Consumer medicine information

Galafold

Migalastat

BRAND INFORMATION

Brand name

Galafold

Active ingredient

Migalastat

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Galafold.

What is in this leaflet

This leaflet answers some common questions about Galafold®. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you being given Galafold® against the expected benefits it will have for you.

If you have any concerns about being given this medicine, ask your doctor.

Keep this leaflet. You may need to read it again.

What Galafold® is used for

Galafold® contains the active substance migalastat.

This medicine is used for the long- term treatment of Fabry disease in adults and adolescents aged 16 years and older who have certain genetic mutations (amenable mutations).

Fabry disease is caused by the lack of or a faulty enzyme called alpha- galactosidase A (α–Gal A).Depending upon the kind of mutation (change) in the gene that produces α– Gal A, the enzyme does not work properly or is completely absent. This enzyme defect leads to abnormal deposits of a fatty substance known as globotriaosylceramide (GL-3) leading to the symptoms of Fabry disease.

This medicine works by stabilising the enzyme that your body produces naturally, so that it can work better to reduce the amount of GL-3 that has accumulated in your cells and tissues.

Ask your doctor if you have any questions about why this medicine has been prescribed for you.

Before you take Galafold®

When you must not take Galafold®

  • if you are allergic to migalastat or any of the other ingredients of this medicine (listed under What Galafold® contains)

You should not use this medicine after the expiry date printed on the Galafold® pack or if the packaging is torn or shows signs of tampering.

Before you start to take Galafold®

Talk to your doctor before taking Galafold® if you are currently taking enzyme replacement therapy.

You should not take Galafold® if you are also receiving enzyme replacement therapy.

Tell your doctor if you have any kidney problems.

If you have not told your doctor about any of the above, tell him/her before you take Galafold®.

Children and adolescents
This medicine has not been studied in children and adolescents under the age of 16 years; therefore, the effects in this age group are not known and use is not recommended.

Pregnancy, breast-feeding, andfertility

Pregnancy
There is very limited experience with the use of this medicine in pregnant women. If you are pregnant, think you may be pregnant, or are planning to have a baby, do not take this medicine until you have checked with your doctor, pharmacist, or nurse. It is not recommended to use Galafold® during pregnancy. While taking Galafold® you should use effective birth control.

Breast-feeding
Do not take this medicine if you are breast-feeding, until you have spoken with your doctor, pharmacist, or nurse. It is not yet known whether this medicine passes into human breast milk. Your doctor will decide whether you need to stop breast- feeding or temporarily stop your medicine.

Fertility
It is not yet known if this medicine affects fertility in both men or women.

If you are planning to have a baby, ask your doctor for advice.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you buy without a prescription from your pharmacy, supermarket, health food shop, naturopath, herbalist or internet.

How to take Galafold®

Always take this medicine exactly as your doctor, pharmacist, or nurse has told you. Check with your doctor, pharmacist, or nurse if you are not sure.

Take one capsule every second day at the same time of the day.

Take the GALAFOLD® capsule on an empty stomach. Do not eat food at least 2 hours before and 2 hours after taking your medicine. Food may interfere with the absorption of the medicine. A minimum of 4 hours fasting around taking your medicine is needed to allow your medicine to be fully absorbed. Clear liquids can be consumed during this period.

How to take Galafold®

Swallow the capsule whole. Do not cut, crush, or chew the capsule.

Refer to Figure 1, below, for further instructions on using the blister pack.

If you forget to take Galafold®

If you forget to take your capsule at the usual time but remember later that day, take the capsule when you remember on the same day.

If you miss a dose of this medicine for an entire day, do not take the missed capsule. Do not take Galafold capsules daily on consecutive days to make up for your missed dose. You should only take Galafold once every other day. Wait another 24 hours and take the next capsule at the time when you would usually take this medicine. Do not take two capsules together to make up for your missed dose.

If you stop taking Galafold®

Do not stop taking this medicine without talking to your doctor.

If you take more Galafold® than you should

If you take more capsules than you should, then you should stop taking the medicine and contact your doctor or pharmacist, or telephone the Poisons Information Centre on 13 11 26. You may get a headache and feel dizzy.

If you have any further questions on the use of this medicine, ask your doctor, pharmacist, or nurse.

While you are taking Galafold®

Things you must do

Keep all of your doctor’s appointments so your progress can be checked.

Your doctor may want to do some blood and other tests from time to time to check on your progress and to check for any unwanted side effects.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Galafold®.

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Do not be alarmed by the following list of side effects, you may not experience any of them.

