migalastat (Rx)

>10%

Headache (35%)

Nasopharyngitis (18%)

Urinary tract infection (15%)

Nausea (12%)

Pyrexia (12%)

1-10%

Abdominal pain (9%)

Back pain (9%)

Cough (9%)

Diarrhea (9%)

Epistaxis (9%)

Contraindications

None reported by the manufacturer

Cautions

This porduct was 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.

Pregnancy

Current study 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; email fabrypregnancy@ubc.com, or visit www.fabrypregnancyregistry.com

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

Infertility

• Effects on fertility in humans not studied; transient and fully reversible infertility in male rats associated with treatment at systemic exposure (AUC) equivalent to human exposure at recommended dose; complete reversibility was seen at 4 weeks after termination of treatment; drug did not affect fertility in female rats

Lactation

Current study 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 Pregnancy Coordinating Center at 1-888-239-0758, email fabrypregnancy@ubc.com, or visit www.fabrypregnancyregistry.com

There are no human data available on the presence of the drug in human milk, the effects on breastfed infant, or on milk production; the drug is present in the milk of lactating rats; when a drug is present in animal milk, it is likely that the drug will be present in human milk; developmental and health benefits of breastfeeding should be considered along with mother’s clinical need for therapy and any potential adverse effects on the breastfed child from drug or from underlying maternal condition

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Binds to and stabilizes endogenous alpha-galactosidase A (alpha-Gal A) that is made in the patient’s own cells, with the intention of enabling its trafficking from the endoplasmic reticulum to lysosomes (designed to act as a “pharmacological chaperone”); once delivered to lysosomes, the alpha-Gal A enzyme can degrade the accumulated glycolipid (globotriaosylceramide [GL-3]) and globotriaosylsphingosine (lyso-Gb3)

Certain GLA variants (mutations) causing Fabry disease result in production of abnormally folded and less stable forms of 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

Absorption

Absolute bioavailability: ~ 75%

Peak plasma time: 3 hr

Plasma exposure (AUC and Cmax): Showed dose-proportional increases at oral doses from 75-1250 mg (doses from 0.5- to 8.3-fold of approved recommended dosage); drug does not accumulate following administration of drug every other day

Effects of food

• Administration 1 hr before a high-fat (850 calories; 56% from fat) or light meal (507 calories; 30% from fat), or 1 hr after a light meal, reduced the mean migalastat AUC by 37-42% and peak plasma concentration by 15-39% compared to fasting state

Distribution

Apparent volume of distribution (Vz/F): 89 L (range: 77-133 L) at steady state in Fabry patients

Metabolism

Based upon in vivo data, drug is a substrate for uridine diphosphate glucuronosyltransferase (UDPGT), a minor elimination pathway

Elimination

Urine (77%) and feces (20%)

Half-life: 4 hr

Clearance: 12.5 L/hr

Oral Administration

Take on empty stomach; do not consume food at least 2 hr before and 2 hr after taking drug to give a minimum 4-hr fast; clear liquids can be consumed during this 4-hour period

Not to be taken on 2 consecutive days

Swallow capsules whole; do not cut, crush, or chew

Missed dose

• If dose missed entirely for the day, take missed dose only if within 12 hours of normal time dose should have been taken; if more than 12 hours passed, resume taking drug at next planned dosing day and time, according to every-other-day dosing schedule

Storage

Store at USP controlled room temperature of 20-25°C (68-77°F), with excursions permitted between 15° and 30°C (59° and 86°F)