PRECAUTIONS
GENERAL
Tumor Growth: Tumors that secrete growth hormone (GH) may expand and cause serious complications. Therefore, all patients with these tumors, including those who are receiving SOMAVERT, should be carefully monitored with periodic imaging scans of the sella turcica. During clinical studies of SOMAVERT, two patients manifested progressive tumor growth. Both patients had, at baseline, large globular tumors impinging on the optic chiasm, which had been relatively resistant to previous anti-acromegalic therapies. Overall, mean tumor size was unchanged during the course of treatment with SOMAVERT in the clinical studies. Glucose Metabolism: GH opposes the effects of insulin on carbohydrate metabolism by decreasing insulin sensitivity; thus, glucose tolerance may increase in some patients treated with SOMAVERT. Although none of the acromegalic patients with diabetes mellitus who were treated with SOMAVERT during the clinical studies had clinically relevant hypoglycemia, these patients should be carefully monitored and doses of anti-diabetic drugs reduced as necessary. GH Deficiency: A state of functional GH deficiency may result from administration of SOMAVERT, despite the presence of elevated serum GH levels. Therefore, during treatment with SOMAVERT, patients should be carefully observed for the clinical signs and symptoms of a GH-deficient state, and serum IGF-I concentrations should be monitored and maintained within the age-adjusted normal range (by adjustment of the dose of SOMAVERT).
LIVER TESTS (LTS)
Elevations of serum concentrations of alanine amino-transferase (ALT) and aspartate aminotransferase (AST) greater than 10 times the upper limit of normal (ULN) were reported in two patients (0.8%) exposed to SOMAVERT during pre-marketing 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.
During the pre-marketing clinical studies, the incidence of elevations in ALT greater than 3 times but less than or equal to 10 times the ULN in patients treated with SOMAVERT and placebo were 1.2% and 2.1%, respectively.
Elevations in ALT and AST levels were not associated with increased levels of serum total bilirubin (TBIL) and alkaline phosphatase (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.
Baseline serum ALT, AST, TBIL, and ALP levels should be obtained prior to initiating therapy with SOMAVERT. Table 3 lists recommendations regarding initiation of treatment with SOMAVERT, based on the results of these liver tests (LTs).
If a patient develops LT elevations, or any other signs or symptoms of liver dysfunc tion while receiving SOMAVERT, the following patient management is recommended (Table 4).
INFORMATION FOR PATIENTS
Patients and any other persons who may administer SOMAVERT should be carefully instructed by a health care professional on how to properly reconstitute and inject the product (see enclosed instructions).
Patients should be informed about the need for serial monitoring of LTs, and told to immediately discontinue therapy and contact their physician if they become jaundiced. In addition, patients should be made aware that serial IGF-I levels will need to be obtained to allow their physician to properly adjust the dose of SOMAVERT.
Table 3. Initiation of Treatment with SOMAVERT Based on Results of Liver Tests
| Baseline LT Levels |
Recommendations |
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Normal
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May treat with SOMAVERT. Monitor LTs at monthly intervals during the first 6 months of treatment, quarterly for the next 6 months, and then biannually for the next year.
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Elevated, but less than or equal to
3 times ULN
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May treat with SOMAVERT; however, monitor LTs monthly for at least one year after initiation of therapy and then biannually for the next year.
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Greater than 3 times ULN
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Do not treat with SOMAVERT until a comprehensive workup establishes the cause of the patient's liver dysfunction. Determine if cholelithiasis or choledocholithiasis is present, particularly in patients with a history of prior therapy with somatostatin analogs. Based on the workup, consider initiation of therapy with SOMAVERT. If the decision is to treat, LTs and clinical symptoms should be monitored very closely.
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Table 4. Continuation of Treatment with SOMAVERT Based on Results of Liver Tests
| LT Levels and Clinical Signs/Symptoms |
Recommendations |
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Greater than or equal to 3 but less than 5 times ULN (without signs/symptoms of hepatitis or other liver injury, or increase in serum TBIL)
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May continue therapy with SOMAVERT. However, monitor LTs weekly to determine if further increases occur (see below). In addition, perform a comprehensive hepatic workup to discern if an alternative cause of liver dysfunction is present.
