This information is intended for use by health professionals

 This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

1. Name of the medicinal product

Galafold 123 mg hard capsules

2. Qualitative and quantitative composition

Each capsule contains migalastat hydrochloride equivalent to 123 mg migalastat.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Hard capsule.

Size 2 hard capsule (6.4x18.0 mm) with an opaque blue cap and opaque white body with “A1001” printed in black, containing white to pale brown powder.

4. Clinical particulars
4.1 Therapeutic indications

Galafold is indicated for long-term treatment of adults and adolescents aged 16 years and older with a confirmed diagnosis of Fabry disease (α-galactosidase A deficiency) and who have an amenable mutation (see the tables in section 5.1).

4.2 Posology and method of administration

Treatment with Galafold should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of Fabry disease. Galafold is not intended for concomitant use with enzyme replacement therapy (see section 4.4).

Posology

The recommended dosage regimen in adults and adolescents 16 years and older is 123 mg migalastat (1 capsule) once every other day at the same time of day.

Missed dose

Galafold should not be taken on 2 consecutive days. If a dose is missed entirely for the day, the patient should take the missed dose of Galafold only if it is within 12 hours of the normal time the dose is taken. If more than 12 hours has passed the patient should resume taking Galafold at the next planned dosing day and time according to the every other day dosing schedule.

Paediatric population

The safety and efficacy of Galafold in children aged 0 to 15 years has not yet been established. No data are available.

Special populations

Elderly population

No dosage adjustment is required based on age (see section 5.2).

Renal impairment

Galafold is not recommended for use in patients with Fabry disease who have estimated GFR less than 30 mL/min/1.73 m2 (see section 5.2).

Hepatic impairment

No dosage adjustment of Galafold is required in patients with hepatic impairment (see section 5.2).

Method of administration

For oral use. Galafold exposure is decreased by approximately 40% when taken with food and therefore food should not be consumed at least 2 hours before and 2 hours after taking Galafold to give a minimum 4 hours fast. Clear liquids, including carbonated drinks, can be consumed during this period. Galafold should be taken every other day at the same time of day to ensure optimal benefits to the patient.

Capsules must be swallowed whole. The capsules must not be cut, crushed, or chewed.

4.3 Contraindications

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

4.4 Special warnings and precautions for use

It is advised to periodically monitor renal function, echocardiographic parameters and biochemical markers (every 6 months) in patients initiated on or switched to Galafold. In case of meaningful clinical deterioration, further clinical evaluation or discontinuation of treatment with Galafold should be considered.

Galafold is not indicated for use in patients with non-amenable mutations (see section 5.1).

No reduction in proteinuria was observed in patients treated with Galafold.

Galafold is not recommended for use in patients with severe renal insufficiency, defined as estimated GFR less than 30 mL/min/1.73m2 (see section 5.2).

Limited data suggest that co-administration of a single dose of Galafold and a standard enzyme replacement therapy infusion results in an increased exposure to agalsidase of up to 5-fold. This study also indicated that agalsidase has no effect on the pharmacokinetics of migalastat. Galafold is not intended for concomitant use with enzyme replacement therapy.

4.5 Interaction with other medicinal products and other forms of interaction

Based upon in vitro data, migalastat is not an inducer of CYP1A2, 2B6, or 3A4. Furthermore, migalastat is not an inhibitor or a substrate of CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4/5. Migalastat is not a substrate for MDR1 or BCRP, nor is it an inhibitor of BCRP, MDR1, or BSEP human efflux transporters. In addition, migalastat is not a substrate for MATE1, MATE2-K, OAT1, OAT3, or OCT2, nor is it an inhibitor of OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, MATE1, or MATE2-K human uptake transporters.

4.6 Fertility, pregnancy and lactation

Women of childbearing potential/Contraception in males and females

Galafold is not recommended in women of childbearing potential not using contraception.

Pregnancy

There are limited data from the use of Galafold in pregnant women. In rabbits, developmental toxicity was observed only at maternally toxic doses (see section 5.3). Galafold is not recommended during pregnancy.

Breast-feeding

It is not known whether Galafold is secreted in human milk. However, migalastat has been shown to be expressed in the milk of lactating rats. Accordingly, a risk of migalastat exposure to the breast-feeding infant cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue Galafold, taking into account the benefit of breast-feeding for the child relative to the benefit of therapy for the mother.

Fertility

The effects of Galafold on fertility in humans have not been studied. Transient and fully reversible infertility in male rats was associated with migalastat treatment at all doses assessed. Complete reversibility was seen after 4 weeks off-dose. Similar findings have been noted pre-clinically following treatment with other iminosugars (see section 5.3). Migalastat did not affect fertility in female rats.

4.7 Effects on ability to drive and use machines

Galafold has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

Summary of the safety profile

The most common adverse reaction was headache, which was experienced by approximately 10% of patients who received Galafold.

Tabulated list of adverse reactions

Frequencies are defined as: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing frequency within each System Organ Class.

Table 1: Adverse reactions with Galafold in clinical trials

System Organ Class

Very common

Common

Psychiatric disorders

Depression

Nervous system disorders

Headache

Paraesthesia

Dizziness

Hypoaesthesia

Ear and labyrinth disorders

Vertigo

Cardiac disorders

Palpitations

Respiratory, thoracic, and mediastinal disorders

Dyspnoea

Epistaxis

Gastrointestinal disorders

Diarrhoea

Nausea

Abdominal pain

Constipation

Dry mouth

Defaecation urgency

Dyspepsia

Skin and subcutaneous tissue disorders

Rash

Pruritus

Musculoskeletal and connective tissue disorders

Muscle spasms

Myalgia

Torticollis

Pain in extremity

Renal and urinary disorders

Proteinuria

General disorders and administration site conditions

Fatigue

Pain

Investigations

Blood creatine phosphokinase increased

Weight increased

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via the national reporting system :

United Kingdom Yellow Card Scheme www.mhra.gov.uk/yellowcard

Ireland HPRA Pharmacovigilance www.hpra.ie

4.9 Overdose

In case of overdose, general medical care is recommended. Headache and dizziness were the most common adverse reactions reported at doses of Galafold of up to 1250 mg and 2000 mg, respectively.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Various alimentary tract and metabolism products ATC code: A16AX14

Fabry disease is a progressive X-linked lysosomal storage disorder which affects males and females. Fabry disease-causing mutations in the GLA gene result in a deficiency of the lysosomal enzyme α-galactosidase A (α-Gal A) that is required for glycosphingolipid substrate (e.g., GL-3, lyso-Gb3) metabolism. Reduced α-Gal A activity is, therefore, associated with the progressive accumulation of substrate in vulnerable organs and tissues, which leads to the morbidity and mortality associated with Fabry disease.

Mechanism of action

Certain GLA mutations can result in the production of abnormally folded and unstable mutant forms of α-Gal A. Migalastat is a pharmacological chaperone that is designed to selectively and reversibly bind with high affinity to the active sites of certain mutant forms of α-Gal A, the genotypes of which are referred to as amenable mutations. Migalastat binding stabilizes these mutant forms of α-Gal A in the endoplasmic reticulum and facilitates their proper trafficking to lysosomes. Once in lysosomes dissociation of migalastat restores α-Gal A activity, leading to the catabolism of GL-3 and related substrates.

The GLA mutations amenable to treatment with Galafold are listed in Table 2 below. The GLA mutations are also accessible by health care providers at www.galafoldamenabilitytable.com.

The nucleotide changes listed represent potential DNA sequence changes that result in the amino acid mutation. The amino acid mutation (protein sequence change) is most relevant when determining amenability. If a double mutation is present on the same chromosome (males and females), that patient is amenable if the double mutation is present in one entry in Table 2 (e.g., D55V/Q57L). If a double mutation is present on different chromosomes (only in females) that patient is amenable if either one of the individual mutations is present in Table 2.

Table 2: Galafold (migalastat) amenability table

Nucleotide change

Nucleotide change

Protein sequence change

c.7C>G

c.C7G

L3V

c.8T>C

c.T8C

L3P

c.[11G>T; 620A>C]

