ANNEX I SUMMARY OF PRODUCT CHARACTERISTICSec.europa.eu/health/documents/community-register/... · Treatment should be initiated under the supervision of a physician experienced in

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ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

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1. NAME OF THE MEDICINAL PRODUCT

SOMAVERT 10 mg powder and solvent for solution for injection.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains 10 mg of pegvisomant.

After reconstitution, 1 ml of solution contains 10 mg pegvisomant.

Pegvisomant is produced in E.Coli by recombinant DNA technology.

For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Powder and solvent for solution for injection.

The powder is white to slightly off-white.

4. CLINICAL PARTICULARS

4.1. Therapeutic indications

Treatment of patients with acromegaly who have had an inadequate response to surgery and/or radiation therapy and in whom an appropriate medical treatment with somatostatin analogues did not normalize IGF-I concentrations or was not tolerated.

4.2. Posology and method of administration

Treatment should be initiated under the supervision of a physician experienced in the treatment of acromegaly.

For the different dosage regimens the following strengths are available: SOMAVERT 10 mg, SOMAVERT 15 mg and SOMAVERT 20 mg.

For instructions on preparation, see section 6.6.

A loading dose of 80 mg pegvisomant should be administered subcutaneously under medical supervision. Following this, SOMAVERT 10 mg reconstituted in 1 ml of solvent should be administered once daily as a subcutaneous injection.

The site of injection should be rotated daily to help prevent lipohypertrophy.

Dose adjustments should be based on serum IGF-I levels. Serum IGF-I concentrations should be measured every four to six weeks and appropriate dose adjustments made in increments of 5 mg/day in order to maintain the serum IGF-I concentration within the age-adjusted normal range and to maintain an optimal therapeutic response.

The maximum dose should not exceed 30 mg/day.

Elderly patients

No dose adjustment is required.

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Paediatric patients

There is no experience in children.

Patients with impaired hepatic or renal function

The safety and effectiveness of SOMAVERT in patients with renal or hepatic insufficiency has not been established.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients.

4.4. Special warnings and precautions for use

Growth hormone-secreting pituitary tumours may sometimes expand, causing serious complications (for example, visual field defects). Treatment by SOMAVERT does not reduce tumour size. All patients with these tumours should be carefully monitored in order to avoid any eventual progression in tumour size under treatment.

SOMAVERT is a potent antagonist of growth hormone action. A growth hormone deficient state may result from SOMAVERT administration, despite the presence of elevated serum growth hormone levels. Serum IGF-I concentrations should be monitored and maintained within the age-adjusted normal range by adjustment of SOMAVERT dosing.

Serum concentrations of alanine aminotransferase (ALT) and aspartate transaminase (AST) should be monitored at four to six week intervals for the first six months of treatment with SOMAVERT, or at any time in patients exhibiting symptoms suggestive of hepatitis. 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. Administration of SOMAVERT should be discontinued if signs of liver disease persist.

The study conducted with SOMAVERT in diabetic patients treated either by insulin or by oral hypoglycaemic medicinal products revealed the risk of hypoglycemia in this population. Therefore, in acromegalic patients with diabetes mellitus, doses of insulin or hypoglycaemic medicinal products may need to be decreased (see also section 4.5).

The therapeutic benefits of a reduction in IGF-I concentration which results in improvement 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 also section 4.6).

4.5. Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed. It should be considered whether to continue treatment with somatostatin analogues. The use of SOMAVERT in combination with other medicinal products for the treatment of acromegaly has not been extensively investigated.

Patients receiving insulin or oral hypoglycaemic medicinal products may require dose reduction of these active substances due to the effect of pegvisomant on insulin sensitivity (see section 4.4).

SOMAVERT has significant structural similarity to growth hormone which causes it to cross-react in commercially available growth hormone assays. Since serum concentrations of therapeutically-effective doses of SOMAVERT are generally 100 to 1000 times higher than the actual serum growth hormone concentrations seen in acromegalics, measurements of serum growth hormone concentrations will be spuriously reported in commercially available growth hormone assays. SOMAVERT

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treatment should therefore not be monitored or adjusted based on serum growth hormone concentrations reported from these assays.

4.6. Pregnancy and lactation

For pegvisomant no clinical data on exposed pregnancies are available.

Animal studies are insufficient with respect to effects on pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3).The potential risk for humans is unknown.

SOMAVERT should not be used during pregnancy unless clearly necessary (see also section 4.4).

Use during lactation

The excretion of pegvisomant in breast milk has not been studied in animals. Clinical data are too limited (one reported case) to draw any conclusion on the excretion of pegvisomant in human breast milk. Therefore, SOMAVERT should not be used in breast-feeding women. However, breast-feeding may be continued if SOMAVERT is discontinued: this decision should take into account the benefit of SOMAVERT therapy to the mother and the benefit of breastfeeding to the child.

4.7. Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed.

4.8. Undesirable effects

Summary of the safety profile

The list below contains adverse reactions seen in clinical trials.

In clinical studies, for patients treated with pegvisomant (n=160), the majority of adverse reactions to pegvisomant were of mild to moderate intensity, of limited duration and did not require discontinuation of treatment.

