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CLINICAL PHARMACOLOGY General In vitro, pre-clinical and clinical testing have demonstrated that somatropin is therapeutically equivalent to pituitary-derived human growth hormone (pit-hGH). Clinical studies in normal adults also demonstrate equivalent pharmacokinetics. a. Tissue Growth The primary and most intensively studied action of somatropin is the stimulation of linear growth. This effect is demonstrated in children with somatropin deficiency. Skeletal growth - the measurable increase in bone length after administration of somatropin results from its effect on the cartilaginous growth areas of long bones. Studies in vitro have shown that the incorporation of sulfate into proteoglycans is not due to a direct effect of somatropin, but rather is mediated by the somatomedins or insulin-like growth factors (IGF). The somatomedins, among them IGF-1, are polypeptide hormones which are synthesized in the liver, kidney, and various other tissues. IGF-1 levels are low in the serum of growth hormone deficient children with short stature and hypophysectomized humans or animals, but its presence can be demonstrated after treatment with somatropin. Cell growth - it has been shown that the total number of skeletal muscle cells is markedly decreased in children with short stature lacking endogenous growth hormone compared with normal children, and that treatment with somatropin results in an increase in both the number and size of muscle cells. Organ growth - somatropin influences the size of internal organs, and it also increases red cell mass. b. Protein Metabolism Linear growth is facilitated in part by increased cellular protein synthesis. This synthesis and growth are reflected by nitrogen retention, which can be quantitated by observing the decline in urinary nitrogen excretion and blood urea nitrogen following the initiation of somatropin therapy. c. Carbohydrate Metabolism Hypopituitary children sometimes experience fasting hypoglycemia that may be improved by treatment with somatropin. In healthy subjects, large doses of somatropin may impair glucose tolerance. Although the precise mechanism of the diabetogenic effect of somatropin is not known, it is attributed to blocking the action of insulin rather than blocking insulin secretion. Insulin levels in serum actually increase as somatropin levels increase. Administration of somatropin to normal adults and patients with growth hormone deficiency (GHD) results in increases in mean serum fasting and postprandial insulin levels, although mean values remain in the normal range. In addition, mean fasting and postprandial glucose and hemoglobin A1C levels remain in the normal range. d. Lipid Metabolism Somatropin stimulates intracellular lipolysis, and administration of somatropin leads to an increase in plasma free fatty acids and triglycerides. Untreated GHD is associated with increased body fat stores, including increased subcutaneous and visceral adipose tissue in the abdomen. Treatment of growth hormone deficient patients with somatropin results in a general reduction of fat stores, in particular in subcutaneous and visceral abdominal tissue and decreased serum levels of low-density lipoprotein (LDL) cholesterol. e. Mineral Metabolism Administration of somatropin results in the retention of total body potassium and phosphorus, and to a lesser extent sodium. This retention is thought to be the result of cell growth. Serum levels of phosphate increase in patients with GHD after somatropin therapy due to metabolic activity associated with bone growth. Serum calcium levels are not altered. Although calcium excretion in the urine is increased, there is a simultaneous increase in calcium absorption from the intestine. Negative calcium balance, however, may occasionally occur during somatropin treatment. f. Connective Tissue Metabolism Somatropin stimulates the synthesis of chondroitin sulfate and collagen as well as the urinary excretion of hydroxyproline. Pharmacokinetics In a single dose study in 24 healthy volunteers, subcutaneous administration of 0.073 mg/kg of body weight of Valtropin (somatropin injection) ® resulted in a mean maximum serum concentration (Cmax) of 43.97 ng/mL and an area under the curve (AUC0-24h) of 369.90 ng·hr/mL. Cmax was reached at 4.00 hr and terminal elimination half-life was 3.03 hr. The metabolic fate of somatropin involves classical protein catabolism in both the liver and kidneys. In renal cells, at least a portion of the breakdown products is returned to the systemic circulation. Special Populations Pediatric - The pharmacokinetics of somatropin is similar in children and adults. Geriatric - The pharmacokinetic properties of somatropin have not been studied in patients greater than 60 years of age. Gender - No gender studies have been performed. Race - No race studies have been performed. Renal Insufficiency - No studies have been performed in patients with renal insufficiency. Hepatic Insufficiency - No studies have been performed in patients with hepatic insufficiency. Clinical Trials Pediatric Patients With Growth Hormone Deficiency (GHD) A one-year, multicenter, multinational, randomized, double-blind, parallel-group, active- controlled study was conducted in treatment-naive children with GHD and short stature comparing the linear growth effect of Valtropin (somatropin injection) ® with another approved formulation of somatropin. All patients were treated with somatropin 0.033 mg/kg/day administered subcutaneously (SC). One hundred and forty nine children were randomized in a 2:1 ratio to receive Valtropin (somatropin injection) ® (n=99) or the active control (n=50). Combining both treatment groups, mean age was 8.2, 60-70% of patients were male, ~95% were Caucasian, baseline height standard deviation score for chronological age (height SDSCA) was -3.43, and pre-treatment height velocity (HV) was 3.34 cm/yr. These demographic and baseline characteristics were similar in the two treatment groups. Greater than 90% of patients completed the study. The results presented below were obtained from the intent-to-treat (ITT) population (which excluded patients whose height had not been measured with the appropriate stadiometer, who discontinued before 6 months on treatment or whose pre-treatment HV was incomplete) with last observation carried forward (LOCF); and consisted of 88 patients in the Valtropin (somatropin injection) ® group and 41 patients in the active control group. As seen in Table 1, the adjusted mean HV ± SE at 12 months was 11.21 ± 0.23 cm/year in the Valtropin (somatropin injection) ® group versus 11.00 ± 0.32 cm/year in the active control group, and the mean treatment difference was 0.21. Therefore, Valtropin (somatropin injection) ® was non-inferior to the active control. Table 1 Difference Between Groups in Height Velocity (Cm/Yr) at Month 12 in a Double Blind Study in Pediatric Patients with GHD ITT population with LOCF Valtropin® Comparator Raw Mean ± SD (n) at Baseline 3.50 ± 1.45 (88) 3.39 ± 1.02 (41) Raw Mean ± SD (n) at Month 12 11.36 ± 2.92 (88) 10.54 ± 2.61 (41) Adjusted Mean ± SE* (n) at Month 12 11.21 ± 0.23 (88) 11.00 ± 0.32 (41) Treatment Difference (Adjusted Mean)* (95% CI)** 0.21 (-0.48, 0.90) *Adjusted least-squares means were obtained using an ANCOVA model, where treatment and country were the fixed factors and baseline HV, CA, and log maximum GH level after stimulation were the covariates. **Confidence Intervals The within-group changes from baseline to Month 12 for the Valtropin (somatropin injection) ® group only for HV, HV SDSCA, height SDSCA, and predicted adult height (PAH) by the Bayley-Pinneau (B-P) method expressed both in cm and as a SDS are displayed in Table 2. All within-group changes were significant. The 1.21 unit change in height SDSCA and the 8.05 unit change in HV SDSCA are robust and indicate substantial catch-up growth. The results observed in the active control group were similar. Table 2 Valtropin (somatropin injection) ® Group Only Within-Group Change from Baseline to Month 12 in Height Velocity and Other Auxological Secondary Efficacy Endpoints ITT with LOCF Efficacy Variable Valtropin®: Mean ± SD (n) Mean Change from Baseline (95% CI) Baseline Month 12 HV (cm/year) 3.50 ± 1.45 (88) 11.36 ± 2.92 (88) 7.87 (7.18, 8.55) HV SDSCA -2.34 ± 1.78 (88) 5.71 ± 3.44 (88) 8.05 (7.16, 8.94) Height SDSCA -3.54 ± 1.24 (88) -2.33 ± 1.01 (88) 1.21 (1.08, 1.34) PAH (B-P) (cm) 162.27 ± 9.7 (32) 165.77 ± 10.0 (32) 3.51 (1.57, 5.44) PAH SDS (B-P) -1.71 ± 1.10 (32) -1.22 ± 1.08 (32) 0.49 (0.22, 0.76) Bone maturation expressed as the ratio of change from baseline to Month 12 in bone age (BA) to change from baseline to Month 12 in CA was 1.5 ± 0.9 in the Valtropin (somatropin injection) ® group and 1.5 ± 0.7 in the active control group, and not accelerated. Furthermore, as expected after somatropin replacement therapy in children with GHD, mean serum insulin-like growth factor 1 (IGF-1) levels in both groups were significantly increased after 12 months of treatment compared to baseline levels. During the 12-month, open-label extension phase, 82 children continued Valtropin (somatropin injection) ® treatment providing 24-month data for Valtropin (somatropin injection) ®, and 40 patients were switched from the active control to Valtropin (somatropin injection) ®. Growth continued at expected levels for patients on continuous Valtropin (somatropin injection) ® treatment and patients on active control/Valtropin (somatropin injection) treatment. Pediatric Patients With Turner Syndrome (TS) Two open-label, single-arm, uncontrolled clinical trials were conducted that evaluated the efficacy and safety of Valtropin (somatropin injection) ® and EutropinTM INJ (a 4 IU formulation qualitatively identical to the 15 IU formulation, Valtropin (somatropin injection) ®) in TS patients with short stature. During Study 1 (conducted at a single center in Russia), 30 Caucasian girls (mean age = 6.9 yr) were treated with Valtropin (somatropin injection) ® 0.053 mg/kg/day SC for 12 months. During Study 2 (conducted at four centers in Korea), 60 Asian girls (mean age = 10.8 yr) were treated with Eutropin™ INJ 0.048 mg/kg/day SC (or 0.056 mg/kg SC 6 days per week) for 12 months. In Studies 1 and 2, pre-treatment HV were 3.75 cm/yr and 3.48 cm/yr, respectively, and baseline height SDSCA were -2.42 and -3.02, respectively. All of the results presented below were obtained from the ITT population. As seen in Table 3, mean change in HV from baseline to Month 12 (the primary efficacy variable for both studies) was 5.98 cm/yr (mean HV at Month 12 = 9.73 cm/yr) and 3.49 cm/yr (mean HV at Month 12 = 6.97 cm/yr) in Studies 1 and 2, respectively. The results obtained with respect to other auxological secondary efficacy parameters are also presented for both studies in Table 3. A significant increase in height SDSCA was observed in both studies (0.88 and 0.35 in Studies 1 and 2, respectively), and a substantial increase in HV SDSCA was seen in Study 1 (6.22). B-P PAH increased significantly as well (~4 cm) in Study 1. Bone maturation (calculated as the ratio of change in BA to change in CA) was not accelerated (1.02 ± 0.35) in Study 1. In Study 2, height