c.G11T/A620C

R4M/Y207S

c.13A>G

c.A13G

N5D

c.15C>G

c.C15G

N5K

c.16C>A

c.C16A

P6T

c.16C>T

c.C16T

P6S

c.17C>A

c.C17A

P6Q

c.17C>G

c.C17G

P6R

c.17C>T

c.C17T

P6L

c.19G>A

c.G19A

E7K

c.20A>T

c.A20T

E7V

c.21A>T

c.A21T

E7D

c.22C>A

c.C22A

L8I

c.23T>A

c.T23A

L8Q

c.23T>C

c.T23C

L8P

c.25C>T

c.C25T

H9Y

c.26A>G

c.A26G

H9R

c.26A>T

c.A26T

H9L

c.27T>A

c.T27A

H9Q

c.28C>A

c.C28A

L10M

c.28C>G

c.C28G

L10V

c.29T>A

c.T29A

L10Q

c.29T>C

c.T29C

L10P

c.29T>G

c.T29G

L10R

c.31G>A

c.G31A

G11S

c.31G>C

c.G31C

G11R

c.31G>T

c.G31T

G11C

c.32G>A

c.G32A

G11D

c.32G>T

c.G32T

G11V

c.34T>A

c.T34A

C12S

c.34T>C

c.T34C

C12R

c.34T>G

c.T34G

C12G

c.35G>A

c.G35A

C12Y

c.37G>A

c.G37A

A13T

c.37G>C

c.G37C

A13P

c.38C>A

c.C38A

A13E

c.38C>G

c.C38G

A13G

c.40C>G

c.C40G

L14V

c.40C>T

c.C40T

L14F

c.41T>A

c.T41A

L14H

c.43G>A

c.G43A

A15T

c.44C>G

c.C44G

A15G

c.49C>A

c.C49A

R17S

c.49C>G

c.C49G

R17G

c.49C>T

c.C49T

R17C

c.50G>A

c.G50A

R17H

c.50G>C

c.G50C

R17P

c.52T>A

c.T52A

F18I

c.53T>G

c.T53G

F18C

c.54C>G

c.C54G

F18L

c.58G>C

c.G58C

A20P

c.59C>A

c.C59A

A20D

c.59C>G

c.C59G

A20G

c.62T>A

c.T62A

L21H

c.64G>A

c.G64A

V22I

c.64G>C

c.G64C

V22L

c.64G>T

c.G64T

V22F

c.65T>C

c.T65C

V22A

c.65T>G

c.T65G

V22G

c.67T>A

c.T67A

S23T

c.67T>C

c.T67C

S23P

c.70T>C or c.70T>A

c.T70C or c.T70A

W24R

c.70T>G

c.T70G

W24G

c.71G>C

c.G71C

W24S

c.72G>C or c.72G>T

c.G72C or c.G72T

W24C

c.73G>C

c.G73C

D25H

c.77T>A

c.T77A

I26N

c.79C>A

c.C79A

P27T

c.79C>G

c.C79G

P27A

c.79C>T

c.C79T

P27S

c.80C>T

c.C80T

P27L

c.82G>C

c.G82C

G28R

c.82G>T

c.G82T

G28W

c.83G>A

c.G83A

G28E

c.85G>C

c.G85C

A29P

c.86C>A

c.C86A

A29D

c.86C>G

c.C86G

A29G

c.86C>T

c.C86T

A29V

c.88A>G

c.A88G

R30G

c.94C>A

c.C94A

L32M

c.94C>G

c.C94G

L32V

c.95T>A

c.T95A

L32Q

c.95T>C

c.T95C

L32P

c.95T>G

c.T95G

L32R

c.97G>C

c.G97C

D33H

c.97G>T

c.G97T

D33Y

c.98A>C

c.A98C

D33A

c.98A>G

c.A98G

D33G

c.98A>T

c.A98T

D33V

c.99C>G

c.C99G

D33E

c.100A>C

c.A100C

N34H

c.100A>G

c.A100G

N34D

c.101A>C

c.A101C

N34T

c.101A>G

c.A101G

N34S

c.102T>G or c.102T>A

c.T102G or c.T102A

N34K

c.103G>C or c.103G>A

c.G103C or c.G103A

G35R

c.104G>A

c.G104A

G35E

c.104G>C

c.G104C

G35A

c.104G>T

c.G104T

G35V

c.106T>A

c.T106A

L36M

c.106T>G

c.T106G

L36V

c.107T>C

c.T107C

L36S

c.107T>G

c.T107G

L36W

c.108G>C or c.108G>T

c.G108C or c.G108T

L36F

c.109G>A

c.G109A

A37T

c.109G>T

c.G109T

A37S

c.110C>A

c.C110A

A37E

c.110C>G

c.C110G

A37G

c.110C>T

c.C110T

A37V

c.112A>G

c.A112G

R38G

c.112A>T

c.A112T

R38W

c.113G>T

c.G113T

R38M

c.114G>C

c.G114C

R38S

c.115A>G

c.A115G

T39A

c.115A>T

c.A115T

T39S

c.116C>A

c.C116A

T39K

c.116C>G

c.C116G

T39R

c.116C>T

c.C116T

T39M

c.121A>G

c.A121G

T41A

c.122C>A

c.C122A

T41N

c.122C>G

c.C122G

T41S

c.122C>T

c.C122T

T41I

c.124A>C or c.124A>T

c.A124C or c.A124T

M42L

c.124A>G

c.A124G

M42V

c.125T>A

c.T125A

M42K

c.125T>C

c.T125C

M42T

c.125T>G

c.T125G

M42R

c.126G>A or c.126G>C or c.126G>T

c.G126A or c.G126C or c.G126T

M42I

c.128G>C

c.G128C

G43A

c.133C>A

c.C133A

L45M

c.133C>G

c.C133G

L45V

c.136C>A

c.C136A

H46N

c.136C>G

c.C136G

H46D

c.137A>C

c.A137C

H46P

c.138C>G

c.C138G

H46Q

c.142G>C

c.G142C

E48Q

c.143A>C

c.A143C

E48A

c.149T>A

c.T149A

F50Y

c.151A>G

c.A151G

M51V

c.152T>A

c.T152A

M51K

c.152T>C

c.T152C

M51T

c.152T>G

c.T152G

M51R

c.153G>A or c.153G>T or c.153G>C

c.G153A or c.G153T or c.G153C

M51I

c.157A>C

c.A157C

N53H

c.[157A>C; 158A>T]

c.A157C/A158T

N53L

c.157A>G

c.A157G

N53D

c.157A>T

c.A157T

N53Y

c.158A>C

c.A158C

N53T

c.158A>G

c.A158G

N53S

c.158A>T

c.A158T

N53I

c.159C>G or c.159C>A

c.C159G or c.C159A

N53K

c.160C>G

c.C160G

L54V

c.160C>T

c.C160T

L54F

c.161T>A

c.T161A

L54H

c.161T>C

c.T161C

L54P

c.161T>G

c.T161G

L54R

c.163G>C

c.G163C

D55H

c.163G>T

c.G163T

D55Y

c.164A>C

c.A164C

D55A

c.164A>G

c.A164G

D55G

c.164A>T

c.A164T

D55V

c.[164A>T; 170A>T]

c.A164T/A170T

D55V/Q57L

c.165C>G

c.C165G

D55E

c.167G>A

c.G167A

C56Y

c.167G>T

c.G167T

C56F

c.168C>G

c.C168G

C56W

c.170A>G

c.A170G

Q57R

c.170A>T

c.A170T

Q57L

c.172G>A

c.G172A

E58K

c.175G>A

c.G175A

E59K

c.175G>C

c.G175C

E59Q

c.176A>C

c.A176C

E59A

c.176A>G

c.A176G

E59G

c.176A>T

c.A176T

E59V

c.177G>C

c.G177C

E59D

c.178C>A

c.C178A

P60T

c.178C>G

c.C178G

P60A

c.178C>T

c.C178T

P60S

c.179C>A

c.C179A

P60Q

c.179C>G

c.C179G

P60R

c.179C>T

c.C179T

P60L

c.182A>T

c.A182T

D61V

c.183T>A

c.T183A

D61E

c.184_185insTAG

c.184_185insTAG

S62delinsLA

c.184T>C

c.T184C

S62P

c.184T>G

c.T184G

S62A

c.185C>A

c.C185A

S62Y

c.185C>G

c.C185G

S62C

c.185C>T

c.C185T

S62F

c.190A>C

c.A190C

I64L

c.190A>G

c.A190G

I64V

c.193A>G

c.A193G

S65G

c.193A>T

c.A193T

S65C

c.195T>A

c.T195A

S65R

c.196G>A

c.G196A

E66K

c.197A>G

c.A197G

E66G

c.197A>T

c.A197T

E66V

c.198G>C

c.G198C

E66D

c.199A>C

c.A199C

K67Q

c.199A>G

c.A199G

K67E

c.200A>C

c.A200C

K67T

c.200A>T

c.A200T

K67M

c.201G>C

c.G201C

K67N

c.202C>A

c.C202A

L68I

c.205T>A

c.T205A

F69I

c.206T>A

c.T206A

F69Y

c.207C>A or c.207C>G

c.C207A or c.C207G

F69L

c.208A>T

c.A208T

M70L

c.209T>A

c.T209A

M70K

c.209T>G

c.T209G

M70R

c.210G>C

c.G210C

M70I

c.211G>C

c.G211C

E71Q

c.212A>C

c.A212C

E71A

c.212A>G

c.A212G

E71G

c.212A>T

c.A212T

E71V

c.213G>C

c.G213C

E71D

c.214A>G

c.A214G

M72V

c.214A>T

c.A214T

M72L

c.215T>C

c.T215C

M72T

c.216G>A or c.216G>T or c.216G>C

c.G216A or c.G216T or c.G216C

M72I

c.217G>A

c.G217A

A73T

c.217G>T

c.G217T

A73S

c.218C>T

c.C218T

A73V

c.220G>A

c.G220A

E74K

c.221A>G

c.A221G

E74G

c.221A>T

c.A221T

E74V

c.222G>C

c.G222C

E74D

c.223C>T

c.C223T

L75F

c.224T>C

c.T224C

L75P

c.226A>G

c.A226G

M76V

c.227T>C

c.T227C

M76T

c.229G>A

c.G229A

V77I

c.229G>C

c.G229C

V77L

c.232T>C

c.T232C

S78P

c.233C>T

c.C233T

S78L

c.235G>A

c.G235A

E79K

c.235G>C

c.G235C

E79Q

c.236A>C

c.A236C

E79A

c.236A>G

c.A236G

E79G

c.236A>T

c.A236T

E79V

c.237A>T

c.A237T

E79D

c.238G>A

c.G238A

G80S

c.238G>T

c.G238T

G80C

c.239G>A

c.G239A

G80D

c.239G>C

c.G239C

G80A

c.239G>T

c.G239T

G80V

c.242G>T

c.G242T

W81L

c.244A>G

c.A244G

K82E

c.245A>C

c.A245C

K82T

c.245A>G

c.A245G

K82R

c.245A>T

c.A245T

K82M

c.246G>C

c.G246C

K82N

c.247G>A

c.G247A

D83N

c.248A>C

c.A248C

D83A

c.248A>G

c.A248G

D83G

c.248A>T

c.A248T

D83V

c.249T>A

c.T249A

D83E

c.250G>A

c.G250A

A84T

c.250G>C

c.G250C

A84P

c.250G>T

c.G250T

A84S

c.251C>A

c.C251A

A84E

c.251C>G

c.C251G

A84G

c.251C>T

c.C251T

A84V

c.253G>A

c.G253A

G85S

c.[253G>A; 254G>A]

