Zomacton Drug Information

Pediatric Patients

ZOMACTON 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 (HSDS) ≤-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

ZOMACTON is indicated for the replacement of endogenous GH in adults with GH deficiency.

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. Fundoscopic examination should be performed routinely before initiating treatment with ZOMACTON to exclude preexisting papilledema, and periodically thereafter. 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 The volume of the syringe should be small enough so that the prescribed dose can be withdrawn from the vial with reasonable accuracy.

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.

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 . Estrogen-replete women and patients receiving oral estrogen may require higher doses. 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.

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 or in neonates , or pregnant or lactating women 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 . 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.

Clinical Trials Experience

Because clinical trials are conducted under varying conditions, adverse reaction rates observed during the clinical trials performed with one somatropin formulation cannot always be directly compared to the rates observed during the clinical trials performed with a different approved 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 ZOMACTON was evaluated in 164 pediatric patients with short stature due to GHD in an open-label study for 24 weeks. The subjects ranged in age from 2.1 to 17.7 years with a mean of 10.8 years.

One hundred twenty (73%) of the subjects were male and 44 (27%) were female. Two subjects were Asian, 12 were Black, 130 were Caucasian, and 20 were categorized as 'other'. Table 1: Adverse Reactions ≥ 5% in Pediatric Patients with Growth Failure Due to GHD Treated with ZOMACTON through 24 Weeks Adverse Reaction 24 Week Exposure to ZOMACTON (n=164) Upper respiratory infection 32% Fever 16% Pharyngitis 12% Headache 11% Otitis Media 10% Increased cough 9% Abdominal pain 7% Anemia 6% Maculopapular rash 6% Diarrhea 5% Pain 5% Rhinitis 5% All pediatric patients were carefully observed for signs or laboratory abnormalities of hypothyroidism. Fifteen patients had T4 values which occasionally fell below the central laboratory's lower limit of normal; T4 levels rose to normal when tested during the next visit for all patients except one who continued to be monitored.

Six of the 15 patients received thyroxine therapy before and throughout the study period, and thyroxine dose adjustments were made during the study in 3/6 subjects. In studies with GH deficient pediatric patients, injection site pain was reported in 1.6% of patients. A mild and transient edema, which appeared in 1.6% of patients, was observed early during the course of treatment.

Short Stature Associated with Turner Syndrome In a randomized, concurrent-controlled, open-label study, there was an increase in the occurrence of otitis media, ear disorders and surgical procedures in patients receiving another somatropin product at a dose of 0.3 mg/kg/week, compared with untreated control patients (Table 2). A similar increase in otitis media was observed in an 18-month placebo-controlled study. Table 2: Adverse Reactions Occurring in Patients with Turner Syndrome Treated with 0.3 mg/kg/week of Another Somatropin product During a

Year Randomized Open-Label Study Untreated (n=62) Somatropin (n=74) Surgical procedure 27% 45%

Otitis media 26% 43% Ear disorders 5% 18% Idiopathic Short Stature Adverse reactions from a randomized, placebo-controlled study of another somatropin product dosed at 0.22 mg/kg/week are presented in Table 3. Mean fasting serum insulin concentration increased 10% in the group treated with another somatropin product at the end of treatment relative to baseline, but remained within the normal reference range. Table 3: Adverse Reactions Occurring in Patients with Idiopathic Short Stature Treated with Another Somatropin product during a

Year Randomized Placebo-Controlled Study Adverse Reactions Placebo (n=31) Another Somatropin product (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 with 239 patients treated for 2 years, mean fasting blood glucose, mean glycosylated hemoglobin, and the incidence of elevated fasting blood glucose concentrations were similar among dose groups. One patient developed glucose intolerance and high serum HbA 1c. Short Stature or Growth Failure in SHOX Deficiency Adverse reactions from a 2-year open-label study with another somatropin product compared to no treatment are presented in Table 4. During the study, the proportion of patients who had at least one IGF-1 concentration greater than

SD above the age- and gender-appropriate mean was 37.0% for the somatropin-treated

group vs. 0% patients for the untreated group. The proportion of patients who had at least one IGFBP-3 concentration greater than

