CLASSES
Fabry Disease Agents
DESCRIPTION
Oral alpha-galactosidase A (alpha-Gal A) pharmacological chaperone
Used for treatment of adults with confirmed diagnosis of Fabry disease and an amenable galactosidase alpha gene (GLA) variant based on in vitro assay
Most common adverse reactions are headache, nasopharyngitis, urinary tract infection, nausea, and fever
COMMON BRAND NAMES
Galafold
HOW SUPPLIED
Galafold Oral Cap: 123mg
DOSAGE & INDICATIONS
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
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.
DOSING CONSIDERATIONS
Hepatic Impairment
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Renal Impairment
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.
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.
STORAGE
Galafold:
- Protect from moisture
- Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
- Store in original container
CONTRAINDICATIONS / PRECAUTIONS
Dialysis, renal failure, renal impairment
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.
Infertility, pregnancy
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.
Breast-feeding
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.
ADVERSE REACTIONS
Moderate
cystitis / Delayed / Incidence not known
Mild
headache / Early / 35.0-35.0
pharyngitis / Delayed / 18.0-18.0
infection / Delayed / 15.0-15.0
fever / Early / 12.0-12.0
nausea / Early / 12.0-12.0
back pain / Delayed / 9.0-9.0
cough / Delayed / 9.0-9.0
epistaxis / Delayed / 9.0-9.0
abdominal pain / Early / 9.0-9.0
diarrhea / Early / 9.0-9.0
vomiting / Early / Incidence not known
DRUG INTERACTIONS
There are no drug interactions associated with Migalastat products.
PREGNANCY AND LACTATION
Pregnancy
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.
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, 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.
PHARMACOKINETICS
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
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.