Migalastat Hydrochloride

Prescription

Tên thương mại: Galafold

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Capsule

Đường dùng

ORAL

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Amicus Therapeutics US, LLC

About This Medication

11 DESCRIPTION Migalastat, an alpha-galactosidase A (alpha-Gal A) pharmacological chaperone, is a low molecular weight iminosugar and an analogue of the terminal galactose of globotriaosylceramide (GL-3). Migalastat is present in the form of a hydrochloride salt in GALAFOLD. The chemical name for migalastat hydrochloride is (+)-(2 R ,3 S ,4 R ,5 S )-2-(hydroxymethyl) piperidine-3,4,5-triol hydrochloride. Its molecular formula is C 6 H 13 NO 4 •HCl, molecular mass is 199.63 g/mol, and its chemical structure is depicted below. Migalastat hydrochloride is a white to almost white crystalline solid. It is freely soluble in aqueous media within the pH range of 1.2 to 7.5. GALAFOLD (migalastat) capsules for oral administration contain 123 mg of migalastat (equivalent to 150 mg migalastat hydrochloride) as a white to pale brown powder and are supplied in a size “2” hard gelatin capsule with an opaque blue cap and an opaque white body imprinted with “A1001” in black ink. The inactive ingredients are magnesium stearate and pregelatinized starch. Capsule shells consist of gelatin, indigotine - FD&C Blue 2, and titanium dioxide. The black ink consists of black iron oxide, potassium hydroxide, and shellac. Chemical Structure

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Thành phần	Hàm lượng
Migalastat Hydrochloride	-

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1 INDICATIONS AND USAGE GALAFOLD is indicated for the treatment of adults with a confirmed diagnosis of Fabry disease and an amenable galactosidase alpha gene ( GLA ) variant based on in vitro assay data [see Dosage and Administration (2.1) and Clinical Pharmacology (12.1) ] . This indication is approved under accelerated approval based on reduction in kidney interstitial capillary cell globotriaosylceramide (KIC GL-3) substrate [see Clinical Studies (14) ] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. GALAFOLD is an alpha-galactosidase A (alpha-Gal A) pharmacological chaperone indicated for the treatment of adults with a confirmed diagnosis of Fabry disease and an amenable galactosidase alpha gene ( GLA ) variant based on in vitro assay data. ( 1 , 12.1 ) This indication is approved under accelerated approval based on reduction in kidney interstitial capillary cell globotriaosylceramide (KIC GL-3) substrate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. ( 1 )

