 mg/kg or 0.36 mg/kg administered in divided doses 3 or 6 times weekly. The mean near-final height of GH-treated patients was 148.7 ± 6.5 cm (n = 31). When compared to historical control data, the mean gain in adult height was approximately 5 cm. The Canadian randomized study compared near-adult height outcomes for GH-treated patients to those of a concurrent control group who received no injections. The somatropin-treated patients received a dosage of 0.3 mg/kg/week given in divided doses 6 times per week from a mean age of 11.7 years for a mean duration of 4.7 years. Puberty was induced with a standardized estrogen regimen initiated at 13 years of age for both treatment groups. The somatropin-treated group (n =27) attained a mean (±SD) near final height of 146.0 ± 6.2 cm; the untreated control group (n =19) attained a near final height of 142.1 ± 4.8 cm. By ANCOVA (with adjustments for baseline height and mid-parental height), the effect of GH-treatment was a mean height increase of 5.4 cm (p = 0.001). In summary, patients with TS (total n = 181 from the 4 studies above) treated to adult height achieved statistically significant average height gains ranging from 5.0-8.3 cm. Table 4 : Summary of Efficacy Results in Turner Syndromea Study Group Study Designb N at Adult Height GH Age (yr) Estrogen Age (yr) GH Duration (yr) Adult Height Gain (cm)c US 1 MHT 17 9.1 15.2 7.6 7.4 US 2 A* MHT 29 9.4 15.0 6.1 8.3 B* 26 9.6 12.3 5.6 5.9 C* 51 12.7 13.7 3.8 5.0 US 3 RDT 31 11.1 8-13.5 5.3 ~5d Canadian RCT 27 11.7 13 4.7 5.4 aData shown are mean values. bRCT: randomized controlled trial; MHT: matched historical controlled trial; RDT: randomized dose-response trial. cAnalysis of covariance vs. controls. dCompared with historical data. * A = GH age < 11 yr, estrogen age 15 yr. B =GH age < 11 yr, estrogen age 12 yr. C = GH age > 11 yr, estrogen at Month 12. Pediatric Patient With Idiopathic Short Stature (ISS) A long-term, open-label, multicenter study was conducted to examine the safety and efficacy of Nutropin in pediatric patients with ISS, also called non-growth hormone deficient short stature. For the first year, 122 pre-pubertal subjects over the age of 5 years with stimulated serum GH ≥ 10 ng/mL were randomized into two treatment groups of approximately equal size; one group was treated with Nutropin 0.3 mg/kg weekly divided into three doses per week and the other group served as untreated controls. For the second and subsequent years of the study, all subjects were re-randomized to receive the same total weekly dose of Nutropin (0.3 mg/kg weekly) administered either daily or three times weekly. Treatment with Nutropin was continued until a subject's bone age was > 15.0 years (boys) or > 14.0 years (girls) and the growth rate was < 2 cm/yr, after which subjects were followed until adult height was achieved. The mean baseline values were: height SDS–2.8, IGF-I SDS -0.9, age 9.4 years, bone age 7.8 years, growth rate 4.4 cm/yr, mid-parental target height SDS –0.7, and Bayley-Pinneau predicted adult height SDS –2.3. Nearly all subjects had predicted adult height that was less than mid-parental target height. During the one-year controlled phase of the study, the mean height velocity increased by 0.5 ± 1.8 cm (mean ±SD) in the no-treatment control group and by 3.1 ± 1.7 cm in the Nutropin group (p < 0.0001). For the same period of treatment the mean height SDS increased by 0.4 ± 0.2 and remained unchanged (0.0 ± 0.2) in the control group (p < 0.001). Of the 118 subjects who were treated with Nutropin (70%) reached near-adult height (hereafter called adult height) after 2-10 years of Nutropin therapy. Their last measured height, including post-treatment follow-up, was obtained at a mean age of 18.3 years in males and 17.3 years in females. The mean duration of therapy was 6.2 and 5.5 years, respectively. Adult height was greater than pretreatment predicted adult height in 49 of 60 males (82%) and 19 of 23 females (83%). The mean difference between adult height and pretreatment predicted adult height was 5.2 cm (2.0 inches) in males and 6.0 cm (2.4 inches) in females (p < 0.0001 for both). The table (below) summarizes the efficacy data. Table 5 : Long-Term Efficacy in ISS (Mean ± SD) Characteristic Males (n = 60) Females (n=23) Adult height (cm) 166.3 ± 5.8 153.1 ± 4.8 Pretreatment predicted adult height (cm) 161.1 ± 5.5 147.1 ± 5.1 Adult height minus pretreatment predicted adult height (cm) + 5.2 ± 5.0a +6.0 ± 5.0a Adult height SDS -1.5 ± 0.8 -1.6 ± 0.7 Pretreatment predicted adult height SDS -2.2 ± 0.8 -2.5 ± 0.8 Adult height minus pretreatment predicted adult height SDS + 0.7 ± 0.7a +0.9 ± 0.8a ap < 0.0001 versus zero. Nutropin therapy resulted in an increase in mean IGF-I SDS from –0.9 ± 1.0 to –0.2 ± 0.9 in Treatment Year 1. During continued treatment, mean IGF-I levels remained close to the normal mean. IGF-I SDS above + 2 occurred sporadically in 14 subjects. Adult Growth Hormone Deficiency Two multicenter, double-blind, placebo-controlled clinical trials were conducted in growth  hormone-deficient adults. Study 1 was conducted in subjects with adult-onset GHD (n = 166), mean  age 48.3 years, at doses of 0.0125 or 0.00625 mg/kg/day; doses of 0.025 mg/kg/day were not  tolerated in these subjects. Study 2 was conducted in previously treated subjects with  childhood-onset GHD (n = 64), mean age 23.8 years, at randomly assigned doses of 0.025 or  0.0125 mg/kg/day. The studies were designed to assess the effects of replacement therapy with  Nutropin on body composition. Significant changes from baseline to Month 12 of treatment in body composition (i.e., total body  % fat mass, trunk % fat mass, and total body % 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 % 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 6 : Mean Changes from Baseline to Month 12 in Proportion of Fat and Lean by DEXA for Adult-and Childhood-Onset GHD Studies Proportion Adult Onset (Study 1) Childhood Onset (Study 2) Placebo (n=62) Nutropin (n=63) Between- Groups 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 Total body percent fat Baseline 36.8 35.0 0.38 35.0 37.1 38.4 0.45 Month 12 36.8 31.5 — 35.2 31.3 32.1 — Baseline to Month 12 change -0.1 -3.6 < 0.0001 + 0.2 -5.8 -6.3 < 0.0001 Post-washout 36.4 32.2 — NA NA NA — Baseline to postwashout change -0.4 -2.8 < 0.0001 NA NA NA — Trunk percent fat Baseline 35.3 33.9 0.50 32.5 37.9 36.7 0.23 Month 12 35.4 29.5 — 33.1 30.6 29.0 — Baseline to Month 12 change 0.0 -4.3 < 0.0001 + 0.6 -7.3 -7.6 < 0.0001 Post-washout 34.9 30.5 — NA NA NA — Baseline to postwashout change -0.3 -3.4 — NA NA NA — Total body percent lean Baseline 60.4 62.2 0.37 62.0 60.0 59.1 0.48 Month 12 60.5 65.7 — 61.8 66.0 65.5 — Baseline to Month 12 change +0.2 + 3.6 < 0.0001 -0.2 + 6.0 + 6.4 < 0.0001 Post-washout 60.9 65.0 — NA NA NA — Baseline to postwashout change + 0.4 + 2.8 < 0.0001 NA NA NA — NA=not available In the adult-onset study, significant decreases from baseline to Month 12 in low-density lipoprotein (LDL) cholesterol and LDL:high-density lipoprotein (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 toMonth 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 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 Nutropin-treated patients. 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 Nutropin therapy were observed in the two studies. A subsequent 32-week, multicenter, open-label, controlled clinical trial was conducted using Nutropin AQ, Nutropin Depot, or no treatment in adults with both adult-onset and childhood-onset GHD. Subjects were randomized into the three groups to evaluate effects on body composition, including change in visceral adipose tissue (VAT) as determined by computed tomography (CT) scan. For subjects evaluable for change in VAT in the Nutropin AQ (n = 44) and untreated (n =19) groups, the mean age was 46.2 years and 78% had adult-onset GHD. Subjects in the Nutropin AQ group were treated at doses up to 0.012 mg/kg per day in women (all of whom received estrogen replacement therapy) and men under age 35 years, and up to 0.006 mg/kg per day in men over age 35 years. The mean absolute change in VAT from baseline to Week 32 was -10.7 cm² in the Nutropin AQ group and + 8.4 cm² in the untreated group (p = 0.013 between groups). There was a 6.7% VAT loss in the Nutropin AQ group (mean percent change from baseline to Week 32) compared with a 7.5% increase in the untreated group (p = 0.012 between groups). The effect of reducing VAT in adult GHD patients with Nutropin AQ on long-term cardiovascular morbidity and mortality has not been determined. Table 7 : Visceral Adipose Tissue by Computed Tomography Scan: Percent Change and Absolute Change from Baseline to Week 32 in Study 3 Nutropin AQ (n = 44) Untreated (n = 19) Treatment Difference (adjusted mean) p-value Baseline VAT (cm²) (mean) 126.2 123.3 Change in VAT (cm²) (adjusted mean) - 10.7 + 8.4 - 19.1 0.013a Percent change in VAT (adjusted mean) - 6.7 +7.5 - 14.2 0.012a aANCOVA using baseline VAT as a covariate VAT = visceral adipose tissue.

