Somatropin

12.1 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 mediated indirectly by IGF-1, including stimulation of chondrocyte differentiation, and proliferation, stimulation 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.

1 INDICATIONS AND USAGE NORDITROPIN is a recombinant human growth hormone indicated for: • Pediatric : Treatment of pediatric patients with growth failure due to inadequate secretion of endogenous growth hormone (GH), short stature associated with Noonan syndrome, short stature associated with Turner syndrome, short stature born small for gestational age (SGA) with no catch-up growth by age 2 to 4 years, Idiopathic Short Stature (ISS), and growth failure due to Prader-Willi Syndrome ( 1.1 ) • Adult : Replacement of endogenous GH in adults with growth hormone deficiency ( 1.2 ) 1.1 Pediatric Patients NORDITROPIN is indicated for the treatment of pediatric patients with: • growth failure due to inadequate secretion of endogenous growth hormone (GH), • short stature associated with Noonan syndrome, • short stature associated with Turner syndrome, • short stature born small for gestational age (SGA) with no catch-up growth by age 2 years to 4 years of age, • Idiopathic Short Stature (ISS), height standard deviation score (SDS) <-2.25, and associated with growth rates unlikely to permit attainment of adult height in the normal range, • growth failure due to Prader-Willi syndrome (PWS). 1.2 Adult Patients NORDITROPIN is indicated for the replacement of endogenous GH in adults with growth hormone deficiency (GHD)

2 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 6, or 7 days per week o GHD: 0.17 mg/kg/week to 0.24 mg/kg/week( 2.2 ) o Noonan Syndrome: Up to 0.46 mg/kg/week ( 2.2 ) o Turner Syndrome: Up to 0.47 mg/kg/week ( 2.2 ) o SGA: Up to 0.47 mg/kg/week ( 2.2 ) o ISS: Up to 0.47 mg/kg/week ( 2.2 ) o Prader-Willi Syndrome: 0.24 mg/kg/week ( 2.2 ) o Adult Dosage: Either of the following two dosing regimens may be used: o Non-weight based dosing: Initiate with a dose of approximately 0.2 mg/day (range, 0.15 mg/day-0.3 mg/day) and increase the dose every 1-2 months by increments of approximately 0.1 mg/day-0.2 mg/day, according to individual patient requirements ( 2.3 ) o Weight-based dosing (Not recommended for obese patients): Initiate at 0.004 mg/kg daily and increase the dose according to individual patient requirements to a maximum of 0.016 mg/kg daily ( 2.3 ) 2.1 Administration and Use Instructions • Therapy with NORDITROPIN should be supervised by a physician who is experienced in the diagnosis and management of patients with the conditions for which NORDITROPIN is indicated [see Indications and Usage (1) ]. • Fundoscopic examination should be performed routinely before initiating treatment with NORDITROPIN to exclude preexisting papilledema, and periodically thereafter [see Warnings and Precautions (5.5) ]. • Administer NORDITROPIN by subcutaneous injection to the back of the upper arm, abdomen, buttocks, or thigh with regular rotation of injection sites to avoid lipoatrophy. • Inspect visually for particulate matter and discoloration. NORDITROPIN should be clear and colorless. If the solution is cloudy or contains particulate matter do not use. • Instructions for delivering the dosage are provided in the PATIENT INFORMATION and INSTRUCTIONS FOR USE leaflets enclosed with the NORDITROPIN FlexPro prefilled pen. 2.2 Pediatric Dosage • Individualize dosage for each patient based on the growth response. • Divide the calculated weekly NORDITROPIN dosage into equal doses given either 6, or 7 days per week. • The recommended weekly dose in milligrams (mg) per kilogram (kg) of body weight for pediatric patients is: o Pediatric GH Deficiency: 0.17 mg/kg/week to 0.24 mg/kg/week (0.024 to 0.034 mg/kg/day) o Noonan Syndrome: Up to 0.46 mg/kg/week (up to 0.066 mg/kg/day) o Turner Syndrome: Up to 0.47 mg/kg/week (up to 0.067 mg/kg/day) o 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 NORDITROPIN (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. o Idiopathic Short Stature: Up to 0.47 mg/kg/week (up to 0.067 mg/kg/day) o Prader-Willi Syndrome: 0.24 mg/kg/week (0.034 mg/kg/day) • Assess compliance and evaluate other causes of poor growth such as hypothyroidism, under-nutrition, advanced bone age and antibodies to recombinant human growth hormone if patients experience failure to increase height velocity, particularly during the first year of treatment. • Discontinue NORDITROPIN 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 NORDITROPIN 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 NORDITROPIN dosing regimens may be used: o Non-weight based • Initiate NORDITROPIN with a dose of approximately 0.2 mg/day (range, 0.15 mg/day to 0.3 mg/day) and increase the dose every 1-2 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. o Weight-based • Initiate NORDITROPIN at 0.004

