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)] Lipoatrophy [see Warnings and Precautions (5.13)] Pancreatitis [see Warnings and Precautions (5.15)] Benzyl alcohol [see Warnings and Precautions (5.16)] Most common adverse reactions are injection site reactions (such as pain, numbness, redness, and swelling), fluid retention, peripheral edema, arthralgia, myalgia, paresthesia, and headache. (6) To report SUSPECTED ADVERSE REACTIONS, contact EMD Serono at 1-800-283-8088 ext 5563 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 second somatropin formulation, and may not reflect the adverse reaction rates observed in practice. Growth Hormone Deficient Pediatric Patients In clinical studies in which SAIZEN was administered to growth hormone deficient children, the following reactions were infrequently seen: local reactions at the injection site (such as pain, numbness, redness and swelling), hypothyroidism, hypoglycemia, seizures, exacerbation of preexisting psoriasis and disturbances in fluid balance. Growth Hormone Deficient Adult Patients For a description of the clinical trials refer to section 14. During the 6-month placebo-controlled study, adverse reactions were reported in 56 patients (93.3%) in the somatropin-treated group and 42 patients (76.4%) in the placebo-treated group. Adverse reactions with an incidence of ≥5% in SAIZEN-treated patients which were more frequent in SAIZEN-treated patients compared with placebo-treated patients are listed in Table 1. Arthralgia, myalgia, peripheral edema, other types of edema, carpal tunnel syndrome, paraesthesia and hypoaesthesia were common in the somatropin-treated patients and reported more frequently than in the placebo group. These types of adverse reactions are thought to be related to the fluid accumulating effects of somatropin. During the placebo-controlled portion of the study, approximately 10% of patients without preexisting diabetes mellitus or impaired glucose tolerance treated with somatropin manifested mild, but persistent, abnormalities of glucose tolerance, compared with none in the placebo group. During the open label phase of the study, approximately 10% of patients treated with somatropin required a small upward adjustment of thyroid hormone replacement therapy for preexisting central hypothyroidism and 1 patient was newly diagnosed with central hypothyroidism. In addition, during the open label phase of the study, when all patients were being treated with somatropin, two patients with preexisting central hypoadrenalism required upward titration of hydrocortisone maintenance therapy which was considered to be suboptimal (unrelated to intercurrent stress, surgery or disease), and 1 patient was diagnosed de novo with central adrenal insufficiency after six months of somatropin treatment. Anti-GH antibodies were not detected. Table 1 Adverse Reactions with ≥5% Overall Incidence in SAIZEN-Treated Patients Which Were More Frequent in SAIZEN-Treated Patients Compared with Placebo-Treated Patients During a 6 Month Study Adverse Reaction SAIZEN-Treated (N=60) Placebo (N=55) N = number of patients Arthralgia 14(23.3%) 7(12.7%) Headache 11(18.3%) 8(14.5%) Edema peripheral 9(15.0%) 2(3.7%) Myalgia 5(8.3%) 2(3.6%) Paraesthesia 4(6.7%) 1(1.8%) Hypoaesthesia 4(6.7%) 0 Edema dependent 3(5.0%) 2(3.6%) Skeletal Pain 3(5.0%) 1(1.8%) Carpal tunnel syndrome 3(5.0%) 1(1.8%) Edema generalized 3(5.0%) 0 Chest pain 3(5.0%) 0 Depression 3(5.0%) 0 Hypothyroidism 3(5.0%) 0 Insomnia 3(5.0%) 0 The adverse reaction pattern observed during the open label phase of the study was similar to the one presented above. 6.2 Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to SAIZEN with the incidence of antibodies to other products may be misleading. In the case of growth hormone, antibodies with binding capacities lower than 2 mg/mL have not been associated with growth attenuation. In a very small number of patients treated with somatropin, when binding capacity was greater than 2 mg/mL, interference with the growth response was observed. 6.3 Post-Marketing Experience The following adverse reactions have been identified during post approval use of SAIZEN. Because these 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. Serious systemic hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with postmarketing use of somatropin products [See Warnings and Precautions (5.6)]. Leukemia has been reported in a small number of growth hormone deficient patients treated with growth hormone. It is uncertain whether this increased risk is related to the pathology of growth hormone deficiency itself, growth hormone therapy, or other associated treatments such as radiation therapy for intracranial tumors. So far, epidemiological data fail to confirm the hypothesis of a relationship between growth hormone therapy and leukemia. The following additional adverse reactions have been observed during the appropriate use of somatropin: headaches (children and adults), gynecomastia (children), and pancreatitis (children and adults) (see Warnings and Precautions [5.14]).