Nutropin Depot® [somatropin (rDNA origin) for] Injectable Suspension DESCRIPTION Nutropin Depot® [somatropin (rDNA origin) for injectable suspension] is a long-acting dosage form of recombinant human growth hormone (rhGH). Somatropin 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 human growth hormone. The protein is synthesized by a specific laboratory strain of E. coli as a precursor consisting of the rhGH molecule preceded by the secretion signal from an E. coli protein. This precursor is directed to the plasma membrane of the cell. The signal sequence is removed and the native protein is secreted into the periplasm so that the protein is folded appropriately as it is synthesized. Somatropin is a highly purified preparation. Biological potency is determined using a cell proliferation bioassay. The Nutropin Depot (somatropin rdna origin for inj) formulation consists of micronized particles of rhGH embedded in biocompatible, biodegradable polylactide-coglycolide (PLG) microspheres. Nutropin Depot (somatropin rdna origin for inj) is packaged in vials as a sterile, white to off-white, preservative-free, free-flowing powder. Before administration, the powder is suspended in Diluent for Nutropin Depot (somatropin rdna origin for inj) (a sterile aqueous solution). Each 13.5 mg 3 cc single-use vial of Nutropin Depot (somatropin rdna origin for inj) contains 13.5 mg somatropin, 1.2 mg zinc acetate, 0.8 mg zinc carbonate, and 68.9 mg PLG. Each 18 mg 3 cc single-use vial of Nutropin Depot (somatropin rdna origin for inj) contains 18 mg somatropin, 1.6 mg zinc acetate, 1.1 mg zinc carbonate, and 91.8 mg PLG. Each 22.5 mg 3 cc single-use vial of Nutropin Depot (somatropin rdna origin for inj) contains 22.5 mg somatropin, 2.0 mg zinc acetate, 1.4 mg zinc carbonate, and 114.8 mg PLG. Each dosage size contains an overage of rhGH microspheres to ensure delivery of labeled contents. Each 1.5 mL single-use vial of Diluent for Nutropin Depot (somatropin rdna origin for inj) contains 30 mg/mL carboxymethylcellulose sodium salt, 1 mg/mL polysorbate 20, 9 mg/mL sodium chloride, and sterile water for injection; pH 5.8-7.2.

Nutropin [somatropin (rDNA origin)] Injection DESCRIPTION Nutropin [somatropin (rDNA origin) for injection] is a human growth hormone (hGH) produced by recombinant DNA technology. Nutropin 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 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 is a sterile, white lyophilized powder intended for subcutaneous administration after reconstitution with Bacteriostatic Water for Injection, USP (benzyl alcohol preserved). The reconstituted product is nearly isotonic at a concentration of 5 mg/mL GH and has a pH of approximately 7.4. Each 10 mg Nutropin vial contains 10 mg (approximately 30 IU) somatropin, lyophilized with 90 mg mannitol, 3.4 mg sodium phosphates (0.8 mg sodium phosphate monobasic and 2.6 mg sodium phosphate dibasic), and 3.4 mg glycine. Bacteriostatic Water for Injection, USP is sterile water containing 0.9 percent benzyl alcohol per mL as an antimicrobial preservative packaged in a multidose vial. The diluent pH is 4.5 - 7.0. [See HOW SUPPLIED/Storage and Handling].

Find Lowest Prices on SEROSTIM [somatropin (rDNA origin)] for Injection DESCRIPTION SEROSTIM is a human growth hormone (hGH) produced by recombinant DNA technology. SEROSTIM has 191 amino acid residues and a molecular weight of 22,125 daltons. Its amino acid sequence and structure are identical to the dominant form of human pituitary growth hormone. SEROSTIM is produced by a mammalian cell line (mouse C127) that has been modified by the addition of the hGH gene. SEROSTIM is secreted directly through the cell membrane into the cell-culture medium for collection and purification. SEROSTIM is a sterile lyophilized powder intended for subcutaneous injection after reconstitution to its liquid form. Vials of SEROSTIM contain either 4 mg, 5 mg, or 6 mg. Each vial contains the following: Vials 4 mg 5 mg 6 mg Component Somatropin 4 mg 5 mg 6 mg Sucrose 27.3 mg 34.2 mg 41 mg Phosphoric acid 0.9 mg 1.2 mg 1.4 mg Each 4 mg multi-vial is supplied in a combination package with Bacteriostatic Water for Injection, USP (0.9% Benzyl Alcohol). The pH is adjusted with sodium hydroxide of phosphoric acid to give a pH of 7.4 to 8.5 after reconstitution. Each 5 mg single-use vial is supplied in a combination package with Sterile Water for Injection, USP. The pH is adjusted with sodium hydroxide or phosphoric acid to give a pH of 6.5 to 8.5 after reconstitution. Each 6 mg single-use vial is supplied in a combination package with Sterile Water for Injection, USP. The pH is adjusted with sodium hydroxide of phosphoric acid to give a pH of 7.4 to 8.5 after reconstitution.

Find Lowest Prices on Nutropin AQ [somatropin (rDNA origin)] Injection DESCRIPTION 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].

