Somavert

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SOMAVERT (SOMAVERT)

Composition:

Active substance: pegvisomant;

1 vial contains 10 mg, 15 mg, 20 mg, or 30 mg of pegvisomant;

Excipients: glycine, mannitol (E 421), sodium hydrogen phosphate anhydrous, sodium dihydrogen phosphate monohydrate.

1 pre-filled syringe with solvent contains water for injections.

Pharmaceutical form. Lyophilisate and solvent for solution for injection.

Main physicochemical properties: lyophilized mass of white to almost white color.

Pharmacotherapeutic group. Other hormones of the anterior pituitary and their analogues. Pegvisomant. ATC code H01AX01.

Pharmacological Properties

Description

Somavert contains pegvisomant, an analogue of human growth hormone that has been structurally modified to act as a growth hormone receptor antagonist.

Pegvisomant is a protein produced by recombinant DNA technology, consisting of a 191-amino acid residue to which several polyethylene glycol (PEG) polymers are covalently attached (predominantly 4–6 PEG molecules per protein). The molecular mass of the pegvisomant protein moiety is 21,998 daltons. The molecular mass of the PEG portion of pegvisomant is approximately 5,000 daltons. Thus, the predominant molecular mass of pegvisomant ranges approximately from 42,000 to 47,000 and up to 52,000 daltons. Pegvisomant is produced by a specific strain of Escherichia coli bacteria genetically modified by introduction of a plasmid carrying the gene for the growth hormone receptor antagonist. Biological activity is determined by a cell proliferation bioassay. Binding of Somavert to the growth hormone receptor disrupts proper interaction with a second growth hormone receptor, thereby inhibiting functional receptor dimerization and subsequent intracellular signaling pathways.

Pharmacodynamics

Pegvisomant selectively binds to the growth hormone receptor on the cell surface and has no cross-reactivity with 19 other cytokine receptors tested, including prolactin. Pegvisomant leads to a reduction in serum concentrations of insulin-like growth factor I (IGF-1), free IGF-1, acid-labile subunit (ALS), and insulin-like growth factor binding protein type 3 (IGFBP-3) (see below "Clinical Studies", Fig. 1).

Mechanism of Action

Pegvisomant selectively binds to growth hormone receptors on the cell surface, blocking the binding of endogenous growth hormone and thereby preventing growth hormone signal transduction.

Inhibition of growth hormone activity results in decreased serum concentrations of IGF-1, as well as other serum proteins sensitive to growth hormone, such as free IGF-1, acid-labile subunit of IGF-1, and IGFBP-3.

Clinical Studies

A total of 112 patients (63 men and 49 women) with acromegaly participated in a 12-week, randomized, double-blind, multicenter study comparing placebo and Somavert. The mean age ± standard deviation (SD) was 48 ± 14 years, and the mean duration of acromegaly was 8 ± 8 years. Of these patients, 93 had previously undergone pituitary surgery, with 57 of them also receiving standard radiation therapy. Six patients received radiation therapy without prior surgery, 9 received only medical therapy, and 4 patients had not received any prior treatment. At study initiation, the mean time ± SD since the last surgery and/or radiation therapy was 6.8 ± 0.93 years (n = 63) and 5.6 ± 0.57 years (n = 93), respectively.

Patients were eligible for inclusion in the study if their serum IGF-1 level, measured after an appropriate washout period of prior medication, was ≥1.3 times above the upper limit of the age-adjusted normal range. At the time of the screening visit, patients were randomly assigned to one of four treatment groups: placebo (n = 32); Somavert 10 mg subcutaneously once daily (n = 26); Somavert 15 mg subcutaneously once daily (n = 26); or Somavert 20 mg subcutaneously once daily (n = 28). The primary efficacy endpoint was the percentage change in IGF-1 concentration from baseline at screening visit to week 12. Statistically significant (p < 0.01) reductions in serum IGF-1 levels were observed in all three Somavert treatment groups compared to the placebo group (Table 1).

Table 1. Mean percentage change in IGF-1 concentration from baseline at screening visit to week 12 in the "as-treated" patient population

Parameters	Placebo n = 31	Somavert
		10 mg/day n = 26	15 mg/day n = 26	20 mg/day n = 28
Mean IGF-1 concentration at baseline visit (ng/mL) (BV)	670 (288)	627 (251)	649 (293)	732 (205)
Mean percent change in IGF-1 concentration from baseline visit (BV)	4.0 (17)	27 (28)	48 (26)	63 (21)
Somavert minus placebo (95% CI for difference between study drugs)		23* (–35; –11)	44* (–56; –33)	59* (–68; –49)

• P < 0.01; n – number of patients; SD – standard deviation.

Also, in the groups receiving Somavert, a decrease in serum levels of free IGF-1, IGFBP-3, and ALS was observed compared to the placebo group at all scheduled study visits (Fig. 1).

SOMAVERTE 15 mg/day (n = 24–26) SOMAVERTE 20 mg/day (n = 27–28)

800 600 400 200

Placebo (n = 31) SOMAVERT 10 mg/day (n = 25–26)

0 2 4 8 12 Week

0 2 4 8 12 Week

Fig. 1. Effect of Somavert on serum markers (mean ± standard error of the mean).