6 ADVERSE REACTIONS The following important adverse reactions are also described elsewhere in the labeling: • Increased mortality in patients with acute critical illness [see Warnings and Precautions (5.1) ] • Sudden death in children with Prader-Willi syndrome [see Warnings and Precautions (5.2) ] • Neoplasms [see Warnings and Precautions (5.3) ] • Glucose intolerance 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 [see Warnings and Precautions (5.7) ] • Hypoadrenalism [see Warnings and Precautions (5.8) ] • Hypothyroidism [see Warnings and Precautions (5.9) ] • Slipped capital femoral epiphysis in pediatric patients [see Warnings and Precautions (5.10) ] • Progression of preexisting scoliosis in pediatric patients [see Warnings and Precautions (5.11) ] • Pancreatitis [see Warnings and Precautions (5.12) ] • Lipoatrophy [see Warnings and Precautions (5.13) ] Common adverse reactions in adult and pediatric patients include: upper respiratory infection, fever, pharyngitis, headache, otitis media, edema, arthralgia, paresthesia, myalgia, peripheral edema, flu syndrome, and impaired glucose tolerance. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk at 1-888-NOVO-444 (1-888-668-6444) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under varying conditions, adverse reaction rates observed during the clinical trials performed with one somatropin product cannot always be directly compared to the rates observed during the clinical trials performed with another somatropin product, and may not reflect the adverse reaction rates observed in practice. Pediatric Patients Growth Failure due to Inadequate Secretion of Endogenous Growth Hormone In one randomized, open label, clinical study the most frequent adverse reactions were headache, pharyngitis, otitis media and fever. There were no clinically significant differences between the three doses assessed in the study (0.025, 0.05 and 0.1 mg/kg/day). Short Stature Associated with Noonan Syndrome NORDITROPIN was studied in 21 pediatric patients, 3 years to 14 years of age at doses of 0.033 mg/kg/day and 0.066 mg/kg/day. After the two-year study, patients continued NORDITROPIN treatment until final height was achieved; randomized dose groups were not maintained. Adverse reactions were later collected retrospectively from 18 pediatric patients; total follow-up was 11 years. An additional 6 pediatric patients were not randomized, but followed the protocol and are included in this assessment of adverse reactions. The most frequent adverse reactions were upper respiratory infection, gastroenteritis, ear infection, and influenza. Cardiac disorders was the system organ class with the second most adverse reactions reported. Scoliosis was reported in 1 and 4 pediatric patients receiving doses of 0.033 mg/kg/day and 0.066 mg/kg/day respectively. The following additional adverse reactions also occurred once: insulin resistance and panic reaction for the 0.033 mg/kg/day dose group; injection site pruritus, bone development abnormal, depression, and self-injurious ideation in the 0.066 mg/kg/day dose group. Headache occurred in 2 cases in the 0.066 mg/kg/day dose group. Short Stature Associated with Turner Syndrome In two clinical studies in pediatric patients that were treated until final height with various doses of NORDITROPIN, the most frequently reported adverse reactions were influenza-like illness, otitis media, upper respiratory tract infection, otitis externa, gastroenteritis, eczema and, impaired fasting glucose. Adverse reactions in study 1 were most frequent in the highest dose groups. Three patients in study 1 had excessive growth of hands and/or feet in the high dose groups. Two patients in study 1 had a serious adverse reaction of exacerbation of preexisting scoliosis in the 0.045 mg/kg/day group. Small for Gestational Age (SGA) with No Catch-up Growth by Age 2-4 Years In a study, 53 pediatric patients were treated with 2 doses of NORDITROPIN (0.033 or 0.067 mg/kg/day) to final height for up to 13 years (mean duration of treatment 7.9 and 9.5 years for girls and boys, respectively). The most frequently reported adverse reactions were influenza-like illness, upper respiratory tract infection, bronchitis, gastroenteritis, abdominal pain, otitis media, pharyngitis, arthralgia, headache, gynecomastia, and increased sweating. One pediatric patient treated with 0.067 mg/kg/day for 4 years was reported with disproportionate growth of the lower jaw, and another patient treated with 0.067 mg/kg/day developed a melanocytic nevus. 4 pediatric patients treated with 0.067 mg/kg/day and 2 pediatric patients treated with 0.033 mg/kg/day of NORDITROPIN had increased fasting blood glucose levels after 1 year of treatment. In addition, small in

