HUMATROPE

1 INDICATIONS AND USAGE 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.

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. 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: Initia…

5 WARNINGS AND PRECAUTIONS Increased Risk of Neoplasm: Second neoplasms have occurred in childhood cancer survivors. Monitor patients with preexisting tumors for progression or recurrence. ( 5.3 ) Glucose Intolerance and Diabetes Mellitus: HUMATROPE may decrease insulin sensitivity, particularly at higher doses. Monitor glucose levels periodically in all patients receiving HUMATROPE, 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 ) 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 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 doses of somatropin [see Contraindications ( 4 )] . Two placebo-controlled clinical studies in non-GH 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 5.3-8.0 mg/day) compared to those receiving placebo. The safety of continuing HUMATROPE treatment in patients receiving replacement doses for approved indications who concurrently develop these illnesses has not been established. HUMATROPE 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 somatropin, 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 somatropin 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 )] . HUMATROPE is not indicated for the treatment of pediatric patients who have growth failure due to Prader-Willi syndrome. 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 HUMATROPE. Discontinue HUMATROPE if there is evidence of recurrent activity. Risk o…

4 CONTRAINDICATIONS 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 )

7 DRUG INTERACTIONS 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 )

8.1 Pregnancy Risk Summary Limited available data with somatropin use in pregnant women are insufficient to determine a drug-associated risk of adverse developmental outcomes. Animal reproduction studies have not been conducted with HUMATROPE. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

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 )] 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 Tre…