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12.1 Mechanism of Action Migalastat is a pharmacological chaperone that reversibly binds to the active site of the alpha-galactosidase A (alpha-Gal A) protein (encoded by the galactosidase alpha gene, GLA ), which is deficient in Fabry disease. This binding stabilizes alpha-Gal A allowing its trafficking from the endoplasmic reticulum into the lysosome where it exerts its action. In the lysosome, at a lower pH and at a higher concentration of relevant substrates, migalastat dissociates from alpha-Gal A allowing it to break down the glycosphingolipids globotriaosylceramide (GL-3) and globotriaosylsphingosine (lyso-Gb 3 ). Certain GLA variants (mutations) causing Fabry disease result in the production of abnormally folded and less stable forms of the alpha-Gal A protein which, however, retain enzymatic activity. Those GLA variants, referred to as amenable variants, produce alpha-Gal A proteins that may be stabilized by migalastat thereby restoring their trafficking to lysosomes and their intralysosomal activity. In Vitro Amenability Assay In an in vitro assay (HEK-293 assay), Human Embryonic Kidney (HEK-293) cell lines were transfected with specific GLA variants which produced variant alpha-Gal A proteins. In the transfected cells, amenability of the GLA variants was assessed after a 5-day incubation with 10 micromol/L migalastat. A GLA variant was categorized as amenable if the resultant variant alpha-Gal A activity (measured in the cell lysates) met two criteria: 1) it showed a relative increase of at least 20% compared to the pre-treatment alpha-Gal A activity, and 2) it showed an absolute increase of at least 3% of the wild-type (normal) alpha-Gal A activity. The in vitro assay did not evaluate trafficking of the variant alpha-Gal A proteins into the lysosome or the dissociation of migalastat from the variant alpha-Gal A proteins within the lysosome. Also, the in vitro assay did not test whether a GLA variant causes Fabry disease or not. The GLA variants that are amenable to treatment with GALAFOLD, either based on the in vitro assay data or on the concept that synonymous nucleotide changes leading to the same variant alpha-Gal A protein as a confirmed amenable GLA variant are amenable without additional testing, are shown in Table 2 . In patients with multiple identified variants, the amenability assessment of each independent variant may not reflect the overall amenability classification of the combination of variants. The specific variant combination must be present within Table 2 (eg, c.[164A>T; 170A>T]) and on a single chromosome (males and females) to be considered amenable to treatment with GALAFOLD. When multiple variants are identified in a female, it is recommended to consult a clinical genetics professional to determine whether the variants are on a single GLA allele. Inclusion of GLA variants in this table does not reflect interpretation of their clinical significance in Fabry disease. Whether a certain amenable GLA variant in a patient with Fabry disease is disease-causing or not should be determined by the prescribing physician (in consultation with a clinical genetics professional, if needed) prior to treatment initiation. Consultation with a clinical genetics professional is strongly recommended in cases where the amenable GLA variant is of uncertain clinical significance (VUS, variant of uncertain significance) or may be benign (not causing Fabry disease). If a GLA variant does not appear in Table 2 , it is either non-amenable (if tested) or has not been tested for in vitro amenability. For further information, please contact Amicus Medical Information at 1-877-4AMICUS or [email protected]. Table 2: Amenable GLA Variants Based on the In Vitro Assay § Based on available published data, the GLA variant c.937G>T, (p.(D313Y)) is considered benign (not causing Fabry disease). Consultation with a clinical genetics professional is strongly recommended in patients with Fabry disease who have this GLA variant as additional evaluations may be indicated. † Multiple variant combination of two or more different variants on a single GLA allele that informs amenability. ‡ Synonymous variants are listed without testing in the in vitro amenability assay. GLA variant(s) with a different nucleotide change affecting the same amino acid position(s) as the tested GLA variant and predicted to encode the same variant alpha-Gal A enzyme are considered synonymous. ¶ c.761_763delTTG has been previously referred to as c.760_762delGTT. DNA Change (Long) DNA Change (Short) Protein Change (1-letter Code) Protein Change (3-letter Code) c.7C>G c.C7G p.