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 antiacromegalic
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 improve
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 antidiabetic 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 aminotransferase (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).
Table 3. Initiation of Treatment with SOMAVERT Based on Results of Liver Tests
If a patient develops LT elevations, or any other signs or symptoms of liver dysfunction
while receiving SOMAVERT, the following patient management is recommended (Table
4).
Table 4. Continuation of Treatment with SOMAVERT Based on Results of Liver Tests
Lipohypertrophy
Lipohypertrophy has been reported in <5% of patients following pegvisomant administration.
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.
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 improve 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.