INSTRUCTIONS FOR USE SECTION.

Nutropin AQ(R) NuSpin(R) (somatropin) injection, for subcutaneous useGenentechRx onlyINSTRUCTIONS FOR USEDescription: The Nutropin AQ NuSpin is multi-dose, dial-a-dose injection device prefilled with Nutropin AQ (somatropin) injection, for subcutaneous use. It features automatic injection of the drug and is disposable. The Nutropin AQ NuSpin (Clear Color, mg/2 mL) delivers doses from 0.05 to 1.75 mg in increments of 0.05 mg.Intended Use: The Nutropin AQ NuSpin is intended to be used by healthcare professional or patient to deliver Nutropin AQ (somatropin) injection, for subcutaneous use, from an injection device. The device can be used in any setting, including the home, and is disposable.IMPORTANT NOTESAlways follow the directions of your healthcare professional and the instructions provided on the back. Contact your healthcare professional if you have any questions.Check the label on the NuSpin to make sure the medicine matches your prescription and it has not expired.Inspect the cartridge before use to ensure that the medicine in it is clear. If it is cloudy or hazy, do not inject. Return the NuSpin to your healthcare professional.Store your NuSpin inside the refrigerator at 2-8C (36-46F). Protect from light.The product can be used for 28 days after it has been primed and kept under proper storage conditions.For the first use of each NuSpin 5, always follow the New NuSpin Set Up Instructions to ensure that air is expelled from the cartridge.Do not store with the needle attached. The needle should be removed and safely disposed of immediately after use.Keep NuSpin and all medicines out of the reach of young children.FREQUENTLY ASKED QUESTIONS1.What type of needles should be used Your Healthcare Professional will recommend needle that is appropriate for you. The following needles will fit and work on the Nutropin AQ NuSpin:BD Ultra-Fine(TM) 29 x 1/2 inch (12.7 mm)BD Ultra-Fine(TM) Ill short pen needle 31 x 5/16 inch (8 mm)NovoFine(R) Autocover(R) 30 (8 mm)Pen needles from other countries may not fit on your NuSpin device. If you travel outside the United States, make sure you take enough needles for the duration of your stay.2.Do need to change the needle every time use my Nutropin AQ NuSpin Yes. new needle must be used for every injection. The needle is sterile only for one single injection.3.Do need to prime the Nutropin AQ NuSpin each time No. The NuSpin only needs to be primed once, at first use. After the first use of each NuSpin 5, follow the instructions and skip Step 2.4.When and how do dispose of my Nutropin AQ NuSpin Your NuSpin is prefilled and the cartridge cannot be replaced. When your NuSpin is empty, dispose of the entire NuSpin as instructed by your healthcare professional. If the empty NuSpin is disposed of with the needle attached, discard the entire device using the same procedure as for needle disposal.5.Where should store my Nutropin AQ NuSpin When not in use, your NuSpin should be stored inside refrigerator at 2-8C (36-46F) to maintain the potency of Nutropin AQ (somatropin) injection, for subcutaneous use. During use, we recommend that you have your NuSpin outside of the refrigerator for no longer than one hour per day. When traveling, place your NuSpin in water-resistant container before placing in cooler. DO NOT FREEZE. KEEP DRY. 6.What should do if my Nutropin AQ NuSpin is dropped or damaged If you drop the NuSpin 5, check to see if it is damaged. You should also check to see that the black dose knob and the Activator are moving properly. If you notice the NuSpin is damaged, contact your healthcare professional or call 1-866-NUTROPIN for advice.7.What should do if my Nutropin AQ NuSpin needs cleaning Use damp cloth to wipe away dirt. Do not place underwater. Do not use alcohol.Genentech, Inc., Member of the Roche Group DNA Way, South San Francisco, CA 94080-4990 Initial US Approval January 2008 NuSpin(R) is registered trademark of Genentech, Inc. Copyright (C) 2016 Genentech, Inc.INSTRUCTIONS FOR USENEW NuSpin SET UP: STEP-BY-STEP INSTRUCTIONS FOR THE FIRST USE OF EACH NEW NUTROPIN AQ NuSpin 5STEP 1: Attach the needleSTEP 2: Prime the Nutropin AQ NuSpinBefore you begin, wash your hands. Twist gently and pull to remove the NuSpin cap. Inspect the cartridge before use to ensure that the medicine in it is clear. If it is cloudy or hazy, do not inject. Open new needle by peeling off the paper tab from the needle package.Attach the needle by carefully screwing the needle onto the needle holder. Do not overtighten. Remove both protective covers from the needle and save the outer cover.Turn the dose knob to the position in the dose window. It may take multiple clicks to get to Hold the NuSpin with the needle pointing upwards. Gently tap the cartridge holder to move any air bubbles to the NuSpin tip.Slide the Activator toward the needle. If you do not see fluid at the needle tip, redial to and slide the Activator forward again. Repeat until you see fluid.ROUTINE USE: DOSING AND ADMINISTRATIONSTEP 3: Set the doseSTEP 4: Give the injectionCheck dose givenMake sure the dose window reads Turn the dose knob until the dose prescribed by your healthcare professional appears in the dose window.If your dose is between two numbers in the dose window, the between those two numbers indicates your dose. Turn the dose knob to The position indicates 0.35 mg dose on your NuSpin 5. If you turn the dose knob too far, simply turn it back to the correct dose. (Example above shows dose of 0.05 mg, represented by ).Select and prepare your injection site as instructed by your healthcare professional. Position your hand so you can easily slide the Activator. Push the needle into the skin.Slide the Activator toward the needle. Hold the Activator down until the dose knob returns to and continue to hold in place for seconds. Withdraw the Nutropin AQ NuSpin until the needle is removed from the skin. If the dose knob returns to you have received your full dose.If the dose knob stops before it returns to your Nutropin AQ NuSpin is empty and you have not received your full dose. The number shown in the dose window is the amount needed to obtain full dose. Your healthcare professional will advise you on the procedure for using the last dose in the NuSpin 5.REMOVAL AND DISPOSAL OF THE NEEDLECarefully place the outer cover of the needle package over the needle, unscrew, and dispose of it as instructed by your healthcare professional.STORAGE AND NEXT USEReplace the cap and store your NuSpin inside the refrigerator at 2-8C (36-46F). Protect from light. For the next use, it is already primed. Follow the instructions and skip Step 2.Genentech. Always follow the directions of your healthcare professional and the instructions provided on the back. Contact your healthcare professional if you have any questions.. Check the label on the NuSpin to make sure the medicine matches your prescription and it has not expired.. Inspect the cartridge before use to ensure that the medicine in it is clear. If it is cloudy or hazy, do not inject. Return the NuSpin to your healthcare professional.. Store your NuSpin inside the refrigerator at 2-8C (36-46F). Protect from light.. The product can be used for 28 days after it has been primed and kept under proper storage conditions.. For the first use of each NuSpin 5, always follow the New NuSpin Set Up Instructions to ensure that air is expelled from the cartridge.. Do not store with the needle attached. The needle should be removed and safely disposed of immediately after use.. Keep NuSpin and all medicines out of the reach of young children.. 