Consumer medicine information

Somavert

Pegvisomant

BRAND INFORMATION

Brand name

Somavert

Active ingredient

Pegvisomant

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Somavert.

SUMMARY CMI

SOMAVERT®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using SOMAVERT?

SOMAVERT contains the active ingredient pegvisomant. SOMAVERT is used to treat acromegaly, a disease caused by the body making too much growth hormone (which controls the growth of tissues, organs and bones). This leads to an enlargement of the bones, especially of the hands and feet, and other possible symptoms.

For more information, see Section 1. Why am I using SOMAVERT? in the full CMI.

2. What should I know before I use SOMAVERT?

Do not use SOMAVERT if you have ever had an allergic reaction to pegvisomant or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use SOMAVERT? in the full CMI.

3. What if I am taking other medicines?

Some medicines and SOMAVERT may interfere with each other.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use SOMAVERT?

  • A starting dose of 80 mg will be given to you by your doctor. Following this your doctor will tell you how much SOMAVERT you must use each day.
  • You will be taught how to mix and inject SOMAVERT.

More instructions can be found in Section 4. How do I use SOMAVERT? in the full CMI.

5. What should I know while using SOMAVERT?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using SOMAVERT.
  • Continue using SOMAVERT for as long as your doctor tells you to.
Things you should not do
  • Do not stop using this medicine suddenly or lower the dose without checking with your doctor.
  • Do not shake the mixed vial. Shaking may damage the medicine.
Driving or using machines
  • Be careful driving or operating machinery until you know how SOMAVERT affects you.
Looking after your medicine
  • Keep the SOMAVERT vials and the diluent syringes in their packs until it is time to use them.
  • Store the SOMAVERT vials in the refrigerator at 2-8°C. Do not freeze.
  • Store the diluent syringes at room temperature (below 25°C) or in the refrigerator at 2-8°C. Do not freeze.

For more information, see Section 5. What should I know while using SOMAVERT? in the full CMI.

6. Are there any side effects?

Common side effects are soreness, swelling or redness at the site of injection, a build-up of fatty tissue under the skin at the injection site, flu-like symptoms, pain, nausea and diarrhoea. Serious side effects may include shortness of breath, wheezing or difficulty breathing, swelling of the face, lips, tongue or other parts of the body, rash, itching or hives on the skin, dizziness. These are symptoms of an allergic reaction.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

SOMAVERT®

Active ingredient(s): pegvisomant (rbe)


Consumer Medicine Information (CMI)

This leaflet provides important information about using SOMAVERT. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using SOMAVERT.

Where to find information in this leaflet:

1. Why am I using SOMAVERT?
2. What should I know before I use SOMAVERT?
3. What if I am taking other medicines?
4. How do I use SOMAVERT?
5. What should I know while using SOMAVERT?
6. Are there any side effects?
7. Product details

1. Why am I using SOMAVERT?

SOMAVERT contains the active ingredient pegvisomant. Pegvisomant is a product of biotechnology and is similar to human growth hormone, which exists naturally in the human body. Pegvisomant works by blocking the action of the body's growth hormone.

SOMAVERT is used to treat acromegaly, a disease caused by the body making too much growth hormone (which controls the growth of tissues, organs and bones). This leads to an enlargement of the bones, especially of the hands and feet, and other possible symptoms.

2. What should I know before I use SOMAVERT?

Warnings

Do not use SOMAVERT if:

  • you are allergic to pegvisomant or any of the ingredients listed at the end of this CMI.
  • Always check the ingredients to make sure you can use this medicine.

Tell your doctor if you:

  • have or have had any of the following medical conditions:
    - a tumour in the pituitary gland (a hormonal gland in the brain)
    - problems with your blood sugar levels, either too high (diabetes) or too low (hypoglycaemia)
    - problems with your blood liver enzyme levels
    - liver disease
    - obstructive biliary tract disease.
  • take any medicines for any other condition.

Your doctor may want to carry out some additional tests or take additional precautions before starting treatment.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Tell your doctor if you are pregnant or intend to become pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

SOMAVERT is not recommended during pregnancy.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and SOMAVERT may interfere with each other. These include:

  • medicines used to treat diabetes such as insulin or oral hypoglycaemic medicines (which lower your blood sugar levels)
  • opioid medicines used to relieve pain.

These medicines may be affected by SOMAVERT or may affect how well it works. You may need different amounts of SOMAVERT, or you may need to take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while using SOMAVERT.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect SOMAVERT.

