{ "meta": { "disclaimer": "Do not rely on openFDA to make decisions regarding medical care. While we make every effort to ensure that data is accurate, you should assume all results are unvalidated. We may limit or otherwise restrict your access to the API in line with our Terms of Service.", "terms": "https://open.fda.gov/terms/", "license": "https://open.fda.gov/license/", "last_updated": "2026-05-14", "results": { "skip": 0, "limit": 10, "total": 3 } }, "results": [ { "spl_product_data_elements": [ "Galafold migalastat hydrochloride SHELLAC MIGALASTAT HYDROCHLORIDE MIGALASTAT MAGNESIUM STEARATE STARCH, CORN GELATIN FD&C BLUE NO. 2 TITANIUM DIOXIDE FERROSOFERRIC OXIDE POTASSIUM HYDROXIDE opaque blue opaque white A1001" ], "indications_and_usage": [ "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 )" ], "dosage_and_administration": [ "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." ], "dosage_forms_and_strengths": [ "3 DOSAGE FORMS AND STRENGTHS Capsules: 123 mg of migalastat in a size “2” capsule with an opaque blue cap and opaque white body with “A1001” printed in black, containing white to pale brown powder. Capsules: 123 mg migalastat. ( 3 )" ], "contraindications": [ "4 CONTRAINDICATIONS None. None. ( 4 )" ], "adverse_reactions": [ "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" ], "adverse_reactions_table": [ "
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 ReactionGALAFOLD % (N = 34)Placebo % (N = 33)
Headache35%21%
Nasopharyngitis18%6%
Urinary tract infection**15%0
Nausea12%6%
Pyrexia12%3%
Abdominal pain9%3%
Back pain9%0
Cough9%0
Diarrhea9%3%
Epistaxis9%3%
" ], "drug_interactions": [ "7 DRUG INTERACTIONS See Full Prescribing Information for clinically significant drug interactions. (7.1) 7.1 Effect of Other Drugs on GALAFOLD Co-administration of GALAFOLD with caffeine decreases migalastat AUC and C max [see Clinical Pharmacology (12.3) ] which may reduce GALAFOLD efficacy. Avoid co-administration of GALAFOLD with caffeine at least 2 hours before and 2 hours after taking GALAFOLD [see Dosage and Administration (2.2) ] ." ], "use_in_specific_populations": [ "8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There were three pregnant women with Fabry disease exposed to GALAFOLD in clinical trials. As such, the available data are not sufficient to assess drug associated risks of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, no adverse developmental effects were observed (see Data ) . The background risk for major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. There is a study that collects data on pregnant women with Fabry disease, either exposed or unexposed to GALAFOLD. Healthcare providers are encouraged to register patients or obtain additional information by contacting the Pregnancy Coordinating Center at 1-888-239-0758, emailing fabrypregnancy@ubc.com, or visiting www.fabrypregnancyregistry.com. Data Animal Data No adverse developmental effects were observed with oral administration of migalastat to pregnant rats and rabbits during organogenesis at doses up to 26 and 54 times, respectively, the recommended dose based on AUC. No effects on post-natal development were observed following oral administration of up to 500 mg/kg migalastat twice daily to pregnant rats (16 times the recommended dose based on AUC) during organogenesis and through lactation. 8.2 Lactation Risk Summary There are no data on the presence of migalastat in human milk, the effects on the breastfed infant, or the effects on milk production. Migalastat is present in the milk of lactating rats (see Data ). When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for GALAFOLD and any potential adverse effects on the breastfed infant from GALAFOLD or from the underlying maternal condition. There is a study that collects data on effects of GALAFOLD on lactation for women with Fabry disease and their neonates and infants up to 1 year of age who are exposed through breast milk. Healthcare providers are encouraged to register patients or obtain additional information by contacting the Pregnancy Coordinating Center at 1-888-239-0758, email fabrypregnancy@ubc.com, or visit www.fabrypregnancyregistry.com. Data Animal Data Migalastat concentrations in milk from rats following oral administration of up to 500 mg/kg twice daily (approximately 16 times the recommended human dose based on AUC) was approximately 2.5 times higher than levels in the rat maternal plasma at 4 hours post-dose. The concentration of migalastat in plasma from pups was approximately 11 times lower than the maternal plasma concentrations at 1-hour post-dose. 8.3 Females and Males of Reproductive Potential Infertility 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 a systemic exposure (AUC) equivalent to the human exposure at the recommended dose. Complete reversibility was seen at 4 weeks after the termination of treatment. Migalastat did not affect fertility in female rats [see Nonclinical Toxicology (13.1) ] . 8.4 Pediatric Use The safety and effectiveness of GALAFOLD have not been established in pediatric patients. 8.5 Geriatric Use Clinical trials of GALAFOLD did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients. 8.6 Renal Impairment Migalastat is substantially excreted by the kidneys. Systemic exposure was significantly increased in subjects with severe renal impairment (eGFR less than 30 mL/min/1.73 m 2 ). GALAFOLD has not been studied in patients with Fabry disease who have an eGFR less than 30 mL/min/1.73 m 2 . GALAFOLD is not recommended for use in patients with severe renal impairment or end-stage renal disease requiring dialysis. No dosage adjustment is required in patients with mild to moderate renal impairment (eGFR at least 30 mL/min/1.73 m 2 and above) [see Clinical Pharmacology (12.3) ] ." ], "pregnancy": [ "8.1 Pregnancy Risk Summary There were three pregnant women with Fabry disease exposed to GALAFOLD in clinical trials. As such, the available data are not sufficient to assess drug associated risks of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, no adverse developmental effects were observed (see Data ) . The background risk for major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. There is a study that collects data on pregnant women with Fabry disease, either exposed or unexposed to GALAFOLD. Healthcare providers are encouraged to register patients or obtain additional information by contacting the Pregnancy Coordinating Center at 1-888-239-0758, emailing fabrypregnancy@ubc.com, or visiting www.fabrypregnancyregistry.com. Data Animal Data No adverse developmental effects were observed with oral administration of migalastat to pregnant rats and rabbits during organogenesis at doses up to 26 and 54 times, respectively, the recommended dose based on AUC. No effects on post-natal development were observed following oral administration of up to 500 mg/kg migalastat twice daily to pregnant rats (16 times the recommended dose based on AUC) during organogenesis and through lactation." ], "pediatric_use": [ "8.4 Pediatric Use The safety and effectiveness of GALAFOLD have not been established in pediatric patients." ], "geriatric_use": [ "8.5 Geriatric Use Clinical trials of GALAFOLD did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients." ], "description": [ "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" ], "clinical_pharmacology": [ "12 CLINICAL PHARMACOLOGY 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 medinfousa@amicusrx.com. 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) 12.2 Pharmacodynamics In Study 1, 31 of 50 patients with amenable GLA variants (18 on GALAFOLD, 13 on placebo) had lyso‑Gb 3 assessments available after 6 months of treatment. The median change from baseline to month 6 in plasma lyso‑Gb 3 (nmol/L) was -2.37 (range -69.7, 1.8) in patients on GALAFOLD and 0.53 (range -21.5, 16.3) in patients on placebo. In the open‑label treatment phase of Study 1, the 13 patients who were initially on placebo for 6 months and who switched to GALAFOLD for another 6 months had a median change in lyso‑Gb 3 (nmol/L) of -2.72 (range -61.1, -0.3). The 18 patients who were treated with GALAFOLD for 6 months and then continued GALAFOLD in the open‑label treatment phase of Study 1 for an additional 6 months had no further changes in plasma lyso‑Gb 3 . In Study 2, 46 of 56 patients with amenable GLA variants (31 on GALAFOLD, 15 on enzyme replacement therapy (ERT)) had lyso‑Gb 3 assessments available after 18 months of treatment. The median change from baseline to month 18 in plasma lyso‑Gb 3 (nmol/L) was 0.53 (range -2.27, 28.3) in patients on GALAFOLD and -0.03 (range -11.9, 2.57) in patients on ERT. Cardiac Electrophysiology At a dose approximately 8 times the recommended dose, GALAFOLD did not prolong the QT interval to any clinically relevant extent. 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) ] ." ], "clinical_pharmacology_table": [ "
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>Gc.C7Gp.(L3V)p.(Leu3Val)
c.8T>Cc.T8Cp.(L3P)p.(Leu3Pro)
c.[11G>T; 620A>C]†c.[G11T; A620C]†p.[(R4M; Y207S)]†p.[(Arg4Met; Tyr207Ser)]†
c.37G>Ac.G37Ap.(A13T)p.(Ala13Thr)
c.37G>Cc.G37Cp.(A13P)p.(Ala13Pro)
c.43G>Ac.G43Ap.(A15T)p.(Ala15Thr)
c.44C>Gc.C44Gp.(A15G)p.(Ala15Gly)
c.53T>Gc.T53Gp.(F18C)p.(Phe18Cys)
c.58G>Cc.G58Cp.(A20P)p.(Ala20Pro)
c.59C>Ac.C59Ap.(A20D)p.(Ala20Asp)
c.65T>Gc.T65Gp.(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>Gc.T70Gp.(W24G)p.(Trp24Gly)
c.72G>C or c.72G>T‡c.G72C or c.G72T‡p.(W24C)p.(Trp24Cys)
c.95T>Cc.T95Cp.(L32P)p.(Leu32Pro)
c.97G>Cc.G97Cp.(D33H)p.(Asp33His)
c.97G>Tc.G97Tp.(D33Y)p.(Asp33Tyr)
c.98A>Gc.A98Gp.(D33G)p.(Asp33Gly)
c.100A>Cc.A100Cp.(N34H)p.(Asn34His)
c.100A>Gc.A100Gp.(N34D)p.(Asn34Asp)
c.101A>Cc.A101Cp.(N34T)p.(Asn34Thr)
c.101A>Gc.A101Gp.(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>Ac.G104Ap.(G35E)p.(Gly35Glu)
c.104G>Tc.G104Tp.(G35V)p.(Gly35Val)
c.107T>Cc.T107Cp.(L36S)p.(Leu36Ser)
c.107T>Gc.T107Gp.(L36W)p.(Leu36Trp)
c.108G>C or c.108G>T‡c.G108C or c.G108T‡p.(L36F)p.(Leu36Phe)
c.109G>Ac.G109Ap.(A37T)p.(Ala37Thr)
c.109G>Tc.G109Tp.(A37S)p.(Ala37Ser)
c.110C>Tc.C110Tp.(A37V)p.(Ala37Val)
c.122C>Tc.C122Tp.(T41I)p.(Thr41Ile)
c.124A>C or c.124A>T‡c.A124C or c.A124T‡p.(M42L)p.(Met42Leu)
c.124A>Gc.A124Gp.(M42V)p.(Met42Val)
c.125T>Ac.T125Ap.(M42K)p.(Met42Lys)
c.125T>Cc.T125Cp.(M42T)p.(Met42Thr)
c.125T>Gc.T125Gp.(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>Cc.A137Cp.(H46P)p.(His46Pro)
c.142G>Cc.G142Cp.(E48Q)p.(Glu48Gln)
c.152T>Ac.T152Ap.(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_158delinsCTc.157_158delinsCTp.(N53L)p.(Asn53Leu)
c.157A>Gc.A157Gp.(N53D)p.(Asn53Asp)
c.160C>Tc.C160Tp.(L54F)p.(Leu54Phe)
c.161T>Cc.T161Cp.(L54P)p.(Leu54Pro)
c.164A>Gc.A164Gp.(D55G)p.(Asp55Gly)
c.164A>Tc.A164Tp.(D55V)p.(Asp55Val)
c.[164A>T; 170A>T]†c.[A164T; A170T]†p.[(D55V; Q57L)]†p.[(Asp55Val; Gln57Leu)]†
c.167G>Ac.G167Ap.(C56Y)p.(Cys56Tyr)
c.167G>Tc.G167Tp.(C56F)p.(Cys56Phe)
c.170A>Gc.A170Gp.(Q57R)p.(Gln57Arg)
c.170A>Tc.A170Tp.(Q57L)p.(Gln57Leu)
c.175G>Ac.G175Ap.(E59K)p.(Glu59Lys)
c.178C>Ac.C178Ap.(P60T)p.(Pro60Thr)
c.178C>Tc.C178Tp.(P60S)p.(Pro60Ser)
c.179C>Tc.C179Tp.(P60L)p.(Pro60Leu)
c.196G>Ac.G196Ap.(E66K)p.(Glu66Lys)
c.197A>Gc.A197Gp.(E66G)p.(Glu66Gly)
c.207C>A or c.207C>G‡c.C207A or c.C207G‡p.(F69L)p.(Phe69Leu)
c.214A>Gc.A214Gp.(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>Tc.C218Tp.(A73V)p.(Ala73Val)
c.227T>Cc.T227Cp.(M76T)p.(Met76Thr)
c.239G>Ac.G239Ap.(G80D)p.(Gly80Asp)
c.239G>Tc.G239Tp.(G80V)p.(Gly80Val)
c.247G>Ac.G247Ap.(D83N)p.(Asp83Asn)
c.253G>Ac.G253Ap.(G85S)p.(Gly85Ser)
c.253_254delinsAAc.253_254delinsAAp.(G85N)p.(Gly85Asn)
c.253_255delinsATGc.253_255delinsATGp.(G85M)p.(Gly85Met)
c.254G>Ac.G254Ap.(G85D)p.(Gly85Asp)
c.261G>C or c.261G>T‡c.G261C or c.G261T‡p.(E87D)p.(Glu87Asp)
c.263A>Gc.A263Gp.(Y88C)p.(Tyr88Cys)
c.265C>Tc.C265Tp.(L89F)p.(Leu89Phe)
c.272T>Cc.T272Cp.(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>Cc.G289Cp.(A97P)p.(Ala97Pro)
c.290C>Tc.C290Tp.(A97V)p.(Ala97Val)
c.305C>Tc.C305Tp.(S102L)p.(Ser102Leu)
c.311G>Tc.G311Tp.(G104V)p.(Gly104Val)
c.316C>Tc.C316Tp.(L106F)p.(Leu106Phe)
c.320A>Gc.A320Gp.(Q107R)p.(Gln107Arg)
c.322G>Ac.G322Ap.(A108T)p.(Ala108Thr)
c.326A>Gc.A326Gp.(D109G)p.(Asp109Gly)
c.334C>Gc.C334Gp.(R112G)p.(Arg112Gly)
c.335G>Ac.G335Ap.(R112H)p.(Arg112His)
c.335G>Tc.G335Tp.(R112L)p.(Arg112Leu)
c.337T>Ac.T337Ap.(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>Tc.C352Tp.(R118C)p.(Arg118Cys)
c.361G>Ac.G361Ap.(A121T)p.(Ala121Thr)
c.368A>Gc.A368Gp.(Y123C)p.(Tyr123Cys)
c.373C>Tc.C373Tp.(H125Y)p.(His125Tyr)
c.374A>Tc.A374Tp.(H125L)p.(His125Leu)
c.376A>Gc.A376Gp.(S126G)p.(Ser126Gly)
c.376A>Tc.A376Tp.(S126C)p.(Ser126Cys)
c.383G>Ac.G383Ap.(G128E)p.(Gly128Glu)
c.399T>Gc.T399Gp.(I133M)p.(Ile133Met)
c.404C>Tc.C404Tp.(A135V)p.(Ala135Val)
c.408T>A or c.408T>G‡c.T408A or c.T408G‡p.(D136E)p.(Asp136Glu)
c.416A>Gc.A416Gp.(N139S)p.(Asn139Ser)
c.419A>Cc.A419Cp.(K140T)p.(Lys140Thr)
c.427G>Ac.G427Ap.(A143T)p.(Ala143Thr)
c.431G>Ac.G431Ap.(G144D)p.(Gly144Asp)
c.431G>Tc.G431Tp.(G144V)p.(Gly144Val)
c.434T>Cc.T434Cp.(F145S)p.(Phe145Ser)
c.436C>Tc.C436Tp.(P146S)p.(Pro146Ser)
c.437C>Gc.C437Gp.(P146R)p.(Pro146Arg)
c.454T>Cc.T454Cp.(Y152H)p.(Tyr152His)
c.454T>Gc.T454Gp.(Y152D)p.(Tyr152Asp)
c.455A>Gc.A455Gp.(Y152C)p.(Tyr152Cys)
c.465T>A or c.465T>G‡c.T465A or c.T465G‡p.(D155E)p.(Asp155Glu)
c.466G>Ac.G466Ap.(A156T)p.(Ala156Thr)
c.466G>Tc.G466Tp.(A156S)p.(Ala156Ser)
c.467C>Tc.C467Tp.(A156V)p.(Ala156Val)
c.471G>C or c.471G>T‡c.G471C or c.G471T‡p.(Q157H)p.(Gln157His)
c.484T>Gc.T484Gp.(W162G)p.(Trp162Gly)
c.493G>Cc.G493Cp.(D165H)p.(Asp165His)
c.494A>Gc.A494Gp.(D165G)p.(Asp165Gly)
c.496_497delinsTCc.496_497delinsTCp.(L166S)p.(Leu166Ser)
c.496C>Gc.C496Gp.(L166V)p.(Leu166Val)
c.496_497delinsGGc.496_497delinsGGp.(L166G)p.(Leu166Gly)
c.499C>Gc.C499Gp.(L167V)p.(Leu167Val)
c.506T>Cc.T506Cp.(F169S)p.(Phe169Ser)
c.511G>Ac.G511Ap.(G171S)p.(Gly171Ser)
c.520T>Cc.T520Cp.(C174R)p.(Cys174Arg)
c.520T>Gc.T520Gp.(C174G)p.(Cys174Gly)
c.525C>G or c.525C>A‡c.C525G or c.C525A‡p.(D175E)p.(Asp175Glu)
c.539T>Gc.T539Gp.(L180W)p.(Leu180Trp)
c.540G>T or c.540G>C‡c.G540T or c.G540C‡p.(L180F)p.(Leu180Phe)
c.548G>Ac.G548Ap.(G183D)p.(Gly183Asp)
c.548G>Cc.G548Cp.(G183A)p.(Gly183Ala)
c.550T>Ac.T550Ap.(Y184N)p.(Tyr184Asn)
c.551A>Cc.A551Cp.(Y184S)p.(Tyr184Ser)
c.551A>Gc.A551Gp.(Y184C)p.(Tyr184Cys)
c.553A>Gc.A553Gp.(K185E)p.(Lys185Glu)
c.559_564dupc.559_564dupp.(M187_S188dup)p.(Met187_Ser188dup)
c.559A>Gc.A559Gp.(M187V)p.(Met187Val)
c.560T>Cc.T560Cp.(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>Ac.T572Ap.(L191Q)p.(Leu191Gln)
c.581C>Tc.C581Tp.(T194I)p.(Thr194Ile)
c.584G>Tc.G584Tp.(G195V)p.(Gly195Val)
c.586A>Gc.A586Gp.(R196G)p.(Arg196Gly)
c.593T>Cc.T593Cp.(I198T)p.(Ile198Thr)
c.595G>Ac.G595Ap.(V199M)p.(Val199Met)
c.596T>Cc.T596Cp.(V199A)p.(Val199Ala)
c.596T>Gc.T596Gp.(V199G)p.(Val199Gly)
c.599A>Gc.A599Gp.(Y200C)p.(Tyr200Cys)
c.602C>Ac.C602Ap.(S201Y)p.(Ser201Tyr)
c.602C>Tc.C602Tp.(S201F)p.(Ser201Phe)
c.608A>Tc.A608Tp.(E203V)p.(Glu203Val)
c.609G>C or c.609G>T‡c.G609C or c.G609T‡p.(E203D)p.(Glu203Asp)
c.611G>Tc.G611Tp.(W204L)p.(Trp204Leu)
c.613C>Ac.C613Ap.(P205T)p.(Pro205Thr)
c.613C>Tc.C613Tp.(P205S)p.(Pro205Ser)
c.614C>Tc.C614Tp.(P205L)p.(Pro205Leu)
c.619T>Cc.T619Cp.(Y207H)p.(Tyr207His)
c.620A>Cc.A620Cp.(Y207S)p.(Tyr207Ser)
c.623T>Gc.T623Gp.(M208R)p.(Met208Arg)
c.628C>Tc.C628Tp.(P210S)p.(Pro210Ser)
c.629C>Tc.C629Tp.(P210L)p.(Pro210Leu)
c.638A>Gc.A638Gp.(K213R)p.(Lys213Arg)
c.638A>Tc.A638Tp.(K213M)p.(Lys213Met)
c.640C>Tc.C640Tp.(P214S)p.(Pro214Ser)
c.641C>Tc.C641Tp.(P214L)p.(Pro214Leu)
c.643A>Gc.A643Gp.(N215D)p.(Asn215Asp)
c.644A>Gc.A644Gp.(N215S)p.(Asn215Ser)
c.[644A>G; 937G>T§]†c.[A644G; G937T§]†p.[(N215S; D313Y§)]†p.[(Asn215Ser; Asp313Tyr§)]†
c.644A>Tc.A644Tp.(N215I)p.(Asn215Ile)
c.646T>Gc.T646Gp.(Y216D)p.(Tyr216Asp)
c.647A>Gc.A647Gp.(Y216C)p.(Tyr216Cys)
c.655A>Cc.A655Cp.(I219L)p.(Ile219Leu)
c.656T>Ac.T656Ap.(I219N)p.(Ile219Asn)
c.656T>Cc.T656Cp.(I219T)p.(Ile219Thr)
c.657C>Gc.C657Gp.(I219M)p.(Ile219Met)
c.659G>Ac.G659Ap.(R220Q)p.(Arg220Gln)
c.659G>Cc.G659Cp.(R220P)p.(Arg220Pro)
c.662A>Cc.A662Cp.(Q221P)p.(Gln221Pro)
c.664T>Gc.T664Gp.(Y222D)p.(Tyr222Asp)
c.671A>Cc.A671Cp.(N224T)p.(Asn224Thr)
c.671A>Gc.A671Gp.(N224S)p.(Asn224Ser)
c.673C>Gc.C673Gp.(H225D)p.(His225Asp)
c.682A>Cc.A682Cp.(N228H)p.(Asn228His)
c.683A>Gc.A683Gp.(N228S)p.(Asn228Ser)
c.687T>G or c.687T>A‡c.T687G or c.T687A‡p.(F229L)p.(Phe229Leu)
c.695T>Cc.T695Cp.(I232T)p.(Ile232Thr)
c.712A>Gc.A712Gp.(S238G)p.(Ser238Gly)
c.713G>Ac.G713Ap.(S238N)p.(Ser238Asn)
c.716T>Cc.T716Cp.(I239T)p.(Ile239Thr)
c.717A>Gc.A717Gp.(I239M)p.(Ile239Met)
c.720G>C or c.720G>T‡c.G720C or c.G720T‡p.(K240N)p.(Lys240Asn)
c.724A>Gc.A724Gp.(I242V)p.(Ile242Val)
c.724A>Tc.A724Tp.(I242F)p.(Ile242Phe)
c.725T>Ac.T725Ap.(I242N)p.(Ile242Asn)
c.725T>Cc.T725Cp.(I242T)p.(Ile242Thr)
c.728T>Cc.T728Cp.(L243S)p.(Leu243Ser)
c.728T>Gc.T728Gp.(L243W)p.(Leu243Trp)
c.729G>C or c.729G>T‡c.G729C or c.G729T‡p.(L243F)p.(Leu243Phe)
c.730G>Ac.G730Ap.(D244N)p.(Asp244Asn)
c.730G>Cc.G730Cp.(D244H)p.(Asp244His)
c.733T>Gc.T733Gp.(W245G)p.(Trp245Gly)
c.740C>Gc.C740Gp.(S247C)p.(Ser247Cys)
c.747C>G or c.747C>A‡c.C747G or c.C747A‡p.(N249K)p.(Asn249Lys)
c.749A>Cc.A749Cp.(Q250P)p.(Gln250Pro)
c.749A>Gc.A749Gp.(Q250R)p.(Gln250Arg)
c.750G>Cc.G750Cp.(Q250H)p.(Gln250His)
c.758T>Cc.T758Cp.(I253T)p.(Ile253Thr)
c.758T>Gc.T758Gp.(I253S)p.(Ile253Ser)
c.761_763delTTGc.761_763delTTG [a.k.a. c.760_762delGTT]p.(V254del)p.(Val254del)
c.769G>Cc.G769Cp.(A257P)p.(Ala257Pro)
c.770C>Gc.C770Gp.(A257G)p.(Ala257Gly)
c.770C>Tc.C770Tp.(A257V)p.(Ala257Val)
c.772G>C or c.772G>A‡c.G772C or c.G772A‡p.(G258R)p.(Gly258Arg)
c.773G>Tc.G773Tp.(G258V)p.(Gly258Val)
