DailyMed Label: Serostim

DailyMed Label: Serostim

2022

DailyMed Prescription

Serostim

somatropin

EMD Serono, Inc.

NDC: 44087-0004

NDC: 44087-0004

NDC: 44087-0005

NDC: 44087-0005

NDC: 44087-0006

NDC: 44087-0006

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 ) 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. 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.

Single-use administration (to be reconstituted with Sterile Water for Injection): SEROSTIM 5 mg per vial SEROSTIM 6 mg per vial Multi-use administration (to be reconstituted with Bacteriostatic Water for Injection): SEROSTIM 4 mg per vial Single-dose administration (to be administered with Sterile Water for Injection) ( 3 ):   SEROSTIM 5 mg/ vial   SEROSTIM 6 mg/ vial Multi-dose administration (to be administered with Bacteriostatic Water for Injection):   SEROSTIM 4 mg/ vial

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 )

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. HIV patients 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 ) 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) ] . 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 HIV patients be maintained on antiretroviral therapy for the duration of SEROSTIM treatment. Because malignancies are more common in HIV positive individuals, the risks and benefits of starting somatropin in HIV positive patients 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. Hyperglycemia may occur in HIV infected individuals 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 HIV patients with 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) ] . 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. 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 (4) ]. 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. 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) ] . 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.

The following important adverse reactions are also described elsewhere in the labeling:

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 ) 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. 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. 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) ] . 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) ] .

Reproduction studies have been performed in rats and rabbits. Doses up to 5 to 10 times the human dose, based on body surface area, have revealed no evidence of impaired fertility or harm to the fetus due to SEROSTIM. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, SEROSTIM should be used during pregnancy only if clearly needed. It is not known whether SEROSTIM is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when SEROSTIM is administered to a nursing woman. 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 to be consistent with safety observations in growth hormone-treated adults with HIV wasting. 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. Clinical studies with SEROSTIM did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. 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 (2) ]. No studies have been conducted for SEROSTIM in patients with hepatic impairment [see Clinical Pharmacology (12.3) ]. Subjects with chronic renal failure tend to have decreased somatropin clearance compared to those with normal renal function. However, no studies have been conducted for SEROSTIM in patients with renal impairment [see Clinical Pharmacology (12.3) ]. Biomedical literature indicates that a gender-related difference in the mean clearance of r-hGH could exist (clearance of r-hGH in males > clearance of r-hGH in females). However, no gender-based analysis is available for SEROSTIM in normal volunteers or patients infected with HIV.

SEROSTIM is available in the following forms: SEROSTIM single-use vials containing 5 mg with Sterile Water for Injection, USP. Package of 7 vials. NDC 44087-0005-7 SEROSTIM single-use vials containing 6 mg with Sterile Water for Injection, USP. Package of 7 vials. NDC 44087-0006-7 SEROSTIM multiple-use vials containing 4 mg with Bacteriostatic Water for Injection, USP (0.9% Benzyl Alcohol). Package of 7 vials. NDC 44087-0004-7 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.