age (HA)/BA ratio increased from 0.85 at baseline to 0.88 at Month 12, indicating that HA advanced more rapidly than BA (Table 3). As expected after somatropin treatment, mean serum IGF-1 levels in both studies were significantly increased after 12 months of treatment compared to baseline levels. Table 3 Change from Baseline to Month 12 in Height Velocity and Other Auxological Secondary Efficacy Endpoints After Treatment with Somatropin in Girls with Short Stature Associated with Turner Syndrome in 2 Open Label Studies Efficacy Variable Study Mean ± SD (n) Mean Change from Baseline (95% CI) Month 0 Month 12 HV (cm/yr)* Study 1 3.75 ± 1.76 (30) 9.73 ± 1.55 (30) 5.98 (5.20, 6.76) Study 2 3.48 ± 1.40 (58) 6.97 ± 1.84 (58) 3.49 (2.94, 4.03) HV SDSCA Study 1 -2.39 ± 1.90 (30) 3.82 ± 1.95 (30) 6.22 (5.22, 7.21) Study 2 NA NA NA NA Height SDSCA Study 1 -2.42 ± 0.91 (30) -1.54 ± 0.94 (30) 0.88 (0.78, 0.98) Study 2 -3.02 ± 0.96 (58) -2.67 ± 0.99 (58) 0.35 (0.23, 0.46) PAH (B-P) (cm) Study 1 152.0 ± 5.23 (14) 156.0 ± 4.21 (14) 4.04 (2.89, 5.19) Study 2 NA NA NA NA HA/BA Study 1 NA NA NA NA Study 2 0.85 ± 0.15 (58) 0.88 ± 0.12 (58) 0.03 (0.00, 0.05) *Change in HV was the primary efficacy endpoint in both studies and the results are therefore boldened and italicized. NA=Not available. Adult Patients With Growth Hormone Deficiency (GHD) A 6-month, multicenter, randomized, double-blind, placebo-controlled, 3-arm (with 2 arms having a crossover design) clinical trial was conducted in 92 adults (mean age 45-55) with either adult onset (AO) (93.5% of the ITT population) or childhood onset (CO) GHD comparing the effects of Eutropin™ INJ (a 4 IU formulation qualitatively identical to the 15 IU formulation, Valtropin (somatropin injection) ®) and placebo. During treatment period 1 (baseline through the end of Month 3), patients in the active treatment arms (groups A and B) were treated with Eutropin™ INJ at an initial dose of 0.33 mg/day administered SC (6 days per week) for 1 month. During the next 2 months, the dose was up-titrated as necessary in small increments to a maximum of 0.66 mg/day (6 days per week) if serum IGF-1 levels were less than optimal or down-titrated in the presence of significant adverse events or inappropriately elevated serum IGF-1 levels. Patients in group C received placebo for the entire 3 month period. During treatment period 2 (Month 4 through the end of Month 6), patients in group A continued to receive Eutropin™ INJ, patients in group B were crossed over to placebo, and patients in group C were crossed over to Eutropin™ INJ. Change in fat mass (FM) was the primary efficacy variable and change in lean body mass (LBM) was the most consequential secondary efficacy variable. The results obtained for changes (decreases) in FM are presented in Tables 4, 5 and 6. As seen in Table 4, after 3 months of treatment with EutropinTM INJ vs. placebo, there was a significant (p=0.003) between-group treatment difference for the change in FM (-1.35 kg). Table 5 depicts the significant (p<0.0001) within-group change in FM (-1.3 kg) after 3 months of treatment with EutropinTM INJ for groups A+B combined (for group A alone, the significant within-group change in FM after 3 months of treatment was -1.7 kg [see Table 6]; during treatment period 2, when patients in group C were crossed over to EutropinTM INJ from placebo, a similar significant within-group change in FM was observed [-1.2 kg; data not shown in a table]). Table 6 also reflects the significant (p<0.0001) within-group change in FM (-2.3 kg) after 6 months of treatment with EutropinTM INJ for group A alone. Furthermore, as seen in Table 6, the within-group change in FM between Month 4 and the end of Month 6 for group A alone was -0.6 kg; this change was not statistically significant suggesting that most of the decrease in FM after treatment with EutropinTM INJ occurred by the end of Month 3. Table 4 Between-Group Change in Fat Mass After 3 Months of Treatment with EutropinTM INJ (Groups A+B) vs. Placebo (Group C) ITT Population with LOCF Groups A and B Combined (n=58) EutropinTM INJ Group C (n=31) Placebo Baseline (Mean ± SD) 23.0 ± 7.7 19.9 ± 3.7 Change from Baseline to Month 3 (Mean ± SD) -1.25 ± 2.18 +0.16 ± 1.50 Change from Baseline to Month 3 (Adjusted Mean ± SE)* -1.17 ± 0.25 +0.18 ± 0.35 Treatment Difference (Adjusted Mean)* (95% CI) p-value -1.35 (-0.48, -2.22) p = 0.003 *Adjusted least-squares means were obtained using an ANCOVA model, where baseline FM and age were the covariates. Table 5 Within-Group Changes in Fat Mass After 3 Months of Treatment With EutropinTM INJ (Groups A+B) vs. Placebo (Group C) Groups A+B Combined EutropinTM INJ Group C Placebo ITT Population n n Baseline (Mean ± SD) 58 23.0 ± 7.7 31 19.9 ± 3.7 Month 3 (Mean ± SD) 58 21.7 ± 7.7 31 20.2 ± 3.5 Paired t-test p-value

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 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 Tissue Growth Skeletal Growth: SAIZEN stimulates skeletal growth in prepubertal children with pituitary growth hormone deficiency. Skeletal growth is accomplished at the epiphyseal plates at the ends of long bone. Growth and metabolism of epiphyseal plate cells are directly stimulated by growth hormone and one of its mediators, insulin-like growth factor-1. Serum levels of insulin-like growth factor-1 (IGF-1) are low in children and adolescents who are growth hormone deficient, but increase during treatment with SAIZEN. Linear growth continues until the growth plates fuse at the end of puberty. Cell Growth: Treatment with pituitary-derived human growth hormone results in an increase in both the number and the size of skeletal muscle cells. Organ Growth: Somatropin influences the size and function of internal organs and increases red cell mass. Protein Metabolism Linear growth is facilitated in part by increased cellular protein synthesis. This is reflected by increased cellular uptake of amino acids and nitrogen retention as demonstrated by a decline in urinary nitrogen excretion and blood urea nitrogen during somatropin therapy. Carbohydrate Metabolism Somatropin is a modulator of carbohydrate metabolism. Children with inadequate secretion of growth hormone sometimes experience fasting hypoglycemia that is improved by treatment with somatropin. SAIZEN therapy may decrease glucose tolerance. Administration of SAIZEN to normal adults and patients with growth hormone deficiency resulted in transient increases in mean serum fasting and postprandial insulin levels. However, glucose levels remained in the normal range. Lipid Metabolism Acute administration of somatropin to humans results in lipid mobilization. Nonesterified fatty acids increase in plasma within one hour of SAIZEN administration. In growth hormone deficient patients, long-term somatropin administration often decreases body fat. Mean cholesterol levels decreased in patients treated with SAIZEN. The clinical significance of this decrease in cholesterol level is unknown. Mineral Metabolism Somatropin administration results in the retention of total body potassium, phosphorus, and sodium. Serum calcium levels appear to be unaffected. Connective Tissue/Bone Metabolism Somatropin 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 ranges between 70 to 90%. Distribution The steady-state volume of distribution (mean +SD) of somatropin following intravenous administration in healthy volunteers was estimated to be 12.0 ± 1.08 L. Metabolism The metabolic fate of somatropin involves classical protein catabolism in both the liver and kidneys. In renal cells, at least a portion of the breakdown products is returned to the systemic circulation. The mean half-life of intravenous somatropin in normal males is around 0.6 hours, whereas subcutaneously and intramuscularly administered somatropin has a half-life of around 2 hours. The longer half-life observed after subcutaneous or intramuscular administration is due to slow absorption from the injection site. Excretion The clearance (mean +SD) of intravenously administered somatropin in six normal male volunteers was 14.6 ± 2.8 L/hr. Specific Populations Pediatric - The pharmacokinetics of somatropin is similar in children and adults. However, no pharmacokinetic studies of SAIZEN have been conducted in pediatric patients. Gender - No gender studies have been performed in children for somatropin. In adults, the clearance of somatropin in both men and women tends to be similar. However, no studies have been conducted to evaluate the effect of gender on pharmacokinetics of SAIZEN. Race - No studies have been conducted to determine the effect of race on the pharmacokinetics of SAIZEN. Renal Impairment - Children and adults with chronic renal failure tend to have decreased somatropin clearance compared to those with normal renal function. However, no studies have been conducted to evaluate the effect of renal impairment on the pharmacokinetics of SAIZEN. Hepatic Impairment - A reduction in somatropin clearance has been noted in patients with hepatic dysfunction as compared with normal controls. Clinical Studies Adult Growth Hormone Deficiency (GHD) A multicenter, randomized, double-blind, placebo-controlled clinical trial was conducted in 115 adults with growth hormone deficiency comparing the effects of SAIZEN and placebo on body composition. Patients in the active treatment arm were treated with SAIZEN at an initial dose of 0.005 mg/kg/day for one month which was increased to 0.01 mg/kg/day if tolerated for the remaining five months of the study. The primary endpoint was the change from baseline in lean body mass measured by dual energy X-ray absorptiometry (DXA) after 6 months. Treatment with SAIZEN produced significant (p < 0.001) increases from baseline in LBM compared to placebo (Table 2). Table 2 : Lean Body Mass (kg) by DXA SAIZEN (n=52) Placebo (n=51) Baseline (mean) 47.7 54.0 Change from baseline at 6 months (mean) +1.9 -0.2 Treatment difference (mean) 2.1 95% confidence interval (1.3, 2.9) p-value < 0.001 Sixty-seven (58%) of the 115 randomized patients were male. The adjusted mean treatment difference on the increase in lean body mass from baseline was significantly greater in males (2.9 kg) than females (0.8 kg). Ninety-seven (84%) of the 115 randomized patients had adult onset GHD. The adjusted mean treatment differences on the increase in lean body mass from baseline were not significantly different in AO GHD (2.1 kg) compared with childhood onset GHD (1.0 kg) patients. However, there were relatively few patients with childhood onset GHD (n=18) on which to base the comparison. Analysis of the treatment difference on the change from baseline in total fat mass (by DXA) revealed a significant decrease (p < 0.001) in the SAIZEN-treated group compared to the placebo group. SAIZEN also produced beneficial effects on several bone turnover markers including bone specific alkaline phosphatase, C-terminal propeptide, osteocalcin, urine deoxypyridinoline and iPTH. One hundred and eleven patients were enrolled in an open label follow up study and treated with SAIZEN for an additional 6-30 months. During this period, the beneficial effects on lean body mass and total fat mass achieved during the initial six months of treatment were maintained.