c.776C>Ac.C776Ap.(P259Q)p.(Pro259Gln)
c.776C>Gc.C776Gp.(P259R)p.(Pro259Arg)
c.776C>Tc.C776Tp.(P259L)p.(Pro259Leu)
c.779G>Ac.G779Ap.(G260E)p.(Gly260Glu)
c.779G>Cc.G779Cp.(G260A)p.(Gly260Ala)
c.781G>Ac.G781Ap.(G261S)p.(Gly261Ser)
c.781G>Cc.G781Cp.(G261R)p.(Gly261Arg)
c.781G>Tc.G781Tp.(G261C)p.(Gly261Cys)
c.788A>Gc.A788Gp.(N263S)p.(Asn263Ser)
c.790G>Tc.G790Tp.(D264Y)p.(Asp264Tyr)
c.794C>Tc.C794Tp.(P265L)p.(Pro265Leu)
c.800T>Cc.T800Cp.(M267T)p.(Met267Thr)
c.805G>Ac.G805Ap.(V269M)p.(Val269Met)
c.805G>Cc.G805Cp.(V269L)p.(Val269Leu)
c.806T>Cc.T806Cp.(V269A)p.(Val269Ala)
c.809T>Cc.T809Cp.(I270T)p.(Ile270Thr)
c.810T>Gc.T810Gp.(I270M)p.(Ile270Met)
c.811G>Ac.G811Ap.(G271S)p.(Gly271Ser)
c.[811G>A; 937G>T§]†c.[G811A; G937T§]†p.[(G271S; D313Y§)]†p.[(Gly271Ser; Asp313Tyr§)]†
c.812G>Ac.G812Ap.(G271D)p.(Gly271Asp)
c.812G>Cc.G812Cp.(G271A)p.(Gly271Ala)
c.823C>Gc.C823Gp.(L275V)p.(Leu275Val)
c.827G>Ac.G827Ap.(S276N)p.(Ser276Asn)
c.829T>Gc.T829Gp.(W277G)p.(Trp277Gly)
c.831G>C or c.831G>T‡c.G831C or c.G831T‡p.(W277C)p.(Trp277Cys)
c.832A>Tc.A832Tp.(N278Y)p.(Asn278Tyr)
c.835C>Gc.C835Gp.(Q279E)p.(Gln279Glu)
c.838C>Ac.C838Ap.(Q280K)p.(Gln280Lys)
c.840A>T or c.840A>C‡c.A840T or c.A840C‡p.(Q280H)p.(Gln280His)
c.844A>Gc.A844Gp.(T282A)p.(Thr282Ala)
c.845C>Tc.C845Tp.(T282I)p.(Thr282Ile)
c.850A>Gc.A850Gp.(M284V)p.(Met284Val)
c.851T>Cc.T851Cp.(M284T)p.(Met284Thr)
c.860G>Tc.G860Tp.(W287L)p.(Trp287Leu)
c.862G>Cc.G862Cp.(A288P)p.(Ala288Pro)
c.866T>Gc.T866Gp.(I289S)p.(Ile289Ser)
c.868A>C or c.868A>T‡c.A868C or c.A868T‡p.(M290L)p.(Met290Leu)
c.869T>Cc.T869Cp.(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>Ac.G871Ap.(A291T)p.(Ala291Thr)
c.877C>Ac.C877Ap.(P293T)p.(Pro293Thr)
c.881T>Cc.T881Cp.(L294S)p.(Leu294Ser)
c.884T>Gc.T884Gp.(F295C)p.(Phe295Cys)
c.886A>Gc.A886Gp.(M296V)p.(Met296Val)
c.886A>C or c.886A>T‡c.A886C or c.A886T‡p.(M296L)p.(Met296Leu)
c.887T>Cc.T887Cp.(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>Gc.A893Gp.(N298S)p.(Asn298Ser)
c.897C>G or c.897C>A‡c.C897G or c.C897A‡p.(D299E)p.(Asp299Glu)
c.898C>Tc.C898Tp.(L300F)p.(Leu300Phe)
c.899T>Cc.T899Cp.(L300P)p.(Leu300Pro)
c.901C>Gc.C901Gp.(R301G)p.(Arg301Gly)
c.902G>Ac.G902Ap.(R301Q)p.(Arg301Gln)
c.902G>Cc.G902Cp.(R301P)p.(Arg301Pro)
c.902G>Tc.G902Tp.(R301L)p.(Arg301Leu)
c.907A>Tc.A907Tp.(I303F)p.(Ile303Phe)
c.908T>Ac.T908Ap.(I303N)p.(Ile303Asn)
c.908T>Cc.T908Cp.(I303T)p.(Ile303Thr)
c.911G>Ac.G911Ap.(S304N)p.(Ser304Asn)
c.911G>Cc.G911Cp.(S304T)p.(Ser304Thr)
c.919G>Ac.G919Ap.(A307T)p.(Ala307Thr)
c.922A>Gc.A922Gp.(K308E)p.(Lys308Glu)
c.924A>C or c.924A>T‡c.A924C or c.A924T‡p.(K308N)p.(Lys308Asn)
c.925G>Cc.G925Cp.(A309P)p.(Ala309Pro)
c.926C>Tc.C926Tp.(A309V)p.(Ala309Val)
c.928C>Tc.C928Tp.(L310F)p.(Leu310Phe)
c.931C>Gc.C931Gp.(L311V)p.(Leu311Val)
c.935A>Gc.A935Gp.(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>Gc.A938Gp.(D313G)p.(Asp313Gly)
c.946G>Ac.G946Ap.(V316I)p.(Val316Ile)
c.947T>Gc.T947Gp.(V316G)p.(Val316Gly)
c.950T>Cc.T950Cp.(I317T)p.(Ile317Thr)
c.955A>Tc.A955Tp.(I319F)p.(Ile319Phe)
c.956T>Cc.T956Cp.(I319T)p.(Ile319Thr)
c.958A>Cc.A958Cp.(N320H)p.(Asn320His)
c.959A>Tc.A959Tp.(N320I)p.(Asn320Ile)
c.962A>Gc.A962Gp.(Q321R)p.(Gln321Arg)
c.962A>Tc.A962Tp.(Q321L)p.(Gln321Leu)
c.963G>C or c.963G>T‡c.G963C or c.G963T‡p.(Q321H)p.(Gln321His)
c.964G>Ac.G964Ap.(D322N)p.(Asp322Asn)
c.964G>Cc.G964Cp.(D322H)p.(Asp322His)
c.966C>A or c.966C>G‡c.C966A or c.C966G‡p.(D322E)p.(Asp322Glu)
c.967C>Ac.C967Ap.(P323T)p.(Pro323Thr)
c.968C>Gc.C968Gp.(P323R)p.(Pro323Arg)
c.973G>Ac.G973Ap.(G325S)p.(Gly325Ser)
c.973G>Cc.G973Cp.(G325R)p.(Gly325Arg)
c.978G>C or c.978G>T‡c.G978C or c.G978T‡p.(K326N)p.(Lys326Asn)
c.979C>Gc.C979Gp.(Q327E)p.(Gln327Glu)
c.980A>Tc.A980Tp.(Q327L)p.(Gln327Leu)
c.983G>Cc.G983Cp.(G328A)p.(Gly328Ala)
c.989A>Gc.A989Gp.(Q330R)p.(Gln330Arg)
c.1001G>Ac.G1001Ap.(G334E)p.(Gly334Glu)
c.1010T>Cc.T1010Cp.(F337S)p.(Phe337Ser)
c.1012G>Ac.G1012Ap.(E338K)p.(Glu338Lys)
c.1013A>Tc.A1013Tp.(E338V)p.(Glu338Val)
c.1016T>Ac.T1016Ap.(V339E)p.(Val339Glu)
c.1027C>Ac.C1027Ap.(P343T)p.(Pro343Thr)
c.1028C>Tc.C1028Tp.(P343L)p.(Pro343Leu)
c.1033T>Cc.T1033Cp.(S345P)p.(Ser345Pro)
c.1046G>Cc.G1046Cp.(W349S)p.(Trp349Ser)
c.1055C>Gc.C1055Gp.(A352G)p.(Ala352Gly)
c.1055C>Tc.C1055Tp.(A352V)p.(Ala352Val)
c.1061T>Ac.T1061Ap.(I354K)p.(Ile354Lys)
c.1066C>Gc.C1066Gp.(R356G)p.(Arg356Gly)
c.1066C>Tc.C1066Tp.(R356W)p.(Arg356Trp)
c.1067G>Ac.G1067Ap.(R356Q)p.(Arg356Gln)
c.1067G>Cc.G1067Cp.(R356P)p.(Arg356Pro)
c.1072G>Cc.G1072Cp.(E358Q)p.(Glu358Gln)
c.1073A>Cc.A1073Cp.(E358A)p.(Glu358Ala)
c.1073A>Gc.A1073Gp.(E358G)p.(Glu358Gly)
c.1074G>T or c.1074G>C‡c.G1074T or c.G1074C‡p.(E358D)p.(Glu358Asp)
c.1076T>Cc.T1076Cp.(I359T)p.(Ile359Thr)
c.1078G>Ac.G1078Ap.(G360S)p.(Gly360Ser)
c.1078G>Cc.G1078Cp.(G360R)p.(Gly360Arg)
c.1078G>Tc.G1078Tp.(G360C)p.(Gly360Cys)
c.1079G>Ac.G1079Ap.(G360D)p.(Gly360Asp)
c.1082G>Ac.G1082Ap.(G361E)p.(Gly361Glu)
c.1082G>Cc.G1082Cp.(G361A)p.(Gly361Ala)
c.1084C>Ac.C1084Ap.(P362T)p.(Pro362Thr)
c.1085C>Tc.C1085Tp.(P362L)p.(Pro362Leu)
c.1087C>Tc.C1087Tp.(R363C)p.(Arg363Cys)
c.1088G>Ac.G1088Ap.(R363H)p.(Arg363His)
c.1102G>Ac.G1102Ap.(A368T)p.(Ala368Thr)
c.1117G>Ac.G1117Ap.(G373S)p.(Gly373Ser)
c.1124G>Ac.G1124Ap.(G375E)p.(Gly375Glu)
c.1139C>Tc.C1139Tp.(P380L)p.(Pro380Leu)
c.1153A>Gc.A1153Gp.(T385A)p.(Tyr385Ala)
c.1163T>Ac.T1163Ap.(L388H)p.(Leu388His)
c.1168G>Ac.G1168Ap.(V390M)p.(Val390Met)
c.1172A>Cc.A1172Cp.(K391T)p.(Lys391Thr)
c.1184G>Ac.G1184Ap.(G395E)p.(Gly395Glu)
c.1184G>Cc.G1184Cp.(G395A)p.(Gly395Ala)
c.1192G>Ac.G1192Ap.(E398K)p.(Glu398Lys)
c.1202_1203insGACTTCc.1202_1203insGACTTCp.(T400_S401dup)p.(Thr400_Ser401dup)
c.1208T>Cc.T1208Cp.(L403S)p.(Leu403Ser)
c.1225C>Ac.C1225Ap.(P409T)p.(Pro409Thr)
c.1225C>Gc.C1225Gp.(P409A)p.(Pro409Ala)
c.1225C>Tc.C1225Tp.(P409S)p.(Pro409Ser)
c.1228A>Gc.A1228Gp.(T410A)p.(Thr410Ala)
c.1229C>Tc.C1229Tp.(T410I)p.(Thr410Ile)
c.1232G>Ac.G1232Ap.(G411D)p.(Gly411Asp)
c.1234A>Cc.A1234Cp.(T412P)p.(Thr412Pro)
c.1235C>Ac.C1235Ap.(T412N)p.(Thr412Asn)
c.1235C>Tc.C1235Tp.(T412I)p.(Thr412Ile)
c.1253A>Gc.A1253Gp.(E418G)p.(Glu418Gly)
c.1261A>Gc.A1261Gp.(M421V)p.(Met421Val)
" ], "mechanism_of_action": [ "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 medinfousa@amicusrx.com. 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)" ], "mechanism_of_action_table": [ "
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>Gc.C7Gp.(L3V)p.(Leu3Val)
c.8T>Cc.T8Cp.(L3P)p.(Leu3Pro)
c.[11G>T; 620A>C]†c.[G11T; A620C]†p.[(R4M; Y207S)]†p.[(Arg4Met; Tyr207Ser)]†
c.37G>Ac.G37Ap.(A13T)p.(Ala13Thr)
c.37G>Cc.G37Cp.(A13P)p.(Ala13Pro)
c.43G>Ac.G43Ap.(A15T)p.(Ala15Thr)
c.44C>Gc.C44Gp.(A15G)p.(Ala15Gly)
c.53T>Gc.T53Gp.(F18C)p.(Phe18Cys)
c.58G>Cc.G58Cp.(A20P)p.(Ala20Pro)
c.59C>Ac.C59Ap.(A20D)p.(Ala20Asp)
c.65T>Gc.T65Gp.(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>Gc.T70Gp.(W24G)p.(Trp24Gly)
c.72G>C or c.72G>T‡c.G72C or c.G72T‡p.(W24C)p.(Trp24Cys)
c.95T>Cc.T95Cp.(L32P)p.(Leu32Pro)
c.97G>Cc.G97Cp.(D33H)p.(Asp33His)
c.97G>Tc.G97Tp.(D33Y)p.(Asp33Tyr)
c.98A>Gc.A98Gp.(D33G)p.(Asp33Gly)
c.100A>Cc.A100Cp.(N34H)p.(Asn34His)
c.100A>Gc.A100Gp.(N34D)p.(Asn34Asp)
c.101A>Cc.A101Cp.(N34T)p.(Asn34Thr)
c.101A>Gc.A101Gp.(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>Ac.G104Ap.(G35E)p.(Gly35Glu)
c.104G>Tc.G104Tp.(G35V)p.(Gly35Val)
c.107T>Cc.T107Cp.(L36S)p.(Leu36Ser)
c.107T>Gc.T107Gp.(L36W)p.(Leu36Trp)
c.108G>C or c.108G>T‡c.G108C or c.G108T‡p.(L36F)p.(Leu36Phe)
c.109G>Ac.G109Ap.(A37T)p.(Ala37Thr)
c.109G>Tc.G109Tp.(A37S)p.(Ala37Ser)
c.110C>Tc.C110Tp.(A37V)p.(Ala37Val)
c.122C>Tc.C122Tp.(T41I)p.(Thr41Ile)
c.124A>C or c.124A>T‡c.A124C or c.A124T‡p.(M42L)p.(Met42Leu)
c.124A>Gc.A124Gp.(M42V)p.(Met42Val)
c.125T>Ac.T125Ap.(M42K)p.(Met42Lys)
c.125T>Cc.T125Cp.(M42T)p.(Met42Thr)
c.125T>Gc.T125Gp.(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>Cc.A137Cp.(H46P)p.(His46Pro)
c.142G>Cc.G142Cp.(E48Q)p.(Glu48Gln)
c.152T>Ac.T152Ap.(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_158delinsCTc.157_158delinsCTp.(N53L)p.(Asn53Leu)
c.157A>Gc.A157Gp.(N53D)p.(Asn53Asp)
c.160C>Tc.C160Tp.(L54F)p.(Leu54Phe)
c.161T>Cc.T161Cp.(L54P)p.(Leu54Pro)
c.164A>Gc.A164Gp.(D55G)p.(Asp55Gly)
c.164A>Tc.A164Tp.(D55V)p.(Asp55Val)
c.[164A>T; 170A>T]†c.[A164T; A170T]†p.[(D55V; Q57L)]†p.[(Asp55Val; Gln57Leu)]†
c.167G>Ac.G167Ap.(C56Y)p.(Cys56Tyr)
c.167G>Tc.G167Tp.(C56F)p.(Cys56Phe)
c.170A>Gc.A170Gp.(Q57R)p.(Gln57Arg)
c.170A>Tc.A170Tp.(Q57L)p.(Gln57Leu)
c.175G>Ac.G175Ap.(E59K)p.(Glu59Lys)
c.178C>Ac.C178Ap.(P60T)p.(Pro60Thr)
c.178C>Tc.C178Tp.(P60S)p.(Pro60Ser)
c.179C>Tc.C179Tp.(P60L)p.(Pro60Leu)
c.196G>Ac.G196Ap.(E66K)p.(Glu66Lys)
c.197A>Gc.A197Gp.(E66G)p.(Glu66Gly)
c.207C>A or c.207C>G‡c.C207A or c.C207G‡p.(F69L)p.(Phe69Leu)
c.214A>Gc.A214Gp.(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>Tc.C218Tp.(A73V)p.(Ala73Val)
c.227T>Cc.T227Cp.(M76T)p.(Met76Thr)
c.239G>Ac.G239Ap.(G80D)p.(Gly80Asp)
c.239G>Tc.G239Tp.(G80V)p.(Gly80Val)
c.247G>Ac.G247Ap.(D83N)p.(Asp83Asn)
c.253G>Ac.G253Ap.(G85S)p.(Gly85Ser)
c.253_254delinsAAc.253_254delinsAAp.(G85N)p.(Gly85Asn)
c.253_255delinsATGc.253_255delinsATGp.(G85M)p.(Gly85Met)
c.254G>Ac.G254Ap.(G85D)p.(Gly85Asp)
c.261G>C or c.261G>T‡c.G261C or c.G261T‡p.(E87D)p.(Glu87Asp)
c.263A>Gc.A263Gp.(Y88C)p.(Tyr88Cys)
c.265C>Tc.C265Tp.(L89F)p.(Leu89Phe)
c.272T>Cc.T272Cp.(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>Cc.G289Cp.(A97P)p.(Ala97Pro)
c.290C>Tc.C290Tp.(A97V)p.(Ala97Val)
c.305C>Tc.C305Tp.(S102L)p.(Ser102Leu)
c.311G>Tc.G311Tp.(G104V)p.(Gly104Val)
c.316C>Tc.C316Tp.(L106F)p.(Leu106Phe)
c.320A>Gc.A320Gp.(Q107R)p.(Gln107Arg)
c.322G>Ac.G322Ap.(A108T)p.(Ala108Thr)
c.326A>Gc.A326Gp.(D109G)p.(Asp109Gly)
c.334C>Gc.C334Gp.(R112G)p.(Arg112Gly)
c.335G>Ac.G335Ap.(R112H)p.(Arg112His)
c.335G>Tc.G335Tp.(R112L)p.(Arg112Leu)
c.337T>Ac.T337Ap.(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>Tc.C352Tp.(R118C)p.(Arg118Cys)
c.361G>Ac.G361Ap.(A121T)p.(Ala121Thr)
c.368A>Gc.A368Gp.(Y123C)p.(Tyr123Cys)
c.373C>Tc.C373Tp.(H125Y)p.(His125Tyr)
c.374A>Tc.A374Tp.(H125L)p.(His125Leu)
c.376A>Gc.A376Gp.(S126G)p.(Ser126Gly)
c.376A>Tc.A376Tp.(S126C)p.(Ser126Cys)
c.383G>Ac.G383Ap.(G128E)p.(Gly128Glu)
c.399T>Gc.T399Gp.(I133M)p.(Ile133Met)
c.404C>Tc.C404Tp.(A135V)p.(Ala135Val)
c.408T>A or c.408T>G‡c.T408A or c.T408G‡p.(D136E)p.(Asp136Glu)
c.416A>Gc.A416Gp.(N139S)p.(Asn139Ser)
c.419A>Cc.A419Cp.(K140T)p.(Lys140Thr)
c.427G>Ac.G427Ap.(A143T)p.(Ala143Thr)
c.431G>Ac.G431Ap.(G144D)p.(Gly144Asp)
c.431G>Tc.G431Tp.(G144V)p.(Gly144Val)
c.434T>Cc.T434Cp.(F145S)p.(Phe145Ser)
c.436C>Tc.C436Tp.(P146S)p.(Pro146Ser)
c.437C>Gc.C437Gp.(P146R)p.(Pro146Arg)
c.454T>Cc.T454Cp.(Y152H)p.(Tyr152His)
c.454T>Gc.T454Gp.(Y152D)p.(Tyr152Asp)
c.455A>Gc.A455Gp.(Y152C)p.(Tyr152Cys)
c.465T>A or c.465T>G‡c.T465A or c.T465G‡p.(D155E)p.(Asp155Glu)
c.466G>Ac.G466Ap.(A156T)p.(Ala156Thr)
c.466G>Tc.G466Tp.(A156S)p.(Ala156Ser)
c.467C>Tc.C467Tp.(A156V)p.(Ala156Val)
c.471G>C or c.471G>T‡c.G471C or c.G471T‡p.(Q157H)p.(Gln157His)
c.484T>Gc.T484Gp.(W162G)p.(Trp162Gly)
c.493G>Cc.G493Cp.(D165H)p.(Asp165His)
c.494A>Gc.A494Gp.(D165G)p.(Asp165Gly)
c.496_497delinsTCc.496_497delinsTCp.(L166S)p.(Leu166Ser)
c.496C>Gc.C496Gp.(L166V)p.(Leu166Val)
c.496_497delinsGGc.496_497delinsGGp.(L166G)p.(Leu166Gly)
c.499C>Gc.C499Gp.(L167V)p.(Leu167Val)
c.506T>Cc.T506Cp.(F169S)p.(Phe169Ser)
c.511G>Ac.G511Ap.(G171S)p.(Gly171Ser)
c.520T>Cc.T520Cp.(C174R)p.(Cys174Arg)
c.520T>Gc.T520Gp.(C174G)p.(Cys174Gly)
c.525C>G or c.525C>A‡c.C525G or c.C525A‡p.(D175E)p.(Asp175Glu)
c.539T>Gc.T539Gp.(L180W)p.(Leu180Trp)
c.540G>T or c.540G>C‡c.G540T or c.G540C‡p.(L180F)p.(Leu180Phe)
c.548G>Ac.G548Ap.(G183D)p.(Gly183Asp)
c.548G>Cc.G548Cp.(G183A)p.(Gly183Ala)
c.550T>Ac.T550Ap.(Y184N)p.(Tyr184Asn)
c.551A>Cc.A551Cp.(Y184S)p.(Tyr184Ser)
c.551A>Gc.A551Gp.(Y184C)p.(Tyr184Cys)
c.553A>Gc.A553Gp.(K185E)p.(Lys185Glu)
c.559_564dupc.559_564dupp.(M187_S188dup)p.(Met187_Ser188dup)
c.559A>Gc.A559Gp.(M187V)p.(Met187Val)
c.560T>Cc.T560Cp.(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>Ac.T572Ap.(L191Q)p.(Leu191Gln)
c.581C>Tc.C581Tp.(T194I)p.(Thr194Ile)
c.584G>Tc.G584Tp.(G195V)p.(Gly195Val)
c.586A>Gc.A586Gp.(R196G)p.(Arg196Gly)
c.593T>Cc.T593Cp.(I198T)p.(Ile198Thr)
c.595G>Ac.G595Ap.(V199M)p.(Val199Met)
c.596T>Cc.T596Cp.(V199A)p.(Val199Ala)
c.596T>Gc.T596Gp.(V199G)p.(Val199Gly)
c.599A>Gc.A599Gp.(Y200C)p.(Tyr200Cys)
c.602C>Ac.C602Ap.(S201Y)p.(Ser201Tyr)
c.602C>Tc.C602Tp.(S201F)p.(Ser201Phe)
c.608A>Tc.A608Tp.(E203V)p.(Glu203Val)
c.609G>C or c.609G>T‡c.G609C or c.G609T‡p.(E203D)p.(Glu203Asp)
c.611G>Tc.G611Tp.(W204L)p.(Trp204Leu)
c.613C>Ac.C613Ap.(P205T)p.(Pro205Thr)
c.613C>Tc.C613Tp.(P205S)p.(Pro205Ser)
c.614C>Tc.C614Tp.(P205L)p.(Pro205Leu)
c.619T>Cc.T619Cp.(Y207H)p.(Tyr207His)
c.620A>Cc.A620Cp.(Y207S)p.(Tyr207Ser)
c.623T>Gc.T623Gp.(M208R)p.(Met208Arg)
c.628C>Tc.C628Tp.(P210S)p.(Pro210Ser)
c.629C>Tc.C629Tp.(P210L)p.(Pro210Leu)
c.638A>Gc.A638Gp.(K213R)p.(Lys213Arg)
c.638A>Tc.A638Tp.(K213M)p.(Lys213Met)
c.640C>Tc.C640Tp.(P214S)p.(Pro214Ser)
c.641C>Tc.C641Tp.(P214L)p.(Pro214Leu)
c.643A>Gc.A643Gp.(N215D)p.(Asn215Asp)
c.644A>Gc.A644Gp.(N215S)p.(Asn215Ser)
c.[644A>G; 937G>T§]†c.[A644G; G937T§]†p.[(N215S; D313Y§)]†p.[(Asn215Ser; Asp313Tyr§)]†
c.644A>Tc.A644Tp.(N215I)p.(Asn215Ile)
c.646T>Gc.T646Gp.(Y216D)p.(Tyr216Asp)
c.647A>Gc.A647Gp.(Y216C)p.(Tyr216Cys)
c.655A>Cc.A655Cp.(I219L)p.(Ile219Leu)
c.656T>Ac.T656Ap.(I219N)p.(Ile219Asn)
c.656T>Cc.T656Cp.(I219T)p.(Ile219Thr)
c.657C>Gc.C657Gp.(I219M)p.(Ile219Met)
c.659G>Ac.G659Ap.(R220Q)p.(Arg220Gln)
c.659G>Cc.G659Cp.(R220P)p.(Arg220Pro)
c.662A>Cc.A662Cp.(Q221P)p.(Gln221Pro)
c.664T>Gc.T664Gp.(Y222D)p.(Tyr222Asp)
c.671A>Cc.A671Cp.(N224T)p.(Asn224Thr)
c.671A>Gc.A671Gp.(N224S)p.(Asn224Ser)
c.673C>Gc.C673Gp.(H225D)p.(His225Asp)
c.682A>Cc.A682Cp.(N228H)p.(Asn228His)
c.683A>Gc.A683Gp.(N228S)p.(Asn228Ser)
c.687T>G or c.687T>A‡c.T687G or c.T687A‡p.(F229L)p.(Phe229Leu)
c.695T>Cc.T695Cp.(I232T)p.(Ile232Thr)
c.712A>Gc.A712Gp.(S238G)p.(Ser238Gly)
c.713G>Ac.G713Ap.(S238N)p.(Ser238Asn)
c.716T>Cc.T716Cp.(I239T)p.(Ile239Thr)
c.717A>Gc.A717Gp.(I239M)p.(Ile239Met)
c.720G>C or c.720G>T‡c.G720C or c.G720T‡p.(K240N)p.(Lys240Asn)
c.724A>Gc.A724Gp.(I242V)p.(Ile242Val)
c.724A>Tc.A724Tp.(I242F)p.(Ile242Phe)
c.725T>Ac.T725Ap.(I242N)p.(Ile242Asn)
c.725T>Cc.T725Cp.(I242T)p.(Ile242Thr)
c.728T>Cc.T728Cp.(L243S)p.(Leu243Ser)
c.728T>Gc.T728Gp.(L243W)p.(Leu243Trp)
c.729G>C or c.729G>T‡c.G729C or c.G729T‡p.(L243F)p.(Leu243Phe)
c.730G>Ac.G730Ap.(D244N)p.(Asp244Asn)
c.730G>Cc.G730Cp.(D244H)p.(Asp244His)
c.733T>Gc.T733Gp.(W245G)p.(Trp245Gly)
c.740C>Gc.C740Gp.(S247C)p.(Ser247Cys)
c.747C>G or c.747C>A‡c.C747G or c.C747A‡p.(N249K)p.(Asn249Lys)
c.749A>Cc.A749Cp.(Q250P)p.(Gln250Pro)
c.749A>Gc.A749Gp.(Q250R)p.(Gln250Arg)
c.750G>Cc.G750Cp.(Q250H)p.(Gln250His)
c.758T>Cc.T758Cp.(I253T)p.(Ile253Thr)
c.758T>Gc.T758Gp.(I253S)p.(Ile253Ser)
c.761_763delTTGc.761_763delTTG [a.k.a. c.760_762delGTT]p.(V254del)p.(Val254del)
c.769G>Cc.G769Cp.(A257P)p.(Ala257Pro)
c.770C>Gc.C770Gp.(A257G)p.(Ala257Gly)
c.770C>Tc.C770Tp.(A257V)p.(Ala257Val)
c.772G>C or c.772G>A‡c.G772C or c.G772A‡p.(G258R)p.(Gly258Arg)
c.773G>Tc.G773Tp.(G258V)p.(Gly258Val)
c.776C>Ac.C776Ap.(P259Q)p.(Pro259Gln)
c.776C>Gc.C776Gp.(P259R)p.(Pro259Arg)
c.776C>Tc.C776Tp.(P259L)p.(Pro259Leu)
c.779G>Ac.G779Ap.(G260E)p.(Gly260Glu)
c.779G>Cc.G779Cp.(G260A)p.(Gly260Ala)
c.781G>Ac.G781Ap.(G261S)p.(Gly261Ser)
c.781G>Cc.G781Cp.(G261R)p.(Gly261Arg)
c.781G>Tc.G781Tp.(G261C)p.(Gly261Cys)
c.788A>Gc.A788Gp.(N263S)p.(Asn263Ser)
c.790G>Tc.G790Tp.(D264Y)p.(Asp264Tyr)
c.794C>Tc.C794Tp.(P265L)p.(Pro265Leu)
c.800T>Cc.T800Cp.(M267T)p.(Met267Thr)
c.805G>Ac.G805Ap.(V269M)p.(Val269Met)
c.805G>Cc.G805Cp.(V269L)p.(Val269Leu)
c.806T>Cc.T806Cp.(V269A)p.(Val269Ala)
c.809T>Cc.T809Cp.(I270T)p.(Ile270Thr)
c.810T>Gc.T810Gp.(I270M)p.(Ile270Met)
c.811G>Ac.G811Ap.(G271S)p.(Gly271Ser)
c.[811G>A; 937G>T§]†c.[G811A; G937T§]†p.[(G271S; D313Y§)]†p.[(Gly271Ser; Asp313Tyr§)]†
c.812G>Ac.G812Ap.(G271D)p.(Gly271Asp)
c.812G>Cc.G812Cp.(G271A)p.(Gly271Ala)
c.823C>Gc.C823Gp.(L275V)p.(Leu275Val)
c.827G>Ac.G827Ap.(S276N)p.(Ser276Asn)
c.829T>Gc.T829Gp.(W277G)p.(Trp277Gly)
c.831G>C or c.831G>T‡c.G831C or c.G831T‡p.(W277C)p.(Trp277Cys)
c.832A>Tc.A832Tp.(N278Y)p.(Asn278Tyr)
c.835C>Gc.C835Gp.(Q279E)p.(Gln279Glu)
c.838C>Ac.C838Ap.(Q280K)p.(Gln280Lys)
c.840A>T or c.840A>C‡c.A840T or c.A840C‡p.(Q280H)p.(Gln280His)
c.844A>Gc.A844Gp.(T282A)p.(Thr282Ala)
c.845C>Tc.C845Tp.(T282I)p.(Thr282Ile)
c.850A>Gc.A850Gp.(M284V)p.(Met284Val)
c.851T>Cc.T851Cp.(M284T)p.(Met284Thr)
c.860G>Tc.G860Tp.(W287L)p.(Trp287Leu)
c.862G>Cc.G862Cp.(A288P)p.(Ala288Pro)
c.866T>Gc.T866Gp.(I289S)p.(Ile289Ser)
c.868A>C or c.868A>T‡c.A868C or c.A868T‡p.(M290L)p.(Met290Leu)
c.869T>Cc.T869Cp.(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>Ac.G871Ap.(A291T)p.(Ala291Thr)
c.877C>Ac.C877Ap.(P293T)p.(Pro293Thr)
c.881T>Cc.T881Cp.(L294S)p.(Leu294Ser)
c.884T>Gc.T884Gp.(F295C)p.(Phe295Cys)
c.886A>Gc.A886Gp.(M296V)p.(Met296Val)
c.886A>C or c.886A>T‡c.A886C or c.A886T‡p.(M296L)p.(Met296Leu)
c.887T>Cc.T887Cp.(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>Gc.A893Gp.(N298S)p.(Asn298Ser)
c.897C>G or c.897C>A‡c.C897G or c.C897A‡p.(D299E)p.(Asp299Glu)
c.898C>Tc.C898Tp.(L300F)p.(Leu300Phe)
c.899T>Cc.T899Cp.(L300P)p.(Leu300Pro)
c.901C>Gc.C901Gp.(R301G)p.(Arg301Gly)
c.902G>Ac.G902Ap.(R301Q)p.(Arg301Gln)
c.902G>Cc.G902Cp.(R301P)p.(Arg301Pro)
c.902G>Tc.G902Tp.(R301L)p.(Arg301Leu)
c.907A>Tc.A907Tp.(I303F)p.(Ile303Phe)
c.908T>Ac.T908Ap.(I303N)p.(Ile303Asn)
c.908T>Cc.T908Cp.(I303T)p.(Ile303Thr)
c.911G>Ac.G911Ap.(S304N)p.(Ser304Asn)
c.911G>Cc.G911Cp.(S304T)p.(Ser304Thr)
c.919G>Ac.G919Ap.(A307T)p.(Ala307Thr)
c.922A>Gc.A922Gp.(K308E)p.(Lys308Glu)
c.924A>C or c.924A>T‡c.A924C or c.A924T‡p.(K308N)p.(Lys308Asn)
c.925G>Cc.G925Cp.(A309P)p.(Ala309Pro)
c.926C>Tc.C926Tp.(A309V)p.(Ala309Val)
c.928C>Tc.C928Tp.(L310F)p.(Leu310Phe)
c.931C>Gc.C931Gp.(L311V)p.(Leu311Val)