c.G253A/G254A

G85N

c.[253G>A; 254G>T; 255T>G]

c.G253A/G254T/T255G

G85M

c.253G>C

c.G253C

G85R

c.253G>T

c.G253T

G85C

c.254G>A

c.G254A

G85D

c.254G>C

c.G254C

G85A

c.257A>T

c.A257T

Y86F

c.260A>G

c.A260G

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c.261G>C or c.261G>T

c.G261C or c.G261T

E87D

c.262T>A

c.T262A

Y88N

c.262T>C

c.T262C

Y88H

c.263A>C

c.A263C

Y88S

c.263A>G

c.A263G

Y88C

c.265C>G

c.C265G

L89V

c.265C>T

c.C265T

L89F

c.271A>C

c.A271C

I91L

c.271A>T

c.A271T

I91F

c.272T>C

c.T272C

I91T

c.272T>G

c.T272G

I91S

c.273T>G

c.T273G

I91M

c.286A>G

c.A286G

M96V

c.286A>T

c.A286T

M96L

c.287T>C

c.T287C

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c.288G>A or c.288G>T or c.288G>C

c.G288A or c.G288T or c.G288C

M96I

c.289G>A

c.G289A

A97T

c.289G>C

c.G289C

A97P

c.289G>T

c.G289T

A97S

c.290C>A

c.C290A

A97D

c.290C>T

c.C290T

A97V

c.293C>A

c.C293A

P98H

c.293C>G

c.C293G

P98R

c.293C>T

c.C293T

P98L

c.295C>G

c.C295G

Q99E

c.296A>C

c.A296C

Q99P

c.296A>G

c.A296G

Q99R

c.296A>T

c.A296T

Q99L

c.301G>C

c.G301C

D101H

c.302A>C

c.A302C

D101A

c.302A>G

c.A302G

D101G

c.302A>T

c.A302T

D101V

c.303T>A

c.T303A

D101E

c.304T>A

c.T304A

S102T

c.304T>C

c.T304C

S102P

c.304T>G

c.T304G

S102A

c.305C>T

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S102L

c.310G>A

c.G310A

G104S

c.311G>A

c.G311A

G104D

c.311G>C

c.G311C

G104A

c.311G>T

c.G311T

G104V

c.313A>G

c.A313G

R105G

c.314G>A

c.G314A

R105K

c.314G>C

c.G314C

R105T

c.314G>T

c.G314T

R105I

c.316C>A

c.C316A

L106I

c.316C>G

c.C316G

L106V

c.316C>T

c.C316T

L106F

c.317T>A

c.T317A

L106H

c.317T>C

c.T317C

L106P

c.319C>A

c.C319A

Q107K

c.319C>G

c.C319G

Q107E

c.320A>G

c.A320G

Q107R

c.321G>C

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c.322G>A

c.G322A

A108T

c.323C>A

c.C323A

A108E

c.323C>T

c.C323T

A108V

c.325G>A

c.G325A

D109N

c.325G>C

c.G325C

D109H

c.325G>T

c.G325T

D109Y

c.326A>C

c.A326C

D109A

c.326A>G

c.A326G

D109G

c.327C>G

c.C327G

D109E

c.328C>A

c.C328A

P110T

c.334C>G

c.C334G

R112G

c.335G>A

c.G335A

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c.335G>T

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R112L

c.337T>A

c.T337A

F113I

c.337T>C or c.339T>A or c.339T>G

c.T337C or c.T339A or c.T339G

F113L

c.337T>G

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F113V

c.338T>A

c.T338A

F113Y

c.341C>T

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P114L

c.343C>A

c.C343A

H115N

c.343C>G

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H115D

c.346G>C

c.G346C

G116R

c.350T>C

c.T350C

I117T

c.351T>G

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c.352C>T

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c.361G>A

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c.362C>T

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A121V

c.367T>A

c.T367A

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c.367T>G

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Y123D

c.368A>C

c.A368C

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c.368A>G

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c.368A>T

c.A368T

Y123F

c.370G>A

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V124I

c.371T>G

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c.373C>A

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H125N

c.373C>G

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c.373C>T

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c.374A>T

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c.376A>G

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c.376A>T

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c.377G>T

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S126I

c.379A>G

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K127E

c.383G>A

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G128E

c.383G>C

c.G383C

G128A

c.385C>G

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L129V

c.388A>C

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c.389A>T

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K130M

c.390G>C

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c.391C>G

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L131V

c.397A>C

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c.397A>T

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I133F

c.398T>C

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c.399T>G

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I133M

c.[399T>G; 434T>C]

c.T399G/T434C

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c.403G>A

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A135T

c.403G>T

c.G403T

A135S

c.404C>A

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A135E

c.404C>G

c.C404G

A135G

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A135V

c.406G>A

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D136N

c.407A>C

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D136A

c.407A>T

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D136V

c.408T>A or c.408T>G

c.T408A or c.T408G

D136E

c.409G>A

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V137I

c.409G>C

c.G409C

V137L

c.410T>A

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V137D

c.410T>C

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V137A

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V137G

c.413G>C

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G138A

c.415A>C

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N139H

c.415A>T

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N139Y

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c.419A>T

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c.420A>T

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K140N

c.421A>T

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T141S

c.427G>A

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A143T

c.428C>A

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A143E

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A143V

c.430G>A

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c.430G>C

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c.430G>T

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G144C

c.431G>A

c.G431A

G144D

c.431G>C

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G144A

c.431G>T

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G144V

c.433T>G

c.T433G

F145V

c.434T>A

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c.434T>C

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c.434T>G

c.T434G

F145C

c.435C>G

c.C435G

F145L

c.436C>A

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P146T

c.436C>G

c.C436G

P146A

c.436C>T

c.C436T

P146S

c.437C>A

c.C437A

P146H

c.437C>G

c.C437G

P146R

c.437C>T

c.C437T

P146L

c.440G>C

c.G440C

G147A

c.442A>G

c.A442G

S148G

c.442A>T

c.A442T

S148C

c.443G>C

c.G443C

S148T

c.446T>G

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F149C

c.449G>A

c.G449A

G150E

c.449G>T

c.G449T

G150V

c.451T>G

c.T451G

Y151D

c.452A>C

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c.454T>A

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Y152N

c.454T>C

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Y152D

c.455A>C

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Y152C

c.455A>T

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Y152F

c.457G>A

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D153N

c.457G>C

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D153H

c.457G>T

c.G457T

D153Y

c.458A>C

c.A458C

D153A

c.458A>T

c.A458T

D153V

c.465T>A or c.465T>G

c.T465A or c.T465G

D155E

c.466G>A

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A156T

c.466G>T

c.G466T

A156S

c.467C>G

c.C467G

A156G

c.467C>T

c.C467T

A156V

c.469C>A

c.C469A

Q157K

c.469C>G

c.C469G

Q157E

c.470A>C

c.A470C

Q157P

c.470A>T

c.A470T

Q157L

c.471G>C or c.471G>T

c.G471C or c.G471T

Q157H

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T158A

c.472A>T

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T158S

c.473C>A

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T158N

c.473C>T

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T158I

c.475T>A

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F159I

c.475T>G

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F159V

c.476T>A

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F159Y

c.476T>G

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F159C

c.477T>A

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c.478G>A

c.G478A

A160T

c.478G>T

c.G478T

A160S

c.479C>A

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c.C479G

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c.481G>A

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c.481G>C

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c.482A>T

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c.485G>C

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c.490G>A

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c.490G>T

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c.491T>C

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c.493G>A

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D165N

c.493G>C

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D165H

c.494A>C

c.A494C

D165A

c.494A>G

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D165G

c.495T>A

c.T495A

D165E

c.496_497delinsTC

c.496_497delinsTC

L166S

c.496C>A

c.C496A

L166M

c.496C>G

c.C496G

L166V

c.[496C>G; 497T>G]