4. How do I use SOMAVERT?

How much to use

  • A starting dose of 80 mg will be given to you by your doctor.
  • Following this, your doctor will tell you how much SOMAVERT to use each day.
  • Follow the instructions provided and use SOMAVERT until your doctor tells you to stop.

When to use SOMAVERT

  • SOMAVERT should be used at about the same time each day. Using it at the same time each day will have the best effect. It will also help you remember when to use it.
  • It does not matter if you use SOMAVERT before or after food.

How to use SOMAVERT

  • SOMAVERT is given by injection under the skin (subcutaneous).
  • It is important to use a different injection site every day to prevent the buildup of fatty tissue under the skin at the injection site.
  • You will be taught how to mix and inject SOMAVERT. It is a good idea to refer to the instruction sheet in the pack each time you mix and inject.
  • Inject your dose of SOMAVERT immediately or within 6 hours after preparation. If storage is necessary, store in the refrigerator at 2-8°C.
  • It is important that you always use SOMAVERT exactly as you have been instructed.

When you mix SOMAVERT, gently swirl the vial to dissolve the powder. Do not shake the vial as this may damage the medicine. After mixing check to make sure that the powder is completely dissolved and the solution is clear. Do not inject if the solution is cloudy or has particles in it.

It is a good idea to refer to the Instructions for Use provided in the pack on the correct way to prepare and inject SOMAVERT each time you use it.

How long to use SOMAVERT

Continue using SOMAVERT for as long as your doctor tells you to.

SOMAVERT helps control your condition, but it does not cure it. It is important to keep using SOMAVERT even if you feel well.

If you forget to use SOMAVERT

SOMAVERT should be used at about the same time each day. If you miss your dose at the usual time, inject the next dose as soon as you remember, and then go back to using SOMAVERT as you would normally.

Do not use a double dose to make up for the dose you missed.

This may increase the chance of you getting unwanted side effects.

If you use too much SOMAVERT

If you think that you have used too much SOMAVERT, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using SOMAVERT?

Things you should do

Keep all your doctor's appointments so that your progress can be checked.

Your doctor will check your liver function and other blood substance levels periodically to prevent unwanted side effects, and to adjust your dose of SOMAVERT.

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are using SOMAVERT.

If you are going to have surgery, tell the surgeon or anaesthetist that you are using SOMAVERT. It may affect other medicines used during surgery.

If you are about to have any blood tests, tell your doctor that you are using SOMAVERT. It may interfere with the results of some tests.

If you become pregnant while using SOMAVERT, tell your doctor immediately.

Remind any doctor, dentist or pharmacist you visit that you are using SOMAVERT.

Things you should not do

  • Do not stop using this medicine suddenly or lower the dose without checking with your doctor. If you stop using SOMAVERT suddenly your condition may worsen or you may have unwanted side effects.
  • Do not heat or freeze your mixed or unmixed SOMAVERT.
  • Do not give your SOMAVERT to anyone else.
  • Do not shake the mixed SOMAVERT vial as shaking may damage the medicine.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how SOMAVERT affects you.

SOMAVERT may cause dizziness in some people. If you feel dizzy, do not drive, operate machinery or do anything else that may be dangerous.

Looking after your medicine

  • Keep the SOMAVERT vials and the diluent syringes in their cartons in order to protect from light.
  • Keep the SOMAVERT vials in the refrigerator at 2-8°C. Do not freeze.
  • The carton(s) containing the SOMAVERT vials may be stored at room temperature (below 25°C) for a single period of up to 30 days. The vials may not be returned to refrigerated storage after storage at room temperature. They must be discarded if not used within the 30 days of storage at room temperature or the expiry date, whichever is earlier.
  • Store the diluent syringes at room temperature (below 25°C) or in the refrigerator at 2-8°C. Do not freeze.

Follow the instructions in the carton on how to take care of your medicine properly.

Do not store or leave SOMAVERT:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep SOMAVERT where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Side effects

Side effectsWhat to do
Administration site disorders:
  • soreness, swelling or redness at the injection site
  • build-up of fatty tissue under the skin at the injection site.
Gastrointestinal disorders:
  • diarrhoea
  • nausea
General disorders:
  • flu-like symptoms
  • pain
Speak to your doctor if you have any of these side effects and they worry you.

