somatropin 8 MG/ML Injectable Solution [Serostim]

INDICATIONS AND USAGE OMNITROPE is a recombinant human growth hormone indicated for: • Pediatric: Treatment of children with growth failure due to growth hormone deficiency (GHD), Prader-Willi Syndrome, Small for Gestational Age, Turner Syndrome, and Idiopathic Short Stature ( 1.1 ) • Adult: Treatment of adults with either adult onset or childhood onset GHD ( 1.2 ) 1.1 Pediatric Patients OMNITROPE is indicated for the treatment of children with growth failure due to inadequate secretion of endogenous growth hormone (GH). OMNITROPE is indicated for the treatment of pediatric patients who have growth failure due to Prader-Willi Syndrome (PWS). The diagnosis of PWS should be confirmed by appropriate genetic testing [see Contraindications ( 4 ) and Warnings and Precautions ( 5.2 )] . OMNITROPE is indicated for the treatment of growth failure in children born small for gestational age (SGA) who fail to manifest catch-up growth by age 2 years. OMNITROPE is indicated for the treatment of growth failure associated with Turner Syndrome. OMNITROPE is indicated for the treatment of idiopathic short stature (ISS), also called non-growth hormone-deficient short stature, defined by height standard deviation score (SDS) ≤ -2.25, and associated with growth rates unlikely to permit attainment of adult height in the normal range, in pediatric patients whose epiphyses are not closed and for whom diagnostic evaluation excludes other causes associated with short stature that should be observed or treated by other means. 1.2 Adult Patients OMNITROPE is indicated for the replacement of endogenous GH in adults with growth hormone deficiency (GHD) who meet either of the following two criteria: • Adult Onset (AO): Patients who have GHD, either alone or associated with multiple hormone deficiencies (hypopituitarism), as a result of pituitary disease, hypothalamic disease, surgery, radiation therapy, or trauma; or • Childhood Onset (CO): Patients who were GH deficient during childhood as a result of congenital, genetic, acquired, or idiopathic causes. Patients who were treated with somatropin for growth hormone deficiency in childhood and whose epiphyses are closed should be reevaluated before continuation of somatropin therapy at the reduced dose level recommended for growth hormone deficient adults. Confirmation of the diagnosis of adult growth hormone deficiency in both groups involves an appropriate growth hormone provocative test with two exceptions: (1) patients with multiple other pituitary hormone deficiencies due to organic disease; and (2) patients with congenital/genetic growth hormone deficiency.

DOSAGE AND ADMINISTRATION Administer by subcutaneous injection to the back of upper arm, abdomen, buttock, or thigh with regular rotation of injection sites ( 2.1 ) Pediatric dosage: Divide the calculated weekly dosage into equal doses given either 3, 6, or 7 days per week ( 2.2 ) GH deficiency : 0.18 mg/kg/week to 0.3 mg/kg/week ( 2.2 ) Turner syndrome: Up to 0.375 mg/kg/week ( 2.2 ) ISS : Up to 0.37 mg/kg/week ( 2.2 ) SHOX deficiency: 0.35 mg/kg/week ( 2.2 ) SGA: Up to 0.47 mg/kg/week ( 2.2 ) Adult dosage: Either of the following two dosing regimens may be used: Non-weight based dosing : Initiate with a dose of approximately 0.2 mg/day (range, 0.15 mg/day to 0.3 mg/day) and increase the dose every 1 to 2 months by increments of approximately 0.1 mg/day to 0.2 mg/day, according to individual patient requirements ( 2.3 ) Weight-based dosing (Not recommended for obese patients) : Initiate at 0.006 mg/kg daily and increase the dose according to individual patient requirements to a maximum of 0.0125 mg/kg daily ( 2.3 ) See Full Prescribing Information for reconstitution instructions ( 2.4 ) 2.1 Administration and Use Instructions Therapy with ZOMACTON should be supervised by a physician who is experienced in the diagnosis and management of patients with the conditions for which ZOMACTON is indicated [see Indications and Usage (1) ]. Fundoscopic examination should be performed routinely before initiating treatment with ZOMACTON to exclude preexisting papilledema, and periodically thereafter [see Warnings and Precautions (5.5) ]. Administer ZOMACTON by subcutaneous injection to the back of the upper arm, abdomen, buttock, or thigh with regular rotation of injection sites to avoid lipoatrophy. ZOMACTON 5 mg and 10 mg can be administered using a standard sterile disposable syringe. For proper use, please refer to the Instructions for Use provided with the administration device. The volume of the syringe should be small enough so that the prescribed dose can be withdrawn from the vial with reasonable accuracy. 