" Citing a lack of cardiovascular benefit, the FDA is taking the unusual step of withdrawing approvals it had previously given for use of niacin and fenofibric acid with statins to treat high cholesterol.
The decision affects niac"...
Mechanism Of Action
Inhibition of GH action results in decreased serum concentrations of IGF-I, as well as other GHresponsive serum proteins such as free IGF-I, the acid-labile subunit of IGF-I (ALS), and insulin-like growth factor binding protein-3 (IGFBP-3).
Pegvisomant binds selectively to the GH receptor, and does not cross-react with 19 other cytokine receptors tested, including prolactin. Pegvisomant leads to decreased serum concentrations of IGF-I, free IGF-I, ALS, and IGFBP-3 [see Clinical Studies (Figure 1)].
Following subcutaneous administration, peak serum pegvisomant concentrations are not generally attained until 33 to 77 hours after administration. The mean extent of absorption of a 20-mg subcutaneous dose was 57%, relative to a 10-mg intravenous dose.
The mean apparent volume of distribution of pegvisomant is 7 L (12% coefficient of variation), suggesting that pegvisomant does not distribute extensively into tissues. After a single subcutaneous administration, exposure (Cmax, AUC) to pegvisomant increases disproportionately with increasing dose. Mean ± SEM serum pegvisomant concentrations after 12 weeks of therapy with daily doses of 10, 15, and 20 mg were 6600 ± 1330; 16,000 ± 2200; and 27,000 ± 3100 ng/mL, respectively.
The relative bioavailability of 1 × 30 mg pegvisomant was compared to 2 × 15 mg pegvisomant in a single dose study. The AUCinf and Cmax of pegvisomant when administered as one injection of 30 mg strength was approximately 6% and 4% greater, respectively, as compared to when administered as two injections of 15 mg strengths.
Metabolism And Elimination
The pegvisomant molecule contains covalently bound polyethylene glycol polymers in order to reduce the clearance rate. Clearance of pegvisomant following multiple doses is lower than seen following a single dose. The mean total body systemic clearance of pegvisomant following multiple doses is estimated to range between 36 to 28 mL/h for subcutaneous doses ranging from 10 to 20 mg/day, respectively. Clearance of pegvisomant was found to increase with body weight. Pegvisomant is eliminated from serum with a mean half-life estimates ranging from 60 to 138 hours following either single or multiple doses. Less than 1% of administered drug is recovered in the urine over 96 hours. The elimination route of pegvisomant has not been studied in humans.
Drug Interaction Studies
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 [see DRUG INTERACTIONS].
No pharmacokinetic studies have been conducted in patients with renal impairment, patients with hepatic impairment, geriatric patients, or pediatric patients and the effects of race on the pharmacokinetics of pegvisomant has not been studied. No gender effect on the pharmacokinetics of pegvisomant was found in a population pharmacokinetic analysis.
A total of one hundred twelve patients (63 men and 49 women) with acromegaly participated in a 12- week, randomized, double-blind, multi-center study comparing placebo and SOMAVERT. The mean ±SD age was 48±14 years, and the mean duration of acromegaly was 8±8 years. Ninety three had undergone previous pituitary surgery, of which 57 had also been treated with conventional radiation therapy. Six patients had undergone irradiation without surgery, nine had received only drug therapy, and four had received no previous therapy. At study start, the mean ± SD time since the subjects' last surgery and/or irradiation therapy, respectively, was 6.8 ± 0.93 years (n=63) and 5.6 ± 0.57 years (n=93).
Subjects were qualified for enrollment if their serum IGF-I, drawn after the required drug washout period, was ≥ 1.3 times the upper limit of the age-adjusted normal range. They were randomly assigned at the baseline visit to one of four treatment groups: placebo (n=32), 10 mg/day (n=26), 15 mg/day (n= 26), or 20 mg/day (n=28) of SOMAVERT subcutaneouslyIGF-I. The primary efficacy endpoint was IGF-I percent change in IGF-I concentrations from baseline to week 12. The three groups that received SOMAVERT showed statistically significant (p < 0.01) reductions in serum levels of IGF-I compared with the placebo group (Table 4).