The most commonly reported adverse reactions considered related to SOMAVERT occurring in 5% of patients with acromegaly during the clinical trials were injection site reactions 11%, hyperhidrosis7%, headache 6% and asthenia 6%.

Tabulated list of adverse reactions

The list below contains adverse reactions seen in clinical trials or that were spontaneously reported, classified by system organ class and frequency. Reports from post-marketing experience are included in italics.

Adverse reactions are listed according to the following categories:Very common: 1/10Common: 1/100 to <1/10Uncommon: 1/1,000 to <1/100Not known (cannot be estimated from the available data)

Blood and lymphatic system disorders:Uncommon: thrombocytopenia, leukopenia, leukocytosis, haemorrhagic diathesis

Metabolism and nutrition disorders:Common: hypercholesterolemia, weight gain, hyperglycemia, hungerUncommon: hypertriglyceridemia, hypoglycemia

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Immune system disorders:Not known: systemic hypersensitivity reactions*

Psychiatric disorders:Common: abnormal dreams, sleep disorderUncommon: anger, apathy, confusion, increased libido, panic attack, short term memory loss

Nervous system disorders:Common: headache, dizziness, somnolence, tremorUncommon: hypoesthesia, dysgeusia, migraine, narcolepsy

Eye disorders:Uncommon: asthenopia, eye pain

Ear and labyrinth disorders:Uncommon: Meniere’s disease

Cardiac disorders:Common: oedema peripheral

Vascular disorders:Common: hypertension

Respiratory, thoracic and mediastinal disorders:Uncommon: dyspnoea

Gastrointestinal disorders:Common: diarrhoea, constipation, nausea, vomiting, abdominal distension, dyspepsia,

flatulenceUncommon: dry mouth, hemorrhoids, salivary hypersecretion, tooth disorder

Hepatobiliary disorders:Common abnormal liver function tests (e.g. transaminase elevation) (see section 4.4)

Skin and subcutaneous tissue disorders:Common: hyperhidrosis, pruritus, rashUncommon: face oedema, dry skin, contusion, increased tendency to bruise, night sweats

Musculoskeletal and connective tissue disorders:Common: arthralgia, myalgiaUncommon: arthritis

Renal and urinary disorders:Uncommon: haematuria, proteinuria, polyuria, renal impairment

General disorders and administration site conditions:Common: influenza-like illness, fatigue, injection site bruising or bleeding, injection site

reaction (including injection site hypersensitivity), injection site hypertrophy (e.g. lipohypertrophy)* ,asthenia

Uncommon: pyrexia, feeling abnormal, impaired healing,

*see Description of selected adverse reactions below.

Description of selected adverse reactions

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Most injection site reactions characterised as localised erythemas and soreness, spontaneouslyresolved with local symptomatic treatment, while SOMAVERT therapy continued. Occurrence of injection site hypertrophy has been observed, including lipohypertrophy.

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

Systemic hypersensitivity reactions including anaphylactic/anaphylactoid reactions, laryngospasm, angioedema, generalized skin reactions (rash, erythema, pruritus, urticaria).have been reported in post marketing use. Some patients required hospitalization. Upon re-administration, symptoms did not re-occur in all patients.

4.9. Overdose

There is limited experience of overdose with SOMAVERT. In the one reported incident of acute overdose, where 80 mg/day was administered for 7 days, the patient experienced a slight increase in fatigue and dry mouth. In the week following discontinuation of treatment the adverse reactions noted were: insomnia, increased fatigue, oedema peripheral, tremor, and weight gain. Two weeks after stopping treatment, leukocytosis and moderate bleeding from injection and vein puncture sites was observed which were considered possibly related to SOMAVERT.

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.

5. PHARMACOLOGICAL PROPERTIES

5.1. Pharmacodynamic properties

Pharmacotherapeutic group: Other anterior pituitary lobe hormones and analogues, ATC code: H01AX01.

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 growth hormone binding, and thus interferes with intracellular growth hormone signal transduction. Pegvisomant is highly selective for the GH receptor, and does not cross-react with 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).

Acromegalic patients (n=112) have been treated in a 12-week, randomised, double-blind, multicentre study comparing placebo and pegvisomant. 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 pegvisomant treatment groups. The serum IGF-1 was 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 12 consecutive months of daily dosing with pegvisomant (mean = 55 weeks). The mean IGF-I concentration in this cohort fell from 917 ng/ml to 299 ng/ml on pegvisomant, with 92% achieving a normal (age-adjusted) IGF-I concentration.

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5.2. Pharmacokinetic properties

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 subcutaneous dose was 57% relative to an intravenous dose.

The apparent volume of distribution of pegvisomant is relatively small (7-12 l). 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. Renal clearance of pegvisomant is negligible and accounts for less than 1% of total body clearance. Pegvisomant is slowly eliminated from serum, with mean estimates of half-life generally ranging from 74 to 172 hours following either single or multiple-doses. The metabolism of pegvisomant is not studied.

After single subcutaneous pegvisomant administration no linearity is observed with rising doses of 10, 15 or 20 mg. Approximately linear pharmacokinetics is observed at steady state in the population pharmacokinetic studies. The data from 145 patients in two long-term studies who received daily doses of 10, 15, or 20 mg, demonstrate pegvisomant mean serum concentrations (± SD) of approximately 8800 ± 6300, 13200 ± 8000 and 15600 ± 10300 ng/ml, respectively.

