HUMATROPE

Somatropin is a human growth hormone (GH) produced by recombinant DNA technology using Escherichia coli. The protein is comprised of 191 amino acid residues and has a molecular weight of about 22,125 daltons. The amino acid sequence is identical to that of human GH of pituitary origin. HUMATROPE (somatropin) for injection is a sterile, white, lyophilized powder intended for subcutaneous injection after reconstitution supplied in a cartridge. Phosphoric acid and/or sodium hydroxide may have been added to adjust the pH. Reconstituted solutions have a pH of approximately 7.5. This product is oxygen sensitive. Cartridge — Each single-patient-use cartridge of HUMATROPE contains either 6 mg (18 IU), 12 mg (36 IU), or 24 mg (72 IU) of somatropin. Each HUMATROPE cartridge contains the following components (see Table 9 ): Table 9: Contents of HUMATROPE Component Cartridge 6 mg (gold) 12 mg (teal) 24 mg (purple) Somatropin 6 mg 12 mg 24 mg Dibasic sodium phosphate 1.36 mg 2.72 mg 5.43 mg Glycine 6 mg 12 mg 24 mg Mannitol 18 mg 36 mg 72 mg Each cartridge is co-packaged with an accompanying syringe containing approximately 3 mL of diluent containing Water for Injection with 0.3% metacresol as a preservative and 1.7%, 0.29%, and 0.29% glycerin in the 6, 12, and 24 mg cartridges, respectively.

HUMATROPE is a recombinant human growth hormone indicated for: Pediatric Patients: growth failure due to inadequate secretion of endogenous growth hormone (GH); short stature associated with Turner syndrome; 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; short stature or growth failure in short stature homeobox-containing gene (SHOX) deficiency; short stature born small for gestational age (SGA) with no catch-up growth by 2 years to 4 years of age. ( 1.1 ) Adult Patients: replacement of endogenous GH in adults with GH deficiency. ( 1.2 ) 1.1 Pediatric Patients HUMATROPE is indicated for the treatment of pediatric patients with: growth failure due to inadequate secretion of endogenous growth hormone (GH), short stature associated with Turner syndrome, 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, short stature or growth failure in short stature homeobox-containing gene (SHOX) deficiency, short stature born small for gestational age (SGA) with no catch-up growth by 2 years to 4 years of age. 1.2 Adult Patients HUMATROPE is indicated for the replacement of endogenous GH in adults with GH deficiency.

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. GHD: 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-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 ) 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 HUMATROPE should be supervised by a physician who is experienced in the diagnosis and management of patients with the conditions for which HUMATROPE is indicated [see Indications and Usage ( 1 )] . Fundoscopic examination should be performed routinely before initiating treatment with HUMATROPE to exclude preexisting papilledema, and periodically thereafter [see Warnings and Precautions ( 5.5 )] . Leave HUMATROPE at room temperature for 10 minutes prior to administration. Administer HUMATROPE by subcutaneous injection to the back of the upper arm, abdomen, buttock, or thigh with regular rotation of injection sites to avoid lipoatrophy. 2.2 Pediatric Dosage Individualize dosage for each patient based on the growth response. Divide the calculated weekly HUMATROPE 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: Pediatric GH Deficiency: 0.18 mg/kg/week to 0.3 mg/kg/week (0.026 to 0.043 mg/kg/day) Turner Syndrome: Up to 0.375 mg/kg/week (up to.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, height SDS less than -3, and older pubertal pediatric patients consider initiating treatment with a larger dose of HUMATROPE (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 height SDS 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 HUMATROPE 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 HUMATROPE than younger individuals [see Use in Specific Populations ( 8.5 )] . Women may require higher doses and patients receiving oral estrogen may require higher doses [see Drug Interactions ( 7 )] . Administer the prescribed dose daily. Either of two HUMATROPE dosing regimens may be used: Non-weight based: Initiate HUMATROPE 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. Use the patient's clinical response, adverse reactions, and determination of age- and gender-adjusted serum IGF-1 concentrations as guidance in dose titration. Maintenance dosages will vary considerably from person to person, and between male and female patients. Weight-based: Initiate HUMATROPE 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. Maintenance dosages will vary considerably from person to person, and between male and female patients Not recommended for obese patients as they are more likely to experience adverse reactions with this regimen. 2.4 Reconstitution of Cartridges Each single-patient-use HUMATROPE cartridge is designed for use only with the appropriate corresponding HumatroPen ® supplied separately. Reconstitute each cartridge of HUMATROPE using only the diluent syringe that accompanies the cartridge. Do not shake. The reconstituted solution should be clear. Inspect visually for particulate matter and discoloration. If the resulting solution is cloudy or contains particulate matter do not use. The somatropin concentrations for the reconstituted HUMATROPE cartridges are as follows in Table 1 : Table 1: Somatropin Concentration of HUMATROPE Cartridges. Cartridge Somatropin Concentration 6 mg 2.08 mg/mL 12 mg 4.17 mg/mL 24 mg 8.33 mg/mL Reconstituted cartridges of HUMATROPE are stable for up to 28 days when refrigerated at 36° to 46°F (2° to 8°C). Do not leave at room temperature more than 30 minutes per day. Avoid freezing the reconstituted cartridge. Protect HUMATROPE from light during storage. For patients with known hypersensitivity to the diluent supplied with the HUMATROPE cartridge [see Warnings and Precautions ( 5.6 )] , do not use HUMATROPE cartridge.