Table 4: Mean Percent Change from Bas eline in IGF-I
at Week 12 for Intentto- Treat Population
|Mean baseline IGF-I (ng/ml) (SD)||670 (288)||627 (251)||649 (293)||732 (205)|
|Mean percent change from baseline in IGF-I (SD)||-4.0 (17)||-27 (28)||-48 (26)||-63 (21)|
|SOMAVERT minus Placebo||-23*||-44*||-59*|
|(95% CI for treatment difference)||(-35, -11)||(-56, -33)||(-68, -49)|
|*P < 0.01; n=number of patients; SD = standard deviation|
There were also reductions in serum levels of free IGF-I, IGFBP-3, and ALS compared with placebo at all post-baseline visits (Figure 1).
Figure 1: Effects of SOMAVERT on Serum Markers (Mean ±
After 12 weeks of treatment, the following percentages of patients had normalized IGF-1 (Figure 2):
Figure 2: Percent of Patients Whos e IGF-I Levels
Normalized at Week 12
Table 5 shows the effect of treatment with SOMAVERT on ring size (standard jeweler's sizes converted to a numeric score ranging from 1 to 63), and on signs and symptoms of acromegaly. Each individual score for a sign or symptom of acromegaly (for soft-tissue swelling, arthralgia, headache, perspiration and fatigue) was based on a nine-point ordinal rating scale (0 = absent and 8 = severe and incapacitating), and the total score for signs or symptoms of acromegaly was derived from the sum of the individual scores. Mean baseline scores were as follows: ring size = 47.1; total signs and symptoms = 15.2; soft tissue swelling = 2.5; arthralgia = 3.2; headache = 2.4; perspiration = 3.3; and fatigue = 3.7.
Table 5: Mean Change from Bas eline (SD) at Week 12
for Ring Size and Signs and Symptoms of Acromegaly
|Ring size||-0.1 (2.3)||-0.8 (1.6)||-1.9 (2.0)||-2.5 (3.3)|
|Total score for signs and symptoms of acromegaly||1.3 (6.0)||-2.5 (4.3)||-4.4 (5.9)||-4.7 (4.7)|
|Soft-tissue swelling||0.3 (2.3)||-0.7 (1.6)||-1.2 (2.3)||-1.3 (1.3)|
|Arthralgia||0.1 (1.8)||-0.3 (1.8)||-0.5 (2.5)||-0.4 (2.1)|
|Headache||0.1 (1.7)||-0.4 (1.6)||-0.3 (1.4)||-0.3 (2.0)|
|Perspiration||0.1 (1.7)||-0.6 (1.6)||-1.1 (1.3)||-1.7 (1.6)|
|Fatigue||0.7 (1.5)||-0.5 (1.4)||-1.3 (1.7)||-1.0 (1.6)|
Serum growth hormone (GH) concentrations, as measured by research assays using antibodies that do not cross-react with pegvisomant, rose within two weeks of beginning treatment with SOMAVERT. The largest increase in GH concentration was seen in patients treated with doses of SOMAVERT 20 mg/day. This effect is presumably the result of diminished inhibition of GH secretion as IGF-I levels fall. As shown in Figure 3, when patients with acromegaly were given a loading dose of SOMAVERT followed by a fixed daily dose, the rise in GH was inversely proportional to the fall in IGF-I and generally stabilized by week 2. Serum GH concentrations remained stable in patients treated with SOMAVERT for the average of 43 weeks (range, 0–82 weeks).
Figure 3: Percent Change in Serum GH and IGF-I
In the open-label extension to the clinical study, 109 subjects (including 6 new patients) with mean treatment exposure of 42.6 weeks (range 1 day – 82 weeks), 93 (85.3%) subjects had an adverse event, 16 (14.7%) had an SAE, and 4 (3.7%) discontinued due to an AE (headaches, elevated liver function tests, pancreatic cancer, and weight gain). A total of 100 (92.6%) of the 108 subjects with available IGF-I data had a normal IGF-I concentration at any visit during the study.
Last reviewed on RxList: 6/7/2016
This monograph has been modified to include the generic and brand name in many instances.
Additional Somavert Information
Somavert - User Reviews
Somavert User Reviews
Now you can gain knowledge and insight about a drug treatment with Patient Discussions.
Report Problems to the Food and Drug Administration
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.
Find out what women really need.