1.What type of needles should be used Your Healthcare Professional will recommend needle that is appropriate for you. The following needles will fit and work on the Nutropin AQ NuSpin:BD Ultra-Fine(TM) 29 x 1/2 inch (12.7 mm)BD Ultra-Fine(TM) Ill short pen needle 31 x 5/16 inch (8 mm)NovoFine(R) Autocover(R) 30 (8 mm)Pen needles from other countries may not fit on your NuSpin device. If you travel outside the United States, make sure you take enough needles for the duration of your stay.. BD Ultra-Fine(TM) 29 x 1/2 inch (12.7 mm). BD Ultra-Fine(TM) Ill short pen needle 31 x 5/16 inch (8 mm). NovoFine(R) Autocover(R) 30 (8 mm). 2.Do need to change the needle every time use my Nutropin AQ NuSpin Yes. new needle must be used for every injection. The needle is sterile only for one single injection.. 3.Do need to prime the Nutropin AQ NuSpin each time No. The NuSpin only needs to be primed once, at first use. After the first use of each NuSpin 5, follow the instructions and skip Step 2.. 4.When and how do dispose of my Nutropin AQ NuSpin Your NuSpin is prefilled and the cartridge cannot be replaced. When your NuSpin is empty, dispose of the entire NuSpin as instructed by your healthcare professional. If the empty NuSpin is disposed of with the needle attached, discard the entire device using the same procedure as for needle disposal.. 5.Where should store my Nutropin AQ NuSpin When not in use, your NuSpin should be stored inside refrigerator at 2-8C (36-46F) to maintain the potency of Nutropin AQ (somatropin) injection, for subcutaneous use. During use, we recommend that you have your NuSpin outside of the refrigerator for no longer than one hour per day. When traveling, place your NuSpin in water-resistant container before placing in cooler. DO NOT FREEZE. KEEP DRY. 6.What should do if my Nutropin AQ NuSpin is dropped or damaged If you drop the NuSpin 5, check to see if it is damaged. You should also check to see that the black dose knob and the Activator are moving properly. If you notice the NuSpin is damaged, contact your healthcare professional or call 1-866-NUTROPIN for advice.. 7.What should do if my Nutropin AQ NuSpin needs cleaning Use damp cloth to wipe away dirt. Do not place underwater. Do not use alcohol.. Image. Image. Image. Image. Image. Image. Image. Image. Image. Image. Image. Image. Image. Image. Image. Image. Image.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following important adverse reactions are also described elsewhere in the labeling:Increased mortality in patients with acute critical illness [see Warnings and Precautions (5.1)] Fatalities in children with Prader-Willi syndrome [see Warnings and Precautions (5.2)] Neoplasms in pediatric patients [see Warnings and Precautions (5.3)] Glucose intolerance and diabetes mellitus [see Warnings and Precautions (5.4)] Intracranial hypertension [see Warnings and Precautions (5.5)] Severe hypersensitivity [see Warnings and Precautions (5.6)] Fluid retention [see Warnings and Precautions (5.7)] Hypoadrenalism [see Warnings and Precautions (5.8)] Hypothyroidism [see Warnings and Precautions (5.9)] Slipped capital femoral epiphysis in pediatric patients [see Warnings and Precautions (5.10)] Progression of preexisting scoliosis in pediatric patients [see Warnings and Precautions (5.11)] Otitis media and cardiovascular disorders in patients with Turner syndrome [see Warnings and Precautions (5.12)] Osteodystrophy in pediatric patients with chronic kidney disease [see Warnings and Precautions (5.13)] Lipoatrophy [see Warnings and Precautions (5.14)] Pancreatitis [see Warnings and Precautions (5.16)] Increased mortality in patients with acute critical illness [see Warnings and Precautions (5.1)] Fatalities in children with Prader-Willi syndrome [see Warnings and Precautions (5.2)] Neoplasms in pediatric patients [see Warnings and Precautions (5.3)] Glucose intolerance and diabetes mellitus [see Warnings and Precautions (5.4)] Intracranial hypertension [see Warnings and Precautions (5.5)] Severe hypersensitivity [see Warnings and Precautions (5.6)] Fluid retention [see Warnings and Precautions (5.7)] Hypoadrenalism [see Warnings and Precautions (5.8)] Hypothyroidism [see Warnings and Precautions (5.9)] Slipped capital femoral epiphysis in pediatric patients [see Warnings and Precautions (5.10)] Progression of preexisting scoliosis in pediatric patients [see Warnings and Precautions (5.11)] Otitis media and cardiovascular disorders in patients with Turner syndrome [see Warnings and Precautions (5.12)] Osteodystrophy in pediatric patients with chronic kidney disease [see Warnings and Precautions (5.13)] Lipoatrophy [see Warnings and Precautions (5.14)] Pancreatitis [see Warnings and Precautions (5.16)] Common somatropin-related adverse reactions include injection site reactions. Additional common adverse reactions in adults include edema, arthralgias, and carpal tunnel syndrome (6.1, 6.2).To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience. Because clinical trials are conducted under varying conditions, adverse reaction rates observed during the clinical trials performed with one somatropin formulation cannot always be directly compared to the rates observed during the clinical trials performed with 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 randomized, controlled trial, there was 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 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 Protocol-Defined Targeted Adverse Events in the ISS NCGS CohortReported EventsNCGS(N 8018)AVN avascular necrosis; SCFE slipped capital femoral epiphysis.Data obtained with several rhGH products (Nutropin, Nutropin AQ, Nutropin Depot and Protropin).Any Adverse Event Overall103 (1.3%)Targeted Adverse Event Overall103 (1.3%) Injection-site reaction28 (0.3%) New onset or progression of scoliosis16 (0.2%) Gynecomastia12 (0.1%) Any new onset or recurring tumor (benign)12 (0.1%) Arthralgia or arthritis10 (0.1%) Diabetes mellitus5 (0.1%) Edema5 (0.1%) Cancer, neoplasm (new onset or recurrence)4 (0.0%) Fracture4 (0.0%) Intracranial hypertension4 (0.0%) Abnormal bone or other growth3 (0.0%) Central nervous system tumor2 (0.0%) New or recurrent SCFE or AVN2 (0.0%) Carpal tunnel syndrome1 (0.0%) In subjects treated in 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 uU/mL at baseline to 13.0 uU/mL at Month 12 with return to the baseline median level after 3-week post-washout period of GH therapy. In the placebo group there was no change from 8.0 uU/mL at baseline to Month 12, and after the post-washout period, the median level was 9.0 uU/mL. The between-treatment group difference on the change from baseline to Month 12 in median fasting insulin level was significant, < 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 uU/mL at baseline to 20.0 uU/mL at Month 12, in the Nutropin 0.0125 mg/kg/day group from 8.5 uU/mL to 11.0 uU/mL, and in the placebo group from 7.0 uU/mL to 8.0 uU/mL. The between-treatment group differences for these changes were significant, = 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, = 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, = 0.009.. 