SD above the age and gender appropriate mean was 59% for the

somatropin treated group vs. 29% for the untreated group. Table 4: Adverse Reactions Occurring in Patients with SHOX Deficiency Treated with Another Somatropin product for 2 years Untreated (n=25) Another Somatropin product (n=27) Arthralgia 8% 11% Gynecomastia 0% 8% Excessive number of cutaneous nevi 0% 7% Scoliosis 0% 4% Small for Gestational Age (SGA) with No Catch-up Growth by 2 Years to 4 Years of Age In a 2-year study, 193 pediatric patients were treated with another somatropin product using 2 different 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). 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 )) had impaired fasting glucose at Year 2. Two of 6 had impaired fasting glucose during the study, and 1 discontinued treatment at month 15 as a consequence. At study completion, 20-25% of patients had serum IGF-1 SDS values > +2. The following adverse reactions were reported from an observational study of 340 pediatric patients who received another somatropin product with an average dosage of 0.041 mg/kg/day for an average of 3 years: type 2 diabetes mellitus (n=1), carpal tunnel syndrome (n=1) and exacerbation of preexisting scoliosis (n=1). Adult Patients Adult-Onset GH Deficiency In the first 6 months of controlled blinded trials during which patients received either another somatropin product or placebo, patients who received this other somatropin product experienced a statistically significant increase in edema (another somatropin product 17% vs. placebo 4%, p=0.043) and peripheral edema (12% vs. 0%, respectively, p=0.017). 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. All adverse reactions with ≥5% overall occurrence rate during 12 or 18 months of replacement therapy with another somatropin product are shown in Table 5 (adult-onset patients) and in Table 6 (childhood-onset patients). Adult patients treated with another somatropin product who had been diagnosed with GH deficiency in childhood reported adverse reactions less frequently than those with adult-onset GH deficiency.

Table 5: Adverse Reactions Occurring ≥5% in Adult-Onset Growth Hormone-Deficient Patients Treated with Another Somatropin product for 18 Months as Compared with 6-Month Placebo and 12-Month Exposure to Another Somatropin product Abbreviations: GH= another somatropin product; n=number of patients receiving treatment in the period stated 18 Months Exposure Adverse Reaction 18 Months GH Exposure (n=46) (n=52) Edema p=0.04 as compared to placebo (6 months). 15% 21% Arthralgia 15% 17% Paresthesia 13% 17% Myalgia 13% 14% Pain 13% 14% Rhinitis 11% 14% Peripheral edema p=0.02 as compared to placebo (6 months). 17% 12% Back pain 11% 10% Headache 11% 8% Hypertension 4% 8% Acne 0% 6% Joint disorder 2% 6% Surgical procedure 2% 6% Flu syndrome 7% 4% Childhood-Onset GH Deficiency Two double-blind, placebo-controlled trials were conducted in 67 adult patients who had received previous somatropin treatment during childhood. Patients were randomized to receive either placebo injections or another somatropin product (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 another somatropin product for the next 12 months for all patients. The patients in these studies reported side effects less frequently than those with adult-onset GH deficiency.

During the placebo-controlled phase (first 6 months) of the study, elevations of serum glutamic oxaloacetic transferase were reported significantly more often for somatropin-treated (12.5%) than placebo-treated patients (0.0%, p=0.031). No other events were reported significantly more often for somatropin-treated patients during the placebo-controlled phase. Table 6: Adverse Reactions Occurring ≥5% in Childhood-Onset Growth Hormone-Deficient Patients Treated with Another Somatropin product for 18 Months as Compared with 6-Month Placebo and 12-Month Exposure to Another Somatropin product Abbreviations: GH=another somatropin product; n=number of patients receiving treatment in the period stated; ALT=alanine aminotransferase, formerly SGPT; AST=aspartate aminotransferase, formerly SGOT. 18 Months Exposure 18 Months GH Exposure Adverse Reaction (n=35) (n=32) Flu syndrome 23% 16% AST increased p=0.03 as compared to placebo (6 months). 6% 13% Headache 11% 9% Asthenia 3% 6% Cough increased 0% 6% Edema 9% 6% Hypesthesia 0% 6% Myalgia 6% 6% Pain 9% 6% Rhinitis 6% 6% ALT increased 6% 6% Respiratory disorder 6% 3% Gastritis 6% 0% Pharyngitis 14% 3% In an ongoing post-marketing observational study of treatment with another somatropin product in 3,102 GH-deficient adults, hypertension, dyspnea, and sleep apnea were reported by 1% to less than 10% of patients after various durations of treatment.

Postmarketing Experience

The following adverse reactions have been identified during post approval use of somatropin or ZOMACTON. Because the following 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. Gastrointestinal disorders — Pancreatitis Immune system disorders — Serious systemic hypersensitivity reactions including anaphylactic reactions and angioedema Metabolism and nutrition disorders — New-onset type 2 diabetes mellitus Musculoskeletal and connective tissue disorders – osteonecrosis in pediatric patients Neoplasms benign, malignant and unspecified — Leukemia has been reported in a small number of GH deficient pediatric patients treated with somatropin, somatrem (methionylated rhGH), and GH of pituitary origin Nervous system disorders — Headaches (common in pediatric patients and occasional in adults) Reproductive system and breast disorders — Gynecomastia Skin and subcutaneous tissue disorders — Increase in size or number of cutaneous nevi

Table 7 includes a list of drugs with clinically important drug interactions when administered concomitantly with ZOMACTON and instructions for preventing or managing them. Table 7: Clinically Important Drug Interactions with ZOMACTON 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. ZOMACTON inhibits 11βHSD-1. Consequently, individuals with untreated GH deficiency have relative increases in 11βHSD-1 and serum cortisol.

