Galafold

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).

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.

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.

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.

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.

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)].

Pediatric Use

The safety and effectiveness of GALAFOLD have not been established in pediatric patients.

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.

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)].

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.

 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