c.C496G/T497G

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c.497T>A

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L166Q

c.499C>A

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L167I

c.499C>G

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L167V

c.505T>A

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F169I

c.505T>G

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F169V

c.506T>A

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c.506T>C

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F169C

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c.511G>A

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G171S

c.512G>C

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c.517T>C

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c.518A>C

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c.520T>C

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C174R

c.520T>G

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c.523G>C

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D175H

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c.524A>G

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c.524A>T

c.A524T

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c.525C>G or c.525C>A

c.C525G or c.C525A

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c.529T>A

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c.529T>G

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c.530T>C

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L177S

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L177W

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c.532G>C

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c.533A>C

c.A533C

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c.538T>A

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L180M

c.538T>G

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L180V

c.539T>C

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L180S

c.539T>G

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L180W

c.540G>C or c.540G>T

c.G540C or c.G540T

L180F

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c.542C>T

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c.544G>T

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c.545A>T

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D182V

c.546T>A

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c.548G>A

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c.548G>C

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c.550T>C

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c.554A>T

c.A554T

K185M

c.555G>C

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c.556C>A

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c.556C>G

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c.C556T

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c.557A>T

c.A557T

H186L

c.558C>G

c.C558G

H186Q

c.559_564dup

c.559_564dup

p.M187_S188dup

c.559A>T

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c.559A>G

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M187V

c.560T>C

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M187T

c.561G>T or c.561G>A or c.561G>C

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M187I

c.562T>A

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L189S

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L189F

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V199M

c.595G>C

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V199L

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V199E

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S201F

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E203Q

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c.A608G

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c.608A>T

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c.638A>T

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c.C640G

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c.641C>A

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c.641C>T

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P214L

c.643A>C

c.A643C

N215H

c.643A>G

c.A643G

N215D

c.643A>T

c.A643T

N215Y

c.644A>C

c.A644C

N215T

c.644A>G

c.A644G

N215S

c.[644A>G; 937G>T]

c.A644G/G937T

N215S/D313Y

c.644A>T

c.A644T

N215I

c.645T>A

c.T645A

N215K

c.646T>A

c.T646A

Y216N

c.646T>C

c.T646C

Y216H

c.646T>G

c.T646G

Y216D

c.647A>C

c.A647C

Y216S

c.647A>G

c.A647G

Y216C

c.647A>T

c.A647T

Y216F

c.649A>C

c.A649C

T217P

c.649A>G

c.A649G

T217A

c.649A>T

c.A649T

T217S

c.650C>A

c.C650A

T217K

c.650C>G

c.C650G

T217R

c.650C>T

c.C650T

T217I

c.652G>A

c.G652A

E218K

c.652G>C

c.G652C

E218Q

c.653A>C

c.A653C

E218A

c.653A>G

c.A653G

E218G

c.653A>T

c.A653T

E218V

c.654A>T

c.A654T

E218D

c.655A>C

c.A655C

I219L

c.655A>T

c.A655T

I219F

c.656T>A

c.T656A

I219N

c.656T>C

c.T656C

I219T

c.656T>G

c.T656G

I219S

c.657C>G

c.C657G

I219M

c.659G>A

c.G659A

R220Q

c.659G>C

c.G659C

R220P

c.659G>T

c.G659T

R220L

c.661C>A

c.C661A

Q221K

c.661C>G

c.C661G

Q221E

c.662A>C

c.A662C

Q221P

c.662A>G

c.A662G

Q221R

c.662A>T

c.A662T

Q221L

c.663G>C

c.G663C

Q221H

c.664T>A

c.T664A

Y222N

c.664T>C

c.T664C

Y222H

c.664T>G

c.T664G

Y222D

c.665A>C

c.A665C

Y222S

c.665A>G

c.A665G

Y222C

c.670A>C

c.A670C

N224H

c.671A>C

c.A671C

N224T

c.671A>G

c.A671G

N224S

c.673C>G

c.C673G

H225D

c.679C>G

c.C679G

R227G

c.682A>C

c.A682C

N228H

c.682A>G

c.A682G

N228D

c.683A>C

c.A683C

N228T

c.683A>G

c.A683G

N228S

c.683A>T

c.A683T

N228I

c.685T>A

c.T685A

F229I

c.686T>A

c.T686A

F229Y

c.686T>C

c.T686C

F229S

c.687T>A or c.687T>G

c.T687A or c.T687G

F229L

c.688G>C

c.G688C

A230P

c.689C>A

c.C689A

A230D

c.689C>G

c.C689G

A230G

c.689C>T

c.C689T

A230V

c.694A>C

c.A694C

I232L

c.694A>G

c.A694G

I232V

c.695T>C

c.T695C

I232T

c.696T>G

c.T696G

I232M

c.698A>C

c.A698C

D233A

c.698A>G

c.A698G

D233G

c.698A>T

c.A698T

D233V

c.699T>A

c.T699A

D233E

c.703T>A

c.T703A

S235T

c.703T>G

c.T703G

S235A

c.710A>T

c.A710T

K237I

c.712A>G

c.A712G

S238G

c.712A>T

c.A712T

S238C

c.713G>A

c.G713A

S238N

c.713G>C

c.G713C

S238T

c.713G>T

c.G713T

S238I

c.715A>T

c.A715T

I239L

c.716T>C

c.T716C

I239T

c.717A>G

c.A717G

I239M

c.718A>G

c.A718G

K240E

c.719A>G

c.A719G

K240R

c.719A>T

c.A719T

K240M

c.720G>C or c.720G>T

c.G720C or c.G720T

K240N

c.721A>T

c.A721T

S241C

c.722G>C

c.G722C

S241T

c.722G>T

c.G722T

S241I

c.724A>C

c.A724C

I242L

c.724A>G

c.A724G

I242V

c.724A>T

c.A724T

I242F

c.725T>A

c.T725A

I242N

c.725T>C

c.T725C

I242T

c.725T>G

c.T725G

I242S

c.726C>G

c.C726G

I242M

c.727T>A

c.T727A

L243M

c.727T>G

c.T727G

L243V

c.728T>C

c.T728C

L243S

c.728T>G

c.T728G

L243W

c.729G>C or c.729G>T

c.G729C or c.G729T

L243F

c.730G>A

c.G730A

D244N

c.730G>C

c.G730C

D244H

c.730G>T

c.G730T

D244Y

c.731A>C

c.A731C

D244A

c.731A>G

c.A731G

D244G

c.731A>T

c.A731T

D244V

c.732C>G

c.C732G

D244E

c.733T>G

c.T733G

W245G

c.735G>C

c.G735C

W245C

c.736A>G

c.A736G

T246A

c.737C>A

c.C737A

T246K

c.737C>G

c.C737G

T246R

c.737C>T

c.C737T

T246I

c.739T>A

c.T739A

S247T

c.739T>G

c.T739G

S247A

c.740C>A

c.C740A

S247Y

c.740C>G

c.C740G

S247C

c.740C>T

c.C740T

S247F

c.742T>G

c.T742G

F248V

c.743T>A

c.T743A

F248Y

c.743T>G

c.T743G

F248C

c.744T>A

c.T744A

F248L

c.745A>C

c.A745C

N249H

c.745A>G

c.A745G

N249D

c.745A>T

c.A745T

N249Y

c.746A>C

c.A746C

N249T

c.746A>G

c.A746G

N249S

c.746A>T

c.A746T

N249I

c.747C>G or c.747C>A

c.C747G or c.C747A

N249K

c.748C>A

c.C748A

Q250K

c.748C>G

c.C748G

Q250E

c.749A>C

c.A749C

Q250P

c.749A>G

c.A749G

Q250R

c.749A>T

c.A749T

Q250L

c.750G>C

c.G750C

Q250H

c.751G>A

c.G751A

E251K

c.751G>C

c.G751C

E251Q

c.752A>G

c.A752G

E251G

c.752A>T

c.A752T

E251V

c.754A>G

c.A754G

R252G

c.757A>G

c.A757G

I253V

c.757A>T

c.A757T

I253F

c.758T>A

c.T758A

I253N

c.758T>C

c.T758C

I253T

c.758T>G

c.T758G

I253S

c.760-762delGTT or c.761-763del

c.760_762delGTT or c.761_763del

p.V254del

c.760G>T

c.G760T

V254F

c.761T>A

c.T761A

V254D

c.761T>C

c.T761C

V254A

c.761T>G

c.T761G

V254G

c.763G>A

c.G763A

D255N

c.763G>C

c.G763C

D255H

c.763G>T

c.G763T

D255Y

c.764A>C

c.A764C

D255A

c.764A>T

c.A764T

D255V

c.765T>A

c.T765A

D255E

c.766G>C

c.G766C

V256L

c.767T>A

c.T767A

V256D

c.767T>G

c.T767G

V256G

c.769G>A

c.G769A

A257T

c.769G>C

c.G769C

A257P

c.769G>T

c.G769T

A257S

c.770C>G

c.C770G

A257G

c.770C>T

c.C770T

A257V

c.772G>C or c.772G>A

c.G772C or c.G772A

G258R

c.773G>A

c.G773A

G258E

c.773G>T

c.G773T

G258V

c.775C>A

c.C775A

P259T

c.775C>G

c.C775G

P259A

c.775C>T

c.C775T

P259S

c.776C>A

c.C776A

P259Q

c.776C>G

c.C776G

P259R

c.776C>T

c.C776T

P259L

c.778G>T

c.G778T

G260W

c.779G>A

c.G779A

G260E

c.779G>C

c.G779C

G260A

c.781G>A

c.G781A

G261S

c.781G>C

c.G781C

G261R

c.781G>T

c.G781T

G261C

c.782G>C

c.G782C

G261A

c.787A>C

c.A787C

N263H

c.788A>C

c.A788C

N263T

c.788A>G

c.A788G

N263S

c.790G>A

c.G790A

D264N

c.790G>C

c.G790C

D264H

c.790G>T

c.G790T

D264Y

c.793C>G

c.C793G

P265A

c.794C>A

c.C794A

P265Q

c.794C>T

c.C794T

P265L

c.799A>G

c.A799G

M267V

c.799A>T

c.A799T

M267L

c.800T>C

c.T800C

M267T

c.802T>A

c.T802A

L268I

c.804A>T

c.A804T

L268F

c.805G>A

c.G805A

V269M

c.805G>C

c.G805C

V269L

c.806T>C

c.T806C

V269A

c.808A>C

c.A808C

I270L

c.808A>G

c.A808G

I270V

c.809T>C

c.T809C

I270T

c.809T>G

c.T809G

I270S

c.810T>G

c.T810G

I270M

c.811G>A

c.G811A

G271S

c.[811G>A; 937G>T]