INDICATIONS Nutropin Depot® [somatropin (rDNA origin) for injectable suspension] is indicated for the long-term treatment of growth failure due to a lack of adequate endogenous GH secretion. Considerations for use: - As with any GH treatment, patients should be monitored closely throughout therapy for growth response to Nutropin Depot (somatropin (rdna origin) for inj) . Failure to respond adequately requires careful assessment, as described under DOSAGE AND ADMINISTRATION. Patients for whom no discernible cause is found should be considered for a course of treatment with a daily form of rhGH. Experience in patients who were treated with daily GH and switched to Nutropin Depot is limited. DOSAGE AND ADMINISTRATION The Nutropin Depot (somatropin (rdna origin) for inj) dosage and administration schedule should be individualized for each patient. Response to GH therapy in pediatric patients tends to decrease over 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, undernutrition, and advanced bone age. Once-Monthly Injection - It is recommended that an SC injection at a dosage of 1.5 mg/kg body weight be administered on the same day of each month. Dosages above the recommended once-monthly regimen have not been studied in clinical trials. Note: subjects over 15 kg will require more than one injection per dose. Twice-Monthly Injections - It is recommended that an SC injection at a dosage of 0.75 mg/kg body weight be administered twice each month on the same days of each month (e.g., Days 1 and 15 of each month). Dosages above the recommended twice-monthly regimen have not been studied in clinical trials. Note: subjects over 30 kg will require more than one injection per dose. The table below indicates the required number of injections per dose. Patient Weight (kg) Number of Injections Per Dose 0.75 mg/kg twice monthly 1.5 mg/kg once monthly ≤ 15 1 1 > 15-30 1 2 > 30-45 2 3 > 45-60 2 * > 60 3 * *Twice-monthly dosing recommended Preparation of Dose Nutropin Depot (somatropin (rdna origin) for inj) powder may only be suspended in Diluent for Nutropin Depot supplied in the kit and administered with the supplied needles. 1. Using the chart below, determine the volume of diluent needed to suspend Nutropin Depot (somatropin (rdna origin) for inj) . Withdraw the diluent into a 3 cc syringe using the needle supplied in the kit. Only the diluent supplied in the kit should be used for reconstitution, and any remaining diluent should be discarded. Vial Size (mg somatropin) Volume of Diluent to Be Added (mL) 13.5 0.8 18 1.0 22.5 1.2 Note: Since the suspension is viscous and prevents complete withdrawal of the entire vial contents, the vials are overfilled to ensure delivery of the labeled amount of somatropin. Using these diluent volumes for final suspension results in a final concentration of 19 mg/mL somatropin in each vial size. 2. Inject the diluent into the vial against the vial wall. Swirl the vial vigorously for up to 2 minutes to disperse the powder in the diluent. Mixing is complete when the suspension appears uniform, thick, and milky, and all the powder is fully dispersed. Do not store the vial after reconstitution or the suspension may settle. 3. Withdraw the required dose. Only one vial should be used for each injection. Replace the needle with a new needle from the kit and administer the dose immediately to avoid settling of the suspension in the syringe. Deliver the dose from the syringe at a continuous rate over not more than 5 seconds. Discard unused vial contents as the product contains no preservative. An extra needle has been provided in the kit. Stability and Storage Before Suspension - Nutropin Depot (somatropin (rdna origin) for inj) and diluent vials must be stored at 2-8°C/36-46°F (under refrigeration). Avoid freezing the vials of Nutropin Depot (somatropin (rdna origin) for inj) and Diluent for Nutropin Depot (somatropin (rdna origin) for inj) . Do not expose the Nutropin Depot (somatropin (rdna origin) for inj) vial to temperatures above 25°C (77°F). Expiration dates are stated on the labels. After Suspension - Because Nutropin Depot (somatropin (rdna origin) for inj) contains no preservatives, all injections must be given immediately. Do not allow the suspension to settle prior to withdrawal of the dose. Suspended solution cannot be stored or used to suspend another vial of Nutropin Depot (somatropin (rdna origin) for inj) . HOW SUPPLIED Nutropin Depot (somatropin (rdna origin) for inj) is supplied as single-use vials with 13.5 mg, 18 mg, or 22.5 mg sterile, preservative-free somatropin powder per vial. Each 13.5 mg kit contains one single-use 13.5 mg vial of Nutropin Depot® [somatropin (rDNA origin) for injectable suspension], one 1.5 mL single-use vial of Diluent for Nutropin Depot (somatropin (rdna origin) for inj) , and three 21-gauge, 1/2" needles: NDC 50242-032-35. Each 18 mg kit contains one single-use 18 mg vial of Nutropin Depot® [somatropin (rDNA origin) for injectable suspension], one 1.5 mL single-use vial of Diluent for Nutropin Depot (somatropin (rdna origin) for inj) , and three 21-gauge, 1/2" needles: NDC 50242-034-41. Each 22.5 mg kit contains one single-use 22.5 mg vial of Nutropin Depot® [somatropin (rDNA origin) for injectable suspension], one 1.5 mL single-use vial of Diluent for Nutropin Depot (somatropin (rdna origin) for inj) , and three 21-gauge, 1/2" needles: NDC 50242-036-54. Nutropin Depot™ [somatropin (rDNA origin) for injectable suspension] and Diluent for Nutropin Depot (somatropin (rdna origin) for inj) are manufactured for: Genentech, Inc. 1 DNA Way, South San Francisco, CA 94080-4990.

INDICATIONS Pediatric Patients Growth Hormone Deficiency (GHD) Nutropin® 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 is indicated for the treatment of growth failure associated with CKD up to the time of renal transplantation. Nutropintherapy should be used in conjunction with optimal management of CKD. Idiopathic Short Stature (ISS) Nutropin 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 is indicated for the treatment of short stature associated with TS. Adult Patients Nutropin is indicated for the replacement of endogenous GH in adults with GHD who meet eitherof 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. DOSAGE AND ADMINISTRATION For subcutaneous injection. Therapy with Nutropin should be supervised by a physician who is experienced in the diagnosisand 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. Dosing for Pediatric Patients Nutropin 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 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 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 least3 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. Dosing for Adult Patients Adult Growth Hormone Deficiency (GHD) Either of two approaches to Nutropin 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 inpatients ≤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 bodyweight. 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. Preparation and Administration After the dose has been determined, reconstitute as follows: each 10 mg vial should be reconstituted with 1 to 10 mL of Bacteriostatic Water for Injection, USP (benzyl alcohol preserved), only. The pH of Nutropin after reconstitution with Bacteriostatic Water for Injection, USP (benzylalcohol preserved), is approximately 7.4. For use in newborns or if sensitivity to the diluent occurs, Nutropin may be reconstituted with Sterile Water for Injection, USP. When Nutropin is reconstituted in this manner, the reconstituted solution should be used immediately and any unused solution should be discarded. [see WARNINGS AND PRECAUTIONS]. To prepare the Nutropin solution, inject the Bacteriostatic Water for Injection, USP (benzylalcohol preserved) into the Nutropin vial, aiming the stream of liquid against the glass wall. Then swirl the product 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. The Nutropin solution should be clear immediately after reconstitution. Occasionally, after refrigeration, you may notice that small colorless particles of protein are present in the Nutropin solution. This is not unusual for solutions containing proteins. If the solution is cloudy immediately after reconstitution or refrigeration, the contents MUST NOT be injected. Before needle insertion, wipe the septum of 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. It is recommended that Nutropin 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. Injection sites should always be rotated to avoid lipotrophy. HOW SUPPLIED Dosage Forms And Strengths Nutropin 10 mg vial and 10 mL diluent. 10 mg per vial and one 10 mL multiple dose vial of NDC 50242-018-21 Bacteriostatic Water for Injection, USP (benzyl alcohol preserved) Storage and Handling Before Reconstitution - Nutropin and Bacteriostatic Water for Injection, USP (benzyl alcohol preserved), must be stored at 2-8°C/36-46°F (under refrigeration). 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 stored at 2-8°C/36-46°F (under refrigeration). Avoid freezing the reconstituted vial of Nutropin and Bacteriostatic Water for Injection, USP (benzyl alcohol preserved). When reconstituting with Sterile Water for Injection, USP, use only one dose per Nutropin vial and discard the unused portion. Manufactured by: Genentech, Inc., A Member of the Roche Group 1 DNA Way, South San Francisco, CA 94080-4990. Bacteriostatic Water for Injection, USP (benzyl alcohol preserved), Manufactured for: Genentech, Inc. A Member of the Roche Group