2.2 Pediatric Dosage Individualize dosage for each patient based on the growth response. Divide the calculated weekly ZOMACTON dosage into equal doses given either 3, 6, or 7 days per week. The recommended weekly dose in milligrams (mg) per kilogram (kg) of body weight for pediatric patients is: Pediatric GH Deficiency: 0.18 mg/kg/week to 0.3 mg/kg/week (0.026 mg/kg/day to 0.043 mg/kg/day) Turner syndrome: Up to 0.375 mg/kg/week (up to 0.054 mg/kg/day) Idiopathic short stature: Up to 0.37 mg/kg/week (up to 0.053 mg/kg/day) SHOX Deficiency: 0.35 mg/kg/week (0.05 mg/kg/day) Small for Gestational Age (SGA): Up to 0.47 mg/kg/week (up to 0.067 mg/kg/day) In very short pediatric patients, HSDS less than -3, and older pubertal pediatric patients consider initiating treatment with a larger dose of ZOMACTON (up to 0.067 mg/kg/day). Consider a gradual reduction in dosage if substantial catch-up growth is observed during the first few years of therapy. In pediatric patients less than 4 years of age with less severe short stature, baseline HSDS values between -2 and -3, consider initiating treatment at 0.033 mg/kg/day and titrate the dose as needed. Assess compliance and evaluate other causes of poor growth such as hypothyroidism, under-nutrition, advanced bone age and antibodies to recombinant human GH if patients experience failure to increase height velocity, particularly during the first year of treatment. Discontinue ZOMACTON for stimulation of linear growth once epiphyseal fusion has occurred [see Contraindications (4) ]. 2.3 Adult Dosage Patients who were treated with somatropin for GH deficiency in childhood and whose epiphyses are closed should be reevaluated before continuation of somatropin for GH deficient adults. Consider using a lower starting dose and smaller dose increment increases for geriatric patients as they may be at increased risk for adverse reactions with ZOMACTON than younger individuals [see Use in Specific Populations (8.5) ] . Estrogen-replete women and patients receiving oral estrogen may require higher doses [see Drug Interactions (7) ]. Administer the prescribed dose daily Either of two ZOMACTON dosing regimens may be used: Non-weight based Initiate ZOMACTON with a dose of approximately 0.2 mg/day (range, 0.15 mg/day to 0.3 mg/day) and increase the dose every 1 to 2 months by increments of approximately 0.1 mg/day to 0.2 mg/day, according to individual patient requirements based on the clinical response and serum insulin-like growth factor 1 (IGF-1) concentrations. Decrease the dose as necessary on the basis of adverse reactions and/or serum IGF-1 concentrations above the age- and gender-specific normal range. Maintenance dosages will vary considerably from person to person, and between male and female patients. Weight-based Initiate ZOMACTON at 0.006 mg/kg daily and increase the dose according to individual patient requirements to a maximum of 0.0125 mg/kg daily. Use the patient's clinical response, adverse reactions, and determination of age- and gender-adjusted serum IGF-1 concentrations as guidance in dose titration. Not recommended for obese patients as they are more likely to experience adverse reactions with this regimen. 2.4 Reconstitution Reconstitute ZOMACTON 5 mg with 1 mL to 5 mL of diluent, Bacteriostatic Sodium Chloride Injection, USP with 0.9% benzyl alcohol as a preservative. Do not use diluent if the patient has a known hypersensitivity to benzyl alcohol [see Contraindications (4) ] or in neonates [see Warnings and Precautions (5.13) ] , or pregnant or lactating women [see Use in Specific Populations (8.1 , 8.2) ] instead reconstitute with 0.9% Sodium Chloride Injection, USP, use only one dose per vial, and discard the unused portion. Reconstitute ZOMACTON 10 mg with 1 mL syringe of diluent, Bacteriostatic Water for Injection, USP with 0.33% metacresol as a preservative. Do not use diluent if the patient has a known hypersensitivity to metacresol [see Contraindications (4) ] . Aim the stream of diluent against the side of the vial to prevent foaming and gently swirl the vial with a rotary motion until the contents are completely dissolved and the solution is clear. Do not shake the vial since shaking or vigorous mixing will cause the solution to be cloudy. Inspect visually for particulate matter and discoloration. If the resulting solution is cloudy or contains particulate matter do not use. Occasionally, after refrigeration, some cloudiness may occur. Allow the product to warm to room temperature. If cloudiness persists or particulate matter is noted do not use.