c.G811A/G937T

G271S/D313Y

c.812G>A

c.G812A

G271D

c.812G>C

c.G812C

G271A

c.814A>G

c.A814G

N272D

c.818T>A

c.T818A

F273Y

c.823C>A

c.C823A

L275I

c.823C>G

c.C823G

L275V

c.827G>A

c.G827A

S276N

c.827G>C

c.G827C

S276T

c.829T>G

c.T829G

W277G

c.830G>T

c.G830T

W277L

c.831G>T or c.831G>C

c.G831T or c.G831C

W277C

c.832A>T

c.A832T

N278Y

c.833A>T

c.A833T

N278I

c.835C>G

c.C835G

Q279E

c.838C>A

c.C838A

Q280K

c.839A>G

c.A839G

Q280R

c.839A>T

c.A839T

Q280L

c.840A>T or c.840A>C

c.A840T or c.A840C

Q280H

c.841G>C

c.G841C

V281L

c.842T>A

c.T842A

V281E

c.842T>C

c.T842C

V281A

c.842T>G

c.T842G

V281G

c.844A>G

c.A844G

T282A

c.844A>T

c.A844T

T282S

c.845C>T

c.C845T

T282I

c.847C>G

c.C847G

Q283E

c.848A>T

c.A848T

Q283L

c.849G>C

c.G849C

Q283H

c.850A>G

c.A850G

M284V

c.850A>T

c.A850T

M284L

c.851T>C

c.T851C

M284T

c.852G>C

c.G852C

M284I

c.853G>A

c.G853A

A285T

c.854C>G

c.C854G

A285G

c.854C>T

c.C854T

A285V

c.856C>G

c.C856G

L286V

c.856C>T

c.C856T

L286F

c.857T>A

c.T857A

L286H

c.860G>T

c.G860T

W287L

c.862G>C

c.G862C

A288P

c.862G>T

c.G862T

A288S

c.863C>G

c.C863G

A288G

c.863C>T

c.C863T

A288V

c.865A>C

c.A865C

I289L

c.865A>G

c.A865G

I289V

c.866T>C

c.T866C

I289T

c.866T>G

c.T866G

I289S

c.868A>C or c.868A>T

c.A868C or c.A868T

M290L

c.868A>G

c.A868G

M290V

c.869T>C

c.T869C

M290T

c.870G>A or c.870G>C or c.870G>T

c.G870A or c.G870C or c.G870T

M290I

c.871G>A

c.G871A

A291T

c.871G>T

c.G871T

A291S

c.872C>G

c.C872G

A291G

c.874G>T

c.G874T

A292S

c.875C>G

c.C875G

A292G

c.877C>A

c.C877A

P293T

c.880T>A

c.T880A

L294I

c.880T>G

c.T880G

L294V

c.881T>C

c.T881C

L294S

c.882A>T

c.A882T

L294F

c.883T>A

c.T883A

F295I

c.883T>G

c.T883G

F295V

c.884T>A

c.T884A

F295Y

c.884T>C

c.T884C

F295S

c.884T>G

c.T884G

F295C

c.886A>G

c.A886G

M296V

c.886A>T or c.886A>C

c.A886T or c.A886C

M296L

c.887T>C

c.T887C

M296T

c.888G>A or c.888G>T or c.888G>C

c.G888A or c.G888T or c.G888C

M296I

c.889T>A

c.T889A

S297T

c.892A>G

c.A892G

N298D

c.893A>C

c.A893C

N298T

c.893A>G

c.A893G

N298S

c.893A>T

c.A893T

N298I

c.895G>A

c.G895A

D299N

c.895G>C

c.G895C

D299H

c.897C>G or c.897C>A

c.C897G or c.C897A

D299E

c.898C>A

c.C898A

L300I

c.898C>G

c.C898G

L300V

c.898C>T

c.C898T

L300F

c.899T>C

c.T899C

L300P

c.901C>G

c.C901G

R301G

c.902G>A

c.G902A

R301Q

c.902G>C

c.G902C

R301P

c.902G>T

c.G902T

R301L

c.904C>A

c.C904A

H302N

c.904C>G

c.C904G

H302D

c.904C>T

c.C904T

H302Y

c.905A>T

c.A905T

H302L

c.907A>G

c.A907G

I303V

c.907A>T

c.A907T

I303F

c.908T>A

c.T908A

I303N

c.908T>C

c.T908C

I303T

c.908T>G

c.T908G

I303S

c.911G>A

c.G911A

S304N

c.911G>C

c.G911C

S304T

c.911G>T

c.G911T

S304I

c.916C>G

c.C916G

Q306E

c.917A>C

c.A917C

Q306P

c.917A>T

c.A917T

Q306L

c.919G>A

c.G919A

A307T

c.919G>C

c.G919C

A307P

c.919G>T

c.G919T

A307S

c.920C>A

c.C920A

A307D

c.920C>G

c.C920G

A307G

c.920C>T

c.C920T

A307V

c.922A>C

c.A922C

K308Q

c.922A>G

c.A922G

K308E

c.923A>G

c.A923G

K308R

c.923A>T

c.A923T

K308I

c.924A>T or c.924A>C

c.A924T or c.A924C

K308N

c.925G>A

c.G925A

A309T

c.925G>C

c.G925C

A309P

c.926C>A

c.C926A

A309D

c.926C>T

c.C926T

A309V

c.928C>A

c.C928A

L310I

c.928C>G

c.C928G

L310V

c.928C>T

c.C928T

L310F

c.931C>A

c.C931A

L311I

c.931C>G

c.C931G

L311V

c.934C>A

c.C934A

Q312K

c.934C>G

c.C934G

Q312E

c.935A>G

c.A935G

Q312R

c.935A>T

c.A935T

Q312L

c.936G>T or c.936G>C

c.G936T or c.G936C

Q312H

c.937G>T

c.G937T

D313Y

c.[937G>T; 1232G>A]

