Humatrope Drug Information

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.

Adult Patients HUMATROPE is indicated for the replacement of endogenous GH in adults with GH deficiency.

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. Fundoscopic examination should be performed routinely before initiating treatment with HUMATROPE to exclude preexisting papilledema, and periodically thereafter. 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.

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. 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.

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. Women may require higher doses and patients receiving oral estrogen may require higher doses.

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.

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.

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, do not use HUMATROPE cartridge.

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.

A similar increase in otitis media was observed in an 18-month placebo-controlled study. 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 In a dose-response study (239 patients treated for 2 years), among Humatrope dose groups, 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. Table 5: Adverse Reactions of Special Interest Occurring in Patients with SHOX Deficiency By Treatment Group in an Open-label Study 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.

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. 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 Childhood-Onset GH Deficiency Two double-blind, placebo-controlled studies were conducted in 67 adult patients who had received previous somatropin treatment during childhood. 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.

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.

Intervention: Patients treated with glucocorticoid replacement for hypoadrenalism may require an increase in their maintenance or stress doses following initiation of HUMATROPE. Patients receiving oral estrogen may require greater HUMATROPE dosages. 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. 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. Cytochrome P450-Metabolized Drugs: HUMATROPE may alter the clearance.

Monitor carefully if used with HUMATROPE. Oral Estrogen: Patients may require larger doses of HUMATROPE. Insulin and/or Other Hypoglycemic Agents: Dose adjustment of insulin or hypoglycemic agent may be required.

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.

Pediatric Use Safety and effectiveness of HUMATROPE in pediatric patients have been established in growth failure due to inadequate secretion of endogenous growth hormone, short stature associated with Turner syndrome, idiopathic short stature (ISS), short stature or growth failure in SHOX deficiency, and short stature in children born small for gestational age (SGA) with no catch-up growth by 2 years to 4 years of age. Growth Failure due to Inadequate Secretion of Endogenous Growth Hormone Safety and effectiveness of HUMATROPE have been established in pediatric patients with growth failure due to growth hormone deficiency based on data from an open-label, uncontrolled, multicenter study with HUMATROPE in 314 pediatric patients conducted for up to 8 years. Short Stature Associated with Turner Syndrome Safety and effectiveness of HUMATROPE have been established in pediatric patients with short stature associated with Turner syndrome based on data from one long-term, randomized, open-label, multicenter, concurrently controlled study; two long-term, open-label multicenter, historically controlled US studies; and one long-term, randomized, US dose-response study with HUMATROPE in 181 pediatric patients.

Idiopathic Short Stature (ISS) Safety and effectiveness of HUMATROPE have been established in pediatric patients with ISS based on data from two randomized, multicenter studies, one placebo-controlled study and one dose-response study with HUMATROPE in 310 pediatric patients. Short Stature or Growth Failure in SHOX Deficiency Safety and effectiveness of HUMATROPE have been established in pediatric patients with short stature or growth failure in SHOX deficiency based on data from a randomized, controlled, two-year, three-arm, open-label study with HUMATROPE in 52 pediatric patients. Short Stature in Children Born Small for Gestational Age (SGA) with No Catch-up Growth by 2 Years to 4 Years of Age Safety and effectiveness of HUMATROPE have been established in pediatric patients with short stature born SGA with no catch-up growth based on data from two clinical studies with HUMATROPE in 214 pediatric patients.

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. 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. Active malignancy.

Known hypersensitivity to somatropin or any of the excipients in HUMATROPE. Systemic hypersensitivity reactions have been reported with postmarketing use of somatropins. Active proliferative or severe non-proliferative diabetic retinopathy.

Pediatric patients with closed epiphyses. Acute critical illness. Active malignancy.

Hypersensitivity to somatropin or excipients.

Acute overdosage could lead initially to hypoglycemia and subsequently to hyperglycemia. Overdose with somatropin is likely to cause fluid retention. Long-term overdosage could result in signs and symptoms of gigantism and/or acromegaly consistent with the known effects of excess endogenous growth hormone.