Somavert

Tell your doctor if you are pregnant or plan to become pregnant. It is not known if Somavert can harm your unborn baby. You and your doctor will have to decide if Somavert is right for you.

• Before you mix the Somavert powder and the liquid:
  • Store Somavert in a refrigerator between 36°F to 46°F (2°C to 8°C).
  • Do not freeze Somavert.
• After you mix the Somavert powder and liquid:
  • Keep the mixed Somavert at room temperature between 59°F to 77°F (15°C to 25°C).
  • Keep Somavert inside the vial or the syringe until you are ready to inject it.
  • You must use the mixed Somavert within 6 hours after you mix it.
  • If you have not used the mixed Somavert within 6 hours, throw the Somavert away.

Keep Somavert and all medicines out of the reach of children.

You should not use pegvisomant if you are allergic to it.

To make sure this medicine is safe for you, tell your doctor if you have:

• diabetes (pegvisomant can lower your blood sugar);

• liver disease;

• a latex allergy; or

• a tumor that secretes growth hormone.

This medicine is not expected to harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant.

It is not known whether pegvisomant passes into breast milk or if it could harm a nursing baby. Tell your doctor if you are breast-feeding a baby.

Pegvisomant is not approved for use by anyone younger than 18 years old.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include feeling very tired.

Specific Drugs or Laboratory Tests

Drug or Test	Interaction	Comments
Antidiabetic agents	Improved insulin sensitivity and glucose tolerance resulting from reduction in IGF-I concentrations1 6 10 11	Adjust dosage of concurrent antidiabetic therapy as necessary in patients with acromegaly and diabetes mellitus1 10
Opiate agonists	Decreased efficacy (higher serum concentrations of pegvisomant needed to produce appropriate suppression of IGF-I)1 10	Increased dosage of pegvisomant may be required1 10
Test, growth hormone concentrations	Pegvisomant cross-reacts with endogenous growth hormone, causing overestimation of endogenous growth hormone concentrations1 10 Even when accurately measured, growth hormone concentrations usually increase during pegvisomant therapy1 6 11	Monitor treatment and adjust dosage based on serum IGF-I concentrations1

• Binds to somatotropin receptors and competitively blocks binding of endogenous growth hormone, thereby interfering with signal transduction and the subsequent production of insulin-like growth factor I (IGF-I).1 3 6 7 IGF-I mediates most of the somatotropic effects of growth hormone.1 3 6 7

• Produces a rapid decrease in serum IGF-I and other growth hormone-responsive serum proteins (e.g., IGF binding protein-3 [IGFBP-3], acid labile subunit of IGFBP-3) in patients with acromegaly.1 3 5 6

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes.
• Dizziness or passing out.
• Chest pain.
• Very bad headache.
• Any unexplained bruising or bleeding.
• Swelling in the arms or legs.
• Change in skin to hard and thick.

• Store unopened vials in a refrigerator. Do not freeze.
• Once mixed, use right away. You may keep at room temperature for up to 6 hours.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

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-I concentrations (serum IGF-I concentrations should be measured every four to six weeks). The dosage should not be based on growth hormone (GH) concentrations or signs and symptoms of acromegaly. It is unknown whether patients who remain symptomatic while achieving normalized IGF-I concentrations would benefit from increased Somavert dosage.

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

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

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).

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 2.25 mL syringes containing diluent (Sterile Water for Injection) 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 the first package (1 vial of lyophilized powder of Somavert containing 20 mg of pegvisomant and one 2.25 mL syringe containing the diluent) from the refrigerator 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 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 20 mg of pegvisomant in 1 mL of solution. (e) Withdraw the 1 mL reconstituted Somavert solution. The solution must be administered within 6 hours of 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).

Maintenance Dose Injection Procedure

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

a) Before administering the dose, remove one package (1 vial of lyophilized powder of Somavert containing 10, 15, 20, 25 or 30 mg of pegvisomant and one 2.25 mL syringe (containing the diluent) from the refrigerator 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, 15, 20, 25 or 30 mg of pegvisomant in 1 mL of solution. e) Withdraw the 1 mL reconstituted Somavert solution. The solution must be administered within 6 hours of reconstitution. f) Inject the reconstituted Somavert solution subcutaneously into the upper arm, upper thigh, abdomen, or buttocks using a 90-degree angle.

None.

In one reported incident of acute overdose with Somavert during pre-marketing clinical studies, a patient self-administered 80 mg/day (2.7 times the maximum recommended maintenance dosage) for seven days. The patient experienced a slight increase in fatigue, had no other complaints, and demonstrated no significant clinical laboratory abnormalities.

In cases of overdose, administration of Somavert should be discontinued and not resumed until IGF-I levels return to within or above the normal range.

A total of one hundred twelve patients (63 men and 49 women) with acromegaly participated in a 12-week, randomized, double-blind, multi-center study comparing placebo and Somavert. The mean ±SD age was 48±14 years, and the mean duration of acromegaly was 8±8 years. Ninety three had undergone previous pituitary surgery, of which 57 had also been treated with conventional radiation therapy. Six patients had undergone irradiation without surgery, nine had received only drug therapy, and four had received no previous therapy. At study start, the mean ± SD time since the subjects' last surgery and/or irradiation therapy, respectively, was 6.8 ± 0.93 years (n=63) and 5.6 ± 0.57 years (n=93).