HUMATROPE is contraindicated in patients with: Acute critical illness after open heart surgery, abdominal surgery or multiple accidental trauma, or those with acute respiratory failure due to the risk of increased mortality with use of pharmacologic doses of somatropin [see Warnings and Precautions ( 5.1 )] . Pediatric patients with Prader-Willi syndrome who are severely obese, have a history of upper airway obstruction or sleep apnea, or have severe respiratory impairment due to the risk of sudden death [see Warnings and Precautions ( 5.2 )] . Active malignancy [see Warnings and Precautions ( 5.3 )] . Known hypersensitivity to somatropin or any of the excipients in HUMATROPE. Systemic hypersensitivity reactions have been reported with postmarketing use of somatropins [see Warnings and Precautions ( 5.6 )] . Active proliferative or severe non-proliferative diabetic retinopathy. Pediatric patients with closed epiphyses. Acute critical illness. ( 4 ) Pediatric patients with Prader-Willi syndrome who are severely obese, have history of upper airway obstruction or sleep apnea, or have severe respiratory impairment due to risk of sudden death. ( 4 ) Active malignancy. ( 4 ) Hypersensitivity to somatropin or excipients. ( 4 ) Active proliferative or severe non-proliferative diabetic retinopathy. ( 4 ) Pediatric patients with closed epiphyses. ( 4 )

