FDA label 4ca63d8e-15cf-4690-b148-2ad415bd0640

5 WARNINGS AND PRECAUTIONS Acute Critical Illness: Increased mortality in patients with acute critical illness 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 ( 5.1 ) Concomitant Antiretroviral Therapy: In vitro experimental systems have demonstrated the potential to potentiate HIV replication. No significant somatropin-associated increase in viral load was observed in clinical trials. Patients with HIV should be maintained on antiretroviral therapy for the duration of SEROSTIM treatment ( 5.2 ) Neoplasms: Monitor all patients with a history of any neoplasm routinely while on somatropin therapy for progression, recurrences, or development of a tumor ( 5.3 ) Impaired Glucose Tolerance/Diabetes: May be unmasked. Periodically monitor glucose levels. Dose adjustment of concurrent antihyperglycemic drugs in diabetics may be required ( 5.4 ) Intracranial Hypertension: Exclude preexisting papilledema. May develop and is usually reversible after discontinuation or dose reduction ( 5.5 ) Hypersensitivity: Serious hypersensitivity reactions may occur. In the event of an allergic reaction, seek prompt medical attention ( 5.6 ) Fluid Retention (edema, arthralgia)/Carpal Tunnel Syndrome: May occur frequently. Reduce dose as necessary ( 5.7 ) Pancreatitis: Consider pancreatitis in patients with persistent severe abdominal pain ( 5.9 ) 5.1 Acute Critical Illness Increased mortality in patients with acute critical illness due to complications following open heart surgery, abdominal surgery or multiple accidental trauma, or those with acute respiratory failure has been reported after treatment with pharmacologic amounts of somatropin. Two placebo-controlled clinical trials in non-growth hormone deficient adult patients (n=522) with these conditions revealed a significant increase in mortality (42% vs. 19%) among somatropin-treated patients (doses 5.3-8 mg/day) compared to those receiving placebo [see Contraindications (4) ] . 5.2 Concomitant Antiretroviral Therapy In some experimental systems, somatropin has been shown to potentiate HIV replication in vitro at concentrations ranging from 50-250 ng/mL. There was no increase in virus production when the antiretroviral agents, zidovudine, didanosine or lamivudine were added to the culture medium. Additional in vitro studies have shown that somatropin does not interfere with the antiviral activity of zalcitabine or stavudine. In the controlled clinical trials, no significant somatropin-associated increase in viral burden was observed. However, the protocol required all participants to be on concomitant antiretroviral therapy for the duration of the study. In view of the potential for acceleration of virus replication, it is recommended that patients with HIV be maintained on antiretroviral therapy for the duration of SEROSTIM treatment. 5.3 Neoplasms Because malignancies are more common in HIV positive individuals, the risks and benefits of starting somatropin in patients with HIV should be carefully considered before initiating SEROSTIM treatment and patients should be monitored carefully for the development of neoplasms if treatment with somatropin is initiated. Monitor all patients with a history of any neoplasm routinely while on somatropin therapy for progression or recurrence of the tumor [see Contraindications (4) ]. Monitor patients on somatropin therapy carefully for increased growth, or potential malignant changes of preexisting nevi. 5.4 Impaired Glucose Tolerance/Diabetes Hyperglycemia may occur in patients with HIV due to a variety of reasons. In wasting patients, treatment with SEROSTIM 0.1 mg/kg daily and 0.1 mg/kg every other day for 12 weeks was associated with approximately 10 mg/dL and 6 mg/dL increases in mean fasting blood glucose concentrations, respectively. The increases occurred early in treatment. Patients with other risk factors for glucose intolerance should be monitored closely during SEROSTIM therapy. During safety surveillance of patients with HIV-associated wasting, cases of new onset impaired glucose tolerance, new onset type 2 diabetes mellitus and exacerbation of preexisting diabetes mellitus have been reported in patients receiving SEROSTIM. Some patients developed diabetic ketoacidosis and diabetic coma. In some patients, these conditions improved when SEROSTIM was discontinued, while in others, the glucose intolerance persisted. Some of these patients required initiation or adjustment of antidiabetic treatment while on SEROSTIM. In clinical trials of SEROSTIM conducted in patients with HIV lipodystrophy (an unapproved indication), evidence of dose-dependent glucose intolerance and related adverse reaction was observed at doses of 4 mg SEROSTIM daily and 4 mg SEROSTIM every other day for 12 weeks [see Adverse Reactions (6.1) ] . 5.5 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 fundoscopy 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. 5.6 Severe Hypersensitivity Serious systemic hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with post-marketing 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 (4) ]. 5.7 Fluid Retention/Carpal Tunnel Syndrome Increased tissue turgor (swelling, particularly in the hands and feet) and musculoskeletal discomfort (pain, swelling and/or stiffness) may occur during treatment with SEROSTIM, but may resolve spontaneously, with analgesic therapy, or after reducing the frequency of dosing [see Dosage and Administration (2.1) ]. Carpal tunnel syndrome may occur during treatment with SEROSTIM. If the symptoms of carpal tunnel syndrome do not resolve by decreasing the weekly number of doses of SEROSTIM, it is recommended that treatment be discontinued. 5.8 Lipoatrophy When somatropin is administered subcutaneously at the same site over a long period of time, tissue atrophy may result. This can be avoided by rotating the injection site [see Dosage and Administration (2.2) ] . 5.9 Pancreatitis Cases of pancreatitis have been reported rarely in children and adults receiving somatropin treatment, with some evidence supporting a greater risk in children compared with adults. Published literature indicates that girls who have Turner syndrome may be at greater risk than other somatropin-treated children. Pancreatitis should be considered in any somatropin-treated patient, especially a child who develops abdominal pain.

