SOMAVERT 10 mg powder and solvent for solution for injection.

SOMAVERT 15 mg Powder and solvent for solution for injection.

SOMAVERT 20 mg Powder and solvent for solution for injection.

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

For a full list of excipients, see section 6.1.

Powder and solvent for solution for injection.

The powder is white to slightly off-white.

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.

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.

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.

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

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).

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

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.

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

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%, hyperhidrosis 7%, 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.

*see Description of selected adverse reactions below.

Description of selected adverse reactions

Most injection site reactions characterised as localised erythemas and soreness, spontaneously resolved 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.

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.

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.

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.

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.

Powder:

Glycine

Mannitol (E421)

Sodium phosphate dibasic anhydrous

Sodium phosphate monobasic monohydrate

Solvent:

Water for Injections

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

3 years.

After reconstitution, the product should be used immediately.

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

After reconstitution:

Use immediately.

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.

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.

Pfizer Limited

Sandwich

Kent CT13 9NJ

United Kingdom

EU/1/02/240/001 - SOMAVERT 10 mg; pack size 30 vials

EU/1/02/240/002 - SOMAVERT 15 mg; pack size 30 vials

EU/1/02/240/003 - SOMAVERT 20 mg; pack size 30 vials

EU/1/02/240/004 - SOMAVERT 20 mg; pack size 1 vial

Date of first authorization: 13/11/2002

Date of last renewal: 20/09/2007

December 2011

Ref: SV9_0