Valtropin® 5 mg (somatropin rDNA origin for injection, USP) DESCRIPTION Valtropin (somatropin injection) ® [somatropin (rDNA origin) for injection] is a polypeptide hormone of recombinant DNA origin. The hormone is produced by recombinant DNA technology in yeast cells (Saccharomyces cerevisiae). Valtropin (somatropin injection) ® 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 human growth hormone (hGH) of pituitary origin. Valtropin (somatropin injection) ® is a sterile, non-pyrogenic, white to almost white, lyophilized powder intended for subcutaneous injection after reconstitution. Each vial contains 5 mg somatropin (approximately 15 International Units), 10 mg glycine, 45 mg mannitol, 0.22 mg monobasic sodium phosphate, and 2.98 mg dibasic sodium phosphate. The pH is adjusted with sodium hydroxide and/or hydrochloric acid. A pre-filled syringe of 1.5 mL clear solution diluent is provided for reconstitution of the powder. The pre-filled syringe contains 1.5 mL Water for Injection and 0.3% w/v metacresol as an antimicrobial preservative. After reconstitution with 1.5 mL diluent, the solution contains 3.33 mg/mL of somatropin.

Find Lowest Prices on SAIZEN [somatropin (rDNA origin)] for Injection DESCRIPTION SAIZEN is a human growth hormone produced by recombinant DNA technology. SAIZEN 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. SAIZEN is produced by a mammalian cell line (mouse C127) that has been modified by the addition of the human growth hormone gene. SAIZEN is a sterile, non pyrogenic, white, lyophilized powder intended for subcutaneous injection after reconstitution with Bacteriostatic Water for Injection, USP (0.9% Benzyl Alcohol). The reconstituted solution has a pH of 6.5 to 8.5. Vials SAIZEN is available in 5 mg and 8.8 mg vials. The quantitative composition per vial is: 5 mg vial Each vial contains 5.0 mg somatropin, 34.2 mg sucrose and 1.16 mg O-phosphoric acid. The pH is adjusted with sodium hydroxide or O-phosphoric acid. 8.8 mg vial Each vial contains 8.8 mg somatropin, 60.2 mg sucrose and 2.05 mg O-phosphoric acid. The pH is adjusted with sodium hydroxide or O-phosphoric acid. Diluent The diluent is Bacteriostatic Water for Injection, USP containing 0.9% Benzyl Alcohol added as an antimicrobial preservative. click.easy® reconstitution device SAIZEN is also available in the click.easy® reconstitution device. The quantitative composition per vial contained in the click.easy® reconstitution device is: 8.8 mg vial contained in the click.easy® device Each vial contains 8.8 mg somatropin, 60.2 mg sucrose and 2.05 mg O-phosphoric acid. The pH is adjusted with sodium hydroxide or O-phosphoric acid. Diluent The diluent contained in click.easy® device is 0.3% (w/v) metacresol in Sterile Water for Injection added as an antimicrobial preservative. The reconstituted solution has a pH of 6.5 to 8.5. saizenprep® reconstitution device SAIZEN 8.8 mg vial supplied with the saizenprep® reconstitution device. Each vial contains 8.8 mg somatropin, 60.2 mg sucrose and 2.05 mg O-phosphoric acid. The pH is adjusted with sodium hydroxide or O-phosphoric acid. Diluent The diluent supplied with saizenprep® reconstitution device is 0.3% (w/v) metacresol in Sterile Water for Injection added as an antimicrobial preservative. The reconstituted solution has a pH of 6.5 to 8.5.

INDICATIONS Pediatric Patients: Valtropin (somatropin injection) ® is indicated for the treatment of pediatric patients who have growth failure due to inadequate secretion of endogenous growth hormone. Valtropin (somatropin injection) ® is indicated for the treatment of growth failure associated with Turner syndrome in patients who have open epiphyses. Adult Patients: Valtropin (somatropin injection) ® is indicated for replacement of endogenous growth hormone in adults with growth hormone deficiency who meet either of the following criteria: Adult Onset: Patients who have growth hormone deficiency, 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 growth hormone deficient during childhood as a result of congenital, genetic, acquired, or idiopathic causes. In general, confirmation of the diagnosis of adult growth hormone deficiency in both groups usually requires an appropriate growth hormone stimulation test. However, confirmatory growth hormone stimulation testing may not be required in patients with congenital/genetic growth hormone deficiency or multiple pituitary hormone deficiencies due to organic disease. DOSAGE AND ADMINISTRATION Dosage Pediatric Patients The Valtropin (somatropin injection) ® dosage and administration schedule should be individualized for each patient. Therapy should not be continued if epiphyseal fusion has occurred. Response to somatropin therapy in pediatric patients tends to decrease with time. However, failure to increase growth rate, particularly during the first year of therapy, should prompt careful assessment of compliance, a determination as to whether anti-rhGH neutralizing antibodies have developed, and an evaluation to rule out other causes of growth failure including hypothyroidism, under-nutrition, advanced bone age. Pediatric Growth Hormone Deficiency (GHD) The amount administered during the pivotal study described herein was 0.23 mg/kg of body weight/week (0.033 mg/kg/day). Generally, the recommended dosage is 0.17 - 0.3 mg/kg of body weight/week. The weekly dose should be divided into equal amounts given either daily or 6 days a week by subcutaneous injection. Children with Turner Syndrome The amount administered during the pivotal study utilizing the 5 mg (15 IU) formulation of Valtropin (somatropin injection) ® described herein was 0.37 mg/kg of body weight/week (0.053 mg/kg/day). Generally, the recommended dose is up to 0.375 mg/kg of body weight/week. The weekly dose should be divided into equal amounts given either daily or 6 days a week by subcutaneous injection. Adult Patients Adult Growth Hormone Deficiency (GHD) Based on the pivotal study described herein, the recommended dosage at the start of therapy is 0.33 mg/day (or 0.1 mL of reconstituted solution) (equivalent to 0.005 mg/kg/day in a 66 kg adult) (6 days/week) given as a subcutaneous injection. The dosage may be increased according to individual patient requirements to a maximum of 0.66 mg/day (equivalent to 0.010 mg/kg/day in a 66 kg adult) (6 days/week) after 4 weeks. Clinical response, side effects, and determination of age- and gender-adjusted serum IGF-I levels may be used as guidance in dose titration. Alternatively, taking into account recent literature, a starting dose of approximately 0.2 mg/day (range, 0.15-0.30 mg/day) may be used. This dose can be increased gradually every 1-2 months by increments of approximately 0.1-0.2 mg/day, according to individual patient requirements based on the clinical response and serum IGF-I concentrations. During therapy, the dose should be decreased if required by the occurrence of adverse events and/or serum IGF-I levels above the age- and gender-specific normal range. Maintenance dosages vary considerably from person to person. 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. Administration The thighs are recommended as the preferred sites of injection and the injection site should be rotated to avoid lipoatrophy. After determining the appropriate patient dose, each vial of Valtropin (somatropin injection) ® should be reconstituted using the accompanying diluent. For use in patients with a known sensitivity to metacresol, Valtropin (somatropin injection) ® should not be reconstituted with the supplied diluent, but instead with water for injection. The diluent supplied in the prefilled syringe or water for injection should be injected entirely into the vial of Valtropin (somatropin injection) ® by aiming the stream of liquid against the glass wall. Following reconstitution, the vial should be swirled with a GENTLE rotary motion until the contents are completely dissolved, providing a 3.33 mg/mL solution of somatropin. DO NOT SHAKE. If the solution is shaken, the solution may become cloudy or develop particulate matter. The Valtropin (somatropin injection) ® solution should be clear immediately after reconstitution. DO NOT INJECT the Valtropin (somatropin injection) ® solution if it is cloudy or contains particulate matter immediately after reconstitution or after refrigeration. These kinds of solutions should be discarded. If reconstituted with water for injection, do not store but discard after use, since it lacks preservative. If reconstituted with the supplied diluent, which contains preservative, label the vial with the date on which you prepared the solution and store in a refrigerator. It is recommended that the volume of reconstituted Valtropin (somatropin injection) ® solution required to provide the prescribed dose of Valtropin (somatropin injection) ® should be withdrawn from the reconstituted solution and administered using sterile, disposable syringes and needles (a new disposable syringe and needle should be used for every injection). The disposable syringes should be of small enough volume that the prescribed dose can be withdrawn from the vial with reasonable accuracy, and the needle should be fine enough to ensure patient comfort. In order to prevent contamination of the contents of the reconstituted vial of Valtropin (somatropin injection) ® by repeated needle insertions, ensure that before every injection, the septum of the vial (e.g., the rubber vial stopper) is wiped with an antiseptic solution before