SOMAVERT® WITH DILUENT VIAL

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

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, each supplied with Sterile Water for Injection, USP in a separate glass vial to be used as diluent.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

6 ADVERSE REACTIONS

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

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Hypoglycemia Associated with GH Lowering in Patients with Diabetes Mellitus [see Warnings and Precautions (5.1)]

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Liver Toxicity [see Warnings and Precautions (5.2)]

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Cross-Reactivity with GH Assays [see Warnings and Precautions (5.3)]

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Lipohypertrophy [see Warnings and Precautions (5.4)]

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Systemic Hypersensitivity [see Warnings and Precautions (5.5)]

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.

7 DRUG INTERACTIONS

8 USE IN SPECIFIC POPULATIONS

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.

Stippled residues indicate PEG attachment sites (Phe1, Lys38, Lys41, Lys70, Lys115, Lys120, Lys140, Lys145, Lys158)

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 separate glass vial containing 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 vials also contain 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 vials also contain 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

13 NONCLINICAL TOXICOLOGY

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:

SOMAVERT (pegvisomant) for injection

Each package of SOMAVERT also includes a single-dose vial containing 5 mL of Sterile Water for Injection, USP.

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:

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Not to use SOMAVERT if they are allergic to SOMAVERT or anything in it.

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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.

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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.

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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.

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Pregnancy: Inform female patients that treatment with SOMAVERT may result in unintended pregnancy [see Females and Males of Reproductive Potential (8.3)].

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

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The most common reported adverse reactions are injection site reaction, elevations of liver tests, pain, nausea, and diarrhea.

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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.

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GH-secreting tumors may enlarge in people with acromegaly and that these tumors need to be watched carefully and monitored by MRI imaging.

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Thickening under the skin may occur at the injection site that could lead to lumps and that switching sites may prevent or lessen this.

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If they have diabetes mellitus, they may require careful monitoring and dose reductions of insulin and/or oral hypoglycemic agents while on SOMAVERT.

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If they take opioids, they may need higher SOMAVERT doses to achieve appropriate IGF-1 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°C to 8°C (36°F to 46°F) prior to use. It should NOT BE FROZEN.

INSTRUCTIONS FOR USE

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

Read this 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.

Important Information:

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SOMAVERT is for use under the skin only (subcutaneous).

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Do not share your SOMAVERT syringes or needles with anyone else. You may give an infection to them or get an infection from them.

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Do not use SOMAVERT after the expiration date (EXP) on the label.

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Inject SOMAVERT within 6 hours of mixing it. If you wait more than 6 hours, you must throw away the medicine without injecting it.

Supplies you need to give each injection of SOMAVERT. See Figure A.

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1 package of SOMAVERT that contains:

o

1 vial of powdered SOMAVERT medicine (powder vial)

o

1 vial of liquid (diluent) labeled "Sterile Water for Injection, USP" to mix the powdered medicine

 

The vials in the package of SOMAVERT have stoppers that are not made with natural rubber latex.

 

The SOMAVERT package does not come with syringes and needles.

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a 1 mL syringe with a 21 gauge to 27 gauge needle that is at least 1 inch long. This is the syringe and needle needed to mix the medicine (diluent syringe).

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a 1 mL insulin syringe with attached needle. This is the syringe needed for your injection.

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2 alcohol swabs

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1 small clean, dry cotton pad

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1 sharps disposal container for throwing away used needles and syringes. See "Disposing of used needles and syringes" at the end of these instructions.

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a clean, flat surface to work on, like a table

Figure A

Preparing and mixing your SOMAVERT medicine

The SOMAVERT medicine comes as a dry powder. Before you use SOMAVERT, you must mix the dry powder with the vial of diluent that comes in the SOMAVERT package.

Do not use any other liquid to mix the medicine.

Note: If you need to give 2 injections for your SOMAVERT dose, you need 2 packages of SOMAVERT to prepare 2 separate vials of medicine.

Step 1. Remove 1 package of SOMAVERT from the refrigerator about 10 minutes before you plan to give your SOMAVERT injection. Let the SOMAVERT stand at room temperature to warm up the medicine.

Step 2. Wash your hands with soap and warm water. Dry your hands well.

Step 3. Remove the plastic caps from the tops of the powder vial and the diluent vial. See Figure B.

Do not touch the rubber vial stoppers. The stoppers are clean. If the stoppers are touched by anything, you must clean them with an alcohol swab before use.

Figure B

Step 4. Carefully remove the cap from the diluent syringe with the larger needle and set the cap aside on the table. See Figure C.

Figure C

Step 5. Pull the plunger of the diluent syringe out to the 1 mL mark. With 1 hand, firmly hold the vial of diluent. With the other hand, push the needle of the diluent syringe straight through the center of the rubber stopper and deep into the vial. Gently push the plunger in until the air is injected into the vial. See Figure D.

Figure D

Step 6. Firmly hold the diluent vial and syringe together, with the needle still in the vial. Then turn the diluent vial with the diluent syringe upside down. Hold them at eye level. See Figure E.

Figure E

Step 7. Slide 1 hand carefully down the diluent vial so you can firmly hold the neck of the vial with your thumb and forefinger. Hold the upper part of the syringe with your other fingers. With the other hand, slowly pull the plunger out to the 1 mL mark on the diluent syringe. See Figure F.

Figure F

Step 8. Check the diluent syringe for air bubbles. If you see bubbles, tap the diluent syringe barrel until the bubbles rise to the top of the syringe. Carefully push the plunger in to push only the air bubbles back into the vial. See Figure G. If you push too much of the liquid back into the vial, pull the plunger out again to the 1 mL mark.