6.2 Immunogenicity. As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Nutropin with the incidence of antibodies to other products may be misleading. In the case of GH, antibodies with binding capacities lower than mg/L have not been associated with growth attenuation. In very small number of patients treated with somatropin, when binding capacity was greater than 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 >= mg/L at six months. In 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 >= mg/L.Additional short-term immunologic and renal function studies were carried out in group of pediatric patients with CKD after approximately one year of treatment to detect other potential adverse effects of antibodies to GH. Testing included measurements of C1q, C3, C4, rheumatoid factor, creatinine, creatinine clearance, and blood urea nitrogen (BUN). No adverse effects of GH antibodies were noted. 6.3 Post-Marketing Experience Because these adverse events are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. The adverse events reported during post-marketing surveillance do not differ from those listed/discussed above in Sections 6.1 and 6.2 in children and adults.Serious systemic hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with postmarketing use of somatropin products [see Warnings and Precautions (5.6)]. Leukemia has been reported in small number of GHD children treated with somatropin, somatrem (methionylated rhGH) and GH of pituitary origin. It is uncertain whether these cases of leukemia are related to GH therapy, the pathology of GHD itself, or other associated treatments such as radiation therapy. On the basis of current evidence, experts have not been able to conclude that GH therapy per se was responsible for these cases of leukemia. The risk for children with GHD, CKD, or TS, if any, remains to be established [see Contraindications (4) and Warnings and Precautions (5.3)]. The following additional adverse reactions have been reported in GH-treated patients: gynecomastia (children), and pancreatitis [(Children and adults, see Warnings and Precautions (5.16)].

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 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 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 consequence of the direct effects of somatropin (e.g., lipolysis) [see Clinical Pharmacology (12.2)]. 12.2 Pharmacodynamics. In vitro and in vivo preclinical and clinical testing have demonstrated that Nutropin AQ is therapeutically equivalent to pituitary-derived hGH. Pediatric patients who lack adequate endogenous growth hormone (GH) secretion, patients with chronic kidney disease (CKD), and patients with Turner syndrome (TS) that were treated with Nutropin AQ or Nutropin resulted in an increase in growth rate and an increase in IGF-1 levels similar to that seen with pituitary-derived hGH.. Tissue GrowthA) Skeletal Growth: Nutropin AQ stimulates skeletal growth in pediatric patients with growth failure due to 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 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.B) Cell Growth: Treatment with somatropin results in an increase in both the number and the size of skeletal muscle cells. C) 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.. A) Skeletal Growth: Nutropin AQ stimulates skeletal growth in pediatric patients with growth failure due to 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 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.. B) Cell Growth: Treatment with somatropin results in an increase in both the number and the size of skeletal muscle cells. C) 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 decline in urinary nitrogen excretion and blood urea nitrogen (BUN) during somatropin therapy.. Carbohydrate Metabolism GH is modulator of carbohydrate metabolism. For example, patients with inadequate secretion of GH sometimes experience fasting hypoglycemia that is improved by treatment with Nutropin AQ. Somatropin therapy may decrease insulin sensitivity. Untreated patients with CKD and TS have an increased incidence of glucose intolerance. Administration of somatropin to adults or children resulted in increases in serum fasting and postprandial insulin levels, more commonly in overweight or obese individuals. In addition, mean fasting and postprandial glucose and hemoglobin A1C levels remained in the normal range.. Lipid Metabolism In GHD patients, administration of somatropin resulted in lipid mobilization, reduction in body fat stores, increased plasma fatty acids, and decreased plasma cholesterol levels.. Mineral Metabolism The retention of total body potassium in response to somatropin administration apparently results from cellular growth. Serum levels of inorganic phosphorus may increase slightly in patients with inadequate secretion of endogenous GH, CKD, or TS during Nutropin AQ therapy due to metabolic activity associated with bone growth as well as increased tubular reabsorption of phosphate by the kidney. Serum calcium is not significantly altered in these patients. Sodium retention also occurs. Adults with childhood-onset GHD show low bone mineral density (BMD). Nutropin AQ therapy results in increases in serum alkaline phosphatase [see Warnings and Precautions (5.14)].. Connective Tissue Metabolism GH stimulates the synthesis of chondroitin sulfate and collagen as well as the urinary excretion of hydroxyproline.. 