c.935A>Gc.A935Gp.(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>Gc.A938Gp.(D313G)p.(Asp313Gly)
c.946G>Ac.G946Ap.(V316I)p.(Val316Ile)
c.947T>Gc.T947Gp.(V316G)p.(Val316Gly)
c.950T>Cc.T950Cp.(I317T)p.(Ile317Thr)
c.955A>Tc.A955Tp.(I319F)p.(Ile319Phe)
c.956T>Cc.T956Cp.(I319T)p.(Ile319Thr)
c.958A>Cc.A958Cp.(N320H)p.(Asn320His)
c.959A>Tc.A959Tp.(N320I)p.(Asn320Ile)
c.962A>Gc.A962Gp.(Q321R)p.(Gln321Arg)
c.962A>Tc.A962Tp.(Q321L)p.(Gln321Leu)
c.963G>C or c.963G>T‡c.G963C or c.G963T‡p.(Q321H)p.(Gln321His)
c.964G>Ac.G964Ap.(D322N)p.(Asp322Asn)
c.964G>Cc.G964Cp.(D322H)p.(Asp322His)
c.966C>A or c.966C>G‡c.C966A or c.C966G‡p.(D322E)p.(Asp322Glu)
c.967C>Ac.C967Ap.(P323T)p.(Pro323Thr)
c.968C>Gc.C968Gp.(P323R)p.(Pro323Arg)
c.973G>Ac.G973Ap.(G325S)p.(Gly325Ser)
c.973G>Cc.G973Cp.(G325R)p.(Gly325Arg)
c.978G>C or c.978G>T‡c.G978C or c.G978T‡p.(K326N)p.(Lys326Asn)
c.979C>Gc.C979Gp.(Q327E)p.(Gln327Glu)
c.980A>Tc.A980Tp.(Q327L)p.(Gln327Leu)
c.983G>Cc.G983Cp.(G328A)p.(Gly328Ala)
c.989A>Gc.A989Gp.(Q330R)p.(Gln330Arg)
c.1001G>Ac.G1001Ap.(G334E)p.(Gly334Glu)
c.1010T>Cc.T1010Cp.(F337S)p.(Phe337Ser)
c.1012G>Ac.G1012Ap.(E338K)p.(Glu338Lys)
c.1013A>Tc.A1013Tp.(E338V)p.(Glu338Val)
c.1016T>Ac.T1016Ap.(V339E)p.(Val339Glu)
c.1027C>Ac.C1027Ap.(P343T)p.(Pro343Thr)
c.1028C>Tc.C1028Tp.(P343L)p.(Pro343Leu)
c.1033T>Cc.T1033Cp.(S345P)p.(Ser345Pro)
c.1046G>Cc.G1046Cp.(W349S)p.(Trp349Ser)
c.1055C>Gc.C1055Gp.(A352G)p.(Ala352Gly)
c.1055C>Tc.C1055Tp.(A352V)p.(Ala352Val)
c.1061T>Ac.T1061Ap.(I354K)p.(Ile354Lys)
c.1066C>Gc.C1066Gp.(R356G)p.(Arg356Gly)
c.1066C>Tc.C1066Tp.(R356W)p.(Arg356Trp)
c.1067G>Ac.G1067Ap.(R356Q)p.(Arg356Gln)
c.1067G>Cc.G1067Cp.(R356P)p.(Arg356Pro)
c.1072G>Cc.G1072Cp.(E358Q)p.(Glu358Gln)
c.1073A>Cc.A1073Cp.(E358A)p.(Glu358Ala)
c.1073A>Gc.A1073Gp.(E358G)p.(Glu358Gly)
c.1074G>T or c.1074G>C‡c.G1074T or c.G1074C‡p.(E358D)p.(Glu358Asp)
c.1076T>Cc.T1076Cp.(I359T)p.(Ile359Thr)
c.1078G>Ac.G1078Ap.(G360S)p.(Gly360Ser)
c.1078G>Cc.G1078Cp.(G360R)p.(Gly360Arg)
c.1078G>Tc.G1078Tp.(G360C)p.(Gly360Cys)
c.1079G>Ac.G1079Ap.(G360D)p.(Gly360Asp)
c.1082G>Ac.G1082Ap.(G361E)p.(Gly361Glu)
c.1082G>Cc.G1082Cp.(G361A)p.(Gly361Ala)
c.1084C>Ac.C1084Ap.(P362T)p.(Pro362Thr)
c.1085C>Tc.C1085Tp.(P362L)p.(Pro362Leu)
c.1087C>Tc.C1087Tp.(R363C)p.(Arg363Cys)
c.1088G>Ac.G1088Ap.(R363H)p.(Arg363His)
c.1102G>Ac.G1102Ap.(A368T)p.(Ala368Thr)
c.1117G>Ac.G1117Ap.(G373S)p.(Gly373Ser)
c.1124G>Ac.G1124Ap.(G375E)p.(Gly375Glu)
c.1139C>Tc.C1139Tp.(P380L)p.(Pro380Leu)
c.1153A>Gc.A1153Gp.(T385A)p.(Tyr385Ala)
c.1163T>Ac.T1163Ap.(L388H)p.(Leu388His)
c.1168G>Ac.G1168Ap.(V390M)p.(Val390Met)
c.1172A>Cc.A1172Cp.(K391T)p.(Lys391Thr)
c.1184G>Ac.G1184Ap.(G395E)p.(Gly395Glu)
c.1184G>Cc.G1184Cp.(G395A)p.(Gly395Ala)
c.1192G>Ac.G1192Ap.(E398K)p.(Glu398Lys)
c.1202_1203insGACTTCc.1202_1203insGACTTCp.(T400_S401dup)p.(Thr400_Ser401dup)
c.1208T>Cc.T1208Cp.(L403S)p.(Leu403Ser)
c.1225C>Ac.C1225Ap.(P409T)p.(Pro409Thr)
c.1225C>Gc.C1225Gp.(P409A)p.(Pro409Ala)
c.1225C>Tc.C1225Tp.(P409S)p.(Pro409Ser)
c.1228A>Gc.A1228Gp.(T410A)p.(Thr410Ala)
c.1229C>Tc.C1229Tp.(T410I)p.(Thr410Ile)
c.1232G>Ac.G1232Ap.(G411D)p.(Gly411Asp)
c.1234A>Cc.A1234Cp.(T412P)p.(Thr412Pro)
c.1235C>Ac.C1235Ap.(T412N)p.(Thr412Asn)
c.1235C>Tc.C1235Tp.(T412I)p.(Thr412Ile)
c.1253A>Gc.A1253Gp.(E418G)p.(Glu418Gly)
c.1261A>Gc.A1261Gp.(M421V)p.(Met421Val)
" ], "pharmacodynamics": [ "12.2 Pharmacodynamics In Study 1, 31 of 50 patients with amenable GLA variants (18 on GALAFOLD, 13 on placebo) had lyso‑Gb 3 assessments available after 6 months of treatment. The median change from baseline to month 6 in plasma lyso‑Gb 3 (nmol/L) was -2.37 (range -69.7, 1.8) in patients on GALAFOLD and 0.53 (range -21.5, 16.3) in patients on placebo. In the open‑label treatment phase of Study 1, the 13 patients who were initially on placebo for 6 months and who switched to GALAFOLD for another 6 months had a median change in lyso‑Gb 3 (nmol/L) of -2.72 (range -61.1, -0.3). The 18 patients who were treated with GALAFOLD for 6 months and then continued GALAFOLD in the open‑label treatment phase of Study 1 for an additional 6 months had no further changes in plasma lyso‑Gb 3 . In Study 2, 46 of 56 patients with amenable GLA variants (31 on GALAFOLD, 15 on enzyme replacement therapy (ERT)) had lyso‑Gb 3 assessments available after 18 months of treatment. The median change from baseline to month 18 in plasma lyso‑Gb 3 (nmol/L) was 0.53 (range -2.27, 28.3) in patients on GALAFOLD and -0.03 (range -11.9, 2.57) in patients on ERT. Cardiac Electrophysiology At a dose approximately 8 times the recommended dose, GALAFOLD did not prolong the QT interval to any clinically relevant extent." ], "pharmacokinetics": [ "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) ] ." ], "nonclinical_toxicology": [ "13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis The carcinogenic potential of migalastat was assessed in a 2‑year study in rats and a 26‑week study in Tg.rasH2 mice. In the 2‑year rat study, migalastat was not tumorigenic at oral doses of up to 600 mg/kg twice daily (24 times the recommended dose based on AUC). In the 26‑week study in Tg.rasH2 mice, migalastat was not tumorigenic at oral doses of up to 1000 mg/kg/day in males and 500 mg/kg/day in females. Mutagenesis Migalastat was negative in the bacterial mutagenicity (Ames) assay, in vitro cell mutation assay in L5178Y mouse lymphoma TK +/- cells, and in vivo micronucleus assay in rats. Impairment of Fertility Oral administration of up to 12.5 mg/kg migalastat twice daily in rats (equivalent to the human AUC at the recommended dose) produced a significant decrease in male fertility. This effect was completely reversed after four weeks of recovery. Female fertility was not affected." ], "carcinogenesis_and_mutagenesis_and_impairment_of_fertility": [ "13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis The carcinogenic potential of migalastat was assessed in a 2‑year study in rats and a 26‑week study in Tg.rasH2 mice. In the 2‑year rat study, migalastat was not tumorigenic at oral doses of up to 600 mg/kg twice daily (24 times the recommended dose based on AUC). In the 26‑week study in Tg.rasH2 mice, migalastat was not tumorigenic at oral doses of up to 1000 mg/kg/day in males and 500 mg/kg/day in females. Mutagenesis Migalastat was negative in the bacterial mutagenicity (Ames) assay, in vitro cell mutation assay in L5178Y mouse lymphoma TK +/- cells, and in vivo micronucleus assay in rats. Impairment of Fertility Oral administration of up to 12.5 mg/kg migalastat twice daily in rats (equivalent to the human AUC at the recommended dose) produced a significant decrease in male fertility. This effect was completely reversed after four weeks of recovery. Female fertility was not affected." ], "clinical_studies": [ "14 CLINICAL STUDIES Study AT1001‑011 (referred to as Study 1; NCT00925301) included a 6‑month randomized, double‑blind, placebo‑controlled phase followed by a 6‑month open‑label treatment phase and a 12‑month open‑label extension phase. Patients received 123 mg GALAFOLD orally every other day taken without consuming food 2 hours before and 2 hours after each dose to give a minimum 4‑hour fast [see Dosage and Administration (2.2) ] . A total of 67 patients with Fabry disease who were naïve to GALAFOLD and enzyme replacement therapy (ERT) or were previously treated with ERT (agalsidase beta or non‑U.S. approved agalsidase alfa) and had been off ERT for at least 6 months were randomized in a 1:1 ratio to receive either GALAFOLD 123 mg every other day or placebo for the first 6 months. In the second 6 months, all patients were treated with GALAFOLD. Results - Patients with Fabry Disease with Amenable GLA Variants Of the 67 enrolled patients, 50 patients (32 females, 18 males) had amenable GLA variants based on the in vitro amenability assay [see Clinical Pharmacology (12.1) ] . The median age of this population was 45 years (range from 16 to 68 years old); 65 were White (97%), and 2 were other racial group (3%). The major efficacy outcome measure of the average number of GL‑3 inclusions per kidney interstitial capillary (KIC) in renal biopsy samples was assessed by light microscopy before and after treatment. Efficacy was evaluated after 6 months of treatment in 45 of 50 patients with amenable GLA variants (29 females and 16 males) and with available histology data both at baseline and month 6. Of the 45 evaluable patients, 25 received GALAFOLD (18 females, 7 males) and 20 received placebo (11 females, 9 males). The proportion of patients with ≥ 50% reduction from baseline in the average number of GL‑3 inclusions per KIC and the median changes from baseline in the average number of GL‑3 inclusions per KIC after 6 months of treatment in Study 1 are shown in Table 3 . Table 3: Changes from Baseline to Month 6 in Average Number of GL‑3 Inclusions per KIC in Adults with Fabry Disease with Amenable GLA Variants in Study 1 (N = 45) GALAFOLD n/N (%) with ≥ 50% reduction Median change from baseline (range) Placebo n/N (%) with ≥ 50% reduction Median change from baseline (range) All patients (N = 45) 13/25 (52%) -0.04 (-1.94, 0.26) 9/20 (45%) -0.03 (-1.00, 1.69) Females (N = 29) 8/18 (44%) -0.02 (-0.46, 0.26) 5/11 (46%) -0.03 (-0.35, 0.10) Males (N = 16) 5/7 (71%) -1.10 (-1.94, -0.02) 4/9 (44%) -0.03 (-1.00, 1.69) Patients with baseline GL-3 ≥ 0.3 (N = 17; 9 males, 8 females) 7/9 (78%) -0.91 (-1.94, 0.19) 2/8 (25%) -0.02 (-1.00, 1.69) Patients with baseline GL-3 < 0.3 (N = 28; 7 males, 21 females) 6/16 (38%) -0.02 (-0.10, 0.26) 7/12 (58%) -0.05 (-0.16, 0.14) Results - Patients with Fabry Disease with Non‑Amenable GLA Variants Of the 67 enrolled patients in Study 1, 17 patients had non‑amenable GLA variants. These patients had no change from baseline in the average number of GL‑3 inclusions per KIC after 6 months of treatment." ], "clinical_studies_table": [ "
Table 3: Changes from Baseline to Month 6 in Average Number of GL‑3 Inclusions per KIC in Adults with Fabry Disease with Amenable GLA Variants in Study 1 (N = 45)
GALAFOLD n/N (%) with ≥ 50% reduction Median change from baseline (range)Placebo n/N (%) with ≥ 50% reduction Median change from baseline (range)
All patients (N = 45)13/25 (52%) -0.04 (-1.94, 0.26)9/20 (45%) -0.03 (-1.00, 1.69)
Females (N = 29)8/18 (44%) -0.02 (-0.46, 0.26)5/11 (46%) -0.03 (-0.35, 0.10)
Males (N = 16)5/7 (71%) -1.10 (-1.94, -0.02)4/9 (44%) -0.03 (-1.00, 1.69)
Patients with baseline GL-3 ≥ 0.3 (N = 17; 9 males, 8 females)7/9 (78%) -0.91 (-1.94, 0.19)2/8 (25%) -0.02 (-1.00, 1.69)
Patients with baseline GL-3 < 0.3 (N = 28; 7 males, 21 females)6/16 (38%) -0.02 (-0.10, 0.26)7/12 (58%) -0.05 (-0.16, 0.14)
" ], "how_supplied": [ "16 HOW SUPPLIED/STORAGE AND HANDLING GALAFOLD capsules are supplied as 123 mg migalastat, size “2” capsules with an opaque blue cap and opaque white body filled with white to pale brown powder and imprinted with “A1001” in black ink. GALAFOLD capsules are packaged as two 7‑count capsules blister strips with aluminum foil lidding encased in cardboard blister cards providing 14 capsules per wallet pack that supplies the drug product for 4 weeks (28 days). Wallet pack containing 14 GALAFOLD capsules NDC 71904‑100‑01. Store at USP Controlled Room Temperature of 20° to 25°C (68° to 77°F). Excursions are permitted between 15° to 30°C (59° to 86°F). Store in the original packaging to protect from moisture." ], "information_for_patients": [ "17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA‑approved patient labeling ( Patient Information and Instructions for Use ). Administration Advise the patient: To take GALAFOLD once every other day at the same time of day and do not take on consecutive days [see Dosage and Administration (2.2) ] . Swallow capsule whole. Do not cut, crush, or chew the capsule [see Dosage and Administration (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 [see Dosage and Administration (2.2) ] . Water (plain, flavored, or sweetened), fruit juices without pulp, and caffeine‑free carbonated beverages can be consumed during the fasting period [see Dosage and Administration (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 [see Dosage and Administration (2.3) ] . To inform the healthcare provider of all medicines the patient takes, including prescription and over‑the‑counter medicines, vitamins, and herbal supplements [see Drug Interactions (7.1) ] . Pregnancy and Lactation Study Inform the patient and/or caregiver that there is a study that collects data on pregnant women with Fabry disease, and data on the effects of GALAFOLD on lactation in women with Fabry disease and their neonates and infants up to 1 year of age who are exposed through breast milk. Encourage the patient and/or caregiver to participate and state that participation is voluntary [see Use in Specific Populations (8.1) ] . Manufactured for: Amicus Therapeutics US, LLC 3675 Market Street Philadelphia, PA 19104 GALAFOLD is a registered trademark of Amicus Therapeutics, Inc." ], "spl_patient_package_insert": [ "This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: June 2023 PATIENT INFORMATION GALAFOLD ® (GAL-a-fold) (migalastat) capsules What is GALAFOLD? GALAFOLD is a prescription medicine used to treat adults with Fabry disease who have a certain genetic change (variant) in the galactosidase alpha gene ( GLA ) that is responsive (amenable) to GALAFOLD. It is not known if GALAFOLD is safe and effective in children. Before taking GALAFOLD, tell your healthcare provider about all of your medical conditions, including if you: have kidney problems. are pregnant or plan to become pregnant. It is not known if GALAFOLD will harm your unborn baby. are breastfeeding or plan to breastfeed. GALAFOLD may pass into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you take GALAFOLD. Pregnancy and Breastfeeding Exposure Study. There is a study that collects information on pregnant women with Fabry disease and women with Fabry disease who take GALAFOLD and breastfeed a baby up to 1 year of age. The purpose of this study is to collect information about the health of you and your baby. Talk to your healthcare provider about how you can take part in this study. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Especially tell your healthcare provider if you take medicines or supplements containing caffeine as these medicines or supplements may affect how GALAFOLD works. Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist each time you get a new medicine. How should I take GALAFOLD? Read the Instructions for Use at the end of this Patient Information leaflet for detailed instructions about the right way to take GALAFOLD. Take 1 GALAFOLD capsule every other day at the same time of day. Do not take GALAFOLD two days in a row. Swallow the GALAFOLD capsule whole. Do not cut, crush, or chew the GALAFOLD capsule. Take GALAFOLD on an empty stomach. Do not eat food, or take or drink any product that contains caffeine at least 2 hours before and 2 hours after taking GALAFOLD to give a minimum 4 hour fast. You may drink water (plain, flavored, or sweetened), fruit juices without pulp, and caffeine-free carbonated beverages during this time when you cannot eat. If you miss a dose of GALAFOLD, take the missed dose of GALAFOLD within 12 hours of your normal schedule. If more than 12 hours have passed, do not make up the missed dose. Take your next dose of GALAFOLD at your next scheduled day and time following your original every-other-day dosing schedule. For example, if you miss a dose that you would normally take at 8:00 AM, then you should take that dose before 8:00 PM on the same day. If you do not take the missed dose before 8:00 PM on the same day, you should take your next dose at 8:00 AM on your next scheduled dosing day. What are the possible side effects of GALAFOLD? The most common side effects of GALAFOLD include: • headache • stuffy or runny nose and sore throat • urinary tract infection • nausea • fever These are not all the possible side effects of GALAFOLD. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Amicus Therapeutics at 1-877-426-4287. How should I store GALAFOLD? • Store GALAFOLD at room temperature between 68°F to 77°F (20°C to 25°C). • Keep GALAFOLD capsules in the blister card they come in to protect from moisture. Keep GALAFOLD and all medicines out of the reach of children. General information about the safe and effective use of GALAFOLD. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use GALAFOLD for a condition for which it was not prescribed. Do not give GALAFOLD to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about GALAFOLD that is written for health professionals. What are the ingredients in GALAFOLD? Active ingredient: migalastat hydrochloride Inactive ingredients: magnesium stearate and pregelatinized starch. Capsule shells contain gelatin, indigotine - FD&C Blue 2, and titanium dioxide. The black ink contains black iron oxide, potassium hydroxide, and shellac. Manufactured for: Amicus Therapeutics US, LLC, 3675 Market Street, Philadelphia, PA 19104 GALAFOLD is a registered trademark of Amicus Therapeutics, Inc. For more information, go to www.GALAFOLD.com or call 1-877-426-4287." ], "spl_patient_package_insert_table": [ "
This Patient Information has been approved by the U.S. Food and Drug Administration.Revised: June 2023
PATIENT INFORMATIONGALAFOLD® (GAL-a-fold) (migalastat) capsules
What is GALAFOLD?GALAFOLD is a prescription medicine used to treat adults with Fabry disease who have a certain genetic change (variant) in the galactosidase alpha gene (GLA) that is responsive (amenable) to GALAFOLD. It is not known if GALAFOLD is safe and effective in children.
