BRIEF SUMMARY

MIGALASTAT- (Aug 2018)

Indn-     To treat adult with  Fabry disease                       

Comp-  ­ Capsules: 123 mg migalastat.                                                                                   • The recommended dosage regimen of GALAFOLD is 123 mg orally once every other day at the same time of day. 

ADR-   Most common adverse drug reactions = 10% are: headache, nasopharyngitis, urinary tract infection, nausea, and pyrexia

CI- ­ None.

Pat Inform 

Advise the patient:                                                                                                                • To take GALAFOLD once every other day at the same time of day. • Take GALAFOLD on an empty stomach. Do not consume food at least 2 hours before and 2 hours after taking GALAFOLD to give a minimum 4 hours fast. Clear liquids can be consumed during this 4-hour period.

• Not to take GALAFOLD 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 GALAFOLD at the next planned dosing day and time, according to the every-other-day dosing schedule.

================================================================

U.S. FDA APPROVED  DRUGS DURING 2018

Sr.No-  30

ADVERSE REACTIONS-

­ Most common adverse drug reactions = 10% are: headache, nasopharyngitis, urinary tract infection, nausea, and pyrexia.

CONTRAINDICATIONS-

­ None.

PATIENT COUNSELING INFORMATION-

Advise the patient to read the FDA-approved patient labeling (Patient Information and

Instructions for Use.

Advise the patient:

• To take GALAFOLD once every other day at the same time of day. • Take GALAFOLD on an empty stomach. Do not consume food at least 2 hours before and 2 hours after taking GALAFOLD to give a minimum 4 hours fast. Clear liquids can be consumed during this 4-hour period.

• Not to take GALAFOLD 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 GALAFOLD at the next planned dosing day and time, according to the every-other-day dosing schedule.

• Swallow capsules whole. Do not cut, crush, or chew.

Manufactured for: Amicus Therapeutics U.S., Inc. 1 Cedar Brook Drive Cranbury, NJ 08512 GALAFOLD™ is a trademark of Amicus Therapeutics, Inc.

CLINICAL PHARMACOLOGY

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.

 * Based on available published data, the GLA variant c.937G>T, (p.(D313Y)) is considered benign (not causing Fabry disease).

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.

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 AUC0-8 by 37% to 42% and Cmax by 15% to 39% compared to the fasting state [see Dosage and Administration (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.

USE IN SPECIFIC POPULATIONS

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

The estimated background risk for major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, 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.

2 Lactation Risk Summary There are no human data available 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 child from GALAFOLD or from the underlying maternal condition

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 

4 Pediatric Use- The safety and effectiveness of GALAFOLD have not been established in pediatric patients.

5 Geriatric Use Clinical trials of GALAFOLD did not include a sufficient number of patients 65 years and older to determine whether they respond differently from younger patients. 

6. Excretion-  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)