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 )] Fatalities 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 reported in adult and pediatric patients include: upper respiratory infection, fever, pharyngitis, headache, otitis media, edema, arthralgia, paresthesia, myalgia, carpal tunnel syndrome, peripheral edema, flu syndrome, hypothyroidism, hyperglycemia, and impaired glucose tolerance. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Studies Experience Because clinical studies are conducted under varying conditions, adverse reaction rates observed during the clinical studies performed with one somatropin formulation cannot always be directly compared to the rates observed during the clinical studies performed with a different somatropin formulation, and may not reflect the adverse reaction rates observed in practice. Pediatric Patients Growth Failure Due to Inadequate Secretion of Endogenous Growth Hormone In an uncontrolled open-label study, 314 treatment-naive children aged >2 years who had GH deficiency were treated with HUMATROPE (0.06 mg/kg 3 times per week) for up to 8 years. Adverse reactions of special interest are reported in Table 2 . Table 2: Adverse Reactions of Special Interest Occurring in Humatrope-Treated Patients with Growth Failure Due to Inadequate Secretion of Endogenous Growth Hormone in an Open-label Study for Up to 8 Years a Dose=0.06 mg/kg 3 times per week for up to 8 years. b n=1 Adverse Reaction HUMATROPE a (n=314) Hypothyroidism 25% Allergic reaction 11% Arthralgia 6% Bone disorder 4% Edema 4% Injection site pain/reaction 4% Neoplasm/tumor 2% Cardiovascular disorders 1% Thyroid disorders 1% Intracranial hypertension 0% b Short Stature Associated with Turner Syndrome In a randomized, concurrent-controlled (untreated), open-label study until attainment of adult height, the adverse reactions of special interest occurring in 74 patients treated with Humatrope at dose 0.3 mg/kg/week (mean duration 4.1 years) and in 62 untreated patients (mean duration 3.7 years) are reported in Table 3 . A similar increase in otitis media was observed in an 18-month placebo-controlled study. Table 3: Adverse Reactions of Special Interest Occurring in Patients with Turner Syndrome in an Open-label Study Until Attainment of Adult Height Untreated (n=62) HUMATROPE (n=74) Surgical procedure 27% 45% Otitis media 26% 43% Ear disorders 5% 18% Idiopathic Short Stature Adverse reactions occurring in a randomized, placebo-controlled study of HUMATROPE treatment (0.22 mg/kg/week) until attainment of adult height (mean duration of HUMATROPE treatment 3.7 years, mean duration of placebo treatment 3.3 years) are reported in Table 4 . Mean fasting serum insulin concentration increased by 10% in the HUMATROPE treatment group at the end of treatment relative to baseline, but remained within the normal reference range. Table 4: Adverse Reactions Occurring in Patients with Idiopathic Short Stature Treated with HUMATROPE in a Randomized Placebo-controlled Study Placebo (n=31) HUMATROPE (n=37) Scoliosis 13% 19% Otitis media 7% 16% Hyperlipidemia 3% 8% Gynecomastia 3% 5% Hip pain 0 3% Arthralgia 3% 11% Arthrosis 7% 11% Myalgia 13% 24% Hypertension 0 3% In a dose-response study (239 patients treated for 2 years), among HUMATROPE dose groups [0.24 mg/kg/week (n=78), 0.37 mg/kg/week (n=83), 0.24 mg/kg/week for the first year and 0.37 mg/kg/week thereafter (n=78)], mean fasting blood glucose, mean glycosylated hemoglobin, and the incidence of elevated fasting blood glucose concentrations were similar. One patient developed glucose intolerance and high serum HbA 1c . Short Stature or Growth Failure in SHOX Deficiency Adverse reactions of special interest from a 2-year randomized, open-label study with HUMATROPE (0.35 mg/kg/wk) compared to no treatment are presented in Table 5 . During the 2-year study period, the proportion of patients who had at least one IGF-I concentration greater than 2.0 SD above the age- and gender-appropriate mean was 10 of 27 (37%) for the HUMATROPE-treated group vs. 0 of 24 patients (0%) for the untreated group. The proportion of patients who had at least one IGFBP-3 concentration greater than 2.0 SD above the age and gender appropriate mean was 16 of 27 (59%) for the HUMATROPE treated group vs. 7 of 24 (29%) for the untreated group. Table 5: Adverse Reactions of Special Interest Occurring in Patients with SHOX Deficiency By Treatment Group in an Open-label Study a Percentage calculated for males only: Untreated (0/1), HUMATROPE (1/12) Untreated (n=25) HUMATROPE (n=27) Arthralgia 8% 11% Gynecomastia a 0% 8% Excessive number of cutaneous nevi 0% 7% Scoliosis 0% 47% Small for Gestational Age (SGA) with No Catch-up Growth by Age 2-4 Years In a 2-year, multicenter, randomized study, 193 pediatric patients were treated with 2 different HUMATROPE treatment regimens: a fixed dose of 0.067 mg/kg/day (FHD group) or an individually adjusted dose regimen (IAD group; starting dose 0.035 mg/kg/day which could be increased as early as Month 3 to 0.067 mg/kg/day based on a validated growth prediction model). Reported adverse reactions included: common childhood infectious diseases, otitis media, headaches, and slipped capital femoral epiphysis (n=1. Six patients (4 in the FHD group and 2 in the IAD group whose dose was increased from 0.035 mg/kg/day to 0.067 mg/kg/day [one at Month 3 and one at Year 1]) had impaired fasting glucose at Year 2. Two of 6 had impaired fasting glucose during the study, and one discontinued HUMATROPE at month 15 as a consequence. At study completion, 20-25% of patients had serum IGF-I SDS values > +2. The following adverse reactions were reported from an observational study of 340 pediatric patients who received HUMATROPE with an average dosage of 0.041 mg/kg/day (maximum dose: 0.084 mg/kg/day) for an average of 3.0 years: type 2 diabetes mellitus (n=1), carpal tunnel syndrome (n=1) and an exacerbation of preexisting scoliosis (n=1). Adult Patients with GH deficiency Adult-Onset GH Deficiency In the first 6 months of controlled blinded studies during which patients received either HUMATROPE or placebo, patients who received HUMATROPE experienced an increase in edema (17% vs. 4%) and peripheral edema (12% vs. 0%). Edema, muscle pain, joint pain, and joint disorder were reported early in therapy and tended to be transient or responsive to dosage titration. Two of 113 patients developed carpal tunnel syndrome after beginning maintenance therapy without a low dose (0.00625 mg/kg/day) lead-in phase. Symptoms abated in these patients after dosage reduction. Adverse reactions with ≥5% overall occurrence rate during 12 or 18 months of replacement therapy with HUMATROPE are shown in Table 6 (adult-onset patients) and in Table 7 (childhood-onset patients). Table 6: Adverse Reactions with ≥5% Overall Occurrence in Adult-Onset Growth Hormone-Deficient Patients Treated with HUMATROPE for 18 Months as Compared with 6-Month Placebo and 12-Month HUMATROPE Exposure Adverse Reaction 18 Months Exposure [Placebo (6 Months)/Humatrope (12 Months)] (n=44) 18 Months Humatrope Exposure (n=52) Edema 11% 21% Arthralgia 14% 17% Paresthesia 14% 17% Myalgia 9% 14% Pain 14% 14% Peripheral edema 18% 12% Headache 7% 8% Hypertension 5% 8% Joint disorder 2% 6% Rhinitis 11% 13% Back pain 9% 10% Acne 0% 6% Surgical procedure 2% 6% Flu syndrome 7% 4% Childhood-Onset GH Deficiency Two double-blind, placebo-controlled studies were conducted in 67 adult patients who had received previous somatropin treatment during childhood. Patients were randomized to receive either placebo injections or HUMATROPE (0.00625 mg/kg/day for the first 4 weeks, then 0.0125 mg/kg/day thereafter) for the first 6 months, followed by open-label use of HUMATROPE for the next 12 months for all patients. During the placebo-controlled phase (first 6 months) of the study, elevations of serum glutamic oxaloacetic transferase were reported more for HUMATROPE-treated (13% vs. 0%) than placebo-treated patients. Table 7: Adverse Reactions with ≥5% Overall Occurrence in Childhood-Onset Growth Hormone-Deficient Patients Treated with HUMATROPE for 18 Months as Compared with 6-Month Placebo and 12-Month HUMATROPE Exposure a Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase Adverse Reaction 18 Months Exposure [Placebo (6 Months)/Humatrope (12 Months)] (n=30) 18 Months Humatrope Exposure (n=32) AST a increased 7% 13% Headache 7% 9% Asthenia 3% 6% Edema 10% 6% Myalgia 7% 6% Pain 10% 6% ALT a increased 7% 6% Flu syndrome 10% 16% Cough increased 0% 6% Hypesthesia 0% 6% Rhinitis 7% 6% Respiratory disorder 7% 3% Gastritis 7% 0% Pharyngitis 7% 3% 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of somatropin or HUMATROPE. Because these adverse events 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. Severe Hypersensitivity Reactions — Serious systemic hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with postmarketing use of somatropins Neurologic — Headaches (common in pediatric patients and occasional in adults) Skin — Increase in size or number of cutaneous nevi Endocrine — Gynecomastia Gastrointestinal — Pancreatitis Metabolic — New-onset type 2 diabetes mellitus Musculoskeletal and connective tissue disorders — Osteonecrosis in pediatric patients Neoplasia — Leukemia has been reported in a small number of GH deficient pediatric patients treated with somatropin