puncturing it with the needle, and after every injection the rubber vial stopper is also wiped with an antiseptic solution. Return the multiuse vial, reconstituted with supplied diluent, to the refrigerator after each use. Stability and Storage Before Reconstitution Valtropin (somatropin injection) ® powder or diluent should be stored under refrigeration (2°C-8°C/36°F-46°F). Do not freeze. Expiration dates are stated on the labels. The product should be refrigerated prior to dispensing, but may be stored at or below 25°C (77°F) for up to three months after dispensing. After Reconstitution With The Diluent Provided When reconstituted with the diluent provided, the reconstituted solution may be stored under refrigeration (2°C-8°C/36°F-46°F) for up to 21 days. Avoid freezing reconstituted vials of Valtropin (somatropin injection) ®. If Reconstituted With Water For Injection When reconstituted with sterile Water for Injection, use only one dose per Valtropin (somatropin injection) ® vial and discard the unused portion if not needed immediately. The use of Sterile Water for Injection without preservative should be reserved only for patients who have an allergy or sensitivity to metacresol or when the supplied diluent is unavailable. HOW SUPPLIED Valtropin (somatropin injection) ® is a sterile, non-pyrogenic, white to almost white, lyophilized powder supplied as a single pack containing: - 1 vial of powder containing 5 mg somatropin - 1 single use pre-filled syringe containing 1.5 mL diluent (Metacresol in Water for Injection). FDA rev date: 4/18/2007

INDICATIONS Pediatric Patients SAIZEN (somatropin) is indicated for the treatment of pediatric patients with growth failure due to inadequate secretion of endogenous growth hormone. Adult Patients SAIZEN is indicated for replacement of endogenous growth hormone in adults with growth hormone deficiency who meet either of the following two criteria: Adult Onset Patients who have growth hormone deficiency, 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 growth hormone deficient during childhood as a result of congenital, genetic, acquired, or idiopathic causes. Patients who were treated with somatropin for growth hormone deficiency in childhood and whose epiphyses are closed should be reevaluated before continuation of somatropin therapy at the reduced dose level recommended for growth hormone deficient adults. Confirmation of the diagnosis of adult growth hormone deficiency in both groups involves an appropriate growth hormone provocative test with two exceptions: (1) patients with multiple other pituitary hormone deficiencies due to organic disease; and (2) patients with congenital/genetic growth hormone deficiency. DOSAGE AND ADMINISTRATION For subcutaneous injection. SAIZEN therapy should be supervised by a physician who is experienced in the diagnosis and management of pediatric patients with growth hormone deficiency or adult patients with either childhood-onset or adult-onset growth hormone deficiency. Pediatric Growth Hormone Deficiency (GHD) SAIZEN dosage and administration schedule should be individualized for each patient. The recommended weekly dosage is 0.18 mg/kg of body weight by subcutaneous injection. It should be divided into equal doses given either on 3 alternate days, 6 times per week or daily. Response to somatropin therapy in pediatric patients tends to decrease with time. However, in pediatric patients, the failure to increase growth rate, particularly during the first year of therapy, indicates the need for close assessment of compliance and evaluation for other causes of growth failure, such as hypothyroidism, undernutrition, advanced bone age and antibodies to recombinant human growth hormone. Treatment with SAIZEN of growth failure due to growth hormone deficiency should be discontinued when the epiphyses are fused. Adult Growth Hormone Deficiency (GHD) Either of two approaches to SAIZEN dosing may be followed: a weight-based regimen or a non-weightbased regimen. Weight-based Based on the dosing utilized in the original pivotal study described herein, the recommended dosage at the start of therapy is not more than 0.005 mg/kg given as a daily subcutaneous injection. The dosage may be increased to not more than 0.01 mg/kg/day after 4 weeks according to individual patient requirements. Clinical response, side effects, and determination of age-and gender-adjusted serum insulin-like growth factor (IGF-1) levels may be used as guidance in dose titration. Non-weight-based Alternatively, taking into account more recent literature, a starting dose of approximately 0.2 mg/day (range, 0.15-0.30 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. During therapy, the dose should be decreased if required by the occurrence of adverse reactions and/or serum IGF-1 levels above the age-and gender-specific normal range. Maintenance dosages vary considerably from person to person. 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 Prior to self-administration of the product at home, ensure to train patients and caregivers how to prepare and administer the product correctly to help avoid wrong technique and dosing errors. Vials To prevent possible contamination, wipe the rubber vial stopper with an antiseptic solution before puncturing it with the needle. It is recommended that SAIZEN 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. After determining the appropriate patient dose, reconstitute each vial of SAIZEN as follows: 5 mg vial with 1 to 3 mL of Bacteriostatic Water for Injection, USP (Benzyl Alcohol preserved); 8.8 mg vial with 23 mL of Bacteriostatic Water for Injection, USP (Benzyl Alcohol preserved). Approximately 10% mechanical loss can be associated with reconstitution and multidose administration. If sensitivity to the diluent occurs, SAIZEN may be reconstituted with Sterile Water for Injection, USP. When SAIZEN is reconstituted in this manner, the reconstituted solution should be used immediately and any unused solution should be discarded [see WARNINGS AND PRECAUTIONS]. To reconstitute SAIZEN, inject the diluent into the vial of SAIZEN 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. SAIZEN MUST NOT BE INJECTED if the solution is cloudy or contains particulate matter. Use it only if it is clear and colorless. click.easy® cartridges For drug preparation instructions for SAIZEN click.easy® cartridges, please refer to the instructions for use provided with click.easy® reconstitution device. saizenprep® cartridges For drug preparation instructions for saizenprep® cartridges, please refer to the Instructions for Use provided with saizenprep® reconstitution device. Injection sites should always be rotated to avoid lipoatrophy. HOW SUPPLIED Dosage Forms And Strengths SAIZEN lyophilized powder (to be reconstituted with Bacteriostatic Water for Injection): 5 mg per vial 8.8 mg per vial SAIZEN click.easy® reconstitution device: One vial SAIZEN containing 8.8 mg somatropin and one cartridge diluent containing 1.51 mL 0.3% (w/v) metacresol in Sterile Water for Injection saizenprep® reconstitution device: One vial SAIZEN containing 8.8 mg somatropin and one cartridge diluent containing 1.51 mL 0.3% (w/v) metacresol in Sterile Water for Injection SAIZEN can be administered using (1) a standard sterile disposable syringe and needle, (2) a compatible SAIZEN needle-free injection device or (3) a compatible SAIZEN needle injection device. For proper use, refer to the Instructions for Use provided with the administration device. SAIZEN is a sterile, non pyrogenic, white, lyophilized powder supplied in packages containing: 1 vial of 5 mg SAIZEN and 1 vial of Bacteriostatic Water for Injection, USP (0.9% Benzyl Alcohol) NDC 44087-1005-2 1 vial of 8.8 mg SAIZEN and 1 vial of Bacteriostatic Water for Injection, USP (0.9% Benzyl Alcohol) NDC 44087-1088-1 1 click.easy® cartridge of 8.8 mg SAIZEN and 1.51 mL Sterile Water for Injection 0.3% (w/v) metacresol as a antimicrobial preservative NDC 44087-1080-1 1 saizenprep® cartridge of 8.8 mg SAIZEN and 1.51 mL Sterile Water for Injection 0.3% (w/v) metacresol as antimicrobial preservative NDC 44087-0016-1 Storage And Handling Before Reconstitution -SAIZEN should be stored at room temperature (15°-30°C/59°-86°F). Expiration dates are stated on the labels. After Reconstitution -SAIZEN 5 mg and 8.8 mg vials reconstituted with the Bacteriostatic Water for Injection, USP (0.9% Benzyl Alcohol) provided should be stored under refrigeration (2°-8°C/36°-46°F) for up to 14 days. SAIZEN 8.8 mg click.easy® cartridge reconstituted with the Sterile Water for Injection, 0.3% (w/v) metacresol provided should be stored under refrigeration (2°-8°C/36°-46°F) for up to 21 days. SAIZEN 8.8 mg saizenprep® cartridge reconstituted with the Sterile Water for Injection, 0.3% (w/v) metacresol provided should be stored under refrigeration (2°-8°C/36°-46°F) for up to 21 days. Avoid freezing reconstituted vials or cartridges of SAIZEN. Manufactured for: EMD Serono, Inc., Rockland, MA 02370 USA. Revised: May 2017

PATIENT INFORMATION Patients being treated with Valtropin (somatropin injection) ® (and/or their parents) should be informed about the potential benefits and risks associated with Valtropin (somatropin injection) ® treatment. 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 Valtropin (somatropin injection) ® should receive appropriate training and instruction on the proper use of Valtropin (somatropin injection) ® 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.

