6 ADVERSE REACTIONS Clinically significant adverse reactions that appear in other section of the labeling include: Hypoglycemia associated with GH lowering in patients with Diabetes Mellitus [see Warnings and Precautions (5.1)] Liver test elevations [see Warnings and Precautions (5.2)] Cross-reactivity with GH assay [see Warnings and Precautions (5.3)] Lipohypertrophy [see Warnings and Precautions (5.4)] Systemic hypersensitivity [see Warnings and Precautions (5.5)] Elevations of serum concentrations of ALT and AST greater than ten times the ULN were reported in two patients (0.8%) exposed to SOMAVERT in pre-approval clinical studies. One patient was rechallenged with SOMAVERT, and the recurrence of elevated transaminase levels suggested a probable causal relationship between administration of the drug and the elevation in liver enzymes. A liver biopsy performed on the second patient was consistent with chronic hepatitis of unknown etiology. In both patients, the transaminase elevations normalized after discontinuation of the drug. Elevations in ALT and AST levels were not associated with increased levels of TBIL and ALP, with the exception of two patients with minimal associated increases in ALP levels (i.e., less than 3 times ULN). The transaminase elevations did not appear to be related to the dose of SOMAVERT administered, generally occurred within 4 to 12 weeks of initiation of therapy, and were not associated with any identifiable biochemical, phenotypic, or genetic predictors. Most common reported adverse reactions (> 6%) are infection, pain, nausea, diarrhea, abnormal liver tests, flu syndrome, injection site reaction (6) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer at (phone 1-800-438-1985 andwww.pfizer.com) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice. In a 12-week randomized, placebo-controlled, double-blind, fixed-dose study of SOMAVERT in subjects with acromegaly, 32 subjects received placebo and 80 subjects received SOMAVERT once daily [see Clinical Studies (14)]. A total of 108 subjects (30 placebo, 78 Somavert) completed 12 weeks of study treatment. Overall, eight patients with acromegaly (5.3%) withdrew from pre-marketing clinical studies because of adverse events, including two patients with marked transaminase elevations, one patient with lipohypertrophy at the injection sites, and one patient with substantial weight gain. Most adverse events did not appear to be dose-dependent. Table 3 shows the incidence of adverse events that were reported in at least two patients treated with SOMAVERT and at frequencies greater than placebo during the 12-week, placebo-controlled study. Table 3. Adverse Reactions in a 12-week Placebo-Controlled Study in Patients with AcromegalyTable includes only those events that were reported in at least 2 patients and at a higher incidence in patients treated with SOMAVERT than in patients treated with placebo. Placebo n=32 SOMAVERT 10 mg/day n=26 15 mg/day n=26 20 mg/day N=28 InfectionThe 6 events coded as "infection" in the group treated with SOMAVERT 10 mg were reported as cold symptoms (3), upper respiratory infection (1), blister (1), and ear infection (1).The 2 events in the placebo group were reported as cold symptoms (1) and chest infection (1). 2 (6%) 6 (23%) 0 0 Pain 2 (6%) 2 (8%) 1 (4%) 4 (14%) Nausea 1 (3%) 0 2 (8%) 4 (14%) Diarrhea 1 (3%) 1 (4%) 0 4 (14%) Abnormal liver function tests 1 (3%) 3 (12%) 1 (4%) 1 (4%) Flu syndrome 0 1 (4%) 3 (12%) 2 (7%) Injection site reaction 0 2 (8%) 1 (4%) 3 (11%) Dizziness 2 (6%) 2 (8%) 1 (4%) 1 (4%) Accidental injury 1 (3%) 2 (8%) 1 (4%) 0 Back pain 1 (3%) 2 (8%) 0 1 (4%) Sinusitis 1 (3%) 2 (8%) 0 1 (4%) Chest pain 0 1 (4%) 2 (8%) 0 Peripheral edema 0 2 (8%) 0 1 (4%) Hypertension 0 0 2 (8%) 0 Paresthesia 2 (6%) 0 0 2 (7%) 6.2 Immunogenicity In pre-marketing clinical studies, approximately 17% of the SOMAVERT-treated patients developed low titer, non-neutralizing anti-GH antibodies. Although the presence of these antibodies did not appear to impact the efficacy of SOMAVERT, the long-term clinical significance of these antibodies is not known. No assay for anti-pegvisomant antibodies is commercially available for patients receiving SOMAVERT. The data above reflect the percentage of patients whose test results were considered positive for antibodies to SOMAVERT. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to SOMAVERT with the incidence of antibodies to other products may be misleading. 6.3 Postmarketing Experience The following adverse reactions have been identified during post-approval use of SOMAVERT. 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. Systemic hypersensitivity reactions including anaphylactic reactions, laryngospasm, angioedema, generalized skin reactions (rash, erythema, pruritus, urticaria) have been reported in post-marketing use. Some patients required hospitalization. Symptoms did not re-occur in all patients after re-challenge [see Warnings and Precautions (5.5)]. Registry of Patients with Acromegaly Treated with SOMAVERT ACROSTUDY is an international observational registry that captures long term safety data in patients with acromegaly treated with SOMAVERT, as used in clinical practice. Treatment dose and schedule were at the discretion of each treating physician. Although safety monitoring as per the recommended schedule was mandatory, not all assessments were performed at all time points for every patient. Because of this, comparison of rates of adverse events to those in the original clinical trial is not appropriate. In an interim report, there were 1288 patients enrolled (mean duration of treatment 3.7 years). At the start of SOMAVERT treatment 648 patients were on SOMAVERT monotherapy for acromegaly. Of the 454 patients who had a normal AST and ALT at baseline, 4 patients had elevated tests >3 times ULN, two of whom had elevated tests >5 times ULN. Lipohypertrophy was reported in 6 (0.5%) patients. MRIs were compared to any previous ones, and a change in tumor volume was reported as significant locally only if the diameter increased by more than 3 mm for microadenomas or volume increased by more than 20% for macroadenomas. All MRI changes considered significant at the local reading were reanalyzed centrally. Of the 747 patients who had a MRI reported at baseline and at least once during follow up in the study, 51 (7%) were reported to have an increase by local MRI. Of these, 16 patients (2%) had confirmation of this increase, 6 patients had a decrease, 12 had "no change"; there was 1 with insufficient data and 16 patients did not have a central MRI reading.