Before taking GALAFOLD, tell your healthcare provider about all of your medical conditions, including if you:have kidney problems.are pregnant or plan to become pregnant. It is not known if GALAFOLD will harm your unborn baby.are breastfeeding or plan to breastfeed. GALAFOLD may pass into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you take GALAFOLD.Pregnancy and Breastfeeding Exposure Study. There is a study that collects information on pregnant women with Fabry disease and women with Fabry disease who take GALAFOLD and breastfeed a baby up to 1 year of age. The purpose of this study is to collect information about the health of you and your baby. Talk to your healthcare provider about how you can take part in this study. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Especially tell your healthcare provider if you take medicines or supplements containing caffeine as these medicines or supplements may affect how GALAFOLD works. Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist each time you get a new medicine.
How should I take GALAFOLD?Read the Instructions for Use at the end of this Patient Information leaflet for detailed instructions about the right way to take GALAFOLD.Take 1 GALAFOLD capsule every other day at the same time of day. Do not take GALAFOLD two days in a row.Swallow the GALAFOLD capsule whole. Do not cut, crush, or chew the GALAFOLD capsule.Take GALAFOLD on an empty stomach.Do not eat food, or take or drink any product that contains caffeine at least 2 hours before and 2 hours after taking GALAFOLD to give a minimum 4 hour fast.You may drink water (plain, flavored, or sweetened), fruit juices without pulp, and caffeine-free carbonated beverages during this time when you cannot eat.If you miss a dose of GALAFOLD, take the missed dose of GALAFOLD within 12 hours of your normal schedule. If more than 12 hours have passed, do not make up the missed dose. Take your next dose of GALAFOLD at your next scheduled day and time following your original every-other-day dosing schedule. For example, if you miss a dose that you would normally take at 8:00 AM, then you should take that dose before 8:00 PM on the same day. If you do not take the missed dose before 8:00 PM on the same day, you should take your next dose at 8:00 AM on your next scheduled dosing day.
What are the possible side effects of GALAFOLD?The most common side effects of GALAFOLD include: • headache • stuffy or runny nose and sore throat • urinary tract infection • nausea • fever These are not all the possible side effects of GALAFOLD. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Amicus Therapeutics at 1-877-426-4287.
How should I store GALAFOLD? • Store GALAFOLD at room temperature between 68°F to 77°F (20°C to 25°C). • Keep GALAFOLD capsules in the blister card they come in to protect from moisture. Keep GALAFOLD and all medicines out of the reach of children.
General information about the safe and effective use of GALAFOLD.Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use GALAFOLD for a condition for which it was not prescribed. Do not give GALAFOLD to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about GALAFOLD that is written for health professionals.
What are the ingredients in GALAFOLD?Active ingredient: migalastat hydrochlorideInactive ingredients: magnesium stearate and pregelatinized starch. Capsule shells contain gelatin, indigotine - FD&C Blue 2, and titanium dioxide. The black ink contains black iron oxide, potassium hydroxide, and shellac. Manufactured for: Amicus Therapeutics US, LLC, 3675 Market Street, Philadelphia, PA 19104GALAFOLD is a registered trademark of Amicus Therapeutics, Inc.For more information, go to www.GALAFOLD.com or call 1-877-426-4287.
" ], "instructions_for_use": [ "INSTRUCTIONS FOR USE GALAFOLD ® (GAL-a-fold) (migalastat) capsules This Instructions for Use contains information on how to take GALAFOLD. Read this Instructions for Use before you start taking GALAFOLD and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. Important Information You Need to Know Before Taking GALAFOLD. Take 1 GALAFOLD capsule every other day at the same time of day. Do not take GALAFOLD two days in a row. Swallow the GALAFOLD capsule whole. Do not cut, crush, or chew the GALAFOLD capsule. Take GALAFOLD on an empty stomach. Do not eat food, or take or drink any product that contains caffeine at least 2 hours before and 2 hours after taking GALAFOLD to give a minimum 4 hour fast. You may drink water (plain, flavored, or sweetened), fruit juices without pulp, and caffeine-free carbonated beverages during this time when you cannot eat. How to remove a capsule: Figure A Step 1. Remove the adhesive seal holding the cover. Lift the cover of your GALAFOLD carton (See Figure A). Figure B. Opened carton Step 2. Press and hold down the purple tab with your thumb on the left side of the carton (See Figure B), and continue to Step 3. Figure C Step 3. Grasp the tab on the right side of the blister card where it says, “PULL OUT HERE” and pull out the folded blister card (See Figure C). Figure D. Front of the blister card Step 4. Unfold the blister card (See Figure D). Taking GALAFOLD capsules: Each GALAFOLD blister card contains 14 GALAFOLD capsules (enough for 28 days of treatment with GALAFOLD) and 14 white cardboard circles. The white cardboard circles are to remind you to take GALAFOLD every other day. The arrow directs you to begin the next 2 weeks of treatment after Day 14 (See Figure E). Figure E. Front of the blister card Figure F. Front of the blister card Step 5. On your first day of taking GALAFOLD from a new blister card, record the date on the blister card next to “Starting date:” (See Figure F). Figure G. Back of the blister card Step 6. Locate the GALAFOLD capsule to remove for the dosing day. Turn the blister card over to show the back of the card. Bend the card as shown (See Figure G). Note: Bending the blister card helps raise the oval perforated cardboard. Figure H. Back of the blister card Step 7. Remove the oval perforated cardboard (See Figure H). Note: After removing the oval cardboard, the white backing of the foil may be present, which is ok. Figure I. Front of the blister card Step 8. Turn the blister card over to show the front of the card. Push the GALAFOLD capsule out (See Figure I). Figure J. Front of the blister card Step 9. On the next day, move to the perforated white cardboard circle on the top row . Press down on the white cardboard circle to remove it (See Figure J). Note: Removing this white cardboard circle will help you remember which day you do not take GALAFOLD. Take 1 GALAFOLD capsule every other day. Fold the blister card, and slide it back into the carton after each use. Change (alternate) each day between taking the GALAFOLD capsule and removing the perforated white cardboard circle until you reach Day 28. Start a new blister card when you are finished with Day 28. How should I store GALAFOLD? • Store GALAFOLD at room temperature between 68°F to 77°F (20°C to 25°C). • Keep GALAFOLD capsules in the blister card they come in to protect from moisture. Keep GALAFOLD and all medicines out of the reach of children. Manufactured for: Amicus Therapeutics US, LLC 3675 Market Street Philadelphia, PA 19104 GALAFOLD is a registered trademark of Amicus Therapeutics, Inc. This Instructions for Use has been approved by the U.S. Food and Drug Administration. Revised: June 2023 Figure A Figure B Figure C Figure D Figure E Figure F Figure G Figure H Figure I Figure J" ], "instructions_for_use_table": [ "
Figure AStep 1. Remove the adhesive seal holding the cover. Lift the cover of your GALAFOLD carton (See Figure A).
Figure B. Opened cartonStep 2. Press and hold down the purple tab with your thumb on the left side of the carton (See Figure B), and continue to Step 3.
Figure CStep 3. Grasp the tab on the right side of the blister card where it says, “PULL OUT HERE” and pull out the folded blister card (See Figure C).
Figure D. Front of the blister card Step 4. Unfold the blister card (See Figure D).
Taking GALAFOLD capsules:Each GALAFOLD blister card contains 14 GALAFOLD capsules (enough for 28 days of treatment with GALAFOLD) and 14 white cardboard circles. The white cardboard circles are to remind you to take GALAFOLD every other day. The arrow directs you to begin the next 2 weeks of treatment after Day 14 (See Figure E). Figure E. Front of the blister card
Figure F. Front of the blister cardStep 5. On your first day of taking GALAFOLD from a new blister card, record the date on the blister card next to “Starting date:” (See Figure F).
Figure G. Back of the blister card Step 6. Locate the GALAFOLD capsule to remove for the dosing day. Turn the blister card over to show the back of the card. Bend the card as shown (See Figure G). Note: Bending the blister card helps raise the oval perforated cardboard.
Figure H. Back of the blister cardStep 7. Remove the oval perforated cardboard (See Figure H). Note: After removing the oval cardboard, the white backing of the foil may be present, which is ok.
Figure I. Front of the blister cardStep 8. Turn the blister card over to show the front of the card. Push the GALAFOLD capsule out (See Figure I).
Figure J. Front of the blister cardStep 9. On the next day, move to the perforated white cardboard circle on the top row. Press down on the white cardboard circle to remove it (See Figure J). Note: Removing this white cardboard circle will help you remember which day you do not take GALAFOLD. Take 1 GALAFOLD capsule every other day. Fold the blister card, and slide it back into the carton after each use.
Change (alternate) each day between taking the GALAFOLD capsule and removing the perforated white cardboard circle until you reach Day 28. Start a new blister card when you are finished with Day 28.
" ], "package_label_principal_display_panel": [ "PRINCIPAL DISPLAY PANEL - NDC: 71904-100-01 - Carton Label (Inner Sleeve) Carton Label (Inner Sleeve)", "PRINCIPAL DISPLAY PANEL - NDC: 71904-100-01 - Carton Label (Outer Sleeve) Carton Label (Outer Sleeve)" ], "set_id": "66dbd928-0f1c-48b1-a832-54e4abd9f1db", "id": "2da6bbb5-63ae-4405-a1ad-25429b9f7139", "effective_time": "20250828", "version": "18", "openfda": { "application_number": [ "NDA208623" ], "brand_name": [ "Galafold" ], "generic_name": [ "MIGALASTAT HYDROCHLORIDE" ], "manufacturer_name": [ "Amicus Therapeutics US, LLC" ], "product_ndc": [ "71904-100" ], "product_type": [ "HUMAN PRESCRIPTION DRUG" ], "route": [ "ORAL" ], "substance_name": [ "MIGALASTAT HYDROCHLORIDE" ], "rxcui": [ "2054257", "2054263", "2054266", "2054275" ], "spl_id": [ "2da6bbb5-63ae-4405-a1ad-25429b9f7139" ], "spl_set_id": [ "66dbd928-0f1c-48b1-a832-54e4abd9f1db" ], "package_ndc": [ "71904-100-01" ], "is_original_packager": [ true ], "upc": [ "0371904100012" ], "unii": [ "CLY7M0XD20" ] } }, { "spl_product_data_elements": [ "ELFABRIO pegunigalsidase alfa PEGUNIGALSIDASE ALFA PEGUNIGALSIDASE ALFA ANHYDROUS CITRIC ACID SODIUM CHLORIDE TRISODIUM CITRATE DIHYDRATE WATER ELFABRIO pegunigalsidase alfa PEGUNIGALSIDASE ALFA PEGUNIGALSIDASE ALFA ANHYDROUS CITRIC ACID SODIUM CHLORIDE TRISODIUM CITRATE DIHYDRATE WATER" ], "boxed_warning": [ "WARNING: HYPERSENSITIVITY REACTIONS INCLUDING ANAPHYLAXIS Patients treated with ELFABRIO have experienced hypersensitivity reactions, including anaphylaxis. Appropriate medical support measures, including cardiopulmonary resuscitation equipment, should be readily available during ELFABRIO administration. If a severe hypersensitivity reaction (e.g., anaphylaxis) occurs, discontinue ELFABRIO immediately and initiate appropriate medical treatment. In patients with severe hypersensitivity reaction, a desensitization procedure to ELFABRIO may be considered [see Warnings and Precautions ( 5.1 )] . WARNING: HYPERSENSITIVITY REACTIONS INCLUDING ANAPHYLAXIS See full prescribing information for complete boxed warning. Appropriate medical support measures, including cardiopulmonary resuscitation equipment, should be readily available. If a severe hypersensitivity reaction occurs, discontinue ELFABRIO immediately and initiate appropriate medical treatment. ( 5.1 )" ], "indications_and_usage": [ "1 INDICATIONS AND USAGE ELFABRIO is indicated for the treatment of adults with confirmed Fabry disease. ELFABRIO is a hydrolytic lysosomal neutral glycosphingolipid-specific enzyme indicated for the treatment of adults with confirmed Fabry disease. ( 1 )" ], "dosage_and_administration": [ "2 DOSAGE AND ADMINISTRATION For pretreatment recommendations, see Full Prescribing Information. ( 2.1 ) Recommended dosage is 1 mg/kg every 2 weeks administered as an intravenous infusion. ( 2.2 ) For dosage and administration modifications due to hypersensitivity reactions or infusion-associated reactions (IARs), see Full Prescribing Information. ( 2.3 ) For instructions on preparation (including dilution), storage, and administration (including rates for the initial 4-6 infusions for ERT-experienced and ERT-naïve patients), see Full Prescribing Information. ( 2.4 , 2.5 , 2.6 ) 2. 1 Recommendations Prior to ELFABRIO Treatment Pretreatment In enzyme replacement therapy (ERT)-experienced patients, if pretreatment with antihistamines, antipyretics, and/or corticosteroids was used prior to ERT administration, consider similar pretreatment with these medications before the first several ELFABRIO infusions. After 4 to 6 ELFABRIO infusions, a stepwise decrease in the pretreatment medication dose(s) and/or discontinuation of the pretreatment medication(s) may be considered if treatment with ELFABRIO was tolerated. In ERT-naïve patients, prior to ELFABRIO administration, pre-treating with antihistamines, antipyretics, and/or corticosteroids may be considered [see Warnings and Precautions ( 5.1 , 5.2 )] . Medical Support Appropriate medical support measures including cardiopulmonary resuscitation equipment should be readily available during ELFABRIO administration. 2. 2 Recommended Dosage and Administration The recommended dosage of ELFABRIO, based on actual body weight, is 1 mg/kg administered by intravenous infusion every 2 weeks. The initial recommended ELFABRIO infusion rates for ERT-experienced or ERT-naïve patients are based on actual body weight [ see Tables 1 and 2 ] . If one or more doses are missed, restart ELFABRIO treatment as soon as possible, maintaining the 2 week interval between infusions thereafter. Do not double a dose to compensate for a missed dose. 2. 3 Administration Modifications Due to Hypersensitivity Reactions and/or Infusion-Associated Reactions In the event of a severe hypersensitivity reaction (e.g., anaphylaxis) or severe infusion-associated reaction (IAR), immediately discontinue ELFABRIO administration and initiate appropriate medical treatment. For additional recommendations in the event of a severe hypersensitivity reaction or IAR, see Warnings and Precautions ( 5.1 , 5.2 ) . In the event of a mild to moderate hypersensitivity reaction or a mild to moderate IAR, consider temporarily holding the infusion for 15 to 30 minutes or slowing the infusion rate by 25% to 50% [ see Dosage and Administration ( 2.6 )] , and initiating appropriate medical treatment [see Warnings and Precautions ( 5.1 , 5.2 )] . If symptoms persist despite holding or slowing the infusion, stop the infusion and monitor the patient. Consider re-initiating the infusion within 7 to 14 days at 25% to 50% of the rate at which the reaction occurred with appropriate pretreatment. If symptoms subside after holding the infusion, resume infusion at a 25% to 50% reduced rate as tolerated. Alternatively, if symptoms subside after slowing the infusion, complete infusion at the reduced rate as tolerated. Starting with the next infusion, increase the infusion rate by increments of 25% every third infusion as tolerated until the infusion rate at which the reaction occurred is reached. Closely monitor the patient. 2. 4 Preparation Instructions Use aseptic technique during preparation. Dilute ELFABRIO in the following manner: Determine the number of ELFABRIO vials to be diluted based on actual body weight in kg and the recommended dose [see Dosage and Administration ( 2.2 ) and Dosage Forms and Strengths ( 3 ) ] . Round the number of vials up to the next whole number. Remove the appropriate number of ELFABRIO vials from the refrigerator and allow the vials to sit for 15-30 minutes at room temperature 20°C to 25°C (68°F to 77°F) before use. Do not use an external heat source to heat the product because heat may damage the product. Visually inspect the solution in the vials for particulate matter and discoloration. The solution should be clear and colorless. Discard if the solution is discolored or if visible particulate matter is present. Dilute the supplied ELFABRIO solution required for a dose in 0.9% Sodium Chloride Injection to a total volume based on actual body weight specified in Tables 1 and 2 below. Prior to adding the volume of ELFABRIO required for the dose, remove the equal volume of 0.9% Sodium Chloride Injection from the infusion bag. Withdraw the volume of ELFABRIO required for the dose from the vials (discard any unused solution remaining in the vial). Inject the ELFABRIO solution directly into the 0.9% Sodium Chloride Injection solution through the port of the infusion bag. Do not inject in the airspace within the infusion bag. Gently invert infusion bag to mix the solution. Avoid vigorous shaking or agitation. 2.5 Storage of the Diluted Solution If the diluted ELFABRIO solution is not used immediately: ○ Refrigerate the diluted solution at 2°C to 8°C (36°F to 46°F) for up to 24 hours. The solution must be infused within 8 hours after removal from the refrigerator, inclusive of the total infusion time, or discarded. ○ Store the diluted solution at room temperature at 20°C to 25°C (68°F to 77°F) for up to 8 hours. The solution must be used within 8 hours, inclusive of infusion time, or discarded. Do not freeze or shake. 2. 6 Administration Instructions Administer ELFABRIO as follows: Use an in-line low protein-binding, 0.2 micron, in-line filter during administration. For the initial 4-6 infusions, infuse ELFABRIO using the infusion rates described in Table 1 for ERT-experienced patients and Table 2 for ERT-naïve patients. If a patient tolerates the initial 4-6 ELFABRIO infusions, the duration of every third infusion may be decreased in decrements of 30 minutes as tolerated. The minimum recommended infusion duration is 1.5 hours. At the end of the infusion, flush the line with 0.9% Sodium Chloride Injection using the same infusion rate as the one used for the last part of the ELFABRIO infusion. Do not infuse ELFABRIO in the same intravenous line with other products. Table 1 presents the recommended infusion rates for the initial 4-6 ELFABRIO infusions based on actual body weight for ERT-experienced patients. Table 1: Recommended Infusion Rate 1 for ERT-Experienced Patients for the Initial 4-6 ELFABRIO Intravenous Infusions Based on Actual Body Weight Actual Body Weight Total Infusion V olume Infusion R ate 1 ˂ 70 kg 150 mL 0.83 mL/min (50 mL/h) 70 -100 kg 250 mL 1.39 mL/min (83 mL/h) > 100 kg 500 mL 2.78 mL/min (167 mL/h) 1 Infusion rate may be increased if the patient tolerates the initial 4-6 infusions (see above). Infusion rate may be slowed in case of a hypersensitivity reaction or an IAR [see Dosage and Administration ( 2.3 )]. Table 2 presents the recommended infusion rates for the initial 4-6 ELFABRIO infusions based on actual body weight for ERT-naïve patients. Table 2: Recommended Infusion Rate 1 for ERT-Naïve Patients for the Initial 4-6 ELFABRIO Intravenous Infusions Based on Actual Body Weight Actual Body Weight Total Infusion Volume Infusion Rate 1 ˂ 70 kg 150 mL 0.63 mL/min (37.5 mL/h) 70 -100 kg 250 mL 1 mL/min (60 mL/h) > 100 kg 500 mL 1.38 mL/min (83 mL/h) 1 Infusion rate may be increased if the patient tolerates the initial 4-6 infusions (see above). Infusion rate may be slowed in case of a hypersensitivity reaction or an IAR [see Dosage and Administration ( 2.3 )]. Administration of ELFABRIO to Patients Previously Treated with ERT w ith an Infusion Duration Over 3 Hours In patients previously treated with an ERT with an infusion duration over 3 hours: Use the same infusion rate for the ELFABRIO infusion. May decrease the duration of every third infusion after the initial 4-6 ELFABRIO infusions in decrements of 30 minutes as tolerated. The recommended minimum infusion duration of the maintenance infusion is 1.5 hours. Home Infusion Home administration under the supervision of a healthcare provider may be considered for patients who have reached an infusion duration that is tolerated well [see Dosage and Administration ( 2.1 , 2.3 )] . The decision to have a patient move to home infusion should be made after evaluation and recommendation by a healthcare provider. The infusion duration should remain constant for home administration and the duration should only be decreased in a healthcare facility. In case of a missed dose or delayed infusion, a healthcare provider should be contacted." ], "dosage_and_administration_table": [ "
Table 1: Recommended Infusion Rate1 for ERT-Experienced Patients for the Initial 4-6 ELFABRIO Intravenous Infusions Based on Actual Body Weight
Actual Body WeightTotal Infusion Volume Infusion Rate1
˂ 70 kg150 mL0.83 mL/min (50 mL/h)
70 -100 kg250 mL1.39 mL/min (83 mL/h)
> 100 kg500 mL2.78 mL/min (167 mL/h)
", "
Table 2: Recommended Infusion Rate1 for ERT-Naïve Patients for the Initial 4-6 ELFABRIO Intravenous Infusions Based on Actual Body Weight
Actual Body WeightTotal Infusion Volume Infusion Rate1
˂ 70 kg150 mL0.63 mL/min (37.5 mL/h)
70 -100 kg250 mL1 mL/min (60 mL/h)
> 100 kg500 mL1.38 mL/min (83 mL/h)