The pharmacokinetics of pegvisomant are similar in normal healthy volunteers and acromegaly patients, although heavier individuals tend to have a higher total body clearance of pegvisomant than lighter individuals, and may thus require greater doses of pegvisomant.

No pharmacokinetic data in special populations (children, populations with renal and hepatic impairment) are available.

5.3. Preclinical safety data

Non-clinical data revealed no special hazard for humans based on studies of repeated dose toxicity in rat and monkey. However, due to the marked pharmacological response in monkey, systemic exposures higher than those achieved in patients at therapeutic doses have not been studied. Except for one segment II test in the rabbit, no other reproductive toxicity studies were conducted.

Malignant fibrous histiocytomas associated with fibrosis and histiocytic inflammation were observed at injection sites in males in the rat carcinogenicity study at exposure levels equivalent to three times the human exposure based on mean plasma concentrations in two long-term studies at a daily dose of 30 mg. The relevance of this response for humans is currently unknown.

6. PHARMACEUTICAL PARTICULARS

6.1. List of excipients

Powder:Glycine Mannitol (E421)Sodium phosphate dibasic anhydrous Sodium phosphate monobasic monohydrate

Solvent:Water for Injections

6.2. Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

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6.3. Shelf life

3 years.

After reconstitution, the product should be used immediately.

6.4. Special precautions for storage

Store in a refrigerator (2C – 8C). Do not freeze. Keep the container in the outer carton in order to protect from light.

After reconstitution:Use immediately.

6.5. Nature and contents of container

Powder in a vial (type I glass) with a rubber stopper (butyl) and 8 ml solvent in a vial (type I glass), with a stopper (rubber butyl). Pack size of 30.

6.6. Special precautions for disposal and other handling

Reconstitute using 1 ml solvent.

Add solvent to vial with powder for injection. Gently dissolve the powder with a slow, swirling motion. Do not shake vigorously, as this might cause denaturation of the active ingredient.

After reconstitution, if the solution is cloudy or contains particulate matter, the product must be discarded.

For single use only. Any unused product or waste material should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

Pfizer LimitedSandwichKent CT13 9NJUnited Kingdom

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/02/240/001

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorization: 13/11/2002Date of last renewal: 20/09/2007

10. DATE OF REVISION OF THE TEXT

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Treatment of patients with acromegaly who have had an inadequate response to surgery and/or radiation therapy and in whom an appropriate medical treatment with somatostatin analogues did not normalize IGF-I concentrations or was not tolerated.









Elderly patients


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Paediatric patients
















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Animal studies are insufficient with respect to effects on pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). The potential risk for humans is unknown.
















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4.9. Overdose





Pharmacotherapeutic group: Other anterior pituitary lobe hormones and analogues, ATC code H01AX01.






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Powder:Glycine Mannitol (E421) Sodium phosphate dibasic anhydrous Sodium phosphate monobasic monohydrate




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6.3. Shelf life

3 years.






Powder in a vial (type I glass) with a rubber stopper (butyl) and 8 ml solvent in a vial (type I glass), with a stopper (rubber butyl). Pack size of 30.









EU/1/02/240/002




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Treatment of patients with acromegaly who have had an inadequate response to surgery and/orradiation therapy and in whom an appropriate medical treatment with somatostatin analogues did not normalize IGF-I concentrations or was not tolerated.









Elderly patients


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Paediatric patients
















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Animal studies are insufficient with respect to effects on pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3).The potential risk for humans is unknown.
















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4.9. Overdose





Pharmacotherapeutic group: Other anterior pituitary lobe hormones and analogues, ATC code H01AX01.






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Powder:Glycine Mannitol (E421)Sodium phosphate dibasic anhydrous Sodium phosphate monobasic monohydrate




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6.3. Shelf life

3 years.






Powder in a vial (type I glass) with a rubber stopper (butyl) and 8 ml solvent in a vial (type I glass), with a stopper (rubber butyl). Pack sizes of 1 or 30. Not all pack sizes may be marketed.









EU/1/02/240/003-004




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ANNEX II

A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVESUBSTANCE(S) AND MANUFACTURING AUTHORISATIONHOLDER(S) RESPONSIBLE FOR BATCH RELEASE

B. CONDITIONS OF THE MARKETING AUTHORISATION

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A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) ANDMANUFACTURING AUTHORISATION HOLDER(S) RESPONSIBLE FOR BATCHRELEASE

Name and address of the manufacturer(s) of the biological active substance(s)

Pfizer Health ABMariefredsvagen 37645 41 SträngnäsSweden

Pfizer Ireland PharmaceuticalsGrange Castle Business ParkClondalkinDublin 22Ireland

Name and address of the manufacturer(s) responsible for batch release

Pfizer Manufacturing Belgium NVRijksweg 12,B-2870 Puurs,Belgium

B. CONDITIONS OF THE MARKETING AUTHORISATION

CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE IMPOSED ONTHE MARKETING AUTHORISATION HOLDER

Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product Characteristics, section 4.2).

CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT

Not applicable.

OTHER CONDITIONS

The MAH will continue to submit yearly PSURs for the following three years, unless otherwise specified by the CHMP.