PATIENT INFORMATION click.easy® Reconstitution Device Saizen® (somatropin) for injection, for subcutaneous use 8.8 mg INSTRUCTIONS FOR USE For complete dosing and safety information, please refer to the SAIZEN Package Insert. Composition Each vial of SAIZEN 8.8 mg contained in the 5.83 mg/mL click.easy® device contains the following ingredients: Active substance: Somatropin (Recombinant Human Growth Hormone) 8.8 mg. Excipients: Sucrose, Phosphoric acid, Sodium Hydroxide; 1 mL of the reconstituted SAIZEN solution contains 5.83 mg of somatropin when reconstituted with the contents of the diluent cartridge. Composition Of Diluent Each cartridge of diluent contained in the click.easy® reconstitution device contains the following ingredients: 5.83 mg/mL click.easy® Active substance: Metacresol USP (4.52 mg), Excipients: Phosphoric acid 85% to adjust pH, Water for Injection, USP (1.51 mL) Patients with a known sensitivity to any of the above active substances or excipients should avoid using this product. Pharmaceutical Form Powder and diluent for solution for injection: Powder and diluent (0.3% (w/v) metacresol in water for injection) for parenteral use. Method And Route Of Administration The product (powder in vials) must be reconstituted with the enclosed diluent (0.3% (w/v) metacresol in water for injection) using the click.easy® reconstitution device. The reconstituted solution is intended for subcutaneous administration (under the skin) and should be clear with no particles. If the solution contains particles, it must not be injected. Important Information Patients should be thoroughly instructed in the reconstitution procedure. For young children, the reconstitution process should be supervised by an adult. For administration of SAIZEN 8.8 mg contained in the click.easy® device, please read the following instructions carefully. Please consult your doctor, nurse or pharmacist if you have any questions concerning the reconstitution process. Check that the click.easy® reconstitution device contains an unused SAIZEN vial (a) and an unused diluent cartridge (c). Do NOT use the device if the vial or cartridge appear empty or used and return it to your pharmacist or doctor. Wash your hands with soap and water. How To Prepare Your Solution Of Saizen® Place the click.easy® device vertically on a clean flat surface with the SAIZEN vial on the bottom and the diluent cartridge outer housing cap (g) on top facing upward. Push on the top diluent cartridge outer housing cap (g) firmly until the SAIZEN vial outer housing (h) is completely inside the main body. This step breaks the tamper evident seal on the vial. Turn the diluent cartridge outer housing cap (g) clockwise until the green square (f) is visible at the lower end of the narrow rectangular opening. Push the diluent cartridge outer housing cap down very slowly until it will go no further and the green colored square appears at the upper end of the narrow rectangular opening. Check that all the diluent has been transferred into the vial. Dissolve the SAIZEN powder with the diluent by gently swirling the click.easy® device (Note: Do not transfer the diluent forcefully or shake the click.easy® device. A fast transfer of the diluent or shaking  of the click.easy® device will create more foam). Let the solution stand for 2-5 minutes until the SAIZEN powder is completely dissolved. Turn the click.easy® device upside down so the SAIZEN vial is now on top and pull the diluent cartridge outer housing cap slowly downwards until the solution is completely drawn back into the cartridge. Check that no more than one or two drops of solution remain in the vial. If there are more than one or two drops of solution remaining in the vial, slowly push the diluent cartridge outer housing cap up until some of the solution is back in the vial and gently tap the click.easy® device. Then draw the solution slowly again back into the cartridge. Remove any excess air that has been drawn into the cartridge by slowly pushing the cap up until no air bubble is visible in the cartridge. There should be no air bubble in the cartridge (Note: Avoid pulling the cap down too fast, as this will draw air into the cartridge). Turn the click.easy® device so that the cap is again on the top. Unscrew the cap and remove it. Remove the cartridge containing the reconstituted SAIZEN solution from the click.easy® device by grasping the end of the cartridge and pulling straight out of the outer housing. Carefully peel off the outer white label on the cartridge using the tab provided by slowly pulling in the direction of the black arrow. Write the reconstitution date on the transparent inner label on the cartridge. This cartridge now contains the reconstituted SAIZEN solution that will be used for your treatment. The cartridge containing the reconstituted SAIZEN solution is now ready to be used (Note: Please read the instruction manual provided with the injection device for instruction on how to inject the reconstituted SAIZEN solution from the cartridge). The SAIZEN reconstituted solution should be stored in a refrigerator (2°-8°C / 36°-46°F) and should be used within 21 days after reconstitution. Do not freeze. Discard the click.easy® device containing the empty SAIZEN vial safely in accordance with your local requirements. It is not necessary to remove the empty SAIZEN vial from the click.easy® device prior to disposal. Injections should be given in different parts of your body. Do not use any areas in which you feel lumps, firm knots, depressions, or pain; talk to your doctor or healthcare professional about anything you find. Clean the skin at the injection site with soap and water. Stability And Storage Vials of SAIZEN 8.8 mg pre-assembled in the click.easy® reconstitution device should be stored in the original package at room temperature (15°-30°C / 59°-86°F). SAIZEN 8.8 mg reconstituted solution should be stored in a refrigerator (2°-8°C / 36°-46°F) and should be used within 21 days after reconstitution. Do not freeze. How Supplied SAIZEN 8.8 mg contained in the click.easy® device is available in the following pack sizes: 1 vial of SAIZEN 8.8 mg product and 1 cartridge of 1.51 mL diluent pre-assembled in 1 reconstitution device (click.easy®) comprising 1 device housing and 1 sterile transfer cannula NDC 44087-1080-1

OVERDOSE Short-term overdosage could lead initially to hypoglycemia and subsequently to hyperglycemia. Moreover, overdose with somatropin is likely to cause fluid retention. Long-term overdosage could result in signs and symptoms of gigantism and/or acromegaly consistent with the known effects of excess hGH. CONTRAINDICATIONS Somatropin should not be used for growth promotion in pediatric patients with closed epiphyses. Somatropin is contraindicated in patients with active proliferative or severe non-proliferative diabetic retinopathy. 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. Since growth hormone deficiency 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. Somatropin should not be used to treat 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-growth hormone deficient adult patients (n=522) with these conditions in intensive care units revealed a significant increase in mortality (41.9% versus 19.3%) among somatropin treated patients (doses 5.3-8 mg/day) compared to those receiving placebo (see WARNINGS). Somatropin 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, Valtropin (somatropin injection) ® 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. Moreover, 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 human growth hormone. 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 [see WARNINGS AND PRECAUTIONS]. Prader-Willi Syndrome In Children Somatropin is contraindicated in patients with Prader-Willi syndrome who are severely obese or have severe respiratory impairment [see WARNINGS AND PRECAUTIONS]. There have been reports of sudden death when somatropin was used in such patients. SAIZEN is not indicated for the long term treatment of pediatric patients who have growth failure due to genetically confirmed Prader-Willi syndrome. 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 may be an early sign of the presence of a pituitary tumor (or, rarely, other brain tumors), the presence of such tumors should be ruled out prior to initiation of treatment. Somatropin should not be used in patients with any evidence of progression or recurrence of an underlying intracranial tumor [See WARNINGS AND PRECAUTIONS]. Hypersensitivity SAIZEN 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. Closed Epiphyses Somatropin should not be used for growth promotion in pediatric patients with closed epiphyses. Benzyl Alcohol SAIZEN reconstituted with Bacteriostatic Water for Injection, USP (0.9% Benzyl Alcohol) should not be administered to patients with a known sensitivity to Benzyl Alcohol [see WARNINGS AND PRECAUTIONS].