" ], "dosage_forms_and_strengths": [ "3 DOSAGE FORMS AND STRENGTHS Injection: 20 mg/10 mL or 5 mg/2.5 mL (2 mg/mL) of pegunigalsidase alfa-iwxj in a clear and colorless solution in a single-dose vial. Injection: 20 mg/10 mL or 5 mg/2.5 mL (2 mg/mL) solution in a single-dose vial. ( 3 )" ], "contraindications": [ "4 CONTRAINDICATIONS None. None. ( 4 )" ], "warnings_and_cautions": [ "5 WARNINGS AND PRECAUTIONS Infusion-Associated Reactions: If severe IARs occur, discontinue ELFABRIO and initiate appropriate medical treatment. ( 5.2 ) Membranoproliferative Glomerulonephritis: Monitor serum creatinine and urinary protein to creatinine ratio. Discontinue ELFABRIO if glomerulonephritis is suspected, until a diagnostic evaluation can be conducted. ( 5.3 ) 5.1 Hypersensitivity Reactions Including Anaphylaxis Hypersensitivity reactions including anaphylaxis have been reported in ELFABRIO-treated patients. In clinical trials, 20 (14%) of ELFABRIO-treated patients experienced hypersensitivity reactions. In these trials, 4 ELFABRIO-treated patients (3%; 1 naïve to enzyme replacement therapy (ERT) and 3 ERT-experienced patients) experienced anaphylaxis during the initial infusion and were positive for anti-pegunigalsidase alfa-iwxj IgE antibodies (referred to as IgE ADA) [see Adverse Reactions ( 6.1 6. 1 ) and Clinical Pharmacology ( 12.6 ) ] . The risk of pegunigalsidase alfa-iwxj-related hypersensitivity may be increased in certain patients with pre-existing ADA from prior ERT [ see Use In Specific Populations ( 8.6 )]. Anaphylaxis (reported as Type I hypersensitivity reaction, hypersensitivity reaction, or bronchospasm) occurred within 5 to 40 minutes of the start of the initial infusion. Signs and symptoms included headache, nausea, vomiting, throat tightness, facial and oral edema, truncal rash, tachycardia, hypotension, rigors, urticaria, intense pruritus, moderate upper airway obstructions, macroglossia, and mild lip edema. Patients received treatment that included epinephrine, antihistamines and/or systemic corticosteroids. Prior to ELFABRIO administration, consider pretreating with antihistamines, antipyretics, and/or corticosteroids. Appropriate medical support measures, including cardiopulmonary resuscitation equipment, should be readily available during ELFABRIO administration. If a severe hypersensitivity reaction (e.g., anaphylaxis) occurs, discontinue ELFABRIO immediately and initiate appropriate medical treatment. Consider the risks and benefits of re-administering ELFABRIO following severe hypersensitivity reactions (including anaphylaxis). Patients may be rechallenged using slower infusion rates. In patients with severe hypersensitivity reaction, desensitization measures to ELFABRIO may be considered. If the decision is made to readminister ELFABRIO, ensure the patient tolerates the infusion. If the patient tolerates the infusion, the rate may be increased to reach the recommended rate. If a mild or moderate hypersensitivity reaction occurs, consider temporarily holding the infusion or slowing the infusion rate [ see Dosage and Administratio n ( 2.3 ) ] . Consider monitoring patients who demonstrate hypersensitivity reactions during ELFABRIO treatment for the presence of IgG and IgE ADA [see Clinical Pharmacology ( 12.6 )] . 5.2 Infusion - Associated Reactions Infusion-associated reactions (IARs) have been reported in ELFABRIO-treated patients. In clinical trials, 41 (29%) of ELFABRIO-treated patients experienced one or more IARs, defined as any adverse reaction with onset after start of the infusion and up to 24 hours after the end of infusion. The risk of pegunigalsidase alfa-iwxj-related IARs may be increased in certain patients with pre-existing ADA from prior ERT [ see Use In Specific Populations ( 8.6 )]. IARs included anaphylaxis reactions during the initial ELFABRIO administration [see Warnings and Precautions ( 5.1 )] . In addition to the hypersensitivity reactions described above [see Warnings and Precautions ( 5.1 )] , other IARs included nausea, chills, pruritus, rash, chest pain, dizziness, vomiting, asthenia, pain, sneezing, dyspnea, nasal congestion, throat irritation, abdominal pain, erythema, diarrhea, burning sensation, neuralgia, headache, paresthesia, tremor, agitation, increased body temperature, flushing, bradycardia, myalgia, hypertension, and hypotension [see Adverse Reactions ( 6.1 )] . Up to 40% of patients were pretreated with diphenhydramine, prednisone and/or acetaminophen at least once during the clinical trials. Severe reactions in the trials were generally managed with administration of antipyretics, antihistamines, corticosteroids, intravenous fluids, and/or oxygen. IARs were more frequently observed in ELFABRIO-treated patients who developed IgG anti-drug antibodies (ADA) including patients who had pre-existing IgG ADA [see Adverse Reactions ( 6.1 6.1 ) and Clinical Pharmacology ( 12.6 ) ] . Consider monitoring patients who demonstrate IARs during ELFABRIO treatment for the presence of IgG and IgE ADA. Patients with advanced Fabry disease may have compromised cardiac function which may predispose them to a higher risk of severe complications from IARs. Closely monitor patients with compromised cardiac function if ELFABRIO is administered to these patients. Prior to ELFABRIO administration, consider pre-treating with antihistamines, antipyretics, and/or corticosteroids to reduce the risk of IARs. However, IARs may still occur in patients after receiving pre-treatment. If a severe IAR occurs, discontinue ELFABRIO immediately and initiate appropriate medical treatment. Consider the risks and benefits of re-administering ELFABRIO following a severe IAR. Patients may be rechallenged using slower infusion rates. Once a patient tolerates the infusion, the infusion rate may be increased to reach the recommended infusion rate. If a mild or moderate IAR occurs, consider temporarily holding the infusion or slowing the infusion rate [see Dosage and Administration ( 2.3 )] . 5.3 Membranoproliferative Glomerulonephritis A case of membranoproliferative glomerulonephritis with immune depositions in the kidney was reported during clinical trials [see Adverse Reactions ( 6.1 ) ] . This event led to a decline in renal function that slowly improved upon discontinuation of ELFABRIO but did not return to baseline by the end of the trial. Monitor serum creatinine and urinary protein to creatinine ratio. If glomerulonephritis is suspected, discontinue ELFABRIO until a diagnostic evaluation can be conducted." ], "adverse_reactions": [ "6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in labeling: Hypersensitivity Reactions Including Anaphylaxis [see Warnings and Precautions ( 5.1 ) ] Infusion-Associated Reactions (IARs) [see Warnings and Precautions ( 5.2 )] Membranoproliferative Glomerulonephritis [see Warnings and Precautions ( 5.3 )] Most common adverse reactions (≥15%) are: infusion-associated reactions, nasopharyngitis, headache, diarrhea, fatigue, nausea, back pain, pain in extremity, and sinusitis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Chiesi USA, Inc. at 1-888-661-9260 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 trial of another drug and may not reflect the rates observed in clinical practice. Adverse Reactions From Trial 2 The safety of ELFABRIO in adults with confirmed Fabry disease who had been previously treated with agalsidase beta was evaluated in Trial 2 which included a total of 52 ELFABRIO-treated patients (29 male, 23 female aged 20 to 60 years old) with Fabry disease [see Clinical Studies ( 14 )] . Patients received 1 mg/kg of ELFABRIO given intravenously every 2 weeks for at least 104 weeks. The most common adverse reactions (≥15%) reported with ELFABRIO were infusion-associated reactions which occurred in 17 patients (32%); followed by, nasopharyngitis and headache each in 11 patients (21%); diarrhea in 10 patients (19%); fatigue and nausea each in 9 patients (17%); and back pain, pain in extremity, and sinusitis each in 8 patients (15%) . One ELFABRIO-treated patient experienced a severe hypersensitivity reaction during the first infusion. The patient withdrew from the trial following a moderate hypersensitivity reaction during the second infusion. Table 3 lists adverse reactions reported in at least 5% of ELFABRIO-treated patients in Trial 2. Table 3: Adverse Reactions in Adults With Fabry Disease (Trial 2) 1 Adverse Reaction ELFABRIO N=52 n (%) Agalsidase beta N=25 n (%) Infusion-Associated Reaction 2,4 17 (32) 8 (32) Nasopharyngitis 11 (21) 4 (16) Headache 11 (21) 5 (20) Diarrhea 10 (19) 6 (24) Fatigue 9 (17) 4 (16) Nausea 9 (17) 3 (12) Back pain 8 (15) 5 (20) Pain in Extremity 8 (15) 4 (16) Sinusitis 8 (15) 3 (12) Abdominal Pain 6 (12) 0 (0) Proteinuria 6 (12) 0 (0) Hypersensitivity 3,4 5 (9) 4 (16) Upper Respiratory Tract Congestion 4 (8) 0 (0) Neuralgia 4 (8) 0 (0) Peripheral Neuropathy 3 (6) 0 (0) Sciatica 3 (6) 0 (0) Infusion Site Extravasation 3 (6) 0 (0) Hematuria 3 (6) 0 (0) 1 Adverse reactions were those that occurred in ≥ 5% of ELFABRIO-treated patients. 2 “Infusion-associated reaction” includes nausea, vomiting, abdominal pain, diarrhea, fatigue, chills, malaise, non-cardiac chest pain, hypersensitivity, body temperature increased, burning sensation, neuralgia, agitation, throat irritation, pruritic rash, and flushing. Events occurring within 24 hours. 3 “Hypersensitivity” includes macular rash, pruritic rash, and face swelling. Events occurring within 24 hours. 4 The events of hypersensitivity and pruritic rash fall in both hypersensitivity and IAR categories. Membranoproliferative Glomerulonephritis A case of membranoproliferative glomerulonephritis with immune depositions in the kidney was reported in an ELFABRIO-treated patient. Immunogenicity: Anti - D rug Antibody-Associated Adverse Reactions Of the patients who experienced serious hypersensitivity reactions during the first ELFABRIO infusion and had pre-infusion samples and samples available for testing at the time of the event, all but one had pre-existing IgE ADAs and all tested positive for IgE ADAs at the time of the reaction. In the overall clinical program, IARs occurred in 51% (19/37) of patients who were IgG ADA positive at baseline compared to 16% (13/84) in IgG ADA negative patients [see Clinical Pharmacology ( 12.6 )] ." ], "adverse_reactions_table": [ "
Table 3: Adverse Reactions in Adults With Fabry Disease (Trial 2)1
Adverse ReactionELFABRIO N=52 n (%)Agalsidase beta N=25 n (%)
Infusion-Associated Reaction2,417 (32)8 (32)
Nasopharyngitis11 (21)4 (16)
Headache11 (21)5 (20)
Diarrhea10 (19)6 (24)
Fatigue9 (17)4 (16)
Nausea9 (17)3 (12)
Back pain8 (15)5 (20)
Pain in Extremity8 (15)4 (16)
Sinusitis8 (15)3 (12)
Abdominal Pain6 (12)0 (0)
Proteinuria6 (12)0 (0)
Hypersensitivity3,45 (9)4 (16)
Upper Respiratory Tract Congestion4 (8)0 (0)
Neuralgia4 (8)0 (0)
Peripheral Neuropathy3 (6)0 (0)
Sciatica3 (6)0 (0)
Infusion Site Extravasation3 (6)0 (0)
Hematuria3 (6)0 (0)
" ], "use_in_specific_populations": [ "8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no available data on ELFABRIO use in pregnant females to evaluate a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes; however, as an enzyme replacement, ELFABRIO is not expected to cause adverse outcomes . Animal reproduction studies have been conducted with pegunigalsidase alfa-iwxj in pregnant rats and rabbits. No adverse effects on embryofetal development were observed in pregnant rats intravenously administered pegunigalsidase alfa-iwxj twice per week at exposures up to 3.6 times that of the maximum recommended human dose (MRHD) (based on area under the concentration-time curve (AUC)). Maternal toxicity was observed in pregnant rabbits intravenously administered pegunigalsidase alfa-iwxj twice per week at doses that were ≥ 3.2 times the MRHD (based on human equivalent dose) [ see Data ] . The estimated background risk of major birth defects and miscarriage in the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. There is a pregnancy safety study for ELFABRIO. If a patient becomes pregnant while receiving ELFABRIO, healthcare providers should report ELFABRIO exposure by calling 1-888-661-9260 or visiting https://chiesirarediseases.com/contact-us/medical-information-form. Data Animal Data In an embryofetal development study in the rat, pegunigalsidase alfa-iwxj was administered during the period of organogenesis on gestation day 6, 9, 12, and 15. No maternal or fetal adverse effects were noted at exposures that were up to 3.6-fold greater than the recommended dose of 1 mg/kg every two weeks. In an embryofetal development study in the rabbit, administration of pegunigalsidase alfa-iwxj during the period of organogenesis on gestation day 6, 9, 12, 15, and 18, resulted in maternal toxicity, including maternal mortality, decreased body weight, and decreased feed consumption. These effects were observed at exposures that were ≥ 3.2-fold greater than the recommended dose of 1 mg/kg every two weeks. Adverse embryofetal effects included abortion, increased late resorptions, number of does with resorptions, and increased post-implantation loss at exposures that were 6.5 fold greater than the recommended dose of 1 mg/kg every two weeks. Decreased fetal body weight was observed at exposures that were ≥ 3.2 times greater than the recommended dose of 1 mg/kg every two weeks. There was no increase in fetal external, skeletal, or visceral malformations. 8.2 Lactation Risk Summary There are no data on the presence of pegunigalsidase alfa-iwxj in either human or animal milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ELFABRIO and any potential adverse effects on the breastfed infant from pegunigalsidase alfa-iwxj or from the underlying maternal condition. 8. 4 Pediatric Use The safety and effectiveness of ELFABRIO have not been established in pediatric patients. 8. 5 Geriatric Use Clinical trials of ELFABRIO did not include patients 65 years of age and older to determine if they respond differently from younger adult patients. 8.6 Patients with Prior Enzyme Replacement Therapy Patients that received prior ERT are more likely to have pre-existing anti-drug antibodies (ADA) to pegunigalsidase alfa-iwxj which could be due to the ADA cross-reactivity to pegunigalsidase alfa-iwxj by prior ERT. When switching from other ERT to ELFABRIO: Pre-existing ADA may reduce the plasma pegunigalsidase alfa-iwxj concentrations, which may reduce ELFABRIO efficacy [see Clinical Pharmacology ( 12.2 , 12.6 ) ]. The risk of ELFABRIO-related hypersensitivity and infusion-associated reactions may be increased in certain patients with pre-existing ADA from prior ERT [ see Warnings and Precautions ( 5.1 , 5.2 ) and Adverse Reactions ( 6.1 )] . Consider monitoring clinical or pharmacodynamic responses (e.g., plasma lyso-Gb3 levels) when switching from agalsidase beta to ELFABRIO, in patients with pre-existing ADA." ], "pregnancy": [ "8.1 Pregnancy Risk Summary There are no available data on ELFABRIO use in pregnant females to evaluate a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes; however, as an enzyme replacement, ELFABRIO is not expected to cause adverse outcomes . Animal reproduction studies have been conducted with pegunigalsidase alfa-iwxj in pregnant rats and rabbits. No adverse effects on embryofetal development were observed in pregnant rats intravenously administered pegunigalsidase alfa-iwxj twice per week at exposures up to 3.6 times that of the maximum recommended human dose (MRHD) (based on area under the concentration-time curve (AUC)). Maternal toxicity was observed in pregnant rabbits intravenously administered pegunigalsidase alfa-iwxj twice per week at doses that were ≥ 3.2 times the MRHD (based on human equivalent dose) [ see Data ] . The estimated background risk of major birth defects and miscarriage in the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. There is a pregnancy safety study for ELFABRIO. If a patient becomes pregnant while receiving ELFABRIO, healthcare providers should report ELFABRIO exposure by calling 1-888-661-9260 or visiting https://chiesirarediseases.com/contact-us/medical-information-form. Data Animal Data In an embryofetal development study in the rat, pegunigalsidase alfa-iwxj was administered during the period of organogenesis on gestation day 6, 9, 12, and 15. No maternal or fetal adverse effects were noted at exposures that were up to 3.6-fold greater than the recommended dose of 1 mg/kg every two weeks. In an embryofetal development study in the rabbit, administration of pegunigalsidase alfa-iwxj during the period of organogenesis on gestation day 6, 9, 12, 15, and 18, resulted in maternal toxicity, including maternal mortality, decreased body weight, and decreased feed consumption. These effects were observed at exposures that were ≥ 3.2-fold greater than the recommended dose of 1 mg/kg every two weeks. Adverse embryofetal effects included abortion, increased late resorptions, number of does with resorptions, and increased post-implantation loss at exposures that were 6.5 fold greater than the recommended dose of 1 mg/kg every two weeks. Decreased fetal body weight was observed at exposures that were ≥ 3.2 times greater than the recommended dose of 1 mg/kg every two weeks. There was no increase in fetal external, skeletal, or visceral malformations." ], "pediatric_use": [ "8. 4 Pediatric Use The safety and effectiveness of ELFABRIO have not been established in pediatric patients." ], "geriatric_use": [ "8. 5 Geriatric Use Clinical trials of ELFABRIO did not include patients 65 years of age and older to determine if they respond differently from younger adult patients." ], "description": [ "11 DESCRIPTION Pegunigalsidase alfa-iwxj, a hydrolytic lysosomal neutral glycosphingolipid-specific enzyme, is a PEGylated and crosslinked, chemically modified, recombinant human alpha-galactosidase A enzyme that is produced by genetically modified Bright Yellow 2 ( Nicotiana tabacum ) plant cells. The amino acid sequence of one subunit of pegunigalsidase alfa-iwxj consists of 405 amino acids, of which 398 amino acids are identical to human alpha-GAL-A with an additional 6 amino acids (SEKDEL) included at the C-terminal to encode an endoplasmic retrieval signal, and an additional glycine at the N-terminus derived from the signal peptide. Pegunigalsidase alfa-iwxj is a homodimeric glycoprotein covalently crosslinked with an average of nine 2.3 kDa PEG per dimer. The total molecular weight of the cross-linked dimer is approximately 116 kDa. Pegunigalsidase alfa-iwxj has specific activity of approximately 35-62 U/mg (one enzyme unit is defined as the amount of enzyme which catalyzes the hydrolysis of one micromole of synthetic substrate, p-nitrophenyl-α-D-galactopyranoside per minute at 37°C). ELFABRIO (pegunigalsidase alfa-iwxj) injection is a sterile, preservative-free, 20 mg/10 mL or 5 mg/2.5 mL (2 mg/mL) solution in a single-dose vial for intravenous infusion after dilution. Each mL contains 2 mg of pegunigalsidase alfa-iwxj, anhydrous citric acid (0.2 mg), sodium chloride (7.06 mg), sodium citrate (6.73 mg), and Water for Injection, USP. The pH is approximately 5.9 to 6.4." ], "clinical_pharmacology": [ "12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Fabry disease is caused by deficiency of the lysosomal enzyme alpha-galactosidase A. ELFABRIO provides an exogenous source of alpha-galactosidase A. ELFABRIO is internalized and transported into lysosomes where it is thought to exert enzymatic activity and reduce accumulated globotriaosylceramide (Gb3). 12.2 Pharmacodynamics Plasma globotriaosylsphingosine (lyso-Gb3, a metabolite of Gb3) concentrations are elevated in patients with Fabry disease. In patients with Fabry disease who were [see Clinical Studies ( 14 )] : ERT-naïve or had not received ERT treatment for at least 26 weeks and had a negative test for anti-pegunigalsidase alfa-iwxj antibodies (Trial 1), ELFABRIO treatment resulted in significant reductions in median plasma lyso-Gb3 concentrations compared to baseline of approximately: ○ -43% (Week 4), -57% (Week 26), -68% (Week 52), and -84% (Week 104) in male patients, and ○ -3% (Week 4), -19% (Week 26), -32% (Week 52), and -75% (Week 104) in female patients. ERT-experienced for at least 104 weeks (Trial 2), switching to ELFABRIO treatment resulted in increases in median plasma lyso-Gb3 concentrations compared to baseline of: ○ Approximately 11% (Week 6), 15% (Week 26), and 18% (Week 104) in male patients, and ○ No significant changes in median plasma lyso-Gb3 concentrations in female patients. Pegunigalsidase alfa-iwxj exposure-response relationship is unknown. 12.3 Pharmacokinetics The pharmacokinetics (PK) of pegunigalsidase alfa-iwxj were evaluated in adult patients with Fabry disease and are presented as mean (standard deviation, SD) unless otherwise specified. The pharmacokinetics of pegunigalsidase alfa-iwxj in plasma following intravenous infusion of ELFABRIO 1 mg/kg every 2 weeks in adult treatment-naïve patients with Fabry disease are summarized in Table 4. The maximum plasma concentration (C max ) and area under the concentration-time curve (AUC) of pegunigalsidase alfa-iwxj increased with longer duration of treatment. In adult ERT-experienced patients with Fabry disease, mean C max ranged from 21.2 to 23.3 μg/mL and mean AUC tau ranged from 958 to 1074 μg·h/mL following intravenous infusion of ELFABRIO 1 mg/kg every 2 weeks. Table 4: Pharmacokinetics of Pegunigalsidase Alfa-iwxj in Adult ERT-Naïve 1 Patients With Fabry Disease Following Intravenous Infusion of ELFABRIO 1 mg/kg Every 2 Weeks PK Parameters Pegunigalsidase Alfa-iwxj Day 1 Week 13 Week 26 Week 52 Mean Infusion Duration (h) 5.5 4.4 3.9 3.3 General Information C max (μg/mL) 11.1±2.4 11.9±2.4 13.3±3.0 17.3±6.1 AUC inf (μg·h/mL) 391±136 510±174 748±200 1428±875 Distribution V (mL/kg) 321±71 271±89 226±116 186±91 Elimination t 1/2 (h) 78.9±10.3 85.7±28.4 96.5±31.4 121±22 CL (mL/h/kg) 2.9±0.7 2.3±0.8 1.6±0.6 1.1±0.7 Metabolism Expected metabolism into small peptides by catabolic pathways C max =maximum plasma concentration; AUC=area under the plasma concentration-time curve; V= terminal volume of distribution; t 1/2 =elimination half-life; CL=clearance 1 Includes patients who had not received ERT for at least 26 Weeks and who tested negative for anti-pegunigalsidase alfa-iwxj antibodies at screening. 12.6 Immunogenicity The observed incidence of IgG anti-drug antibodies (ADA) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of ADA in the studies described below with the incidence of ADA in other studies, including those of pegunigalsidase alfa-iwxj ELFABRIO or of other pegunigalsidase alfa products. The incidences of IgG ADA in ELFABRIO-treated patients with Fabry disease in Trials 1 and 2 are shown in Table 5. Immunogenicity in ERT-Naïve Patients or Those Who Did Not Receive ERT for 26 Weeks In Trial 1 (ERT-naïve patients with Fabry disease or those who did not receive ERT for 26 weeks) [see Clinical Studies ( 14 )] : Four of the 14 ELFABRIO-treated who were IgG anti-pegunigalsidase alfa-iwxj antibodies (anti-drug antibodies or ADA) negative at baseline became ADA positive during ELFABRIO treatment. The onset of ADA positivity in 3 of these patients occurred within 26 weeks after starting ELFABRIO treatment. Two patients had ADA prior to receiving their first ELFABRIO dose. One of these patients remained ADA positive after receiving ELFABRIO treatment (this patient had boosted antibody titers during ELFABRIO treatment). Immunogenicity in ERT-Experienced Patients In Trial 2 (ERT-experienced patients with Fabry disease who switched from agalsidase beta [see Clinical Studies ( 14 )] : Three of the 34 ELFABRIO-treated patients who were ADA negative at baseline became ADA positive during ELFABRIO treatment. The onset of ADA positivity occurred within 26 weeks after starting ELFABRIO treatment in 1 patient and more than 52 weeks in the remaining 2 patients. Eighteen ELFABRIO-treated patients had ADA prior to receiving their first ELFABRIO dose: ○ 17 (94%) patients remained ADA positive after receiving ELFABRIO treatment at 1 or more timepoints. ○ 3 (17%) patients had boosted ADA titers during ELFABRIO treatment. Table 5: ADA Incidence in ELFABRIO-Treated Patients with Fabry Disease (Trials 1 and 2) Trial 1 ERT-Naïve 1 Patients Trial 2 ERT- Experienced Patients Baseline Male (N=11) Female (N=7) Male (N=29) Female (N=23) ADA 1 (9%) 1 (14%) 18 (62%) 0 Neutralizing antibody 2 0 0 17/18 0 Anti-enzyme antibody 3 1/1 1/1 18/18 0 Anti-PEG antibody 4 0 0 2/18 0 Anti-plant gly c an antibody 5 1/1 1/1 0 0 At any time during ELFABRIO treatment* Male (N=9) Female (N=7) Male (N=29) Female (N=23) ADA 5 (56%) 0 17 (59%) 3 (13%) Neutralizing antibody 2 3/5 0 14/17 1/3 Anti-enzyme antibody 3 4/5 0 17/17 1/3 Anti-PEG antibody 4 1/5 0 2/17 1/3 Anti-plant gly c an antibody 5 2/5 0 0 0 ADA, anti-drug antibodies *ADA incidence after ELFABRIO treatment was determined if positive at any timepoint during ELFABRIO treatment. In Trial 1, of those that were positive at baseline (N=2) or any timepoint during ELFABRIO treatment (N=5), 4 became negative for ADA during Trial 1 through their last timepoint on study. In Trial 2, of those that were positive at baseline (N=18) or any timepoint during ELFABRIO treatment (N=20), 8 became negative for ADA during Trial 2 through their last timepoint on study. 1 Includes patients who had not received ERT for at least 26 Weeks and who tested negative for anti-pegunigalsidase alfa-iwxj antibodies at screening. 2 Neutralizing antibodies that inhibit enzyme activity, tested for IgG ADA positive samples only. Assessments for neutralizing antibodies that inhibit cellular uptake of enzyme have not been performed. 3 Anti-pegunigalsidase alfa-iwxj antibodies specific to the enzyme moiety on pegunigalsidase alfa-iwxj, tested for IgG ADA positive samples only 4 Anti-pegunigalsidase alfa-iwxj antibodies specific to the PEG moieties on pegunigalsidase alfa-iwxj, tested for IgG ADA positive samples only 5 Anti-pegunigalsidase alfa-iwxj antibodies specific to the plant glycan motifs on pegunigalsidase alfa-iwxj, tested for IgG ADA positive samples only A DA Effects on Safety and Efficacy IARs occurred more frequently in ELFABRIO-treated patients who were IgG ADA positive compared to those that were IgG ADA negative [see Warnings and Precautions ( 5.2 ) and Adverse Reactions ( 6.1 )] . The effect of IgE ADA on hypersensitivity reactions of ELFABRIO treatment has not been fully characterized [see Warnings and Precautions ( 5.1 )] . The effect of IgG ADA on the effectiveness of ELFABRIO has not been fully characterized [see Use in Specific Populations ( 8.6 )] . A DA Effects on Pharmacodynamics In Trial 2, baseline and post-treatment plasma lyso-Gb3 levels were higher in ELFABRIO-treated patients who were IgG ADA positive at baseline or at any time during the treatment compared with patients who were IgG ADA negative at baseline and at any time during the treatment [see Clinical Pharmacology ( 12.2 ) ] . The IgG ADA positive patient who had plasma pegunigalsidase alfa-iwxj concentrations below the limit of quantification of the assay had the highest plasma lyso-Gb3 levels among ELFABRIO-treated patients. A DA Effects on Pharmacokinetics IgG ADA including pre-existing IgG ADA reduced plasma pegunigalsidase alfa-iwxj concentrations in ELFABRIO-treated patients with Fabry disease. Patients with higher ADA titers had lower pegunigalsidase alfa-iwxj concentrations compared to those with lower ADA titers. In Trial 1 in patients who were negative for ADA at screening, 3 patients developed ADA following ELFABRIO treatment and had plasma pegunigalsidase alfa-iwxj concentration measures. Of these three patients: The plasma pegunigalsidase alfa-iwxj concentrations were transiently decreased in two of the patients who received 0.2 mg/kg of ELFABRIO intravenously every other week (0.2 times the approved recommended dosage), and No ADA effect on pegunigalsidase alfa-iwxj concentrations was observed in the third patient who received 1 mg/kg of ELFABRIO intravenously every other week. In Trial 2, 3 of 17 patients who had plasma pegunigalsidase alfa-iwxj concentration measures had pre-existing ADA at baseline and maintained ADA positive status following ELFABRIO treatment [see Use in Specific Populations ( 8.6 )] . Of these three patients: 1 patient with the highest ADA titer had plasma pegunigalsidase alfa-iwxj concentrations that were below the limit of quantification of the assay at all trial visits with pharmacokinetic assessments, and 2 patients had low plasma pegunigalsidase alfa-iwxj AUC, approximately 5% of the expected AUC for ADA-negative ELFABRIO-treated patients." ], "clinical_pharmacology_table": [ "
