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.

What is in this leaflet

This leaflet answers some common questions about SOMAVERT. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you using SOMAVERT against the benefits they expect it will have for you.

If you have any concerns about using SOMAVERT, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What SOMAVERT is used for

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.

SOMAVERT is a product of biotechnology and contains the active substance pegvisomant. Pegvisomant is similar to human growth hormone, which exists naturally in the human body.

SOMAVERT works by blocking the action of the body's growth hormone.

Ask your doctor if you have any questions about why SOMAVERT has been prescribed for you. Your doctor may have prescribed it for another reason.

SOMAVERT is not addictive.

SOMAVERT is available only with a doctor’s prescription.

Before you start to use it

When you must not use it

Do not use SOMAVERT if you have an allergy to:

  • pegvisomant
  • any of the ingredients listed at the end of this leaflet

Some of the symptoms of an allergic reaction 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.

Do not use SOMAVERT after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start using SOMAVERT, talk to your doctor.

Before you start to use it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

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.

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

Tell your doctor if you are pregnant or plan to become pregnant or are breast-feeding. SOMAVERT is not recommended during pregnancy.

If you have not told your doctor about any of the above, tell him/her before you start using SOMAVERT.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you get 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.

How to use SOMAVERT

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions in the pack, ask your doctor or pharmacist for help.

How much to use

A starting dose of 80 mg of SOMAVERT will be given to you by your doctor.

Following this, your doctor will tell you how much SOMAVERT you must use each day.

How to use it

SOMAVERT is given by injection under the skin (subcutaneous).

It is important to use a different 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.

It is very important that you always use SOMAVERT exactly as you have been instructed.

If you are not sure what to do, ask your doctor or pharmacist.

When to use it

Use SOMAVERT 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 long to use it

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

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

If you forget to use it

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 that you missed. This may increase the chance of you getting an unwanted side effect.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to use SOMAVERT, ask your pharmacist for some hints.

If you use too much (overdose)

Immediately telephone your doctor or Poisons Information Centre (telephone 131 126) or go to Accident and Emergency (Casualty) at your nearest hospital if you think you or anyone else may have used too much SOMAVERT. Do this even if there are no signs of discomfort or poisoning.

No serious reactions have been reported after an overdose of SOMAVERT.

While you are using SOMAVERT

Things you must 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 from happening, 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.

Tell any other doctors, dentists, and pharmacists who treat you 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 become pregnant while using SOMAVERT, tell your doctor immediately.

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.

Things you must not do

Do not use SOMAVERT to treat any other complaints unless your doctor tells you to.

Do not give SOMAVERT to anyone else, even if they have the same condition as you.

Do not stop using SOMAVERT or lower the dosage without checking with your doctor. If you stop using it suddenly, your condition may worsen or you may have unwanted side effects.

Things to be careful of

Be careful driving or operating machinery 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 could be dangerous.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are using SOMAVERT.

SOMAVERT helps most people with acromegaly, but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following list of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor or pharmacist if you notice any of the following:

  • soreness, swelling or redness at the injection site
  • build-up of fatty tissue under the skin at the injection site
  • flu like symptoms
  • pain
  • nausea
  • diarrhoea.

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.

Mild and serious allergic reactions have been reported in some patients using SOMAVERT.

Tell your doctor immediately or go to Accident and Emergency at your nearest hospital if you notice any of the following

  • swelling of the face, tongue, lips or throat
  • wheezing or trouble breathing
  • generalised skin rash or itching
  • dizziness.

These are symptoms of a serious allergic reaction and you may need urgent medical attention or hospitalisation.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some people.

After using SOMAVERT

Storage

Keep the vials and diluent syringes in their packs until it is time to use them. If you take them out of their packs they may not keep well.

Keep the SOMAVERT vials in your refrigerator where the temperature stays between 2° and 8° Celsius. Do not freeze.

Store the diluent syringes at room temperature (below 30°C) or in the refrigerator at 2°C to 8°C. Do not freeze.

Inject your dose of SOMAVERT immediately or within 6 hours after preparation.

If storage is necessary, store in the refrigerator at 2°C to 8°C.

Do not store SOMAVERT or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop using SOMAVERT or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product Description

What it 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's. The 20 mg strength is available in packs of 1's and 30's.

Ingredients

Active Ingredients

SOMAVERT vials contain 10 mg, 15 mg or 20 mg of the active ingredient pegvisomant.

Inactive Ingredients

Each vial of SOMAVERT contains the following inactive ingredients:

  • glycine
  • mannitol
  • dibasic sodium phosphate
  • monobasic sodium phosphate monohydrate

The diluent syringes contain sterile Water for Injections.

Supplier

SOMAVERT is supplied in Australia by:

Pfizer Australia Pty Ltd
Sydney NSW

Toll Free Number: 1800 675 229

Australian Registration Numbers

SOMAVERT 10 mg AUST R 286628

SOMAVERT 15 mg AUST R 286629

SOMAVERT 20 mg AUST R 286630

This leaflet was prepared in July 2020

© Pfizer Australia Pty Ltd 2019

® Registered Trademark

Published by MIMS September 2020

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.

Growth hormone-secreting pituitary tumours may sometimes expand, causing serious complications (for example, visual field defects).
Treatment by Somavert does not reduce tumour size. Therefore, all patients with these tumours should be carefully monitored in order to detect any potential progression in tumour size.
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, pruritis, 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 vials of powder in their carton in order to protect from light.
Store the pre-filled diluent syringes at room temperature (below 30°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.


PEG attachment sites: Phe1, Lys38, Lys41, Lys70, Lys115, Lys120, Lys140, Lys145, Lys158.

CAS number.

218620-50-9.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription only medicine.

Summary Table of Changes