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At least 5 times ULN, or transaminase elevations at least 3 times ULN associated with any increase in serum TBIL (with or without signs/symptoms of hepatitis or other liver injury)
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Discontinue SOMAVERT immediately. Perform a comprehensive hepatic workup, including serial LTs, to determine if and when serum levels return to normal. If LTs normalize (regardless of whether an alternative cause of the liver dysfunction is discovered), consider cautious reinitiation of therapy with SOMAVERT, with frequent LT monitoring.
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Signs or symptoms suggestive of hepatitis or other liver injury (e.g., jaundice, bilirubinuria, fatigue, nausea, vomiting, right upper quadrant pain, ascites, unexplained edema, easy bruisability)
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Immediately perform a comprehensive hepatic workup. If liver injury is confirmed, the drug should be discontinued.
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LABORATORY TESTS
Liver Tests: Recommendations for monitoring LTs are stated above (see PRECAUTIONS, Liver Tests [LTs]).
IGF-I Levels: Treatment with SOMAVERT should be evaluated by monitoring serum IGF-I concentrations four to six weeks after therapy is initiated or any dose adjustments are made and at least every six months after IGF-I levels have normalized. The goals of treatment should be to maintain a patient's serum IGF-I concentration within the age-adjusted normal range and to control the signs and symptoms of acromegaly.
GH Levels: Pegvisomant interferes with the measurement of serum GH concentrations by commercially available GH assays (see Drug/Laboratory Test Interactions). Furthermore, even when accurately determined, GH levels usually increase during therapy with SOMAVERT. Therefore, treatment with SOMAVERT should not be adjusted based on serum GH concentrations.
DRUG INTERACTIONS
Acromegalic patients with diabetes mellitus being treated with insulin and/or oral hypoglycemic agents may require dose reductions of these therapeutic agents after the initiation of therapy with SOMAVERT.
In clinical studies, patients on opioids often needed higher serum pegvisomant concentrations to achieve appropriate IGF-I suppression compared with patients not receiving opioids. The mechanism of this interaction is not known.
DRUG/LABORATORY TEST INTERACTIONS
Pegvisomant has significant structural similarity to GH, which causes it to cross-react in commercially available GH assays. Because serum concentrations of pegvisomant at therapeutically effective doses are generally 100 to 1000 times higher than endogenous serum GH levels seen in patients with acromegaly, commercially available GH assays will overestimate true GH levels. Treatment with SOMAVERT should therefore not be monitored or adjusted based on serum GH concentrations reported from these assays. Instead, monitoring and dose adjustments should only be based on serum IGF-I levels.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
Standard two-year rodent bioassays have not been performed with pegvisomant. Pegvisomant was not mutagenic in the Ames assay or clastogenic in the in vitro chromosomal aberration test in human lymphocytes. Pegvisomant was found to have no effect on fertility and reproductive performance of female rabbits at subcutaneous doses up to 10 mg/kg/day (10 times the maximum human therapeutic exposure based on body surface area, mg/m2).
PREGNANCY: PREGNANCY CATEGORY B
Early embryonic development and teratology studies were conducted in pregnant rabbits with pegvisomant at subcutaneous doses of 1, 3, and 10 mg/kg/day.There was no evidence of teratogenic effects associated with pegvisomant treatment during organogenesis. At the 10-mg/kg/day dose (10 times the maximum human therapeutic dose based on body surface area), a reproducible, slight increase in post-implantation loss was observed in both studies. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human responses, SOMAVERT should be used during pregnancy only if clearly needed.
NURSING MOTHERS
It is not known whether pegvisomant is excreted in human milk. Because many drugs are excreted in milk, caution should be exercised when SOMAVERT is administered to a nursing woman.
PEDIATRIC USE
The safety and effectiveness of SOMAVERT in pediatric patients have not been established.
GERIATRIC USE
Clinical studies of SOMAVERT did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
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