Subjects were qualified for enrollment if their serum IGF-I, drawn after the required drug washout period, was ≥1.3 times the upper limit of the age-adjusted normal range. They were randomly assigned at the baseline visit to one of four treatment groups: placebo (n=32), 10 mg/day (n=26), 15 mg/day (n= 26), or 20 mg/day (n=28) of Somavert subcutaneouslyIGF-I. The primary efficacy endpoint was IGF-I percent change in IGF-I concentrations from baseline to week 12. The three groups that received Somavert showed statistically significant (p<0.01) reductions in serum levels of IGF-I compared with the placebo group (Table 4).

Table 4. Mean Percent Change from Baseline in IGF-I at Week 12 for Intent-to-Treat Population

	Placebo n=31	Somavert
		10 mg/day n=26	15 mg/day n=26	20 mg/day n=28
* P<0.01; n=number of patients; SD = standard deviation
Mean baseline IGF-I (ng/ml) (SD)	670 (288)	627 (251)	649 (293)	732 (205)
Mean percent change from baseline in IGF-I (SD)	-4.0 (17)	-27 (28)	-48 (26)	-63 (21)
Somavert minus Placebo (95% CI for treatment difference)		-23* (-35, -11)	-44* (-56, -33)	-59* (-68, -49)

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

Figure 1. Effects of Somavert on Serum Markers (Mean ± 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-I Levels Normalized at Week 12

Table 5 shows the effect of treatment with Somavert on ring size (standard jeweler's sizes converted to a numeric score ranging from 1 to 63), and on signs and symptoms of acromegaly. Each individual score for a sign or symptom of acromegaly (for soft-tissue swelling, arthralgia, headache, perspiration and fatigue) was based on a nine-point ordinal rating scale (0 = absent and 8 = severe and incapacitating), and the total score for signs or symptoms of acromegaly was derived from the sum of the individual scores. Mean baseline scores were as follows: ring size = 47.1; total signs and symptoms = 15.2; soft tissue swelling = 2.5; arthralgia = 3.2; headache = 2.4; perspiration = 3.3; and fatigue = 3.7.

Table 5. Mean Change from Baseline (SD) at Week 12 for Ring Size and Signs and Symptoms of Acromegaly

	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 for signs and symptoms of acromegaly	1.3 (6.0)	-2.5 (4.3)	-4.4 (5.9)	-4.7 (4.7)
Soft-tissue swelling	0.3 (2.3)	-0.7 (1.6)	-1.2 (2.3)	-1.3 (1.3)
Arthralgia	0.1 (1.8)	-0.3 (1.8)	-0.5 (2.5)	-0.4 (2.1)
Headache	0.1 (1.7)	-0.4 (1.6)	-0.3 (1.4)	-0.3 (2.0)
Perspiration	0.1 (1.7)	-0.6 (1.6)	-1.1 (1.3)	-1.7 (1.6)
Fatigue	0.7 (1.5)	-0.5 (1.4)	-1.3 (1.7)	-1.0 (1.6)

Serum growth hormone (GH) concentrations, as measured by research assays using antibodies that do not cross-react with pegvisomant, rose within two weeks of beginning treatment with Somavert. The largest increase in GH concentration was seen in patients treated with doses of Somavert 20 mg/day. This effect is presumably the result of diminished inhibition of GH secretion as IGF-I levels fall. As shown in Figure 3, when patients with acromegaly were given a loading dose of Somavert followed by a fixed daily dose, the rise in GH was inversely proportional to the fall in IGF-I and generally stabilized by week 2. Serum GH concentrations remained stable in patients treated with Somavert for the average of 43 weeks (range, 0-82 weeks).

Figure 3. Percent Change in Serum GH and IGF-I 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-I data had a normal IGF-I concentration at any visit during the study.

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.

Important:

• Do not share your Somavert syringes or needles with other people. You may give other people a serious infection, or get an infection from them.
• Somavert comes in a vial as a white block of powder. You must mix Somavert with a liquid (diluent) before you can use it. The liquid comes in a single-dose pre-filled syringe labeled 'Sterile Water for Injection'. Do not use any other liquid to mix with Somavert.
• You must use the mixed Somavert within 6 hours after you mix it. If you have not used the mixed Somavert within 6 hours, throw the Somavert away.

Step 1. Things you need

A single Somavert pack containing:

• A vial of Somavert powder.
• A pre-filled syringe.
• A safety needle.

You will also need:

• A cotton ball.
• An alcohol swab.
• A sharps disposal container. See "Dispose" at the end of these instructions.