Table 8 includes a list of drugs with clinically important drug interactions when administered concomitantly with HUMATROPE and instructions for preventing or managing them. Table 8: Clinically Important Drug Interactions with HUMATROPE Replacement Glucocorticoid Treatment 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. HUMATROPE inhibits 11βHSD-1. Consequently, individuals with untreated GH deficiency have relative increases in 11βHSD-1 and serum cortisol. Initiation of HUMATROPE 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 HUMATROPE [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. Non-Replacement Glucocorticoid Treatment in Pediatric Patients Clinical Impact: Non-replacement glucocorticoid treatment, including supraphysiologic glucocorticoid treatment, may attenuate the growth promoting effects of HUMATROPE in pediatric patients. Intervention: Carefully adjust glucocorticoid 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. HUMATROPE may alter the clearance of compounds known to be metabolized by CP450 liver enzymes. Intervention: Careful monitoring is advisable when HUMATROPE 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 HUMATROPE. Intervention: Patients receiving oral estrogen may require greater HUMATROPE dosages [see Dosage and Administration ( 2.3 )] . Insulin and/or Other Hypoglycemic Agents Clinical Impact: Treatment with HUMATROPE 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 )]. Replacement Glucocorticoid Treatment: Patients treated with glucocorticoids for hypoadrenalism may require an increase in their maintenance or stress doses following initiation of HUMATROPE. ( 7 ) Non-Replacement Glucocorticoid Treatment in Pediatric Patients: Adjust glucocorticoid dosing in pediatric patients receiving glucocorticoid treatment to avoid both hypoadrenalism and an inhibitory effect on growth. ( 7 ) Cytochrome P450-Metabolized Drugs: HUMATROPE may alter the clearance. Monitor carefully if used with HUMATROPE. ( 7 ) Oral Estrogen: Patients may require larger doses of HUMATROPE. ( 7 ) Insulin and/or Other Hypoglycemic Agents: Dose adjustment of insulin or hypoglycemic agent may be required. ( 5.4 , 7 )

16.2 Storage and Handling Cartridges Refrigerate cartridges of HUMATROPE and Diluent for HUMATROPE at 36° to 46°F (2° to 8°C). Avoid freezing Diluent for HUMATROPE. Store in the original carton to protect HUMATROPE from light.