WARNINGS AND PRECAUTIONS • Increased Risk of Neoplasms : Second neoplasms have occurred in childhood cancer survivors. Monitor patients with preexisting tumors for progression or recurrence. ( 5.3 ) • Glucose Intolerance and Diabetes Mellitus : NORDITROPIN may decrease insulin sensitivity, particularly at higher doses. Monitor glucose levels periodically in all patients receiving NORDITROPIN, especially in patients with existing diabetes mellitus or at risk for development. ( 5.4 ) • Intracranial Hypertension (IH) : Has been reported usually within 8 weeks of initiation. Perform fundoscopic examinations prior to initiation and periodically thereafter. If papilledema occurs, stop treatment. ( 5.5 ) • Severe Hypersensitivity : Serious hypersensitivity reactions may occur. In the event of an allergic reaction, seek prompt medical attention. ( 5.6 ) • Fluid Retention : May occur in adults and may be dose dependent. ( 5.7 ) • Hypoadrenalism : Monitor patients for reduced serum cortisol levels and/or need for glucocorticoid dose increases in those with known hypoadrenalism. ( 5.8 ) • Hypothyroidism : Monitor thyroid function periodically as hypothyroidism may occur or worsen after initiation of somatropin. ( 5.9 ) • Slipped Capital Femoral Epiphysis in Pediatric Patients : May occur; evaluate patients with onset of a limp or hip/knee pain. ( 5.10 ) • Progression of Preexisting Scoliosis in Pediatric Patients : Monitor patients with scoliosis for progression. ( 5.11 ) • Pancreatitis : Has been reported; consider pancreatitis in patients with abdominal pain, especially pediatric patients. ( 5.12 ) 5.1 Increased Mortality in Patients with Acute Critical Illness Increased mortality in patients with acute critical illness due to complications following open heart surgery, abdominal surgery or multiple accidental trauma, or those with acute respiratory failure has been reported after treatment with pharmacologic amounts of somatropin [see Contraindications (4) ]. Two placebo-controlled clinical trials in non-growth hormone deficient adult patients (n=522) with these conditions in intensive care units revealed a significant increase in mortality (42% vs. 19%) among somatropin-treated patients (doses 5.3-8 mg/day) compared to those receiving placebo. The safety of continuing NORDITROPIN treatment in patients receiving replacement doses for approved indications who concurrently develop these illnesses has not been established. NORDITROPIN is not indicated for the treatment of non-GH deficient adults. 5.2 Sudden Death in Pediatric Patients with Prader-Willi Syndrome There have been reports of sudden death after initiating therapy with somatropin in pediatric patients with Prader-Willi syndrome who had one or more of the following risk factors: severe obesity, history of upper airway obstruction or sleep apnea, or unidentified respiratory infection. Male patients with one or more of these factors may be at greater risk than females. Patients with Prader-Willi syndrome should be evaluated for signs of upper airway obstruction and sleep apnea before initiation of treatment with somatropin. If, during treatment with NORDITROPIN, patients show signs of upper airway obstruction (including onset of or increased snoring) and/or new onset sleep apnea, treatment should be interrupted. All patients with Prader-Willi syndrome treated with NORDITROPIN should also have effective weight control and be monitored for signs of respiratory infection, which should be diagnosed as early as possible and treated aggressively [see Contraindications (4) ] . 5.3 Increased Risk of Neoplasms Active Malignancy There is an increased risk of malignancy progression with somatropin treatment in patients with active malignancy [See Contraindications (4) ]. Any preexisting malignancy should be inactive and its treatment complete prior to instituting therapy with NORDITROPIN. Discontinue NORDITROPIN if there is evidence of recurrent activity. Risk of Second Neoplasm in Pediatric Patients There is an increased risk of a second neoplasm in pediatric cancer survivors who were treated with radiation to the brain/head and who developed subsequent GH deficiency and were treated with somatropin. Intracranial tumors, in particular meningiomas, were the most common of these second neoplasms. In adults, it is unknown whether there is any relationship between somatropin replacement therapy and CNS tumor recurrence. Monitor all patients receiving NORDITROPIN who have a history of GH deficiency secondary to an intracranial neoplasm for progression or recurrence of the tumor. New Malignancy During Treatment Because pediatric patients with certain rare genetic causes of short stature have an increased risk of developing malignancies, thoroughly consider the risks and benefits of starting NORDITROPIN in these patients. If NORDITROPIN is initiated, carefully monitor patients for development of neoplasms. Monitor all patients receiving NORDITROPIN carefully for increased growth, or potential malignant changes, of preexisting nevi. Advise patients/caregivers to report