Initiation of ZOMACTON 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 ZOMACTON. Examples: Cortisone acetate and prednisone may be affected 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 ZOMACTON 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. ZOMACTON may alter the clearance of compounds known to be metabolized by CP450 liver enzymes. Intervention: Careful monitoring is advisable when ZOMACTON 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 ZOMACTON. Intervention: Patients receiving oral estrogen replacement may require greater ZOMACTON dosages . Insulin and/or Other Hypoglycemic Agents Clinical Impact: Treatment with ZOMACTON 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. Glucocorticoids: Patients treated with glucocorticoid for hypoadrenalism may require an increase in their maintenance or stress doses following initiation of ZOMACTON 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.

Cytochrome P450-Metabolized Drugs: ZOMACTON may alter the clearance. Monitor carefully if used with ZOMACTON Oral Estrogen: Larger doses of ZOMACTON may be required Insulin and/or Other Hypoglycemic Agents: Dose adjustment of insulin or hypoglycemic agent may be required

Pregnancy Risk Summary The ZOMACTON 5 mg diluent contains benzyl alcohol. Because benzyl alcohol is rapidly metabolized by a pregnant woman, benzyl alcohol exposure in the fetus is unlikely. However, adverse reactions have occurred in premature neonates and low birth weight infants who received intravenously administered benzyl alcohol-containing drugs.

Therefore, if ZOMACTON 5mg is needed during pregnancy, reconstitute with 0.9% sodium chloride injection, use only one dose per vial, and discard the unused portion, or use a ZOMACTON 10 mg benzyl alcohol-free formulation. Limited published data do not report an association with somatropin and major birth defects, miscarriage, or adverse maternal or fetal outcomes when somatropin is used in pregnancy. Published reports indicate that somatropin does not cross the placenta.

Animal reproduction studies have not been conducted with ZOMACTON. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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 ZOMACTON 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 ZOMACTON have been established in pediatric patients with growth failure due to growth hormone deficiency based on data from a multi-center, open-label study in 164 pediatric patients conducted for a two-year period. Short Stature associated with Turner Syndrome Safety and effectiveness of ZOMACTON have been established in pediatric patients with short stature associated with Turner syndrome based on data from one long-term, randomized, open-label, Canadian multicenter, concurrently controlled study; two long-term, open-label multicenter, historically controlled US studies; and one long-term, randomized, US dose-response study with another somatropin product in 181 pediatric patients.

Idiopathic Short Stature (ISS) Safety and effectiveness of ZOMACTON 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 another somatropin product in 310 pediatric patients. Short Stature or Growth Failure in SHOX Deficiency Safety and effectiveness of ZOMACTON 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 another somatropin product in 52 pediatric patients. Short Stature in Children Born Small for Gestational Age (SGA) with No Catch-up Growth by Age 2 Years to 4 Years of Age Safety and effectiveness of ZOMACTON have been established in pediatric patients with short stature born SGA with no catch-up growth based on data from two clinical studies with another somatropin product in 228 pediatric patients.

Toxicity (Gasping Syndrome) with Benzyl Alcohol-Preserved Solution Serious adverse reactions including fatal reactions and the "gasping syndrome" occurred in premature neonates and infants in the intensive care unit who received drugs containing benzyl alcohol as a preservative. In these cases, benzyl alcohol dosages of 99 mg/kg/day to 234 mg/kg/day produced high levels of benzyl alcohol and its metabolites in the blood and urine (blood levels of benzyl alcohol were 0.61 mmol/L to 1.378 mmol/L). The maximal daily uptake of benzyl alcohol is 39 mg at ZOMACTON doses of 0.067 mg/kg/day. Additional adverse reactions included gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse.

Preterm, low-birth weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol. When administering ZOMACTON 5 mg to infants, reconstitute with 0.9% sodium chloride injection, not with the diluent provided. Use only one dose per vial and discard the unused portion.

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 to any excipients of ZOMACTON. Systemic hypersensitivity reactions, including anaphylaxis and angioedema, have been reported with postmarketing use of somatropins . Active proliferative or severe non-proliferative diabetic retinopathy. Pediatric patients with closed epiphyses. Acute critical illness 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 risk of sudden death Active malignancy Hypersensitivity to ZOMACTON, its excipients, or diluents Active proliferative or severe non-proliferative diabetic retinopathy Pediatric patients with closed epiphyses

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