SIDE EFFECTS Pediatric Patients With GHD In a clinical study in which Valtropin (somatropin injection) ® 0.053mg/kg/day (vs. the same dose of an active somatropin control) was administered to 98 children with GHD for 12 months, the following adverse events were seen most frequently (≥5.0% in either treatment group): headache, pyrexia, cough, respiratory tract infection, diarrhea, vomiting and pharyngitis (see Table 7). The incidence of all of these adverse events were similar in the 2 treatment groups, and these adverse events reflect very common pediatric illnesses. Table 7 Adverse Events Observed In Children With GHD Treated with Valtropin (somatropin injection) ® vs. Comparator for 12 Months Adverse events (Incidence ≥5.0% in either group) Valtropin® (n=98) Comparator (n=49) Headache 10 (10.2%) 8 (16.3%) Pyrexia 9 (9.2%) 8 (16.3%) Cough 5 (5.1%) 3 (6.1%) Respiratory tract infection (NOS)* 5 (5.1%) 1 (2.0%) Diarrhea 3 (3.1%) 4 (8.2%) Vomiting 4 (4.1%) 4 (8.2%) Pharyngitis 3 (3.1%) 4 (8.2%) n = number of patients * NOS = not otherwise specified During this study, a very modest degree of glucose intolerance was observed in the 98 patients treated with Valtropin (somatropin injection) ® for 12 months (which was comparable to that observed in the comparator group). No de novo cases of overt diabetes mellitus were diagnosed. See PRECAUTIONS, General regarding somatropin-induced glucose intolerance. Out of 98 patients with pediatric GHD randomized to treatment with Valtropin (somatropin injection) ® in the pivotal study described above, 26 (26.5%) had preexisting central hypothyroidism. Exacerbation of this preexisting central hypothyroidism appeared to be common. During 12 months of Valtropin (somatropin injection) ® treatment, 18 out of these 26 patients (~69%) with preexisting central hypothyroidism (who were being treated with a thyroxine preparation prior to study entry) required up-titration of their thyroxine replacement dose (primarily based on declining levels of free T4). On the other hand, none of the 72 patients without preexisting central hypothyroidism manifested de novo central hypothyroidism while on-study. See PRECAUTIONS, DRUG INTERACTIONS. The 1 patient with preexisting central hypoadrenalism enrolled in this study required a slight increase in her maintenance hydrocortisone replacement dose after treatment with Valtropin (somatropin injection) ®, possibly compatible with somatropin-induced exacerbation of preexisting central hypoadrenalism. None of the remaining 97 patients without preexisting central hypoadrenalism manifested de novo central hypoadrenalism while on-study. See PRECAUTIONS, DRUG INTERACTIONS. In addition, during the clinical trial described above, low titer anti-rhGH antibodies* were reported in 3 patients treated with Valtropin (somatropin injection) ® (vs. 1 patient treated with the comparator), and low titer anti-host cell protein antibodies were observed in 2 patients treated with Valtropin (somatropin injection) ®. These antibodies appeared after 6 months of treatment, disappeared after 12 months of treatment, and did not attenuate the growth response of these children. *As with all protein pharmaceuticals, a small percentage of patients may develop antibodies to the protein. Anti-growth hormone antibodies with binding capacity lower than 2 mg/L have not been associated growth attenuation. In some patients, when binding capacity was greater than 2 mg/L, interference with growth response was observed in published data. Any patient with well documented pediatric GHD who fails to respond to Valtropin (somatropin injection) ® therapy should be tested for neutralizing antibodies to rhGH and undergo a careful evaluation to rule out other causes of growth failure (see DOSAGE AND ADMINISTRATION). In published literature, leukemia has been reported in a small number of pediatric GHD patients treated with somatropin. It is uncertain whether this increased risk is related to the pathology of GHD itself, somatropin therapy, or other associated treatments such as radiation therapy for intracranial tumors. So far, epidemiological data have failed to confirm the hypothesis of a relationship between somatropin therapy and leukemia. Pediatric Patients With Turner Syndrome TS children with short stature were treated with 0.37 mg/kg/week of Valtropin (somatropin injection) ® (5 mg = 15 IU formulation) (n=30) and 0.33 mg/kg/week of Eutropin™ INJ (1.33 mg = 4 IU formulation qualitatively identical to Valtropin (somatropin injection) ®) (n=60) during Study 1 and Study 2, respectively. Adverse events were reported by 10 (33.3%) children during Study 1. Most of these adverse events reflect very common pediatric illnesses. The most frequently (≥1.0%) reported adverse events were respiratory tract infections and ear infections (see Table 8). Turner syndrome patients are more prone to ear disorders and treatment with somatropin may increase the occurrence of these problems. One patient developed low titer antibodies to rhGH, and one other patient developed low titer anti-yeast antibodies which proved to be transient. During Study 2, a similar pattern of adverse events was observed (data not shown). Two patients developed low titer anti-rhGH antibodies at Month 12. Of interest, there were no reports in either study of benign intracranial hypertension, aggravation of preexisting scoliosis, slipped capital femoral epiphysis and hypertension. Somatropin-induced glucose intolerance will be discussed separately in the next paragraph. All patients with reported adverse events recovered during continued treatment. Table 8 Adverse Events Observed In Children With Turner Syndrome Treated with Valtropin (somatropin injection) ® for 12 Months Adverse Events (Incidence ≥1.0%) Valtropin® (n=30) n % Respiratory tract infection (NOS)* 4 13.3 Ear infection (NOS) 2 6.7 Otitis media (NOS) 1 3.3 Anti-rhGH antibody positive 1 3.3 Anti-yeast antibody positive 1 3.3 Edema peripheral 1 3.3 Respiratory tract infection viral (NOS)* 1 3.3 Rhinitis NOS* 1 3.3 Sinusitis NOS* 1 3.3 Influenza 1 3.3 Injection site pain 1 3.3 Pyrexia 1 3.3 n = number of patients *NOS = not otherwise specified During Study 1, a modest degree of glucose intolerance was observed in the 30 patients treated with Eutropin™ INJ for 12 months. No de novo cases of overt diabetes mellitus were diagnosed. On the other hand, during Study 2, a much greater amount of glucose intolerance was observed: a) 3 patients (with normal fasting blood glucose [FBG] values at baseline [<100 mg/dL]) had FBG values between 130 and 145 mg/dL at Month 12 as well as at other study time points and (given the absence of follow-up data after study termination) may have developed somatropin-induced de novo diabetes mellitus; and b) 16 out of 41 patients (with normal FBG values at baseline) had FBG values between 100-126 mg/dL at Month 12 (and 3 of these 16 patients had FBG values >126 mg/dL transiently during the study). Since the amount of somatropin administered in Study 2 (0.33 mg/kg/week) was slightly less than the amount administered in Study 1 (0.37 mg/kg/week), these findings are difficult to interpret. It is possible that some of these patients were not actually fasting when blood samples were taken. See PRECAUTIONS (General) regarding the well known potential of somatropin drug products to cause or unmask glucose intolerance, especially in patients at greater inherent risk for diabetes mellitus, i.e. patients with Turner syndrome. Adult Patients With GHD Adult GHD patients were treated with Eutropin™ INJ (1.33 mg = 4 IU formulation; qualitatively identical to Valtropin (somatropin injection) ®, a 5 mg = 15 IU formulation) vs. placebo during the pivotal clinical study. Ninety two patients received at least 3 months of treatment with Eutropin™ INJ (31 of these patients were treated with Eutropin™ INJ for an additional 3 months), and 61 patients received 3 months of treatment with placebo. Adverse events with an incidence of ≥5.0% are presented in Table 9. The most frequent adverse event during treatment with Eutropin™ INJ was edema, which was reported more frequently than during placebo treatment. In some of these patients, edema resulted in down-titration of the dose of Eutropin™ INJ as per protocol. Myalgia was reported by 2 patients receiving Eutropin™ INJ and 2 patients treated with placebo. Arthralgia was reported by 2 patients receiving Eutropin™ INJ. There were no reports of carpal tunnel syndrome. These types of adverse events are thought to be related to the fluid accumulating effects of somatropin. Most adverse events reported during the study were mild in severity. Table 9 Adverse Events Observed In Adults With GHD Treated With Eutropin™ INJ vs. Placebo Adverse events (Incidence ≥5.0% in either group) n = number of patients Eutropin™ INJ (n = 92) Placebo (n = 61) n % n % Edema 11 12.0 5 8.2 Upper respiratory tract infection 6 6.5 1 1.6 Urticaria 2 2.2 4 6.6 During the pivotal study in adult GHD patients, a modest degree of glucose intolerance was observed in the 92 patients treated with Eutropin™ INJ for at least 3 months (31 of whom were treated for an additional 3 months). Of note, however, is the fact that 2 of the 26 patients in Group C with normal FBG values at baseline (who were treated with Eutropin™ INJ for 3 months from Month 4 through the end of Month 6 after being crossed over from placebo) had FBG values at Month 6 of 251 and 132 mg/dL. Absent follow-up data after study termination, these patients may have developed somatropin-induced de novo diabetes mellitus. In addition, 4 of these 26 patients had FBG values between 100-126 at Month 6. See PRECAUTIONS (General) regarding the well known potential of somatropin drug products to cause or unmask glucose intolerance. Eight of the 92 patients in this study were enrolled (as per protocol) with a preexisting diagnosis of diabetes mellitus (3 of these 8 patients in fact were being treated with oral agent combination therapy and the remaining 5 patients were without drug therapy). In general, these diabetic patients tolerated treatment with Eutropin™ INJ reasonably well, i.e. no post-treatment FBG values exceeded 164 mg/dL on-study. Seventy five out of the 92 adult GHD patients in the pivotal study (~81%) had preexisting central hypothyroidism and most of them were being treated with thyroxine replacement therapy - usually in conjunction with panhypopituitarism. None of these patients manifested clinical signs/symptoms of an exacerbation of preexisting central hypothyroidism (serial thyroid function tests were not obtained per protocol) during treatment with Eutropin™ INJ, i.e. there were no changes in maintenance thyroxine dose nor adverse events related to the thyroid during Eutropin™ INJ therapy. Furthermore, none of the remaining 17 patients enrolled in this study manifested clinical evidence of de novo central hypothyroidism. See PRECAUTIONS, DRUG INTERACTIONS. Seventy five out of the 92 adult GHD patients in the pivotal study (~81%) also had preexisting central hypoadrenalism and most of them were being treated with glucocorticoid replacement therapy. None of these patients demonstrated convincing clinical evidence of an exacerbation of preexisting central hypoadrenalism; 2 patients required an increase in hydrocortisone replacement dosages while they were taking placebo approximately 2 months removed from treatment with Eutropin™ INJ. Furthermore, none of the remaining 17 patients enrolled in this study manifested clinical evidence of de novo central hypoadrenalism. See PRECAUTIONS, DRUG INTERACTIONS. DRUG INTERACTIONS Somatropin inhibits 11β-hydroxysteroid dehydrogenase type 1 (11βHSD-1) in adipose/hepatic tissue and may significantly impact the metabolism of cortisol and cortisone. As a consequence, in patients treated with somatropin, previously undiagnosed central (secondary) hypoadrenalism may be unmasked requiring glucocorticoid replacement therapy. In addition, patients treated with glucocorticoid replacement therapy for previously diagnosed hypoadrenalism may require an increase in their maintenance or stress doses; 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 the 11βHSD-1 enzyme. Excessive glucocorticoid therapy 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. Limited published data indicate that somatropin treatment increases cytochrome P450 (CP450) mediated antipyrine clearance in man. These data suggest that somatropin administration may alter the clearance of compounds known to be metabolized by CP450 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 CP450 liver enzymes. However, formal drug interaction studies have not been conducted. In adult women on oral estrogen replacement, a larger dose of somatropin may be required to achieve the defined treatment goal (see DOSAGE AND ADMINISTRATION). In patients with diabetes mellitus requiring drug therapy, the dose of insulin and/or oral agent may require adjustment when somatropin therapy is initiated (see PRECAUTIONS, General).