INDICATIONS SEROSTIM (somatropin) is indicated for the treatment of HIV patients with wasting or cachexia to increase lean body mass and body weight, and improve physical endurance. Concomitant antiretroviral therapy is necessary. DOSAGE AND ADMINISTRATION SEROSTIM is administered by subcutaneous injection. SEROSTIM therapy should be carried out under the regular guidance of a physician who is experienced in the diagnosis and management of HIV infection. HIV-associated Wasting Or Cachexia The usual starting dose of SEROSTIM is 0.1 mg/kg subcutaneously once daily (up to a total dose of 6 mg). SEROSTIM should be administered subcutaneously once daily at bedtime according to the following body weight-based dosage recommendations: Weight Range Dose > 55kg ( > 121 lb) 6 mg* SC daily 45-55 kg (99-121 lb) 5 mg* SC daily 35-45 kg (75-99 lb) 4 mg* SC daily < 35 kg ( < 75 lb) 0.1 mg/kg SC daily *Based on an approximate daily dosage of 0.1 mg/kg. Treatment with SEROSTIM 0.1 mg/kg every other day was associated with fewer side effects, and resulted in a similar improvement in work output, as compared with SEROSTIM 0.1 mg/kg daily. Therefore, a starting dose of SEROSTIM 0.1 mg/kg every other day should be considered in patients at increased risk for adverse effects related to recombinant human growth hormone therapy (i.e., glucose intolerance). In general, dose reductions (i.e., reducing the total daily dose or the number of doses per week) should be considered for side effects potentially related to recombinant human growth hormone therapy. Most of the effect of SEROSTIM on work output and lean body mass was apparent after 12 weeks of treatment. The effect was maintained during an additional 12 weeks of therapy. There are no safety or efficacy data available from controlled studies in which patients were treated with SEROSTIM continuously for more than 48 weeks. There are no safety or efficacy data available from trials in which patients with HIV wasting or cachexia were treated intermittently with SEROSTIM. Preparation And Administration Each vial of SEROSTIM 5 mg or 6 mg is reconstituted with 0.5 to 1 mL Sterile Water for Injection, USP. Each vial of SEROSTIM 4 mg is reconstituted in 0.5 to 1 mL of Bacteriostatic Water for Injection, USP (0.9% Benzyl Alcohol preserved). For patients sensitive to Benzyl Alcohol, SEROSTIM may be reconstituted with Sterile Water for Injection, USP [see Pediatric Use]. When SEROSTIM is reconstituted with Sterile Water for Injection, USP, the reconstituted solution should be used immediately and any unused portion should be discarded. When SEROSTIM is reconstituted with Bacteriostatic Water for Injection, USP (0.9% Benzyl Alcohol preserved) the reconstituted solution may be refrigerated (2-8°C/36-46°F) for up to 14 days. Approximately 10% mechanical loss can be associated with reconstitution and administration from multi-dose vials. To reconstitute SEROSTIM, inject the diluent into the vial of SEROSTIM aiming the liquid against the glass vial wall. Swirl the vial with a GENTLE rotary motion until contents are dissolved completely. DO NOT SHAKE. Parenteral drug products should always be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. SEROSTIM MUST NOT BE INJECTED if the solution is cloudy or contains particulate matter. Use it only if it is clear and colorless. SEROSTIM can be administered using (1) a standard sterile, disposable syringe and needle, (2) a compatible SEROSTIM needle-free injection device or (3) a compatible SEROSTIM needle injection device. For proper use, refer to the Instructions for Use provided with the administration device. Injection sites, which may be located on the thigh, upper arm, abdomen or buttock, should be rotated to avoid local irritation. HOW SUPPLIED Dosage Forms And Strengths Single-use administration (to be reconstituted with Sterile Water for Injection): SEROSTIM 5 mg per vial SEROSTIM 6 mg per vial Multi-use administration (to be reconstituted with Bacteriostatic Water for Injection): SEROSTIM 4 mg per vial SEROSTIM is available in the following forms: SEROSTIM single-use vials containing 5 mg with Sterile Water for Injection, USP. Package of 7 vials. NDC 44087-0005-7 SEROSTIM single-use vials containing 6 mg with Sterile Water for Injection, USP. Package of 7 vials. NDC 44087-0006-7 SEROSTIM multiple-use vials containing 4 mg with Bacteriostatic Water for Injection, USP (0.9% Benzyl Alcohol). Package of 7 vials. NDC 44087-0004-7 Storage And Handling Before reconstitution: Vials of SEROSTIM and diluent should be stored at room temperature, (15°30°C/59°-86°F). Expiration dates are stated on product labels. Single-use vials: After reconstitution with Sterile Water for Injection, USP, the reconstituted solution should be used immediately and any unused portion should be discarded. Multi-use vials: After reconstitution with Bacteriostatic Water for Injection, USP (0.9% Benzyl Alcohol), the reconstituted solution should be stored under refrigeration (2-8°C/36-46°F) for up to 14 days. Avoid freezing reconstituted vials of SEROSTIM. Manufactured for: EMD Serono, Inc., Rockland, MA 02370. Revised: May 2017

INDICATIONS 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. 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. DOSAGE AND ADMINISTRATION 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. 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. 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. 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]. 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. HOW SUPPLIED Dosage Forms And Strengths Nutropin AQ is available in the following pen cartridge and NuSpin forms: Pen Cartridge: 10 mg/2 mL (yellow color band), and 20 mg/2 mL (purple color band) NuSpin: 5 mg/2 mL (clear device), 10 mg/2 mL (green device), and 20 mg/2 mL (blue device) Pen Cartridge (2 mL): 10 mg NDC 50242-043-14 20 mg NDC 50242-073-01 Nutropin AQ NuSpin (2 mL): 5 mg NDC 50242-075-01 10 mg NDC 50242-074-01 20 mg NDC 50242-076-01 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. Manufactured by: Genentech, Inc., A Member of the Roche Group, 1 DNA Way, South San Francisco, CA 94080–4990. Revised: March 2014

PATIENT INFORMATION Patients being treated with Nutropin Depot (somatropin (rdna origin) for inj) and/or their parents should be informed of 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 Patient Information Insert. This information is intended to aid in the safe and effective administration of the medication. It is not a disclosure of all possible adverse or intended effects. If home use is prescribed, a puncture-resistant container for the disposal of used syringes and needles should be recommended to the patient. Patients and/or parents should be thoroughly instructed in the importance of proper disposal and cautioned against any reuse of needles and syringes (see Patient Information Insert).

PATIENT INFORMATION Patients being treated with Nutropin (and/or their parents) should be informed about the potential benefits and risks associated with Nutropin treatment [see ADVERSE REACTIONS], 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 should receive appropriate training and instruction on the proper use of Nutropin 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.

PATIENT INFORMATION Patients being treated with SEROSTIM should be informed of the potential benefits and risks associated with treatment. Patients should be instructed to contact their physician should they experience any side effects or discomfort during treatment with SEROSTIM. It is recommended that SEROSTIM be administered using sterile, disposable syringes and needles. Patients should be thoroughly instructed in the importance of proper disposal and cautioned against any reuse of needles and syringes. An appropriate container for the disposal of used syringes and needles should be employed. Patients should be instructed to rotate injection sites to avoid localized tissue atrophy. Never Share a SEROSTIM Pen or Needle Between Patients Counsel patients that they should never share SEROSTIM or SEROSTIM injection devices with another person, even if the needle or nozzle is changed. Sharing of SEROSTIM or SEROSTIM injection devices between patients may pose a risk of transmission of infection. Patients should be informed about the management of common side effects related to tissue turgor, glucose intolerance and musculoskeletal discomfort.

PATIENT 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 [see ADVERSE REACTIONS], 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.

OVERDOSE The recommended dosage of Nutropin Depot (somatropin (rdna origin) for inj) should not be exceeded. Acute overdosage could lead to fluid retention, headache, nausea, vomiting, and/or hyperglycemia. Long-term overdosage could result in signs and symptoms of gigantism and/or acromegaly, consistent with the known effects of excess GH. (See recommended dosage instructions given below.) CONTRAINDICATIONS Growth hormone should not be initiated to treat patients with acute critical illness due to complications following open heart or abdominal surgery, multiple accidental trauma, or to patients having acute respiratory failure. Two placebo-controlled clinical trials in non-growth hormone-deficient adult patients (n = 522) with these conditions revealed a significant increase in mortality (41.9% vs. 19.3%) among somatropin-treated patients (doses 5.3-8 mg/day) compared to those receiving placebo (see WARNINGS). Nutropin Depot (somatropin (rdna origin) for inj) should not be used for growth promotion in pediatric patients with closed epiphyses. Nutropin Depot (somatropin (rdna origin) for inj) should not be used in patients with active neoplasia. GH therapy should be discontinued if evidence of neoplasia develops. Growth hormone is contraindicated in patients with Prader-Willi syndrome who are severely obese or have severe respiratory impairment (see WARNINGS). Unless patients with Prader-Willi syndrome also have a diagnosis of growth hormone deficiency, Nutropin Depot (somatropin (rdna origin) for inj) is not indicated for the long term treatment of pediatric patients who have growth failure due to genetically confirmed Prader-Willi syndrome.

OVERDOSE 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]. CONTRAINDICATIONS 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. 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 (41.9% vs. 19.3%) among somatropin-treated patients (doses 5.3-8 mg/day)compared to those receiving placebo [see WARNINGS AND PRECAUTIONS]. 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 is not indicated for the treatment of pediatric patients who have growth failure due to genetically confirmed PWS. [see WARNINGS AND PRECAUTIONS]. Active MalignancyIn 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. 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. Hypersensitivity Nutropin is contraindicated in patients with a known hypersensitivity to somatropin, excipients, or diluent. Localized reactions are the most common hypersensitivity reaction.

OVERDOSE Short-Term Acute overdosage could lead initially to hypoglycemia and subsequently to hyperglycemia. Long-Term Long-term overdosage could result in signs and symptoms of acromegaly consistent with the known effects of excess growth hormone. CONTRAINDICATIONS Acute Critical Illness Growth hormone therapy should not be initiated in patients with acute critical illness due to complications following open heart or abdominal surgery, multiple accidental trauma or acute respiratory failure [see WARNINGS AND PRECAUTIONS]. Active Malignancy In general, somatropin is contraindicated in the presence of active malignancy. Any preexisting 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 [see WARNINGS AND PRECAUTIONS]. Hypersensitivity SEROSTIM 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]. Diabetic Retinopathy Somatropin is contraindicated in patients with active proliferative or severe non-proliferative diabetic retinopathy.