Tell your doctor if you notice any of the following common side effects and they worry you:

Very common: may affect more than 1 in 10 people

  • Headache

Common: may affect up to 1 in 10 people

  • Palpitations (the feeling of a pounding heart)
  • Sensation of spinning (vertigo)
  • Diarrhoea
  • Feeling sick (nausea)
  • Stomach ache
  • Constipation
  • Dry mouth
  • Sudden need to pass stools
  • Indigestion (dyspepsia)
  • Tiredness
  • Raised levels of creatine phosphokinase in blood tests
  • Weight gain
  • Muscle spasms
  • Muscle pain (myalgia)
  • Painful stiff neck (torticollis)
  • Tingling in extremities (paraesthesia)
  • Dizziness
  • Reduced sense of touch or sensation (hypoaesthesia)
  • Depression
  • Protein in the urine (proteinuria)
  • Shortness of breath (dyspnoea)
  • Nose bleed (epistaxis)
  • Rash
  • Persistent itch (pruritus)

Other side effects not listed above may occur in some people. Tell your doctor or pharmacist if you notice anything else that is making you feel unwell.

How to store Galafold®

Keep your capsules in the pack until it is time to take them. If you take the capsules out of the pack they may not keep well.

Keep your capsules in a cool dry place where the temperature stays below 30°C.

Do not store Galafold® or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and- a-half meteres above the ground is a good place to store medicines.

Disposal

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

Product description

What Galafold® looks like and contents of the pack

Opaque, blue, and white hard capsules, marked with “A1001” in black ink, containing white to pale brown powder.

Galafold® is available in a blister pack containing 14 capsules.

What Galafold® contains

The active ingredient is migalastat. Each capsule contains migalastat hydrochloride equivalent to 123 mg migalastat

The inactive ingredients are:

Capsule contents: Pregelatinised maize starch and magnesium stearate

Capsule shell: Gelatin, titanium dioxide, and indigo carmine

Printing ink: Shellac, iron oxide black, and potassium hydroxide

Sponsor

Amicus Therapeutics Pty Ltd
21 Dorset Road
Northbridge, NSW 2063
Australia

Galafold® is a registered trademark of Amicus Therapeutics, Inc.

This leaflet was prepared in July 2018.

Copyright 2016. All rights reserved.

Published by MIMS December 2018

BRAND INFORMATION

Brand name

Galafold

Active ingredient

Migalastat

Schedule

S4

 

1 Name of Medicine

Migalastat.

2 Qualitative and Quantitative Composition

Galafold capsule contains 123 mg migalastat equivalent to 150 mg migalastat hydrochloride.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Galafold capsule is a size 2 hard capsule (6.4 x 18.0 mm) with an opaque blue cap and opaque white body with "A1001" printed in black.

4 Clinical Particulars

4.1 Therapeutic Indications

Galafold is indicated for long-term treatment of adult and adolescent patients 12 years and older with a confirmed diagnosis of Fabry disease (α-galactosidase A deficiency) and who have an amenable mutation (see Section 5.1 Pharmacodynamic Properties, Mechanism of action, Tables 2 and 3).

4.2 Dose and Method of Administration

Dosage (dose and interval).

Treatment with Galafold should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of Fabry disease. Galafold is not intended for concomitant use with enzyme-replacement therapy (ERT).
The recommended dosage regimen in adults is 123 mg migalastat (1 capsule) taken orally once every other day at the same time of day.
The recommended dosage regimen in adolescents aged 12 years to < 18 years and weighing ≥ 45 kg is 123 mg migalastat (1 capsule) taken orally once every other day at the same time of day.
Galafold should not be taken on 2 consecutive days. Capsules must be swallowed whole. The capsules must not be cut, crushed, or chewed.

Missed dose.

If the usual dosing time is missed, the patient should take the missed dose of Galafold only if it is within 12 hours of the normal time the dose is taken. If more than 12 hours has passed, the patient should resume taking Galafold at the next planned dosing day and time according to the every other day dosing schedule.

Dosage adjustment.

Paediatric population.

Adolescents aged 12 to < 18 years and weighing ≥ 45 kg.

123 mg migalastat (1 capsule) taken once every other day at the same time of the day (see Section 5.2 Pharmacokinetic Properties).

Children < 12 years.

The safety and efficacy of Galafold in children below the age of 12 years have not yet been established. No data are available.
Use in the elderly. No dosage adjustment is required based on age.
Use in renal impairment. Galafold is not recommended for use in patients with Fabry disease who have estimated GFR less than 30 mL/min/1.73 m2 (see Section 5.2 Pharmacokinetic Properties).
Use in hepatic impairment. No dosage adjustment of Galafold is required in patients with hepatic impairment (see Section 5.2 Pharmacokinetic Properties).

Method of administration.

