These highlights do not include all the information needed to use SOMAVERT safely and effectively. See full prescribing information for SOMAVERT.SOMAVERT (pegvisomant) for injection, for subcutaneous use Initial U.S. Approval: 2003

1 INDICATIONS AND USAGE

SOMAVERT is indicated 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. The goal of treatment is to normalize serum insulin-like growth factor-1 (IGF-1) levels.

2 DOSAGE AND ADMINISTRATION

2.1 Dosage 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-1 concentrations (serum IGF-1 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-1 concentrations would benefit from increased SOMAVERT dosage.

The recommended dosage range is between 10 mg to 30 mg given subcutaneously once daily and the maximum daily dosage is 30 mg given subcutaneously once daily.

• •Increase the dosage by 5 mg increments every 4–6 weeks if IGF-1 concentrations are elevated.
• •Decrease the dosage by 5 mg decrements every 4–6 weeks if IGF-1 concentrations are below the normal range.
• •IGF-1 levels should also be monitored when a SOMAVERT dose given in multiple injections is converted to a single daily injection [see Clinical Pharmacology (12)].

2.2 Assess Liver Tests Prior to Initiation of SOMAVERT

Prior to the start of SOMAVERT, patients should have an assessment of baseline levels of liver tests [serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), serum total bilirubin (TBIL), and alkaline phosphatase (ALP)]. For recommendations regarding initiation of SOMAVERT based on baseline liver tests and recommendations for monitoring of liver tests while on SOMAVERT, refer to Table 1 in Warning and Precautions (5.2).

2.3 Loading Dose Injection Procedure

The following instructions are for the healthcare provider to reconstitute and prepare the 40 mg loading dose. The healthcare provider will need to reconstitute 2 vials of lyophilized powder of SOMAVERT each containing 20 mg of pegvisomant with supplied diluent [two vials of lyophilized powder and two syringes containing 1 mL of diluent (Sterile Water for Injection, USP) will be needed for the 40 mg loading dose]. The healthcare provider will also need to inject the reconstituted SOMAVERT solution twice into the patient's upper arm, upper thigh, abdomen, or buttocks (each injection in a different area).

• a)Before administering the loading dose, remove 1 vial of lyophilized powder of SOMAVERT containing 20 mg of pegvisomant and one syringe containing 1 mL of diluent from the refrigerator, if refrigerated, about 10 minutes prior to the planned injection time.
• b)Reconstitute the first 20 mg vial of lyophilized powder of SOMAVERT containing 20 mg of pegvisomant with diluent. When using the diluent in the syringe, inject the contents of the syringe slowly onto the sides of the vial containing lyophilized powder of SOMAVERT. Do not inject the diluent directly on the powder.
• c)Do not invert the vial or shake the solution as this may cause denaturation of the pegvisomant protein. Slowly swirl the solution to ensure that all of the lyophilized powder has gone into solution. If foaming of the reconstituted SOMAVERT solution is seen, the solution is likely damaged and therefore inappropriate to inject.
• d)Visually inspect the reconstituted SOMAVERT solution for particulate matter and discoloration prior to administration. The reconstituted solution should be clear. If the solution is cloudy, do not use it. Once reconstituted, the solution will contain 20 mg of pegvisomant in 1 mL of solution.
• e)Withdraw the 1 mL reconstituted SOMAVERT solution. The solution must be administered immediately after reconstitution.
• f)Inject the first reconstituted SOMAVERT solution (20 mg/mL) subcutaneously into the patient's upper arm, upper thigh, abdomen, or buttocks using a 90-degree angle.
• g)Repeat steps (a) to (e) to reconstitute the second SOMAVERT dose of 20mg.
• h)Finally, inject the second reconstituted SOMAVERT solution (20 mg/mL) subcutaneously into the patient's upper arm, upper thigh, abdomen, or buttocks using a 90-degree angle (different area than the first injection).