12.3 Pharmacokinetics. Absorption The absolute bioavailability of somatropin after subcutaneous administration in healthy adult males has been determined to be 81 +- 20%. The mean terminal t1/2 after subcutaneous administration is significantly longer than that seen after intravenous administration (2.1 +- 0.43 hours vs. 19.5 +- 3.1 minutes) indicating that the subcutaneous absorption of the compound is slow and rate-limiting.. Distribution Animal studies with somatropin showed that GH localizes to highly perfused organs, particularly the liver and kidney. The volume of distribution at steady state for somatropin in healthy adult males is about 50 mL/kg body weight, approximating the serum volume.. Metabolism Both the liver and kidney have been shown to be important metabolizing organs for GH. Animal studies suggest that the kidney is the dominant organ of clearance. GH is filtered at the glomerulus and reabsorbed in the proximal tubules. It is then cleaved within renal cells into its constituent amino acids, which return to the systemic circulation.. Elimination The mean terminal t1/2 after intravenous administration of somatropin in healthy adult males is estimated to be 19.5 +- 3.1 minutes. Clearance of rhGH after intravenous administration in healthy adults and children is reported to be in the range of 116-174 mL/hr/kg.. Bioequivalence of Formulations Nutropin AQ has been determined to be bioequivalent to Nutropin based on the statistical evaluation of area under the curve (AUC) and maximum concentration (Cmax).. Special Populations. Pediatric: Available literature data suggests that somatropin clearances are similar in adults and children.. Geriatrics: Limited published data suggest that the plasma clearance and average steady-state plasma concentration of somatropin may not be different between young and elderly patients.. Race: Reported values for half-lives for endogenous GH in normal adult black males are not different from observed values for normal adult white males. No data for other races are available.. Growth Hormone Deficiency: Reported values for clearance of somatropin in adults and children with GHD range 138-245 mL/hr/kg and are similar to those observed in healthy adults and children. Mean terminal t1/2 values following intravenous and subcutaneous administration in adult and pediatric GHD patients are also similar to those observed in healthy adult males.. Chronic Kidney Disease: Children and adults with CKD and end-stage renal disease (ESRD) tend to have decreased clearance compared to normals. In study with six pediatric patients 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: 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 Summary of Nutropin AQ Pharmacokinetic Parameters in Healthy Adult Males 0.1 mg (approximately 0.3 IUBased on current International Standard of IU 1 mg.)/kg SCCmax (ug/L)Tmax (hr)t1/2 (hr)AUC0- (ug hr/L)CL/Fsc (mL/[hr kg])Abbreviations: AUC0- area under the curve, Cmax maximum concentration, CL/Fsc systemic clearance, CV% coefficient of variation in %; SC subcutaneous, Fsc subcutaneous bioavailability (not determined), t1/2 half-life.MEANn 36. 71.13.92.3677150CV%1756181313Figure 1Single Dose Mean Growth Hormone Concentrations in Healthy Adult Males. Figure 1.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 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 mean duration of 2.7 +- 1.2 years, by analysis of covariance (ANCOVA) adjusting for baseline height, is shown below.Table Last Measured HeightAdjusted for baseline height by Sex and Nutropin Dose for Pubertal Patients with GHDLast Measured Height (cm) Height Difference Between Groups (cm)Age (yr)0.3 mg/kg/wk0.7 mg/kg/wkMean +- SD (range)Mean +- SDMean +- SDMean +- SEMale17.2 +- 1.3(13.6 to 19.4)170.9 +- 7.9(n 42)174.5 +- 7.9(n 41)3.6 +- 1.7Female15.8 +- 1.8(11.9 to 19.3)154.7 +- 6.3(n 7)157.6 +- 6.3(n 7)2.9 +- 3.4 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, = 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, = 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, = 21). Over 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.. 14.2 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 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 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 significant increase in mean height SDS in the Nutropin group (-2.9 at baseline to -1.5 at Month 24, = 62) but no significant change in the controls (-2.8 at baseline to -2.9 at Month 24, = 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 years post-transplant, the corresponding changes in height SDS were also similar between groups. 14.3 Pediatric Patients with Turner Syndrome (TS). Three US studies, two long-term, open-label, multicenter, historically controlled studies (Studies 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 and 2, the effect of long-term GH treatment (0.375 mg/kg/week given either 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 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 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 mean adult height gain of 5.0 cm (n 51). Thus, in Studies 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, randomized, blinded dose-response study, patients were treated from mean age of 11.1 years for mean duration of 5.3 years with weekly GH dose of either 0.27 mg/kg or 0.36 mg/kg administered in divided doses or 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 cm. The Canadian randomized study compared near-adult height outcomes for GH-treated patients to those of concurrent control group who received no injections. The somatropin-treated patients received dosage of 0.3 mg/kg/week given in divided doses times per week from mean age of 11.7 years for mean duration of 4.7 years. Puberty was induced with standardized estrogen regimen initiated at 13 years of age for both treatment groups. The somatropin-treated group (n 27) attained mean (+- SD) near final height of 146.0 +- 6.2 cm; the untreated control group (n 19) attained 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 mean height increase of 5.4 cm (p 0.001). In summary, patients with TS (total = 181 from the studies above) treated to adult height achieved statistically significant average height gains ranging from 5.0-8.3 cm.Table Summary of Efficacy Results in Turner Syndrome Data shown are mean values. StudyGroupStudy DesignRCT: randomized controlled trial; MHT: matched historical controlled trial;RDT: randomized dose-response trial. at Adult HeightGH Age (yr)Estrogen Age (yr)GH Duration (yr)Adult Height Gain (cm)Analysis of covariance vs. controls. US 1MHT179.115.27.67.4US 2AA 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. MHT299.415.06.18.3B 269.612.35.65.9C 5112.713.73.85.0US 3RDT3111.18-13.55.3~5Compared with historical data. CanadianRCT2711.7134.75.4. 14.4 Pediatric Patient with Idiopathic Short Stature (ISS). 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 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 subjects 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 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 Long-Term Efficacy in ISS (Mean +- SD)CharacteristicMales (n 60)Females (n 23)Adult height (cm)166.3 +- 5.8153.1 +- 4.8Pretreatment predicted adult height (cm)161.1 +- 5.5147.1 +- 5.1Adult height minus pretreatment predicted adult height (cm)+ 5.2 +- 5.0p 0.0001 versus zero. 6.0 +- 5.0 Adult height SDS-1.5 +- 0.8-1.6 +- 0.7Pretreatment predicted adult height SDS-2.2 +- 0.8-2.5 +- 0.8Adult height minus pretreatment predicted adult height SDS+ 0.7 +- 0.7 0.9 +- 0.8 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.. 