(L3V) p.(Leu3Val) c.8T>C c.T8C p.(L3P) p.(Leu3Pro) c.[11G>T; 620A>C] † c.[G11T; A620C] † p.[(R4M; Y207S)] † p.[(Arg4Met; Tyr207Ser)] † c.37G>A c.G37A p.(A13T) p.(Ala13Thr) c.37G>C c.G37C p.(A13P) p.(Ala13Pro) c.43G>A c.G43A p.(A15T) p.(Ala15Thr) c.44C>G c.C44G p.(A15G) p.(Ala15Gly) c.53T>G c.T53G p.(F18C) p.(Phe18Cys) c.58G>C c.G58C p.(A20P) p.(Ala20Pro) c.59C>A c.C59A p.(A20D) p.(Ala20Asp) c.65T>G c.T65G p.(V22G) p.(Val22Gly) c.[70T>A; 1255A>G] † c.[T70A; A1255G] † p.[(W24R; N419D)] † p.[(Trp24Arg; Asn419Asp)] † c.70T>A or c.70T>C ‡ c.T70A or c.T70C ‡ p.(W24R) p.(Trp24Arg) c.70T>G c.T70G p.(W24G) p.(Trp24Gly) c.72G>C or c.72G>T ‡ c.G72C or c.G72T ‡ p.(W24C) p.(Trp24Cys) c.95T>C c.T95C p.(L32P) p.(Leu32Pro) c.97G>C c.G97C p.(D33H) p.(Asp33His) c.97G>T c.G97T p.(D33Y) p.(Asp33Tyr) c.98A>G c.A98G p.(D33G) p.(Asp33Gly) c.100A>C c.A100C p.(N34H) p.(Asn34His) c.100A>G c.A100G p.(N34D) p.(Asn34Asp) c.101A>C c.A101C p.(N34T) p.(Asn34Thr) c.101A>G c.A101G p.(N34S) p.(Asn34Ser) c.102T>A or c.102T>G ‡ c.T102A or c.T102G ‡ p.(N34K) p.(Asn34Lys) c.103G>A or c.103G>C ‡ c.G103A or c.G103C ‡ p.(G35R) p.(Gly35Arg) c.104G>A c.G104A p.(G35E) p.(Gly35Glu) c.104G>T c.G104T p.(G35V) p.(Gly35Val) c.107T>C c.T107C p.(L36S) p.(Leu36Ser) c.107T>G c.T107G p.(L36W) p.(Leu36Trp) c.108G>C or c.108G>T ‡ c.G108C or c.G108T ‡ p.(L36F) p.(Leu36Phe) c.109G>A c.G109A p.(A37T) p.(Ala37Thr) c.109G>T c.G109T p.(A37S) p.(Ala37Ser) c.110C>T c.C110T p.(A37V) p.(Ala37Val) c.122C>T c.C122T p.(T41I) p.(Thr41Ile) c.124A>C or c.124A>T ‡ c.A124C or c.A124T ‡ p.(M42L) p.(Met42Leu) c.124A>G c.A124G p.(M42V) p.(Met42Val) c.125T>A c.T125A p.(M42K) p.(Met42Lys) c.125T>C c.T125C p.(M42T) p.(Met42Thr) c.125T>G c.T125G p.(M42R) p.(Met42Arg) c.126G>A or c.126G>C ‡ or c.126G>T ‡ c.G126A or c.G126C ‡ or c.G126T ‡ p.(M42I) p.(Met42Ile) c.137A>C c.A137C p.(H46P) p.(His46Pro) c.142G>C c.G142C p.(E48Q) p.(Glu48Gln) c.152T>A c.T152A p.(M51K) p.(Met51Lys) c.153G>A or c.153G>T ‡ or c.153G>C ‡ c.G153A or c.G153T ‡ or c.G153C ‡ p.(M51I) p.(Met51Ile) c.157_158delinsCT c.157_158delinsCT p.(N53L) p.(Asn53Leu) c.157A>G c.A157G p.(N53D) p.(Asn53Asp) c.160C>T c.C160T p.(L54F) p.(Leu54Phe) c.161T>C c.T161C p.(L54P) p.(Leu54Pro) c.164A>G c.A164G p.(D55G) p.(Asp55Gly) c.164A>T c.A164T p.(D55V) p.(Asp55Val) c.[164A>T; 170A>T] † c.[A164T; A170T] † p.[(D55V; Q57L)] † p.[(Asp55Val; Gln57Leu)] † c.167G>A c.G167A p.(C56Y) p.(Cys56Tyr) c.167G>T c.G167T p.(C56F) p.(Cys56Phe) c.170A>G c.A170G p.(Q57R) p.(Gln57Arg) c.170A>T c.A170T p.(Q57L) p.(Gln57Leu) c.175G>A c.G175A p.(E59K) p.(Glu59Lys) c.178C>A c.C178A p.(P60T) p.(Pro60Thr) c.178C>T c.C178T p.(P60S) p.(Pro60Ser) c.179C>T c.C179T p.(P60L) p.(Pro60Leu) c.196G>A c.G196A p.(E66K) p.(Glu66Lys) c.197A>G c.A197G p.(E66G) p.(Glu66Gly) c.207C>A or c.207C>G ‡ c.C207A or c.C207G ‡ p.(F69L) p.(Phe69Leu) c.214A>G c.A214G p.(M72V) p.(Met72Val) c.216G>A or c.216G>T ‡ or c.216G>C ‡ c.G216A or c.G216T ‡ or c.G216C ‡ p.(M72I) p.(Met72Ile) c.218C>T c.C218T p.(A73V) p.(Ala73Val) c.227T>C c.T227C p.(M76T) p.(Met76Thr) c.239G>A c.G239A p.(G80D) p.(Gly80Asp) c.239G>T c.G239T p.(G80V) p.(Gly80Val) c.247G>A c.G247A p.(D83N) p.(Asp83Asn) c.253G>A c.G253A p.(G85S) p.(Gly85Ser) c.253_254delinsAA c.253_254delinsAA p.(G85N) p.(Gly85Asn) c.253_255delinsATG c.253_255delinsATG p.(G85M) p.(Gly85Met) c.254G>A c.G254A p.(G85D) p.(Gly85Asp) c.261G>C or c.261G>T ‡ c.G261C or c.G261T ‡ p.(E87D) p.(Glu87Asp) c.263A>G c.A263G p.(Y88C) p.(Tyr88Cys) c.265C>T c.C265T p.(L89F) p.(Leu89Phe) c.272T>C c.T272C p.(I91T) p.(Ile91Thr) c.288G>A or c.288G>T ‡ or c.288G>C ‡ c.G288A or c.G288T ‡ or c.G288C ‡ p.(M96I) p.(Met96Ile) c.289G>C c.G289C p.(A97P) p.(Ala97Pro) c.290C>T c.C290T p.(A97V) p.(Ala97Val) c.305C>T c.C305T p.(S102L) p.(Ser102Leu) c.311G>T c.G311T p.(G104V) p.(Gly104Val) c.316C>T c.C316T p.(L106F) p.(Leu106Phe) c.320A>G c.A320G p.(Q107R) p.(Gln107Arg) c.322G>A c.G322A p.(A108T) p.