Serostim

1 INDICATIONS AND USAGE SEROSTIM (somatropin) is indicated for the treatment of adults with HIV and wasting or cachexia to increase lean body mass and body weight, and improve physical endurance. Concomitant antiretroviral therapy is necessary. SEROSTIM is a human growth hormone (somatropin) indicated for the treatment of adults with HIV and wasting or cachexia to increase lean body mass and body weight, and improve physical endurance ( 1 )

2 DOSAGE AND ADMINISTRATION SEROSTIM is administered by subcutaneous injection. SEROSTIM therapy should be carried out under the regular guidance of a physician who is experienced in the diagnosis and management of HIV infection. The recommended dosage of SEROSTIM is 0.1 mg/kg subcutaneously once daily (up to 6 mg) at bedtime ( 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. subcutaneously once daily 45-55 kg (99-121 lb) 5 mg subcutaneously once daily 35-45 kg (75-99 lb) 4 mg subcutaneously once daily <35 kg (<75 lb) 0.1 mg/kg subcutaneously once 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-associated wasting or cachexia were treated intermittently with SEROSTIM. 2.2 Preparation and Administration Reconstitute SEROSTIM 5 mg vial or 6 mg vial with 0.5 mL to 1 mL of diluent, Sterile Water for Injection. Use the reconstituted solution immediately and use only one dose per vial for one patient. Discard any unused portion. Reconstitute SEROSTIM 4 mg vial with 0.5 mL to 1 mL of diluent, Bacteriostatic Water for Injection with 0.9% benzyl alcohol as a preservative. Do not use this diluent if the patient has a known hypersensitivity to benzyl alcohol [see Contraindications (4) ] or in pregnant or lactating women [see Use in Specific Populations (8.1 , 8.2) ], instead reconstitute with Sterile Water for Injection and use only one dose per vial . Aim the stream of diluent against the glass vial wall to prevent foaming. 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 the reconstituted solution only if it is clear or slightly opalescent. SEROSTIM 4 mg vial reconstituted with Bacteriostatic Water for Injection with 0.9% benzyl alcohol as preservative may be refrigerated at 2°C to 8°C (36°F to 46°F) for up to 14 days. Administer SEROSTIM using a standard sterile, disposable syringe and needle. Injection sites, which may be located on the thigh, upper arm, abdomen or buttock, should be rotated to avoid local irritation.

3 DOSAGE FORMS AND STRENGTHS For injection: 4 mg white to off-white lyophilized powder in a single-patient-use vial for reconstitution with co-packaged vial of Bacteriostatic Water for Injection (containing 0.9% benzyl alcohol as a preservative) For injection: 5 mg or 6 mg white to off-white lyophilized powder in a single-dose vial for reconstitution with co-packaged vial of Sterile Water for Injection For injection: 4 mg of somatropin as a lyophilized powder in a single-patient-use vial for reconstitution ( 3 ) For injection: 5 mg or 6 mg of somatropin in a lyophilized powder in a single-dose vial for reconstitution ( 3 )

4 CONTRAINDICATIONS Acute Critical Illness Growth hormone therapy should not be initiated in patients with acute critical illness due to complications following open heart or abdominal surgery, multiple accidental trauma or acute respiratory failure [see Warnings and Precautions (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 post-marketing 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 )

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 …

7 DRUG INTERACTIONS Formal drug interaction studies have not been conducted. No data are available on drug interactions between SEROSTIM and HIV protease inhibitors or the non-nucleoside reverse transcriptase inhibitors. 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) ] .