2.4 Maintenance Dose Injection Procedure

For patient or caregiver instructions for reconstitution and administration of daily doses (10 mg to 30 mg), see the Patient's Instructions for Use.

• a)Before administering the dose, remove 1 vial of lyophilized powder of SOMAVERT containing 10 mg, 15 mg, 20 mg, 25 mg or 30 mg of pegvisomant and one syringe containing 1 mL of diluent from the refrigerator, if refrigerated, about 10 minutes prior to the planned injection time.
• b)Reconstitute the lyophilized powder of SOMAVERT with diluent. When using the diluent in the 2.25 mL syringe, inject the contents of the syringe slowly onto the sides of the vial containing lyophilized powder of SOMAVERT. Do not inject the diluent directly on the powder.
• c)Do not invert the vial or shake the solution as this may cause denaturation of the pegvisomant protein. Slowly swirl the solution to ensure that all of the lyophilized powder has gone into solution. If foaming of the reconstituted SOMAVERT solution is seen, the solution is likely damaged and therefore inappropriate to inject.
• d)Visually inspect the reconstituted SOMAVERT solution for particulate matter and discoloration prior to administration. The reconstituted solution should be clear. If the solution is cloudy, do not use it. Once reconstituted, the solution will contain 10 mg, 15 mg, 20 mg, 25 mg or 30 mg of pegvisomant in 1 mL of solution.
• e)Withdraw the 1 mL reconstituted SOMAVERT solution. The solution must be administered immediately after reconstitution.
• f)Inject the reconstituted SOMAVERT solution subcutaneously into the upper arm, upper thigh, abdomen, or buttocks using a 90-degree angle.

3 DOSAGE FORMS AND STRENGTHS

For injection: 10 mg, 15 mg, 20 mg, 25 mg or 30 mg white lyophilized powder in a single-dose vial for reconstitution supplied with a prefilled syringe containing 1 mL of diluent (Sterile Water for Injection, USP).

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 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.

5.2 Liver Toxicity

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. Postmarketing reports have identified elevations in serum hepatic transaminases up to greater than 20 times ULN associated with elevation in total bilirubin greater than 2 times ULN. In many of these cases, discontinuation of SOMAVERT therapy resulted in improvement or resolution of hepatic laboratory abnormalities.

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).

Table 2. Clinical Recommendations Based on Liver Test Results While on SOMAVERT

5.3 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.

5.4 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).

5.5 Systemic Hypersensitivity

In patients with systemic hypersensitivity reactions, caution and close monitoring should be exercised when re-initiating SOMAVERT therapy [see Adverse Reactions (6.2)].

6 ADVERSE REACTIONS

Clinically significant adverse reactions that appear in other section of the labeling include:

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.

• •Hypoglycemia Associated with GH Lowering in Patients with Diabetes Mellitus [see Warnings and Precautions (5.1)]
• •Liver Toxicity [see Warnings and Precautions (5.2)]
• •Cross-Reactivity with GH Assays [see Warnings and Precautions (5.3)]
• •Lipohypertrophy [see Warnings and Precautions (5.4)]
• •Systemic Hypersensitivity [see Warnings and Precautions (5.5)]

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.

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)].

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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.

7 DRUG INTERACTIONS

7.1 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 [see Warnings and Precautions (5.1)].

7.2 Opioids

In clinical studies, patients taking opioids often needed higher SOMAVERT doses to normalize IGF-1 concentrations compared with patients not receiving opioids. The mechanism of this interaction is not known.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

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Risk Summary

Postmarketing reports of SOMAVERT use in pregnant women are insufficient to establish a drug-associated risk for major birth defects, miscarriage or adverse maternal or fetal outcomes. Acromegaly may improve during pregnancy (see Clinical Considerations). In animal reproduction studies, fetotoxicity was observed at a dose that was 6 times the maximum recommended human dose based on body surface area following subcutaneous administration of pegvisomant during organogenesis or during the preimplantation period (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.