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ANNEX III

LABELLING AND PACKAGE LEAFLET

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A. LABELLING

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER CARTON


SOMAVERT 10 mg powder and solvent for solution for injectionPegvisomant

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each vial contains 10 mg pegvisomant

3. LIST OF EXCIPIENTS

Excipients:GlycineMannitol (E421)Sodium phosphate dibasic anhydrousSodium phosphate monobasic monohydrate

4. PHARMACEUTICAL FORM AND CONTENTS

Powder and solvent for solution for injection

30 vials of powder for solution for injection30 vials of water for injections

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use. Subcutaneous use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE REACH AND SIGHT OF CHILDREN

Keep out of the reach and sight of children

7. OTHER SPECIAL WARNING(S), IF NECESSARY

Use immediately after reconstitution. For single use only.

8. EXPIRY DATE

EXP: MM/YYYY

9. SPECIAL STORAGE CONDITIONS

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Store in a refrigerator. Do not freeze.Keep the container in the outer carton in order to protect from light.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER



EU/1/02/240/001

13. BATCH NUMBER

Lot: XXXXX

14. GENERAL CLASSIFICATION FOR SUPPLY

Medicinal product subject to medical prescription

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

SOMAVERT 10 mg

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MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

VIAL

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

SOMAVERT 10 mg powder for solution for injectionPegvisomantSubcutaneous use

2. METHOD OF ADMINISTRATION

3. EXPIRY DATE

EXP: MM/YYYY

4. BATCH NUMBER

Lot: XXXXX

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

10 mg

6. OTHER

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OUTER CARTON
















8. EXPIRY DATE

EXP: MM/YYYY


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EU/1/02/240/002

13. BATCH NUMBER

Lot: XXXXX





SOMAVERT 15 mg

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VIAL




3. EXPIRY DATE

EXP: MM/YYYY

4. BATCH NUMBER

Lot: XXXXX


15 mg

6. OTHER

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OUTER CARTON













Keep out of the reach and sight of children.



8. EXPIRY DATE

EXP: MM/YYYY


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EU/1/02/240/003

13. BATCH NUMBER

Lot: XXXXX





SOMAVERT 20 mg

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OUTER CARTON









1 vial of powder for solution for injection1 vial of water for injections







8. EXPIRY DATE

EXP: MM/YYYY


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EU/1/02/240/004

13. BATCH NUMBER

Lot: XXXXX





SOMAVERT 20 mg

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VIAL




3. EXPIRY DATE

EXP: MM/YYYY

4. BATCH NUMBER

Lot: XXXXX


20 mg

6. OTHER

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VIAL


Solvent for SOMAVERT Subcutaneous use


Read the package leaflet before use.

3. EXPIRY DATE

EXP: MM/YYYY

4. BATCH NUMBER

Lot: XXXXX


8 ml water for injections

6. OTHER

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B. PACKAGE LEAFLET

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PACKAGE LEAFLET: INFORMATION FOR THE USER

SOMAVERT 10 mg powder and solvent for solution for injectionSOMAVERT 15 mg powder and solvent for solution for injectionSOMAVERT 20 mg powder and solvent for solution for injection

Pegvisomant

Read all of this leaflet carefully before you start using this medicine.- Keep this leaflet. You may need to read it again- If you have any further questions, ask your doctor or pharmacist.- This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even

if their symptoms are the same as yours.- If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,

please tell your doctor or pharmacist.

In this leaflet:

1. What SOMAVERT is and what it is used for2. Before you use SOMAVERT3. How to use SOMAVERT4. Possible side effects5. How to store SOMAVERT6. Further information

1. WHAT SOMAVERT IS AND WHAT IT IS USED FOR

SOMAVERT is used for the treatment of acromegaly, a hormonal disorder resulting from the increased secretion of growth hormone (GH) and IGF-I (Insulin-like growth factors), which is characterised by overgrowth of bone, soft tissue swelling, heart disease and related disorders.

SOMAVERT is a product of biotechnology. The active substance in SOMAVERT, pegvisomant is known as a growth hormone receptor antagonist. These substances decrease the action of GH and levels of IGF-I circulating in the blood.

2. BEFORE YOU USE SOMAVERT

Do not use SOMAVERT

If you are allergic (hypersensitive) to pegvisomant or any of the other ingredients of SOMAVERT.

Take special care with SOMAVERT

- If you experience disturbed vision or headaches while using SOMAVERT you must contact your doctor immediately.

- Your doctor or nurse will monitor the levels of IGF-I (Insulin-like growth factors) circulating in the blood and adjust the dose of SOMAVERT if necessary.

- Your doctor should also monitor your adenoma (benign tumour).

- Your doctor or nurse will monitor the level of liver enzymes in the blood every 4-6 weeks for the first six months of treatment with SOMAVERT. Administration of SOMAVERT should bediscontinued if signs of liver disease persist.

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- If you are diabetic, your doctor may need to adjust the amount of insulin or other medicines you are using.

- Female patients should use adequate contraception as fertility may be increased. See also the section about Pregnancy below.

Using other medicines

You must tell your doctor if you have previously used other medicines for the treatment of acromegalyor medicines for the treatment of diabetes.

Please tell your doctor or pharmacist if you are using or have recently used any other medicines, including medicines obtained without a prescription.