After 12 weeks of therapy, normalized IGF-1 concentrations were observed in the percentage of patients indicated below (Fig. 2).

SOMAVERT 20 mg/day

SOMAVERT 15 mg/day

SOMAVERT 10 mg/day

Placebo

Fig. 2. Percentage of patients in whom IGF-1 concentrations normalized by week 12 of treatment.

Table 2 shows the effect of treatment with Somavert on ring size (standard jewelry sizes converted to a numerical scale from 1 to 63 points) as well as on signs and symptoms of acromegaly. Each individual sign or symptom of acromegaly (soft tissue swelling, arthralgia, headache, sweating, and fatigue) was assessed using a nine-point ordinal scale (0 – absent, 8 – severe and disabling), and the total score for assessment of acromegaly signs and symptoms was calculated as the sum of scores on individual scales. Mean baseline scores were as follows: ring size – 47.1; total score for signs and symptoms – 15.2; soft tissue swelling – 2.5; arthralgia – 3.2; headache – 2.4; sweating – 3.3; and fatigue – 3.7.

Table 2. Mean change in ring size and in signs and symptoms of acromegaly at week 12 compared to baseline visit (BV).

Parameters	Placebo n = 30	Somavert
		10 mg/day n = 26	15 mg/day n = 24–25	20 mg/day n = 26–27
Ring size	0.1 (2.3)	0.8 (1.6)	1.9 (2.0)	2.5 (3.3)
Total score in assessment of 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)
Sweating	0.1 (1.7)	0.6 (1.6)	1.1 (1.3)	1.7 (1.6)
Increased fatigue	0.7 (1.5)	0.5 (1.4)	1.7 (1.3)	1.0 (1.6)

Serum growth hormone concentrations, measured using quantitative assays developed for the study and employing antibodies without cross-reactivity with pegvisomant, increased during the two weeks following initiation of therapy with Somavert. The greatest increase in growth hormone concentration was observed in patients receiving Somavert at a dose of 20 mg/day. This effect is most likely due to reduced inhibition of growth hormone secretion resulting from decreased IGF-1 levels. As shown in Fig. 3, when patients with acromegaly received a loading dose of Somavert followed by fixed daily doses, the increase in growth hormone concentration was inversely proportional to the reduction in IGF-1 levels and typically stabilized by week 2. Serum growth hormone concentrations remained stable in patients receiving Somavert for a mean duration of 43 weeks (range 0–82 weeks).

Placebo

Week Week Week Week Week 0 2 4 8 12

20 mg/day

15 mg/day

10 mg/day

Fig. 3. Percent change in serum growth hormone and IGF-1 concentrations.

In the open-label extension phase of the clinical study, 109 patients participated (including 6 new patients), with a mean duration of treatment of 42.6 weeks (range 1 day – 82 weeks). Adverse reactions occurred in 93 (85.3%) patients; serious adverse reactions (SARs) were observed in 16 (14.7%) patients, and treatment was discontinued due to adverse reactions in 4 (3.7%) patients (headache, increased liver function biochemical parameters, pancreatic cancer, and weight gain). Overall, 100 (92.6%) of 108 participants with available IGF-1 measurement data had normal IGF-1 concentrations at any visit during the study.

In various studies, including the ACROSTUDY, pegvisomant normalized IGF-1 levels in a large proportion of patients (> 70%) and significantly reduced fasting plasma glucose (FPG) and fasting plasma insulin (FPI).

Pegvisomant also improves insulin sensitivity, which is likely related to blockade of GH receptors in tissues, primarily in the liver, as well as adipose tissue, kidneys, and skeletal muscles, thereby eliminating the harmful effects of GH on insulin signaling pathways, lipolysis, and gluconeogenesis. However, the exact mechanism of this effect is not well established. Diabetic patients with acromegaly may require dose reductions of insulin or antihyperglycemic medications (see sections "Special warnings and precautions for use", "Interaction with other medicinal products and other forms of interaction").

Pharmacokinetics.

Absorption. Following subcutaneous administration, peak serum concentrations of pegvisomant are typically achieved no earlier than 33–77 hours after administration. The mean extent of absorption of a 20 mg subcutaneous dose is 57% compared to that following a 10 mg intravenous dose.

Distribution. The mean apparent volume of distribution of pegvisomant is 7 L (coefficient of variation 12%), indicating minimal tissue distribution. After single subcutaneous administration, exposure (Cmax, AUC) of pegvisomant increases disproportionately with increasing dose. The mean ± standard error of the mean (SEM) serum concentration of pegvisomant after 12 weeks of daily doses of 10, 15, and 20 mg was 6600 ± 1330, 16,000 ± 2200, and 27,000 ± 3100 ng/mL, respectively.

The relative bioavailability of a single 30 mg dose of pegvisomant was compared to two 15 mg doses in a single-dose study. The AUCinf and Cmax values of pegvisomant following administration as a single 30 mg injection were approximately 6% and 4% higher, respectively, compared to administration as two 15 mg injections.