6 ADVERSE REACTIONS The following important adverse reactions are also described elsewhere in the labeling: Acute Critical Illness [see Warnings and Precautions (5.1) ] Neoplasms [see Warnings and Precautions (5.3) ] Impaired glucose tolerance and diabetes mellitus [see Warnings and Precautions (5.4) ] Intracranial hypertension [see Warnings and Precautions (5.5) ] Severe hypersensitivity [see Warnings and Precautions (5.6) ] Fluid retention/Carpal tunnel syndrome [see Warnings and Precautions (5.7) ] Lipoatrophy [see Warnings and Precautions (5.8) ] Pancreatitis [see Warnings and Precautions (5.9) ] Most common adverse reactions include (incidence >10%) tissue turgor (edema, myalgia, hypoesthesia) and musculoskeletal discomfort (arthralgia, pain in extremities) ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact EMD Serono at 1-800-283-8088 ext 5563 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Clinical trials in HIV-associated wasting or cachexia: In the 12-week, placebo-controlled Clinical Trial 2, 510 patients were treated with SEROSTIM. The most common adverse reactions judged to be associated with SEROSTIM were musculoskeletal discomfort and increased tissue turgor (swelling, particularly of the hands or feet), and were more frequently observed when SEROSTIM 0.1 mg/kg was administered on a daily basis [Table 1 and Warnings and Precautions (5)]. These symptoms often subsided with continued treatment or dose reduction. Approximately 23% of patients receiving SEROSTIM 0.1 mg/kg daily and 11% of patients receiving 0.1 mg/kg every other day required dose reductions. Discontinuations as a result of adverse reactions occurred in 10.3% of patients receiving SEROSTIM 0.1 mg/kg daily and 6.6% of patients receiving 0.1 mg/kg every other day. The most common reasons for dose reduction and/or drug discontinuation were arthralgia, myalgia, edema, carpal tunnel syndrome, elevated glucose levels, and elevated triglyceride levels. Clinical adverse reactions which occurred during the first 12 weeks of study in at least 5% of the patients in either active treatment group and at an incidence greater than placebo are listed below, without regard to causality assessment. Table 1: Controlled Clinical Trial 2 Adverse Reactions Occurring in at least 5% of Patients in one of the Treatment Groups, and at an Incidence Greater than Placebo Placebo 0.1 mg/kg every other day SEROSTIM 0.1 mg/kg daily SEROSTIM Patients (n=247) Patients (n=257) Patients (n=253) Body System Preferred Term % % % Musculoskeletal System Disorders Arthralgia 11.3 24.5 36.4 Myalgia 11.7 17.9 30.4 Arthrosis 3.6 7.8 10.7 Gastrointestinal System Disorders Nausea 4.9 5.4 9.1 Body As A Whole - General Disorders Edema Peripheral 2.8 11.3 26.1 Fatigue 4.5 3.5 5.1 Endocrine Disorders Gynecomastia 0.4 3.5 5.5 Central and Peripheral Nervous System Disorders Paresthesia 4.5 7.4 7.9 Hypoesthesia 2.4 1.6 5.1 Metabolic and Nutritional Disorders Edema Generalized 1.2 1.2 5.9 Adverse reactions that occurred in 1% to less than 5% of trial participants receiving SEROSTIM during the first 12 weeks of Clinical Trial 2 thought to be related to SEROSTIM included dose dependent edema, periorbital edema, carpal tunnel syndrome, hyperglycemia and hypertriglyceridemia. During the 12-week, placebo-controlled portion of Clinical Trial 2, the incidence of hyperglycemia reported as an adverse reaction was 3.6% for the placebo group, 1.9% for the 0.1 mg/kg every other day group and 3.2% for the 0.1 mg/kg daily group. One case of diabetes mellitus was noted in the 0.1 mg/kg daily group during the first 12-weeks of therapy. In addition, during the extension phase of