(Ala108Thr) c.326A>G c.A326G p.(D109G) p.(Asp109Gly) c.334C>G c.C334G p.(R112G) p.(Arg112Gly) c.335G>A c.G335A p.(R112H) p.(Arg112His) c.335G>T c.G335T p.(R112L) p.(Arg112Leu) c.337T>A c.T337A p.(F113I) p.(Phe113Ile) c.337T>C or c.339T>A ‡ or c.339T>G ‡ c.T337C or c.T339A ‡ or c.T339G ‡ p.(F113L) p.(Phe113Leu) c.352C>T c.C352T p.(R118C) p.(Arg118Cys) c.361G>A c.G361A p.(A121T) p.(Ala121Thr) c.368A>G c.A368G p.(Y123C) p.(Tyr123Cys) c.373C>T c.C373T p.(H125Y) p.(His125Tyr) c.374A>T c.A374T p.(H125L) p.(His125Leu) c.376A>G c.A376G p.(S126G) p.(Ser126Gly) c.376A>T c.A376T p.(S126C) p.(Ser126Cys) c.383G>A c.G383A p.(G128E) p.(Gly128Glu) c.399T>G c.T399G p.(I133M) p.(Ile133Met) c.404C>T c.C404T p.(A135V) p.(Ala135Val) c.408T>A or c.408T>G ‡ c.T408A or c.T408G ‡ p.(D136E) p.(Asp136Glu) c.416A>G c.A416G p.(N139S) p.(Asn139Ser) c.419A>C c.A419C p.(K140T) p.(Lys140Thr) c.427G>A c.G427A p.(A143T) p.(Ala143Thr) c.431G>A c.G431A p.(G144D) p.(Gly144Asp) c.431G>T c.G431T p.(G144V) p.(Gly144Val) c.434T>C c.T434C p.(F145S) p.(Phe145Ser) c.436C>T c.C436T p.(P146S) p.(Pro146Ser) c.437C>G c.C437G p.(P146R) p.(Pro146Arg) c.454T>C c.T454C p.(Y152H) p.(Tyr152His) c.454T>G c.T454G p.(Y152D) p.(Tyr152Asp) c.455A>G c.A455G p.(Y152C) p.(Tyr152Cys) c.465T>A or c.465T>G ‡ c.T465A or c.T465G ‡ p.(D155E) p.(Asp155Glu) c.466G>A c.G466A p.(A156T) p.(Ala156Thr) c.466G>T c.G466T p.(A156S) p.(Ala156Ser) c.467C>T c.C467T p.(A156V) p.(Ala156Val) c.471G>C or c.471G>T ‡ c.G471C or c.G471T ‡ p.(Q157H) p.(Gln157His) c.484T>G c.T484G p.(W162G) p.(Trp162Gly) c.493G>C c.G493C p.(D165H) p.(Asp165His) c.494A>G c.A494G p.(D165G) p.(Asp165Gly) c.496_497delinsTC c.496_497delinsTC p.(L166S) p.(Leu166Ser) c.496C>G c.C496G p.(L166V) p.(Leu166Val) c.496_497delinsGG c.496_497delinsGG p.(L166G) p.(Leu166Gly) c.499C>G c.C499G p.(L167V) p.(Leu167Val) c.506T>C c.T506C p.(F169S) p.(Phe169Ser) c.511G>A c.G511A p.(G171S) p.(Gly171Ser) c.520T>C c.T520C p.(C174R) p.(Cys174Arg) c.520T>G c.T520G p.(C174G) p.(Cys174Gly) c.525C>G or c.525C>A ‡ c.C525G or c.C525A ‡ p.(D175E) p.(Asp175Glu) c.539T>G c.T539G p.(L180W) p.(Leu180Trp) c.540G>T or c.540G>C ‡ c.G540T or c.G540C ‡ p.(L180F) p.(Leu180Phe) c.548G>A c.G548A p.(G183D) p.(Gly183Asp) c.548G>C c.G548C p.(G183A) p.(Gly183Ala) c.550T>A c.T550A p.(Y184N) p.(Tyr184Asn) c.551A>C c.A551C p.(Y184S) p.(Tyr184Ser) c.551A>G c.A551G p.(Y184C) p.(Tyr184Cys) c.553A>G c.A553G p.(K185E) p.(Lys185Glu) c.559_564dup c.559_564dup p.(M187_S188dup) p.(Met187_Ser188dup) c.559A>G c.A559G p.(M187V) p.(Met187Val) c.560T>C c.T560C p.(M187T) p.(Met187Thr) c.561G>A or c.561G>T ‡ or c.561G>C ‡ c.G561A or c.G561T ‡ or c.G561C ‡ p.(M187I) p.(Met187Ile) c.567G>C or c.567G>T ‡ c.G567C or c.G567T ‡ p.(L189F) p.(Leu189Phe) c.572T>A c.T572A p.(L191Q) p.(Leu191Gln) c.581C>T c.C581T p.(T194I) p.(Thr194Ile) c.584G>T c.G584T p.(G195V) p.(Gly195Val) c.586A>G c.A586G p.(R196G) p.(Arg196Gly) c.593T>C c.T593C p.(I198T) p.(Ile198Thr) c.595G>A c.G595A p.(V199M) p.(Val199Met) c.596T>C c.T596C p.(V199A) p.(Val199Ala) c.596T>G c.T596G p.(V199G) p.(Val199Gly) c.599A>G c.A599G p.(Y200C) p.(Tyr200Cys) c.602C>A c.C602A p.(S201Y) p.(Ser201Tyr) c.602C>T c.C602T p.(S201F) p.(Ser201Phe) c.608A>T c.A608T p.(E203V) p.(Glu203Val) c.609G>C or c.609G>T ‡ c.G609C or c.G609T ‡ p.(E203D) p.(Glu203Asp) c.611G>T c.G611T p.(W204L) p.(Trp204Leu) c.613C>A c.C613A p.(P205T) p.(Pro205Thr) c.613C>T c.C613T p.(P205S) p.(Pro205Ser) c.614C>T c.C614T p.(P205L) p.(Pro205Leu) c.619T>C c.T619C p.(Y207H) p.(Tyr207His) c.620A>C c.A620C p.(Y207S) p.(Tyr207Ser) c.623T>G c.T623G p.(M208R) p.(Met208Arg) c.628C>T c.C628T p.(P210S) p.(Pro210Ser) c.629C>T c.C629T p.(P210L) p.(Pro210Leu) c.638A>G c.A638G p.(K213R) p.(Lys213Arg) c.638A>T c.A638T p.(K213M) p.(Lys213Met) c.640C>T c.C640T p.(P214S) p.(Pro214Ser) c.641C>T c.C641T p.(P214L) p.(Pro214Leu) c.643A>G c.A643G p.(N215D) p.(Asn215Asp) c.644A>G c.A644G p.(N215S) p.(Asn215Ser) c.[644A>G; 937G>T § ] † c.[A644G; G937T § ] † p.[(N215S; D313Y § )] † p.[(Asn215Ser; Asp313Tyr § )] † c.644A>T c.A644T p.(N215I) p.(Asn215Ile) c.646T>G c.T646G p.(Y216D) p.(Tyr216Asp) c.647A>G c.A647G p.(Y216C) p.(Tyr216Cys) c.655A>C c.A655C p.(I219L) p.(Ile219Leu) c.656T>A c.T656A p.(I219N) p.(Ile219Asn) c.656T>C c.T656C p.(I219T) p.(Ile219Thr) c.657C>G c.C657G p.(I219M) p.(Ile219Met) c.659G>A c.G659A p.