14.5 Adult Growth Hormone Deficiency. Two multicenter, double-blind, placebo-controlled clinical trials were conducted in growth hormone-deficient adults. Study 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 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 weeks after completion of therapy; mean lean body mass in the Nutropin group was 65.0%, change of 2.8% from baseline, compared with 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 Mean Changes from Baseline to Month 12 in Proportion of Fat and Lean by DEXA for Adult- and Childhood- Onset GHD StudiesAdult Onset(Study 1)Childhood Onset(Study 2)ProportionPlacebo (n 62)Nutropin (n 63)Between-Groups t-test p-valuePlacebo (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-valueNA not availableTotal body percent fatBaseline36.835.00.3835.037.138.40.45Month 1236.831.5--35.231.332.1--Baseline to Month 12 change-0.1-3.6< 0.0001+ 0.2-5.8-6.3< 0.0001Post-washout36.432.2--NANANA--Baseline to post-washout change-0.4-2.8< 0.0001NANANA--Trunk percent fatBaseline35.333.90.5032.537.936.70.23Month 1235.429.5--33.130.629.0--Baseline to Month 12 change0.0-4.3< 0.0001+ 0.6-7.3-7.6< 0.0001Post-washout34.930.5--NANANA--Baseline to post-washout change-0.3-3.4--NANANA--Total body percent leanBaseline60.462.20.3762.060.059.10.48Month 1260.565.7--61.866.065.5--Baseline to Month 12 change+ 0.2+ 3.6< 0.0001-0.2+ 6.0+ 6.4< 0.0001Post-washout60.965.0--NANANA--Baseline to post-washout change+ 0.4+ 2.8< 0.0001NANANA-- 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, < 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, < 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, < 0.03); 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. 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. 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 6.7% VAT loss in the Nutropin AQ group (mean percent change from baseline to Week 32) compared with 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 Visceral Adipose Tissue by Computed Tomography Scan: Percent Change and Absolute Change from Baseline to Week 32 in Study 3Nutropin AQ (n 44)Untreated (n 19)Treatment Difference (adjusted mean)p-valueVAT visceral adipose tissue.Baseline VAT (cm2) (mean)126.2123.3Change in VAT (cm2) (adjusted mean)- 10.7+ 8.4- 19.10.013ANCOVA using baseline VAT as covariate Percent change in VAT (adjusted mean)- 6.7+ 7.5- 14.20.012.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. For subcutaneous injection. Therapy with Nutropin AQ should be supervised by physician who is experienced in the diagnosis and management of pediatric patients with short stature associated with growth hormone deficiency (GHD), chronic kidney disease, Turner syndrome, idiopathic short stature, or adult patients with either childhood-onset or adult-onset GHD. Nutropin AQ should be administered subcutaneously (2).Injection sites should always be rotated to avoid lipoatrophy (2.3).Pediatric GHD: Up to 0.3 mg/kg/week (2.1)Pubertal Patients: Up to 0.7 mg/kg/week (2.1)Idiopathic Short Stature: Up to 0.3 mg/kg/week (2.1)Chronic Kidney Disease: Up to 0.35 mg/kg/week (2.1)Turner Syndrome: Up to 0.375 mg/kg/week (2.1)Adult GHD: Either non-weight based or weight-based dosing regimen may be followed, with doses adjusted based on treatment response and IGF-I concentrations (2.2). Non-weight-based: starting dose of approximately 0.2 mg/day (range 0.15-0.3 mg/day) increased gradually every 1-2 months by increments of approximately 0.1-0.2 mg/day. Weight-based: Initiate from not more than 0.006 mg/kg/day; the dose may be increased up to maximum of 0.025 mg/kg/day in patients <= 35 years old or 0.0125 mg/kg/day in patients 35 years old.. Pediatric GHD:. Up to 0.3 mg/kg/week (2.1). Pubertal Patients:. Up to 0.7 mg/kg/week (2.1). Idiopathic Short Stature:. Up to 0.3 mg/kg/week (2.1). Chronic Kidney Disease:. Up to 0.35 mg/kg/week (2.1). Turner Syndrome:. Up to 0.375 mg/kg/week (2.1). Adult GHD: Either non-weight based or weight-based dosing regimen may be followed, with doses adjusted based on treatment response and IGF-I concentrations (2.2). Non-weight-based: starting dose of approximately 0.2 mg/day (range 0.15-0.3 mg/day) increased gradually every 1-2 months by increments of approximately 0.1-0.2 mg/day. Weight-based: Initiate from not more than 0.006 mg/kg/day; the dose may be increased up to maximum of 0.025 mg/kg/day in patients <= 35 years old or 0.0125 mg/kg/day in patients 35 years old.. 2.1 Dosing for Pediatric Patients. Nutropin AQ dosage and administration schedule should be individualized for each patient. Response to growth hormone (GH) therapy in pediatric patients tends to decrease with time. However, in pediatric patients failure to increase growth rate, particularly during the first year of therapy, suggests the need for close assessment of compliance and evaluation of other causes of growth failure, such as hypothyroidism, under-nutrition, advanced bone age and antibodies to recombinant human GH (rhGH). Treatment with Nutropin AQ for short stature should be discontinued when the epiphyses are fused.. Pediatric Growth Hormone Deficiency (GHD) weekly dosage of up to 0.3 mg/kg of body weight divided into daily subcutaneous injection is recommended. In pubertal patients, weekly dosage of up to 0.7 mg/kg divided daily may be used.. Growth Failure Secondary to Chronic Kidney Disease (CKD) 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 to 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.. Hemodialysis patients should receive their injection at night just prior to going to sleep or at least to 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) 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) weekly dosage of up to 0.375 mg/kg of body weight divided into equal doses to times per week by subcutaneous injection is recommended.. 2.2 Dosing for Adult Patients. Adult Growth Hormone Deficiency (GHD) Either of two approaches to Nutropin AQ dosing may be followed: weight-based regimen or 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 maximum of 0.025 mg/kg daily in patients <= 35 years and to 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, 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 to 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. 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 weight-based regimen. In order to reach the defined treatment goal, estrogen-replete women may need higher doses than men. Oral estrogen administration may increase the dose requirements in women.. 