Clinical Trial 2, two patients converted from placebo to full dose SEROSTIM, and 1 patient converted from placebo to half-dose SEROSTIM, were discontinued because of the development of diabetes mellitus. The types and incidences of adverse reactions reported during the Clinical Trial 2 extension phase were not different from, or greater in frequency than those observed during the 12-week, placebo-controlled portion of Clinical Trial 2. Adverse reactions from treatment with SEROSTIM in clinical trials in HIV lipodystrophy SEROSTIM was evaluated for the treatment of patients with HIV lipodystrophy in two double-blind, placebo-controlled trials that excluded patients with a history of diabetes, impaired fasting glucose or impaired glucose (approximately 20% of the patients screened were excluded from study enrollment as a result of a diagnosis of diabetes or glucose intolerance). The studies included a 12-week double-blind, placebo-controlled, parallel group "induction" phase followed by maintenance phases of different durations (12 and 24 weeks, respectively). In the initial 12-week treatment periods of the two, placebo-controlled clinical trials, 406 patients were treated with SEROSTIM. Clinical adverse reactions which occurred during the first 12 weeks of both studies combined in at least 5% of the patients in either of the two active treatment groups are listed by treatment group in Table 2, without regard to causality assessment. The most common adverse reactions judged to be associated with SEROSTIM were edema, arthralgia, pain in extremity, hypoesthesia, myalgia, and blood glucose increased, all of which were more frequently observed when SEROSTIM 4 mg was administered on a daily basis compared with alternate days. These symptoms often subsided with dose reduction. During the 12-week induction phase, 1) approximately 26% of patients receiving SEROSTIM 4 mg daily and 19% of patients receiving SEROSTIM 4 mg every other day required dose reductions; and 2) discontinuations as a result of adverse reactions occurred in 13% of patients receiving SEROSTIM 4 mg daily and 5% of patients receiving SEROSTIM 4 mg every other day. The most common reasons for dose reduction and/or drug discontinuation were peripheral edema, hyperglycemia (including blood glucose increased, blood glucose abnormal, and hyperglycemia), and arthralgia. Table 2: Controlled HIV Lipodystrophy Studies 1 and 2 Combined – Adverse Reactions with >5% Incidence in Either Active Treatment Arm Placebo SEROSTIM 4 mg every other day Study 22388 only SEROSTIM 4 mg daily Patients (n=159) Patients (n=80) Patients (n=326) System Organ Class Preferred Term % % % Musculoskeletal and connective tissue disorders Arthralgia 11.9 27.8 37.1 Pain in extremity 3.8 5.0 19.3 Myalgia 3.8 2.5 12.6 Musculoskeletal stiffness 1.9 3.8 8.0 Joint stiffness 1.3 3.8 7.7 Joint swelling 0.6 5.0 6.1 General disorders and administration site conditions Edema peripheral 3.8 18.8 45.4 Fatigue 1.9 6.3 8.9 Nervous system disorders Hypoesthesia 0.6 8.8 15.0 Paraesthesia 2.5 12.5 11.0 Investigations (Laboratory Evaluations) Blood glucose increased similar terms were grouped together and reported below 2.5 3.8 13.8 Metabolism and nutrition disorders Hyperglycemia 0.6 8.8 7.1 Fluid retention 0.6 2.5 5.2 Gastrointestinal disorders Nausea 2.5 1.3 6.1 Glucose metabolism related adverse reactions: During the initial 12-week treatment periods of Studies 1 and 2, the incidence of glucose-related adverse reactions was 4% for the placebo group, 13% for the 4 mg every other day group and 22% for the 4 mg daily group. Twenty-three patients discontinued due to hyperglycemia while receiving