marked changes in behavior, onset of headaches, vision disturbances and/or changes in skin pigmentation or changes in the appearance of pre-existing nevi. 5.4 Glucose Intolerance and Diabetes Mellitus Treatment with somatropin may decrease insulin sensitivity, particularly at higher doses. New onset type 2 diabetes mellitus has been reported in patients taking somatropin. Previously undiagnosed impaired glucose tolerance and overt diabetes mellitus may be unmasked. Monitor glucose levels periodically in all patients receiving NORDITROPIN, especially in those with risk factors for diabetes mellitus, such as obesity, Turner syndrome, or a family history of diabetes mellitus. Patients with preexisting type 1 or type 2 diabetes mellitus or impaired glucose tolerance should be monitored closely. The doses of antidiabetic agents may require adjustment when NORDITROPIN is initiated. 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 somatropins. 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 NORDITROPIN to exclude preexisting papilledema, and periodically thereafter. If papilledema is observed by funduscopy during somatropin treatment, treatment should be stopped. If somatropin-induced IH is diagnosed, treatment with NORDITROPIN can be restarted at a lower dose after IH-associated signs and symptoms have resolved. Patients with Turner syndrome may be at increased risk for the development of IH. 5.6 Severe Hypersensitivity Serious systemic hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with postmarketing use of somatropins. 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 Fluid retention during somatropin replacement therapy in adults may frequently occur. Clinical manifestations of fluid retention (e.g. edema, arthralgia, myalgia, nerve compression syndromes including carpal tunnel syndrome/paraesthesias) are usually transient and dose dependent. 5.8 Hypoadrenalism Patients receiving somatropin therapy who have or are at risk for pituitary hormone deficiency(s) may be at risk for reduced serum cortisol levels and/or unmasking of central (secondary) hypoadrenalism. In addition, patients treated with glucocorticoid replacement for previously diagnosed hypoadrenalism may require an increase in their maintenance or stress doses following initiation o

CONTRAINDICATIONS OMNITROPE is contraindicated in patients with: • Acute Critical Illness Treatment with pharmacologic amounts of somatropin is contraindicated in patients with acute critical illness due to complications following open heart surgery, abdominal surgery or multiple accidental trauma, or those with acute respiratory failure [see Warnings and Precautions ( 5.1 )] . • Prader-Willi Syndrome in Children Somatropin is contraindicated in patients with Prader-Willi Syndrome who are severely obese, have a history of upper airway obstruction or sleep apnea, or have severe respiratory impairment. There have been reports of sudden death when somatropin was used in such patients [see Warnings and Precautions ( 5.2 )] . • 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. Since GHD may be an early sign of the presence of a pituitary tumor (or, rarely, other brain tumors), the presence of such tumors should be ruled out prior to initiation of treatment. Somatropin should not be used in patients with any evidence of progression or recurrence of an underlying intracranial tumor [see Warnings and Precautions ( 5.3 )] . • Hypersensitivity OMNITROPE 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 somatropins [see Warnings and Precautions ( 5.6 )]. • Diabetic Retinopathy Somatropin is contraindicated in patients with active proliferative or severe non-proliferative diabetic retinopathy. • Closed Epiphyses Somatropin should not be used for growth promotion in pediatric patients with closed epiphyses. • Acute Critical Illness ( 4 ) • Children with Prader-Willi Syndrome who are severely obese or have severe respiratory impairment - reports of sudden death ( 4 ) • Active Malignancy ( 4 ) • Hypersensitivity to somatropin or its excipients ( 4 ) • Active Proliferative or Severe Non-Proliferative Diabetic Retinopathy ( 4 ) • Children with closed epiphyses ( 4 )

Mechanism of Action Somatropin binds to dimeric GH receptors located within the cell membranes of target tissue cells. This interaction results in intracellular signal transduction and subsequent induction of transcription and translation of GH-dependent proteins including IGF-1, IGF BP-3 and acid-labile subunit. Somatropin has direct tissue and metabolic effects or effects mediated indirectly by IGF-1, including stimulation of chondrocyte differentiation, and proliferation, stimulation of hepatic glucose output, protein synthesis, and lipolysis. Somatropin stimulates skeletal growth in pediatric patients with GHD as a result of effects on the growth plates (epiphyses) of long bones. The stimulation of skeletal growth increases linear growth rate (height velocity) in most somatropin-treated pediatric patients. Linear growth is facilitated in part by increased cellular protein synthesis.