Pegvisomant

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# Overview
Pegvisomant is a growth hormone receptor antagonist that is FDA approved for the treatment of acromegaly in patients who have had an inadequate response to surgery or radiation therapy, or for whom these therapies are not appropriate.   Common adverse reactions include infection, pain, nausea, diarrhea, abnormal liver tests, flu syndrome, injection site reaction.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- The recommended loading dose of SOMAVERT is 40 mg given subcutaneously, under healthcare provider supervision. Provide proper training in subcutaneous injection technique to patients or their caregivers so they can receive once daily subcutaneous injections. On the next day following the loading dose, instruct patients or their caregivers to begin daily subcutaneous injections of 10 mg of SOMAVERT.
- Titrate the dosage to normalize serum IGF-I concentrations (serum IGF-I concentrations should be measured every four to six weeks). The dosage should not be based on growth hormone (GH) concentrations or signs and symptoms of acromegaly. It is unknown whether patients who remain symptomatic while achieving normalized IGF-I concentrations would benefit from increased SOMAVERT dosage.
- Increase the dosage by 5 mg increments every 46 weeks if IGF-I concentrations are elevated.
- Decrease the dosage by 5 mg decrements every 46 weeks if IGF-I concentrations are below the normal range.
- IGF-I levels should also be monitored when a Somavert dose given in multiple injections is converted to a single daily injection.
- The recommended dosage range is between 10 to 30 mg given subcutaneously once daily and the maximum daily dosage is 30 mg given subcutaneously once daily.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pegvisomant in adult patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Pegvisomant in adult patients.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Pegvisomant in pediatric patients.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pegvisomant in pediatric patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Pegvisomant in pediatric patients.

# Contraindications
- None.

# Warnings

### Precautions
- Hypoglycemia associated with GH lowering in patients with Diabetes Mellitus
- GH opposes the effects of insulin on carbohydrate metabolism by decreasing insulin sensitivity; thus, glucose tolerance may improve in some patients treated with SOMAVERT. Patients should be carefully monitored and doses of anti-diabetic drugs reduced as necessary to avoid hypoglycemia in patients with diabetes mellitus.
- Liver Test Elevations
- Baseline serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), serum total bilirubin (TBIL), and alkaline phosphatase (ALP) levels should be obtained prior to initiating therapy with SOMAVERT. Table 1 lists recommendations regarding initiation of treatment with SOMAVERT, based on the results of these liver tests (LTs).
- Asymptomatic, transient elevations in transaminases up to 15 times ULN have been observed in < 2% of subjects among two open-label trials (with a total of 147 patients). These reports were not associated with an increase in bilirubin. Transaminase elevations normalized with time, most often after suspending treatment (SOMAVERT should be used in accordance with the information presented in Table 2 with respect to liver test abnormalities while on Somavert treatment).
- 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 2).
- Cross-Reactivity with GH Assays
- SOMAVERT has significant structural similarity to growth hormone (GH) which causes it to cross-react in commercially available GH assays. Since serum concentrations of therapeutically effective doses of SOMAVERT are generally 100 to 1000 times higher than the actual serum GH concentrations seen in patients with acromegaly, measurements of serum GH concentrations will appear falsely elevated.
- Lipohypertrophy
- There have been cases of lipohypertrophy in patients treated with SOMAVERT. In a double-blind, 12-week, placebo-controlled study, there was one case (1.3%) of injection site lipohypertrophy reported in a subject receiving 10 mg/day. The subject recovered while on treatment. Among two open-label trials (with a total of 147 patients), there were two subjects, both receiving 10 mg/day, who developed lipohypertrophy. One case recovered while on treatment, and one case resulted in a discontinuation of treatment. Injection sites should be rotated daily to help prevent lipohypertrophy (different area than the last injection).
- Systemic Hypersensitivity
- In subjects with systemic hypersensitivity reactions, caution and close monitoring should be exercised when re-initiating Somavert therapy.