SEROSTIM during any phase of these studies (3.2% in the 12-week induction phases and 2.1% in the extension phases). Breast-Related Terms: When grouped together, breast-related adverse reactions (e.g. nipple pain, gynecomastia, breast pain/mass/tenderness/swelling/edema/hypertrophy) had an incidence of 1% for the placebo group, 3% for the SEROSTIM 4 mg every other day group and 6% for the SEROSTIM 4 mg daily group. Adverse reactions that occurred in 1% to less than 5% of trial participants receiving SEROSTIM during the first 12 weeks of HIV Lipodystrophy Studies 1 and 2 thought to be related to SEROSTIM include carpal tunnel syndrome, Tinel's sign and facial edema. The adverse reactions reported for SEROSTIM 4 mg every other day during the maintenance phase of HIV Lipodystrophy Study 1 (Week 12 to Week 24) were similar in frequency and quality to those observed after treatment with SEROSTIM 4 mg every other day during the 12-week induction phase. IGF-1 serum concentrations increased statistically in SEROSTIM-treated patients when compared to placebo (Table 3). In the SEROSTIM treated patients at baseline, the proportion of subjects with serum IGF-1 SDS levels ≥ +2 was approximately 10 to 20%, while with treatment with either dose regimen of SEROSTIM the percentage increased to 80 to 90% by Week 12. Table 3: Change from Baseline to Week 12 in Serum IGF-1 SDS After Treatment with SEROSTIM 4 mg daily vs. Placebo (Modified ITT Population; Studies 1 and 2 Combined) Placebo SEROSTIM 4 mg every other day SEROSTIM 4 mg daily Time Point Statistic (n=145) (n=79) (n=290) Baseline Mean (SD) Range 0.4 (1.4) (-2.5, 4.8) 1.3 (2.1) (-2.0, 13.7) 0.0 (1.6) (-3.0, 11.9) Week 12 Mean (SD) Range 0.8 (1.6) (-2.6, 6.7) 5.1 (3.4) (-0.7, 17.2) 6.1 (5.0) (-1.8, 29.2) Change from Baseline to Mean (SD) Range 0.4 (1.3) (-2.9, 7.7) 3.9 (3.1) (-9.4, 11.8) 6.1 (4.6) (-2.4, 24.3) Week 12 p-value P-value from a Wilcoxon Signed Rank test on the change from baseline to Week 12. <0.001 <0.001 <0.001 Mean Proportionally weighted least squares means from a two-way ANOVA model on raw data including effects for treatment, sex, and the treatment by sex interaction. diff (SEM) 3.5 (0.5) 5.7 (0.4) p-value P-value from a two-way ANOVA model on ranked data including effects for treatment, sex, and the treatment by sex interaction. <0.001 <0.001 As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influences by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to SEROSTIM with the incidence of antibodies to other products may be misleading. After 12 weeks of treatment, none of the 651 study participants with HIV-associated wasting treated with SEROSTIM for the first time developed detectable antibodies to growth hormone (> 4 pg binding). Patients were not rechallenged. Data beyond 3 months is not available. 6.2 Post Marketing Experience The following adverse reactions have been identified during post approval use of SEROSTIM. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hypersensitivity: Serious systemic hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with post-marketing use of somatropin products [see Warnings and Precautions (5.6) ]. Endocrine: new onset impaired glucose tolerance new onset type 2 diabetes mellitus exacerbation of preexisting diabetes mellitus diabetic ketoacidosis diabetic coma In some patients, these conditions improved when SEROSTIM was discontinued, while in others the glucose intolerance persisted. Some of these patients required initiation or adjustment of antidiabetic treatment while on SEROSTIM [see Warnings and Precautions (5.4) ] . Gastrointestinal: Pancreatitis [see Warnings and Precautions (5.9) ] .