As part of your treatment you may be given other medicines. It is important to keep using all your medicines as well as SOMAVERT unless you are told otherwise by your doctor or pharmacist.

Pregnancy and breast-feeding

The effects of SOMAVERT in pregnant women are not known, and so the use of SOMAVERT in pregnant women is not recommended. You are advised to not become pregnant while taking SOMAVERT therapy. In case you become pregnant, you must consult your doctor. Ask your doctor or pharmacist for advice before taking any medicine.

It is not known if SOMAVERT passes into breast milk. You should not breast-feed while taking SOMAVERT unless your doctor has discussed this with you.

Driving and using machines


Important information about some of the ingredients of SOMAVERT

This medicinal product contains less than 1 mmol sodium (23 mg) per 10 mg dose, less than 1 mmol sodium (23 mg) per 15 mg dose, or less than 1 mmol sodium (23 mg) per 20 mg dose i.e. essentially ‘sodium-free’.

3. HOW TO USE SOMAVERT

Always inject SOMAVERT exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure.

A starting dose of 80 mg of SOMAVERT will be given subcutaneously (just under the skin) by your doctor. Following this, the usual daily dose of SOMAVERT is 10 mg, which is given by subcutaneous injection (just under the skin).

Every four to six weeks your doctor will make appropriate dose adjustments, made in increments of 5 mg pegvisomant/day, based on your so-called serum IGF-I levels to maintain an optimal therapeutic response.

Method and route of administration

SOMAVERT is injected under the skin. The injection can be self-administered or given by another person, for example your doctor or his/her assistant. The detailed instructions on injection procedure

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provided at the end of this leaflet must be followed. You should continue to inject SOMAVERT for as long as instructed by your doctor.

SOMAVERT must be dissolved before use. The injection must not be mixed in the same syringe or vial as any other medicine.

Fatty tissue of the skin can build-up at the site of injection. To avoid this, use a slightly different place for your injection each time, as described in Step 2 of the ‘Instructions for Preparing and Giving an Injection of Somavert’ section of this leaflet. This gives your skin and the area under your skin time to recover from one injection before it receives another one in the same place.

If you have the impression that the effect of SOMAVERT is too strong or too weak, talk to your doctor or pharmacist.

If you inject more SOMAVERT than you should

If you accidentally inject more SOMAVERT than told to by your doctor it is unlikely to be serious, but you should contact your doctor or pharmacist immediately.

If you forget to use SOMAVERT

If you forget to give yourself an injection you should inject the next dose as soon as you remember and then continue to inject SOMAVERT as prescribed by your doctor. Do not inject a double dose to make up for forgotten individual doses.

If you have any further questions on the use of this product, ask your doctor or pharmacist.

4. POSSIBLE SIDE EFFECTS

Like all medicines, SOMAVERT can cause side effects, although not everybody gets them.

Common side effects (likely to occur in fewer than 1 in 10 patients) include:

Headache, dizziness, sleepiness, uncontrolled trembling. Diarrhoea, constipation, feeling sick, being sick, feeling bloated, indigestion, gas. Sweating, itching, rash. Joint pain, muscle pain. Increased blood cholesterol, weight gain, increased blood glucose, increased appetite. Increased blood pressure. Bruising or bleeding at injection site, soreness or swelling at injection site, build up of fat

below the surface of the skin at injection site, swelling of the extremities, weakness. Flu-like illness, fatigue. Increased levels of substances that measure the function of the liver. These can be seen in the

results of blood tests. Abnormal dreams, problems sleeping.

Uncommon side effects (likely to occur in fewer than 1 in 100 patients) include:

Decreased platelets in the blood, increased or decreased white cells in the blood, tendency to bleed.

Decreased sense of touch, abnormal sense of taste, migraine. Eyestrain, eye pain, inner ear problems. Shortness of breath. Dry mouth, increased saliva, tooth problems, hemorrhoids. Blood in the urine, protein in the urine, increased urine, kidney problems.

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Facial swelling, dry skin, tendency to bruise, night sweats. Arthritis. Increased fatty substances in the blood, decreased blood glucose. Fever, feeling abnormal, impaired healing. Anger, lack of interest, feeling confused, increased sex drive, panic attack, loss of memory.

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

About 17% of patients will develop antibodies to growth hormone during treatment. The antibodies do not seem to stop SOMAVERT from working.

Mild to serious allergic (anaphylactic) reactions have been reported in some patients taking SOMAVERT. Symptoms of a serious allergic reaction may include one or more of the following: swelling of the face, tongue, lips, or throat; wheezing or trouble breathing (spasm of the larynx); generalized skin rash, nettle rash (urticaria) or itching; or dizziness. Contact your doctor immediately if you develop any of these symptoms.

5. HOW TO STORE SOMAVERT


Do not use SOMAVERT after the expiry date which is stated on the vial and the carton after EXP. The expiry date refers to the last day of that month.

Store in a refrigerator (2C – 8C). Do not freeze. Keep the vials in the outer carton in order to protect from light.

After preparing the SOMAVERT solution it must be used immediately. Carefully dispose of any SOMAVERT solution that has not been injected.