Metabolism and elimination. The pegvisomant molecule contains covalently bound polyethylene glycol polymers to reduce clearance rate. The clearance of pegvisomant after multiple dosing is lower than that observed after single administration. The mean total systemic clearance of pegvisomant in the body after multiple dosing is estimated to range from 36 to 28 mL/h for subcutaneous doses ranging from 10 to 20 mg daily, respectively. Pegvisomant clearance has been found to increase with body weight. Pegvisomant is eliminated from serum with a mean half-life ranging from 60 to 138 hours after single or multiple administration. Less than 1% of the administered dose is recovered in urine within 96 hours. The elimination pathways of pegvisomant in humans have not been studied.

Drug interaction studies

In clinical trials, patients receiving opioids often required higher serum concentrations of pegvisomant to achieve adequate suppression of IGF-1 compared to patients not receiving opioids. The mechanism of this interaction is unknown (see section "Interaction with other medicinal products and other forms of interaction").

Special patient groups

Pharmacokinetic studies in patients with impaired renal function, hepatic impairment, elderly patients, or pediatric patients have not been conducted. The effect of patient race on the pharmacokinetics of pegvisomant has not been studied. Population pharmacokinetic analysis revealed no differences in pegvisomant pharmacokinetics based on patient gender.

Immunogenicity

The observed frequency of antibodies to the drug is highly dependent on the sensitivity and specificity of the analytical method. Differences in analytical methods preclude meaningful comparison of antibody frequencies across the studies described below with those from other studies, including studies of Somavert or other growth hormone analogs.

In pre-approval clinical trials, approximately 17% of patients receiving Somavert developed low titers of neutralizing antibodies to growth hormone. Although the presence of these antibodies appears not to affect the efficacy of Somavert, the long-term clinical significance of developing these antibodies is unknown. Currently, there are no commercially available diagnostic kits for detecting antibodies to pegvisomant in patients receiving Somavert.

The data above reflect the percentage of patients in whom test results were considered positive for antibodies to Somavert. Detection of antibody formation is highly dependent on the sensitivity and specificity of the assay method. Additionally, the observed frequency of positive antibody test results may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications, and underlying disease. Therefore, comparisons of the frequency of antibody development to Somavert with that of other drugs may lead to misleading conclusions.

Clinical characteristics.

Indications.

Somavert is indicated for the treatment of acromegaly in patients who have had an inadequate response to surgery or radiotherapy, or for whom these therapies are not suitable. The goal of treatment is to normalize serum insulin-like growth factor-1 (IGF-1) levels.

Contraindications.

Somavert must not be administered to patients who are allergic to the active substance or to any of the other ingredients of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

Insulin and/or oral hypoglycemic agents

After initiation of Somavert therapy, patients with acromegaly and diabetes mellitus who are receiving insulin and/or oral hypoglycemic agents may require a reduction in the dose of insulin and/or oral hypoglycemic agents (see section "Special warnings and precautions for use").

Opioids

In clinical studies, patients receiving opioids often required higher doses of Somavert to normalize IGF-1 concentrations compared to patients not receiving opioids. The mechanism of this interaction is unknown.

Special precautions for use.

Hypoglycemia associated with decreased growth hormone levels in patients with diabetes mellitus

Growth hormone antagonizes the effects of insulin on carbohydrate metabolism by reducing insulin sensitivity. Therefore, in some patients receiving Somavert, glucose tolerance may improve. Patients with diabetes mellitus should be closely monitored, and if necessary, doses of antidiabetic agents should be reduced to avoid hypoglycemia.

Hepatotoxicity

Prior to initiating therapy with Somavert, baseline assessment of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, and alkaline phosphatase levels should be performed. Table 3 provides recommendations for initiating Somavert therapy based on liver function test (LFT) results.

Asymptomatic, transient elevations in transaminase levels up to 15 times the upper limit of normal (ULN) were observed in < 2% of patients during two open-label studies (involving a total of 147 patients). These elevated transaminase levels were not accompanied by increases in bilirubin. Elevated transaminase levels returned to normal over time, usually after temporary discontinuation of therapy. Post-marketing reports have identified elevations in serum hepatic transaminases to more than 20 times the ULN, associated with increases in total bilirubin to more than twice the ULN. In many of these cases, discontinuation of Somavert therapy resulted in reduction or resolution of the abnormal liver test results.

During therapy, Somavert should be administered according to the information regarding abnormalities in liver biochemistry parameters as outlined in Table 4.

Table 3. Recommendations for initiating Somavert therapy based on baseline liver biochemistry parameters and for periodic monitoring of liver biochemistry parameters during Somavert therapy

Baseline liver function tests	Recommendations
Normal	Pegvisomant therapy is permitted. Monitor liver function tests monthly for the first 6 months of therapy, quarterly for the next 6 months, and then twice yearly thereafter.
Elevated but ≤ 3 × ULN	Pegvisomant may be used; however, liver function tests should be monitored monthly for at least one year after initiation of therapy, then twice yearly in the following year.
More than 3 times ULN	Pegvisomant should not be used until a comprehensive evaluation is performed to determine the cause of liver dysfunction in the patient. Assess for presence of gallstones or choledocholithiasis, particularly in patients with prior somatostatin analog therapy in their history. Based on evaluation results, consider the appropriateness of initiating Pegvisomant therapy. If a decision is made to use this drug, clinical symptoms and liver function tests must be closely monitored.