SEROSTIM is an anabolic and anticatabolic agent which exerts its influence by interacting with specific 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). Effects on Protein, Lipid and Carbohydrate Metabolism A one-week study in 6 patients with HIV-associated wasting has shown that treatment with SEROSTIM 0.1 mg/kg/day improved nitrogen balance, increased protein-sparing lipid oxidation, and had little effect on overall carbohydrate metabolism. Decreases in trunk fat and total body fat, and increases in lean body mass were observed during two double-blind, placebo-controlled studies wherein SEROSTIM vs. placebo were administered daily for 12 weeks to patients with HIV Lipodystrophy [see Clinical Studies (14) ] . Effects on Nitrogen and Mineral Retention In the one-week study in 6 patients with HIV-associated wasting, treatment with SEROSTIM resulted in the retention of phosphorous, potassium, nitrogen, and sodium. The ratio of retained potassium and nitrogen during SEROSTIM therapy was consistent with retention of these elements in lean tissue. Physical Performance Cycle ergometry work output and treadmill performance were examined in separate 12-week, placebo-controlled trials [see Clinical Studies (14) ]. In both studies, work output improved significantly in the group receiving SEROSTIM 0.1 mg/kg/day subcutaneously vs placebo. Isometric muscle performance, as measured by grip strength dynamometry, declined, probably as a result of a transient increase in tissue turgor known to occur with SEROSTIM therapy. Absorption: The absolute bioavailability after subcutaneous administration was determined to be 70 to 90%. The mean t½ after subcutaneous administration is significantly longer than that seen after intravenous administration in normal male volunteers down-regulated with somatostatin (approximately 4.0 hrs. vs. 0.6 hrs.), indicating that the subcutaneous absorption of somatropin is a rate-limiting process. Distribution: The steady-state volume of distribution (Mean ± SD) following intravenous administration of somatropin in normal male volunteers is 12.0 ± 1.08 L. Metabolism: Although the liver plays a role in the metabolism of GH, GH is primarily cleaved in the kidney. GH undergoes glomerular filtration and, after cleavage within the renal cells, the peptides and amino acids are returned to the systemic circulation. Elimination: The t½ in nine patients with HIV-associated wasting with an average weight of 56.7 ± 6.8 kg, given a fixed dose of 6.0 mg somatropin subcutaneously was 4.28 ± 2.15 hrs, similar to that observed in normal male volunteers. The renal clearance of r-hGH after subcutaneous administration in nine patients with HIV-associated wasting was 0.0015 ± 0.0037 L/h. No significant accumulation of r-hGH appears to occur after 6 weeks of daily dosing as indicated. Specific Populations: Pediatric: Available evidence suggests that r-hGH clearances are similar in adults and children, but no pharmacokinetic studies have been conducted in children with HIV. Gender: Biomedical literature indicates that a gender-related difference in the mean clearance of r-hGH could exist (clearance of r-hGH in males > clearance of r-hGH in females). However, no gender-based analysis is available in normal volunteers or patients infected with HIV. Race: No studies have been conducted to determine the effect of race on the pharmacokinetics of SEROSTIM. Renal Impairment: Subjects with chronic renal failure tend to have decreased somatropin clearance compared to those with normal renal function. However, no studies have been conducted to determine the effect of renal impairment on the pharmacokinetics of SEROSTIM. Hepatic Impairment: No studies have been conducted to determine the effect of hepatic impairment on the pharmacokinetic of SEROSTIM.

Long-term animal studies for carcinogenicity have not been performed with SEROSTIM. There is no evidence from animal studies to date of SEROSTIM-induced mutagenicity or impairment of fertility.