c.G937T/G1232A

D313Y/G411D

c.938A>G

c.A938G

D313G

c.938A>T

c.A938T

D313V

c.939T>A

c.T939A

D313E

c.940A>G

c.A940G

K314E

c.941A>C

c.A941C

K314T

c.941A>T

c.A941T

K314M

c.942G>C

c.G942C

K314N

c.943G>A

c.G943A

D315N

c.943G>C

c.G943C

D315H

c.943G>T

c.G943T

D315Y

c.944A>C

c.A944C

D315A

c.944A>G

c.A944G

D315G

c.944A>T

c.A944T

D315V

c.946G>A

c.G946A

V316I

c.946G>C

c.G946C

V316L

c.947T>C

c.T947C

V316A

c.947T>G

c.T947G

V316G

c.949A>C

c.A949C

I317L

c.949A>G

c.A949G

I317V

c.950T>C

c.T950C

I317T

c.951T>G

c.T951G

I317M

c.952G>A

c.G952A

A318T

c.952G>C

c.G952C

A318P

c.953C>A

c.C953A

A318D

c.953C>T

c.C953T

A318V

c.955A>T

c.A955T

I319F

c.956T>C

c.T956C

I319T

c.957C>G

c.C957G

I319M

c.958A>C

c.A958C

N320H

c.959A>C

c.A959C

N320T

c.959A>G

c.A959G

N320S

c.959A>T

c.A959T

N320I

c.961C>A

c.C961A

Q321K

c.962A>G

c.A962G

Q321R

c.962A>T

c.A962T

Q321L

c.963G>C or c.963G>T

c.G963C or c.G963T

Q321H

c.964G>A

c.G964A

D322N

c.964G>C

c.G964C

D322H

c.965A>C

c.A965C

D322A

c.965A>T

c.A965T

D322V

c.966C>A or c.966C>G

c.C966A or c.C966G

D322E

c.967C>A

c.C967A

P323T

c.968C>G

c.C968G

P323R

c.970T>G

c.T970G

L324V

c.971T>G

c.T971G

L324W

c.973G>A

c.G973A

G325S

c.973G>C

c.G973C

G325R

c.973G>T

c.G973T

G325C

c.974G>C

c.G974C

G325A

c.974G>T

c.G974T

G325V

c.976A>C

c.A976C

K326Q

c.976A>G

c.A976G

K326E

c.977A>C

c.A977C

K326T

c.977A>G

c.A977G

K326R

c.977A>T

c.A977T

K326M

c.978G>C or c.978G>T

c.G978C or c.G978T

K326N

c.979C>G

c.C979G

Q327E

c.980A>C

c.A980C

Q327P

c.980A>T

c.A980T

Q327L

c.981A>T

c.A981T

Q327H

c.983G>C

c.G983C

G328A

c.985T>A

c.T985A

Y329N

c.985T>C

c.T985C

Y329H

c.985T>G

c.T985G

Y329D

c.986A>G

c.A986G

Y329C

c.986A>T

c.A986T

Y329F

c.988C>A

c.C988A

Q330K

c.988C>G

c.C988G

Q330E

c.989A>C

c.A989C

Q330P

c.989A>G

c.A989G

Q330R

c.990G>C

c.G990C

Q330H

c.991C>G

c.C991G

L331V

c.992T>A

c.T992A

L331H

c.992T>C

c.T992C

L331P

c.992T>G

c.T992G

L331R

c.994A>G

c.A994G

R332G

c.995G>C

c.G995C

R332T

c.995G>T

c.G995T

R332I

c.996A>T

c.A996T

R332S

c.997C>G

c.C997G

Q333E

c.998A>C

c.A998C

Q333P

c.998A>T

c.A998T

Q333L

c.1000G>C

c.G1000C

G334R

c.1001G>A

c.G1001A

G334E

c.1001G>T

c.G1001T

G334V

c.1003G>T

c.G1003T

D335Y

c.1004A>C

c.A1004C

D335A

c.1004A>G

c.A1004G

D335G

c.1004A>T

c.A1004T

D335V

c.1005C>G

c.C1005G

D335E

c.1006A>G

c.A1006G

N336D

c.1006A>T

c.A1006T

N336Y

c.1007A>C

c.A1007C

N336T

c.1007A>G

c.A1007G

N336S

c.1007A>T

c.A1007T

N336I

c.1009T>G

c.T1009G

F337V

c.1010T>A

c.T1010A

F337Y

c.1010T>C

c.T1010C

F337S

c.1010T>G

c.T1010G

F337C

c.1011T>A

c.T1011A

F337L

c.1012G>A

c.G1012A

E338K

c.1013A>C

c.A1013C

E338A

c.1013A>G

c.A1013G

E338G

c.1013A>T

c.A1013T

E338V

c.1014A>T

c.A1014T

E338D

c.1015G>A

c.G1015A

V339M

c.1016T>A

c.T1016A

V339E

c.1016T>C

c.T1016C

V339A

c.1021G>C

c.G1021C

E341Q

c.1022A>C

c.A1022C

E341A

c.1027C>A

c.C1027A

P343T

c.1027C>G

c.C1027G

P343A

c.1027C>T

c.C1027T

P343S

c.1028C>T

c.C1028T

P343L

c.1030C>G

c.C1030G

L344V

c.1030C>T

c.C1030T

L344F

c.1031T>G

c.T1031G

L344R

c.1033T>C

c.T1033C

S345P

c.1036G>T

c.G1036T

G346C

c.1037G>A

c.G1037A

G346D

c.1037G>C

c.G1037C

G346A

c.1037G>T

c.G1037T

G346V

c.1039T>A

c.T1039A

L347I

c.1043C>A

c.C1043A

A348D

c.1046G>C

c.G1046C

W349S

c.1046G>T

c.G1046T

W349L

c.1047G>C

c.G1047C

W349C

c.1048G>A

c.G1048A

A350T

c.1048G>T

c.G1048T

A350S

c.1049C>G

c.C1049G

A350G

c.1049C>T

c.C1049T

A350V

c.1052T>A

c.T1052A

V351E

c.1052T>C

c.T1052C

V351A

c.1054G>A

c.G1054A

A352T

c.1054G>T

c.G1054T

A352S

c.1055C>G

c.C1055G

A352G

c.1055C>T

c.C1055T

A352V

c.1057A>T

c.A1057T

M353L

c.1058T>A

c.T1058A

M353K

c.1058T>C

c.T1058C

M353T

c.1061T>A

c.T1061A

I354K

c.1061T>G

c.T1061G

I354R

c.1063A>C

c.A1063C

N355H

c.1063A>G

c.A1063G

N355D

c.1063A>T

c.A1063T

N355Y

c.1064A>G

c.A1064G

N355S

c.1066C>G

c.C1066G

R356G

c.1066C>T

c.C1066T

R356W

c.1067G>A

c.G1067A

R356Q

c.1067G>C

c.G1067C

R356P

c.1067G>T

c.G1067T

R356L

c.1069C>G

c.C1069G

Q357E

c.1072G>C

c.G1072C

E358Q

c.1073A>C

c.A1073C

E358A

c.1073A>G

c.A1073G

E358G

c.1074G>T or c.1074G>C

c.G1074T or c.G1074C

E358D

c.1075A>C

c.A1075C

I359L

c.1075A>G

c.A1075G

I359V

c.1075A>T

c.A1075T

I359F

c.1076T>A

c.T1076A

I359N

c.1076T>C

c.T1076C

I359T

c.1076T>G

c.T1076G

I359S

c.1078G>A

c.G1078A

G360S

c.1078G>C

c.G1078C

G360R

c.1078G>T

c.G1078T

G360C

c.1079G>A

c.G1079A

G360D

c.1079G>C

c.G1079C

G360A

c.1082G>A

c.G1082A

G361E

c.1082G>C

c.G1082C

G361A

c.1084C>A

c.C1084A

P362T

c.1084C>G

c.C1084G

P362A

c.1084C>T

c.C1084T

P362S

c.1085C>A

c.C1085A

P362H

c.1085C>G

c.C1085G

P362R

c.1085C>T

c.C1085T

P362L

c.1087C>A

c.C1087A

R363S

c.1087C>G

c.C1087G

R363G

c.1087C>T

c.C1087T

R363C

c.1088G>A

c.G1088A

R363H

c.1088G>T

c.G1088T

R363L

c.1090T>C

c.T1090C

S364P

c.1091C>G

c.C1091G

S364C

c.1093T>A

c.T1093A

Y365N

c.1093T>G

c.T1093G

Y365D

c.1094A>C

c.A1094C

Y365S

c.1094A>T

c.A1094T

Y365F

c.1096A>C

c.A1096C

T366P

c.1096A>T

c.A1096T

T366S

c.1097C>A

c.C1097A

T366N

c.1097C>T

c.C1097T

T366I

c.1099A>C

c.A1099C

I367L

c.1099A>T

c.A1099T

I367F

c.1101C>G

c.C1101G

I367M

c.1102G>A

c.G1102A

A368T

c.1102G>C

c.G1102C

A368P

c.1103C>G

c.C1103G

A368G

c.1105G>A

c.G1105A

V369I

c.1105G>C

c.G1105C

V369L

c.1105G>T

c.G1105T

V369F

c.1106T>C

c.T1106C

V369A

c.1106T>G

c.T1106G

V369G

c.1108G>A

c.G1108A

A370T

c.1108G>C

c.G1108C

A370P

c.1109C>A

c.C1109A

A370D

c.1109C>G

c.C1109G

A370G

c.1109C>T

c.C1109T

A370V

c.1111T>A

c.T1111A

S371T

c.1112C>G

c.C1112G

S371C

c.1117G>A

c.G1117A

G373S

c.1117G>T

c.G1117T

G373C

c.1118G>C

c.G1118C

G373A

c.1120A>G

c.A1120G

K374E

c.1121A>C

c.A1121C

K374T

c.1121A>G

c.A1121G

K374R

c.1121A>T

c.A1121T

K374I

c.1123G>C

c.G1123C

G375R

c.1124G>A

c.G1124A

G375E

c.1124G>C

c.G1124C

G375A

c.1126G>A

c.G1126A

V376M

c.1126G>C

c.G1126C

V376L

c.1127T>A

c.T1127A

V376E

c.1127T>G

c.T1127G

V376G

c.1129G>A

c.G1129A

A377T

c.1129G>C

c.G1129C

A377P

c.1129G>T

c.G1129T

A377S

c.1130C>G

c.C1130G

A377G

c.1135A>G

c.A1135G

N379D

c.1136A>C

c.A1136C

N379T

c.1136A>T

c.A1136T

N379I

c.1137T>A

c.T1137A

N379K

c.1138C>A

c.C1138A

P380T

c.1138C>G

c.C1138G

P380A

c.1139C>A

c.C1139A

P380H

c.1139C>G

c.C1139G

P380R

c.1139C>T

c.C1139T

P380L

c.1142C>A

c.C1142A

A381D

c.1147T>A

c.T1147A

F383I

c.1148T>A

c.T1148A

F383Y

c.1148T>G

c.T1148G

F383C

c.1150A>T

c.A1150T

I384F

c.1151T>C

c.T1151C

I384T

c.1152C>G

c.C1152G

I384M

c.1153A>G

c.A1153G

T385A

c.1154C>T

c.C1154T

T385I

c.1156C>A

c.C1156A

Q386K

c.1157A>T

c.A1157T

Q386L

c.1158G>C

c.G1158C

Q386H

c.1159C>A

c.C1159A

L387I

c.1159C>T

c.C1159T

L387F

c.1160T>A

c.T1160A

L387H

c.1160T>G

c.T1160G

L387R

c.1162C>A

c.C1162A

L388I

c.1162C>G

c.C1162G

L388V

c.1162C>T

c.C1162T

L388F

c.1163T>A

c.T1163A

L388H

c.1163T>G

c.T1163G

L388R

c.1168G>A

c.G1168A

V390M

c.1171A>C

c.A1171C

K391Q

c.1171A>G

c.A1171G

K391E

c.1172A>C

c.A1172C

K391T

c.1172A>G

c.A1172G

K391R

c.1172A>T

c.A1172T

K391I

