Migalastat is an oral 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. Fabry disease is a rare, X-linked lysosomal storage disorder caused by mutations in the GLA gene encoding the enzyme alpha-Gal A. Complete or partial deficiency in this enzyme leads to intracellular accumulation of the glycosphingolipids, globotriaosylceramide (GL-3) and globotriaosylsphingosine (lyso-Gb3). Glycosphingolipids accumulate in the lining of blood vessels in the heart, kidney, and other organs in patients without an adequate presence of alpha-Gal A. Crises of severe pain in the extremities (acroparesthesias), hypohidrosis, corneal opacities, and dysfunction of several organs (kidney, brain, heart) are the primary manifestations, and patients often have decreased life expectancy and experience renal failure, cardiomyopathy, and cerebrovascular accidents. A correct diagnosis of Fabry disease has considerable implications regarding treatment, management, and counseling. Prior to migalastat treatment, the amenable GLA variant must be interpreted by a clinical genetics professional as causing Fabry disease (pathogenic, likely pathogenic) in the clinical context of the patient. 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), consultation with a clinical genetics professional is strongly recommended. In a clinical trial of 45 adults with Fabry disease, patients treated with migalastat for 6 months had a greater reduction in GL-3 in blood vessels of the kidneys, measured by biopsy samples, compared to patients receiving placebo. Migalastat is well tolerated with the most common adverse drug reactions being headache, nasopharyngitis, urinary tract infection, nausea, and fever.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
-Administer on an empty stomach; do not consume food at least 2 hours before and 2 hours after taking migalastat to allow a minimum of 4 hours fast. Clear liquids may be consumed during the 4 hour period.
-Swallow capsules intact; do not cut, chew, or crush.
-Do not take on 2 consecutive days. If a dose is missed entirely for the day, take the missed dose only if it is within 12 hours of the normal time that the dose should have been taken. If more than 12 hours have passed, resume taking migalastat at the next planned dosing day and time, according to the every-other-day dosing schedule.
Adverse reactions reported in at least 5% of migalastat-treated patients (n = 34) in a 6-month, placebo-controlled trial included headache (35%), naso-pharyngitis (18%), urinary tract infection (urinary tract infection, cystitis, kidney infection; 15%), fever (12%), back pain (9%), cough (9%), and epistaxis (9%).
Gastrointestinal adverse reactions reported in at least 5% of migalastat-treated patients (n = 34) in a 6-month, placebo-controlled trial included nausea (12%), abdominal pain (9%), and diarrhea (9%). Vomiting was also reported in additional studies with migalastat.
Migalastat exposure is significantly increased in patients with severe renal impairment (eGFR less than 30 mL/minute/1.732); therefore, use is not recommended in patients with severe renal impairment, renal failure, or end-stage renal disease requiring dialysis.
There is not sufficient available data regarding migalastat use during pregnancy to inform a drug-associated risk. Animal data did not reveal evidence of developmental effects to the fetus when administered to pregnant rats and rabbits during organogenesis at doses causing plasma exposures up to 21 and 54 times, respectively, the exposure at the recommended human dose. Based on animal data, migalastat may cause transient and fully reversible male infertility; there is no human data regarding fertility. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to migalastat; information about the registry can be obtained at www.fabrypregnancyregistry.com or by calling 1-855-239-0758.
There are no data on the presence of migalastat in human milk, the effects on a breast-fed infant, or the effects on milk production. Migalastat is present in the milk of lactating rats. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.
For the treatment of Fabry disease in adults with an amenable galactosidase alpha gene (GLA) variant:
NOTE: Migalastat has been designated as an orphan drug for this indication by the FDA.
Oral dosage:
Adults: 123 mg PO once every other day at the same time of the day. Administer on an empty stomach; do not consume food at least 2 hours before and 2 hours after taking migalastat to allow a minimum of 4 hours fast. Clear liquids may be consumed during the 4 hour period.
Maximum Dosage Limits:
-Adults
123 mg PO once every other day.
-Geriatric
123 mg PO once every other day.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
eGFR 30 mL/minute/1.73m2 or more: No dosage adjustment necessary.
eGFR less than 30 mL/minute/1.73m2: Use is not recommended in patients with severe renal impairment or end-stage renal disease requiring dialysis. Migalastat is substantially excreted by the kidneys, but has not been studied in patients with Fabry disease who have an eGFR less than 30 mL/minute/1.73m2.
*non-FDA-approved indication
Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Separate the administration of oral caffeine and migalastat by at least 2 hours if concomitant use is necessary. Simultaneous coadministration may decrease migalastat exposure and efficacy. Coadministration of 190 mg caffeine reduced the mean migalastat AUC by 55%.
Acetaminophen; Caffeine: (Moderate) Separate the administration of oral caffeine and migalastat by at least 2 hours if concomitant use is necessary. Simultaneous coadministration may decrease migalastat exposure and efficacy. Coadministration of 190 mg caffeine reduced the mean migalastat AUC by 55%.
Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Separate the administration of oral caffeine and migalastat by at least 2 hours if concomitant use is necessary. Simultaneous coadministration may decrease migalastat exposure and efficacy. Coadministration of 190 mg caffeine reduced the mean migalastat AUC by 55%.
Acetaminophen; Caffeine; Pyrilamine: (Moderate) Separate the administration of oral caffeine and migalastat by at least 2 hours if concomitant use is necessary. Simultaneous coadministration may decrease migalastat exposure and efficacy. Coadministration of 190 mg caffeine reduced the mean migalastat AUC by 55%.
