SEROSTIM

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

SEROSTIM (somatropin) is indicated for the treatment of HIV patients with wasting or cachexia to increase lean body mass and body weight, and improve physical endurance. Concomitant antiretroviral therapy is necessary. SEROSTIM is indicated for the treatment of HIV patients with wasting or cachexia to increase lean body mass and body weight, and improve physical endurance ( 1 )

SEROSTIM is administered by subcutaneous injection. SEROSTIM therapy should be carried out under the regular guidance of a physician who is experienced in the diagnosis and management of HIV infection. The recommended dose of SEROSTIM is 0.1 mg/kg subcutaneously (SC) daily (up to 6 mg) at bedtime for HIV patients with wasting or cachexia ( 2.1 ) Injection sites, which may be located on thigh, upper arm, abdomen or buttock, should be rotated to avoid local irritation ( 2.2 ) 2.1 HIV-associated wasting or cachexia The usual starting dose of SEROSTIM is 0.1 mg/kg subcutaneously once daily (up to a total dose of 6 mg). SEROSTIM should be administered subcutaneously once daily at bedtime according to the following body weight-based dosage recommendations: Weight Range Dose >55kg (>121 lb) 6 mg Based on an approximate daily dosage of 0.1 mg/kg. SC daily 45-55 kg (99-121 lb) 5 mg SC daily 35-45 kg (75-99 lb) 4 mg SC daily <35 kg (<75 lb) 0.1 mg/kg SC daily Treatment with SEROSTIM 0.1 mg/kg every other day was associated with fewer side effects, and resulted in a similar improvement in work output, as compared with SEROSTIM 0.1 mg/kg daily. Therefore, a starting dose of SEROSTIM 0.1 mg/kg every other day should be considered in patients at increased risk for adverse effects related to recombinant human growth hormone therapy (i.e., glucose intolerance). In general, dose reductions (i.e., reducing the total daily dose or the number of doses per week) should be considered for side effects potentially related to recombinant human growth hormone therapy. Most of the effect of SEROSTIM on work output and lean body mass was apparent after 12 weeks of treatment. The effect was maintained during an additional 12 weeks of therapy. There are no safety or efficacy data available from controlled studies in which patients were treated with SEROSTIM continuously for more than 48 weeks. There are no safety or efficacy data available from trials in which patients with HIV wasting or cachexia were treated intermittently with SEROSTIM. 2.2 Preparation and Administration Each vial of SEROSTIM 5 mg or 6 mg is reconstituted with 0.5 to 1 mL Sterile Water for Injection, USP. Each vial of SEROSTIM 4 mg is reconstituted in 0.5 to 1 mL of Bacteriostatic Water for Injection, USP (0.9% Benzyl Alcohol preserved). For patients sensitive to Benzyl Alcohol, SEROSTIM may be reconstituted with Sterile Water for Injection, USP [see Pediatric Use (8.4) ]. When SEROSTIM is reconstituted with Sterile Water for Injection, USP, the reconstituted solution should be used immediately and any unused portion should be discarded. When SEROSTIM is reconstituted with Bacteriostatic Water for Injection, USP (0.9% Benzyl Alcohol preserved) the reconstituted solution may be refrigerated (2-8°C/36-46°F) for up to 14 days. Approximately 10% mechanical loss can be associated with reconstitution and administration from multi-dose vials. To reconstitute SEROSTIM, inject the diluent into the vial of SEROSTIM aiming the liquid against the glass vial wall. Swirl the vial with a GENTLE rotary motion until contents are dissolved completely. DO NOT SHAKE. Parenteral drug products should always be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. SEROSTIM MUST NOT BE INJECTED if the solution is cloudy or contains particulate matter. Use it only if it is clear and colorless. SEROSTIM can be administered using (1) a standard sterile, disposable syringe and needle, (2) a compatible SEROSTIM needle-free injection device or (3) a compatible SEROSTIM needle injection device. For proper use, refer to the Instructions for Use provided with the administration device. Injection sites, which may be located on the thigh, upper arm, abdomen or buttock, should be rotated to avoid local irritation.