7 DRUG INTERACTIONS Table 2 includes a list of drugs with clinically important drug interactions when administered concomitantly with NORDITROPIN and instructions for preventing or managing them. Table 2: Clinically Important Drug Interactions with NORDITROPIN Glucocorticoids Clinical Impact: 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. NORDITROPIN inhibits 11βHSD-1. Consequently, individuals with untreated GH deficiency have relative increases in 11βHSD-1 and serum cortisol. Initiation of NORDITROPIN may result in inhibition of 11βHSD-1 and reduced serum cortisol concentrations. Intervention: Patients treated with glucocorticoid replacement for hypoadrenalism may require an increase in their maintenance or stress doses following initiation of NORDITROPIN [see Warnings and Precautions (5.8) ]. Examples: Cortisone acetate and prednisone may be effected more than others since conversion of these drugs to their biologically active metabolites is dependent on the activity of 11βHSD-1. Pharmacologic Glucocorticoid Therapy and Supraphysiologic Glucocorticoid Treatment Clinical Impact: Pharmacologic glucocorticoid therapy and supraphysiologic glucocorticoid treatment may attenuate the growth promoting effects of NORDITROPIN in pediatric patients. Intervention: Carefully adjust glucocorticoid replacement dosing in pediatric patients receiving glucocorticoid treatments to avoid both hypoadrenalism and an inhibitory effect on growth. Cytochrome P450-Metabolized Drugs Clinical Impact: Limited published data indicate that somatropin treatment increases cytochrome P450 (CP450)-mediated antipyrine clearance. NORDITROPIN may alter the clearance of compounds known to be metabolized by CP450 liver enzymes. Intervention: Careful monitoring is advisable when NORDITROPIN is administered in combination with drugs metabolized by CP450 liver enzymes. Oral Estrogen Clinical Impact: Oral estrogens may reduce the serum IGF-1 response to NORDITROPIN. Intervention: Patients receiving oral estrogen replacement may require greater NORDITROPIN dosages [see Dosage and Administration (2.3) ] . Insulin and/or Other Hypoglycemic Agents Clinical Impact: Treatment with NORDITROPIN may decrease insulin sensitivity, particularly at higher doses. Intervention: Patients with diabetes mellitus may require adjustment of their doses of insulin and/or other hypoglycemic agents [see Warnings and Precautions (5.4) ]. • Glucocorticoids : Patients treated with glucocorticoid for hypoadrenalism may require an increase in their maintenance or stress doses following initiation of NORDITROPIN ( 7 ) • Pharmacologic Glucocorticoid Therapy and Supraphysiologic Glucocorticoid Treatment : Adjust glucocorticoid replacement dosing in pediatric patients receiving glucocorticoid treatment to avoid both hypoadrenalism and an inhibitory effect on growth. ( 7 ) • Cytochrome P450-Metabolized Drugs : NORDITROPIN may alter the clearance. Monitor carefully if used with NORDITROPIN ( 7 ) • Oral Estrogen : Larger doses of NORDITROPIN may be required ( 7 ) • Insulin and/or Other Hypoglycemic Agents : Dose adjustment of insulin or hypoglycemic agent may be required ( 5.4 , 7 )