SOMAVERT 10mg powder + solvent for injection medication leaflet

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

SOMAVERT 25 mg powder and solvent for solution for injection

SOMAVERT 30 mg powder and solvent for solution for injection

SOMAVERT 10 mg powder and solvent for solution for injection

One vial contains 10 mg of pegvisomant.

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

The 10 mg strength of the medicinal product contains 0.4 mg of sodium per vial of powder.

SOMAVERT 15 mg powder and solvent for solution for injection

One vial contains 15 mg of pegvisomant.

After reconstitution, 1 ml of solution contains 15 mg of pegvisomant.*

The 15 mg strength of the medicinal product contains 0.4 mg of sodium per vial of powder.

SOMAVERT 20 mg powder and solvent for solution for injection

One vial contains 20 mg of pegvisomant.

After reconstitution, 1 ml of solution contains 20 mg of pegvisomant.*

The 20 mg strength of the medicinal product contains 0.4 mg of sodium per vial of powder.

SOMAVERT 25 mg powder and solvent for solution for injection

One vial contains 25 mg of pegvisomant.

After reconstitution, 1 ml of solution contains 25 mg of pegvisomant.*

The 25 mg strength of the medicinal product contains 0.5 mg of sodium per vial of powder.

SOMAVERT 30 mg powder and solvent for solution for injection

One vial contains 30 mg of pegvisomant.

After reconstitution, 1 ml of solution contains 30 mg of pegvisomant.*

The 30 mg strength of the medicinal product contains 0.6 mg of sodium per vial of powder.

*produced in Escherichia coli cells by recombinant DNA technology.

For the full list of excipients, see section 6.1.

Powder and solvent for solution for injection (powder for injection).

The powder is white to slightly off-white.

Treatment of adult 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 notnormalise IGF-I concentrations or was not tolerated.

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

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

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

Assessment of baseline levels of liver enzymes prior to initiation of SOMAVERT

Prior to the start of SOMAVERT, patients should have an assessment of baseline levels of liver tests(LTs) [serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), serum total bilirubin(TBIL), and alkaline phosphatase (ALP)]. For recommendations regarding initiation of SOMAVERTbased on baseline LTs and recommendations for monitoring of LTs while on SOMAVERT, refer to

Table A in Special warnings and precautions for use (4.4).

The maximum dose should not exceed 30 mg/day.

For the different dose regimens, the following strengths are available: SOMAVERT 10 mg,

SOMAVERT 15 mg, SOMAVERT 20 mg, SOMAVERT 25 mg and SOMAVERT 30 mg.

The safety and efficacy of SOMAVERT in children aged 0 to 17 years have not been established. Nodata are available.

No dose adjustment is required.

Hepatic or renal impairment

The safety and efficacy of SOMAVERT in patients with renal or hepatic insufficiency has not beenestablished.

Pegvisomant should be administered by subcutaneous injection.

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

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.

Growth hormone-secreting tumours

As growth hormone-secreting pituitary tumours may sometimes expand, causing seriouscomplications (e.g. visual field defects), it is essential that all patients be carefully monitored. Ifevidence of tumour expansion appears, alternative procedures may be advisable.

Serum IGF-1 monitoring

Pegvisomant is a potent antagonist of growth hormone action. A growth hormone deficient state mayresult from administration of this medicinal product, despite the presence of elevated serum growthhormone levels. Serum IGF-I concentrations should be monitored and maintained within theage-adjusted normal range by adjustment of the pegvisomant dose.

ALT or AST elevations

Prior to the start of SOMAVERT, patients should have an assessment of baseline levels of liver tests[serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), serum total bilirubin(TBIL), and alkaline phosphatase (ALP)].

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 ofpegvisomant should be discontinued if signs of liver disease persist.

For recommendations regarding initiation of SOMAVERT, based on baseline liver tests (LTs) andrecommendations for monitoring of liver tests while on SOMAVERT, refer to Table A.