Figure G

Step 9. Make sure that 1 mL of diluent remains in the diluent syringe. Pull the needle out of the vial. The vial should still have diluent in it. Do not use the leftover diluent in the vial.

Step 10. Push the needle of the diluent syringe straight through the stopper of the vial of powdered SOMAVERT.

Then, tilt the diluent syringe to the side and gently push the plunger to inject the diluent down the inner side of the SOMAVERT powder vial. Be sure the diluent does not fall directly on the powder, but flows down the inside wall of the vial. See Figure H.

Figure H

Step 11. When the diluent syringe is empty, pull the needle out of the powder vial.

Throw away the diluent vial with the leftover liquid in it. Throw away the diluent syringe and needle in the sharps container. See "Disposing of used needles and syringes" at the end of these instructions.

Step 12. Hold the medicine vial of SOMAVERT upright between your hands and gently roll it to dissolve the powder into a solution. See Figure I.

Figure I

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Do not shake the medicine vial. Shaking may destroy the medicine.

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The liquid medicine should be clear after the powder is dissolved. Do not use the vial if:

o

the liquid medicine looks cloudy, hazy, or slightly colored or

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you see solid particles in the liquid medicine or

o

you see foam in the vial

 

Tell your pharmacist and ask for another vial. Do not throw the vial away because the pharmacist may ask that you return it.

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Inject SOMAVERT within 6 hours of mixing it. If you wait more than 6 hours, you must throw away the medicine without injecting it.

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Each mixed medicine vial contains 1 dose of SOMAVERT. Do not split the liquid medicine into multiple doses.

Preparing your SOMAVERT injection syringe:

Step 13. Clean the rubber stopper of the vial of SOMAVERT with an alcohol swab.

•

Carefully remove the cap from the insulin syringe and set the cap on the table.

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Pull the insulin syringe plunger out to the 1 mL mark. With 1 hand, firmly hold the vial. With the other hand, push the needle straight through the center of the rubber stopper and deep into the vial. Gently push the plunger in until the air is injected into the medicine vial. See Figure J.

Figure J

Step 14. Firmly hold the medicine solution vial and insulin syringe together, with the needle still deeply inserted into the vial. Carefully turn the vial and syringe together upside down. Hold them at eye level. See Figure K.

Figure K

Step 15. Slide 1 hand carefully down the medicine solution vial so you can firmly hold the neck of the vial with your thumb and forefinger. Hold the upper part of the syringe with your other fingers. With the other hand, slowly pull the plunger out to the 1 mL mark on the insulin syringe. See Figure L.

Figure L

Step 16. Check the insulin syringe for air bubbles. If you see bubbles, tap the insulin syringe barrel until the bubbles rise to the top of the syringe. Carefully push the plunger in to push only the air bubbles back into the vial. See Figure M.

Figure M

Step 17. Withdraw the entire 1 mL of medicine solution from the vial. If your dose of SOMAVERT is less than 1 mL, your healthcare provider will tell you how much medicine solution to withdraw. Slowly withdraw the needle to keep the tip in the liquid until you get all the medicine solution you need out of the vial. See Figure N.

Note:

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If your dose of SOMAVERT is less than 1 mL, your healthcare provider will tell you how much medicine solution to withdraw.

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If your dose of SOMAVERT is more than 1 mL, your healthcare provider will tell you how much more medicine solution to withdraw from a second vial into another syringe, and where to give your second injection.

Set the syringe and needle on the table without anything touching the needle.

Figure N

Selecting your SOMAVERT injection site:

Step 18. SOMAVERT is injected under the skin (subcutaneous). Injection sites may include your upper arm, upper thigh, stomach area (abdomen) and buttocks. See Figure O.

Figure O

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Choose your injection site from 1 of the areas your healthcare provider told you to use. Only a caregiver can inject in your upper arm.

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Choose a different injection site each day so lumps do not develop in your skin. Keep a record of each day's injection site as you inject your daily dose of SOMAVERT.

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Do not use an area of your body that has:

o

a rash

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broken skin

o

bruising

o

lumps in your skin

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If you need to give 2 injections for your dose of SOMAVERT, choose a different site for your second injection.

Giving your SOMAVERT injection:

Step 19. Clean your injection site with an alcohol swab. See Figure P.

Let your skin dry before you inject your medicine.

Figure P

Step 20. With 1 hand, gently pinch up your skin at your injection site. See Figure Q.

Figure Q

Step 21. Carefully pick up the insulin syringe with your other hand and hold it like a pen. In a single, smooth motion, push the needle straight down and completely into your skin (at a 90-degree angle).

•

Keep the needle pushed all the way into your skin while you slowly push the syringe plunger in with the index finger of your other hand. See Figure R.

•

Keep the needle all the way into your skin until all of the medicine is injected under your skin and the insulin syringe is empty.

Figure R

Step 22. Release your pinched skin and pull the needle straight out. See Figure S.

Figure S

Step 23. Do not rub your injection area. A small amount of bleeding may happen.

If you have a small amount of bleeding, press a small clean, dry cotton pad over the area and press gently for 1 or 2 minutes, or until the bleeding has stopped. See Figure T.

Figure T

Disposing of used needles and syringes:

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Put your used needles and syringes in a FDA-cleared sharps disposal container right away after use. See Figure U. Do not throw away (dispose of) loose needles and syringes in your household trash.

Figure U

•

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

o

made of a heavy-duty plastic,

o

can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out,

o

upright and stable during use,

o

leak-resistant, and

o

properly labeled to warn of hazardous waste inside the container.

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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.

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Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container.

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

U.S. License No. 1216
LAB-1362-3.0
Revised: July 2023

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-0196-23.0