The above list includes the more common side effects of SOMAVERT. They are usually mild and short-lived.

SOMAVERT can also cause changes in the levels of certain substances in your blood. These can only be found when your doctor does tests from time to time to check your progress.

Serious side effects

Serious side effectsWhat to do
Allergic reactions:
  • swelling of the face, tongue, lips, throat or other parts of the body
  • wheezing or trouble breathing
  • generalised skin rash, hives (urticaria) or itching
  • dizziness.
Call your doctor straight away or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What SOMAVERT contains

Active ingredient
(main ingredient)
pegvisomant
Other ingredients
(inactive ingredients)
glycine, mannitol, dibasic sodium phosphate, monobasic sodium phosphate monohydrate, water for injections

Do not use this medicine if you are allergic to any of these ingredients.

What SOMAVERT looks like

SOMAVERT comes as a white powder that is mixed with a diluent to form a clear solution for injection.

SOMAVERT powder is contained in a glass vial and the diluent (water for injections) is contained in a glass syringe.

SOMAVERT comes in three strengths: 10 mg, 15 mg and 20 mg.

The 10 mg and 15 mg strengths are available in packs of 30. The 20 mg strength is available in packs of 1 and 30.

SOMAVERT 10 mg: AUST R 286628

SOMAVERT 15 mg: AUST R 286629

SOMAVERT 20 mg: AUST R 286630

Who distributes SOMAVERT

Pfizer Australia Pty Ltd
Sydney NSW
Toll Free Number: 1800 675 229
www.pfizermedinfo.com.au

This leaflet was prepared in January 2023.

Published by MIMS March 2023

BRAND INFORMATION

Brand name

Somavert

Active ingredient

Pegvisomant

Schedule

S4

 

1 Name of Medicine

Pegvisomant (rbe).

2 Qualitative and Quantitative Composition

Somavert is available in single-dose sterile vials containing 10, 15, or 20 mg of pegvisomant protein (approximately 10, 15, and 20 U activity, respectively).
Vials containing 10, 15, and 20 mg of pegvisomant protein correspond to approximately 21, 32, and 43 mg pegvisomant, respectively.

Excipient(s) with known effect.

Mannitol.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Powder for injection.
Somavert is a sterile, white to slightly off-white lyophilised powder intended for subcutaneous injection after reconstitution with 1 mL of sterile water for injections included in the pack.

4 Clinical Particulars

4.1 Therapeutic Indications

The treatment of acromegaly in patients who have had inadequate response to surgery and/or radiation and/or other medical therapies or for whom these therapies are not appropriate. The treatment goal is to normalise IGF-I levels.

4.2 Dose and Method of Administration

Treatment should be initiated under the supervision of a physician experienced in the treatment of acromegaly.
It should be considered whether to continue treatment with somatostatin analogues as the use in combination with Somavert has not been studied.
For the different dosage regimens the following strengths are available: Somavert 10 mg, Somavert 15 mg and Somavert 20 mg.
Prior to the start of pegvisomant, 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 pegvisomant based on baseline liver tests and recommendations for monitoring of liver tests while on pegvisomant, see Section 4.4 Special Warnings and Precautions for Use, Table 1.
Serum IGF-I levels should be obtained prior to initiating therapy. A loading dose of 80 mg of Somavert should be administered subcutaneously under medical supervision. Thereafter, the patient should begin daily subcutaneous injections of 10 mg of Somavert. Serum IGF-I levels should be obtained every 4 to 6 weeks and appropriate dose adjustments made in increments of 5 mg/day in order to maintain the serum IGF-I level within the age-adjusted normal range and alleviate the signs and symptoms of acromegaly.
The maximum daily maintenance dose should not exceed 30 mg.
The site of injection should be rotated daily to help prevent lipohypertrophy.

Diabetic patients.

During treatment with Somavert, patients on anti-diabetic therapy may need reduced doses of insulin or oral hypoglycaemic agents because Somavert increases insulin sensitivity and glucose tolerance (see Section 4.4 Special Warnings and Precautions for Use, Glucose metabolism).

Elderly patients.

Clinical studies of Somavert did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy (see Section 4.4 Special Warnings and Precautions for Use, Use in the elderly).
Heavier individuals tend to have a higher total body clearance of pegvisomant than lighter individuals, and may thus require greater doses of pegvisomant (see Section 5.2 Pharmacokinetic Properties, Metabolism and excretion).
In clinical studies, patients on opioids often needed higher serum pegvisomant concentrations to achieve appropriate IGF-I suppression compared with patients not receiving opioids. The mechanism of this interaction is not known (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Instructions for use and handling.