Table A: Recommendations for initiation of SOMAVERT treatment based on baseline LTs andfor periodic monitoring of LTs during SOMAVERT treatment

Baseline LT Levels Recommendations

- May treat with SOMAVERT.

- Serum concentrations of ALT and AST should be

Normal monitored at 4- to 6-week intervals for the first 6 monthsof treatment with SOMAVERT, or at any time in patientsexhibiting symptoms suggestive of hepatitis.

Elevated, but less than or equal to - May treat with SOMAVERT; however, monitor LTs3 times ULN monthly for at least 1 year after initiation of therapy andthen bi-annually for the next year.

- Do not treat with SOMAVERT until a comprehensiveworkup establishes the cause of the patient’s liverdysfunction.

- Determine if cholelithiasis or choledocholithiasis ispresent, particularly in patients with a history of prior

Greater than 3 times ULNtherapy with somatostatin analogues.

- Based on the workup, consider initiation of therapy with

SOMAVERT.

- If the decision is to treat, LTs and clinical symptomsshould be monitored very closely.

Abbreviations: ALT = alanine aminotransferase; AST = aspartate transaminase; LT = liver test;

ULN = upper limit of normal.

If a patient develops LT elevations, or any other signs or symptoms of liver dysfunction whilereceiving SOMAVERT, the following patient management is recommended (Table B).

Table B. Clinical recommendations based on abnormal liver test results while on SOMAVERT

LT Levels and Clinical Recommendations

Signs/Symptoms

Elevated, but less than or equal to - May continue therapy with SOMAVERT. However, monitor3 times ULN LTs monthly to determine if further increases occur.

Greater than 3 but less than 5 times - May continue therapy with SOMAVERT. However, monitor

ULN (without signs/symptoms of LTs weekly to determine if further increases occur (seehepatitis or other liver injury, or below).increase in serum TBIL) - Perform a comprehensive hepatic workup to discern if analternative cause of liver dysfunction is present.

At least 5 times ULN, or transaminase - Discontinue SOMAVERT immediately.elevations at least 3 times ULN - Perform a comprehensive hepatic workup, including serialassociated with any increase in serum LTs, to determine if and when serum levels return to normal.

TBIL (with or without - If LTs normalise (regardless of whether an alternative causesigns/symptoms of hepatitis or other of the liver dysfunction is discovered), consider cautiousliver injury) reinitiation of therapy with SOMAVERT, with frequent LTmonitoring.

Signs or symptoms suggestive of - Immediately perform a comprehensive hepatic workup.hepatitis or other liver injury (e.g. - If liver injury is confirmed, the drug should be discontinued.jaundice, bilirubinuria, fatigue,nausea, vomiting, right upper quadrantpain, ascites, unexplained oedema,easy bruisability)

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

Improved fertility

The therapeutic benefits of a reduction in IGF-I concentration which results in improvement of thepatient’s clinical condition could potentially also improve fertility in female patients (see section 4.6).

Acromegaly control may improve during pregnancy. Pegvisomant is not recommended duringpregnancy (see section 4.6). If pegvisomant is used during pregnancy, IGF-I levels should be closelymonitored and pegvisomant doses may need to be adjusted (see section 4.2) based on IGF-I values.

This medicinal product contains less than 1 mmol sodium (23 mg) per dose. Patients on low sodiumdiets can be informed that this medicinal product is essentially ‘sodium-free’.

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

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

Pegvisomant has significant structural similarity to growth hormone which causes it to cross-react incommercially available growth hormone assays. Since serum concentrations oftherapeutically-effective doses of this medicine are generally 100 to 1 000 times higher than the actualserum growth hormone concentrations seen in acromegalics, measurements of serum growth hormoneconcentrations will be spuriously reported in commercially available growth hormone assays.

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

There are limited amount of data from the use of pegvisomant in pregnant women. Animal studies areinsufficient with respect to reproductive toxicity (see section 5.3).