If during Somavert treatment a patient's IGF-P level increases or any other signs or symptoms of impaired liver function appear, the following management is recommended (Table 4).

Table 4. Clinical recommendations based on assessment of liver function biochemical parameters during Somavert treatment

ALT level and clinical signs/symptoms	Recommendations
Greater than or equal to 3 × ULN but less than 5 × ULN (without signs/symptoms of hepatitis or other liver injury or without increased serum total bilirubin)	Treatment with Somavert may continue. However, weekly monitoring of ALT levels is required to determine whether levels continue to rise (see below). Perform a comprehensive liver evaluation to determine whether there is an alternative cause of liver dysfunction.
At least 5 times the ULN or transaminase levels at least 3 times the ULN accompanied by any increase in serum total bilirubin (with or without signs/symptoms of hepatitis or other liver injury)	Immediately discontinue treatment with Somavert. Perform a comprehensive liver evaluation, including periodic assessment of liver function tests, to determine whether serum levels return to normal and when this occurs. If liver enzymes normalize (regardless of whether an alternative cause of liver dysfunction was identified), resumption of Somavert treatment may be considered, but with frequent monitoring of liver function tests.
Signs or symptoms suggestive of hepatitis or other liver injury (e.g., jaundice, bilirubinuria, increased fatigue, nausea, vomiting, right upper quadrant abdominal pain, ascites, edema of unknown etiology, tendency to bruising)	Immediately perform a comprehensive liver evaluation. If liver injury is confirmed, the drug should be discontinued.

Patients should have blood drawn to analyze IGF-1 levels and liver function biochemical parameters before and during treatment with Somavert; the dose of the drug may be adjusted based on the results of these tests.

Cross-reactivity with growth hormone immunoassays

Somavert has substantial structural similarity to growth hormone, resulting in cross-reactivity when using immunoassay kits for quantitative measurement of growth hormone. Since serum concentrations of Somavert achieved with therapeutic doses are typically 100–1000 times higher than actual serum growth hormone concentrations in patients with acromegaly, measurements of serum growth hormone levels may yield falsely elevated results.

Growth of growth hormone-secreting tumors

Pituitary tumors producing growth hormone may occasionally enlarge, leading to serious complications (e.g., visual field defects); therefore, it is important that all patients be carefully monitored. If signs of tumor growth occur, alternative procedures may be recommended.

Lipohypertrophy

Cases of lipohypertrophy have been observed in patients treated with Somavert. In a double-blind, 12-week, placebo-controlled study, one case (1.3%) of lipohypertrophy at the injection site was reported in a patient receiving 10 mg/day. The condition resolved while continuing therapy. In two open-label studies (involving a total of 147 patients), two patients (both receiving 10 mg/day) developed lipohypertrophy. In one case, the condition resolved during continued treatment; in the other, it led to discontinuation of therapy. To prevent lipohypertrophy, the injection site should be rotated daily (i.e., the drug should be administered at a different site each time).

Renal impairment

Somavert has not been studied in patients with renal impairment, and the safety and efficacy of the drug in such patients are unknown.

Use in elderly patients

The number of participants aged 65 years and older in clinical studies of Somavert was insufficient to determine whether they respond differently from younger patients. In general, dose selection for elderly patients should be cautious, usually starting at the lower end of the dosing range, due to the higher likelihood of decreased hepatic, renal, or cardiac function and the presence of concomitant diseases or other drug therapies.

Sodium content

This medicinal product contains less than 1 mmol of sodium (23 mg) per dose. Patients on a low-sodium diet may be informed that this medicinal product can be considered sodium-free.

Use during pregnancy or breastfeeding

Pregnancy

Overview of risk information

There are insufficient postmarketing data on the use of Somavert in pregnant women to establish a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. The clinical course of acromegaly may improve during pregnancy (see section "Overview of clinical data"). In animal reproduction studies, fetotoxicity was observed at a dose 6 times the maximum recommended human dose based on body surface area, following subcutaneous administration of pegvisomant during organogenesis or the pre-implantation period (see section "Data"). The estimated background risk of major birth defects and miscarriage in the target 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.

Overview of clinical data

Maternal and/or embryofetal risks related to the disease

Published case reports, case series, and a small interventional study in pregnant women with acromegaly indicate that the clinical course of acromegaly may improve or stabilize without treatment during pregnancy, particularly if acromegaly was treated prior to pregnancy. In rare cases, acromegaly may worsen during pregnancy. Because hormone levels may physiologically change during pregnancy and interpretation of growth hormone levels in pregnant women with acromegaly may be unreliable, clinical monitoring is recommended. The use of the drug in pregnant women has not been studied; therefore, patients should inform their physician immediately if they become pregnant.