# Adverse Reactions

## 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. 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.

## 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.
- 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.

# Drug Interactions
- Insulin and/or Oral hypoglycemic Agents
- After initiation of SOMAVERT, patients with acromegaly and diabetes mellitus treated with insulin and/or oral hypoglycemic agents may require dose reductions of insulin and/or oral hypoglycemic agents.
- Opioids
- In clinical studies, patients taking opioids often needed higher SOMAVERT doses to normalize IGF-I concentrations compared with patients not receiving opioids. The mechanism of this interaction is not known.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- There are no adequate and well-controlled studies in pregnant women. 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. Because animal reproduction studies are not always predictive of human responses, SOMAVERT should be used during pregnancy only if clearly needed.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Pegvisomant in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Pegvisomant during labor and delivery.

### 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.

### Geriatic Use
- Clinical studies of SOMAVERT did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. 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.

### Gender
There is no FDA guidance on the use of Pegvisomant with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Pegvisomant with respect to specific racial populations.

### Renal Impairment
There is no FDA guidance on the use of Pegvisomant in patients with renal impairment.

### Hepatic Impairment
There is no FDA guidance on the use of Pegvisomant in patients with hepatic impairment.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Pegvisomant in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Pegvisomant in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- Subcutaneous

### Monitoring
There is limited information regarding Monitoring of Pegvisomant in the drug label.

# IV Compatibility
There is limited information regarding IV Compatibility of Pegvisomant in the drug label.

# Overdosage

## Acute Overdose
- In one reported incident of acute overdose with SOMAVERT during pre-marketing clinical studies, a patient self-administered 80 mg/day (2.7 times the maximum recommended maintenance dosage) for seven days. The patient experienced a slight increase in fatigue, had no other complaints, and demonstrated no significant clinical laboratory abnormalities.
- In cases of overdose, administration of SOMAVERT should be discontinued and not resumed until IGF-I levels return to within or above the normal range.

## Chronic Overdose
There is limited information regarding Chronic Overdose of Pegvisomant in the drug label.

# Pharmacology

## Mechanism of Action
- Pegvisomant selectively binds to growth hormone (GH) receptors on cell surfaces, where it blocks the binding of endogenous GH, and thus interferes with GH signal transduction.
- Inhibition of GH action results in decreased serum concentrations of IGF-I, as well as other GH-responsive 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).

## Structure
- SOMAVERT contains pegvisomant, an analog of human growth hormone (GH) that has been structurally altered to act as a GH receptor antagonist.
- Pegvisomant is a protein of recombinant DNA origin containing 191 amino acid residues to which several polyethylene glycol (PEG) polymers are covalently bound (predominantly 4 to 6 PEG/protein molecule). The molecular weight of the protein of pegvisomant is 21,998 Daltons. The molecular weight of the PEG portion of pegvisomant is approximately 5000 Daltons. The predominant molecular weights of pegvisomant are thus approximately 42,000, 47,000, and 52,000 Daltons. The schematic shows the amino acid sequence of the pegvisomant protein (PEG polymers are shown attached to the 5 most probable attachment sites). Pegvisomant is synthesized by a specific strain of Escherichia coli bacteria that has been genetically modified by the addition of a plasmid that carries a gene for GH receptor antagonist. Biological potency is determined using a cell proliferation bioassay. Binding of Somavert to the GH receptor results in disruption of the proper binding of the second GH receptor with inhibition of functional receptor dimerization and subsequent intracellular signaling.
- SOMAVERT for injection is supplied as a sterile, white lyophilized powder intended for subcutaneous injection after reconstitution with 1 mL of Sterile Water for Injection. SOMAVERT is available in single-dose sterile vials containing 10, 15, 20, 25 or 30 mg of pegvisomant protein (approximately 10, 15, 20, 25 and 30 U activity, respectively). Each vial 10, 15 and 20 also contains 1.36 mg of glycine, 36.0 mg of mannitol, 1.04 mg of sodium phosphate dibasic anhydrous, and 0.36 mg of sodium phosphate monobasic monohydrate. Each 25 mg vial also contains 1.7 mg of glycine, 46.1 mg of mannitol, 1.3 mg of sodium phosphate dibasic anhydrous, and 0.5 mg of sodium phosphate monobasic monohydrate. Each 30 mg vial also contains 2.1 mg of glycine, 56.5 mg of mannitol, 1.6 mg of sodium phosphate dibasic anhydrous, and 0.6 mg of sodium phosphate monobasic monohydrate.
- SOMAVERT is supplied in packages that include a vial containing diluent. Sterile Water for Injection, USP, is a sterile, nonpyrogenic preparation of water for injection that contains no bacteriostat, antimicrobial agent, or added buffer, and is supplied in single-dose containers to be used as a diluent.