c.1173A>T

c.A1173T

K391N

c.1174A>G

c.A1174G

R392G

c.1174A>T

c.A1174T

R392W

c.1175G>A

c.G1175A

R392K

c.1175G>C

c.G1175C

R392T

c.1175G>T

c.G1175T

R392M

c.1177A>C

c.A1177C

K393Q

c.1177A>G

c.A1177G

K393E

c.1178A>C

c.A1178C

K393T

c.1179G>C

c.G1179C

K393N

c.1180C>A

c.C1180A

L394I

c.1181T>A

c.T1181A

L394Q

c.1181T>C

c.T1181C

L394P

c.1181T>G

c.T1181G

L394R

c.1183G>C

c.G1183C

G395R

c.1184G>A

c.G1184A

G395E

c.1184G>C

c.G1184C

G395A

c.1186T>A

c.T1186A

F396I

c.1186T>G

c.T1186G

F396V

c.1187T>G

c.T1187G

F396C

c.1188C>G

c.C1188G

F396L

c.1189T>A

c.T1189A

Y397N

c.1189T>C

c.T1189C

Y397H

c.1190A>C

c.A1190C

Y397S

c.1190A>G

c.A1190G

Y397C

c.1190A>T

c.A1190T

Y397F

c.1192G>A

c.G1192A

E398K

c.1192G>C

c.G1192C

E398Q

c.1193A>G

c.A1193G

E398G

c.1195T>A

c.T1195A

W399R

c.1195T>G

c.T1195G

W399G

c.1198A>C

c.A1198C

T400P

c.1198A>G

c.A1198G

T400A

c.1198A>T

c.A1198T

T400S

c.1199C>A

c.C1199A

T400N

c.1199C>T

c.C1199T

T400I

c.1201T>A

c.T1201A

S401T

c.1201T>G

c.T1201G

S401A

c.1202_1203insGACTTC

c.1202_1203insGACTTC

p.T400_S401dup

c.1202C>T

c.C1202T

S401L

c.1204A>G

c.A1204G

R402G

c.1204A>T

c.A1204T

R402W

c.1205G>C

c.G1205C

R402T

c.1205G>T

c.G1205T

R402M

c.1206G>C

c.G1206C

R402S

c.1207T>G

c.T1207G

L403V

c.1208T>C

c.T1208C

L403S

c.1209A>T

c.A1209T

L403F

c.1210A>G

c.A1210G

R404G

c.1211G>A

c.G1211A

R404K

c.1211G>C

c.G1211C

R404T

c.1211G>T

c.G1211T

R404I

c.1212A>T

c.A1212T

R404S

c.1213A>G

c.A1213G

S405G

c.1216C>G

c.C1216G

H406D

c.1217A>T

c.A1217T

H406L

c.1218C>G

c.C1218G

H406Q

c.1219A>T

c.A1219T

I407L

c.1220T>C

c.T1220C

I407T

c.1221A>G

c.A1221G

I407M

c.1222A>C

c.A1222C

N408H

c.1222A>G

c.A1222G

N408D

c.1222A>T

c.A1222T

N408Y

c.1223A>C

c.A1223C

N408T

c.1225C>A

c.C1225A

P409T

c.1225C>G

c.C1225G

P409A

c.1225C>T

c.C1225T

P409S

c.1226C>T

c.C1226T

P409L

c.1228A>G

c.A1228G

T410A

c.1228A>T

c.A1228T

T410S

c.1229C>T

c.C1229T

T410I

c.1231G>A

c.G1231A

G411S

c.1231G>T

c.G1231T

G411C

c.1232G>A

c.G1232A

G411D

c.1232G>C

c.G1232C

G411A

c.1232G>T

c.G1232T

G411V

c.1234A>C

c.A1234C

T412P

c.1234A>G

c.A1234G

T412A

c.1234A>T

c.A1234T

T412S

c.1235C>A

c.C1235A

T412N

c.1235C>T

c.C1235T

T412I

c.1237G>A

c.G1237A

V413I

c.1237G>T

c.G1237T

V413F

c.1238T>G

c.T1238G

V413G

c.1240T>G

c.T1240G

L414V

c.1242G>C

c.G1242C

L414F

c.1243C>A

c.C1243A

L415I

c.1244T>A

c.T1244A

L415H

c.1246C>G

c.C1246G

Q416E

c.1247A>T

c.A1247T

Q416L

c.1248G>C

c.G1248C

Q416H

c.1249C>A

c.C1249A

L417I

c.1252G>A

c.G1252A

E418K

c.1252G>C

c.G1252C

E418Q

c.1253A>C

c.A1253C

E418A

c.1253A>G

c.A1253G

E418G

c.1254A>T

c.A1254T

E418D

c.1255A>G

c.A1255G

N419D

c.1255A>T

c.A1255T

N419Y

c.1256A>C

c.A1256C

N419T

c.1256A>G

c.A1256G

N419S

c.1256A>T

c.A1256T

N419I

c.1258A>C

c.A1258C

T420P

c.1258A>T

c.A1258T

T420S

c.1259C>A

c.C1259A

T420K

c.1259C>G

c.C1259G

T420R

c.1261A>G

c.A1261G

M421V

c.1261A>T

c.A1261T

M421L

c.1262T>A

c.T1262A

M421K

c.1262T>C

c.T1262C

M421T

c.1262T>G

c.T1262G

M421R

c.1263G>C

c.G1263C

M421I

c.1265A>C

c.A1265C

Q422P

c.1267A>T

c.A1267T

M423L

c.1268T>A

c.T1268A

M423K

c.1268T>C

c.T1268C

M423T

c.1269G>C

c.G1269C

M423I

c.1271C>T

c.C1271T

S424L

c.1275A>C

c.A1275C

L425F

c.1279G>A

c.G1279A

D427N

c.1286T>G

c.T1286G

L429R

Pharmacodynamic effects

Treatment with Galafold in Phase 2 pharmacodynamic trials generally resulted in increases in endogenous α-Gal A activity in WBCs, as well as in skin and kidney for the majority of patients. In patients with amenable mutations, GL-3 levels tended to decrease in urine and in kidney interstitial capillaries.

Clinical efficacy and safety

The clinical efficacy and safety of Galafold have been evaluated in two Phase 3 pivotal trials and two open-label extension (OLE) trials. All patients received the recommended dosage of 123 mg Galafold every other day.

The first Phase 3 trial (ATTRACT) was a randomised open-label active comparator trial that evaluated the efficacy and safety of Galafold compared to enzyme replacement therapy (ERT) (agalsidase beta, agalsidase alfa) in 52 male and female patients with Fabry disease who were receiving ERT prior to trial entry and who have amenable mutations (ERT-experienced trial). The study was structured in two periods. During the first period (18-months) ERT-experienced patients were randomised to switch from ERT to Galafold or continue with ERT. The second period was an optional 12-month open-label extension in which all subjects received Galafold.

The second Phase 3 trial (FACETS) was a 6-month randomised double-blind placebo-controlled trial (through month 6) with an 18-month open-label period to evaluate the efficacy and safety of Galafold in 50 male and female patients with Fabry disease who were naïve to ERT, or had previously been on ERT and had stopped for at least 6 months and who have amenable mutations (ERT-naïve trial).

The first OLE trial (AT1001-041) included patients from Phase 2 and Phase 3 studies and has completed. The mean extent of exposure to the marketed dose of Galafold 123 mg QOD in patients completing study AT1001-041 was 3.57 (±1.23) years (n=85). The maximum exposure was 5.6 years.

The second OLE trial (AT1001-042) included patients that both transferred from OLE study AT1001-041 and directly from Phase 3 study ATTRACT, and is ongoing.

Renal Function

In the ERT-experienced trial, renal function remained stable for up to 18 months of treatment with Galafold. Mean annualised rate of change in eGFRCKD-EPI was -0.40 mL/min/1.73 m2 (95% CI: -2.272, 1.478; n=34) in the Galafold group compared to -1.03 mL/min/1.73 m2 (95% CI: -3.636, 1.575; n=18) in the ERT group. The mean annualised rate of change from baseline in eGFRCKD-EPI in patients treated for 30 months with Galafold was -1.72 mL/min/1.73 m2 (95% CI: -2.653, -0.782; n=31).

In the ERT-naïve trial and open-label extension, renal function remained stable for up to 5 years of treatment with Galafold. After an average of 3.4 years of treatment, the mean annualised rate of change in eGFRCKD-EPI was -0.74 mL/min/1.73 m2 (95% CI: -1.89, 0.40; n=41). No clinically significant differences were observed during the initial 6-month placebo-controlled period.

Left Ventricular Mass Index (LVMi)

In the ERT-experienced trial, following 18 months of treatment with Galafold there was a statistically significant decrease in LVMi (p<0.05). The baseline values were 95.3 g/m2 for the Galafold arm and 92.9 g/m2 for the ERT arm and the mean change from baseline in LVMi at Month 18 was -6.6 (95% CI: -11.0, -2.1; n=31) for Galafold and -2.0 (95% CI: -11.0, 7.0; n=13) for ERT. The change from baseline to Month 18 in LVMi (g/m2) in patients with left ventricular hypertrophy (females with baseline LVMi >95 g/m2 and males with baseline LVMi >115 g/m2) was -8.4 (95% CI: -15.7, 2.6; n=13) for migalastat and 4.5 (95% CI: -10.7, 18.4; n=5) for ERT. After 30 months treatment with Galafold, the mean change from baseline in LVMi was -3.8 (95% CI: -8.9, 1.3; n=28) and the mean change from baseline in LVMi in patients with left ventricular hypertrophy at baseline was -10.0 (95% CI: -16.6, -3.3; n=10).