Data

Animal reproduction studies

The effects of pegvisomant on early embryonic development and embryofetal development were evaluated in two separate studies in pregnant rabbits administered pegvisomant subcutaneously at doses of 1, 3, and 10 mg/kg/day. There was no evidence of teratogenic effects associated with pegvisomant administration during organogenesis. At the dose of 10 mg/kg/day (6 times the maximum recommended human dose based on body surface area), a reproducible slight increase in post-implantation losses was observed in both studies.

Breastfeeding

Overview of risk information

According to limited clinical case information, published reports indicate that pegvisomant levels in human breast milk were below the level of detection. There is no available information on the effect of the drug on breastfed infants or on the effect of the drug on milk production. Consideration should be given to the benefits of breastfeeding for the child's development and health, the mother's clinical need for Somavert, and any potential adverse effects of Somavert on the breastfed child or the underlying maternal condition.

Patients should inform their physician if they plan to breastfeed.

Females and males of reproductive potential

The possibility of unintended pregnancy should be discussed with premenopausal women, as the therapeutic benefits of lowering growth hormone (GH) levels and normalizing insulin-like growth factor 1 (IGF-1) concentrations in women with acromegaly receiving pegvisomant may lead to improved fertility.

Effect on ability to drive and use machines

Studies on the effect of the medicinal product on the ability to drive vehicles or operate machinery have not been conducted.

Method of Administration and Dosage

Dosing Information

The recommended loading dose of Somavert is 80 mg administered subcutaneously under medical supervision. Proper instruction on the technique of subcutaneous injection must be provided. Starting the day after administration of the loading dose, patients should receive daily subcutaneous injections of Somavert at a dose of 10 mg.

The dose should then be titrated to normalize serum IGF-1 concentration (serum IGF-1 levels should be measured every 4–6 weeks). Dose selection should not be based on growth hormone concentration or signs and symptoms of acromegaly. It is unknown whether patients who still have symptoms after achieving normal IGF-1 levels would benefit from increasing the dose of Somavert.

• If IGF-1 concentration is elevated, the dose of the drug should be increased by 5 mg every 4–6 weeks.

• If IGF-1 concentration is below the normal range, the dose of the drug should be reduced by 5 mg every 4–6 weeks.

• IGF-1 levels should also be monitored when transitioning a patient from a daily regimen requiring multiple injections to a daily regimen with the required dose administered as a single injection (see section "Pharmacological Properties").

The recommended dosage range is 10 to 30 mg administered subcutaneously once daily. The maximum daily dose is 30 mg administered subcutaneously once daily.

Assessment of Hepatic Function Prior to Initiating Somavert Therapy

Prior to initiating therapy with Somavert, baseline assessment of liver function tests should be performed (serum alanine aminotransferase [ALT], aspartate aminotransferase [AST], serum total bilirubin [STB], and alkaline phosphatase). Recommendations for initiating Somavert therapy based on baseline liver function and recommendations for monitoring liver function during Somavert therapy are provided in Table 3 (see section "Special Considerations").

Procedure for Administering the Loading Dose Injection

The instructions below pertain to reconstitution and preparation of the 80 mg loading dose and are intended for healthcare professionals. The healthcare professional must reconstitute the lyophilized powder in 4 vials of Somavert, each containing 20 mg of pegvisomant, using the diluent supplied (4 vials of lyophilized powder and 4 syringes of 2.25 mL diluent [sterile water for injection] are required to prepare the 80 mg loading dose). The healthcare professional must also administer 4 subcutaneous injections of the reconstituted solution at different sites on the patient’s body (e.g., arm, thigh, abdomen, or buttock), each at a separate site.

• Approximately 10 minutes before the scheduled injection time, remove the first package (1 vial of lyophilized Somavert powder containing 20 mg pegvisomant and 1 syringe of 2.25 mL diluent) from the refrigerator.
  • Reconstitute the 20 mg pegvisomant lyophilized powder in the first vial using the supplied diluent. When using the 2.25 mL syringe of diluent, slowly inject the contents of the syringe down the side of the vial containing the lyophilized powder. Do not direct the stream of diluent directly onto the powder.
    • Do not invert or shake the vial, as this may cause denaturation of the pegvisomant protein. Gently mix the solution by swirling to ensure complete dissolution of the lyophilized powder. If foaming occurs in the reconstituted solution, the solution may be compromised and should not be used.
      • Visually inspect the reconstituted Somavert solution for foreign particles or discoloration before administration. The reconstituted solution should be clear. Do not use if the solution is cloudy. After reconstitution, the solution contains 20 mg of pegvisomant in 1 mL of solution.
        • Draw up 1 mL of the reconstituted Somavert solution. The solution must be used within 6 hours after reconstitution.
          • Administer the first subcutaneous injection of the reconstituted Somavert solution (20 mg/mL) into the patient’s arm, thigh, abdomen, or buttock at a 90-degree angle.
            • Repeat steps (a) through (d) to reconstitute the second, third, and fourth 20 mg doses of Somavert.
              • Then administer the second (followed by the third and fourth) subcutaneous injection of the reconstituted Somavert solution (20 mg/mL) into a different injection site on the patient’s arm, thigh, abdomen, or buttock (select a different site from previous injections) at a 90-degree angle.

