6 ADVERSE REACTIONS
Clinically significant adverse reactions that appear in other section of the labeling include:
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- Hypoglycemia Associated with GH Lowering in Patients with Diabetes Mellitus [see Warnings and Precautions (5.1)]
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- Liver Toxicity [see Warnings and Precautions (5.2)]
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- Cross-Reactivity with GH Assays [see Warnings and Precautions (5.3)]
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- Lipohypertrophy [see Warnings and Precautions (5.4)]
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- 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.
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the 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.
| Placebo n=32 | SOMAVERT | |||
|---|---|---|---|---|
| 10 mg/day n=26 | 15 mg/day n=26 | 20 mg/day N=28 | ||
| ||||
Infection† | 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 Postmarketing Experience
Adverse Reactions from Postmarketing Spontaneous Reports
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)].
Adverse Reactions from an Observational Study
ACROSTUDY was an international observational registry that captured long term safety data in 2221 patients with acromegaly treated with SOMAVERT for a mean treatment duration of 8.5 years. Patients could also receive other therapy for acromegaly during the registry period. Treatment dose and schedule were at the discretion of each treating healthcare provider. 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. Of the 1327 patients who had a normal AST and ALT at baseline, 20 (1.5%) patients had elevated tests >3-5 times ULN, and 22 (1.7%) patients had elevated tests >5 times ULN. Lipohypertrophy was reported in 35 (1.6%) patients. Of the 1795 patients who had a MRI reported at baseline and at least once during follow up in the study, MRI results showed that 128 (7.1%) were reported to have an increase, 310 (17.3%) were reported to have a decrease, 81 (4.5%) had both increase and decrease, and 1276 (71.1%) had no change.