Table 4: Pharmacokinetics of Pegunigalsidase Alfa-iwxj in Adult ERT-Naïve1 Patients With Fabry Disease Following Intravenous Infusion of ELFABRIO 1 mg/kg Every 2 Weeks
PK ParametersPegunigalsidase Alfa-iwxj
Day 1Week 13Week 26Week 52
Mean Infusion Duration (h)5.54.43.93.3
General Information
Cmax (μg/mL)11.1±2.411.9±2.413.3±3.017.3±6.1
AUCinf (μg·h/mL)391±136510±174748±2001428±875
Distribution
V (mL/kg)321±71271±89226±116186±91
Elimination
t1/2 (h)78.9±10.385.7±28.496.5±31.4121±22
CL (mL/h/kg)2.9±0.72.3±0.81.6±0.61.1±0.7
MetabolismExpected metabolism into small peptides by catabolic pathways
", "
Table 5: ADA Incidence in ELFABRIO-Treated Patients with Fabry Disease (Trials 1 and 2)
Trial 1 ERT-Naïve1 PatientsTrial 2 ERT-Experienced Patients
Baseline
Male (N=11)Female (N=7)Male (N=29)Female (N=23)
ADA1 (9%)1 (14%)18 (62%)0
Neutralizing antibody20017/180
Anti-enzyme antibody31/11/118/180
Anti-PEG antibody4002/180
Anti-plant glycan antibody51/11/100
At any time during ELFABRIO treatment*
Male (N=9)Female (N=7)Male (N=29)Female (N=23)
ADA5 (56%)017 (59%)3 (13%)
Neutralizing antibody23/5014/171/3
Anti-enzyme antibody34/5017/171/3
Anti-PEG antibody41/502/171/3
Anti-plant glycan antibody52/5000
" ], "mechanism_of_action": [ "12.1 Mechanism of Action Fabry disease is caused by deficiency of the lysosomal enzyme alpha-galactosidase A. ELFABRIO provides an exogenous source of alpha-galactosidase A. ELFABRIO is internalized and transported into lysosomes where it is thought to exert enzymatic activity and reduce accumulated globotriaosylceramide (Gb3)." ], "pharmacodynamics": [ "12.2 Pharmacodynamics Plasma globotriaosylsphingosine (lyso-Gb3, a metabolite of Gb3) concentrations are elevated in patients with Fabry disease. In patients with Fabry disease who were [see Clinical Studies ( 14 )] : ERT-naïve or had not received ERT treatment for at least 26 weeks and had a negative test for anti-pegunigalsidase alfa-iwxj antibodies (Trial 1), ELFABRIO treatment resulted in significant reductions in median plasma lyso-Gb3 concentrations compared to baseline of approximately: ○ -43% (Week 4), -57% (Week 26), -68% (Week 52), and -84% (Week 104) in male patients, and ○ -3% (Week 4), -19% (Week 26), -32% (Week 52), and -75% (Week 104) in female patients. ERT-experienced for at least 104 weeks (Trial 2), switching to ELFABRIO treatment resulted in increases in median plasma lyso-Gb3 concentrations compared to baseline of: ○ Approximately 11% (Week 6), 15% (Week 26), and 18% (Week 104) in male patients, and ○ No significant changes in median plasma lyso-Gb3 concentrations in female patients. Pegunigalsidase alfa-iwxj exposure-response relationship is unknown." ], "pharmacokinetics": [ "12.3 Pharmacokinetics The pharmacokinetics (PK) of pegunigalsidase alfa-iwxj were evaluated in adult patients with Fabry disease and are presented as mean (standard deviation, SD) unless otherwise specified. The pharmacokinetics of pegunigalsidase alfa-iwxj in plasma following intravenous infusion of ELFABRIO 1 mg/kg every 2 weeks in adult treatment-naïve patients with Fabry disease are summarized in Table 4. The maximum plasma concentration (C max ) and area under the concentration-time curve (AUC) of pegunigalsidase alfa-iwxj increased with longer duration of treatment. In adult ERT-experienced patients with Fabry disease, mean C max ranged from 21.2 to 23.3 μg/mL and mean AUC tau ranged from 958 to 1074 μg·h/mL following intravenous infusion of ELFABRIO 1 mg/kg every 2 weeks. Table 4: Pharmacokinetics of Pegunigalsidase Alfa-iwxj in Adult ERT-Naïve 1 Patients With Fabry Disease Following Intravenous Infusion of ELFABRIO 1 mg/kg Every 2 Weeks PK Parameters Pegunigalsidase Alfa-iwxj Day 1 Week 13 Week 26 Week 52 Mean Infusion Duration (h) 5.5 4.4 3.9 3.3 General Information C max (μg/mL) 11.1±2.4 11.9±2.4 13.3±3.0 17.3±6.1 AUC inf (μg·h/mL) 391±136 510±174 748±200 1428±875 Distribution V (mL/kg) 321±71 271±89 226±116 186±91 Elimination t 1/2 (h) 78.9±10.3 85.7±28.4 96.5±31.4 121±22 CL (mL/h/kg) 2.9±0.7 2.3±0.8 1.6±0.6 1.1±0.7 Metabolism Expected metabolism into small peptides by catabolic pathways C max =maximum plasma concentration; AUC=area under the plasma concentration-time curve; V= terminal volume of distribution; t 1/2 =elimination half-life; CL=clearance 1 Includes patients who had not received ERT for at least 26 Weeks and who tested negative for anti-pegunigalsidase alfa-iwxj antibodies at screening." ], "pharmacokinetics_table": [ "
Table 4: Pharmacokinetics of Pegunigalsidase Alfa-iwxj in Adult ERT-Naïve1 Patients With Fabry Disease Following Intravenous Infusion of ELFABRIO 1 mg/kg Every 2 Weeks
PK ParametersPegunigalsidase Alfa-iwxj
Day 1Week 13Week 26Week 52
Mean Infusion Duration (h)5.54.43.93.3
General Information
Cmax (μg/mL)11.1±2.411.9±2.413.3±3.017.3±6.1
AUCinf (μg·h/mL)391±136510±174748±2001428±875
Distribution
V (mL/kg)321±71271±89226±116186±91
Elimination
t1/2 (h)78.9±10.385.7±28.496.5±31.4121±22
CL (mL/h/kg)2.9±0.72.3±0.81.6±0.61.1±0.7
MetabolismExpected metabolism into small peptides by catabolic pathways
" ], "nonclinical_toxicology": [ "13 NONCLIN I CAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Animal studies to evaluate the carcinogenic potential of pegunigalsidase alfa-iwxj have not been conducted. No effect on fertility was observed when pegunigalsidase alfa-iwxj was administered to adult rats at exposures ≤ 3.6-fold greater than the recommended dose of 1 mg/kg every two weeks." ], "clinical_studies": [ "14 CLINICAL STUDIES Trial 1 was an open-label dose-ranging trial in adults diagnosed with Fabry disease (NCT01678898). Patients received ELFABRIO at 0.2 mg/kg, 1 mg/kg, or 2 mg/kg given intravenously every other week for 52 weeks. The 0.2 mg/kg and 2 mg/kg dosage regimens are not approved and are not recommended [see Dosage and Administration ( 2.2 )]. Trial 1 enrolled 18 patients who were ERT-naïve or who had not received ERT for more than 26 weeks and had a negative test for anti-pegunigalsidase alfa-iwxj IgG antibodies prior to enrollment. Two patients in the 1 mg/kg treatment group discontinued the trial after their first infusion; one of them discontinued due to severe hypersensitivity reaction. Among the remaining 16 patients who completed Trial 1, 9 (56%) were males and 7 (44%) were females ranging in age from 17 to 54 years with a median age of 30 years. Twelve patients were White (75%) and 3 were Black or African American (19%). Three patients were Hispanic/Latino and 13 patients were not Hispanic/Latino. Of the 9 males, 7 (78%) had the classic phenotype. The median baseline eGFR and proteinuria was 115 mL/min/1.73 m 2 and 0.11 g/g respectively. Among the male patients, the median value of residual alpha-galactosidase A activity was 2.4% (range: 0.0%-9.3%) in plasma and 1.3% (range: 0.0%-3.4%) in leukocytes. The average number of globotriaosylceramide (Gb3) inclusions per renal peritubular capillary (PTC) in renal biopsy specimens of patients was assessed by light microscopy using the quantitative Barisoni Lipid Inclusion Scoring System (BLISS). Evaluable renal biopsies were obtained at baseline and at 26 weeks of treatment in 14 of the 16 patients who completed Trial 1. Table 6 shows the changes from baseline to 26 weeks in the BLISS score (average number of Gb3 inclusions per renal PTC) for these 14 ELFABRIO-treated patients. Table 6: Summary of the Renal Biopsy BLISS Score 1 of Gb3 Inclusions at Baseline and after 26 Weeks of ELFABRIO Treatment in Adults with Fabry Disease (Trial 1) All Patients Males Female s (N = 14) (N = 8) (N = 6) Median ( range) Baseline 3.2 (0.4, 9.0) 6.8 (0.4, 9.0) 1.2 (0.8, 3.3) Week 26 0.7 (0.3, 2.5) 0.7 (0.3, 2.5) 0.7 (0.3, 1.4) Change at Week 26 -2.5 (-8.5, 0.5) -5.3 (-8.5, 0.5) -0.7 (-2.5, 0.1) Mean Change at Week 26 (95% CI) -3.1 (-4.8, -1.4) -4.7 (-7.1, -2.3) -1.0 (-2.1, 0.1) 1 The BLISS methodology counts the number of Gb3 inclusions in each renal PTC contained in a biopsy specimen. For each biopsy specimen (slide), approximately 300 renal PTCs were scored, and the final biopsy score for each patient was determined as the average number of Gb3 inclusions per PTC. Trial 2 was a randomized, double-blind, and active-controlled trial (NCT02795676) in ERT-experienced adults diagnosed with Fabry disease. Eligible patients were treated with agalsidase beta for at least one year prior to trial entry (the mean duration of agalsidase beta treatment prior to enrollment was 5.7 years). Patients were randomized 2:1 to receive ELFABRIO (1 mg/kg intravenous infusion) or agalsidase beta (1 mg/kg intravenous infusion) every 2 weeks for 104 weeks. A total of 77 patients were randomized and received at least one dose of ELFABRIO (N = 52, 68%) or agalsidase beta (N = 25, 32%). Of these patients, 47 (61%) were males and 30 (39%) were females. Patients were 18 to 60 years of age with a median age of 46 years at baseline; 72 (94%) were White, 3 (4%) were Black or African American and 2 (3%) were Asian. Two patients were Hispanic/Latino and 75 patients were not Hispanic/Latino. Forty-one (53%) patients had the classic phenotype. The median baseline eGFR and proteinuria was 75 mL/min/1.73 m 2 and 0.11 g/g, respectively. The primary efficacy endpoint was the annualized rate of change in eGFR (eGFR slope) assessed over 104 weeks. The estimated mean eGFR slope was -2.4 and -2.3 mL/min/1.73 m 2 /year on ELFABRIO and agalsidase beta respectively. The estimated treatment difference was -0.1 (95% CI: -2.3, 2.1) mL/min/1.73 m 2 /year." ], "clinical_studies_table": [ "
Table 6: Summary of the Renal Biopsy BLISS Score1 of Gb3 Inclusions at Baseline and after 26 Weeks of ELFABRIO Treatment in Adults with Fabry Disease (Trial 1)
All PatientsMalesFemales
(N = 14)(N = 8)(N = 6)
Median (range)
Baseline3.2 (0.4, 9.0)6.8 (0.4, 9.0)1.2 (0.8, 3.3)
Week 260.7 (0.3, 2.5)0.7 (0.3, 2.5)0.7 (0.3, 1.4)
Change at Week 26-2.5 (-8.5, 0.5)-5.3 (-8.5, 0.5)-0.7 (-2.5, 0.1)
Mean Change at Week 26 (95% CI)-3.1 (-4.8, -1.4)-4.7 (-7.1, -2.3)-1.0 (-2.1, 0.1)
" ], "how_supplied": [ "16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied ELFABRIO (pegunigalsidase alfa-iwxj) injection is a sterile, preservative-free, clear and colorless solution supplied in a single-dose vial. Each vial contains 20 mg/10 mL or 5 mg/2.5 mL (2 mg/mL) of pegunigalsidase alfa-iwxj. ELFABRIO is available as: One single-dose 20 mg/10 mLvial in a carton (NDC 10122-160-02) One single-dose 5 mg/2.5 mL vial in a carton (NDC 10122-165-02) Five single-dose 20 mg/10 mL vials in a carton (NDC 10122-160-05) Ten single-dose 20 mg/10 mL vials in a carton (NDC 10122-160-10) Storage and Handling Store refrigerated at 2°C to 8°C (36°F to 46°F). Do not freeze. Do not shake." ], "information_for_patients": [ "17 PATIENT COUNSELING INFORMATION Hypersensitivity Reactions Including Anaphylaxis and Infusion-Associated Reactions (IAR s) Advise the patient and/or caregiver that reactions related to the infusion may occur during and after ELFABRIO treatment, including anaphylactic reactions, other serious or severe hypersensitivity reactions, and IARs. Inform the patient and/or caregiver of the signs and symptoms of hypersensitivity reactions and IARs and to seek immediate medical care should these signs and symptoms occur [see Warnings and Precautions ( 5.1 , 5.2 )] . Preg n ancy Safety Study Advise a patient who is exposed to ELFABRIO during pregnancy that there is a pregnancy safety study that monitors pregnancy outcomes. Encourage the patient to report the pregnancy to Chiesi USA, Inc. at 1-888-661-9260 and https://chiesirarediseases.com/contact-us/medical-information-form [see Use in Specific Populations ( 8.1 ) ]. Manufactured by: Chiesi Farmaceutici S.p.A. Via Palermo 26/A, 43122 Parma, Italy U.S. License No. 2245 Manufactured at: Chiesi Farmaceutici S.p.A. 43122 Parma, Italy Manufactured for: Chiesi USA, Inc. Cary NC, 27518, USA Product of Israel. ELFABRIO is a registered trademark of Chiesi Farmaceutici S.p.A. Licensed from Protalix Ltd. CTPA-001-0324-01-W" ], "package_label_principal_display_panel": [ "PRINCIPAL DISPLAY PANEL NDC 10122-160-02 ELFABRIO (pegunigalsidase alfa-iwxj) Injection 20 mg/ 10 mL (2 mg/ml) For Intravenous Infusion After Dilution Rx Only 1 x 10 mL single-dose vial Discard unused portion. NDC 10122-160-02 ELFABRIO (pegunigalsidase alfa-iwxj) Injection 20 mg/ 10 mL (2 mg/ml) For Intravenous Infusion After Dilution Rx Only 1 x 10 mL single-dose vial Discard unused portion.", "PRINCIPAL DISPLAY PANEL NDC 10122-165-02 ELFABRIO (pegunigalsidase alfa-iwxj) Injection 5 mg/ 2.5 mL (2 mg/ml) For Intravenous Infusion After Dilution Rx Only 1 x 2.5 mL single-dose vial Discard unused portion. 5 mg/2.5 mL" ], "set_id": "6fb674bf-744e-431f-92ef-b2a5a66c8cf3", "id": "ca12aa63-7344-4996-bfb4-d2289c245f4a", "effective_time": "20240708", "version": "7", "openfda": { "application_number": [ "BLA761161" ], "brand_name": [ "ELFABRIO" ], "generic_name": [ "PEGUNIGALSIDASE ALFA" ], "manufacturer_name": [ "Chiesi USA, Inc." ], "product_ndc": [ "10122-160", "10122-165" ], "product_type": [ "HUMAN PRESCRIPTION DRUG" ], "route": [ "INTRAVENOUS" ], "substance_name": [ "PEGUNIGALSIDASE ALFA" ], "rxcui": [ "2637456", "2637462", "2676759", "2676760" ], "spl_id": [ "ca12aa63-7344-4996-bfb4-d2289c245f4a" ], "spl_set_id": [ "6fb674bf-744e-431f-92ef-b2a5a66c8cf3" ], "package_ndc": [ "10122-160-01", "10122-160-02", "10122-160-05", "10122-160-10", "10122-165-02" ], "is_original_packager": [ true ], "nui": [ "M0000794", "N0000175822" ], "pharm_class_cs": [ "alpha-Glucosidases [CS]" ], "pharm_class_epc": [ "Hydrolytic Lysosomal Neutral Glycosphingolipid-specific Enzyme [EPC]" ], "unii": [ "8M7V7Q6537" ] } }, { "spl_product_data_elements": [ "Fabrazyme AGALSIDASE BETA AGALSIDASE BETA AGALSIDASE BETA MANNITOL SODIUM PHOSPHATE, MONOBASIC, MONOHYDRATE SODIUM PHOSPHATE, DIBASIC, HEPTAHYDRATE Fabrazyme AGALSIDASE BETA AGALSIDASE BETA AGALSIDASE BETA MANNITOL SODIUM PHOSPHATE, MONOBASIC, MONOHYDRATE SODIUM PHOSPHATE, DIBASIC, HEPTAHYDRATE" ], "boxed_warning": [ "WARNING: HYPERSENSITIVITY REACTIONS INCLUDING ANAPHYLAXIS Patients treated with enzyme replacement therapies have experienced life-threatening hypersensitivity reactions, including anaphylaxis. Anaphylaxis has occurred during the early course of enzyme replacement therapy and after extended duration of therapy. Initiate FABRAZYME in a healthcare setting with appropriate medical monitoring and support measures, including access to cardiopulmonary resuscitation equipment. If a severe hypersensitivity reaction (e.g., anaphylaxis) occurs, discontinue FABRAZYME and immediately initiate appropriate medical treatment, including use of epinephrine. Inform patients of the symptoms of life-threatening hypersensitivity reactions, including anaphylaxis and to seek immediate medical care should symptoms occur. [see Warnings and Precautions (5.1) ] . WARNING: HYPERSENSITIVITY REACTIONS INCLUDING ANAPHYLAXIS See full prescribing information for complete boxed warning Anaphylaxis has occurred during the early course of enzyme replacement therapy and after extended duration of therapy. Initiate FABRAZYME in a healthcare setting with appropriate medical monitoring and support measures, including access to cardiopulmonary resuscitation equipment. If a severe hypersensitivity reaction (e.g., anaphylaxis) occurs, discontinue FABRAZYME and immediately initiate appropriate medical treatment, including use of epinephrine. ( 5.1 )" ], "recent_major_changes": [ "Boxed Warning XX/2024 Dosage and Administration ( 2.1 ) XX/2024 Warnings and Precautions ( 5.1 ) 2/2024" ], "recent_major_changes_table": [ "
Boxed WarningXX/2024
Dosage and Administration (2.1)XX/2024
Warnings and Precautions (5.1)2/2024
" ], "indications_and_usage": [ "1 INDICATIONS AND USAGE FABRAZYME ® is indicated for the treatment of adult and pediatric patients 2 years of age and older with confirmed Fabry disease. FABRAZYME is a hydrolytic lysosomal neutral glycosphingolipid-specific enzyme indicated for the treatment of adult and pediatric patients 2 years of age and older with confirmed Fabry disease. ( 1 )" ], "dosage_and_administration": [ "2 DOSAGE AND ADMINISTRATION Administration of FABRAZYME should be supervised by a healthcare provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis. ( 2.1 ) The recommended dosage is 1 mg/kg body weight given every two weeks as an intravenous infusion. ( 2.2 ) See the full prescribing information for rechallenge, preparation, storage, and administration instructions. ( 2.3 , 2.4 , 2.5 , 2.6 ) 2.1 Recommendations Prior to FABRAZYME Treatment Administration of FABRAZYME should be supervised by a healthcare provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis [see Warnings and Precautions (5.1) ]. Initiate FABRAZYME in a healthcare setting with appropriate medical monitoring and support measures, including access to cardiopulmonary resuscitation equipment [see Warnings and Precautions (5.1) ]. Prior to FABRAZYME administration, consider pretreating with antihistamines, antipyretics, and/or corticosteroids [see Warnings and Precautions (5.1 , 5.2) ] . FABRAZYME must be reconstituted and diluted prior to use [see Dosage and Administration (2.4) ] 2.2 Recommended Dosage and Administration The recommended dosage of FABRAZYME is 1 mg/kg body weight infused every two weeks as an intravenous infusion. The initial recommended infusion rate is 0.25 mg/min (15 mg/hour) [see Dosage and Administration (2.6) ] . 2.3 Rechallenge Instructions Patients who have had a positive skin test to FABRAZYME or who have tested positive for anti-FABRAZYME IgE may be successfully rechallenged with FABRAZYME. The initial rechallenge administration should be a low dose at a lower infusion rate, e.g., one-half the therapeutic dose (0.5 mg/kg) at 1/25 th of the initial standard recommended rate (0.01 mg/min or 0.6 mg/hr). Once a patient tolerates the infusion, the dose may be increased to reach the approved dose of 1 mg/kg and the infusion rate may be increased by slowly titrating upwards (doubled every 30 minutes up to a maximum rate of 0.25 mg/minute), as tolerated [see Adverse Reactions (6.2) ] . 2.4 Preparation Instructions Use aseptic technique during preparation. Reconstitute and dilute FABRAZYME in the following manner: Reconstitution Instructions 1. Determine the number of 35 mg and 5 mg FABRAZYME vials to be reconstituted based on actual body weight (kg) and the recommended dose [see Dosage and Administration (2.2) ] . 2. Remove the required number of 35 mg and 5 mg FABRAZYME vials from the refrigerator and allow the vials to sit for approximately 30 minutes at room temperature 20°C to 25°C (68°F to 77°F) before use. 3. Reconstitute each vial by directing the diluent down the inside wall of each vial then gently tilt and roll each vial. Use the following volumes for reconstitution: 7.2 mL of FABRAZYME Sterile Water for Injection into the 35 mg vial. Total extractable amount per vial is 35 mg, 7 mL. 1.1 mL of Sterile Water for Injection into the 5 mg vial. Total extractable amount per vial is 5 mg, 1 mL. 4. Each reconstituted vial will yield a concentration of 5 mg/mL of agalsidase beta. 5. Do not shake or agitate the product. 6. Visually inspect the reconstituted solution in the vials for particulate matter and discoloration. The reconstituted solution should be clear and colorless. Discard if visible particulate matter is present or the solution is discolored. Dilution Instructions 7. Select an appropriate size 0.9% Sodium Chloride Injection infusion bag and prepare by removing a volume equal to the required FABRAZYME volume to achieve a total volume per Table 1. 8. Slowly withdraw the required volume of reconstituted solution from the FABRAZYME vial(s). Discard any unused reconstituted solution remaining in the vial. Table 1: Total Infusion Volume Based on Patient Weight Patient Weight (kg) Total Volume (mL) ≤35 50 35.1 to 70 100 70.1 to 100 250 >100 500 9. Gently inject the FABRAZYME reconstituted solution into the port of the 0.9% Sodium Chloride Injection infusion bag. Do not inject into the airspace within the infusion bag. 10. Gently invert the infusion bag to mix the solution. Do not shake or agitate the product. After dilution, the solution will have a final concentration of 0.2 to 0.7 mg/mL of agalsidase beta. 2.5 Storage Instructions for the Reconstituted and Diluted Product Dilute the reconstituted solution without delay and use immediately. If immediate use is not possible, the reconstituted and diluted solution may be stored at 2°C to 8°C (36°F to 46°F) for up to 24 hours. 2.6 Administration Instructions The initial recommended infusion rate is 0.25 mg/min (15 mg/hour). For patients weighing: 30 kg or more, in the absence of hypersensitivity and/or infusion-associated reactions (IARs), increase the infusion rate in increments of 0.05 to 0.08 mg/min (3 to 5 mg/hour) with each subsequent infusion. The minimum infusion duration is 1.5 hours (based on individual patient tolerability) [see Dosage and Administration (2.6) ] . Less than 30 kg, the maximum infusion rate is 0.25 mg/minute (15 mg/hour) [see Dosage and Administration (2.6) ] . Do not infuse FABRAZYME in the same intravenous line with other products. Administer FABRAZYME using an in-line low protein binding 0.2 µm filter." ], "dosage_and_administration_table": [ "
Table 1: Total Infusion Volume Based on Patient Weight
Patient Weight (kg)Total Volume (mL)
≤3550
35.1 to 70100
70.1 to 100250
>100500
