Somatropinside effects

The following important adverse reactions are also described elsewhere in the labeling: Increased mortality in patients with acute critical illness Fatalities in pediatric patients with Prader-Willi syndrome Neoplasms Glucose intolerance and diabetes mellitus Intracranial hypertension Severe hypersensitivity Fluid retention Hypoadrenalism Hypothyroidism Slipped capital femoral epiphysis in pediatric patients Progression of preexisting scoliosis in pediatric patients Pancreatitis Risk of Serious Adverse Reactions in Infants due to Benzyl Alcohol Preservative Lipoatrophy 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. To report SUSPECTED ADVERSE REACTIONS, contact Ferring Pharmaceuticals Inc. at 1-888-337-7464 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 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

4.7 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

4.4 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 2.0 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 2.0 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 [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 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 [Placebo (6 Months)/GH (12 Months)] 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 [Placebo (6 Months)/GH (12 Months)] (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.

6.2 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