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.

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.

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.

7.1 Effect of Other Drugs on GALAFOLD

Co-administration of GALAFOLD with caffeine decreases migalastat AUC and Cmax [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)].

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 [email protected], or visiting www.fabrypregnancyregistry.com.

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 [email protected], or visit www.fabrypregnancyregistry.com.

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 m2).

GALAFOLD has not been studied in patients with Fabry disease who have an eGFR less than 30 mL/min/1.73 m2. 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 m2 and above) [see Clinical Pharmacology (12.3)].

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-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, 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 (mutations) which produced mutant 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 mutant 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 mutant alpha-Gal A proteins into the lysosome or the dissociation of migalastat from the mutant 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 which are amenable to treatment with GALAFOLD, based on the in vitro assay data, are shown in Table 2. Inclusion of GLA variants in this table does not reflect interpretation of their clinical significance in Fabry disease. Whether a certain amenable GLA variant in a patient with Fabry disease is disease-causing or not should be determined by the prescribing physician (in consultation with a clinical genetics professional, if needed) prior to treatment initiation. Consultation with a clinical genetics professional is strongly recommended in cases where the amenable GLA variant is of uncertain clinical significance (VUS, variant of uncertain significance) or may be benign (not causing Fabry disease).

If a GLA variant does not appear in Table 2, it is either non-amenable (if tested) or has not been tested for in vitro amenability. For further information, please contact Amicus Medical Information at 1‑877‑4AMICUS or [email protected].

12.2 Pharmacodynamics

In Study 1, 31 of 50 patients with amenable GLA variants (18 on GALAFOLD, 13 on placebo) had lyso‑Gb3 assessments available after 6 months of treatment. The median change from baseline to month 6 in plasma lyso‑Gb3 (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‑Gb3 (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‑Gb3.

In Study 2, 46 of 56 patients with amenable GLA variants (31 on GALAFOLD, 15 on enzyme replacement therapy (ERT)) had lyso‑Gb3 assessments available after 18 months of treatment. The median change from baseline to month 18 in plasma lyso‑Gb3 (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 (tmax) was approximately 3 hours. Plasma migalastat exposure (AUC0‑∞ and Cmax) 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 AUC0‑∞ by 37% to 42% and Cmax by 15% to 39% compared to the fasting state [see Dosage and Administration (2.2)].

Distribution

The apparent volume of distribution (Vz/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 [14C]‑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 [14C]‑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 (t½) 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 m2), moderate (eGFR 30 to 59 mL/min/1.73 m2), and severe renal impairment (eGFR less than 30 mL/min/1.73 m2), respectively, while the Cmax 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 AUC0‑∞ by 55% and Cmax by 60% compared to without caffeine co‑administration. The tmax 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), Drug Interactions (7.1)].

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.