" ], "dosage_forms_and_strengths": [ "3 DOSAGE FORMS AND STRENGTHS For injection: 5 mg or 35 mg of agalsidase beta as a white to off-white, lyophilized cake or powder in a single-dose vial for reconstitution. For injection: 5 mg or 35 mg of agalsidase beta as a lyophilized cake or powder in a single-dose vial for reconstitution. ( 3 )" ], "contraindications": [ "4 CONTRAINDICATIONS None. None. ( 4 )" ], "warnings_and_cautions": [ "5 WARNINGS AND PRECAUTIONS Infusion-Associated Reactions : If a severe infusion-associated reaction occurs, discontinue FABRAZYME immediately and initiate appropriate medical treatment. ( 5.2 ) 5.1 Hypersensitivity Reactions Including Anaphylaxis Life-threatening hypersensitivity reactions, including anaphylaxis, have been reported in FABRAZYME-treated patients. In clinical trials and postmarketing safety experience with FABRAZYME, approximately 1% of patients developed anaphylaxis or severe hypersensitivity reactions. Reactions have included localized angioedema (including swelling of the face, mouth, and throat), bronchospasm, hypotension, generalized urticaria, dysphagia, rash, dyspnea, flushing, chest discomfort, pruritus, and nasal congestion. In clinical trials with FABRAZYME, 10 of 238 patients developed IgE antibodies or skin test reactivity specific to FABRAZYME. Two of six patients in the rechallenge study discontinued treatment with FABRAZYME prematurely due to recurrent infusion-associated reactions. Four serious infusion-associated reactions occurred in three patients during FABRAZYME infusions, including bronchospasm, urticaria, hypotension, and development of FABRAZYME-specific antibodies. Other infusion-associated reactions occurring in more than one patient during the study included rigors, hypertension, nausea, vomiting, and pruritus. Higher incidences of hypersensitivity reactions were observed in adult patients with persistent anti-FABRAZYME antibodies and in adult patients with high antibody titer compared to that in antibody-negative adult patients [see Adverse Reactions (6.2) ] . Prior to FABRAZYME administration, consider pretreating with antihistamines, antipyretics, and/or corticosteroids. Administration of FABRAZYME should be supervised by a healthcare provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis. Anaphylaxis has occurred during the early course of enzyme replacement therapy and after extended duration of therapy. Initiate FABRAZYME in a healthcare setting with appropriate medical monitoring and support measures, including access to cardiopulmonary resuscitation equipment. If a severe hypersensitivity reaction (e.g., anaphylaxis) occurs, discontinue FABRAZYME and immediately initiate appropriate medical treatment, including use of epinephrine. Consider the risks and benefits of re-administering FABRAZYME following severe hypersensitivity reactions (including anaphylaxis). Inform patients of the symptoms of life-threatening hypersensitivity reactions, including anaphylaxis and to seek immediate medical care should symptoms occur. Consider testing for IgE antibodies in FABRAZYME-treated patients who experienced severe hypersensitivity reactions, including anaphylaxis and consider the risks and benefits of continued treatment in patients with anti-FABRAZYME IgE antibodies. There are no marketed tests for antibodies against FABRAZYME. If testing is warranted, contact Genzyme Corporation at 1-800-745-4447 [see Adverse Reactions (6.2) ] . Patients who have had a positive skin test to FABRAZYME or who have tested positive for FABRAZYME-specific IgE antibodies have been rechallenged with FABRAZYME using a rechallenge protocol. Rechallenge of these patients should only occur under the direct supervision of qualified personnel with appropriate medical monitoring and support measures readily available [see Dosage and Administration (2.3) and Adverse Reactions (6.2) ] . 5.2 Infusion-Associated Reactions In clinical trials of FABRAZYME, 59% of patients experienced infusion-associated reactions (IARs) during FABRAZYME administration, some of which were severe. Infusion-associated reactions are defined as adverse reactions occurring on the same day as the infusion. The incidence of infusion-associated reactions was higher in patients who were positive for anti-FABRAZYME antibodies than in patients who were negative for anti-FABRAZYME antibodies [see Adverse Reactions (6.2) ] . Severe infusion-associated reactions experienced by more than one patient in clinical trials of FABRAZYME included chills, vomiting, hypotension, and paresthesia. Other infusion-associated reactions included pyrexia, feeling hot or cold, dyspnea, nausea, flushing, headache, fatigue, pruritus, pain in extremity, hypertension, chest pain, throat tightness, abdominal pain, dizziness, tachycardia, nasal congestion, diarrhea, edema peripheral, myalgia, urticaria, bradycardia, and somnolence [see Adverse Reactions (6.1) ] . Prior to FABRAZYME administration, consider pre-treatment with antihistamines, antipyretics, and/or corticosteroids to reduce the risk of infusion-associated reactions (IARs). However, IARs may still occur in patients after receiving pre-treatment. IARs tended to decline in frequency with continued use of FABRAZYME. However, IARs may still occur despite extended duration of FABRAZYME treatment. Appropriate medical monitoring and support measures, including cardiopulmonary resuscitation equipment, should be readily during FABRAZYME administration. If a severe IAR occurs, discontinue FABRAZYME immediately and initiate appropriate medical treatment. Consider the risks and benefits of re-administering FABRAZYME following a severe IAR and monitor patients closely upon re-administration of FABRAZYME. If a mild or moderate IAR occurs, consider temporarily holding the infusion, slowing the infusion rate, and/or reducing the FABRAZYME dosage. Patients with advanced Fabry disease may have compromised cardiac function which may predispose them to a higher risk of severe complications from IARs. Closely monitor patients with compromised cardiac function if FABRAZYME is administered to these patients." ], "adverse_reactions": [ "6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in labeling: Hypersensitivity Reactions Including Anaphylaxis [see Warnings and Precautions (5.1) ] Infusion-Associated Reactions [see Warnings and Precautions (5.2) ] Most common adverse reactions (≥20%) are: upper respiratory tract infection, chills, pyrexia, headache, cough, paresthesia, fatigue, peripheral edema, dizziness, and rash. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Genzyme at 1-800-633-1610 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 clinical trials of a drug cannot be directly compared to rates in the clinical trial of another drug and may not reflect the rates observed in patients in clinical practice. The data described below reflect exposure of 80 patients, ages 16 to 61 years, to 1 mg/kg FABRAZYME every two weeks in two separate double-blind, placebo-controlled clinical trials, for periods ranging from 1 to 35 months (mean 15.5 months). All 58 patients enrolled in one of the two studies continued into an open-label extension study of FABRAZYME treatment for up to 54 additional months. Patients were treated with antipyretics and antihistamines prior to the infusions. Most Common Adverse Reactions Table 2 enumerates adverse reactions that occurred during the double-blind treatment periods of the two placebo-controlled trials (Study 1 and Study 2) [see Clinical Studies (14) ] . The most common adverse reactions reported with FABRAZYME were infusion-associated reactions, (FABRAZYME 59% vs placebo 27%) some of which were severe (FABRAZYME 5.0% vs placebo 1.7%). Infusion-associated reactions are defined as adverse reactions occurring on the same day as the infusion. Common adverse reactions which occurred in ≥20% of patients treated with FABRAZYME and >2.5% compared to placebo are: upper respiratory tract infection, chills, pyrexia, headache, cough, paresthesia, fatigue, peripheral edema, dizziness and rash. Table 2: Summary of Common Adverse Reactions Reported at rate of at least 5% in FABRAZYME-treated patients and greater than 2.5% compared to placebo-treated patients. in Clinical Trials (Study 1 and 2) of Patients with Fabry Disease Adverse Reaction FABRAZYME (n=80) % Placebo (n=60) % Upper respiratory tract infection Includes reports of upper respiratory infection, nasal congestion, sinusitis, respiratory tract congestion, and pharyngitis. 53 42 Chills Includes reports of chills and feeling cold. 49 13 Pyrexia 39 22 Headache 39 28 Cough 33 25 Paresthesia 31 18 Fatigue 24 17 Peripheral edema 21 7 Dizziness 21 8 Rash 20 10 Pain in extremity 19 8 Myalgia Includes reports of myalgia and muscle spasms. 18 7 Lower respiratory tract infection 18 7 Pain 16 13 Back pain 16 10 Hypertension 14 5 Pruritus 10 3 Tachycardia 9 3 Excoriation 9 2 Increased blood creatinine 9 5 Tinnitus 8 3 Dyspnea 8 2 Fall 6 3 Burning sensation 6 0 Anxiety 6 3 Depression 6 2 Wheezing 6 0 Hypoacusis 5 0 Chest discomfort 5 2 Fungal infection 5 0 Viral infection 5 0 Hot flush 5 0 Most infusion-associated reactions requiring intervention were ameliorated with slowing of the infusion rate, temporarily stopping the infusion, and/or administration of antipyretics, antihistamines, or steroids. Adverse Reactions in Pediatric Patients In Study 3, the safety profile of FABRAZYME in pediatric Fabry disease patients, ages 8 to 16 years, was similar to that seen in adults. The most common adverse reactions (>20%) were headache, abdominal pain, pharyngitis, fever, nausea, vomiting, rhinitis, diarrhea, arthralgia, and dizziness [see Use in Specific Populations (8.4) and Clinical Studies (14) ] . 6.2 Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to FABRAZYME in the studies described below with the incidence of antibodies in other studies or to other agalsidase beta products may be misleading. Patients with classic Fabry disease in Study 1, Study 2, and extension studies were tested at multiple time points for antibodies to agalsidase beta during the 55 to 58-month period. Approximately 83% (110 of 133) of adult patients receiving agalsidase beta developed antibodies; 77% (102/133) of patients developed neutralizing antibody (NAb) that inhibited in vitro agalsidase beta catalytic activity, which declined over time, and 6% (8/133) of patients developed NAb that inhibited cellular uptake. In pediatric patients with Fabry disease in Study 3 receiving the recommended dose who were 8 to <16 years of age, antibodies to agalsidase beta were detected in approximately 69% (11/16) of patients. Most patients who developed antibodies did so within the first 3 months of treatment. Antibody titers generally declined over time. Approximately 18% of adult patients who developed antibodies became antibody negative by 74 weeks (median time) from the time of seroconversion; however, none of the pediatric patients became antibody negative. Female patients generally had lower incidence of antibodies and lower antibody titers compared to male patients. In Study 5, patients with truncating GLA mutations had higher incidence of antibodies and higher antibody titers compared to patients with nontruncating GLA mutations. Patients with plasma α-galactosidase A activity ≤1.5 nmol/hr/mL had higher incidence of antibodies and higher antibody titers compared to patients with plasma α-galactosidase A activity >1.5 nmol/hr/mL. In general, over 90% of adult and pediatric patients treated with agalsidase beta achieved and maintained normalization of plasma globotriaosylceramide (GL-3) levels irrespective of developing antibodies to agalsidase beta. Study 4 was an open-label, rechallenge study to evaluate the safety of FABRAZYME treatment in patients who had a positive skin test to FABRAZYME or who had tested positive for FABRAZYME-specific IgE antibodies. In this study, six adult male patients, who had experienced multiple or recurrent infusion-associated reactions during previous clinical trials of FABRAZYME, were rechallenged with FABRAZYME administered as a graded infusion for up to 52 weeks of treatment. The initial two rechallenge doses of FABRAZYME were administered as a 0.5 mg/kg dose per week at an initial infusion rate of 0.01 mg/min for the first 30 minutes (1/25 th the usually recommended maximum infusion rate). The infusion rate was doubled every 30 minutes thereafter, as tolerated, for the remainder of the infusion up to a maximum rate of 0.25 mg/min. If the patient tolerated the infusion, the dose was increased to 1 mg/kg every two weeks and the infusion rate was increased by slow upwards titration [see Dosage and Administration (2.1) ] . Pretreatment was not permitted for at least the first 4 infusions in order to allow early recognition of acute systemic hypersensitivity reactions. Four of the six patients treated in this study received at least 26 weeks of FABRAZYME (2 patients received 26 weeks and 2 patients received 52 weeks), and two patients discontinued prematurely due to recurrent infusion-associated reactions [see Warnings and Precautions (5.1 , 5.2) ] . Testing for IgE antibodies was performed in approximately 60 patients in clinical trials who experienced moderate to severe infusion-associated reactions or in whom mast cell activation was suspected. Seven of these patients tested positive for FABRAZYME-specific IgE antibodies or had a positive skin test to FABRAZYME. Patients who have had a positive skin test to FABRAZYME, or who have tested positive for FABRAZYME-specific IgE antibodies in clinical trials with FABRAZYME have been rechallenged [see Dosage and Administration (2.1) and Warnings and Precautions (5.1 , 5.2) ] . The incidences of hypersensitivity reactions were 51% (41/80) and 60% (25/42) in adult patients with persistent anti-FABRAZYME antibodies and in adult patients with high antibody titer, respectively, compared to 30% (7/23) in antibody-negative adult patients [see Warnings and Precautions (5.1) ] . The incidence of infusion-associated reactions was 76% (84/110) in antibody-positive adult patients compared to 30% (7/23) in antibody-negative adult patients. The incidence of infusion-associated reactions was 46% (5/11) in antibody positive pediatric patients compared to 20% (1/5) in antibody negative pediatric patients [see Warnings and Precautions (5.2) ] . 6.3 Postmarketing Experience The following adverse reactions have been identified during postapproval use of FABRAZYME. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiovascular: cardiorespiratory arrest, cardiac failure, myocardial infarction, palpitations Hypersensitivity reactions: anaphylaxis [see Warnings and Precautions (5.1) ] , localized angioedema (including auricular swelling, eye swelling, dysphagia, lip swelling, edema, pharyngeal edema, face swelling, and swollen tongue), and bronchospasm General: hyperhidrosis, asthenia, infusion site reaction Lymphatic: lymphadenopathy Musculoskeletal: arthralgia Neurologic: cerebrovascular accident, hypoesthesia, oral hypoesthesia Pulmonary: respiratory failure, hypoxia Renal: renal failure Vascular: leukocytoclastic vasculitis" ], "adverse_reactions_table": [ "
Table 2: Summary of Common Adverse ReactionsReported at rate of at least 5% in FABRAZYME-treated patients and greater than 2.5% compared to placebo-treated patients. in Clinical Trials (Study 1 and 2) of Patients with Fabry Disease
Adverse ReactionFABRAZYME (n=80) %Placebo (n=60) %
Upper respiratory tract infectionIncludes reports of upper respiratory infection, nasal congestion, sinusitis, respiratory tract congestion, and pharyngitis.5342
ChillsIncludes reports of chills and feeling cold.4913
Pyrexia3922
Headache3928
Cough3325
Paresthesia3118
Fatigue2417
Peripheral edema217
Dizziness218
Rash2010
Pain in extremity198
MyalgiaIncludes reports of myalgia and muscle spasms.187
Lower respiratory tract infection187
Pain1613
Back pain1610
Hypertension145
Pruritus103
Tachycardia93
Excoriation92
Increased blood creatinine95
Tinnitus83
Dyspnea82
Fall63
Burning sensation60
Anxiety63
Depression62
Wheezing60
Hypoacusis50
Chest discomfort52
Fungal infection50
Viral infection50
Hot flush50
" ], "use_in_specific_populations": [ "8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Available data from a pregnancy sub-study within the Fabry Disease registry, post-marketing case reports, and case series with FABRAZYME use during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes (see Data ). Reproduction studies performed in rats at doses up to 68 times the human dose have revealed no evidence of effects on embryo-fetal development (see Data ) . The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Human Data Available data from a pregnancy sub-study within the Fabry Disease registry, post-marketing case reports, and case series with FABRAZYME use during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. In the Fabry Disease registry pregnancy sub-study, 33 pregnancies exposed to FABRAZYME prior to or during pregnancy had a known outcome; 5 were reported as exposed in the first trimester. Animal Data The effects of agalsidase beta on embryo-fetal development in rats were evaluated at doses of 3, 10, and 30 mg/kg/day (up to 68 times the human dose of 1 mg/kg every 2 weeks on a body surface area basis) during gestation days 7 to 17. Hepatocellular necrosis consistent with accumulation of test article was evident in maternal livers in the 10 and 30 mg/kg/day groups (23 and 68 times the human dose on a body surface area basis). There were no adverse effects of agalsidase beta on embryo-fetal development in rats. 8.2 Lactation Risk Summary The available human data detected small amounts of agalsidase beta in human milk. Available data from the clinical study, global pharmacovigilance database, and published scientific literature are insufficient to determine the effects of FABRAZYME on the breastfed infant or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for FABRAZYME and any potential adverse effects on the breastfed child from FABRAZYME or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of FABRAZYME have been established in pediatric patients based on adequate and well-controlled studies in adults, a single-arm, open-label study in 16 pediatric patients with Fabry disease aged 8 to 16 years, and additional data in 24 patients with Fabry disease aged 2 to 7 years [see Clinical Pharmacology (12.2) and Clinical Studies (14) ] . The overall safety profile of FABRAZYME was similar between the pediatric and the adult population [see Adverse Reactions (6.1) and Clinical Studies (14) ] . 8.5 Geriatric Use Clinical studies of FABRAZYME did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects." ], "pregnancy": [ "8.1 Pregnancy Risk Summary Available data from a pregnancy sub-study within the Fabry Disease registry, post-marketing case reports, and case series with FABRAZYME use during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes (see Data ). Reproduction studies performed in rats at doses up to 68 times the human dose have revealed no evidence of effects on embryo-fetal development (see Data ) . The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Human Data Available data from a pregnancy sub-study within the Fabry Disease registry, post-marketing case reports, and case series with FABRAZYME use during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. In the Fabry Disease registry pregnancy sub-study, 33 pregnancies exposed to FABRAZYME prior to or during pregnancy had a known outcome; 5 were reported as exposed in the first trimester. Animal Data The effects of agalsidase beta on embryo-fetal development in rats were evaluated at doses of 3, 10, and 30 mg/kg/day (up to 68 times the human dose of 1 mg/kg every 2 weeks on a body surface area basis) during gestation days 7 to 17. Hepatocellular necrosis consistent with accumulation of test article was evident in maternal livers in the 10 and 30 mg/kg/day groups (23 and 68 times the human dose on a body surface area basis). There were no adverse effects of agalsidase beta on embryo-fetal development in rats." ], "pediatric_use": [ "8.4 Pediatric Use The safety and effectiveness of FABRAZYME have been established in pediatric patients based on adequate and well-controlled studies in adults, a single-arm, open-label study in 16 pediatric patients with Fabry disease aged 8 to 16 years, and additional data in 24 patients with Fabry disease aged 2 to 7 years [see Clinical Pharmacology (12.2) and Clinical Studies (14) ] . The overall safety profile of FABRAZYME was similar between the pediatric and the adult population [see Adverse Reactions (6.1) and Clinical Studies (14) ] ." ], "geriatric_use": [ "8.5 Geriatric Use Clinical studies of FABRAZYME did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects." ], "description": [ "11 DESCRIPTION Agalsidase beta is a recombinant human α-galactosidase A enzyme with the same amino acid sequence as the native enzyme. Purified agalsidase beta is a homodimeric glycoprotein with a molecular weight of approximately 100 kD. The mature protein is comprised of two subunits of 398 amino acids (approximately 51 kD), each of which contains three N-linked glycosylation sites. The enzyme α-galactosidase A catalyzes the hydrolysis of GL-3 and other α-galactyl-terminated neutral glycosphingolipids, such as galabiosylceramide and blood group B substances to ceramide dihexoside and galactose. The specific activity of agalsidase beta is approximately 70 U/mg (one unit is defined as the amount of activity that results in the hydrolysis of 1 µmole of a synthetic substrate, p-nitrophenyl-α-D-galactopyranoside, per minute under the assay conditions). Agalsidase beta is produced by recombinant DNA technology in a Chinese hamster ovary mammalian cell expression system. FABRAZYME (agalsidase beta) for injection is intended for intravenous infusion. It is supplied as a sterile, nonpyrogenic, preservative-free, white to off-white, lyophilized cake or powder for reconstitution with Sterile Water for Injection, USP. Each 35 mg vial contains 37 mg of agalsidase beta, as well as 222 mg mannitol, 20.4 mg sodium phosphate monobasic monohydrate, and 59.2 mg sodium phosphate dibasic heptahydrate. Following reconstitution as directed, 35 mg of agalsidase beta (7 mL) may be extracted from each 35 mg vial. Each 5 mg vial contains 5.5 mg of agalsidase beta, as well as 33.0 mg mannitol, 3.0 mg sodium phosphate monobasic monohydrate, and 8.8 mg sodium phosphate dibasic heptahydrate. Following reconstitution as directed, 5 mg of agalsidase beta (1 mL) may be extracted from each 5 mg vial." ], "clinical_pharmacology": [ "12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action FABRAZYME (agalsidase beta) provides an exogenous source of α-galactosidase A in Fabry disease patients. Agalsidase beta is internalized and transported into lysosomes where it exerts enzymatic activity and reduces accumulated GL-3. 12.2 Pharmacodynamics In Study 1, baseline mean values for plasma GL-3 were similar in the FABRAZYME (14.4 µg/mL) and the placebo (14.7 µg/mL) treatment groups. In the FABRAZYME treatment group, all 29 patients experienced normalization of plasma GL-3 levels (≤7.03 µg/mL) and they maintained normal plasma GL-3 levels for up to 60 months of treatment. Follow-up heart and kidney biopsies were assessed at month 54 in only 8 of the 44 patients, which showed sustained GL-3 clearance in the capillary endothelium of the kidney in 8 patients, and sustained GL-3 clearance in the capillary endothelium of the heart in 6 patients. The reduction in tissue GL-3 is summarized in the clinical studies section (Table 4) [see Clinical Studies (14) ] . In Study 2, patients in the FABRAZYME treatment group had mean plasma GL-3 levels that decreased from 9.0 µg/mL at baseline (N=49) to 4.8 µg/mL at one year (N=37) and 4.8 µg/mL at two years (N=18). In the placebo group, the mean plasma GL-3 was 9.1 µg/mL at baseline (N=31), 8.8 µg/mL at one year (N=21), and 9.4 µg/mL at two years (N=7). In Study 3, at baseline, all 14 males had elevated plasma GL-3 levels (i.e., >7.03 µg/mL), whereas the two female patients had normal plasma GL-3 levels. At weeks 24 and 48 of treatment, all 14 males had plasma GL-3 within the normal range. The two female patients' plasma GL-3 levels remained normal through study week 48. Histological evaluation of the capillary endothelium (vasculature), deep vessel endothelium, deep vessel smooth muscle cells, and perineurium of biopsied skin was conducted using histochemistry with light microscopy. Scoring was on a scale of 0 to 3 (0 defined as none; 1 as mild, 2 as moderate, and 3 as severe). At baseline, 12 of the 14 males had GL-3 inclusions present on skin biopsy (scores 1, 2, or 3) and all 12 achieved GL-3 inclusion scores of 0 at weeks 24 and 48 of treatment. The two females had no GL-3 inclusions in skin at baseline. In Study 5, in an analysis of 24 FABRAZYME-treated pediatric patients with Fabry disease aged 2 to <8 years at FABRAZYME initiation and with elevated plasma GL-3 levels (i.e., >7.03 μg/mL) at baseline, plasma GL-3 levels fell within the normal range (i.e., ≤7.03 μg/mL) in 91% (20/22), 95% (18/19), and 92% (12/13) of patients at 6, 12, and 24 months, respectively. 12.3 Pharmacokinetics The pharmacokinetics of FABRAZYME in clinical studies with adult and pediatric patients with Fabry disease is summarized in Table 3. FABRAZYME exhibited nonlinear pharmacokinetics following intravenous infusions at 0.3 (30% of the approved recommended dosage), 1 mg/kg, and 3 mg/kg (3 times the approved recommended dosage) in adult patients. The area under the plasma concentration-time curve (AUC inf ) and the maximum plasma concentration (C max ) increased greater than dose proportional with increasing doses. The AUC inf and C max following multiple dose administrations were comparable to their values at the first dose. In pediatric patients 8 to 16 years of age with body weight ranging from 27 to 65 kg, the AUC inf and C max following multiple dose administrations were higher compared to their values at the first dose. The increased plasma concentrations following multiple dose administration in pediatric patients could be due to formation of antidrug antibodies; however, such impact was not observed in adult patients [see Adverse Reactions (6.2) and Use in Specific Populations (8.4) ] . Table 3: FABRAZYME Pharmacokinetic Summary Dose Regimen Mean Infusion Length (min) Infusion number (n=patients) AUC inf µg min/mL C max µg/mL Half-life min CL mL/min/kg Vss Vss = volume of distribution at steady state. mL/kg All data reported as the mean ± standard deviation. Study FB9702-01: Phase 1/2 Study in Adult Patients with Fabry Disease 0.3 mg/kg q14 days × 5 132 1 (n=3) 79 ± 24 0.6 ± 0.2 92 ± 27 4.1 ± 1.2 225 ± 62 128 5 (n=3) 74 ± 30 0.6 ± 0.2 78 ± 67 4.6 ± 2.2 330 ± 231 1 mg/kg q14 days × 5 115 1 (n=3) 496 ± 137 5.0 ± 1.1 67 ± 12 2.1 ± 0.7 112 ± 13 120 5 (n=2) 466 ± 382 4.74 ± 4.3 45 ± 3 3.2 ± 2.6 243 ± 236 3 mg/kg q14 days × 5 129 1 (n=2) 4168 ± 1401 29.7 ± 14.6 102 ± 4 0.8 ± 0.3 81 ± 45 300 5 (n=2) 4327 ± 2074 19.8 ± 5.8 87 ± 21 0.8 ± 0.4 165 ± 80 Study 1: Phase 3 Study in Adult Patients with Fabry Disease 1 mg/kg q14 days × 11 280 1–3 (n=11) 649 ± 226 3.5 ± 1.6 89 ± 20 1.8 ± 0.8 120 ± 80 280 7 (n=11) 372 ± 223 2.1 ± 1.14 82 ± 25 4.9 ± 5.6 570 ± 710 300 11 (n=11) 784 ± 521 3.5 ± 2.2 119 ± 49 2.3 ± 2.2 280 ± 230 Study 3: Phase 2 Study in Pediatric Patients with Fabry Disease 1 mg/kg q14 days × 24 208 1 (n=8–9) 344 ± 307 2.2 ± 1.9 86 ± 27 5.8 ± 4.6 1097 ± 912 111 12 (n=15) 1007 ± 688 4.9 ± 2.4 130 ± 41 1.6 ± 1.2 292 ± 185 108 24 (n=9–10) 1238 ± 547 7.1 ± 4.4 151 ± 59 1.1 ± 0.8 247 ± 146" ], "clinical_pharmacology_table": [ "
Table 3: FABRAZYME Pharmacokinetic Summary
DoseRegimenMean Infusion Length (min)Infusion number (n=patients)AUCinf µg min/mLCmax µg/mLHalf-life minCL mL/min/kgVssVss = volume of distribution at steady state. mL/kg
All data reported as the mean ± standard deviation.