(R220Q) p.(Arg220Gln) c.659G>C c.G659C p.(R220P) p.(Arg220Pro) c.662A>C c.A662C p.(Q221P) p.(Gln221Pro) c.664T>G c.T664G p.(Y222D) p.(Tyr222Asp) c.671A>C c.A671C p.(N224T) p.(Asn224Thr) c.671A>G c.A671G p.(N224S) p.(Asn224Ser) c.673C>G c.C673G p.(H225D) p.(His225Asp) c.682A>C c.A682C p.(N228H) p.(Asn228His) c.683A>G c.A683G p.(N228S) p.(Asn228Ser) c.687T>G or c.687T>A ‡ c.T687G or c.T687A ‡ p.(F229L) p.(Phe229Leu) c.695T>C c.T695C p.(I232T) p.(Ile232Thr) c.712A>G c.A712G p.(S238G) p.(Ser238Gly) c.713G>A c.G713A p.(S238N) p.(Ser238Asn) c.716T>C c.T716C p.(I239T) p.(Ile239Thr) c.717A>G c.A717G p.(I239M) p.(Ile239Met) c.720G>C or c.720G>T ‡ c.G720C or c.G720T ‡ p.(K240N) p.(Lys240Asn) c.724A>G c.A724G p.(I242V) p.(Ile242Val) c.724A>T c.A724T p.(I242F) p.(Ile242Phe) c.725T>A c.T725A p.(I242N) p.(Ile242Asn) c.725T>C c.T725C p.(I242T) p.(Ile242Thr) c.728T>C c.T728C p.(L243S) p.(Leu243Ser) c.728T>G c.T728G p.(L243W) p.(Leu243Trp) c.729G>C or c.729G>T ‡ c.G729C or c.G729T ‡ p.(L243F) p.(Leu243Phe) c.730G>A c.G730A p.(D244N) p.(Asp244Asn) c.730G>C c.G730C p.(D244H) p.(Asp244His) c.733T>G c.T733G p.(W245G) p.(Trp245Gly) c.740C>G c.C740G p.(S247C) p.(Ser247Cys) c.747C>G or c.747C>A ‡ c.C747G or c.C747A ‡ p.(N249K) p.(Asn249Lys) c.749A>C c.A749C p.(Q250P) p.(Gln250Pro) c.749A>G c.A749G p.(Q250R) p.(Gln250Arg) c.750G>C c.G750C p.(Q250H) p.(Gln250His) c.758T>C c.T758C p.(I253T) p.(Ile253Thr) c.758T>G c.T758G p.(I253S) p.(Ile253Ser) c.761_763delTTG c.761_763delTTG [a.k.a. c.760_762delGTT ¶ ] p.(V254del) p.(Val254del) c.769G>C c.G769C p.(A257P) p.(Ala257Pro) c.770C>G c.C770G p.(A257G) p.(Ala257Gly) c.770C>T c.C770T p.(A257V) p.(Ala257Val) c.772G>C or c.772G>A ‡ c.G772C or c.G772A ‡ p.(G258R) p.(Gly258Arg) c.773G>T c.G773T p.(G258V) p.(Gly258Val) c.776C>A c.C776A p.(P259Q) p.(Pro259Gln) c.776C>G c.C776G p.(P259R) p.(Pro259Arg) c.776C>T c.C776T p.(P259L) p.(Pro259Leu) c.779G>A c.G779A p.(G260E) p.(Gly260Glu) c.779G>C c.G779C p.(G260A) p.(Gly260Ala) c.781G>A c.G781A p.(G261S) p.(Gly261Ser) c.781G>C c.G781C p.(G261R) p.(Gly261Arg) c.781G>T c.G781T p.(G261C) p.(Gly261Cys) c.788A>G c.A788G p.(N263S) p.(Asn263Ser) c.790G>T c.G790T p.(D264Y) p.(Asp264Tyr) c.794C>T c.C794T p.(P265L) p.(Pro265Leu) c.800T>C c.T800C p.(M267T) p.(Met267Thr) c.805G>A c.G805A p.(V269M) p.(Val269Met) c.805G>C c.G805C p.(V269L) p.(Val269Leu) c.806T>C c.T806C p.(V269A) p.(Val269Ala) c.809T>C c.T809C p.(I270T) p.(Ile270Thr) c.810T>G c.T810G p.(I270M) p.(Ile270Met) c.811G>A c.G811A p.(G271S) p.(Gly271Ser) c.[811G>A; 937G>T § ] † c.[G811A; G937T § ] † p.[(G271S; D313Y § )] † p.[(Gly271Ser; Asp313Tyr § )] † c.812G>A c.G812A p.(G271D) p.(Gly271Asp) c.812G>C c.G812C p.(G271A) p.(Gly271Ala) c.823C>G c.C823G p.(L275V) p.(Leu275Val) c.827G>A c.G827A p.(S276N) p.(Ser276Asn) c.829T>G c.T829G p.(W277G) p.(Trp277Gly) c.831G>C or c.831G>T ‡ c.G831C or c.G831T ‡ p.(W277C) p.(Trp277Cys) c.832A>T c.A832T p.(N278Y) p.(Asn278Tyr) c.835C>G c.C835G p.(Q279E) p.(Gln279Glu) c.838C>A c.C838A p.(Q280K) p.(Gln280Lys) c.840A>T or c.840A>C ‡ c.A840T or c.A840C ‡ p.(Q280H) p.(Gln280His) c.844A>G c.A844G p.(T282A) p.(Thr282Ala) c.845C>T c.C845T p.(T282I) p.(Thr282Ile) c.850A>G c.A850G p.(M284V) p.(Met284Val) c.851T>C c.T851C p.(M284T) p.(Met284Thr) c.860G>T c.G860T p.(W287L) p.(Trp287Leu) c.862G>C c.G862C p.(A288P) p.(Ala288Pro) c.866T>G c.T866G p.(I289S) p.(Ile289Ser) c.868A>C or c.868A>T ‡ c.A868C or c.A868T ‡ p.(M290L) p.(Met290Leu) c.869T>C c.T869C p.(M290T) p.(Met290Thr) c.870G>C or c.870G>A ‡ or c.870G>T ‡ c.G870C or c.G870A ‡ or c.G870T ‡ p.(M290I) p.(Met290Ile) c.871G>A c.G871A p.(A291T) p.(Ala291Thr) c.877C>A c.C877A p.(P293T) p.(Pro293Thr) c.881T>C c.T881C p.(L294S) p.(Leu294Ser) c.884T>G c.T884G p.(F295C) p.(Phe295Cys) c.886A>G c.A886G p.(M296V) p.(Met296Val) c.886A>C or c.886A>T ‡ c.A886C or c.A886T ‡ p.(M296L) p.(Met296Leu) c.887T>C c.T887C p.(M296T) p.(Met296Thr) c.888G>A or c.888G>T ‡ or c.888G>C ‡ c.G888A or c.G888T ‡ or c.G888C ‡ p.(M296I) p.(Met296Ile) c.893A>G c.A893G p.(N298S) p.(Asn298Ser) c.897C>G or c.897C>A ‡ c.C897G or c.C897A ‡ p.(D299E) p.(Asp299Glu) c.898C>T c.C898T p.(L300F) p.(Leu300Phe) c.899T>C c.T899C p.(L300P) p.(Leu300Pro) c.901C>G c.C901G p.(R301G) p.(Arg301Gly) c.902G>A c.G902A p.(R301Q) p.(Arg301Gln) c.902G>C c.G902C p.(R301P) p.