<table width="90%" ID="Table1"><caption>Table 1: Controlled Clinical Trial 2 Adverse Reactions Occurring in at least 5% of Patients in one of the Treatment Groups, and at an Incidence Greater than Placebo </caption><col width="35%" align="left" valign="top"/><col width="18%" align="center" valign="top"/><col width="27%" align="center" valign="top"/><col width="20%" align="center" valign="top"/><thead><tr><th styleCode="Lrule Rrule"/><th styleCode="Rrule" valign="middle">Placebo</th><th styleCode="Rrule">0.1 mg/kg every other day SEROSTIM</th><th styleCode="Rrule" valign="middle">0.1 mg/kg daily SEROSTIM</th></tr><tr styleCode="Botrule"><th styleCode="Lrule Rrule"/><th styleCode="Rrule Toprule" align="center">Patients (n=247)</th><th styleCode="Rrule Toprule">Patients (n=257)</th><th styleCode="Rrule Toprule">Patients (n=253)</th></tr><tr><th styleCode="Lrule Rrule">Body System Preferred Term</th><th styleCode="Rrule" align="center">%</th><th styleCode="Rrule">%</th><th styleCode="Rrule">%</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Musculoskeletal System Disorders</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Arthralgia</td><td styleCode="Rrule">11.3</td><td styleCode="Rrule">24.5</td><td styleCode="Rrule">36.4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Myalgia</td><td styleCode="Rrule">11.7</td><td styleCode="Rrule">17.9</td><td styleCode="Rrule">30.4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Arthrosis</td><td styleCode="Rrule">3.6</td><td styleCode="Rrule">7.8</td><td styleCode="Rrule">10.7</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Gastrointestinal System Disorders</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Nausea</td><td styleCode="Rrule">4.9</td><td styleCode="Rrule">5.4</td><td styleCode="Rrule">9.1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Body As A Whole - General Disorders</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Edema Peripheral</td><td styleCode="Rrule">2.8</td><td styleCode="Rrule">11.3</td><td styleCode="Rrule">26.1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Fatigue</td><td styleCode="Rrule">4.5</td><td styleCode="Rrule">3.5</td><td styleCode="Rrule">5.1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Endocrine Disorders</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Gynecomastia</td><td styleCode="Rrule">0.4</td><td styleCode="Rrule">3.5</td><td styleCode="Rrule">5.5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Central and Peripheral Nervous System Disorders</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Paresthesia</td><td styleCode="Rrule">4.5</td><td styleCode="Rrule">7.4</td><td styleCode="Rrule">7.9</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Hypoesthesia</td><td styleCode="Rrule">2.4</td><td styleCode="Rrule">1.6</td><td styleCode="Rrule">5.1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Metabolic and Nutritional Disorders</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr><td styleCode="Lrule Rrule"> Edema Generalized</td><td styleCode="Rrule">1.2</td><td styleCode="Rrule">1.2</td><td styleCode="Rrule">5.9</td></tr></tbody></table>

<table width="90%" ID="Table2"><caption>Table 2: Controlled HIV Lipodystrophy Studies 1 and 2 Combined &#x2013; Adverse Reactions with &gt;5% Incidence in Either Active Treatment Arm</caption><col width="38%" align="left" valign="top"/><col width="20%" align="center" valign="top"/><col width="22%" align="center" valign="top"/><col width="20%" align="center" valign="top"/><thead><tr><th styleCode="Lrule Rrule"/><th styleCode="Rrule" valign="middle">Placebo</th><th styleCode="Rrule" valign="middle">SEROSTIM 4 mg every other day<footnote ID="table2a">Study 22388 only</footnote></th><th styleCode="Rrule" valign="middle">SEROSTIM 4 mg daily</th></tr><tr styleCode="Botrule"><th styleCode="Lrule Rrule"/><th styleCode="Rrule Toprule" align="center">Patients (n=159)</th><th styleCode="Rrule Toprule" valign="middle">Patients (n=80)</th><th styleCode="Rrule Toprule" valign="middle">Patients (n=326)</th></tr><tr><th styleCode="Lrule Rrule">System Organ Class Preferred Term</th><th styleCode="Rrule" align="center">%</th><th styleCode="Rrule">%</th><th styleCode="Rrule">%</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Musculoskeletal and connective tissue disorders</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Arthralgia</td><td styleCode="Rrule">11.9</td><td styleCode="Rrule">27.8</td><td styleCode="Rrule">37.1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Pain in extremity</td><td styleCode="Rrule">3.8</td><td styleCode="Rrule">5.0</td><td styleCode="Rrule">19.3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Myalgia</td><td styleCode="Rrule">3.8</td><td styleCode="Rrule">2.5</td><td styleCode="Rrule">12.6</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Musculoskeletal stiffness</td><td styleCode="Rrule">1.9</td><td styleCode="Rrule">3.8</td><td