SOMAVERT is not recommended during pregnancy and in women of childbearing potential not usingcontraception.

If pegvisomant is used during pregnancy, IGF-I levels should be closely monitored, especially duringthe first trimester. It may be necessary to adjust the dose of pegvisomant during pregnancy (see section4.4).

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

For pegvisomant no data on fertility are available.

The therapeutic benefits of a reduction in IGF-I concentration which results in improvement of thepatient’s clinical condition could potentially also improve fertility in female patients.

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

The list below contains adverse reactions seen in clinical trials with SOMAVERT.

In clinical studies, for patients treated with pegvisomant (n = 550), the majority of adverse reactions topegvisomant were of mild to moderate intensity, of limited duration and did not requirediscontinuation of treatment.

The most commonly reported adverse reactions occurring in  10% of patients with acromegalytreated with pegvisomant during the clinical trials were headache 25%, arthralgia 16% and diarrhoea13%.

The list below contains adverse reactions seen in clinical trials or that were spontaneously reported,classified by system organ class and frequency.

Adverse reactions are listed according to the following categories:

Very common:  1/10

Common:  1/100 to < 1/10

Uncommon:  1/1 000 to < 1/100

Not known (cannot be estimated from the available data)

System Organ Class Very Common Uncommon Frequency

Common (≥ 1/100 to (≥ 1/1 000 to Not Known(≥ 1/10) < 1/10) < 1/100) (Cannot Be

Estimated

From

Available

Data)

Blood and lymphatic thrombocytopenia,system disorders leukopenia,leukocytosis,haemorrhagicdiathesis

Immune system hypersensitivity anaphylacticdisorders reactionsb reactionb,anaphylactoidreactionb

System Organ Class Very Common Uncommon Frequency

Common (≥ 1/100 to (≥ 1/1 000 to Not Known(≥ 1/10) < 1/10) < 1/100) (Cannot Be

Estimated

From

Available

Data)

Metabolism and hypercholesterol hypertriglyceridemianutrition disorders aemia,hyperglycaemia,hypoglycaemia,weight increased

Psychiatric disorders abnormal panic attack, short angerdreams term memory loss,apathy, confusion,sleep disorder,libido increased

Nervous system headache somnolence, narcolepsy,disorders tremor, migraine, dysgeusiadizziness,hypoaesthesia

Eye disorders eye pain asthenopia

Ear and labyrinth Meniere’s diseasedisorders

Cardiac disorders oedemaperipheral

Vascular disorders hypertension

Respiratory, thoracic dyspnoea laryngospasmband mediastinaldisorders

Gastrointestinal diarrhoea vomiting, haemorrhoids,disorders constipation, salivarynausea, hypersecretion, dryabdominal mouth, toothdistension, disorderdyspepsia,flatulence

Hepatobiliary abnormal liverdisorders function tests(e.g.transaminaseelevation) (seesection 4.4)

Skin and hyperhidrosis, face oedema, dry angioedemabsubcutaneous tissue contusion, skin, increaseddisorders pruritusb, rashb tendency to bruise,night sweats,erythemab, urticariab

Musculoskeletal and arthralgia myalgia, arthritisconnective tissuedisorders

Renal and urinary haematuria proteinuria,disorders polyuria, renalimpairment

System Organ Class Very Common Uncommon Frequency

Common (≥ 1/100 to (≥ 1/1 000 to Not Known(≥ 1/10) < 1/10) < 1/100) (Cannot Be

Estimated

From

Available

Data)

General disorders and injection site feeling abnormal,administration site reaction impaired healing,conditions (including hungerinjection sitehypersensitivity), injection sitebruising orbleeding,injection sitehypertrophy(e.g. lipohypertrophy)a,influenza-likeillness, fatigue,asthenia, pyrexiaa see Description of selected adverse reactions belowb ADR related to hypersensitivity reaction

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

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

Systemic hypersensitivity reactions including anaphylactic/anaphylactoid reactions, laryngospasm,angioedema, generalised skin reactions (rash, erythema, pruritus, urticaria) have been reported in postmarketing use. Some patients required hospitalisation. Upon re-administration, symptoms did notre-occur in all patients.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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

In cases of overdose, administration of this medicine 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 agrowth 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 signaltransduction. Pegvisomant is highly selective for the GH receptor, and does not cross-react with othercytokine receptors, including prolactin.