HIV-Associated Wasting or Cachexia The clinical efficacy of SEROSTIM in HIV-associated wasting or cachexia was assessed in two placebo-controlled trials. All study subjects received concomitant antiretroviral therapy. There was no increase in the incidence of Kaposi's sarcoma (KS), lymphoma, or in the progression of cutaneous Kaposi's sarcoma in clinical studies of SEROSTIM. Patients with internal KS lesions were excluded from the studies. Potential effects on other malignancies are unknown. Clinical Trial 1: A 12-week, randomized, double-blind, placebo-controlled study followed by an open-label extension phase enrolled 178 patients with severe HIV wasting taking nucleoside analogue therapy (pre-HAART era). The primary endpoint was body weight. Body composition was assessed using dual energy X-ray absorptiometry (DXA) and physical function was assessed by treadmill exercise testing. Patients meeting the inclusion/exclusion criteria were treated with either placebo or SEROSTIM 0.1 mg/kg daily. Ninety-six percent (96%) were male. The average baseline CD4 count/microliter was 85. The results from one hundred forty (140) evaluable patients were analyzed (those completing the 12-week course of treatment and who were at least 80% compliant with study drug). After 12 weeks of therapy, the mean difference in weight increase between the SEROSTIM-treated group and the placebo-treated group was 1.6 kg (3.5 lb). Mean difference in lean body mass (LBM) change between the SEROSTIM-treated group and the placebo-treated group was 3.1 kg (6.8 lbs) as measured by DXA. Mean increase in weight and LBM, and mean decrease in body fat, were significantly greater in the SEROSTIM-treated group than in the placebo group (p=0.011, p<0.001, p<0.001, respectively) after 12 weeks of treatment (Figure 1). There were no significant changes with continued treatment beyond 12 weeks suggesting that the original gains of weight and LBM were maintained (Figure 1). Treatment with SEROSTIM resulted in a significant increase in physical function as assessed by treadmill exercise testing. The median treadmill work output increased by 13% (p=0.039) at 12 weeks in the group receiving SEROSTIM (Figure 2). There was no improvement in the placebo-treated group at 12 weeks. Changes in treadmill performance were significantly correlated with changes in LBM. Figure 1: Mean Changes in Body Composition Figure 2: Median Treadmill Work Output Figure 1 Figure 2 Clinical Trial 2: A 12-week, randomized, double-blind, placebo-controlled study enrolled 757 patients with HIV-associated wasting, or cachexia. The primary efficacy endpoint was physical function as measured by cycle ergometry work output. Body composition was assessed using bioelectrical impedance spectroscopy (BIS) and also by dual energy X-ray absorptiometry (DXA) at a subset of centers. Patients meeting the inclusion/exclusion criteria were treated with either placebo, approximately 0.1 mg/kg every other day (qod) of SEROSTIM, or approximately 0.1 mg/kg daily at bedtime of SEROSTIM. All results were analyzed in intent-to-treat populations (for cycle ergometry work output, n=670). Ninety-one percent (91%) were male and 88% were on HAART anti-retroviral therapy. The average baseline CD4 count/µL was 446. Six hundred forty-six patients (646) completed the 12-week study and continued in the SEROSTIM treatment extension phase of the trial. Clinical Trial 2 results are summarized in Tables 4 and 5: Table 4: Mean (Median) of Cycle Work Output (kJ) Response after 12 weeks of Treatment ITT Population Placebo Half-Dose SEROSTIM approximately 0.1 mg/kg every other day Full-Dose SEROSTIM approximately 0.1 mg/kg daily Cycle work output (kJ) n=222 n=230 n=218 Baseline 25.92 (25.05) 27.79 (26.65) 27.57 (26.30) Change from baseline -0.05 (-0.25) 2.48 (2.30) 2.52 (2.40) Percent change from baseline 0.2% 8.9% 9.1% Difference from Placebo Mean (2-sided 95% C.I.) - 2.53 p<0.01 (0.81, 4.25) 2.57 (0.83, 4.31) Median - 2.55 2.65 Table 5: Mean (Median) Change from Baseline for Lean Body Mass, Fat Mass and Body Weight Placebo Half-Dose SEROSTIM approximately 0.1 mg/kg every other day Full-Dose SEROSTIM approximately 0.1 mg/kg daily N Mean (Median) n Mean (Median) n Mean (Median) Lean body mass (kg) (by BIS) 222 0.97 (0.67) 223 3.89 (3.65) 205 5.84 (5.47) Fat mass (kg) (by DXA) 94 0.03 (0.01) 100 -1.25 (-1.23) 85 -1.72 (-1.51) Body weight (kg) 247 0.69 (0.68) 257 2.18 (2.15) 253 2.79 (2.65) The mean maximum cycle work output until exhaustion increased after 12 weeks by 2.57 kilojoules (kJ) in the SEROSTIM 0.1 mg/kg daily group (p<0.01) and by 2.53 kJ in the SEROSTIM 0.1 mg/kg every other day group (p<0.01) compared with placebo (Table 4). Cycle work output improved approximately 9% in both active treatment arms and decreased <1% in the placebo group. Lean body mass (LBM) and body weight (BW) increased, and fat mass decreased, in a dose-related fashion after treatment with SEROSTIMand placebo (Table 5). The LBM results obtained by BIS were confirmed with DXA. Patients' perceptions of the impact of 12 weeks of treatment on their wasting symptoms as assessed by the Bristol-Meyers Anorexia/Cachexia Recovery Instrument improved with both doses of SEROSTIMin Clinical Trial 2. Extension Phase: All patients (n=646) completing the 12-week placebo-controlled phase of Clinical Trial 2 continued SEROSTIM treatment into an extension phase. Five hundred and forty eight of these patients completed an additional 12 weeks of active treatment. In these patients, changes in cycle ergometry work output, LBM, BW, and fat mass either improved further or were maintained with continued SEROSTIM treatment.

Serostim ® 4 mg (somatropin) for injection 4 mg For subcutaneous injection Rx Only 7 vials of SEROSTIM 7 vials of Bacteriostatic Water for Injection, USP (0.9 % Benzyl Alcohol) NDC 44087-0004-7 EMD Serono PRINCIPAL DISPLAY PANEL - 4 mg Kit Carton