Somavert is supplied as a lyophilised powder. Reconstitute Somavert by injecting the diluent provided in the pack (sterile Water for Injections) into the vial of Somavert powder, aiming the stream of liquid against the wall of the vial. Hold the vial and diluent syringe in one hand and gently swirl the liquid to dissolve the powder. Do not shake the vial, as this may cause denaturation of pegvisomant. After reconstitution, each vial contains 10, 15 or 20 mg of pegvisomant in 1 mL of solution. The solution should be clear after reconstitution. If the solution is cloudy or contains particles, do not inject it.
Detailed instructions for the preparation and administration of Somavert are contained in the leaflet provided in the pack.
To reduce microbiological hazard, use as soon as practicable after reconstitution. If storage is necessary, hold at 2°C - 8°C for not more than 6 hours.
This product contains no antimicrobial agent. Somavert is for single use in one patient only. Discard any residue.

4.3 Contraindications

Somavert is contraindicated in patients with a history of hypersensitivity to pegvisomant or any of the excipients.

4.4 Special Warnings and Precautions for Use

Tumour growth.

As growth hormone-secreting pituitary tumours may sometimes expand, causing serious complications (e.g. visual field defects), it is essential that all patients be carefully monitored. If evidence of tumour expansion appears, alternative procedures may be advisable.
During clinical studies with Somavert, two patients manifested progressive tumour growth. Both patients had, at baseline, large globular tumours impinging on the optic chiasm, which had been relatively resistant to previous anti-acromegalic therapies. Overall, mean tumour size was unchanged during the course of treatment with Somavert in the clinical studies.

Glucose metabolism.

Growth hormone opposes the effects of insulin on carbohydrate metabolism by decreasing insulin sensitivity and patients with acromegaly therefore have significant insulin resistance; thus, glucose tolerance may increase in some patients treated with Somavert. No case of clinically relevant hypoglycaemia was observed in acromegalic patients with diabetes mellitus who were treated with Somavert during the clinical studies; however, these patients should be carefully monitored and doses of anti-diabetic drugs reduced as necessary (see Section 4.2 Dose and Method of Administration).

Growth hormone deficiency.

Somavert is a potent antagonist of growth hormone action. A state of functional growth hormone (GH) deficiency may result from administration of Somavert, despite the presence of elevated serum GH levels, if serum IGF-I levels drop below the age-adjusted normal range. Serum IGF-I levels should therefore be monitored and maintained within the age-adjusted normal range by adjustment of the dose of Somavert.
Pegvisomant has significant structural similarity to growth hormone (GH) which causes it to cross-react in commercially available GH assays. In addition, treatment with pegvisomant results in elevated growth hormone levels. Somavert treatment should therefore not be monitored or adjusted based on serum GH concentrations. Instead, monitoring and dose adjustments should be based on serum IGF-I levels.

Liver function tests.

Elevations of serum concentrations of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) greater than 10 times the upper limit of normal (ULN) were reported in two patients (0.8%) treated with Somavert during the clinical studies. The event resolved in one patient upon dechallenge and recurred on rechallenge. A liver biopsy performed on the second patient was consistent with chronic hepatitis of unknown aetiology, which was considered unlikely to be related to Somavert treatment. In both patients, the transaminase elevations normalised after discontinuation of Somavert.
During the clinical studies, the incidence of elevations in ALT greater than 3 times but less than or equal to 10 times the ULN in patients treated with Somavert and placebo were 1.2% and 2.1%, respectively.
The transaminase elevations did not appear to be related to the dose or duration of Somavert treatment, generally occurred within 4 to 12 weeks of initiation of therapy, and were not associated with any identifiable biochemical, phenotypic, or genetic predictors.
Prior to the start of pegvisomant, 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)]. Evidence of obstructive biliary tract disease should be ruled out in patients with elevations of ALT and AST or in patients with a prior history of treatment with any somatostatin analogue. Pegvisomant should not be initiated or continued if signs of liver disease are present, pending a comprehensive hepatic evaluation. For recommendations regarding initiation of pegvisomant based on baseline liver tests and recommendations for monitoring of liver tests while on pegvisomant, see Table 1.
If a patient develops LT elevations, or any other signs or symptoms of liver dysfunction while receiving pegvisomant, the following patient management is recommended (see Table 2).