2.3 Preparation and Administration. The solution should be clear immediately after removal from the refrigerator. Occasionally, after refrigeration, you may notice that small colorless particles of protein are present in the solution. This is not unusual for solutions containing proteins. Allow the pen cartridge or NuSpin(R) 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 CartridgeThe Nutropin AQ Pen 10 and 20 mg Cartridges are color-banded to help ensure appropriate use with the Nutropin AQ Pen delivery device. Each cartridge must be used with its corresponding color-coded Nutropin AQ Pen [See Dosage Forms and Strengths (3)]. Wipe the septum of the Nutropin AQ Pen Cartridge with rubbing alcohol or an antiseptic solution to prevent contamination of the contents by microorganisms that may be introduced by repeated needle insertions. It is recommended that Nutropin AQ be administered using sterile, disposable needles. Follow the directions provided in the Nutropin AQ Pen Instructions for Use. The Nutropin AQ Pen 10 allows for administration of minimum dose of 0.1 mg to maximum dose of 4.0 mg, in 0.1 mg increments. The Nutropin AQ Pen 20 allows for administration of minimum dose of 0.2 mg to 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 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 allows for administration of minimum dose of 0.05 mg to maximum dose of 1.75 mg, in increments of 0.05 mg. The Nutropin AQ NuSpin 10 allows for administration of minimum dose of 0.1 mg to maximum dose of 3.5 mg, in increments of 0.1 mg. The Nutropin AQ NuSpin 20 allows for administration of minimum dose of 0.2 mg to maximum dose of 7.0 mg, in increments of 0.2 mg.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Inhibition of 11 -Hydroxysteroid Dehydrogenase Type 1: May require the initiation of glucocorticoid replacement therapy. Patients treated with glucocorticoid replacement for previously diagnosed hypoadrenalism may require an increase in their maintenance doses (7.1, 7.2).Glucocorticoid replacement: Should be carefully adjusted (7.2).Cytochrome P450 Metabolized Drugs: Monitor carefully if used with somatropin (7.3).Oral estrogen: Larger doses of somatropin may be required in women (7.4).Insulin and/or other hypoglycemic agents: May require adjustment (7.5).. Inhibition of 11 -Hydroxysteroid Dehydrogenase Type 1: May require the initiation of glucocorticoid replacement therapy. Patients treated with glucocorticoid replacement for previously diagnosed hypoadrenalism may require an increase in their maintenance doses (7.1, 7.2).. Glucocorticoid replacement: Should be carefully adjusted (7.2).. Cytochrome P450 Metabolized Drugs: Monitor carefully if used with somatropin (7.3).. Oral estrogen: Larger doses of somatropin may be required in women (7.4).. Insulin and/or other hypoglycemic agents: May require adjustment (7.5).. 7.1 11 -Hydroxysteroid Dehydrogenase Type (11HSD-1). The microsomal enzyme 11HSD-1 is required for conversion of cortisone to its active metabolite, cortisol, in hepatic and adipose tissue. Growth hormone (GH) and somatropin inhibit 11HSD-1. Consequently, individuals with untreated GH deficiency have relative increases in 11HSD-1 and serum cortisol. Introduction of somatropin treatment may result in inhibition of 11HSD-1 and reduced serum cortisol concentrations. As 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 11HSD-1.. 7.2 Pharmacologic Glucocorticoid Therapy and Supraphysiologic Glucocorticoid Treatment. Pharmacologic glucocorticoid therapy and supraphysiologic glucocorticoid treatment may attenuate the growth-promoting effects of somatropin in children. Therefore, glucocorticoid replacement therapy should be carefully adjusted in children with concomitant GH and glucocorticoid deficiency to avoid both hypoadrenalism and an inhibitory effect on growth. The use of Nutropin AQ in patients with Chronic Kidney Disease (CKD) requiring glucocorticoid therapy has not been evaluated. Concomitant glucocorticoid therapy may inhibit the growth promoting effect of Nutropin AQ. Therefore, if glucocorticoid replacement is required for CKD, the glucocorticoid dose should be carefully adjusted to avoid an inhibitory effect on growth. In the clinical trials there was no evidence of drug interactions with Nutropin and commonly used drugs used in the management of CKD.. 7.3 Cytochrome P450 (CYP450)-Metabolized Drugs. Limited published data indicate that somatropin treatment increases CYP450-mediated antipyrine clearance in man. These data suggest that somatropin administration may alter the clearance of compounds known to be metabolized by CYP450 liver enzymes (e.g., corticosteroids, sex steroids, anticonvulsants, cyclosporine). Careful monitoring is advisable when somatropin is administered in combination with other drugs known to be metabolized by CYP450 liver enzymes. However, formal drug interaction studies have not been conducted.. 7.4 Oral Estrogen. Because oral estrogens may reduce insulin-like growth factor (IGF-1) response to somatropin treatment, girls and women receiving oral estrogen replacement may require greater somatropin dosages [see Dosage and Administration (2.2)].. 7.5 Insulin and/or Oral/Injectable Hypoglycemic Agents. In patients with diabetes mellitus requiring drug therapy, the dose of insulin and/or oral/injectable hypoglycemic agents may require adjustment when somatropin therapy is initiated [see Warnings and Precautions (5.4)].

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. In vitro and in vivo preclinical and clinical testing have demonstrated that Nutropin AQ is therapeutically equivalent to pituitary-derived hGH. Pediatric patients who lack adequate endogenous growth hormone (GH) secretion, patients with chronic kidney disease (CKD), and patients with Turner syndrome (TS) that were treated with Nutropin AQ or Nutropin resulted in an increase in growth rate and an increase in IGF-1 levels similar to that seen with pituitary-derived hGH.. Tissue GrowthA) Skeletal Growth: Nutropin AQ stimulates skeletal growth in pediatric patients with growth failure due to 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 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.B) Cell Growth: Treatment with somatropin results in an increase in both the number and the size of skeletal muscle cells. C) 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.. A) Skeletal Growth: Nutropin AQ stimulates skeletal growth in pediatric patients with growth failure due to 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 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.. B) Cell Growth: Treatment with somatropin results in an increase in both the number and the size of skeletal muscle cells. C) 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 decline in urinary nitrogen excretion and blood urea nitrogen (BUN) during somatropin therapy.. Carbohydrate Metabolism GH is modulator of carbohydrate metabolism. For example, patients with inadequate secretion of GH sometimes experience fasting hypoglycemia that is improved by treatment with Nutropin AQ. Somatropin therapy may decrease insulin sensitivity. Untreated patients with CKD and TS have an increased incidence of glucose intolerance. Administration of somatropin to adults or children resulted in increases in serum fasting and postprandial insulin levels, more commonly in overweight or obese individuals. In addition, mean fasting and postprandial glucose and hemoglobin A1C levels remained in the normal range.. Lipid Metabolism In GHD patients, administration of somatropin resulted in lipid mobilization, reduction in body fat stores, increased plasma fatty acids, and decreased plasma cholesterol levels.. Mineral Metabolism The retention of total body potassium in response to somatropin administration apparently results from cellular growth. Serum levels of inorganic phosphorus may increase slightly in patients with inadequate secretion of endogenous GH, CKD, or TS during Nutropin AQ therapy due to metabolic activity associated with bone growth as well as increased tubular reabsorption of phosphate by the kidney. Serum calcium is not significantly altered in these patients. Sodium retention also occurs. Adults with childhood-onset GHD show low bone mineral density (BMD). Nutropin AQ therapy results in increases in serum alkaline phosphatase [see Warnings and Precautions (5.14)].. Connective Tissue Metabolism GH stimulates the synthesis of chondroitin sulfate and collagen as well as the urinary excretion of hydroxyproline.