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Clinical Considerations

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Disease-associated maternal and/or embryofetal risk

Published data from case reports, case series, and a small interventional study in pregnant women with acromegaly have demonstrated that acromegaly may improve or stabilize without treatment during pregnancy, particularly if acromegaly is treated before pregnancy. In rare cases, acromegaly may worsen during pregnancy. Since IGF-1 levels may change physiologically during pregnancy and interpreting IGF-1 and growth hormone levels in pregnant women with acromegaly may be unreliable, clinical monitoring is recommended.

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Data

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Animal Data

The effects of pegvisomant on early embryonic development and embryo-fetal development were evaluated in two separate studies, which 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 administration during organogenesis. At the 10-mg/kg/day dose (6 times the maximum human therapeutic dose based on body surface area), a reproducible, slight increase in post-implantation loss was observed in both studies.

8.2 Lactation

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Risk Summary

Limited information from a case report in published literature reported that the level of pegvisomant in human milk was below the level of detection. There is no information available on the effects of the drug on the breastfed infant or the effects of the drug on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for SOMAVERT and any potential adverse effects on the breastfed child from SOMAVERT or from the underlying maternal condition.

8.3 Females and Males of Reproductive Potential

Discuss the potential for unintended pregnancy with premenopausal women as the therapeutic benefits of a reduction in growth hormone (GH) levels and normalization of insulin-like growth factor 1 (IGF-1) concentration in acromegalic females treated with pegvisomant may lead to improved fertility.

8.4 Pediatric Use

The safety and effectiveness of SOMAVERT in pediatric patients have not been established.

8.5 Geriatric 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.

8.6 Renal Impairment

SOMAVERT was not studied in patients with renal impairment and the safety and efficacy in these patients is not known.

10 OVERDOSAGE

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-1 levels return to within or above the normal range.

11 DESCRIPTION

Pegvisomant is an analog of human growth hormone (GH) of recombinant DNA origin that acts as a GH receptor antagonist.

It contains 191 amino acid residues. The molecular weight of pegvisomant is 22 kDa. The molecular weight of the PEG portion of pegvisomant is approximately 5 kDa. The predominant molecular weights of pegvisomant are thus approximately 42, 47, and 52 kDa. 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.

Shown below are the amino acid substitutions in pegvisomant, relative to human GH.

SOMAVERT (pegvisomant) for injection is a sterile, white lyophilized powder intended for subcutaneous injection after reconstitution. SOMAVERT is supplied in packages that include a single-dose prefilled syringe containing 1 mL of Sterile Water for Injection, USP, that is a sterile, nonpyrogenic preparation of water for injection that contains no bacteriostat, antimicrobial agent, or added buffer, to be used as a diluent.

SOMAVERT is available in single-dose sterile vials containing 10 mg, 15 mg, 20 mg, 25 mg or 30 mg of pegvisomant. SOMAVERT 10 mg, 15 mg, and 20 mg vials also contain glycine (1.36 mg), mannitol (36 mg), sodium dihydrogen phosphate monohydrate (0.36 mg), and sodium phosphate dibasic anhydrous (1.04 mg). After reconstitution with 1 mL of Water for Injection, USP, the resulting concentration is 10 mg/mL, 15 mg/mL and 20 mg/mL, respectively, with a pH of 7.1 – 7.7.

SOMAVERT 25 mg vial also contains glycine (1.7 mg), mannitol (45 mg), sodium dihydrogen phosphate monohydrate (0.45 mg), and sodium phosphate dibasic anhydrous (1.3 mg). After reconstitution with 1 mL of Water for Injection, USP, the resulting concentration is 25 mg/mL with a pH of 7.1 – 7.7.

SOMAVERT 30 mg vial also contains glycine (2.04 mg), mannitol (54 mg), sodium dihydrogen phosphate monohydrate (0.54 mg), and sodium phosphate dibasic anhydrous (1.56 mg). After reconstitution with 1 mL of Water for Injection, USP, the resulting concentration is 30 mg/mL with a pH of 7.1 – 7.7.