Inhibition of growth hormone action with pegvisomant leads to decreased serum concentrations ofinsulin-like growth factor-I (IGF-I), as well as other growth hormone-responsive serum proteins suchas 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, multicentrestudy comparing placebo and pegvisomant. Dose-dependent, statistically significant reductions inmean IGF-I (p<0.0001), free IGF-I (p<0.05), IGFBP-3 (p<0.05) and ALS (p<0.05) were observed atall post-baseline visits in the pegvisomant treatment groups. The serum IGF-1 was normalised at theend 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 pegvisomant respectively.

Statistically significant differences from placebo (p<0.05) were observed for improvements in the totalsigns 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 studyfor 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.

In different studies and also in Acrostudy, pegvisomant normalised IGF-1 levels in a high percentageof patients (> 70%) and significantly decreased fasting plasma glucose (FPG) and fasting plasmainsulin (FPI) levels.

Pegvisomant also improves insulin sensitivity, this is likely due to a blockade of the GH receptors ontissues, mainly the liver and also adipose tissue, kidneys, and skeletal muscles, thereby removing thedetrimental effect of GH on insulin signalling, lipolysis, and gluconeogenesis. However, themechanism of action of all these effects is not known with certainty. A decrease in doses of insulin orhypoglycaemic medicinal products may be needed in acromegalic patients with diabetes mellitus (seesections 4.4 and 4.5).

Absorption of pegvisomant following subcutaneous administration is slow and prolonged, and peakserum 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 metabolism of pegvisomant has not been studied.

The mean total body systemic clearance of pegvisomant following multiple doses is estimated to be28 ml/h for subcutaneous doses ranging from 10 to 20 mg/day. Renal clearance of pegvisomant isnegligible and accounts for less than 1% of total body clearance. Pegvisomant is slowly eliminatedfrom serum, with mean estimates of half-life generally ranging from 74 to 172 hours following eithersingle or multiple-doses.

After single subcutaneous pegvisomant administration no linearity is observed with rising doses of10, 15 or 20 mg. Approximately linear pharmacokinetics is observed at steady state in the populationpharmacokinetic studies. The data from 145 patients in two long-term studies who received dailydoses of 10, 15, or 20 mg, demonstrate pegvisomant mean serum concentrations (± SD) ofapproximately 8 800 ± 6 300, 13 200 ± 8 000 and 15 600 ± 10 300 ng/ml, respectively.

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

Non-clinical data revealed no special hazard for humans based on studies of repeated dose toxicity inrat and monkey. However, due to the marked pharmacological response in monkey, systemicexposures higher than those achieved in patients at therapeutic doses have not been studied.

Malignant fibrous histiocytomas associated with fibrosis and histiocytic inflammation were observedat injection sites in males in the rat carcinogenicity study at exposure levels equivalent to three timesthe human exposure based on mean plasma concentrations in two long-term studies at a daily dose of30 mg. The relevance of this response for humans is currently unknown. The increased incidence ofinjection site tumours was most probably caused by irritation and the high sensitivity of the rat torepeated subcutaneous injections.

Early embryonic development and embryo-foetal development studies were conducted in pregnantrabbits with pegvisomant at subcutaneous doses of 1, 3, and 10 mg/kg/day. There was no evidence ofteratogenic effects associated with pegvisomant administration during organogenesis. At10 mg/kg/day (6 times the maximum human therapeutic dose based on body surface area), an increasein post-implantation loss was observed in both studies. No fertility study has been conducted.