styleCode="Rrule">8.0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Joint stiffness</td><td styleCode="Rrule">1.3</td><td styleCode="Rrule">3.8</td><td styleCode="Rrule">7.7</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Joint swelling</td><td styleCode="Rrule">0.6</td><td styleCode="Rrule">5.0</td><td styleCode="Rrule">6.1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">General disorders and administration site conditions</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Edema peripheral</td><td styleCode="Rrule">3.8</td><td styleCode="Rrule">18.8</td><td styleCode="Rrule">45.4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Fatigue</td><td styleCode="Rrule">1.9</td><td styleCode="Rrule">6.3</td><td styleCode="Rrule">8.9</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Nervous system disorders</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Hypoesthesia</td><td styleCode="Rrule">0.6</td><td styleCode="Rrule">8.8</td><td styleCode="Rrule">15.0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Paraesthesia</td><td styleCode="Rrule">2.5</td><td styleCode="Rrule">12.5</td><td styleCode="Rrule">11.0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Investigations (Laboratory Evaluations)</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Blood glucose increased<footnote ID="table2b">similar terms were grouped together and reported below</footnote></td><td styleCode="Rrule">2.5</td><td styleCode="Rrule">3.8</td><td styleCode="Rrule">13.8</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Metabolism and nutrition disorders</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Hyperglycemia<footnoteRef IDREF="table2b"/></td><td styleCode="Rrule">0.6</td><td styleCode="Rrule">8.8</td><td styleCode="Rrule">7.1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Fluid retention</td><td styleCode="Rrule">0.6</td><td styleCode="Rrule">2.5</td><td styleCode="Rrule">5.2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Gastrointestinal disorders</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr><td styleCode="Lrule Rrule"> Nausea</td><td styleCode="Rrule">2.5</td><td styleCode="Rrule">1.3</td><td styleCode="Rrule">6.1</td></tr></tbody></table>

<table width="90%" ID="Table3"><caption>Table 3: Change from Baseline to Week 12 in Serum IGF-1 SDS After Treatment with SEROSTIM 4 mg daily vs. Placebo (Modified ITT Population; Studies 1 and 2 Combined)</caption><col width="22%" align="left" valign="top"/><col width="22%" align="left" valign="top"/><col width="20%" align="center" valign="top"/><col width="16%" align="center" valign="top"/><col width="20%" align="center" valign="top"/><thead><tr styleCode="Botrule"><th styleCode="Lrule Rrule"/><th styleCode="Rrule"/><th styleCode="Rrule" valign="middle">Placebo</th><th styleCode="Rrule" valign="middle">SEROSTIM 4 mg every other day</th><th styleCode="Rrule" valign="top">SEROSTIM 4 mg daily</th></tr><tr><th styleCode="Lrule Rrule">Time Point</th><th styleCode="Rrule">Statistic</th><th styleCode="Rrule">(n=145)</th><th styleCode="Rrule">(n=79)</th><th styleCode="Rrule">(n=290)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Baseline</td><td styleCode="Rrule">Mean (SD) Range</td><td styleCode="Rrule">0.4 (1.4) (-2.5, 4.8)</td><td styleCode="Rrule">1.3 (2.1) (-2.0, 13.7)</td><td styleCode="Rrule">0.0 (1.6) (-3.0, 11.9)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Week 12</td><td styleCode="Rrule">Mean (SD) Range</td><td styleCode="Rrule">0.8 (1.6) (-2.6, 6.7)</td><td styleCode="Rrule">5.1 (3.4) (-0.7, 17.2)</td><td styleCode="Rrule">6.1 (5.0) (-1.8, 29.2)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Change from Baseline to</td><td styleCode="Rrule">Mean (SD) Range</td><td styleCode="Rrule">0.4 (1.3) (-2.9, 7.7)</td><td styleCode="Rrule">3.9 (3.1) (-9.4, 11.8)</td><td styleCode="Rrule">6.1 (4.6) (-2.4, 24.3)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Week 12</td><td styleCode="Rrule">p-value<footnote ID="table3b">P-value from a Wilcoxon Signed Rank test on the change from baseline to Week 12.</footnote></td><td styleCode="Rrule">&lt;0.001</td><td styleCode="Rrule">&lt;0.001</td><td styleCode="Rrule">&lt;0.001</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"/><td styleCode="Rrule">Mean<footnote ID="table3a">Proportionally weighted least squares means from a two-way ANOVA model on raw data including effects for treatment, sex, and the treatment by sex interaction.</footnote> diff (SEM)</td><td styleCode="Rrule"/><td styleCode="Rrule">3.5 (0.5)</td><td styleCode="Rrule">5.7 (0.4)</td></tr><tr><td styleCode="Lrule Rrule"/><td styleCode="Rrule">p-value<footnote ID="table3c">P-value from a two-way ANOVA model on ranked data including effects for treatment, sex, and the treatment by sex interaction.</footnote></td><td styleCode="Rrule"/><td styleCode="Rrule">&lt;0.001</td><td styleCode="Rrule">&lt;0.001</td></tr></tbody></table>