SIDE EFFECTS The following important adverse reactions are also described elsewhere in the labeling: Increased mortality in patients with acute critical illness [see WARNINGS AND PRECAUTIONS] Fatalities in children with Prader-Willi syndrome [see WARNINGS AND PRECAUTIONS] Neoplasms [see WARNINGS AND PRECAUTIONS] Glucose intolerance and diabetes mellitus [see WARNINGS AND PRECAUTIONS] Intracranial hypertension [see WARNINGS AND PRECAUTIONS] Severe hypersensitivity [see WARNINGS AND PRECAUTIONS] Fluid retention [see WARNINGS AND PRECAUTIONS] Hypoadrenalism [see WARNINGS AND PRECAUTIONS] Hypothyroidism [see WARNINGS AND PRECAUTIONS] Slipped capital femoral epiphysis in pediatric patients [see WARNINGS AND PRECAUTIONS] Progression of preexisting scoliosis in pediatric patients [see WARNINGS AND PRECAUTIONS] Lipoatrophy [see WARNINGS AND PRECAUTIONS] Pancreatitis [see WARNINGS AND PRECAUTIONS] Benzyl alcohol [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. Growth Hormone Deficient Pediatric Patients In clinical studies in which SAIZEN was administered to growth hormone deficient children, the following reactions were infrequently seen: local reactions at the injection site (such as pain, numbness, redness and swelling), hypothyroidism, hypoglycemia, seizures, exacerbation of preexisting psoriasis and disturbances in fluid balance. Growth Hormone Deficient Adult Patients For a description of the clinical trials refer to section 14. During the 6-month placebo-controlled study, adverse reactions were reported in 56 patients (93.3%) in the somatropin-treated group and 42 patients (76.4%) in the placebo-treated group. Adverse reactions with an incidence of ≥ 5% in SAIZEN-treated patients which were more frequent in SAIZEN-treated patients compared with placebo-treated patients are listed in Table 1. Arthralgia, myalgia, peripheral edema, other types of edema, carpal tunnel syndrome, paraesthesia and hypoaesthesia were common in the somatropin-treated patients and reported more frequently than in the placebo group. These types of adverse reactions are thought to be related to the fluid accumulating effects of somatropin. During the placebo-controlled portion of the study, approximately 10% of patients without preexisting diabetes mellitus or impaired glucose tolerance treated with somatropin manifested mild, but persistent, abnormalities of glucose tolerance, compared with none in the placebo group. During the open label phase of the study, approximately 10% of patients treated with somatropin required a small upward adjustment of thyroid hormone replacement therapy for preexisting central hypothyroidism and 1 patient was newly diagnosed with central hypothyroidism. In addition, during the open label phase of the study, when all patients were being treated with somatropin, two patients with preexisting central hypoadrenalism required upward titration of hydrocortisone maintenance therapy which was considered to be suboptimal (unrelated to intercurrent stress, surgery or disease), and 1 patient was diagnosed de novo with central adrenal insufficiency after six months of somatropin treatment. Anti-GH antibodies were not detected. Table 1 : Adverse Reactions with ≥ 5% Overall Incidence in SAIZEN-Treated Patients Which Were More Frequent in SAIZEN-Treated Patients Compared with Placebo-Treated Patients During a 6 Month Study Adverse Reaction SAIZEN-Treated (N=60) Placebo (N=55) Arthralgia 14 (23.3%) 7 (12.7%) Headache 11 (18.3%) 8 (14.5%) Edema peripheral 9 (15.0%) 2 (3.7%) Myalgia 5 (8.3%) 2 (3.6%) Paraesthesia 4 (6.7%) 1 (1.8%) Hypoaesthesia 4 (6.7%) 0 Edema dependent 3 (5.0%) 2 (3.6%) Skeletal Pain 3 (5.0%) 1 (1.8%) Carpal tunnel syndrome 3 (5.0%) 1 (1.8%) Edema generalized 3 (5.0%) 0 Chest pain 3 (5.0%) 0 Depression 3 (5.0%) 0 Hypothyroidism 3 (5.0%) 0 Insomnia 3 (5.0%) 0 N = number of patients The adverse reaction pattern observed during the open label phase of the study was similar to the one presented above. 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 SAIZEN with the incidence of antibodies to other products may be misleading. In the case of growth hormone, antibodies with binding capacities lower than 2 mg/mL 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/mL, interference with the growth response was observed. Post-Marketing Experience The following adverse reactions have been identified during post approval use of SAIZEN. 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. Serious systemic hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with postmarketing use of somatropin products [See WARNINGS AND PRECAUTIONS]. Leukemia has been reported in a small number of growth hormone deficient patients treated with growth hormone. It is uncertain whether this increased risk is related to the pathology of growth hormone deficiency itself, growth hormone therapy, or other associated treatments such as radiation therapy for intracranial tumors. So far, epidemiological data fail to confirm the hypothesis of a relationship between growth hormone therapy and leukemia. The following additional adverse reactions have been observed during the appropriate use of somatropin: headaches (children and adults), gynecomastia (children), and pancreatitis (children and adults) (see WARNINGS AND PRECAUTIONS). DRUG INTERACTIONS Inhibition Of 11β-Hydroxysteroid Dehydrogenase Type 1 (11βHSD-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. 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 11βHSD1 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 [see WARNINGS AND PRECAUTIONS]. 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 dosing should be carefully adjusted in children receiving concomitant somatropin and glucocorticoid treatments to avoid both hypoadrenalism and an inhibitory effect on growth. 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 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 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 Oral/Injectable Hypoglycemic Agents In patients with diabetes mellitus requiring drug therapy, the dose of insulin and/or oral/injectable agent may require adjustment when somatropin therapy is initiated [see WARNINGS AND PRECAUTIONS].