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Available data with somatropin use in pregnant women are insufficient to identify a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. In animal reproduction studies, no adverse developmental effects were observed when somatropin was administered subcutaneously to pregnant rats and rabbits during the period of organogenesis at doses up to 5 to 10 times the human dose, respectively (see Data ) . The estimated background risk of birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data Reproductive and developmental toxicity studies were performed in rats and rabbits by the subcutaneous route of administration. Somatropin doses of 0.033, 0.33 and 3.33 mg/kg (0.1, 1 and 10 IU/kg) were used in each of the studies. The highest doses were approximately 5 times and 10 times the maximum recommended human dose based on body surface area (BSA) in rats and rabbits, respectively. In an embryofetal development study in rats that included assessments of F1 growth and development, somatropin was administered to pregnant females during the period of organogenesis from day 6 to day 17 of gestation. There were no compound-related embryotoxic or teratogenic effects on the fetuses or on F1 postnatal survival, development, or reproductive performance at up to 5-times the maximum human dose based on BSA. In an embryofetal development study in rabbits, there were no adverse effects on fetal development when somatropin was administered to pregnant females from day 6 to day 18 of gestation at up to approximately 10 times the maximum human dose by BSA. In a pre- and postnatal development study in rats, females were treated with somatropin from day 15 of gestation to day 21 of lactation. There were no adverse effects on gestation, parturition or on the postnatal survival, development, and reproductive function of the F1 generation. A study performed with radioactive labelled 125 I recombinant human growth hormone in pregnant rats showed radioactivity in fetuses indicating transfer of somatropin from the mother to the fetus. 8.2 Lactation Risk Summary There are no data on the presence of SEROSTIM in human milk, the effects on the breastfed infant, or the effects on milk production. Somatropin was detected in milk of lactating rats administered somatropin. When a drug is present in animal milk, it is likely that the drug will be present in human milk (see Data ). The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for SEROSTIM and any potential adverse effects on the breast-fed infant from SEROSTIM or from the underlying maternal condition. Data Animal Data Radioactive labelled 125 I recombinant human growth hormoneadministered subcutaneously to lactating rats was observed in milk, confirming the presence of somatropin in milk of lactating animals. 8.4 Pediatric Use Safety and effectiveness in pediatric patients with HIV have not been established. Available evidence suggests that somatropin clearance is similar in adults and children, but no pharmacokinetic studies have been conducted in children with HIV. In two small studies, 11 children with HIV-associated failure to thrive were treated subcutaneously with human growth hormone. In one study, five children (age range, 6 to 17 years) were treated with 0.04 mg/kg/day for 26 weeks. In a second study, six children (age range, 8 to 14 years) were treated with 0.07 mg/kg/day for 4 weeks. Treatment appeared to be well tolerated in both studies. The preliminary data collected on a limited number of patients with HIV-associated failure to thrive appear …

12.1 Mechanism of Action Somatropin is an anabolic and anticatabolic agent which exerts its influence by interacting with growth hormone receptors on a variety of cell types including myocytes, hepatocytes, adipocytes, lymphocytes, and hematopoietic cells. Some, but not all of its effects, are mediated by insulin-like growth factor-1 (IGF-1).

11 DESCRIPTION Somatropin is a human growth hormone (r-hGH) produced by recombinant DNA technology using a mammalian cell line (mouse C127). The protein is comprised of 191 amino acid residues and a molecular weight of 22,125 daltons. The amino acid sequence is identical to that of human growth hormone of pituitary origin. SEROSTIM (somatropin) for injection is a sterile, white to off-white lyophilized powder for subcutaneous use after reconstitution with accompanying diluent. SEROSTIM is supplied as either 4 mg per vial, 5 mg per vial, or 6 mg per vial. Sodium hydroxide or phosphoric acid may have been added to adjust the pH. 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 SEROSTIM 4 mg single-patient-use vials are co-packaged with diluent vials of Bacteriostatic Water for Injection, USP (containing 0.9% benzyl alcohol as a preservative). After each vial is reconstituted with 0.5 mL to 1 mL, the pH is 7.4 to 8.5. SEROSTIM 5 mg single-dose vials are co-packaged with diluent vials of Sterile Water for Injection, USP. After each vial is reconstituted with 0.5 mL to 1 mL, the pH is 6.5 to 8.5. SEROSTIM 6 mg single-dose vials are co-packaged with diluent vials of Sterile Water for Injection, USP. After each vial is reconstituted with 0.5 mL to 1 mL, the pH is 7.4 to 8.5.

10 OVERDOSAGE Short-Term Acute overdosage could lead initially to hypoglycemia and subsequently to hyperglycemia. Long-Term Long-term overdosage could result in signs and symptoms of acromegaly consistent with the known effects of excess growth hormone.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied SEROSTIM (somatropin) for injection is a sterile, white to off-white lyophilized powder for subcutaneous use after reconstitution. SEROSTIM is supplied as either 4 mg, 5 mg, or 6 mg per vial and is available in the following packaging configurations: NDC SEROSTIM Co-Packaged Diluent NDC 44087-0004-7 4 mg single-patient-use vials 7 vials Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol as preservative) 3.5 mL multiple-dose vials 7 vials NDC 44087-0005-7 5 mg single-dose vials 7 vials Sterile Water for Injection, USP 1 mL single-dose vials 7 vials NDC 44087-0006-7 6 mg single-dose vials 7 vials Sterile Water for Injection, USP 1 mL single-dose vials 7 vials 16.2 Storage and Handling Before reconstitution: Store cartons containing SEROSTIM vials and diluent vials at room temperature between 15°C to 30°C (59°F to 86°F). After reconstitution: Immediately use single-dose vials (SEROSTIM 5 mg or 6 mg) reconstituted with Sterile Water for Injection, USP. Discard any unused portion. Single-patient use vials (SEROSTIM 4 mg) reconstituted with Bacteriostatic Water for Injection, USP (containing 0.9% benzyl alcohol as a preservative), store refrigerated between 2°C to 8° C (36°F to 46°F) for up to 14 days [see Dosage and Administration (2.2) ]. Do not freeze reconstituted SEROSTIM vials.