(Arg301Pro) c.902G>T c.G902T p.(R301L) p.(Arg301Leu) c.907A>T c.A907T p.(I303F) p.(Ile303Phe) c.908T>A c.T908A p.(I303N) p.(Ile303Asn) c.908T>C c.T908C p.(I303T) p.(Ile303Thr) c.911G>A c.G911A p.(S304N) p.(Ser304Asn) c.911G>C c.G911C p.(S304T) p.(Ser304Thr) c.919G>A c.G919A p.(A307T) p.(Ala307Thr) c.922A>G c.A922G p.(K308E) p.(Lys308Glu) c.924A>C or c.924A>T ‡ c.A924C or c.A924T ‡ p.(K308N) p.(Lys308Asn) c.925G>C c.G925C p.(A309P) p.(Ala309Pro) c.926C>T c.C926T p.(A309V) p.(Ala309Val) c.928C>T c.C928T p.(L310F) p.(Leu310Phe) c.931C>G c.C931G p.(L311V) p.(Leu311Val) c.935A>G c.A935G p.(Q312R) p.(Gln312Arg) c.936G>C or c.936G>T ‡ c.G936C or c.G936T ‡ p.(Q312H) p.(Gln312His) c.937G>T § c.G937T § p.(D313Y § ) p.(Asp313Tyr § ) c.[937G>T § ; 1232G>A] † c.[G937T § ; G1232A] † p.[D313Y § ; G411D] † p.[Asp313Tyr § ; Gly411Asp] † c.938A>G c.A938G p.(D313G) p.(Asp313Gly) c.946G>A c.G946A p.(V316I) p.(Val316Ile) c.947T>G c.T947G p.(V316G) p.(Val316Gly) c.950T>C c.T950C p.(I317T) p.(Ile317Thr) c.955A>T c.A955T p.(I319F) p.(Ile319Phe) c.956T>C c.T956C p.(I319T) p.(Ile319Thr) c.958A>C c.A958C p.(N320H) p.(Asn320His) c.959A>T c.A959T p.(N320I) p.(Asn320Ile) c.962A>G c.A962G p.(Q321R) p.(Gln321Arg) c.962A>T c.A962T p.(Q321L) p.(Gln321Leu) c.963G>C or c.963G>T ‡ c.G963C or c.G963T ‡ p.(Q321H) p.(Gln321His) c.964G>A c.G964A p.(D322N) p.(Asp322Asn) c.964G>C c.G964C p.(D322H) p.(Asp322His) c.966C>A or c.966C>G ‡ c.C966A or c.C966G ‡ p.(D322E) p.(Asp322Glu) c.967C>A c.C967A p.(P323T) p.(Pro323Thr) c.968C>G c.C968G p.(P323R) p.(Pro323Arg) c.973G>A c.G973A p.(G325S) p.(Gly325Ser) c.973G>C c.G973C p.(G325R) p.(Gly325Arg) c.978G>C or c.978G>T ‡ c.G978C or c.G978T ‡ p.(K326N) p.(Lys326Asn) c.979C>G c.C979G p.(Q327E) p.(Gln327Glu) c.980A>T c.A980T p.(Q327L) p.(Gln327Leu) c.983G>C c.G983C p.(G328A) p.(Gly328Ala) c.989A>G c.A989G p.(Q330R) p.(Gln330Arg) c.1001G>A c.G1001A p.(G334E) p.(Gly334Glu) c.1010T>C c.T1010C p.(F337S) p.(Phe337Ser) c.1012G>A c.G1012A p.(E338K) p.(Glu338Lys) c.1013A>T c.A1013T p.(E338V) p.(Glu338Val) c.1016T>A c.T1016A p.(V339E) p.(Val339Glu) c.1027C>A c.C1027A p.(P343T) p.(Pro343Thr) c.1028C>T c.C1028T p.(P343L) p.(Pro343Leu) c.1033T>C c.T1033C p.(S345P) p.(Ser345Pro) c.1046G>C c.G1046C p.(W349S) p.(Trp349Ser) c.1055C>G c.C1055G p.(A352G) p.(Ala352Gly) c.1055C>T c.C1055T p.(A352V) p.(Ala352Val) c.1061T>A c.T1061A p.(I354K) p.(Ile354Lys) c.1066C>G c.C1066G p.(R356G) p.(Arg356Gly) c.1066C>T c.C1066T p.(R356W) p.(Arg356Trp) c.1067G>A c.G1067A p.(R356Q) p.(Arg356Gln) c.1067G>C c.G1067C p.(R356P) p.(Arg356Pro) c.1072G>C c.G1072C p.(E358Q) p.(Glu358Gln) c.1073A>C c.A1073C p.(E358A) p.(Glu358Ala) c.1073A>G c.A1073G p.(E358G) p.(Glu358Gly) c.1074G>T or c.1074G>C ‡ c.G1074T or c.G1074C ‡ p.(E358D) p.(Glu358Asp) c.1076T>C c.T1076C p.(I359T) p.(Ile359Thr) c.1078G>A c.G1078A p.(G360S) p.(Gly360Ser) c.1078G>C c.G1078C p.(G360R) p.(Gly360Arg) c.1078G>T c.G1078T p.(G360C) p.(Gly360Cys) c.1079G>A c.G1079A p.(G360D) p.(Gly360Asp) c.1082G>A c.G1082A p.(G361E) p.(Gly361Glu) c.1082G>C c.G1082C p.(G361A) p.(Gly361Ala) c.1084C>A c.C1084A p.(P362T) p.(Pro362Thr) c.1085C>T c.C1085T p.(P362L) p.(Pro362Leu) c.1087C>T c.C1087T p.(R363C) p.(Arg363Cys) c.1088G>A c.G1088A p.(R363H) p.(Arg363His) c.1102G>A c.G1102A p.(A368T) p.(Ala368Thr) c.1117G>A c.G1117A p.(G373S) p.(Gly373Ser) c.1124G>A c.G1124A p.(G375E) p.(Gly375Glu) c.1139C>T c.C1139T p.(P380L) p.(Pro380Leu) c.1153A>G c.A1153G p.(T385A) p.(Tyr385Ala) c.1163T>A c.T1163A p.(L388H) p.(Leu388His) c.1168G>A c.G1168A p.(V390M) p.(Val390Met) c.1172A>C c.A1172C p.(K391T) p.(Lys391Thr) c.1184G>A c.G1184A p.(G395E) p.(Gly395Glu) c.1184G>C c.G1184C p.(G395A) p.(Gly395Ala) c.1192G>A c.G1192A p.(E398K) p.(Glu398Lys) c.1202_1203insGACTTC c.1202_1203insGACTTC p.(T400_S401dup) p.(Thr400_Ser401dup) c.1208T>C c.T1208C p.(L403S) p.(Leu403Ser) c.1225C>A c.C1225A p.(P409T) p.(Pro409Thr) c.1225C>G c.C1225G p.(P409A) p.(Pro409Ala) c.1225C>T c.C1225T p.(P409S) p.(Pro409Ser) c.1228A>G c.A1228G p.(T410A) p.(Thr410Ala) c.1229C>T c.C1229T p.(T410I) p.(Thr410Ile) c.1232G>A c.G1232A p.(G411D) p.(Gly411Asp) c.1234A>C c.A1234C p.(T412P) p.(Thr412Pro) c.1235C>A c.C1235A p.(T412N) p.(Thr412Asn) c.1235C>T c.C1235T p.(T412I) p.(Thr412Ile) c.1253A>G c.A1253G p.(E418G) p.(Glu418Gly) c.1261A>G c.A1261G p.(M421V) p.(Met421Val)