Acute Critical Illness Growth hormone therapy should not be initiated in patients with acute critical illness due to complications following open heart or abdominal surgery, multiple accidental trauma or acute respiratory failure [see Warnings and Precautions (5.1) ]. Active Malignancy In general, somatropin is contraindicated in the presence of active malignancy. Any preexisting malignancy should be inactive and its treatment complete prior to instituting therapy with somatropin. Somatropin should be discontinued if there is evidence of recurrent activity [see Warnings and Precautions (5.3) ] . Hypersensitivity SEROSTIM is contraindicated in patients with a known hypersensitivity to somatropin or any of its excipients. Systemic hypersensitivity reactions have been reported with postmarketing use of somatropin products [see Warnings and Precautions (5.6) ]. Diabetic Retinopathy Somatropin is contraindicated in patients with active proliferative or severe non-proliferative diabetic retinopathy. Acute Critical Illness ( 4 ) Active Malignancy ( 4 ) Diabetic Retinopathy ( 4 ) Hypersensitivity to somatropin or excipients ( 4 )

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 SEROSTIM4 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 postmarketing 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) ] .

Formal drug interaction studies have not been conducted. No data are available on drug interactions between SEROSTIM and HIV protease inhibitors or the non-nucleoside reverse transcriptase inhibitors. Inhibition of 11β-Hydroxysteroid Dehydrogenase Type 1: May require the initiation of glucocorticoid replacement therapy. Patients treated with glucocorticoid replacement for previously diagnosed hypoadrenalism may require an increase in their maintenance doses ( 7.1 ) Cytochrome P450-Metabolized Drugs: Monitor carefully if used with somatropin ( 7.2 ) Oral Estrogen: Larger doses of somatropin may be required in women ( 7.3 ) Insulin and/or Oral/Injectable Hypoglycemic Agents: May require adjustment ( 7.4 ) 7.1 11β-Hydroxysteroid Dehydrogenase Type 1 The microsomal enzyme 11β-hydroxysteroid dehydrogenase type 1 (11βHSD-1) is required for conversion of cortisone to its active metabolite, cortisol, in hepatic and adipose tissue. Somatropin inhibits 11βHSD-1. Patients treated with glucocorticoid replacement for previously diagnosed hypoadrenalism may require an increase in their maintenance or stress doses following initiation of somatropin treatment; this may be especially true for patients treated with cortisone acetate and prednisone since conversion of these drugs to their biologically active metabolites is dependent on the activity of 11βHSD-1. 7.2 Cytochrome P450-metabolized drugs Limited published data indicate that somatropin treatment increases cytochrome P450 (CYP450)-mediated antipyrine clearance in man. These data suggest that somatropin administration may alter the clearance of compounds metabolized by CYP450 liver enzymes (e.g., corticosteroids, sex steroids, anticonvulsants, cyclosporine). Therefore, careful monitoring is advised when somatropin is administered in combination with drugs metabolized by CYP450 liver enzymes. However, formal drug interaction studies have not been conducted. 7.3 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 (2) ] . 7.4 Insulin and/or Other Oral/Injectable Hypoglycemic Agents Patients with diabetes mellitus who receive concomitant treatment with somatropin may require adjustment of their doses of insulin and/or other hypoglycemic agents [see Warnings and Precautions (5.4) ] .

16.2 Storage and Handling Before reconstitution: Vials of SEROSTIM and diluent should be stored at room temperature, (15°-30°C/59°-86°F). Expiration dates are stated on product labels. Single-use vials: After reconstitution with Sterile Water for Injection, USP, the reconstituted solution should be used immediately and any unused portion should be discarded. Multi-use vials: After reconstitution with Bacteriostatic Water for Injection, USP (0.9% Benzyl Alcohol), the reconstituted solution should be stored under refrigeration (2-8°C/36-46° F) for up to 14 days. Avoid freezing reconstituted vials of SEROSTIM.