Do not use SOMAVERT if you notice that the solution is cloudy or contains particulate matter.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

6. FURTHER INFORMATION

What SOMAVERT contains

- The active substance is pegvisomant.- One vial of powder contains either 10 mg, 15 mg, or 20 mg. After reconstitution with 1 ml of

solvent, 1 ml of the clear solution contains either 10 mg, 15 mg or 20 mg pegvisomant.- The other ingredients are glycine, mannitol (E421), sodium phosphate dibasic anhydrous and

sodium phosphate monobasic monohydrate.- The solvent is water for injections. One vial of solvent contains 8 ml water for injections.

What SOMAVERT looks like and contents of the pack

SOMAVERT is presented as a powder and a solvent for injection, in a vial. Powder in a vial (either 10 mg, 15 mg, or 20 mg pegvisomant) and solvent in a vial (8 ml). Pack sizes of 1 and 30. Not all pack sizes are marketed. The powder is white and the solvent is clear and colourless.

Marketing Authorisation Holder:

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Manufacturer:

Pfizer Manufacturing Belgium NVRijksweg 122870 PuursBelgium

For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder.

België/Belgique/Belgien Luxembourg/LuxemburgPfizer S.A./N.V. Pfizer S.A.Tél/Tel: +32 (0)2 554 62 11 Tél/Tel: +32 (0)2 554 62 11

България MagyarországПфайзер Люксембург САРЛ, Клон България Pfizer Kft.Тел.: +359 2 970 4333 Tel.: + 36 1 488 37 00

Česká republika MaltaPfizer s.r.o. V.J. Salomone Pharma Ltd.Tel: +420 283 004 111 Tel: + 356 21 22 01 74

Danmark NederlandPfizer ApS Pfizer bvTlf: +45 44 20 11 00 Tel: +31 (0)10 406 43 01

Deutschland NorgePfizer Pharma GmbH Pfizer ASTel: +49 (0)30 550055 51000 Tlf: +47 67 52 61 00

Eesti ÖsterreichPfizer Luxembourg SARL Eesti filiaal Pfizer Corporation Austria Ges.m.b.H.Tel: +372 6 405 328 Tel: +43 (0)1 521 15-0

Ελλάδα PolskaPFIZER ΕΛΛΑΣ Α.Ε. Pfizer Polska Sp. z o.o.Τηλ: +30 210 6785800 Tel.: +48 22 335 61 00

España PortugalPfizer S.L. Laboratórios Pfizer, Lda.Tel: +34 91 490 99 00 Tel: +351 21 423 5500

France RomâniaPfizer Pfizer România S.R.L.Tél: +33 (0)1 58 07 34 40 Tel: +40 (0)21 207 28 00

Hrvatska SlovenijaPfizer Croatia d.o.o. Pfizer Luxembourg SARL, Pfizer, podružnica za

svetovanje s področja farmacevtske dejavnosti, Ljubljana

Tel: + 385 1 3908 777 Tel: + 386 (0)1 52 11 400

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Ireland Slovenská republikaPfizer Healthcare Ireland Pfizer Luxembourg SARL, organizačná zložkaTel: 1800 633 363 (toll free) +44 (0)1304 616161

Tel: + 421 2 3355 5500

Ísland Suomi/FinlandIcepharma hf. Pfizer OySími: + 354 540 8000 Puh/Tel: +358 (0)9 43 00 40

Italia Sverige Pfizer Italia S.r.l. Pfizer ABTel: +39 06 33 18 21 Tel: +46 (0)8 55052000

Κύπρος United KingdomPFIZER ΕΛΛΑΣ Α.Ε. (Cyprus Branch) Pfizer LimitedΤηλ: +357 22 817690 Tel: +44 (0)1304 616161

Latvija

Pfizer Luxembourg SARL filiāle LatvijāTel: +371 670 35 775

LietuvaPfizer Luxembourg SARL filialas LietuvojeTel. +3705 2514000

This leaflet was last revised in {MM/YYYY}.

Detailed information on this medicine is available on the European Medicines Agency (EMEA) web site:http://www.ema.europa.eu. There are also links to other websites about rare diseases and treatments.

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INSTRUCTIONS FOR PREPARING AND GIVING AN INJECTION OF SOMAVERT

Introduction

The following instructions explain how to prepare and inject SOMAVERT. Please read the instructions carefully and follow them step by step. You will be instructed by your doctor or his/her assistant on the technique of self-injection. Do not attempt to self-inject until you are sure that you understand how to prepare and give an injection.The powder must be dissolved with the solvent before use.This injection should not be mixed in the same syringe or vial with any other medicine.

STEP 1. CHOOSING THE METHOD FOR PREPARING THE SOMAVERT SOLUTION

There are 2 methods for preparing the SOMAVERT solution. Please discuss with your doctor or nursewhich method is best for you:a) The Vial Adapter Method (MIXJECT) - not marketed in all countriesb) The Non-Vial Adapter Method.

a) VIAL ADAPTER METHOD (MIXJECT)

GETTING STARTED

Wash your hands thoroughly. Collect:

1 vial of powder (SOMAVERT),1 vial of solvent (Water for Injections), 1 luer-lock syringe of 1ml (for both reconstituting the SOMAVERT solution and giving the injection) is recommended. However, other sizes and types of syringes can be used for the preparation and injection of SOMAVERT. Please consult your healthcare professional for further information. 2 MIXJECT vial adapters, 1 detachable needle (25 to 30 gauge), Alcohol or antiseptic swabs and a proper disposal container for used needles and syringes.