Procedure for Administering the Maintenance Dose Injection

Instructions for the patient or caregiver on reconstitution and administration of daily doses (ranging from 10 to 30 mg) are provided below in the "Step-by-Step Instructions for Administering Somavert."

1. Approximately 10 minutes before the scheduled injection time, remove from the refrigerator 1 vial of lyophilized Somavert powder (containing 10 mg, 15 mg, 20 mg, or 30 mg pegvisomant) and one 2.25 mL syringe of diluent.
2. Reconstitute the lyophilized Somavert powder using the diluent. When using the 2.25 mL syringe of diluent, slowly inject the contents of the syringe down the side of the vial containing the lyophilized powder. Do not direct the stream of diluent directly onto the powder.
3. Do not invert or shake the vial, as this may cause denaturation of the pegvisomant protein. Gently mix the solution by swirling to ensure complete dissolution of the lyophilized powder. If foaming occurs in the reconstituted solution, the solution may be compromised and should not be used.
4. Visually inspect the reconstituted Somavert solution for foreign particles or discoloration before administration. The reconstituted solution should be clear. Do not use if the solution is cloudy. After reconstitution, the solution contains 10 mg, 15 mg, 20 mg, or 30 mg of pegvisomant in 1 mL of solution.
5. Draw up 1 mL of the reconstituted Somavert solution. The solution must be used within 6 hours after reconstitution.

Administer the subcutaneous injection of the reconstituted Somavert solution into the arm, thigh, abdomen, or buttock at a 90-degree angle.

Step-by-Step Instructions for Administering Somavert

Step 1. Supplies Needed

One package of Somavert contains a vial of Somavert powder, a pre-filled syringe, and a safety needle.

You will also need: a cotton swab, an alcohol wipe, and a sharps container for disposal of used needles.

finger rest on the syringe

flask stopper (with removed flask cap)

needle cap

Safety needle

Syringe

needle protective cap

syringe plunger rod

syringe tip

syringe barrel

syringe cap

expiry date

flask cap

opening in the stopper

Flacon

Step 2. Preparation

Before starting:

• Mix Somavert and liquid only when you are ready to administer the dose.
• Remove one package of Somavert from the refrigerator and allow the medication to warm to room temperature in a safe place for at least 10 minutes before use.
• Do not heat the Somavert package using a heat source, such as hot water or a microwave oven. The medication should warm on its own.
• Wash your hands with soap and water and dry them completely.
• Open the package containing the syringe and safety needle so that each necessary item is easily accessible during preparation for injection.
• Do not use syringes or vials if:
  • they are damaged or defective;
  • the expiration date has passed;
  • they have been frozen, even if they are now thawed (this applies only to syringes).

Step 3. Choosing the injection site

Selection of injection site

Abdomen Stay at least 5 cm away from the navel

Thighs

Shoulder or lower back Back side of the upper arm (for healthcare provider or caregiver only)

• For each injection, select a different site within the injection areas.
• Avoid areas near bones or areas with bruises, redness, pain, or lumps, as well as areas with scars or skin conditions.
• Wipe the injection site with an alcohol swab.
• Allow the injection site to dry.

Step 4. Removing the cap from the vial

Removing the cap from the vial

• Remove the cap from the vial.
• Discard the cap. You will not need it anymore.

Caution! Do not touch the vial stopper with anything.

Step 5. Removing the cap from the syringe

Removing the cap from the syringe

Clicking

• Remove the cap from the syringe, leaving the syringe tip in place. You may need to use more force than you expect to remove the cap.
• Discard the syringe cap. It is no longer needed.
• Hold the syringe upright to prevent leakage of liquid.

Caution! Do not touch the tip of the syringe to any surface once the cap has been removed.

Step 6. Attaching the safety needle

Attaching a safety needle

• Press and twist the safety needle onto the syringe until it stops.

Step 7. Removing the needle cap

Removing the needle cap

• Remove the protective needle cover from the path of the needle cap.
• Carefully remove the cap from the needle.
• Discard the needle cap. You will not need it anymore.

Caution! Do not touch anything with the needle.

Step 8. Inserting the needle

Needle insertion

• Pierce the center of the vial stopper with the needle, as shown in the figure.
• Hold the syringe steady while the needle remains in the vial stopper to prevent needle bending.

Step 9. Adding liquid

Addition of liquid

• Tilt the vial and syringe at an angle, as shown in the figure.
• Slowly press the syringe plunger until all the liquid has transferred into the vial.
• Caution! Do not direct the liquid stream directly onto the powder, as this may cause foaming, rendering the preparation unsuitable for use.
• Do not remove the needle yet.

Step 10. Mix the solution by rotating movements

Mixing the solution with circular movements

• Hold the syringe and vial in one hand, as shown in the illustration.
• Carefully and slowly mix the solution by moving the vial in a circular motion on a flat surface.
• Continue mixing the liquid with circular movements until all the powder is completely dissolved.