Aspirin, ASA; Butalbital; Caffeine: (Moderate) Separate the administration of oral caffeine and migalastat by at least 2 hours if concomitant use is necessary. Simultaneous coadministration may decrease migalastat exposure and efficacy. Coadministration of 190 mg caffeine reduced the mean migalastat AUC by 55%.
Aspirin, ASA; Caffeine: (Moderate) Separate the administration of oral caffeine and migalastat by at least 2 hours if concomitant use is necessary. Simultaneous coadministration may decrease migalastat exposure and efficacy. Coadministration of 190 mg caffeine reduced the mean migalastat AUC by 55%.
Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) Separate the administration of oral caffeine and migalastat by at least 2 hours if concomitant use is necessary. Simultaneous coadministration may decrease migalastat exposure and efficacy. Coadministration of 190 mg caffeine reduced the mean migalastat AUC by 55%.
Butalbital; Acetaminophen; Caffeine: (Moderate) Separate the administration of oral caffeine and migalastat by at least 2 hours if concomitant use is necessary. Simultaneous coadministration may decrease migalastat exposure and efficacy. Coadministration of 190 mg caffeine reduced the mean migalastat AUC by 55%.
Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Separate the administration of oral caffeine and migalastat by at least 2 hours if concomitant use is necessary. Simultaneous coadministration may decrease migalastat exposure and efficacy. Coadministration of 190 mg caffeine reduced the mean migalastat AUC by 55%.
Butalbital; Aspirin; Caffeine; Codeine: (Moderate) Separate the administration of oral caffeine and migalastat by at least 2 hours if concomitant use is necessary. Simultaneous coadministration may decrease migalastat exposure and efficacy. Coadministration of 190 mg caffeine reduced the mean migalastat AUC by 55%.
Caffeine: (Moderate) Advise patients to avoid consuming caffeine at least 2 hours before or after taking migalastat to give a minimum 4 hour fast. Simultaneous use may decrease migalastat exposure and efficacy. Coadministration of 190 mg caffeine reduced the mean migalastat AUC by 55%. (Moderate) Separate the administration of oral caffeine and migalastat by at least 2 hours if concomitant use is necessary. Simultaneous coadministration may decrease migalastat exposure and efficacy. Coadministration of 190 mg caffeine reduced the mean migalastat AUC by 55%.
Caffeine; Sodium Benzoate: (Moderate) Separate the administration of oral caffeine and migalastat by at least 2 hours if concomitant use is necessary. Simultaneous coadministration may decrease migalastat exposure and efficacy. Coadministration of 190 mg caffeine reduced the mean migalastat AUC by 55%.
Ergotamine; Caffeine: (Moderate) Separate the administration of oral caffeine and migalastat by at least 2 hours if concomitant use is necessary. Simultaneous coadministration may decrease migalastat exposure and efficacy. Coadministration of 190 mg caffeine reduced the mean migalastat AUC by 55%.
Food: (Moderate) Advise patients to take migalastat on an empty stomach and avoid food at least 2 hours before or after taking migalastat to give a minimum 4 hour fast. Simultaneous use may decrease migalastat exposure and efficacy.
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, migalastat dissociates from alpha-Gal A allowing it to break down the glycosphingolipids, globotriaosylceramide (GL-3) and globotriaosylsphingosine (lyso-Gb3). 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 retain enzymatic activity. Those GLA variants produce alpha-Gal A proteins that may be stabilized by migalastat thereby restoring their trafficking to lysosomes and their intralysosomal activity. Without alpha-Gal A, globotriaosylceramide accumulates in the lysosomes. Prolonged elevated concentrations of glycosphingolipids, especially globotriaosylceramide, in many body tissues promote the clinical manifestations of Fabry disease, such as renal failure, cardiomyopathy and cerebrovascular accidents.
Migalastat is administered orally. There was no detectable plasma protein binding after administration of [14C]-migalastat in the concentration range between 1 to 100 microM. At steady state, the mean volume of distribution was 89 L (range: 77 to 133 L). Based on in vivo data, migalastat is a substrate for uridine diphosphate glucuronosyltransferase (UDPGT), a minor elimination pathway. After a radiolabeled dose of migalastat in healthy subjects, about 77% of the dose was excreted in the urine and 20% in the feces. The mean total body clearance and elimination half-life were 12.5 L/hour and 4 hours, respectively.
Affected cytochrome P450 isoenzymes and drug transporters: none
-Route-Specific Pharmacokinetics
Oral Route
After a single dose of 123 mg PO, the bioavailability of migalastat was approximately 75% and the time to peak plasma concentration was approximately 3 hours. Plasma migalastat exposure demonstrated dose-proportional increases at oral doses from 75 mg to 1,250 mg. There was no accumulation after the administration of migalastat 123 mg PO every other day. Administration of migalastat 1 hour before a high-fat or light meal, or 1 hour after a light meal, reduced the mean migalastat AUC by 37% to 42% and Cmax by 15% to 39% compared to the fasting state.
-Special Populations
Renal Impairment
Increasing renal dysfunction is associated with an increased migalastat AUC, while the Cmax remains unchanged. In a single-dose study in patients with varying degrees of renal impairment, migalastat AUC was increased by 1.2-, 1.8-, and 4.3-fold in patients with mild (eGFR 60 to 90 mL/minute/1.73m2), moderate (eGFR 30 to 59 mL/minute/1.73m2), and severe renal impairment (eGFR less than 30 mL/minute/1.73m2), respectively.
Gender Differences
Gender has no clinically significant impact on the systemic exposure of migalastat.
Ethnic Differences
Race has no clinically significant impact on the systemic exposure of migalastat.