In the ERT-naïve trial, Galafold resulted in a statistically significant decrease in LVMi (p<0.05); the mean change from baseline in LVMi at Month 18 to 24 was -7.7 (95% CI: -15.4, -0.01; n=27). After follow up in the OLE, the mean change from baseline in LVMi at Month 36 was -8.3 (95% CI: -17.1, 0.4; n=25) and at Month 48 was -9.1 (95% CI: -20.3, 2.0; n=18). The mean change from baseline in LVMi at Month 18 to 24 in patients with left ventricular hypertrophy at baseline (females with baseline LVMi >95 g/m2 or males with baseline LVMi >115 g/m2) was -18.6 (95% CI: -38.2, 1.0; n=8). After follow up in the OLE, the mean change from baseline in LVMi in patients with left ventricular hypertrophy at baseline at Month 36 was -30.0 (95%) CI: -57.9, -2.2; n=4) and at Month 48 was -33.1 (CI: -60.9, -5.4; n=4). No clinically significant differences in LVMi were observed during the initial 6-month placebo-controlled period.

Disease Substrate

In the ERT-experienced trial, plasma lyso-Gb3 levels slightly increased but remained low in patients with amenable mutations treated with Galafold for the 30 month duration of the study. Plasma lyso-Gb3 levels also remained low in patients on ERT for up to 18 months.

In the ERT- naïve trial, Galafold showed statistically significant reductions in plasma lyso-Gb3 concentrations and kidney interstitial capillary GL-3 inclusions in patients with amenable mutations. Patients randomised to Galafold in Stage 1 demonstrated statistically significant greater reduction (±SEM) in mean interstitial capillary GL-3 deposition (-0.25±0.10; -39%) at month 6 compared to placebo (+0.07 ± 0.13; +14%) (p=0.008). Patients randomised to placebo in Stage 1 and switched to Galafold at month 6 (Stage 2) also demonstrated statistically significant decreases in interstitial capillary GL-3 inclusions at month 12 (-0.33±0.15; -58%) (p=0.014). Qualitative reductions in GL-3 levels were observed in multiple renal cell types: podocytes, mesangial cells, and glomerular endothelial cells, respectively, over 12 months of treatment with Galafold.

Composite Clinical Outcomes

In the ERT-experienced trial, an analysis of a composite clinical outcome composed of renal, cardiac, and cerebrovascular events, or death, showed that the frequency of events observed in the Galafold treatment group was 29% compared to 44% in the ERT group over 18 months. The frequency of events in patients treated with Galafold over 30 months (32%) was similar to the 18 month period.

Patient-Reported Outcome - Gastrointestinal Symptoms Rating Scale

In the ERT-naïve trial, analyses of the Gastrointestinal Symptoms Rating Scale demonstrated that treatment with Galafold was associated with statistically significant (p<0.05) improvements versus placebo from baseline to month 6 in the diarrhoea domain, and in the reflux domain for patients with symptoms at baseline. During the open-label extension, statistically significant (p<0.05) improvements from baseline were observed in the diarrhoea and indigestion domains, with a trend of improvement in the constipation domain.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with Galafold in one or more subsets of the paediatric population in the treatment of Fabry disease (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

Absorption

The absolute bioavailability (AUC) for a single oral 150 mg migalastat hydrochloride dose or a single 2-hour 150 mg intravenous infusion was approximately 75%. Following a single oral dose of 150 mg migalastat hydrochloride solution, the time to peak plasma concentration was approximately 3 hours. Plasma migalastat exposure (AUC0-∞) and Cmax demonstrated dose-proportional increases at migalastat hydrochloride oral doses from 50 mg to 1,250 mg.

Migalastat administered with a high-fat meal, or 1 hour before a high-fat or light meal, or 1 hour after a light meal, resulted in significant reductions of 37% to 42% in mean total migalastat exposure (AUC0-∞) and reductions of 15% to 40% in mean peak migalastat exposure (Cmax) compared with the fasting state (see section 4.2).

Distribution

In healthy volunteers, the volume of distribution (Vz/F) of migalastat following ascending single oral doses (25-675 mg migalastat HCl) ranged from 77 to 133 L, indicating it is well distributed into tissues and greater than total body water (42 litres). There was no detectable plasma protein binding following administration of [14C]-migalastat hydrochloride in the concentration range between 1 and 100 μM.

Biotransformation

Based upon in vivo data, migalastat is a substrate for UGT, being a minor elimination pathway. Migalastat is not a substrate for P-glycoprotein (P-gP) in vitro and it is considered unlikely that migalastat would be subject to drug-drug interactions with cytochrome P450s. A pharmacokinetic trial in healthy male volunteers with 150 mg [14C]-migalastat HCl revealed that 99% of the radiolabeled dose recovered in plasma was comprised of unchanged migalastat (77%) and 3 dehydrogenated O-glucuronide conjugated metabolites, M1to M3 (13%). Approximately 9% of the total radioactivity was unassigned.

Elimination

A pharmacokinetic trial in healthy male volunteers with 150 mg [14C]-migalastat hydrochloride revealed that approximately 77% of the radiolabeled dose was recovered in urine of which 55% of was excreted as unchanged migalastat and 4% as combined metabolites M1, M2 and M3. Approximately 5% of the total sample radioactivity was unassigned components. Approximately 20% of the total radiolabeled dose was excreted in faeces, with unchanged migalastat being the only measured component.

Following ascending single oral doses (25-675 mg migalastat hydrochloride), no trends were found for clearance, CL/F). At the 150 mg dose, CL/F was approximately 11 to 14 L/hr. Following administration of the same doses, the mean elimination half-life (t1/2) ranged from approximately 3 to 5 hours.

Special populations

Patients with renal impairment

Galafold has not been studied in patients with Fabry disease who have a GFR less than 30 mL/min/1.73 m2. In a single dose study with Galafold in non-Fabry subjects with varying degrees of renal insufficiency, exposures were increased by 4.3-fold in subjects with severe renal impairment (GFR < 30 mL/min/1.73 m2).

Patients with hepatic impairment

No studies have been carried out in subjects with impaired hepatic function. From the metabolism and excretion pathways, it is not expected that a decreased hepatic function may affect the pharmacokinetics of migalastat.

Elderly (>65 years)

Clinical studies of Galafold included small number of patients aged 65 and over. The effect of age was evaluated in a population pharmacokinetic analysis on plasma migalastat clearance in the ERT-naïve study population. The difference in clearance between Fabry patients ≥65 years and those <65 years was 20%, which was not considered clinically significant.

Gender

The pharmacokinetic characteristics of migalastat were not significantly different between females and males in either healthy volunteers or in patients with Fabry disease.

5.3 Preclinical safety data

Non-clinical studies suggest no specific hazard for humans on the basis of single-and repeat-dose studies, with the exception of transient and fully reversible infertility in male rats associated with migalastat treatment. The infertility associated with migalastat treatment was reported at clinically relevant exposures. Complete reversibility was seen after 4 weeks off-dose. Similar findings have been noted pre-clinically following treatment with other iminosugars. In the rabbit embryo-foetal toxicity study, findings including embryo-foetal death, a reduction in mean foetal weight, retarded ossification, and slightly increased incidences of minor skeletal abnormalities were observed only at doses associated with maternal toxicity.

In a rat 104-week carcinogenicity study, there was an increased incidence of pancreatic islet cell adenomas in males at a dose level 19-fold higher than the exposure (AUC) at the clinically efficacious dose. This is a common spontaneous tumour in ad libitum-fed male rats. In the absence of similar findings in females, no findings in the genotoxicity battery or in the carcinogenicity study with Tg.rasH2 mice, and no pre-neoplastic pancreatic findings in the rodents or monkeys, this observation in male rats is not considered related to treatment and its relevance to humans is unknown.

6. Pharmaceutical particulars
6.1 List of excipients

Capsule contents

Pregelatinised starch (maize)

Magnesium stearate

Capsule shell

Gelatin

Titanium dioxide (E171)

Indigotine (E132)

Printing ink

Shellac

Black iron oxide

Potassium hydroxide

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

4 years

6.4 Special precautions for storage

This medicinal product does not require any special temperature storage conditions. Store in the original package in order to protect from moisture.

6.5 Nature and contents of container

PVC / PCTFE / PVC/Al blister.

Pack size of 14 capsules.

6.6 Special precautions for disposal and other handling

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. Marketing authorisation holder

Amicus Therapeutics Europe Limited

Block 1, Blanchardstown Corporate Park

Ballycoolin Road

Blanchardstown, Dublin

D15 AKK1

Ireland

Tel: +353 (0) 1 588 0836

Fax: +353 (0) 1 588 6851

e-mail: [email protected]

8. Marketing authorisation number(s)

EU/1/15/1082/001

9. Date of first authorisation/renewal of the authorisation

26 May 2016

10. Date of revision of the text

14 May 2020

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.