WARNINGS In the case of patients with a known sensitivity to the supplied diluent (metacresol) or, if sensitivity to metacresol becomes apparent after treatment has been initiated, Valtropin (somatropin injection) ® should be reconstituted with 1.5 mL Water for Injection and used as a single use vial (see STABILITY AND STORAGE). See CONTRAINDICATIONS for information on 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. 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 experiencing acute critical illnesses should be weighed against the potential risk. There have been reports of fatalities after initiating therapy with somatropin 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 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 Prader-Willi syndrome 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). Unless patients with Prader-Willi syndrome also have a diagnosis of growth hormone deficiency, Valtropin (somatropin injection) ® is not indicated for the long-term treatment of pediatric patients who have growth failure due to genetically confirmed Prader-Willi syndrome. PRECAUTIONS General Therapy with Valtropin (somatropin injection) ® should be directed by physicians who are experienced in the diagnosis and management of pediatric patients with growth hormone deficiency and Turner syndrome, or adult patients with either childhood-onset or adult-onset growth hormone deficiency. Treatment with somatropin may decrease insulin sensitivity, particularly at higher doses in susceptible patients. As a result, previously undiagnosed impaired glucose tolerance and overt diabetes mellitus may be unmasked during somatropin treatment. Therefore, glucose levels should be monitored periodically in all patients treated with somatropin, especially in those with risk factors for diabetes mellitus, such as obesity (including obese patients with Prader-Willi syndrome), Turner syndrome, or a family history of diabetes mellitus. Patients with preexisting type 1 or type 2 diabetes mellitus or impaired glucose tolerance should be monitored closely during somatropin therapy. The doses of antihyperglycemic drugs (i.e., insulin or oral agents) may require adjustment when somatropin therapy is instituted in these patients. Patients with preexisting tumors or growth hormone deficiency 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. 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 occur 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 Turner syndrome, chronic renal insufficiency, and Prader-Willi syndrome may be at increased risk for the development of IH. In patients with hypopituitarism (multiple hormone deficiencies), standard hormonal replacement therapy should be monitored closely when somatropin therapy is administered. Undiagnosed/untreated hypothyroidism may prevent an optimal response to somatropin, in particular, the growth response in children. Patients with Turner syndrome have an inherently increased risk of developing autoimmune thyroid disease and primary hypothyroidism. In patients with growth hormone deficiency, 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. Patients should be monitored carefully for any malignant transformation of skin lesions. 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/Patient should be informed that such reactions are possible and that prompt medical attention should be sought if allergic reactions occur. Pediatric Patients (See PRECAUTIONS, General) Slipped capital femoral epiphysis may occur more frequently in patients with endocrine disorders (including pediatric growth hormone deficiency and Turner syndrome) 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 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 Turner syndrome patients. Scoliosis is also commonly seen in untreated patients with Prader-Willi syndrome. Physicians should be alert to these abnormalities, which may manifest during somatropin therapy. Patients with Turner syndrome should be evaluated carefully for otitis media and other ear disorders since these patients have an increased risk of ear and hearing disorders (see ADVERSE REACTIONS). Somatropin treatment may increase the occurrence of otitis media in patients with Turner syndrome. In addition, patients with Turner syndrome should be monitored closely for cardiovascular disorders (e.g., stroke, aortic aneurysm/dissection, hypertension) as these patients are also at risk for these conditions. Adult Patients (See PRECAUTIONS, General) Patients with epiphyseal closure who were treated with somatropin replacement therapy in childhood should be reevaluated according to the criteria in INDICATIONS AND USAGE before continuation of somatropin therapy at the reduced dose level recommended for growth hormone deficient adults. Fluid retention during somatropin replacement therapy in adults may occur. Clinical manifestations of fluid retention are usually transient and dose dependent (see ADVERSE REACTIONS). Experience with prolonged treatment in adults is limited. Laboratory Tests Serum levels of inorganic phosphorus, alkaline phosphatase, parathyroid hormone (PTH) and IGF-I may increase during somatropin therapy. Carcinogenicity studies have not been conducted with somatropin. Somatropin was not genotoxic with and without metabolic activation in the Ames bacterial mutagenicity assay, the in vitro Chinese Hamster Ovary and Chinese Hamster Lung cell chromosomal aberration assay, and the in vivo mouse micronucleus assay. Male and female rats given SC doses of 1, 3, 10 IU/kg/day of somatropin from premating day 60 and premating day 14 to gestation day 7, respectively, did not show any adverse effect on fertility, mating or early development. This represents systemic exposures 1 to 15 times the human therapeutic levels based on body surface area comparisons. Pregnancy Pregnancy Category B. There are no adequate and well controlled studies of Valtropin (somatropin injection) ® in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Subcutaneous reproduction studies have been performed with somatropin in rats and rabbits at doses up to 15 and 30 times, respectively, human therapeutic levels based on body surface area comparisons. In pregnant rats given SC doses of 1, 3, 10 IU/kg/day of somatropin from gestation day 7 and 17 through organogenesis, an increase in embryolethality was observed in all somatropin-treated groups (3.88, 4.85, 4.72 %) compared to control (0.54%), representing systemic exposures 1 to 14 times human therapeutic levels based on body surface area comparisons. In pregnant rabbits given SC doses of 1, 3, 10 IU/kg/day of somatropin from gestation days 6 and 18 through organogenesis at doses up to 30 times the human dose, no developmental adverse effects were observed. In perinatal and post-natal studies in rats, somatropin at doses of 1, 3, 10 IU/kg/day given from gestation day 7 to lactation day 21, did not result in adverse effects on gestation, morphogenesis, parturition, lactation or post-natal weight of offspring (the only parameter evaluated), representing systemic exposures 1 to 14 times human therapeutic levels based on body surface area comparisons. Nursing Mothers There have been no studies conducted with Valtropin (somatropin injection) ® in nursing mothers. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Valtropin (somatropin injection) ® is administered to a nursing woman. Geriatric Use The safety and effectiveness of Valtropin (somatropin injection) ® in patients aged 65 and over has not been evaluated in clinical studies. 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).

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 [see CONTRAINDICATIONS]. Two placebo-controlled clinical trials in non-growth hormone deficient adult patients (n=522) with these conditions in intensive care units revealed a significant increase in mortality (42% vs. 19%) among somatropin-treated patients (doses 5.3-8 mg/day) compared to those receiving placebo. The safety of continuing somatropin treatment in patients receiving replacement doses for approved indications who concurrently develop these illnesses has not been established. Therefore, the potential benefit of treatment continuation with somatropin in patients having acute critical illnesses should be weighed against the potential risk. Prader-Willi Syndrome In Children There have been reports of fatalities after initiating therapy with somatropin 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 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 Prader-Willi syndrome 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]. SAIZEN is not indicated for the long term treatment of pediatric patients who have growth failure due to genetically confirmed Prader-Willi syndrome. 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 monitored carefully for development of neoplasms. Monitor patients on somatropin therapy carefully for increased growth, or potential malignant changes of preexisting nevi. Glucose Intolerance/Diabetes Mellitus Treatment with somatropin may decrease insulin sensitivity, particularly at higher doses in susceptible patients. As a result, previously undiagnosed impaired glucose tolerance and overt diabetes mellitus may be unmasked during somatropin treatment and new onset type 2 diabetes mellitus has been reported in patients. Therefore, glucose levels should be monitored periodically in all patients treated with somatropin, especially in those with risk factors for diabetes mellitus, such as obesity, Turner syndrome, or a family history of diabetes mellitus. Patients with preexisting type 1 or type 2 diabetes mellitus or impaired glucose tolerance should be monitored closely during somatropin therapy. The doses of antihyperglycemic drugs (i.e., insulin or oral 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 Turner syndrome, chronic renal insufficiency, and Prader-Willi syndrome may be at increased risk for the development of IH. 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 Fluid retention during somatropin replacement therapy in adults may occur. Clinical manifestations of fluid retention (e.g. edema, arthralgia, myalgia, nerve compression syndromes including carpal tunnel syndrome/paraesthesias) are usually transient and dose dependent. Hypoadrenalism Patients receiving somatropin therapy who have or are at risk for pituitary hormone deficiency(s) may be at risk for reduced serum cortisol levels and/or unmasking of central (secondary) hypoadrenalism. In addition, patients treated with glucocorticoid replacement for previously diagnosed hypoadrenalism may require an increase in their maintenance or stress doses following initiation of somatropin treatment [see DRUG INTERACTIONS, Inhibition of 11-β Hydroxysteroid Dehydrogenase Type 1]. Hypothyroidism Undiagnosed/untreated hypothyroidism may prevent an optimal response to somatropin, in particular, the growth response in children. Patients with Turner syndrome have an inherently increased risk of developing autoimmune thyroid disease and primary hypothyroidism. In patients with growth hormone deficiency, 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 In Pediatric Patients Slipped capital femoral epiphysis may occur more frequently in patients with endocrine disorders (including pediatric growth hormone deficiency and Turner syndrome) 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 Turner syndrome patients. Scoliosis is also commonly seen in untreated patients with Prader-Willi syndrome. Physicians should be alert to these abnormalities, which may manifest during somatropin therapy. Reevaluation Of Childhood Onset Adult GHD Patients with epiphyseal closure who were treated with somatropin replacement therapy in childhood should be reevaluated according to the criteria in INDICATIONS AND USAGE before continuation of somatropin therapy at the reduced dose level recommended for growth hormone deficient adults. Experience with prolonged treatment in adults is limited. 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]. Laboratory Tests Serum levels of inorganic phosphorus, alkaline phosphatase, parathyroid hormone (PTH), and IGF-1 may increase with 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 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 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. Patient Counseling Information Prior to self-administration of the product at home, ensure to train patients and caregivers how to prepare and administer the product correctly to help avoid wrong technique and dosing errors. Patients being treated with SAIZEN (and/or their parents) should be informed about the potential benefits and risks associated with SAIZEN treatment. 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 SAIZEN should receive appropriate training and instruction on the proper use of SAIZEN 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. To reconstitute SAIZEN, inject the diluent into the vial of SAIZEN 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. SAIZEN MUST NOT BE INJECTED if the solution is cloudy or contains particulate matter. Use it only if it is clear and colorless. Never Share a SAIZEN Needle Between Patients Counsel patients that they should never share a SAIZEN needle with another person, even if the needle is changed. Sharing of the pen between patients may pose a risk of transmission of infection. For drug preparation instructions for SAIZEN click.easy® cartridges, please refer to the Instructions for Use provided with click.easy® reconstitution device. For drug preparation instructions for saizenprep® cartridges, please refer to the Instructions for Use provided with saizenprep® reconstitution device. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility Long-term animal studies for carcinogenicity have not been performed with SAIZEN. There is no evidence from animal studies to date of SAIZEN-induced mutagenicity or impairment of fertility. Use In Specific Populations Pregnancy Teratogenic Effects Pregnancy Category B. Reproduction studies have been performed in rats and rabbits at doses up to 31 and 62 times, respectively, the human (child) weekly dose based on body surface area. The results have revealed no evidence of impaired fertility or harm to the fetus due to SAIZEN. There are, however, no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Nursing Mothers It is not known whether SAIZEN is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when SAIZEN is administered to a nursing woman. Geriatric Use The safety and effectiveness of SAIZEN in patients aged 65 and over has not been evaluated in clinical studies. Elderly patients may be more sensitive to the action of SAIZEN, 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 A reduction in somatropin clearance has been noted in patients with hepatic dysfunction as compared with normal controls. However, no studies have been conducted for SAIZEN in patients with hepatic impairment [see CLINICAL PHARMACOLOGY]. Renal Impairment Subjects with chronic renal failure tend to have decreased clearance of somatropin compared to those with normal renal function. However, no studies have been conducted for SAIZEN in patients with renal impairment [see CLINICAL PHARMACOLOGY]. Gender Effect In adults, the clearance of somatropin in both men and women tends to be similar. No gender studies have been performed in children.