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Absorption The absolute bioavailability of somatropin after subcutaneous administration in healthy adult males has been determined to be 81 +- 20%. The mean terminal t1/2 after subcutaneous administration is significantly longer than that seen after intravenous administration (2.1 +- 0.43 hours vs. 19.5 +- 3.1 minutes) indicating that the subcutaneous absorption of the compound is slow and rate-limiting.. Distribution Animal studies with somatropin showed that GH localizes to highly perfused organs, particularly the liver and kidney. The volume of distribution at steady state for somatropin in healthy adult males is about 50 mL/kg body weight, approximating the serum volume.. Metabolism Both the liver and kidney have been shown to be important metabolizing organs for GH. Animal studies suggest that the kidney is the dominant organ of clearance. GH is filtered at the glomerulus and reabsorbed in the proximal tubules. It is then cleaved within renal cells into its constituent amino acids, which return to the systemic circulation.. Elimination The mean terminal t1/2 after intravenous administration of somatropin in healthy adult males is estimated to be 19.5 +- 3.1 minutes. Clearance of rhGH after intravenous administration in healthy adults and children is reported to be in the range of 116-174 mL/hr/kg.. Bioequivalence of Formulations Nutropin AQ has been determined to be bioequivalent to Nutropin based on the statistical evaluation of area under the curve (AUC) and maximum concentration (Cmax).. Special Populations. Pediatric: Available literature data suggests that somatropin clearances are similar in adults and children.. Geriatrics: Limited published data suggest that the plasma clearance and average steady-state plasma concentration of somatropin may not be different between young and elderly patients.. Race: Reported values for half-lives for endogenous GH in normal adult black males are not different from observed values for normal adult white males. No data for other races are available.. Growth Hormone Deficiency: Reported values for clearance of somatropin in adults and children with GHD range 138-245 mL/hr/kg and are similar to those observed in healthy adults and children. Mean terminal t1/2 values following intravenous and subcutaneous administration in adult and pediatric GHD patients are also similar to those observed in healthy adult males.. Chronic Kidney Disease: Children and adults with CKD and end-stage renal disease (ESRD) tend to have decreased clearance compared to normals. In study with six pediatric patients 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: 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 Summary of Nutropin AQ Pharmacokinetic Parameters in Healthy Adult Males 0.1 mg (approximately 0.3 IUBased on current International Standard of IU 1 mg.)/kg SCCmax (ug/L)Tmax (hr)t1/2 (hr)AUC0- (ug hr/L)CL/Fsc (mL/[hr kg])Abbreviations: AUC0- area under the curve, Cmax maximum concentration, CL/Fsc systemic clearance, CV% coefficient of variation in %; SC subcutaneous, Fsc subcutaneous bioavailability (not determined), t1/2 half-life.MEANn 36. 71.13.92.3677150CV%1756181313Figure 1Single Dose Mean Growth Hormone Concentrations in Healthy Adult Males. Figure 1.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Acute critical illness: Evaluate potential benefit of treatment continuation against potential risk (5.1).PWS: Evaluate for signs of upper airway obstruction and sleep apnea before initiating therapy. Discontinue treatment if these signs occur. (5.2).Neoplasm: Monitor patients with preexisting tumors for progression or reoccurrence. Increased risk of second neoplasm in childhood cancer survivors treated with somatropin in particular meningiomas in patients treated with radiation to the head for their first neoplasm. (5.3).Impaired glucose tolerance (IGT) and Diabetes Mellitus (DM): Periodically monitor glucose levels in all patients, as IGT and DM may be unmasked during somatropin therapy. Doses of concurrent antihyperglycemic drugs in patients with DM may require adjustment. (5.4).Intracranial hypertension (IH): Exclude preexisting papilledema. IH may develop, but is usually reversible after discontinuation or dose reduction (5.5).Hypersensitivity: Serious hypersensitivity reactions may occur. In the event of an allergic reaction, seek prompt medical attention (5.6).Fluid retention (e.g., edema, arthralgia, carpal tunnel syndrome- especially in adults): Reduce dose as necessary if such signs develop (5.7).Hypoadrenalism: Monitor patients for reduced serum cortisol levels and/or need for glucocorticoid dose increase in those with known hypoadrenalism (5.8).Hypothyroidism: Monitor thyroid function periodically as it may first become evident or worsen after initiation of somatropin (5.9).Slipped capital femoral epiphysis (SCFE): Evaluate any child with onset of limp or hip/knee pain for possible SCFE (5.10).Progression of preexisting scoliosis: Monitor any child with scoliosis for progression of the curve (5.11).Pancreatitis: Consider pancreatitis in patients with persistent severe abdominal pain (5.16). Acute critical illness: Evaluate potential benefit of treatment continuation against potential risk (5.1).. PWS: Evaluate for signs of upper airway obstruction and sleep apnea before initiating therapy. Discontinue treatment if these signs occur. (5.2).. Neoplasm: Monitor patients with preexisting tumors for progression or reoccurrence. Increased risk of second neoplasm in childhood cancer survivors treated with somatropin in particular meningiomas in patients treated with radiation to the head for their first neoplasm. (5.3).. Impaired glucose tolerance (IGT) and Diabetes Mellitus (DM): Periodically monitor glucose levels in all patients, as IGT and DM may be unmasked during somatropin therapy. Doses of concurrent antihyperglycemic drugs in patients with DM may require adjustment. (5.4).. Intracranial hypertension (IH): Exclude preexisting papilledema. IH may develop, but is usually reversible after discontinuation or dose reduction (5.5).. Hypersensitivity: Serious hypersensitivity reactions may occur. In the event of an allergic reaction, seek prompt medical attention (5.6).. Fluid retention (e.g., edema, arthralgia, carpal tunnel syndrome- especially in adults): Reduce dose as necessary if such signs develop (5.7).. Hypoadrenalism: Monitor patients for reduced serum cortisol levels and/or need for glucocorticoid dose increase in those with known hypoadrenalism (5.8).. Hypothyroidism: Monitor thyroid function periodically as it may first become evident or worsen after initiation of somatropin (5.9).. Slipped capital femoral epiphysis (SCFE): Evaluate any child with onset of limp or hip/knee pain for possible SCFE (5.10).. Progression of preexisting scoliosis: Monitor any child with scoliosis for progression of the curve (5.11).. Pancreatitis: Consider pancreatitis in patients with persistent severe abdominal pain (5.16). 