Note. This may take up to 5 minutes. Do not shake.

Step 11. Check the solution

Inspection of the solution

• While holding the needle in the vial, carefully examine the solution. It should be clear and free of foreign particles.
• Do not use the medication if:

• the solution is not clear or appears cloudy;
• the solution is discolored;
• there are any particles or foam present in the vial.

Step 12. Moving the needle

Needle movement

• Turn the vial upside down so that you can see the opening in the stopper, as shown in the figure.
• Position the needle downward so that the tip of the needle is in the lowest point of the liquid. This will allow you to withdraw as much liquid as possible from the vial.
• Make sure the syringe plunger is not moved. If the syringe plunger has moved, push it back into the syringe. This allows you to remove all air from the syringe before you begin drawing up the dose.

Step 13. Drawing up the dose

Dosage titration

• Slowly pull back the plunger of the syringe to withdraw as much solution from the vial as possible.

Note: If you see air bubbles in the syringe, tap the syringe barrel gently to allow the bubbles to rise to the top, then carefully expel the bubbles back into the vial.

• Remove the needle from the vial.

Step 14. Inserting the needle

Needle insertion

• Carefully grasp the skin fold at the injection site.
• Insert the needle fully into the skin fold.

Step 15. Administering the medication injection

Administration of the drug injection

• Slowly push the syringe plunger down until the syringe barrel is empty.

Note. Make sure you have inserted the needle fully.

• Release the skin fold and withdraw the needle at a right angle.

Step 16. Needle safety

Click!

Needle safety

• Lower the needle guard over the needle.

Carefully press down on the guard using a hard surface to return it to its original position.

• Note: You will hear a click when the protective guard locks into place.

Step 17. Disposal

• Place used syringes into a sharps disposal container.
• Do not dispose of (do not throw away) syringes with household waste.

Step 18. After the injection

• If needed, take a clean gauze pad and gently press it against the injection site.
• Do not rub the injection site.

Children

The safety and efficacy of Somavert in children have not been established.

Overdose

During post-marketing clinical experience, one case of acute overdose with Somavert has been reported: a patient self-administered injections at a dose of 80 mg/day (2.7 times higher than the maximum recommended maintenance dose) for seven days. The patient experienced a slight increase in fatigue, without any other complaints or clinically significant abnormalities in laboratory test results.

In case of overdose, Somavert administration should be discontinued and not resumed until IGF-1 levels return to normal.

Adverse Reactions

Clinically significant adverse reactions mentioned in the section "Special Warnings and Precautions for Use" include:

• hypoglycemia associated with decreased growth hormone levels in patients with diabetes mellitus;
• hepatotoxicity;
• cross-reactivity with immunoassays for growth hormone;
• lipohypertrophy;
• systemic hypersensitivity reactions.

During pre-approval clinical trials, serum concentrations of ALT and AST increased more than 10-fold above the upper limit of normal (ULN) in two patients (0.8%) receiving Somavert. One patient underwent rechallenge with Somavert, after which a recurrence of elevated transaminases was observed, indicating a probable causal relationship between drug administration and increased liver enzymes. Liver biopsy findings in the second patient were consistent with chronic hepatitis of unknown etiology. In both patients, elevated transaminase levels returned to normal after discontinuation of the drug.

Elevations in ALT and AST were not accompanied by increases in total bilirubin or alkaline phosphatase, except in two patients who had minimal associated increases in alkaline phosphatase (i.e., less than 3 × ULN). Transaminase elevations are likely not dose-dependent and typically occur within 4–12 weeks after initiation of therapy. No biochemical, phenotypic, or genetic predictive factors associated with this phenomenon have been identified.

Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, the frequency of adverse reactions observed in the clinical trials of one drug cannot be directly compared to those of another and may not reflect the frequencies observed in clinical practice.

In a 12-week randomized, placebo-controlled, double-blind, fixed-dose study of Somavert in patients with acromegaly, 32 patients received placebo and 80 received Somavert once daily (see section "Pharmacological Properties" ("Clinical Studies")). Overall, 108 patients (30 in the placebo group, 78 in the Somavert group) completed 12 weeks of therapy.

Overall, eight patients with acromegaly (5.3%) were withdrawn from pre-approval clinical trials due to adverse reactions, including two patients with marked elevation of transaminase levels, one patient with injection-site lipohypertrophy, and one patient with significant weight gain. Most adverse reactions appear not to be dose-dependent. Table 5 lists adverse reactions reported in at least two patients receiving Somavert and occurring at a higher frequency than in the placebo group in the 12-week placebo-controlled study.