Use in patients with impaired hepatic function.

The safety and effectiveness of Somavert in patients with hepatic insufficiency has not been established.

Use in patients with impaired renal function.

The safety and effectiveness of Somavert in patients with renal insufficiency has not been established.

Use in the elderly.

Clinical studies of Somavert did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Paediatric use.

The safety and effectiveness of Somavert in paediatric patients has not been established.

Effects on laboratory tests.

Liver function tests.

Recommendations for monitoring liver function tests are stated above (see Section 4.4 Special Warnings and Precautions for Use, Effects on laboratory tests, Liver function tests).

IGF-I levels.

Treatment with Somavert should be evaluated by monitoring serum IGF-I concentrations four to six weeks after therapy is initiated or any dose adjustments are made and at least every six months after IGF-I levels have normalised. The goals of treatment should be to maintain a patient's serum IGF-I concentration within the age-adjusted normal range and to control the signs and symptoms of acromegaly.

GH levels.

Pegvisomant has significant structural similarity to growth hormone (GH) which causes it to cross react in commercially available GH assays. In addition, treatment with pegvisomant results in elevated growth hormone levels. Somavert treatment should therefore not be monitored or adjusted based on serum GH concentrations. Instead, monitoring and dose adjustments should be based on serum IGF-I levels.

Use in pregnancy.

Acromegaly control may improve during pregnancy (see Section 4.6 Fertility, Pregnancy and Lactation) and Somavert doses may need to be adjusted (see Section 4.2 Dose and Method of Administration) based on IGF-I values.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Interactions between Somavert and other medicinal products have not been evaluated in formal studies.
Patients receiving insulin or oral hypoglycaemic medicinal products may require dose reduction of these therapeutic agents due to the effect of Somavert on insulin sensitivity (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use, Glucose metabolism).
In clinical studies, patients on opioids often needed higher serum pegvisomant concentrations to achieve appropriate IGF-I suppression compared with patients not receiving opioids. The mechanism of this interaction is not known.

4.6 Fertility, Pregnancy and Lactation

Women of childbearing potential.

Pegvisomant may indirectly impact childbearing potential as it relates to fertility and pregnancy as noted below.

Effects on fertility.

The effects of Somavert on fertility and reproductive performance are not known. No study has been conducted in animals to investigate the effects of pegvisomant on fertility or general reproductive performance and there is no clinical experience of the use of Somavert in women of reproductive age.
The therapeutic benefits of a reduction in IGF-I concentration, which results in improvements of the patient's clinical condition, could potentially increase fertility in female patients. Patients should be advised to use adequate contraception if necessary. Somavert is not recommended during pregnancy (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy).
(Category B3)
In studies in pregnant rabbits, pegvisomant was not teratogenic when administered subcutaneously during organogenesis at doses up to 10 mg/kg/day (5.5 times the maximum human therapeutic dose of 30 mg/day, based on body surface area). At 10 mg/kg/day, a reproducible small increase in post-implantation loss was observed. The potential developmental toxicity of pegvisomant has not been investigated in a second animal species. There are no studies in pregnant women. Somavert is not recommended during pregnancy and should be used only if the anticipated therapeutic benefit clearly outweighs the potential risk.
If Somavert is used during pregnancy, IGF-I levels should be closely monitored, especially during the first trimester. It may be necessary to adjust the dose of Somavert during pregnancy (see Section 4.4 Special Warnings and Precautions for Use).
The potential effects of pegvisomant on post-natal development have not been investigated in animals. It is not known whether Somavert is excreted in human milk. Because many drugs are excreted in milk, caution should be exercised when Somavert is administered to a breastfeeding woman.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effect of Somavert on the ability to drive and use machines have been performed. However, adverse effects of Somavert include dizziness which could affect the ability to drive or use machines (see Section 4.8 Adverse Effects (Undesirable Effects)).

4.8 Adverse Effects (Undesirable Effects)

In clinical studies, the majority of adverse reactions to Somavert were of mild to moderate intensity, of limited duration and did not require discontinuation of treatment. Most adverse events did not appear to be dose dependent.
Nine acromegalic patients (9.6%) withdrew from pre-marketing clinical studies because of adverse events, including two patients with marked transaminase elevations, one patient with lipohypertrophy at the injection sites, and one patient with substantial weight gain.
Table 3 shows the incidence of treatment-emergent adverse events that were reported in at least two patients treated with Somavert and at frequencies greater than placebo during the 12-week, placebo-controlled study.