5.1 Acute Critical Illness. Increased mortality in patients with acute critical illnesses due to complications following open heart surgery, abdominal surgery or multiple accidental trauma, or those with acute respiratory failure has been reported after treatment with pharmacologic amounts of somatropin [see Contraindications (4)]. Two placebo-controlled clinical trials in non-GHD adult patients (n 522) with these conditions in intensive care units revealed significant increase in mortality (42% vs. 19%) among somatropin-treated patients (doses 5.3-8 mg/day) compared to those receiving placebo. The safety of continuing somatropin treatment in patients receiving replacement doses for approved indications who concurrently develop these illnesses has not been established. Therefore, the potential benefit of treatment continuation with somatropin in patients having acute critical illnesses should be weighed against the potential risk.. 5.2 Prader-Willi Syndrome (PWS) in Children. There have been reports of fatalities after initiating therapy with somatropin in pediatric patients with PWS who had one or more of the following risk factors: severe obesity, history of upper airway obstruction or sleep apnea, or unidentified respiratory infection. Male patients with one or more of these factors may be at greater risk than females. Patients with PWS syndrome should be evaluated for signs of upper airway obstruction and sleep apnea before initiation of treatment with somatropin. If during treatment with somatropin, patients show signs of upper airway obstruction (including onset of or increased snoring) and/or new onset sleep apnea, treatment should be interrupted. All patients with PWS treated with somatropin should also have effective weight control and be monitored for signs of respiratory infection, which should be diagnosed as early as possible and treated aggressively [see Contraindications (4)]. Nutropin AQ is not indicated for the treatment of pediatric patients who have growth failure due to genetically confirmed PWS.. 5.3 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 second neoplasm has been reported. Intracranial tumors, in particular meningiomas, were the most common of these second neoplasms. In adults, it is unknown whether there is any relationship between somatropin replacement therapy and CNS tumor recurrence [see Contraindications (4)]. Monitor all patients with 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.. 5.4 Glucose Intolerance and Diabetes Mellitus. Treatment with somatropin may decrease insulin sensitivity, particularly at higher doses in susceptible patients. As result, previously undiagnosed impaired glucose tolerance (IGT) and overt diabetes mellitus may be unmasked during somatropin treatment, and new onset type 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 family history of diabetes mellitus. Patients with preexisting type or type 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.. 5.5 Intracranial Hypertension. Intracranial Hypertension (IH) with papilledema, visual changes, headache, nausea, and/or vomiting has been reported in 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 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 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.. 5.6 Severe Hypersensitivity. Serious systemic hypersensitivity reactions including anaphylactic reaction and angioedema have been reported with postmarketing use of somatropin products. Patients and caregivers should be informed that such reactions are possible and that prompt medical attention should be sought if an allergic reaction occurs.. 5.7 Fluid Retention. Fluid retention during somatropin replacement therapy in adults may occur. Clinical manifestations of fluid retention (e.g., edema, arthralgia, myalgia, nerve compression syndromes including carpal tunnel syndrome/paraesthesias) are usually transient and dose dependent.. 5.8 Hypoadrenalism. Patients receiving somatropin therapy who have or are at risk for pituitary hormone deficiency(s) may be at risk for reduced serum cortisol levels and/or unmasking of central (secondary) hypoadrenalism. In addition, patients treated with glucocorticoid replacement for previously diagnosed hypoadrenalism may require an increase in their maintenance or stress doses following initiation of somatropin treatment [see Section 7.1, 11- Hydroxysteroid Dehydrogenase Type 1]. 5.9 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.. 5.10 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 limp or complaints of hip or knee pain during somatropin therapy should be carefully evaluated.. 5.11 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 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.. 5.12 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.. 5.13 Osteodystrophy in Pediatric Patients with Chronic Kidney Disease. Children with growth failure secondary to CKD should be examined periodically for evidence of progression of renal osteodystrophy. SCFE or avascular necrosis of the femoral head may be seen in children with advanced renal osteodystrophy, and it is uncertain whether these problems are affected by somatropin therapy. X-rays of the hip should be obtained prior to initiating somatropin therapy in CKD patients and physicians and parents should be alert to the development of 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.. 5.14 Lipoatrophy When somatropin is administered subcutaneously at the same site over long period of time, tissue atrophy may result. This can be avoided by rotating the injection site [see Dosage and Administration (2.3)].. 5.15Laboratory Tests. Serum levels of inorganic phosphorus, alkaline phosphatase, and parathyroid hormone (PTH), and IGF-1 may increase during somatropin therapy.. 5.16 Pancreatitis. Cases of pancreatitis have been reported rarely in children and adults receiving somatropin treatment, with some evidence supporting 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 child, who develops persistent severe abdominal pain.