Inspect the expiry dates on both the vial label and the syringe label. They should not be used after the month and year shown.

After reconstitution with 1 ml of solvent, 1 ml of the clear solution contains either 10 mg, 15 mg, or 20 mg pegvisomant.

PREPARING THE SOMAVERT DOSE FOR INJECTION

Figure 1

1. Remove the protective plastic caps from the tops of both vial of solvent and vial of SOMAVERT (Fig. 1). Take care not to touch the rubber vial stoppers. At this point, the stoppers are clean. If the stoppers are touched or otherwise contaminated, you must clean them with an antiseptic or alcohol swab before inserting a vial adapter through the stopper.

2. Open only one of the vial adapters by peeling back the protective cover. Leave the adapter in the plastic packaging and do not touch the spike of the adapter.

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Figure 2

3. While holding the plastic adapter packaging, attach the vial adapter to the solvent vial by pushing vertically down against the flat surface until it snaps in place and the spike penetrates the rubber stopper of the solvent (Fig. 2). Remove the plastic packaging from the vial adapter and discard.

Figure 3

4. Remove the syringe from the protective packaging. Pull the plunger of the syringe out to the 1 ml mark. Hold the solvent vial, placed on a flat surface, with one hand and connect the tip of the syringe to the vial adapter by twisting the syringe on the vial adapter clockwise (Fig. 3). Gently push the plunger until the air is injected into the vial.

ADDING SOLVENT

Figure 4

5. Securely grasp the solvent vial, adapter and syringe assembly. Carefully turn the vial, adapter and syringe assembly upside down. Bring to eye level (Fig. 4).

6. Slide one hand carefully down the solvent vial so that with your thumb and forefinger you can securely grasp the neck of the vial, and with your other fingers, the upper part of the syringe. With the other hand, slowly pull the syringe plunger down to slightly past the 1 ml mark.

Examine the solution in the syringe for air bubbles. If bubbles are present, tap the syringe barrel until the bubbles rise to the top of the syringe. Carefully push the plunger up to eject only the air bubbles back into the vial. Recheck that 1 ml of solvent remains in the syringe.

Carefully turn the solvent vial, adapter and syringe assembly and place them upright on a clean surface. Do not remove the syringe from the adapter at this point.

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Figure 5

7. As explained for the first vial adapter, open now the second vial adapter by peeling back the protective cover. Do not touch the vial adapter. While holding the plastic adapter packaging, attach the vial adapter to the SOMAVERT vial by pushing vertically down against the flat surface until it snaps in place and the spike penetrates the rubber stopper of the SOMAVERT vial (Fig. 5). Remove the plastic packaging from the vial adapter and discard.

Figure 6

8. Disconnect the syringe from the solvent vial adapter (by turning counter-clockwise) and attach it to the vial adapter on the vial of SOMAVERT (by turning clockwise). Tilt the vial of SOMAVERT, adapter and syringe assembly to the side and gently inject the solvent down the inner side of the vial of SOMAVERT (Fig 6). Discard the solvent vial as directed by your healthcare provider.

Figure 7

9. Hold the vial of SOMAVERT with the adapter and syringe still attached upright between your hands and gently roll it to dissolve the powder (Fig. 7). DO NOT SHAKE THE VIAL. The solution should be clear after the powder is dissolved. If the solution is cloudy or hazy, do not inject it. Notify your pharmacy and request a replacement vial. Do not throw the vial away because the pharmacy may request that you return it.

PREPARING THE INJECTION

10. Securely grasp the vial containing the SOMAVERT reconstituted solution, vial adapter and syringe assembly. Carefully turn the vial, adapter and syringe assembly upside down. Bring to eye level.

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Figure 8

11. As before, slide one hand carefully down the vial so that with your thumb and forefinger you can securely grasp the neck of the vial, and with your other fingers, the upper portion of the syringe. With the other hand, slowly pull the syringe plunger down to withdraw the full contents of the vial (1 ml). (Fig.8).

Visually inspect the syringe for air bubbles. If bubbles are present, tap the syringe barrel until the bubbles rise to the top of the syringe. Carefully push the plunger up to eject only the air bubbles back into the vial. Recheck that 1 ml of the solution remains in the syringe. Carefully turn the vial containing the SOMAVERT reconstituted solution, adapter and syringe assemblyand place them upright on a clean surface. Do not remove the syringe from the adapter at this point.

Figure 912. Open the needle packaging so that only the end of the needle to be connected to the syringe is

exposed. The needle should be partially left in its protective packaging. Lay the needle with its protective packaging on the tabletop. Disconnect the syringe from the vial adapter/connector by turning it counter clockwise. Discard the protective packaging and attach the needle to the syringe. Keep the plastic cap on the needle while preparing the site for injection (Fig. 9). Once reconstituted, SOMAVERT should be used immediately. Please proceed to “STEP 2. GIVING THE INJECTION”.

b) NON VIAL ADAPTER METHOD

Getting Started

Wash your hands thoroughly. Collect one vial of powder (SOMAVERT) and one vial of solvent (Water for Injections), one 3-ml

syringe with a 21-gauge, 1-inch detachable needle, one standard 1 ml insulin syringe, alcohol or antiseptic swabs and a proper disposal container for used needles.