OVERDOSE 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]. CONTRAINDICATIONS 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. 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 (41.9% vs. 19.3%) among somatropin-treated patients (doses 5.3-8 mg/day) compared to those receiving placebo [see WARNINGS AND PRECAUTIONS]. 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]. 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. 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. Hypersensitivity Nutropin AQ is contraindicated in patients with a known hypersensitivity to somatropin, excipients, or diluent. Localized reactions are the most common hypersensitivity reaction.

SIDE EFFECTS As with all protein pharmaceuticals, patients may develop antibodies to the protein. GH antibody-binding capacities below 2 mg/L have not been associated with growth attenuation. In some cases when binding capacity exceeds 2 mg/L, growth attenuation has been observed. In clinical studies of pediatric patients who were treated with Nutropin Depot (somatropin (rdna origin) for inj) , 0/138 patients with GHD screened for antibody production developed antibodies with binding capacities ≥ 2 mg/L at any time during a treatment period of up to 17.4 months. In addition to an evaluation of compliance with the prescribed treatment program and thyroid status, testing for antibodies to GH should be carried out in any patient who fails to respond to therapy. In studies involving 138 pediatric patients treated with Nutropin Depot (somatropin (rdna origin) for inj) , the most frequent adverse reactions were injection-site reactions, which occurred in nearly all patients. On average, 2 to 3 injection-site adverse reactions were reported per injection. These reactions included nodules (61% of injections), erythema (53%), pain post-injection (47%), pain during injection (43%), bruising (20%), itching (13%), lipoatrophy (13%), and swelling or puffiness (8%). The intensity of these reactions was generally rated mild to moderate, with pain during injection occasionally rated as severe (7%). Adverse reactions observed less frequently in the Nutropin Depot (somatropin (rdna origin) for inj) studies which were considered possibly, probably, or definitely related to the drug by the treating physician (usually occurring 1–3 days postdose) included: headache (13% of subjects), nausea (8%), lower extremity pain (7%), fever (7%), and vomiting (5%). These symptoms were generally self-limited and well-tolerated. One patient experienced a generalized body rash that was most likely an allergic reaction to Nutropin Depot (somatropin (rdna origin) for inj) . Leukemia has been reported in a small number of GHD patients treated with GH. It is uncertain whether this increased risk is related to the pathology of GH deficiency itself, GH therapy, or other associated treatments such as radiation therapy for intracranial tumors. On the basis of current evidence, experts cannot conclude that GH therapy is responsible for these occurrences. Other adverse drug reactions that have been reported in GH-treated patients include the following: 1) Metabolic: mild, transient peripheral edema; 2) Musculoskeletal: arthralgia, carpal tunnel syndrome; 3) Skin: rare increased growth of pre-existing nevi; patients should be monitored for malignant transformation; 4) Endocrine: gynecomastia; and 5) Rare pancreatitis. Of these reactions, only edema ( < 1% of patients) and arthralgia (4%) were reported as related to drug in the Nutropin Depot (somatropin (rdna origin) for inj) studies. DRUG INTERACTIONS Excessive glucocorticoid therapy will inhibit the growth-promoting effect of human GH. Patients with ACTH deficiency should have their glucocorticoid-replacement dose carefully adjusted to avoid an inhibitory effect on growth. Limited published data indicate that GH treatment increases cytochrome P450 (CP450) mediated antipyrine clearance in humans. These data suggest that GH administration may alter the clearance of compounds known to be metabolized by CP450 liver enzymes (e.g., corticosteroids, sex steroids, anticonvulsants, cyclosporin). Careful monitoring is advisable when GH is administered in combination with other drugs known to be metabolized by CP450 liver enzymes.

SIDE EFFECTS Most Serious and/or Most Frequently Observed Adverse Reactions This list presents the most seriousa and/or most frequently observedb adverse reactions during treatment with somatropin: aSudden death in pediatric patients with Prader-Willi syndrome (PWS) with risk factors includingsevere obesity, history of upper airway obstruction or sleep apnea and unidentified respiratoryinfection [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS]. aIntracranial tumors, in particular meningiomas, in teenagers/young adults treated with radiationto the head as children for a first neoplasm and somatropin [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS]. a [see WARNINGS AND PRECAUTIONS] a,bGlucose intolerance including impaired glucose tolerance/impaired fasting glucose as well asovert diabetes mellitus [see WARNINGS AND PRECAUTIONS]. aIntracranial hypertension [see WARNINGS AND PRECAUTIONS]. aSignificant diabetic retinopathy [see CONTRAINDICATIONS]. aSlipped capital femoral epiphysis in pediatric patients [see WARNINGS AND PRECAUTIONS]. aProgression of preexisting scoliosis in pediatric patients [see WARNINGS AND PRECAUTIONS]. bFluid retention manifested by edema, arthralgia, myalgia, nerve compression syndromes including carpal tunnel syndrome/paraesthesias [see WARNINGS AND PRECAUTIONS]. aUnmasking of latent central hypothyroidism [see WARNINGS AND PRECAUTIONS]. aInjection site reactions/rashes and lipoatrophy (as well as rare generalized hypersensitivity reactions) [see WARNINGS AND PRECAUTIONS]. 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 childrens witched from another somatropin product to Nutropin. 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. Data obtained with several rhGH products (Nutropin, Nutropin AQ, Nutropin Depot and Protropin). 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 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. Post-Marketing Experience 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. 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 and WARNINGS AND PRECAUTIONS]. The following additional adverse reactions have been reported in GH-treated patients: gynecomastia (children), and pancreatitis [(Children and adults, see WARNINGS AND PRECAUTIONS]. 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. DRUG INTERACTIONS 11β-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 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. 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]. 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].

