Somatropinside effects

The following important adverse reactions are also described elsewhere in the labeling:

Increased mortality in patients with acute critical illness

Sudden death in children 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

Lipoatrophy Common adverse reactions in adult and pediatric patients include: upper respiratory infection, fever, pharyngitis, headache, otitis media, edema, arthralgia, paresthesia, myalgia, peripheral edema, flu syndrome, and impaired glucose tolerance. To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk at 1-888-NOVO-444 (1-888-668-6444) 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 product cannot always be directly compared to the rates observed during the clinical trials performed with another somatropin product, and may not reflect the adverse reaction rates observed in practice. Pediatric Patients Growth Failure due to Inadequate Secretion of Endogenous Growth Hormone In one randomized, open label, clinical study the most frequent adverse reactions were headache, pharyngitis, otitis media and fever. There were no clinically significant differences between the three doses assessed in the study (0.025, 0.05 and 0.1 mg/kg/day). Short Stature Associated with Noonan Syndrome NORDITROPIN was studied in 21 pediatric patients, 3 years to 14 years of age at doses of 0.033 mg/kg/day and 0.066 mg/kg/day. After the two-year study, patients continued NORDITROPIN treatment until final height was achieved; randomized dose groups were not maintained. Adverse reactions were later collected retrospectively from 18 pediatric patients; total follow-up was 11 years. An additional 6 pediatric patients were not randomized, but followed the protocol and are included in this assessment of adverse reactions. The most frequent adverse reactions were upper respiratory infection, gastroenteritis, ear infection, and influenza. Cardiac disorders was the system organ class with the second most adverse reactions reported. Scoliosis was reported in 1 and 4 pediatric patients receiving doses of 0.033 mg/kg/day and 0.066 mg/kg/day respectively. The following additional adverse reactions also occurred once: insulin resistance and panic reaction for the 0.033 mg/kg/day dose group; injection site pruritus, bone development abnormal, depression, and self-injurious ideation in the 0.066 mg/kg/day dose group. Headache occurred in 2 cases in the 0.066 mg/kg/day dose group. Short Stature Associated with Turner Syndrome In two clinical studies in pediatric patients that were treated until final height with various doses of NORDITROPIN, the most frequently reported adverse reactions were influenza-like illness, otitis media, upper respiratory tract infection, otitis externa, gastroenteritis, eczema and, impaired fasting glucose. Adverse reactions in study 1 were most frequent in the highest dose groups. Three patients in study 1 had excessive growth of hands and/or feet in the high dose groups. Two patients in study 1 had a serious adverse reaction of exacerbation of preexisting scoliosis in the 0.045 mg/kg/day group. Small for Gestational Age (SGA) with No Catch-up Growth by Age 2-4 Years In a study, 53 pediatric patients were treated with 2 doses of NORDITROPIN (0.033 or 0.067 mg/kg/day) to final height for up to 13 years (mean duration of treatment 7.9 and 9.5 years for girls and boys, respectively). The most frequently reported adverse reactions were influenza-like illness, upper respiratory tract infection, bronchitis, gastroenteritis, abdominal pain, otitis media, pharyngitis, arthralgia, headache, gynecomastia, and increased sweating. One pediatric patient treated with 0.067 mg/kg/day for 4 years was reported with disproportionate growth of the lower jaw, and another patient treated with 0.067 mg/kg/day developed a melanocytic nevus. 4 pediatric patients treated with 0.067 mg/kg/day and 2 pediatric patients treated with 0.033 mg/kg/day of NORDITROPIN had increased fasting blood glucose levels after 1 year of treatment. In addition, small increases in mean fasting blood glucose and insulin levels after 1 and 2 years of NORDITROPIN treatment appeared to be dose-dependent. In a second study, 98 Japanese pediatric patients were treated with 2 doses of NORDITROPIN (0.033 or 0.067 mg/kg/day) for 2 years or were untreated for 1 year. Adverse reactions were otitis media, arthralgia and impaired glucose tolerance. Arthralgia and transiently impaired glucose tolerance were reported in the 0.067 mg/kg/day treatment group. Idiopathic Short Stature In two open-label clinical studies with another somatropin product in pediatric patients, the most common adverse reactions were upper respiratory tract infections, influenza, tonsillitis, nasopharyngitis, gastroenteritis, headaches, increased appetite, pyrexia, fracture, altered mood, and arthralgia. Growth Failure Due to Prader-Willi Syndrome In two clinical studies in pediatric patients with PWS carried out with another somatropin product, the following adverse reactions were reported: edema, aggressiveness, arthralgia, benign intracranial hypertension, hair loss, headache, and myalgia. Adult Patients Adults with Growth Hormone Deficiency Adverse reactions with an incidence of ≥5% occurring in patients with AO GHD during the 6 month placebo-controlled portion of a clinical trial for NORDITROPIN are presented in Table 1. Table 1 – Adverse Reactions with ≥5% Overall Incidence in Adult Onset Growth Hormone Deficient Patients Treated with NORDITROPIN During a Six Month Placebo-Controlled Clinical Trial Placebo (N=52) NORDITROPIN (N=53) Adverse Reactions % % Peripheral Edema 8 42 Edema 0 25 Arthralgia 15 19 Leg Edema 4 15 Myalgia 8 15 Infection (non-viral) 8 13 Paraesthesia 6 11 Skeletal Pain 2 11 Headache 6 9 Bronchitis 0 9 Flu-like symptoms 4 8 Hypertension 2 8 Gastroenteritis 8 8 Other Non-Classifiable Disorders (excludes accidental injury) 6 8 Increased sweating 2 8 Glucose tolerance abnormal 2 6 Laryngitis 6 6 Type 2 diabetes mellitus 0 5

6.2 Postmarketing

Experience The following adverse reactions have been identified during post-approval use of somatropin or NORDITROPIN. Because these adverse reactions 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. Immune system disorders — Serious systemic hypersensitivity reactions including anaphylactic reactions and angioedema Skin — Increase in size or number of cutaneous nevi Endocrine disorders — Hypothyroidism - Gynecomastia Metabolism and nutrition disorders — Hyperglycemia Musculoskeletal and connective tissue disorders — Slipped capital femoral epiphysis and osteonecrosis (including Legg-Calvé-Perthes disease) have been reported in pediatric patients treated with growth hormone. Cases have been reported with NORDITROPIN. Investigations — Increase in blood alkaline phosphatase level — Decrease in serum thyroxin (T4) levels Gastrointestinal — Pancreatitis Neoplasm — Leukemia has been reported in a small number of GH deficient children treated with somatropin, somatrem (methionylated rhGH) and GH of pituitary origin