Immunogenicity.

The development of isolated low-titre non-neutralising anti-growth hormone antibodies was observed in 16.9% of patients treated with Somavert. The clinical significance of these antibodies is unknown.

Post-marketing experience.

Occurrence of injection site hypersensitivity and injection site hypertrophy (e.g. lipohypertrophy) has been observed.
The following adverse reactions have been identified during post-approval use of Somavert. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency.

Immune system disorders.

Systemic hypersensitivity reactions including anaphylactic/anaphylactoid reactions, laryngospasm, angioedema, generalised skin reactions (rash, erythema, pruritus, urticaria). Some patients required hospitalisation.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

Signs and symptoms.

There is limited experience of overdosage with Somavert. A patient who self-administered 80 mg/day of Somavert for seven days did not show clinically significant adverse events that were considered related to the overdose.

Recommended treatment.

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.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: ATC code: H01AX01.
Pegvisomant is an analogue of human growth hormone (GH) that has been structurally altered to act as a GH receptor antagonist.
Pegvisomant is a protein of recombinant DNA origin containing 191 amino acid residues to which several polyethylene glycol (PEG) polymers are covalently bound (predominantly 4 to 6 PEG/protein molecule). The molecular weight of the protein of pegvisomant is 21,998 Daltons. The molecular weight of the PEG portion of pegvisomant is approximately 5000 Daltons. The predominant molecular weights of pegvisomant are thus approximately 42,000, 47,000 and 52,000 Daltons. The schematic below shows the amino acid sequence of the pegvisomant protein (PEG polymers are shown attached to the 5 most probable attachment sites). Pegvisomant is synthesised by a specific strain of Escherichia coli bacteria that has been genetically modified by the addition of a plasmid that carries a gene for GH receptor antagonist. Biological potency is determined using a cell proliferation bioassay.

Mechanism of action.

Pegvisomant is an analogue of human growth hormone that has been genetically modified to be a growth hormone receptor antagonist.
Pegvisomant binds to growth hormone receptors on cell surfaces, where it blocks the binding of endogenous growth hormone, and thus interferes with intracellular growth hormone signal transduction. Limited in vitro studies suggest that pegvisomant does not bind to other cytokine receptors, including prolactin. Inhibition of growth hormone action with pegvisomant leads to decreased serum concentrations of insulin-like growth factor-I (IGF-I), as well as other growth hormone-responsive serum proteins such as free IGF-I, the acid-labile subunit of IGF-I (ALS), and insulin-like growth factor binding protein-3 (IGFBP-3).

Clinical trials.

Acromegalic patients (n=112) previously treated with surgery, radiation therapy and/or medical therapies participated in a 12-week, randomised, double-blind, multicentre study comparing placebo and Somavert. Following withdrawal from previous medical therapy, the 80 patients randomised to treatment with Somavert received an 80 mg subcutaneous (SC) loading dose, followed by 10, 15 or 20 mg/day SC. Dose dependent, statistically significant reductions in mean IGF-I (p < 0.0001), free IGF-I (p < 0.05), IGFBP-3 (p < 0.05) and ALS (p < 0.05) were observed at all post-baseline visits in the Somavert treatment groups (see Figure 1 and Table 4).
Serum IGF-I levels were normalised at the end of the study (week 12) in 9.7%, 38.5%, 75% and 82% of subjects treated with placebo, 10 mg/day, 15 mg/day or 20 mg/day Somavert respectively.
Statistically significant differences from placebo (p < 0.05) were observed for improvements in the total signs and symptoms score for all dose groups compared to placebo.
A cohort of 38 acromegalic subjects has been followed in a long-term, open-label, dose-titration study for at least 19 consecutive months of daily dosing with Somavert (mean = 84.7 weeks). The mean IGF-I concentration in this cohort fell from 917 nanogram/mL to 303 nanogram/mL on Somavert, with 94.7% achieving a normal (age-adjusted) IGF-I concentration. After the first visit at which a normal IGF-I concentration was observed, IGF-I levels remained within the normal range over a mean duration of 19 consecutive months.

5.2 Pharmacokinetic Properties

Absorption.