## Pharmacodynamics
- 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.

## Pharmacokinetics
- Absorption: 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.
- Distribution: 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.
- Specific Populations
- 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.

## Nonclinical Toxicology
- Carcinogenesis
- Pegvisomant was administered subcutaneously to rats daily for 2 years at doses of 2, 8 and 20 mg/kg (about 2, 10 and 25-fold a single 20 mg dose in humans on an AUC basis). Long term treatment with pegvisomant at 8 and 20 mg/kg caused an increase in malignant fibrous histiocytoma at injection sites in males. Injection site tumors were not seen in female rats at the same doses. The increased incidence of injection site tumors was most probably caused by irritation and the high sensitivity of the rat to repeated subcutaneous injections.
- Mutagenesis
- Pegvisomant did not cause genetic damage in standard in vitro assays (bacterial mutation, human lymphocyte chromosome aberration).
- Impairment of Fertility
- Pegvisomant was found to have no effect on fertility or reproductive performance of female rabbits at subcutaneous doses up to 10 mg/kg/day (10-fold the recommended human dose on a body surface area basis).

# Clinical Studies
- 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 4814 years, and the mean duration of acromegaly was 88 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-Ipercent change in IGF-I concentrations from baseline to week 12. The three groups that received SOMAVERT showed statistically.
- 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).
- After 12 weeks of treatment, the following percentages of patients had normalized IGF-1 (Figure 2):
- 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.
- 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, 082 weeks).
- 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.

# How Supplied
- SOMAVERT (pegvisomant) is supplied in the following strengths and package configurations:
- Each package of SOMAVERT also includes a single-dose vial containing Sterile Water for Injection, USP.
- Storage
- Prior to reconstitution, SOMAVERT should be stored in a refrigerator at 2 to 8C (36 to 46F). Do not freeze.

## Storage
There is limited information regarding Pegvisomant Storage in the drug label.

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
- Inform patients (and/or their caregivers) of the following information to aid in the safe and effective use of SOMAVERT:
- Not to use SOMAVERT if they are allergic to SOMAVERT or anything in it.
- They will need blood testing to check IGF-I levels and liver tests before and during treatment with SOMAVERT and that the dose of SOMAVERT may be changed based on the results of these tests
- SOMAVERT has not been studied in pregnant women and instruct them to notify their healthcare provider as soon as they are aware that they are pregnant.
- It is not known whether SOMAVERT is excreted in human milk and instruct them to notify their healthcare provider if they plan to do so.
- Advise patients (and/or their caregivers) of the following adverse reactions:
- The most common reported adverse reactions are injection site reaction, elevations of liver tests, pain, nausea, and diarrhea.
- If they have liver test elevations they may need to have more frequent liver tests and/or discontinue SOMAVERT. Instruct patients to immediately discontinue therapy and contact their physician if they become jaundiced.
- GH-secreting tumors may enlarge in people with acromegaly and that these tumors need to be watched carefully and monitored by MRI imaging.
- Thickening under the skin may occur at the injection site that could lead to lumps and that switching sites may prevent or lessen this.
- If they have diabetes mellitus, they may require careful monitoring and dose reductions of insulin and/or oral hypoglycemic agents while on SOMAVERT.
- If they take opioids, they may need higher SOMAVERT doses to achieve appropriate IGF-I suppression.
- Advise patients that SOMAVERT is supplied as lyophilized powder in different strengths of 10 mg, 15 mg, 20 mg, 25 mg, and 30 mg in a sterile glass vial within a package also containing a single-dose flip top vial of sterile water (diluent) for injection. Advise patients that the stoppers on both vials are not made with natural rubber latex. Advise patients to follow the directions for reconstitution provided with each package including shaking may cause denaturation (destruction) of the active ingredient (therefore do not shake).
- Advise patients that the package of SOMAVERT should be stored in a refrigerator 2 to 8C (36 to 46F) prior to use. It should NOT BE FROZEN.

# Precautions with Alcohol
- Alcohol-Pegvisomant interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
- SOMAVERT

# Look-Alike Drug Names
There is limited information regarding Pegvisomant Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price