12 CLINICAL PHARMACOLOGY

12.1 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-1, as well as other GH-responsive serum proteins such as free IGF-1, the acid-labile subunit of IGF-1 (ALS), and insulin-like growth factor binding protein-3 (IGFBP-3).

12.2 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-1, free IGF-1, ALS, and IGFBP-3 [see Clinical Studies (14, Figure 1)].

12.3 Pharmacokinetics

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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.

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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.

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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.

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Drug Interaction Studies

In clinical studies, patients on opioids often needed higher serum pegvisomant concentrations to achieve appropriate IGF-1 suppression compared with patients not receiving opioids. The mechanism of this interaction is not known [see Drug Interactions (7.2)].

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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.

12.6 Immunogenicity

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of SOMAVERT or other growth hormone analogs.

In pre-marketing clinical studies, approximately 17% of the SOMAVERT-treated patients developed low titer, non‑neutralizing anti-GH antibodies. Although the presence of these antibodies did not appear to impact the efficacy of SOMAVERT, the long term clinical significance of these antibodies is not known. No assay for anti-pegvisomant antibodies is commercially available for patients receiving SOMAVERT.

The data above reflect the percentage of patients whose test results were considered positive for antibodies to SOMAVERT. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to SOMAVERT with the incidence of antibodies to other products may be misleading.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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Carcinogenesis

Pegvisomant was administered subcutaneously to rats daily for 2 years at doses of 2, 8, and 20 mg/kg (about 2, 9, and 22-fold a single 30 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.

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Mutagenesis

Pegvisomant did not cause genetic damage in standard in vitro assays (bacterial mutation, human lymphocyte chromosome aberration).

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Impairment of Fertility

Fertility studies have not been conducted with pegvisomant.

14 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 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-1, 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 subcutaneously IGF-1. The primary efficacy endpoint was IGF-1 percent change in IGF-1 concentrations from baseline to week 12. The three groups that received SOMAVERT showed statistically significant (p<0.01) reductions in serum levels of IGF-1 compared with the placebo group (Table 4).

There were also reductions in serum levels of free IGF-1, IGFBP-3, and ALS compared with placebo at all post-baseline visits (Figure 1).

Figure 1. Effects of SOMAVERT on Serum Markers (Mean ± Standard Error)

After 12 weeks of treatment, the following percentages of patients had normalized IGF-1 (Figure 2):

Figure 2. Percent of Patients Whose IGF-1 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.

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-1 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-1 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-1 Concentrations

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-1 data had a normal IGF-1 concentration at any visit during the study.

16 HOW SUPPLIED/STORAGE AND HANDLING

SOMAVERT (pegvisomant) for injection is a white lyophilized powder supplied in the following strengths and package configurations:

STORAGE AND HANDLING SECTION

Storage

Prior to reconstitution:

Discard the SOMAVERT vial(s) after the expiration date printed on the carton or the discard date, whichever is sooner.

The prefilled syringe(s) may be stored at a temperature up to 30°C (86°F) until the expiration date printed on the carton, at which point they should be discarded.

Do not freeze.

• •The One Day Package of SOMAVERT should be stored in a refrigerator at 2°C to 8°C (36°F to 46°F).
• •For the 30-Day Package, remove the three intermediate cartons containing the SOMAVERT vials and store in a refrigerator at 2°C to 8°C (36°F to 46°F).
• •For convenience, the One Day Package and intermediate cartons in the 30-Day Package containing the SOMAVERT vial(s), may be stored at room temperature up to 25°C (77°F) for a single period of up to 30 days. oIn the space provided on the carton, record the date when the carton was removed from the refrigerator and the discard date (30 days after removal from the refrigerator).oOnce the carton has been stored at room temperature, it should not be placed back into the refrigerator. If not used within 30 days at room temperature, the vial(s) should be discarded.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

Inform patients (and/or their caregivers) of the following information to aid in the safe and effective use of SOMAVERT:

Advise patients (and/or their caregivers) of the following adverse reactions:

Inform patients (and/or their caregivers) about the storage options prior to reconstitution of the product [see How Supplied/Storage and Handling (16)].