SIDE EFFECTS The following important adverse reactions are also described elsewhere in the labeling: Acute Critical Illness [see WARNINGS AND PRECAUTIONS] Neoplasms [see WARNINGS AND PRECAUTIONS] Impaired glucose tolerance and diabetes mellitus [see WARNINGS AND PRECAUTIONS] Intracranial hypertension [see WARNINGS AND PRECAUTIONS] Severe hypersensitivity [see WARNINGS AND PRECAUTIONS] Fluid retention/Carpal tunnel syndrome [see WARNINGS AND PRECAUTIONS] Lipoatrophy [see WARNINGS AND PRECAUTIONS] Pancreatitis [see WARNINGS AND PRECAUTIONS] Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Clinical Trials in HIV-Associated Wasting Or Cachexia In the 12-week, placebo-controlled Clinical Trial 2, 510 patients were treated with SEROSTIM. The most common adverse reactions judged to be associated with SEROSTIM were musculoskeletal discomfort and increased tissue turgor (swelling, particularly of the hands or feet), and were more frequently observed when SEROSTIM 0.1 mg/kg was administered on a daily basis [Table 1 and Warnings and Precautions (5)]. These symptoms often subsided with continued treatment or dose reduction. Approximately 23% of patients receiving SEROSTIM 0.1 mg/kg daily and 11% of patients receiving 0.1 mg/kg every other day required dose reductions. Discontinuations as a result of adverse reactions occurred in 10.3% of patients receiving SEROSTIM 0.1 mg/kg daily and 6.6% of patients receiving 0.1 mg/kg every other day. The most common reasons for dose reduction and/or drug discontinuation were arthralgia, myalgia, edema, carpal tunnel syndrome, elevated glucose levels, and elevated triglyceride levels. Clinical adverse reactions which occurred during the first 12 weeks of study in at least 5% of the patients in either active treatment group and at an incidence greater than placebo are listed below, without regard to causality assessment. Table 1: Controlled Clinical Trial 2 Adverse Reactions Occurring in at least 5% of Patients in one of the Treatment Groups, and at an Incidence Greater than Placebo Body System Preferred Term Placebo 0.1 mg/kg every other day SEROSTIM 0.1 mg/kg daily SEROSTIM Patients (n=247)% Patients (n=257)% Patients (n=253)% Musculoskeletal System Disorders Arthralgia 11.3 24.5 36.4 Myalgia 11.7 17.9 30.4 Arthrosis 3.6 7.8 10.7 Gastrointestinal System Disorders Nausea 4.9 5.4 9.1 Body As A Whole - General Disorders Edema Peripheral 2.8 11.3 26.1 Fatigue 4.5 3.5 5.1 Endocrine Disorders Gynecomastia 0.4 3.5 5.5 Central and Peripheral Nervous System Disorders Paresthesia 4.5 7.4 7.9 Hypoesthesia 2.4 1.6 5.1 Metabolic and Nutritional Disorders Edema Generalized 1.2 1.2 5.9 Adverse reactions that occurred in 1% to less than 5% of trial participants receiving SEROSTIM during the first 12 weeks of Clinical Trial 2 thought to be related to SEROSTIM included dose dependent edema, periorbital edema, carpal tunnel syndrome, hyperglycemia and hypertriglyceridemia. During the 12-week, placebo-controlled portion of Clinical Trial 2, the incidence of hyperglycemia reported as an adverse reaction was 3.6% for the placebo group, 1.9% for the 0.1 mg/kg every other day group and 3.2% for the 0.1 mg/kg daily group. One case of diabetes mellitus was noted in the 0.1 mg/kg daily group during the first 12-weeks of therapy. In addition, during the extension phase of Clinical Trial 2, two patients converted from placebo to full dose SEROSTIM, and 1 patient converted from placebo to half-dose SEROSTIM, were discontinued because of the development of diabetes mellitus. The types and incidences of adverse reactions reported during the Clinical Trial 2 extension phase were not different from, or greater in frequency than those observed during the 12-week, placebo-controlled portion of Clinical Trial 2. Adverse Reactions From Treatment With SEROSTIM in Clinical Trials in HIV Lipodystrophy SEROSTIM was evaluated for the treatment of patients with HIV lipodystrophy in two double-blind, placebo-controlled trials that excluded patients with a history of diabetes, impaired fasting glucose or impaired glucose (approximately 20% of the patients screened were excluded from study enrollment as a result of a diagnosis of diabetes or glucose intolerance). The studies included a 12-week double-blind, placebo-controlled, parallel group “induction” phase followed by maintenance phases of different durations (12 and 24 weeks, respectively). In the initial 12-week treatment periods of the two, placebo-controlled clinical trials, 406 patients were treated with SEROSTIM. Clinical adverse reactions which occurred during the first 12 weeks of both studies combined in at least 5% of the patients in either of the two active treatment groups are listed by treatment group in Table 2, without regard to causality assessment. The most common adverse reactions judged to be associated with SEROSTIM were edema, arthralgia, pain in extremity, hypoesthesia, myalgia, and blood glucose increased, all of which were more frequently observed when SEROSTIM 4 mg was administered on a daily basis compared with alternate days. These symptoms often subsided with dose reduction. During the 12-week induction phase, 1) approximately 26% of patients receiving SEROSTIM 4 mg daily and 19% of patients receiving SEROSTIM 4 mg every other day required dose reductions; and 2) discontinuations as a result of adverse reactions occurred in 13% of patients receiving SEROSTIM 4 mg daily and 5% of patients receiving SEROSTIM 4 mg every other day. The most common reasons for dose reduction and/or drug discontinuation were peripheral edema, hyperglycemia (including blood glucose increased, blood glucose abnormal, and hyperglycemia), and arthralgia. Table 2: Controlled HIV Lipodystrophy Studies 1 and 2 Combined - Adverse Reactions with > 5% Incidence in Either Active Treatment Arm System Organ Class /Preferred Term Placebo SEROSTIM 4 mg every other day1 SEROSTIM 4 mg daily Patients (n=159)% Patients (n=80)% Patients (n=326)% Musculoskeletal and connective tissue disorders Arthralgia 11.9 27.8 37.1 Pain in extremity 3.8 5.0 19.3 Myalgia 3.8 2.5 12.6 Musculoskeletal stiffness 1.9 3.8 8.0 Joint stiffness 1.3 3.8 7.7 Joint swelling 0.6 5.0 6.1 General disorders and administration site conditions Edema peripheral 3.8 18.8 45.4 Fatigue 1.9 6.3 8.9 Nervous system disorders Hypoesthesia 0.6 8.8 15.0 Paraesthesia 2.5 12.5 11.0 Investigations (Laboratory Evaluations) Blood glucose increased2 2.5 3.8 13.8 Metabolism and nutrition disorders Hyperglycemia2 0.6 8.8 7.1 Fluid retention 0.6 2.5 5.2 Gastrointestinal disorders Nausea 2.5 1.3 6.1 1 Study 22388 only 2 similar terms were grouped together and reported below Glucose metabolism related adverse reactions: During the initial 12-week treatment periods of Studies 1 and 2, the incidence of glucose-related adverse reactions was 4% for the placebo group, 13% for the 4 mg every other day group and 22% for the 4 mg daily group. Twenty-three patients discontinued due to hyperglycemia while receiving SEROSTIM during any phase of these studies (3.2% in the 12-week induction phases and 2.1% in the extension phases). Breast-Related Terms: When grouped together, breast-related adverse reactions (e.g. nipple pain, gynecomastia, breast pain/mass/tenderness/swelling/edema/hypertrophy) had an incidence of 1% for the placebo group, 3% for the SEROSTIM 4 mg every other day group and 6% for the SEROSTIM 4 mg daily group. Adverse reactions that occurred in 1% to less than 5% of trial participants receiving SEROSTIM during the first 12 weeks of HIV Lipodystrophy Studies 1 and 2 thought to be related to SEROSTIM include carpal tunnel syndrome, Tinel's sign and facial edema. The adverse reactions reported for SEROSTIM 4 mg every other day during the maintenance phase of HIV Lipodystrophy Study 1 (Week 12 to Week 24) were similar in frequency and quality to those observed after treatment with SEROSTIM 4 mg every other day during the 12-week induction phase. IGF-1 serum concentrations increased statistically in SEROSTIM-treated patients when compared to placebo (Table 3). In the SEROSTIM treated patients at baseline, the proportion of subjects with serum IGF-1 SDS levels ≥ +2 was approximately 10 to 20%, while with treatment with either dose regimen of SEROSTIM the percentage increased to 80 to 90% by Week 12. Table 3: Change from Baseline to Week 12 in Serum IGF-1 SDS After Treatment with SEROSTIM 4 mg daily vs. Placebo (Modified ITT Population; Studies 1 and 2 Combined) Placebo SEROSTIM 4 mg every other day SEROSTIM 4 mg daily Time Point Statistic (n=145) (n=79) (n=290) Baseline Mean (SD) 0.4 (1.4) 1.3 (2.1) 0.0 (1.6) Range (-2.5, 4.8) (-2.0, 13.7) (-3.0, 11.9) Week 12 Mean (SD) 0.8 (1.6) 5.1 (3.4) 6.1 (5.0) Range (-2.6, 6.7) (-0.7, 17.2) (-1.8, 29.2) Change from Baseline to Mean (SD) 0.4 (1.3) 3.9 (3.1) 6.1 (4.6) Range (-2.9, 7.7) (-9.4, 11.8) (-2.4, 24.3) Week 12 p-valueb < 0.001 < 0.001 < 0.001 Meana diff (SEM) 3.5 (0.5) 5.7 (0.4) p-valuec < 0.001 < 0.001 a Proportionally weighted least squares means from a two-way ANOVA model on raw data including effects for treatment, sex, and the treatment by sex interaction. b P-value from a Wilcoxon Signed Rank test on the change from baseline to Week 12. c P-value from a two-way ANOVA model on ranked data including effects for treatment, sex, and the treatment by sex interaction. 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 influences 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 SEROSTIM with the incidence of antibodies to other products may be misleading. After 12 weeks of treatment, none of the 651 study participants with HIV-associated wasting treated with SEROSTIM for the first time developed detectable antibodies to growth hormone ( > 4 pg binding). Patients were not rechallenged. Data beyond 3 months is not available. Post-Marketing Experience The following adverse reactions have been identified during post approval use of SEROSTIM. Because these reactions 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. Hypersensitivity: Serious systemic hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with postmarketing use of somatropin products [see WARNINGS AND PRECAUTIONS]. Endocrine: new onset impaired glucose tolerance new onset type 2 diabetes mellitus exacerbation of preexisting diabetes mellitus diabetic ketoacidosis diabetic coma In some patients, these conditions improved when SEROSTIM was discontinued, while in others the glucose intolerance persisted. Some of these patients required initiation or adjustment of antidiabetic treatment while on SEROSTIM [see WARNINGS AND PRECAUTIONS]. Gastrointestinal: Pancreatitis [see WARNINGS AND PRECAUTIONS]. DRUG INTERACTIONS Formal drug interaction studies have not been conducted. No data are available on drug interactions between SEROSTIM and HIV protease inhibitors or the non-nucleoside reverse transcriptase inhibitors. 11β-Hydroxysteroid Dehydrogenase Type 1 The microsomal enzyme 11β-hydroxysteroid dehydrogenase type 1 (11βHSD-1) is required for conversion of cortisone to its active metabolite, cortisol, in hepatic and adipose tissue. Somatropin inhibits 11βHSD-1. 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. Cytochrome P450-metabolized drugs Limited published data indicate that somatropin treatment increases cytochrome P450 (CYP450)mediated antipyrine clearance in man. These data suggest that somatropin administration may alter the clearance of compounds metabolized by CYP450 liver enzymes (e.g., corticosteroids, sex steroids, anticonvulsants, cyclosporine). Therefore, careful monitoring is advised when somatropin is administered in combination with drugs metabolized by CYP450 liver enzymes. However, formal drug interaction studies have not been conducted. Oral Estrogen Because oral estrogens may reduce the serum IGF-1 response to somatropin treatment, girls and women receiving oral estrogen replacement may require greater somatropin dosages [see DOSAGE AND ADMINISTRATION]. Insulin And/Or Other Oral/Injectable Hypoglycemic Agents Patients with diabetes mellitus who receive concomitant treatment with somatropin may require adjustment of their doses of insulin and/or other hypoglycemic agents [see WARNINGS AND PRECAUTIONS].