Step 2. Getting ready

Before you start:

• Only mix Somavert and the liquid when you are ready to inject your dose.
• Remove a single Somavert pack from the refrigerator and allow it to come to room temperature in a safe place at least 10 minutes before you need to use it.
• Do not heat the Somavert pack by using a heat source such as hot water or microwave. Let it warm up on its own.
• Wash your hands with soap and water, and dry completely.
• Peel open the packaging of the syringe and safety needle to make it easier to pick up each item as you prepare for your injection.
• Do not use the syringe or vial if:
  • they are damaged or faulty
  • the expiration date has passed
  • it has been frozen, even if it has now thawed (syringe only)

Step 3. Choose injection area

• Choose a different location within an area for each injection.
• Avoid bony areas or areas that are bruised, red, sore or hard, or areas that have scars or skin conditions.
• Clean the injection area with the alcohol swab as instructed by your healthcare provider.
• Allow the injection area to dry.

Step 4. Remove vial cap

• Remove the cap from the vial.
• Throw the cap away. It is not needed again.
  Caution: Do not let anything touch the vial stopper.

Step 5. Remove syringe cap

• Snap off the syringe cap leaving the syringe collar in place. It may take more effort to snap off than you might expect.
• Throw the syringe cap away. It is not needed again.
• Keep the syringe upright to avoid leakage.
  Caution: Do not let the end of the syringe touch anything when the syringe cap is off.

Step 6. Attach safety needle

• Push down and twist the safety needle firmly onto the syringe as far as it will go.

Step 7. Remove needle cover

• Fold the needle guard out of the way of the needle cover.
• Carefully pull the needle cover straight off.
• Throw the needle cover away. It is not needed again.
  Caution: Do not let the needle touch anything.

Step 8. Insert needle

• Push the needle through the center of vial stopper, as shown.
• Support the syringe while the needle is in the vial stopper to prevent bending the needle.

Step 9. Add liquid

• Tilt both the vial and syringe at an angle, as shown.
• Push the plunger rod down slowly until all the liquid has emptied into the vial.
• Caution: Do not squirt the liquid directly onto the powder. This creates foam. Foam makes the medicine unusable.
• Do not withdraw the needle yet.

Step 10. Swirl vial

• Support both the syringe and vial in 1 hand, as shown.
• Gently and slowly swirl the liquid, sliding the vial in a circular motion on a flat surface.
• Continue swirling the liquid until all the powder has fully dissolved.
  Note: This may take up to 5 minutes.
  Do not shake.

Step 11. Check medicine

• Keeping the needle in the vial, look carefully at the medicine. It must be clear and free of particles.
• Do not use if:
  • the medicine is cloudy or hazy
  • the medicine has any color at all
  • there are any particles or foam in the vial
• If you have any doubts about your medication go to www.Somavert.com or call 1-800-645-1280.

Step 12. Reposition needle

• Turn the vial so that you can see the stopper gap, as shown.
• Pull the needle down so that the needle tip is at the lowest point in the liquid. This will help you to draw off as much liquid as possible.
• Check that the plunger rod has not moved. If the plunger rod has moved, then push it back all the way into the syringe. This ensures that all air is removed from the syringe before you draw off the dose.

Step 13. Draw off dose

• Slowly pull back the plunger rod to withdraw as much medicine as possible from the vial.
  Note: If you see air in the syringe, tap the barrel to float the bubbles to the top, and then gently push the bubbles out into the vial.
• Pull the needle out of the vial.

Step 14. Insert needle

• Gently pinch the skin at the site of injection.
• Insert the needle to its full depth into the pinched skin.

Step 15. Inject medicine

• Push the plunger rod down slowly until the barrel is empty.
  Note: Make sure you keep the needle in at full depth.
• Release the pinched skin and pull the needle straight out.

Step 16. Make needle safe

• Fold the needle guard over the needle.
  Gently apply pressure using a hard surface to lock the needle guard in place.
• Note: You will hear a click when the needle guard has been locked.

Step 17. Dispose

• Put your used syringes in a FDA cleared sharps disposal container right away after use.
• Do not throw away (dispose of) syringes in your household trash.
  Note: If you do not have a FDA cleared sharps disposal container, please refer to the safe syringe disposal information on the right hand side of this leaflet.

Step 18. After injection

• If necessary, use a clean cotton ball and press lightly on the injection area.
• Do not rub the area.

NDC 0009-5175-02

Pfizer

Somavert®
pegvisomant for injection

10 mg (as protein)

For Subcutaneous Use Only
single dose vial

1 Vial
Rx only

Pfizer
Somavert®
pegvisomant for injection
10 mg (as protein)

For Subcutaneous Injection Only
single dose vial

Package also contains
Prefilled Diluent Syringe, USP

PAA073011

TEAR HERE

Use the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not use extra medicine to make up the missed dose.

Get emergency medical help if you have signs of an allergic reaction to Somavert: hives; wheezing, difficult breathing; feeling like you might pass out; swelling of your face, lips, tongue, or throat.

Stop using Somavert and call your doctor at once if you have:

• thickening of the skin or a hard lump where you injected the medicine;

• easy bruising; or

• liver problems--nausea, upper stomach pain, itching, tired feeling, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes).

Common Somavert side effects may include:

• pain;

• fever, chills, body aches, flu symptoms;

• nausea, diarrhea;

• abnormal liver function tests; or

• pain or irritation where the medicine was injected.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.