Advise patients to follow the directions for reconstitution provided in the Instructions for Use. Include that spraying the diluent directly onto the powder may cause foaming and that shaking may induce denaturation (destruction) of the active ingredient (therefore do not shake).

U.S. License No. 1216

This product's labeling may have been updated. For the most recent prescribing information, please visit www.pfizer.com.

LAB-0782-4.0

• •Not to use SOMAVERT if they are allergic to SOMAVERT or anything in it.
• •They will need blood testing to check IGF-1 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.
• •Pregnancy: Inform female patients that treatment with SOMAVERT may result in unintended pregnancy [see Females and Males of Reproductive Potential (8.3)].

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INSTRUCTIONS FOR USE

SOMAVERT® (SOM-ah-vert)(pegvisomant)for injection, for subcutaneous use

Read these Instructions for Use before you start using SOMAVERT and each time you get a refill. There may be new information. This leaflet does not take the place of talking to your healthcare provider about your medical condition or your treatment. Your healthcare provider should show you or a caregiver how to inject SOMAVERT the right way before you inject it for the first time.

SOMAVERT is available in two types of packaging:

Important:

Step 1. Things you need

You will also need:

Step 2. Getting ready

Before you start:

Step 3. Choose injection area

Step 4. Remove vial cap

Step 5. Remove syringe cap

Step 6. Attach safety needle

Step 7. Remove needle cover

Step 8. Insert needle

Step 9. Add liquid

Step 10. Swirl vial

Step 11. Check medicine

Step 12. Reposition needle

Step 13. Draw off dose

Step 14. Insert needle

Step 15. Inject medicine

Step 16. Make needle safe

Step 17. Dispose

Step 18. After injection

QUESTIONS AND ANSWERS

What should I do if anything has accidentally touched the vial stopper?

What should I do with the syringe if it has been dropped?

How many times can I safely insert the needle into the vial stopper?

Is it okay to shake the vial if the powder is not dissolving?

How can I tell if there is any foam in the vial?

How can I prevent the medicine from foaming?

I can see some air in the syringe. Is this okay?

Why can I not get all of the medicine out of the vial?

What should I do if I have any doubts about my medicine?

Safe syringe disposal information

If you do not have a FDA-cleared sharps disposal container, you may use a household container that is:

When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes.

For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA's website at: http://www.fda.gov/safesharpdisposal

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

U.S. License No. 1216LAB-0784-3.0Revised: July 2023

• •One Day Package (containing one single-dose vial of SOMAVERT powder, a prefilled syringe, and a safety needle)
• •30-Day Package (containing three intermediate cartons of 10 single-dose vials of SOMAVERT powder, 30 prefilled syringes, and 30 safety needles)
• •Before you mix the SOMAVERT powder and the liquid:oStore SOMAVERT in a refrigerator at 36 ºF to 46 ºF (2 ºC to 8 ºC).oThe One Day Package and intermediate cartons in the 30-Day Package containing the SOMAVERT vials, may be stored at room temperature up to 77°F (25°C) for a single period of up to 30 days. oIn the space provided on the carton, record the date when the carton was removed from the refrigerator and the discard date (30 days after removal from the refrigerator). oAfter the carton has been stored at room temperature, it should not be placed back into the refrigerator. If not used within 30 days at room temperature, the vials should be thrown away.
• •Throw away the SOMAVERT vials after the expiration date printed on the carton or the discard date, whichever is sooner.
• •The prefilled syringes may be stored at a temperature up to 86°F (30°C) until the expiration date printed on the carton. After that time, they should be thrown away.
• •Do not freeze SOMAVERT.