SIDE EFFECTS Most Serious And/Or Most Frequently Observed Adverse Reactions This list presents the most seriousa and/or most frequently observedb adverse reactions during treatment with somatropin: aSudden death in pediatric patients with Prader-Willi syndrome (PWS) with risk factors including severe obesity, history of upper airway obstruction or sleep apnea and unidentified respiratory infection [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS]. aIntracranial tumors, in particular meningiomas, in teenagers/young adults treated with radiation to the head as children for a first neoplasm and somatropin [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS]. aPancreatitis [see WARNINGS AND PRECAUTIONS] a,bGlucose intolerance including impaired glucose tolerance/impaired fasting glucose as well as overt diabetes mellitus [see WARNINGS AND PRECAUTIONS]. aIntracranial hypertension [see WARNINGS AND PRECAUTIONS]. aSignificant diabetic retinopathy [see CONTRAINDICATIONS]. aSlipped capital femoral epiphysis in pediatric patients [see WARNINGS AND PRECAUTIONS]. aProgression of preexisting scoliosis in pediatric patients [see WARNINGS AND PRECAUTIONS]. bFluid retention manifested by edema, arthralgia, myalgia, nerve compression syndromes including carpal tunnel syndrome/paraesthesias [see WARNINGS AND PRECAUTIONS]. aUnmasking of latent central hypothyroidism [see WARNINGS AND PRECAUTIONS]. aInjection site reactions/rashes and lipoatrophy (as well as rare generalized hypersensitivity reactions) [see WARNINGS AND PRECAUTIONS]. 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. Data obtained with several rhGH products (Nutropin, Nutropin AQ, Nutropin Depot and Protropin). 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 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. Post-Marketing Experience 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. 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 and WARNINGS AND PRECAUTIONS]. The following additional adverse reactions have been reported in GH-treated patients: gynecomastia (children), and pancreatitis [(Children and adults, see WARNINGS AND PRECAUTIONS]. 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. DRUG INTERACTIONS 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. 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]. 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].

WARNINGS See CONTRAINDICATIONS for information on increased mortality in patients with acute critical illnesses in intensive care units due to complications following open heart or abdominal surgery, multiple accidental trauma, or with acute respiratory failure. 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 acute critical illnesses 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 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 Depot is not indicated for the long term treatment of pediatric patients who have growth failure due to genetically confirmed Prader-Willi syndrome. PRECAUTIONS General Nutropin Depot (somatropin (rdna origin) for inj) should be prescribed by physicians experienced in the diagnosis and management of patients with GHD. Because GH may reduce insulin sensitivity, patients should be monitored 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. Patients with symptomatic hypoglycemia associated with GHD should be closely monitored. Patients with a history of an intracranial lesion should be examined frequently for progression or recurrence of the lesion. In pediatric patients, clinical literature has demonstrated no relationship between GH replacement therapy and central nervous system (CNS) tumor recurrence or new extracranial tumors. Slipped capital femoral epiphysis may occur more frequently in patients with endocrine disorders or in patients undergoing rapid growth. Progression of scoliosis can occur in patients who experience rapid growth. Because GH increases growth rate, patients with a history of scoliosis who are treated with GH should be monitored for progression of scoliosis. GH has not been shown to increase the incidence of scoliosis. Intracranial hypertension (IH) with papilledema, visual changes, headache, nausea, and/or vomiting has been reported in a small number of patients treated with GH products. Symptoms usually occurred within the first 8 weeks of the initiation of GH therapy. In all reported cases, IH-associated signs and symptoms resolved after termination of therapy or a reduction of the GH dose. Funduscopic examination of patients is recommended at the initiation and periodically during the course of GH therapy. As with any protein, 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 (see ADVERSE REACTIONS). Laboratory Tests Serum levels of inorganic phosphorus, alkaline phosphatase, and parathyroid hormone (PTH) may increase with GH therapy. Untreated hypothyroidism prevents optimal response to GH. Changes in thyroid hormone laboratory measurements may develop during GH treatment. Therefore, patients should have periodic thyroid function tests and should be treated with thyroid hormone when indicated. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity, mutagenicity, and fertility studies have not been conducted with Nutropin Depot (somatropin (rdna origin) for inj) . Pregnancy Category C Animal reproduction studies have not been conducted with Nutropin Depot (somatropin (rdna origin) for inj) . It is also not known whether Nutropin Depot (somatropin (rdna origin) for inj) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Nutropin Depot (somatropin (rdna origin) for inj) should be given to a pregnant woman only if clearly needed. Nursing Mothers It is not known whether GH is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Nutropin Depot (somatropin (rdna origin) for inj) is administered to a nursing mother.

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Acute Critical Illness Increased mortality in patients with acute critical illnesses due to complications following openheart 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]. 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 patient shaving 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]. Nutropin is not indicated for the treatment of pediatric patients who have growth failure due to genetically confirmed PWS. Neoplasms Patients with preexisting tumors or growth hormone deficiency (GHD) secondary to an intracranial lesion should be examined routinely for progression or recurrence of the underlying disease process. In pediatric patients, clinical literature has revealed no relationship between somatropin replacement therapy and central nervous system (CNS) tumor recurrence or new extracranial tumors. However, in childhood cancer survivors, an increased risk of a second neoplasm has been reported in patients treated with somatropin after their first neoplasm. Intracranial tumors, in particular meningiomas, in patients treated with radiation to the head for their first neoplasm, 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. Patients should be monitored carefully for any malignant transformation of skin lesions. Glucose Intolerance and Diabetes Mellitus Treatment with somatropin may decrease insulin sensitivity, particularly at higher doses insusceptible 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 therapyor 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. Fluid Retention Fluid retention during somatropin replacement therapy in adults may occur. Clinical manifestations of fluid retention are usually transient and dose dependent. Hypopituitarism Patients with hypopituitarism (multiple hormone deficiencies) should have their other hormonal replacement treatments closely monitored during somatropin treatment. 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. Any pediatric patient with the onset of a limp or complaints of hip or knee pain during somatropin therapy should be carefully evaluated. 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 the sepatients 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. Chronic Kidney Disease in Pediatric Patients 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. No studies have been completed evaluating Nutropin therapy in patients who have received renal transplants. Currently, treatment of patients with functioning renal allografts is not indicated. Local and Systemic Reactions 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]. As with any protein, local or systemic allergic reactions may occur. Parents/patients should be informed that such reactions are possible and that prompt medical attention should be sought if allergic reactions occur. Laboratory Tests Serum levels of inorganic phosphorus, alkaline phosphatase, and parathyroid hormone (PTH), andIGF-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. Benzyl Alcohol Benzyl alcohol, a component of this product, has been associated with serious adverse events and death, particularly in pediatric patients. The “gasping syndrome,” (characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated with benzyl alcohol dosages >99 mg/kg/day in neonates and low-birth weight neonates. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity, mutagenicity, and reproduction studies have not been conducted with Nutropin. Use In Specific Populations Pregnancy Pregnancy Category C. Animal 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 Mothers There have been no studies conducted with Nutropin in nursing mothers. It is not known whether Nutropin 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. Geriatric Use Clinical studies of Nutropin did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Elderly patients may be more sensitive to the action of somatropin, and therefore may be more prone to develop adverse reactions. A lower starting dose and smaller dose increments should be considered for older patients [see DOSAGE AND ADMINISTRATION]. Hepatic Impairment No studies have been conducted for Nutropin in patients with hepatic impairment. [see CLINICAL PHARMACOLOGY]. Renal Impairment Subjects with chronic renal failure tend to have decreased somatropin clearance compared to those with normal renal function. [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY]. Gender Effect No gender-specific pharmacokinetic studies have been done with Nutropin. The available literature indicates that the pharmacokinetics of somatropin are similar in men and women.