Table 5. Adverse reactions observed in the 12-week placebo-controlled study in patients with acromegaly*

Adverse Reactions	Placebo n = 32	Somavert
		10 mg/day n = 26	15 mg/day n = 26	20 mg/day N = 28
Infection†	2 (6 %)	6 (23 %)	0	0
Pain	2 (6 %)	2 (8 %)	1 (4 %)	4 (14 %)
Nausea	1 (3 %)	0	2 (8 %)	4 (14 %)
Diarrhea	1 (3 %)	1 (4 %)	0	4 (14 %)
Liver function biochemical test abnormalities	1 (3 %)	3 (12 %)	1 (4 %)	1 (4 %)
Influenza-like syndrome	0	1 (4 %)	3 (12 %)	2 (7 %)
Injection site reaction	0	2 (8 %)	1 (4 %)	3 (11 %)
Dizziness	2 (6 %)	2 (8 %)	1 (4 %)	1 (4 %)
Accidental injury	1 (3 %)	2 (8 %)	1 (4 %)	0
Back pain	1 (3 %)	2 (8 %)	0	1 (4 %)
Sinusitis	1 (3 %)	2 (8 %)	0	1 (4 %)
Chest pain	0	1 (4 %)	2 (8 %)	0
Peripheral edema	0	2 (8 %)	0	1 (4 %)
Arterial hypertension	0	0	2 (8 %)	0
Paresthesia	2 (6 %)	0	0	2 (7 %)

* The table includes only reactions that were reported in at least 2 patients and occurred more frequently in patients receiving Somavert than in placebo-treated patients.

† In the group receiving Somavert 10 mg, 6 reactions coded as "infection" were reported: cold symptoms (3), upper respiratory tract infection (1), blisters (1), and ear infection (1). In the placebo group, 2 such reactions were recorded: cold symptoms (1) and chest infection (1).

Post-marketing experience

Adverse reactions from post-marketing spontaneous reports

During the post-marketing period of Somavert use, the following adverse reactions have been identified. Because these reports are submitted voluntarily from a population of unknown 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, and generalized skin reactions (rash, erythema, pruritus, urticaria), have been reported during the post-marketing period. Some patients required hospitalization. Upon re-challenge, symptoms did not recur in any patient (see section "Dosage and Administration" ("Systemic Hypersensitivity Reactions")).

Adverse reactions from observational study

ACROSTUDY is an international observational registry collecting long-term safety data from 2221 patients with acromegaly treated with Somavert, with a median treatment duration of 8.5 years. Patients were allowed to receive other acromegaly treatments during the observation period. The dose and regimen were determined at the discretion of each prescribing physician. Although safety monitoring according to the recommended schedule was required, not all assessments were performed at all time points for every patient. Therefore, comparison of adverse reaction frequencies with those observed in the original clinical trial is not feasible.

Among 1327 patients with normal baseline AST and ALT levels, elevations >3–5 times above ULN were observed in 20 (1.5%) patients, and elevations >5 times above ULN occurred in 22 (1.7%) patients. Lipohypertrophy was reported in 35 (1.6%) patients.

Among 1795 study participants with available baseline and at least one follow-up MRI, MRI results showed an increase in 128 (7.1%), a decrease in 310 (17.3%), both increase and decrease in 81 (4.5%), and no change in 1276 (71.1%).

Patients (and/or caregivers) should be informed about the potential development of the following adverse reactions:

• The most commonly reported adverse reactions were injection site reactions, increased liver function biochemical test levels, pain, nausea, and diarrhea.
• If patients develop elevated liver function biochemical test levels, they may require more frequent blood testing to monitor liver function and/or discontinuation of Somavert. Inform patients that they should immediately stop treatment and contact their physician if jaundice occurs.
• In patients with acromegaly, growth hormone-secreting tumors may enlarge and should be carefully monitored using magnetic resonance imaging (MRI).
• Subcutaneous injection site nodules may develop, potentially leading to lipoatrophy; rotating injection sites may help prevent or minimize this effect.
• For patients with diabetes mellitus, careful monitoring and possible dose reduction of insulin and/or oral hypoglycemic agents may be required during treatment with Somavert.
• Patients receiving opioids may require higher doses of Somavert to achieve adequate IGF-1 suppression.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals, as well as patients or their legal representatives, are encouraged to report any suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

Shelf life.

3 years.

Storage conditions.

Store vials of lyophilized powder in the original packaging to protect from light at 2–8°C in a refrigerator. Do not freeze.

The medicine in vials within the original packaging may be stored at temperatures not exceeding 25°C for a single period of up to 30 days. The cardboard box should be marked with the date by which the product must be used (within 30 days from removal from the refrigerator). Vials must be protected from light and must not be returned to the refrigerator. The product must be discarded if not used within 30 days of storage at room temperature or after the expiry date indicated on the box, whichever comes first.

The solvent in pre-filled syringes should be stored at temperatures not exceeding 30°C or at 2–8°C in a refrigerator. Do not freeze.

The reconstituted solution should be used immediately or within 6 hours after preparation.

Keep out of the reach of children.

Packaging.

10 vials of lyophilized powder in a secondary cardboard box; 3 secondary cardboard boxes, 30 pre-filled syringes with 1 ml solvent, 30 safety needles in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Pfizer Manufacturing Belgium NV.

Manufacturer's location and address of place of business.

Rijksweg 12, Puurs-Sint-Amands, 2870, Belgium.