Glycine

Mannitol (E421)

Disodium phosphate anhydrous

Sodium dihydrogen phosphate monohydrate

Water for Injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

3 years.

After reconstitution, the product should be used immediately.

Store the powder vial(s) in a refrigerator (2°C - 8°C). Do not freeze. Keep the vial(s) in their carton(s)in order to protect from light.

The carton(s) containing the SOMAVERT powder vial(s) may be stored at room temperature up to amaximum of 25°C for a single period of up to 30 days. The Use by date should be written on thecarton (up to 30 days from the date removed from the refrigerator). The vial(s) must be protected fromlight and should not be placed back into the refrigerator. The SOMAVERT powder vial(s) must bediscarded if not used within the 30 days of room temperature storage or the expiry date printed on thecarton, whichever is earlier.

Store the pre-filled syringe(s) below 30°C or store in a refrigerator (2ºC - 8°C). Do not freeze.

For storage conditions after reconstitution of the medicinal product, see section 6.3.

10 mg or 15 mg or 20 mg or 25 mg or 30 mg of pegvisomant in powder in a vial (type I flint glass)with a stopper (chlorobutyl rubber) and 1 ml solvent (water for injections) in a pre-filled syringe(type I borosilicate glass) with a plunger stopper (bromobutyl rubber) and a tip cap (bromobutylrubber). The colour of the protective plastic cap is specific to the strength of the product.

SOMAVERT 10 mg and 15 mg

Pack size of 30 vials, pre-filled syringes and safety needles.

SOMAVERT 20 mg, 25 mg and 30 mg

Pack sizes of 1 and 30 vial(s), pre-filled syringe(s) and safety needle(s).

Not all pack sizes may be marketed.

The syringe and safety needle used to administer the injection are provided with the medicinalproduct.

Before attaching the supplied safety needle the syringe cap will need to be removed from the pre-filledsyringe. This is achieved by snapping it off. The syringe should be kept upright to avoid leakage andthe end of the syringe should not be allowed to contact anything.

The powder should be reconstituted with 1 ml solvent. When adding the solvent from the syringe thevial and syringe should held at an angle as shown in the diagram below.

Add the solvent to the vial of powder. The solvent should be emptied into the vial slowly to avoid thepossibility of a foam forming. This would make the medicine unusable. Gently dissolve the powderwith a slow, swirling motion. Do not shake vigorously, as this might cause denaturation of the activesubstance.

After reconstitution, the reconstituted solution should be inspected visually for extraneous (or for anyforeign) particulate matter or any variation in physical appearance prior to administration. In the eventof either being observed, discard the medicinal product.

Before withdrawing the dissolved SOMAVERT invert the vial with the syringe still inserted into itand ensure the gap in the stopper can be seen as shown in the diagram below:

Pull the needle down so that the needle tip is at its lowest point in the liquid. Slowly withdraw theplunger in the syringe to withdraw the medicine from the vial. If air is seen in the syringe, tap thebarrel to float the bubbles to the top, and then gently push the bubbles out into the vial.

Before disposing of the syringe and needle fold the needle guard over the needle and ensure it clicksinto place. The syringe and needle should never be reused.

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

Pfizer Europe MA EEIG

Boulevard de la Plaine 171050 Bruxelles

Belgium

EU/1/02/240/001 10 mg 30 vials

EU/1/02/240/002 15 mg 30 vials

EU/1/02/240/004 20 mg 1 vial

EU/1/02/240/003 20 mg 30 vials

EU/1/02/240/009 25 mg 1 vial

EU/1/02/240/010 25 mg 30 vials

EU/1/02/240/011 30 mg 1 vial

EU/1/02/240/012 30 mg 30 vials

Date of first authorisation: 13 November 2002

Date of latest renewal: 20 September 2007

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.