Absorption of pegvisomant following subcutaneous administration is slow and prolonged, and peak serum pegvisomant concentrations are not generally attained until 33-77 hours after administration. The mean extent of absorption of a 20 mg subcutaneous dose was 57%, relative to a 10 mg intravenous dose.

Distribution.

The mean apparent volume of distribution of pegvisomant is relatively small (7 L, with a coefficient of variation of 12%).
After single subcutaneous pegvisomant administration no linearity is observed with rising doses of 10, 15 or 20 mg. Approximately linear pharmacokinetics are observed at steady state in the population pharmacokinetic studies. Mean ± SEM serum pegvisomant concentrations after 12 weeks of therapy with daily doses of 10, 15, and 20 mg were 6600 ± 1330; 16,000 ± 2200; and 27,000 ± 3100 nanogram/mL, respectively.

Metabolism and excretion.

The pegvisomant molecule contains covalently bound polyethylene glycol polymers in order to reduce the clearance rate. Clearance of pegvisomant following multiple doses is lower than seen following a single dose. The mean total body systemic clearance of pegvisomant following multiple doses is estimated to be 28 mL/h for subcutaneous doses ranging from 10 to 20 mg/day. Clearance of pegvisomant was found to increase with body weight. Pegvisomant is slowly eliminated from serum, with a mean half-life of approximately 6 days (138 hours) following either single or multiple doses. Renal clearance of pegvisomant is negligible and accounts for less than 1% of total body clearance. The elimination route of pegvisomant has not been studied in humans.
The pharmacokinetics of pegvisomant are similar in normal healthy volunteers and acromegaly patients. Heavier individuals tend to have a higher total body clearance of pegvisomant than lighter individuals, and may thus require greater doses of pegvisomant.

Special populations.

No pharmacokinetic data in special populations (children, elderly, populations with renal or hepatic impairment) are available.
The effect of race on the pharmacokinetics of pegvisomant has not been studied.
No gender effect on the pharmacokinetics of pegvisomant was found in a population pharmacokinetic analysis.

5.3 Preclinical Safety Data

Genotoxicity.

Somavert was not mutagenic in the Ames assays or clastogenic in the in vitro chromosomal aberration test in human lymphocytes.

Carcinogenicity.

A two year carcinogenicity study was performed in rats at subcutaneous doses up to 20 mg/kg/day. Malignant fibrous histiocytomas were found at injection sites in male rats only, but not in female rats, at doses ≥ 8 mg/kg/day (producing 10-25 times the systemic exposure in humans at a dose of 0.3 mg/kg/day). The incidence of these tumours was dose dependent and correlated with a dose dependent increase in irritation and inflammation at the injection sites. This response is consistent with literature reports of inert, nongenotoxic biomaterials producing this type of neoplasm in rodents after chronic subcutaneous injection, and the finding is not considered to indicate a carcinogenic hazard to humans.

6 Pharmaceutical Particulars

6.1 List of Excipients

Powder: glycine (1.36 mg), mannitol (36.0 mg), dibasic sodium phosphate (1.04 mg), monobasic sodium phosphate monohydrate (0.36 mg).
Diluent: water for injections.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store the vials of powder at 2°C to 8°C (Refrigerate. Do not freeze). Keep the vial(s) of powder in their carton(s) in order to protect from light.
The carton(s) containing the Somavert powder vial(s) may be stored at room temperature up to a maximum of 25°C for a single period of up to 30 days. The Use By Date should be written on the carton (up to 30 days from the date removed from the refrigerator). Keep the vial(s) in their carton(s) in order to protect from light. The vial(s) may not be returned to refrigerated storage after storage at room temperature. The Somavert powder vial(s) must be discarded if not used within the 30 days of room temperature storage or if not used within the manufacturers' expiry date printed on the carton, whichever is earlier.
Store the pre-filled diluent syringe(s) at room temperature (below 25°C) or in a refrigerator (2°C to 8°C). Do not freeze.
The reconstituted solution should be administered as soon as possible (within 6 hours). If storage is necessary, hold at 2°C to 8°C for not more than 6 hours.

6.5 Nature and Contents of Container

Somavert is supplied as lyophilised powder in glass vials and Water for Injections (diluent) in glass syringes. Somavert 10 mg and 15 mg are available in packs of 30 vials plus 30 diluent syringes. Somavert 20 mg is available in pack(s) of 1 or 30 vials plus equal number diluent syringes.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical structure.


CAS number.

218620-50-9.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription only medicine.

Summary Table of Changes