Liều dùng & Cách dùng

2 DOSAGE AND ADMINISTRATION Select adults with confirmed Fabry disease who have an amenable GLA variant for treatment with GALAFOLD. ( 2.1 ) Treatment is indicated for patients with an amenable GLA variant that is interpreted by a clinical genetics professional as causing Fabry disease (pathogenic, likely pathogenic) in the clinical context of the patient. Consultation with a clinical genetics professional is strongly recommended in cases where the amenable GLA variant is of uncertain clinical significance (VUS, variant of uncertain significance) or may be benign (not causing Fabry disease). ( 2.1 , 12.1 ) The recommended dosage of GALAFOLD is 123 mg orally once every other day. Take GALAFOLD at the same time of day and do not take on consecutive days. Swallow capsule whole. Do not cut, crush, or chew the capsule. ( 2.2 ) Take GALAFOLD on an empty stomach. Do not consume food or caffeine at least 2 hours prior to and 2 hours after taking GALAFOLD to give a minimum 4 hour fast. ( 2.2 ) If the GALAFOLD dose is missed, take the missed dose if it is within 12 hours of the time that the dose should have been taken. If more than 12 hours have passed, take GALAFOLD at the next planned dosing day and time following the original every-other-day dosing schedule. ( 2.3 ) 2.1 Patient Selection Select adults with confirmed Fabry disease who have an amenable GLA variant for treatment with GALAFOLD [see Clinical Pharmacology (12.1) ] . Treatment is indicated for patients with an amenable GLA variant that is interpreted by a clinical genetics professional as causing Fabry disease (pathogenic, likely pathogenic) in the clinical context of the patient. Consultation with a clinical genetics professional is strongly recommended in cases where the amenable GLA variant is of uncertain clinical significance (VUS, variant of uncertain significance) or may be benign (not causing Fabry disease). 2.2 Recommended Dosage and Administration The recommended dosage of GALAFOLD is 123 mg orally once every other day. Take GALAFOLD at the same time of day and do not take on consecutive days. Swallow capsule whole. Do not cut, crush, or chew the capsule. Take GALAFOLD on an empty stomach. Do not consume food or caffeine at least 2 hours prior to and 2 hours after taking GALAFOLD to give a minimum 4 hour fast [see Clinical Pharmacology (12.3) ] . Water (plain, flavored, or sweetened), fruit juices without pulp, and caffeine-free carbonated beverages can be consumed during the fasting period. 2.3 Recommendations for a Missed Dose If the GALAFOLD dose is missed, take the missed dose if it is within 12 hours of the time that the dose should have been taken. If more than 12 hours have passed, take GALAFOLD at the next planned dosing day and time following the original every-other-day dosing schedule.

Side Effects Overview

6 ADVERSE REACTIONS Most common adverse drug reactions ≥ 10% are: headache, nasopharyngitis, urinary tract infection, nausea, and pyrexia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Amicus Therapeutics at 1-877-4AMICUS or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In clinical trials, 139 patients with Fabry disease (79 females, 60 males, 92% Caucasian, ages 16 to 72 years), who were naïve to GALAFOLD or previously treated with enzyme replacement therapy, were exposed to at least one dose of GALAFOLD. Of the 139 patients, 127 patients were exposed to GALAFOLD 123 mg every other day for 6 months and 123 patients were exposed for greater than one year. The clinical trials included one randomized, double-blind, placebo-controlled clinical trial of 6 months duration followed by a 6-month open-label treatment phase (Study 1) [see Clinical Studies (14) ] . A second trial was a randomized, open-label, active-controlled clinical trial of 18 months duration in patients with Fabry disease receiving enzyme replacement therapy who were randomized to either switch to GALAFOLD or continue enzyme replacement therapy (Study 2; NCT01218659). In addition, there were two open-label, long-term extension trials. The most common adverse reactions reported with GALAFOLD (≥ 10%) during the 6-month placebo-controlled, double-blind phase of Study 1 were headache, nasopharyngitis, urinary tract infection, nausea, and pyrexia. Table 1 shows adverse reactions that occurred in at least 5% of patients treated with GALAFOLD during the 6-month placebo-controlled, double-blind phase of Study 1. Table 1: Adverse Reactions* in Patients with Fabry Disease (Study 1) * Adverse reactions were those that occurred in at least 5% of patients treated with GALAFOLD. ** Included urinary tract infection, cystitis, and kidney infection Adverse Reaction GALAFOLD % (N = 34) Placebo % (N = 33) Headache 35% 21% Nasopharyngitis 18% 6% Urinary tract infection** 15% 0 Nausea 12% 6% Pyrexia 12% 3% Abdominal pain 9% 3% Back pain 9% 0 Cough 9% 0 Diarrhea 9% 3% Epistaxis 9% 3% Adverse reactions that occurred in > 5% of patients who received GALAFOLD in the 6-month open-label treatment phase of Study 1, in Study 2, and in the long-term extension trials (N = 115, mean duration of treatment 2.7 years) included those in Table 1 with the addition of vomiting. 6.2 Postmarketing Experience The following adverse reaction has been identified during post-approval use of GALAFOLD. Because this reaction is reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate its frequency or establish a causal relationship to drug exposure. General disorder: angioedema