Study FB9702-01: Phase 1/2 Study in Adult Patients with Fabry Disease
0.3 mg/kgq14 days × 51321 (n=3)79 ± 240.6 ± 0.292 ± 274.1 ± 1.2225 ± 62
1285 (n=3)74 ± 300.6 ± 0.278 ± 674.6 ± 2.2330 ± 231
1 mg/kgq14 days × 51151 (n=3)496 ± 1375.0 ± 1.167 ± 122.1 ± 0.7112 ± 13
1205 (n=2)466 ± 3824.74 ± 4.345 ± 33.2 ± 2.6243 ± 236
3 mg/kgq14 days × 51291 (n=2)4168 ± 140129.7 ± 14.6102 ± 40.8 ± 0.381 ± 45
3005 (n=2)4327 ± 207419.8 ± 5.887 ± 210.8 ± 0.4165 ± 80
Study 1: Phase 3 Study in Adult Patients with Fabry Disease
1 mg/kgq14 days × 112801–3 (n=11)649 ± 2263.5 ± 1.689 ± 201.8 ± 0.8120 ± 80
2807 (n=11)372 ± 2232.1 ± 1.1482 ± 254.9 ± 5.6570 ± 710
30011 (n=11)784 ± 5213.5 ± 2.2119 ± 492.3 ± 2.2280 ± 230
Study 3: Phase 2 Study in Pediatric Patients with Fabry Disease
1 mg/kgq14 days × 242081 (n=8–9)344 ± 3072.2 ± 1.986 ± 275.8 ± 4.61097 ± 912
11112 (n=15)1007 ± 6884.9 ± 2.4130 ± 411.6 ± 1.2292 ± 185
10824 (n=9–10)1238 ± 5477.1 ± 4.4151 ± 591.1 ± 0.8247 ± 146
" ], "mechanism_of_action": [ "12.1 Mechanism of Action FABRAZYME (agalsidase beta) provides an exogenous source of α-galactosidase A in Fabry disease patients. Agalsidase beta is internalized and transported into lysosomes where it exerts enzymatic activity and reduces accumulated GL-3." ], "pharmacodynamics": [ "12.2 Pharmacodynamics In Study 1, baseline mean values for plasma GL-3 were similar in the FABRAZYME (14.4 µg/mL) and the placebo (14.7 µg/mL) treatment groups. In the FABRAZYME treatment group, all 29 patients experienced normalization of plasma GL-3 levels (≤7.03 µg/mL) and they maintained normal plasma GL-3 levels for up to 60 months of treatment. Follow-up heart and kidney biopsies were assessed at month 54 in only 8 of the 44 patients, which showed sustained GL-3 clearance in the capillary endothelium of the kidney in 8 patients, and sustained GL-3 clearance in the capillary endothelium of the heart in 6 patients. The reduction in tissue GL-3 is summarized in the clinical studies section (Table 4) [see Clinical Studies (14) ] . In Study 2, patients in the FABRAZYME treatment group had mean plasma GL-3 levels that decreased from 9.0 µg/mL at baseline (N=49) to 4.8 µg/mL at one year (N=37) and 4.8 µg/mL at two years (N=18). In the placebo group, the mean plasma GL-3 was 9.1 µg/mL at baseline (N=31), 8.8 µg/mL at one year (N=21), and 9.4 µg/mL at two years (N=7). In Study 3, at baseline, all 14 males had elevated plasma GL-3 levels (i.e., >7.03 µg/mL), whereas the two female patients had normal plasma GL-3 levels. At weeks 24 and 48 of treatment, all 14 males had plasma GL-3 within the normal range. The two female patients' plasma GL-3 levels remained normal through study week 48. Histological evaluation of the capillary endothelium (vasculature), deep vessel endothelium, deep vessel smooth muscle cells, and perineurium of biopsied skin was conducted using histochemistry with light microscopy. Scoring was on a scale of 0 to 3 (0 defined as none; 1 as mild, 2 as moderate, and 3 as severe). At baseline, 12 of the 14 males had GL-3 inclusions present on skin biopsy (scores 1, 2, or 3) and all 12 achieved GL-3 inclusion scores of 0 at weeks 24 and 48 of treatment. The two females had no GL-3 inclusions in skin at baseline. In Study 5, in an analysis of 24 FABRAZYME-treated pediatric patients with Fabry disease aged 2 to <8 years at FABRAZYME initiation and with elevated plasma GL-3 levels (i.e., >7.03 μg/mL) at baseline, plasma GL-3 levels fell within the normal range (i.e., ≤7.03 μg/mL) in 91% (20/22), 95% (18/19), and 92% (12/13) of patients at 6, 12, and 24 months, respectively." ], "pharmacokinetics": [ "12.3 Pharmacokinetics The pharmacokinetics of FABRAZYME in clinical studies with adult and pediatric patients with Fabry disease is summarized in Table 3. FABRAZYME exhibited nonlinear pharmacokinetics following intravenous infusions at 0.3 (30% of the approved recommended dosage), 1 mg/kg, and 3 mg/kg (3 times the approved recommended dosage) in adult patients. The area under the plasma concentration-time curve (AUC inf ) and the maximum plasma concentration (C max ) increased greater than dose proportional with increasing doses. The AUC inf and C max following multiple dose administrations were comparable to their values at the first dose. In pediatric patients 8 to 16 years of age with body weight ranging from 27 to 65 kg, the AUC inf and C max following multiple dose administrations were higher compared to their values at the first dose. The increased plasma concentrations following multiple dose administration in pediatric patients could be due to formation of antidrug antibodies; however, such impact was not observed in adult patients [see Adverse Reactions (6.2) and Use in Specific Populations (8.4) ] . Table 3: FABRAZYME Pharmacokinetic Summary Dose Regimen Mean Infusion Length (min) Infusion number (n=patients) AUC inf µg min/mL C max µg/mL Half-life min CL mL/min/kg Vss Vss = volume of distribution at steady state. mL/kg All data reported as the mean ± standard deviation. Study FB9702-01: Phase 1/2 Study in Adult Patients with Fabry Disease 0.3 mg/kg q14 days × 5 132 1 (n=3) 79 ± 24 0.6 ± 0.2 92 ± 27 4.1 ± 1.2 225 ± 62 128 5 (n=3) 74 ± 30 0.6 ± 0.2 78 ± 67 4.6 ± 2.2 330 ± 231 1 mg/kg q14 days × 5 115 1 (n=3) 496 ± 137 5.0 ± 1.1 67 ± 12 2.1 ± 0.7 112 ± 13 120 5 (n=2) 466 ± 382 4.74 ± 4.3 45 ± 3 3.2 ± 2.6 243 ± 236 3 mg/kg q14 days × 5 129 1 (n=2) 4168 ± 1401 29.7 ± 14.6 102 ± 4 0.8 ± 0.3 81 ± 45 300 5 (n=2) 4327 ± 2074 19.8 ± 5.8 87 ± 21 0.8 ± 0.4 165 ± 80 Study 1: Phase 3 Study in Adult Patients with Fabry Disease 1 mg/kg q14 days × 11 280 1–3 (n=11) 649 ± 226 3.5 ± 1.6 89 ± 20 1.8 ± 0.8 120 ± 80 280 7 (n=11) 372 ± 223 2.1 ± 1.14 82 ± 25 4.9 ± 5.6 570 ± 710 300 11 (n=11) 784 ± 521 3.5 ± 2.2 119 ± 49 2.3 ± 2.2 280 ± 230 Study 3: Phase 2 Study in Pediatric Patients with Fabry Disease 1 mg/kg q14 days × 24 208 1 (n=8–9) 344 ± 307 2.2 ± 1.9 86 ± 27 5.8 ± 4.6 1097 ± 912 111 12 (n=15) 1007 ± 688 4.9 ± 2.4 130 ± 41 1.6 ± 1.2 292 ± 185 108 24 (n=9–10) 1238 ± 547 7.1 ± 4.4 151 ± 59 1.1 ± 0.8 247 ± 146" ], "pharmacokinetics_table": [ "
Table 3: FABRAZYME Pharmacokinetic Summary
DoseRegimenMean Infusion Length (min)Infusion number (n=patients)AUCinf µg min/mLCmax µg/mLHalf-life minCL mL/min/kgVssVss = volume of distribution at steady state. mL/kg
All data reported as the mean ± standard deviation.
Study FB9702-01: Phase 1/2 Study in Adult Patients with Fabry Disease
0.3 mg/kgq14 days × 51321 (n=3)79 ± 240.6 ± 0.292 ± 274.1 ± 1.2225 ± 62
1285 (n=3)74 ± 300.6 ± 0.278 ± 674.6 ± 2.2330 ± 231
1 mg/kgq14 days × 51151 (n=3)496 ± 1375.0 ± 1.167 ± 122.1 ± 0.7112 ± 13
1205 (n=2)466 ± 3824.74 ± 4.345 ± 33.2 ± 2.6243 ± 236
3 mg/kgq14 days × 51291 (n=2)4168 ± 140129.7 ± 14.6102 ± 40.8 ± 0.381 ± 45
3005 (n=2)4327 ± 207419.8 ± 5.887 ± 210.8 ± 0.4165 ± 80
Study 1: Phase 3 Study in Adult Patients with Fabry Disease
1 mg/kgq14 days × 112801–3 (n=11)649 ± 2263.5 ± 1.689 ± 201.8 ± 0.8120 ± 80
2807 (n=11)372 ± 2232.1 ± 1.1482 ± 254.9 ± 5.6570 ± 710
30011 (n=11)784 ± 5213.5 ± 2.2119 ± 492.3 ± 2.2280 ± 230
Study 3: Phase 2 Study in Pediatric Patients with Fabry Disease
1 mg/kgq14 days × 242081 (n=8–9)344 ± 3072.2 ± 1.986 ± 275.8 ± 4.61097 ± 912
11112 (n=15)1007 ± 6884.9 ± 2.4130 ± 411.6 ± 1.2292 ± 185
10824 (n=9–10)1238 ± 5477.1 ± 4.4151 ± 591.1 ± 0.8247 ± 146
" ], "nonclinical_toxicology": [ "13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility There are no animal or human studies to assess the carcinogenic or mutagenic potential of FABRAZYME. A study to evaluate the effects of agalsidase beta on fertility and general reproduction was performed in male and female rats at doses up to 10 mg/kg/day (23 times the human dose, on a body surface area basis). There were no adverse effects of agalsidase beta on fertility and early embryonic development in rats." ], "carcinogenesis_and_mutagenesis_and_impairment_of_fertility": [ "13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility There are no animal or human studies to assess the carcinogenic or mutagenic potential of FABRAZYME. A study to evaluate the effects of agalsidase beta on fertility and general reproduction was performed in male and female rats at doses up to 10 mg/kg/day (23 times the human dose, on a body surface area basis). There were no adverse effects of agalsidase beta on fertility and early embryonic development in rats." ], "clinical_studies": [ "14 CLINICAL STUDIES The safety and efficacy of FABRAZYME were assessed in four clinical studies in patients with Fabry disease and one matched analysis based on data from observational studies. Study 1 was a randomized, double-blind, placebo-controlled, multinational, multicenter study of 58 patients with Fabry disease (56 males and 2 females), ages 16 to 61 years, all naive to enzyme replacement therapy [see Clinical Pharmacology (12.2) ] . Patients were randomized 1:1 to receive either FABRAZYME 1 mg/kg every 2 weeks or placebo for 20 weeks. Patients had a median age of 24 years in the placebo group and 33 years in the FABRAZYME group at baseline. At baseline, all patients had plasma αGAL activity below the detection limit and 79% had leukocyte αGAL activity below the detection limit. The median plasma GL-3 at baseline was 14.4 ng/uL in the placebo group and 14.7 ng/uL in the FABRAZYME group with the overall range of <1.2 to 36 ng/uL. The median eGFR at baseline was 98.5 mL/hr in the placebo group and 83.0 mL/hr in the FABRAZYME group (overall range 24 to 153 mL/hr). All patients were pretreated with acetaminophen and an antihistamine. Oral steroids were an additional option to the pretreatment regimen for patients who exhibited severe or recurrent infusion-associated reactions. Tissue biopsy specimens (kidney, heart, skin) were evaluated at baseline and at week 20 by light microscopy for the presence and number of GL-3 inclusions using a semi-quantitative methodology. Renal interstitial capillaries were scored based on the number of GL-3 inclusions on a scale of 0 to 3 (0 defined as \"nearly none\" or \"trace,\" 1 defined as \"mild,\" 2 defined as \"moderate,\" and 3 defined as \"severe\"). The primary endpoint was the proportion of patients in either group with a renal capillary GL-3 inclusion score of zero at week 20. In the FABRAZYME group, 20 of 29 (69%) patients achieved a score of zero while 0 of 29 placebo-treated patients achieved a score of zero (p<0.001). Similar reductions in GL-3 inclusions were observed in the capillary endothelium of the heart and skin (Table 4). All 58 patients who completed Study 1 were subsequently treated with FABRAZYME 1 mg/kg every two weeks in an open-label extension study. After six months of open-label treatment, most patients with available biopsy data achieved a GL-3 inclusion score of 0 in capillary endothelium (Table 4). Table 4: Proportion of Patients with Tissue GL-3 Inclusion Score of Zero (Study 1 and open-label treatment) 20 weeks of randomized treatment in Study 1 6 months of FABRAZYME open-label treatment Placebo (n=29) FABRAZYME (n=29) Placebo/FABRAZYME (n=29) Results reported where biopsies were available. FABRAZYME/FABRAZYME (n=29) Kidney 0/29 20/29 24/24 23/25 Heart 1/29 21/29 13/18 19/22 Skin 1/29 29/29 25/26 26/27 Study 2 was a randomized (2:1 FABRAZYME to placebo), double-blind, placebo-controlled, multinational, multicenter study of 82 patients (72 males and 10 females) with Fabry disease, all naive to enzyme replacement therapy [see Clinical Pharmacology (12.2) ] . Of the 82 enrolled patients, 51 and 31 patients were randomized to the FABRAZYME and placebo groups, respectively. Patients were 20 to 72 years of age with a median age of 45 years at baseline, a median age of 36 years at Fabry disease diagnosis, and at a median of 10 years at symptom onset. The median plasma GL-3 at baseline was 9.3 ug/mL in the placebo group and 8.9 ug/mL in the FABRAZYME group with the overall range of 2.8 to 18.9 ug/mL. At baseline, patients had median plasma αGAL activity 1.5 nmol/hour/mL (range: 0 to 1.5), leukocyte αGAL activity 1.8 nmol/hour/mL (range: 0 to 4.0), eGFR 52 mL/min/1.73 m 2 (range: 25 to 113), and protein to creatinine ratio 0.9 mg/mg (range: 0 to 7.3). Patients received either 1 mg/kg FABRAZYME IV or placebo every two weeks for up to 35 months (median follow-up 18.5 months). The primary efficacy endpoint was the time to first occurrence of a clinically significant event (renal, cardiac, or cerebrovascular event, or death). A total of 14 of 51 (28%) FABRAZYME-treated patients and 13 of 31 (42%) placebo-treated patients experienced a clinically significant event (HR 0.57, 95% CI: 0.27, 1.22). Study 3 (Pediatric Study) was an open-label, single-arm, multinational, multicenter study in 16 pediatric patients with Fabry disease (14 males, 2 females), aged 8 to 16 years (median 12 years) [see Clinical Pharmacology (12.2) ] . At baseline, patients had median plasma αGAL activity 0.2 nmol/hour/mL (range: 0.0, 2.0) and median leukocyte αGAL activity 0.5 nmol/hour/mg (range: 0.0, 12.5). All 14 males had elevated plasma GL-3 levels (i.e., >7.03 µg/mL) at baseline, whereas the two females had normal plasma GL-3 levels. Median eGFR was normal (112.1 mL/min/1.73 m 2 ) at baseline and did not change during treatment, and median urinary protein was 151.0 mg/24 hr (range: 70.0, 431.0). All patients received FABRAZYME 1 mg/kg every two weeks for up to 48 weeks. Study 5 was a long-term, observational study assessing the rate of decline in renal function (eGFR slope) in 122 patients with Fabry disease aged 16 years and older treated with FABRAZYME. Treated patients were matched 1:1 based on age (at FABRAZYME initiation), sex, Fabry disease subtype (classic or non-classic), and baseline eGFR to a historical cohort of untreated patients with Fabry disease. The median follow-up time was 3 years in the untreated group and 4.5 years in the treated group (maximum follow-up time 5 years in both groups). In the matched cohort, the median age (at FABRAZYME initiation) was 35 years, 72% of patients were male, 84% of patients had the classic Fabry disease subtype, and the median baseline eGFR was 93 mL/min/1.73 m 2 . The estimated mean eGFR slope was -1.5 mL/min/1.73 m 2 /year in the FABRAZYME-treated group and -3.2 mL/min/1.73 m 2 /year in the untreated group (eGFR slope difference: 1.7 mL/min/1.73 m 2 /year; 95% CI: 0.5, 3.0)." ], "clinical_studies_table": [ "
Table 4: Proportion of Patients with Tissue GL-3 Inclusion Score of Zero (Study 1 and open-label treatment)
20 weeks of randomized treatment in Study 16 months of FABRAZYME open-label treatment
Placebo (n=29) FABRAZYME (n=29) Placebo/FABRAZYME (n=29)Results reported where biopsies were available.FABRAZYME/FABRAZYME (n=29)
Kidney0/2920/2924/2423/25
Heart1/2921/2913/1819/22
Skin1/2929/2925/2626/27
" ], "how_supplied": [ "16 HOW SUPPLIED/STORAGE AND HANDLING FABRAZYME (agalsidase beta) for injection is supplied as a sterile, nonpyrogenic, white to off-white lyophilized cake or powder in single-dose vials. 35 mg vial: NDC 58468-0040-1 5 mg vial: NDC 58468-0041-1 Refrigerate vials of FABRAZYME at 2°C to 8°C (36°F to 46°F). Do not use FABRAZYME after the expiration date on the vial. This product contains no preservatives. Reconstituted and diluted solutions of FABRAZYME should be used immediately. If immediate use is not possible, the reconstituted and diluted solution may be stored for up to 24 hours at 2°C to 8°C (36°F to 46°F) [see Dosage and Administration (2.2) ] ." ], "storage_and_handling": [ "Refrigerate vials of FABRAZYME at 2°C to 8°C (36°F to 46°F). Do not use FABRAZYME after the expiration date on the vial. This product contains no preservatives. Reconstituted and diluted solutions of FABRAZYME should be used immediately. If immediate use is not possible, the reconstituted and diluted solution may be stored for up to 24 hours at 2°C to 8°C (36°F to 46°F) [see Dosage and Administration (2.2) ] ." ], "information_for_patients": [ "17 PATIENT COUNSELING INFORMATION Hypersensitivity Reactions Including Anaphylaxis and Infusion-Associated Reactions (IARs) Advise the patient and caregiver that life-threatening hypersensitivity reactions, including anaphylaxis, and IARs may occur with FABRAZYME treatment. Advise the patient or caregiver that anaphylaxis has occurred during the early course of enzyme replacement therapy and after extended duration therapy. Inform the patient and caregiver of the symptoms of life-threatening hypersensitivity reactions, including anaphylaxis, and IARs and to seek immediate medical care should symptoms occur [see Warnings and Precautions (5.1 , 5.2) ]. FABRAZYME Exposure During Pregnancy or Lactation Advise a pregnant or lactating woman exposed to FABRAZYME to report FABRAZYME exposure to her healthcare provider and by calling 1-800-633-1610, option 1 [see Use in Specific Populations (8.1 ., 8.2) ] . Patient Registry Inform the patient and/or caregiver that a registry has been established for Fabry patients in order to better understand the variability and progression of Fabry disease in the population as a whole, and in women along with monitoring and evaluating long-term treatment effects of FABRAZYME. Additionally, the registry also monitors the effect of FABRAZYME on pregnant women and their offspring. Encourage the patient and/or caregiver to contact the registry program by visiting www. registrynxt.com or by calling 1-800-745-4447, extension 15500." ], "spl_unclassified_section": [ "Manufactured by: Genzyme Corporation 450 Water Street Cambridge, MA 02141 A SANOFI COMPANY U.S. License Number: 1596 FABRAZYME and Genzyme are registered trademarks of Genzyme Corporation" ], "package_label_principal_display_panel": [ "PRINCIPAL DISPLAY PANEL - 5 mg Vial Carton NDC 58468-0041-1 Rx only Fabrazyme ® agalsidase beta 5 mg per vial for Injection For Intravenous Infusion after Dilution One single-dose vial Discard unused portion sanofi PRINCIPAL DISPLAY PANEL - 5 mg Vial Carton", "PRINCIPAL DISPLAY PANEL - 35 mg Vial Carton NDC 58468-0040-1 Rx only Fabrazyme ® agalsidase beta 35 mg per vial for Injection For Intravenous Infusion after Dilution One single-dose vial Discard unused portion sanofi PRINCIPAL DISPLAY PANEL - 35 mg Vial Carton" ], "set_id": "988513ab-b06f-4dd0-93f7-d2d4531dcce4", "id": "9b786f81-f4d8-4bc6-8f5f-68adbbfb60d1", "effective_time": "20250822", "version": "35", "openfda": { "application_number": [ "BLA103979" ], "brand_name": [ "Fabrazyme" ], "generic_name": [ "AGALSIDASE BETA" ], "manufacturer_name": [ "Genzyme Corporation" ], "product_ndc": [ "58468-0040", "58468-0041" ], "product_type": [ "HUMAN PRESCRIPTION DRUG" ], "route": [ "INTRAVENOUS" ], "substance_name": [ "AGALSIDASE BETA" ], "rxcui": [ "1804755", "1804758", "1804760", "1804762" ], "spl_id": [ "9b786f81-f4d8-4bc6-8f5f-68adbbfb60d1" ], "spl_set_id": [ "988513ab-b06f-4dd0-93f7-d2d4531dcce4" ], "package_ndc": [ "58468-0041-1", "58468-0040-1" ], "is_original_packager": [ true ], "nui": [ "M0000794", "N0000175822" ], "pharm_class_cs": [ "alpha-Glucosidases [CS]" ], "pharm_class_epc": [ "Hydrolytic Lysosomal Neutral Glycosphingolipid-specific Enzyme [EPC]" ], "unii": [ "RZD65TSM9U" ] } } ] }