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Acute Critical Illness Increased mortality 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 has been reported after treatment with pharmacologic amounts of somatropin. Two placebo-controlled clinical trials in non-growth hormone deficient adult patients (n=522) with these conditions revealed a significant increase in mortality (42% vs. 19%) among somatropin-treated patients (doses 5.3-8 mg/day) compared to those receiving placebo [see CONTRAINDICATIONS]. Concomitant Antiretroviral Therapy In some experimental systems, somatropin has been shown to potentiate HIV replication in vitro at concentrations ranging from 50-250 ng/mL. There was no increase in virus production when the antiretroviral agents, zidovudine, didanosine or lamivudine were added to the culture medium. Additional in vitro studies have shown that somatropin does not interfere with the antiviral activity of zalcitabine or stavudine. In the controlled clinical trials, no significant somatropin-associated increase in viral burden was observed. However, the protocol required all participants to be on concomitant antiretroviral therapy for the duration of the study. In view of the potential for acceleration of virus replication, it is recommended that HIV patients be maintained on antiretroviral therapy for the duration of SEROSTIM treatment. Neoplasms Because malignancies are more common in HIV positive individuals, the risks and benefits of starting somatropin in HIV positive patients should be carefully considered before initiating SEROSTIM treatment and patients should be monitored carefully for the development of neoplasms if treatment with somatropin is initiated. Monitor all patients with a history of any neoplasm routinely while on somatropin therapy for progression or recurrence of the tumor [see CONTRAINDICATIONS]. Monitor patients on somatropin therapy carefully for increased growth, or potential malignant changes of preexisting nevi. Impaired Glucose Tolerance/Diabetes Hyperglycemia may occur in HIV infected individuals due to a variety of reasons. In wasting patients, treatment with SEROSTIM 0.1 mg/kg daily and 0.1 mg/kg every other day for 12 weeks was associated with approximately 10 mg/dL and 6 mg/dL increases in mean fasting blood glucose concentrations, respectively. The increases occurred early in treatment. Patients with other risk factors for glucose intolerance should be monitored closely during SEROSTIM therapy. During safety surveillance of patients with HIV-associated wasting, cases of new onset impaired glucose tolerance, new onset type 2 diabetes mellitus and exacerbation of preexisting diabetes mellitus have been reported in patients receiving SEROSTIM. Some patients developed diabetic ketoacidosis and diabetic coma. In some patients, these conditions improved when SEROSTIM was discontinued, while in others, the glucose intolerance persisted. Some of these patients required initiation or adjustment of antidiabetic treatment while on SEROSTIM. In clinical trials of SEROSTIM conducted in HIV patients with lipodystrophy (an unapproved indication), evidence of dose-dependent glucose intolerance and related adverse reaction was observed at doses of 4 mg SEROSTIM daily and 4 mg SEROSTIM every other day for 12 weeks [see ADVERSE REACTIONS]. 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. Severe Hypersensitivity Serious systemic hypersensitivity reactions including anaphylactic reactions 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 [see CONTRAINDICATIONS]. Fluid Retention/Carpal Tunnel Syndrome Increased tissue turgor (swelling, particularly in the hands and feet) and musculoskeletal discomfort (pain, swelling and/or stiffness) may occur during treatment with SEROSTIM, but may resolve spontaneously, with analgesic therapy, or after reducing the frequency of dosing [see DOSAGE AND ADMINISTRATION]. Carpal tunnel syndrome may occur during treatment with SEROSTIM. If the symptoms of carpal tunnel syndrome do not resolve by decreasing the weekly number of doses of SEROSTIM, it is recommended that treatment be discontinued. 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]. 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 Turner syndrome may be at greater risk than other somatropin-treated children. Pancreatitis should be considered in any somatropin-treated patient, especially a child who develops abdominal pain. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility Long-term animal studies for carcinogenicity have not been performed with SEROSTIM. There is no evidence from animal studies to date of SEROSTIM-induced mutagenicity or impairment of fertility. Use In Specific Populations Pregnancy Pregnancy Category B. Reproduction studies have been performed in rats and rabbits. Doses up to 5 to 10 times the human dose, based on body surface area, have revealed no evidence of impaired fertility or harm to the fetus due to SEROSTIM. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, SEROSTIM should be used during pregnancy only if clearly needed. Nursing Women It is not known whether SEROSTIM is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when SEROSTIM is administered to a nursing woman. Pediatric Use Safety and effectiveness in pediatric patients with HIV have not been established. Available evidence suggests that somatropin clearance is similar in adults and children, but no pharmacokinetic studies have been conducted in children with HIV. In two small studies, 11 children with HIV-associated failure to thrive were treated subcutaneously with human growth hormone. In one study, five children (age range, 6 to 17 years) were treated with 0.04 mg/kg/day for 26 weeks. In a second study, six children (age range, 8 to 14 years) were treated with 0.07 mg/kg/day for 4 weeks. Treatment appeared to be well tolerated in both studies. The preliminary data collected on a limited number of patients with HIV-associated failure to thrive appear to be consistent with safety observations in growth hormone-treated adults with HIV wasting. Benzyl alcohol, a component of this product, has been associated with serious adverse events and death, particularly in pediatric patients. The “gasping syndrome,” (characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated with benzyl alcohol dosages > 99 mg/kg/day in neonates and low-birth weight neonates. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources. Geriatric Use Clinical studies with SEROSTIM did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Elderly patients may be more sensitive to the action of somatropin, and therefore, may be more prone to develop adverse reactions. A lower starting dose and smaller dose increments should be considered for older patients [see DOSAGE AND ADMINISTRATION]. Hepatic Impairment No studies have been conducted for SEROSTIM in patients with hepatic impairment [see CLINICAL PHARMACOLOGY]. Renal Impairment Subjects with chronic renal failure tend to have decreased somatropin clearance compared to those with normal renal function. However, no studies have been conducted for SEROSTIM in patients with renal impairment [see CLINICAL PHARMACOLOGY]. Gender Effect Biomedical literature indicates that a gender-related difference in the mean clearance of r-hGH could exist (clearance of r-hGH in males > clearance of r-hGH in females). However, no gender-based analysis is available for SEROSTIM in normal volunteers or patients infected with HIV.

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS 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]. 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]. 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]. 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. Fluid Retention Fluid retention during somatropin replacement therapy in adults may occur. Clinical manifestations of fluid retention are usually transient and dose dependent. Hypopituitarism Patients with hypopituitarism (multiple hormone deficiencies) should have their other hormonal replacement treatments closely monitored during somatropin treatment. 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. Any pediatric patient with the onset of a limp or complaints of hip or knee pain during somatropin therapy should be carefully evaluated. 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. Chronic Kidney Disease In Pediatric Patients 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. Local And Systemic Reactions 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]. As with any protein, local or systemic allergic reactions may occur. Parents/patients should be informed that such reactions are possible and that prompt medical attention should be sought if allergic reactions occur. Laboratory Tests Serum levels of inorganic 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-treatedchildren. 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. Use In Specific Populations Pregnancy Pregnancy Category C Animal reproduction studies have not been conducted with Nutropin AQ. It is also not known whether Nutropin AQ can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Nutropin AQ should be given to a pregnant woman only if clearly needed. Nursing Mothers There have been no studies conducted with Nutropin AQ in nursing mothers. It is not known whether Nutropin AQ is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Nutropin AQ is administered to a nursing mother. Geriatric Use Clinical studies of Nutropin AQ did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Elderly patients may be more sensitive to the action of somatropin, and therefore may be more prone to develop adverse reactions. A lower starting dose and smaller dose increments should be considered for older patients [see DOSAGE AND ADMINISTRATION]. Hepatic Impairment No studies have been conducted for Nutropin AQ in patients with hepatic impairment. [see CLINICAL PHARMACOLOGY]. Renal Impairment Subjects with chronic renal failure tend to have decreased somatropin clearance compared to those with normal renal function. [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY]. Gender Effect 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.