Chống chỉ định

4 CONTRAINDICATIONS None. None. ( 4 )

Dược động học

12.3 Pharmacokinetics Absorption Following a single GALAFOLD oral dose of 123 mg, the absolute bioavailability (AUC) of migalastat was approximately 75% and the time to peak plasma concentration (t max ) was approximately 3 hours. Plasma migalastat exposure (AUC 0‑∞ and C max ) demonstrated dose‑proportional increases at oral doses from 75 mg to 1250 mg (doses from 0.5 to 8.3‑fold of the approved recommended dosage). Migalastat does not accumulate following administration of 123 mg GALAFOLD every other day. Effect of Food: Administration of GALAFOLD one hour before a high‑fat (850 calories; 56% from fat) or light meal (507 calories; 30% from fat), or one hour after a light meal, reduced the mean migalastat AUC 0‑∞ by 37% to 42% and C max by 15% to 39% compared to the fasting state [see Dosage and Administration (2.2) ] . Distribution The apparent volume of distribution (V z /F) of migalastat in Fabry patients was approximately 89 L (range: 77 to 133 L) at steady state. There was no detectable plasma protein binding following administration of [ 14 C]‑migalastat in the concentration range between 1 to 100 microM. Elimination Metabolism: Based upon in vivo data, migalastat is a substrate for uridine diphosphate glucuronosyltransferase (UDPGT), a minor elimination pathway. Excretion: In a mass balance study in healthy male subjects, following oral administration of 123 mg [ 14 C]‑migalastat, approximately 77% of the total radiolabeled dose was recovered in urine and 20% of the total radiolabeled dose was recovered in feces with an overall total recovery of 98% within 96 hours post‑dose. In urine, unchanged migalastat accounted for 80% of the radioactivity, which equates to 62% of the administered dose. In feces, unchanged migalastat was the only drug‑related component. In plasma, unchanged migalastat accounted for approximately 77% of the plasma radioactivity and three dehydrogenated O‑glucuronide conjugated metabolites, M1 to M3, together accounted for approximately 13% of the plasma radioactivity, none of which comprised more than 6% of the radiolabeled dose. Approximately 9% of the total radioactivity in plasma was unassigned. Following a single oral dose of 123 mg GALAFOLD, migalastat is cleared from plasma with a mean half‑life (t ½ ) of approximately 4 hours and apparent clearance of 12.5 L/hr. Specific Populations Male and Female Patients: The pharmacokinetic characteristics of migalastat were not significantly different between healthy male and female subjects or patients with Fabry disease. Racial or Ethnic Groups: Clinical data indicate no ethnic differences in patient populations studied with migalastat. Patients with Renal Impairment: In a single‑dose study in subjects with varying degrees of renal impairment, exposure to migalastat (AUC) was increased by 1.2-, 1.8-, and 4.3-fold in subjects with mild (eGFR 60 to 90 mL/min/1.73 m 2 ), moderate (eGFR 30 to 59 mL/min/1.73 m 2 ), and severe renal impairment (eGFR less than 30 mL/min/1.73 m 2 ), respectively, while the C max remained unchanged with severity of renal impairment [see Use in Specific Populations (8.6) ] . Drug Interaction Studies In Vitro Studies Migalastat is not a known inhibitor or inducer of cytochrome P450 (CYP450) enzymes, nor is it an inhibitor of BCRP, MDR1, P‑glycoprotein (P‑gp), or BSEP human efflux transporters, or OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, MATE1, or MATE2‑K human uptake transporters. Migalastat is not a substrate of P‑gp, BCRP, MDR1 or MATE1, MATE2‑K, OAT1, OAT3, or OCT2. Migalastat showed low affinity for SGLT1, as both a substrate and an inhibitor, and showed no activity for SGLT2. Clinical Studies: Effects of other Drugs on Migalastat Co‑administration of 190 mg caffeine reduced the mean migalastat AUC 0‑∞ by 55% and C max by 60% compared to without caffeine co‑administration. The t max of migalastat was not affected by co‑administration of caffeine. No clinically significant pharmacokinetic changes were observed for migalastat when co‑administered with sucrose, aspartame or acesulfame potassium [see Dosage and Administration (2.2) and Drug Interactions (7.1) ] .

Frequently Asked Questions

1 INDICATIONS AND USAGE GALAFOLD is indicated for the treatment of adults with a confirmed diagnosis of Fabry disease and an amenable galactosidase alpha gene ( GLA ) variant based on in vitro assay data [see Dosage and Administration (2.1) and Clinical Pharmacology (12.1) ] . This indication is approved under accelerated approval based on reduction in kidney interstitial capillary cell globotriaosylceramide (KIC GL-3) substrate [see Clinical Studies (14) ] . Continued approval for this indication may be contingent upon …

2 DOSAGE AND ADMINISTRATION Select adults with confirmed Fabry disease who have an amenable GLA variant for treatment with GALAFOLD. ( 2.1 ) Treatment is indicated for patients with an amenable GLA variant that is interpreted by a clinical genetics professional as causing Fabry disease (pathogenic, likely pathogenic) in the clinical context of the patient. Consultation with a clinical genetics professional is strongly recommended in cases where the amenable GLA variant is of uncertain clinical significance (VUS, variant of uncertain …

4 CONTRAINDICATIONS None. None. ( 4 )

Migalastat Hydrochloride is a prescription medication. You will need a valid prescription from a licensed healthcare provider.

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References & Data Sources

• DailyMed — Migalastat Hydrochloride drug label (National Library of Medicine)
• openFDA — Migalastat Hydrochloride label data (U.S. Food & Drug Administration)
• RxNorm — RXCUI 2054257 (NLM Normalized Drug Names)
• NDC Directory — Migalastat Hydrochloride (FDA National Drug Code)

Tuyên bố miễn trách nhiệm y tế

Thông tin trên trang này chỉ nhằm mục đích giáo dục và không nên được sử dụng thay thế cho lời khuyên y tế chuyên nghiệp, chẩn đoán hoặc điều trị.

Luôn tìm kiếm lời khuyên của bác sĩ hoặc nhà cung cấp dịch vụ y tế có chuyên môn khác đối với bất kỳ câu hỏi nào bạn có về tình trạng bệnh hoặc thuốc.

Nguồn dữ liệu: DailyMed (NLM), openFDA, MFDS