Inspect the expiry dates on both the vial label and the syringe label. They should not be used after the month and year shown.

After reconstitution with 1 ml of solvent, 1 ml of the clear solution contains either 10 mg, 15 mg, or 20 mg pegvisomant.

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PREPARING THE SOMAVERT DOSE FOR INJECTION

Remove the protective plastic caps from the tops of both vials. Take care not to touch the rubber vial stoppers. At this point, the stoppers are clean. If the stoppers are touched or otherwise contaminated, you must clean them with an antiseptic or alcohol swab before inserting a needle through the stopper.

Carefully remove the cap from the needle of the larger syringe (3 ml). This is the solvent syringe.

Figure 1

1. Pull the plunger of the solvent syringe down to the1 ml mark. With one hand, securely hold the vial of solvent and, with the other hand, insert the needle of the solvent syringe straight through the center of the rubber stopper and deep into the vial. Gently push the plunger until the air is injected into the vial. (Fig. 1)

ADDING SOLVENT

Figure 2

2. Securely grasp the solvent vial and syringe assembly, with the needle still deeply inserted into the vial. Carefully turn the vial and syringe assembly upside down. Bring to eye level. (Fig. 2)

Figure 3

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3. Slide one hand carefully down the solvent vial so that with your thumb and forefinger you can securely grasp the neck of the vial, and with your other fingers, the upper part of the syringe. With the other hand, slowly pull the syringe plunger down to slightly past the 1 ml mark.

Examine the solution in the syringe for air bubbles. If bubbles are present, tap the syringe barrel until the bubbles rise to the top of the syringe. Carefully push the plunger up to eject only the air bubbles back into the vial. Recheck that 1 ml of solvent remains in the syringe, then withdraw the needle from the vial. (Fig 3)

Figure 4

4. Insert the needle of the solvent syringe straight through the stopper of the vial with the powder (SOMAVERT). Tilt the syringe to the side and gently inject the solvent down the inner side of the vial of SOMAVERT. When the solvent syringe is empty, withdraw it from the vial. Discard the solvent vial, syringe, and needle as directed by your healthcare provider. (Fig 4)

Figure 5

5. Hold the vial of SOMAVERT upright between your hands and gently roll it to dissolve the powder. DO NOT SHAKE THE VIAL. The solution should be clear after the powder is dissolved. If the solution is cloudy or hazy, do not inject it. Notify your pharmacy and request a replacement vial. Do not throw the vial away because the pharmacy may request that you return it. Inject SOMAVERT immediately. (Fig. 5)

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PREPARING THE INJECTION

Figure 6

6. Clean the rubber stopper of the vial of SOMAVERT with an antiseptic or alcohol swab. Remove the cap from the needle on the syringe (1 ml). Pull the syringe plunger down to the 1-ml mark. With one hand, securely hold the vial. With the other hand, insert the needle straight through the center of the rubber stopper and deep into the vial. Gently push the plunger until the air is injected into the vial. Securely grasp the vial and syringe assembly, with the needle still deeply inserted into the vial. Carefully turn the vial and syringe assembly upside down. Bring to eye level. (Fig. 6)

Figure 7

7. As before, slide one hand carefully down the vial so that with your thumb and forefinger you can securely grasp the neck of the vial, and with your other fingers, the upper portion of the syringe. With the other hand, slowly pull the syringe plunger down to withdraw the full contents of the vial (1 ml). To keep the needle tip within the liquid, you may have to slowly back it out of the stopper as you draw out the liquid.

Visually inspect the syringe for air bubbles. If bubbles are present, tap the syringe barrel until the bubbles rise to the top of the syringe. Carefully push the plunger up to eject only the air bubbles back into the vial. Recheck that 1 ml of the solution remains in the syringe, then withdraw the needle from the vial. (Fig. 7)

STEP 2. GIVING THE INJECTION

Choose an injection site on the upper arm, upper thigh, abdomen or buttocks. Always move on to a different area with each day’s injection. It may be helpful to keep a record of each day’s injection site as you take your daily dose of SOMAVERT. Do not use an area that has a rash or broken skin, or is bruised or lumpy.

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Clean the site with an antiseptic or alcohol swab, let the skin dry before injecting the product.

Figure A

a. With one hand, gently pinch up the skin at the site of injection. Hold the syringe with the other hand, and in a single, smooth motion, push the needle completely into the skin straight down (at a 90-degree angle). (Fig. A)

Figure B

b. Be sure to keep the needle all the way into the skin while you slowly push the syringe plunger down until the barrel is empty.

Release the pinched skin and pull the needle straight out. (Fig. B)

Figure C

c. Do not rub the injection area. A small amount of bleeding may occur. If necessary, apply a clean, dry cotton swab over the area and press gently for 1 or 2 minutes, or until the bleeding has stopped. (Fig. C)

Disposing of Supplies

The syringe and needle should NEVER be reused. Dispose of the needle and syringe as instructed by your doctor, nurse or pharmacist and in accordance with local health and safety laws.

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All questions should be handled by a doctor, nurse or pharmacist familiar with SOMAVERT.

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