Galafold exposure is decreased by approximately 40% when taken with food and 60% when taken with coffee (see Section 5.2 Pharmacokinetic Properties). Food and caffeine should not be consumed at least 2 hours before and 2 hours after taking Galafold to give a minimum 4 hours fast.
Water (plain, flavoured, sweetened), fruit juices without pulp, and caffeine-free carbonated beverages can be consumed during the 4-hour fasting period.
Galafold should be taken every other day at the same time of day to ensure optimal benefits to the patient.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.

4.4 Special Warnings and Precautions for Use

It is advised to periodically monitor (6 months, or at the usual regular intervals according to national practices) renal function, echocardiographic parameters, and biochemical markers in patients initiated on or switched to Galafold. In case of meaningful clinical deterioration, further clinical evaluation or discontinuation of treatment with Galafold should be considered.
Galafold is not indicated for use in patients with non-amenable mutations (see Section 5.1 Pharmacodynamic Properties).
Limited data suggest that co-administration of a single dose of Galafold and a standard ERT infusion results in increased exposure to agalsidase up to 5-fold. This study also indicated that agalsidase has no effect on the pharmacokinetics (PK) of migalastat. Galafold is not intended for concomitant use with ERT.
Galafold is not recommended in women of childbearing potential not using contraception.

Use in renal impairment.

No reduction in proteinuria was observed in patients treated with Galafold.
Galafold is not recommended for use in patients with severe renal insufficiency, defined as estimated GFR less than 30 mL/min/1.73 m2.

Use in the elderly.

No dosage adjustment is required based on age.

Paediatric use.

Galafold is not suitable for adolescents aged 12 years to < 18 years and weighing < 45 kg (see Section 5.2 Pharmacokinetic Properties). Galafold has not been studied in paediatric subjects below the age of 12 years.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Based upon in vitro data, migalastat is not an inducer of CYP1A2, 2B6, or 3A4.
Furthermore, migalastat is not an inhibitor or a substrate of CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4/5. Migalastat is not a substrate for MDR1 or BCRP, nor is it an inhibitor of BCRP, MDR1, or BSEP human efflux transporters. In addition, migalastat is not a substrate for MATE1, MATE2-K, OAT1, OAT3, or OCT2, nor is it an inhibitor of OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, MATE1, or MATE2-K human uptake transporters.

Effect of other drugs on Galafold.

Co-administration of Galafold with caffeine decreases migalastat systemic exposure (AUC and Cmax) which may reduce Galafold efficacy (see Section 5.2 Pharmacokinetic Properties). Avoid co-administration of Galafold with caffeine at least 2 hours before and 2 hours after taking Galafold (see Section 4.2 Dose and Method of Administration).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

The effects of Galafold on fertility in humans have not been studied. Non-clinical studies suggest no specific hazard for humans on the basis of single- and repeat-dose studies, with the exception of transient but fully reversible infertility in male rats associated with migalastat treatment at ≥ 2.5 mg/kg/day (≥ 0.2 times the clinical exposure based on AUC). The infertility associated with migalastat treatment was reported at subclinical relative exposures. Complete reversibility was seen after 4 weeks off-dose. Similar findings have been noted pre-clinically following treatment with other iminosugars. Galafold did not affect fertility in female rats.
(Category B3)
There are limited data from the use of Galafold in pregnant women. In the rabbit embryo-foetal toxicity study, findings including embryo-foetal death, a reduction in mean foetal weight, retarded ossification, and slightly increased incidences of minor skeletal abnormalities were observed only at doses of ≥ 300 mg/kg/day (≥ 240 times the clinical exposure based on AUC), which were associated with maternal toxicity. No Galafold-related embryofetal development issues were reported up to 1500 mg/kg/day in rats (> 50 times the clinical exposure) or 120 mg/kg/day in rabbits (74 times clinical exposure). Galafold is not recommended during pregnancy.
 It is not known whether Galafold is secreted in human milk. However, migalastat has been shown to be secreted in the milk of lactating rats. Accordingly, a risk of migalastat exposure to the breast-feeding infant cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue Galafold, taking into account the benefit of breast-feeding for the child relative to the benefit of therapy for the mother.

4.7 Effects on Ability to Drive and Use Machines

No specific studies have been conducted to assess the direct effect of Galafold on the ability to drive and use machines.

4.8 Adverse Effects (Undesirable Effects)

Experience from clinical trials.

The most common adverse reaction was headache, which was experienced by approximately 10% of patients who received Galafold.

Tabulated list of adverse reactions.

Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing frequency within each system organ class. See Table 1.

Paediatric population.

The safety assessment in 21 adolescents (12 to < 18 years of age and weighing ≥ 45 kg) is based on 1-year safety data from the open-label AT1001-020 trial in which subjects received the same dosage regimen as adults (see Section 5.2 Pharmacokinetic Properties). No age-specific differences in adverse reactions were observed between adolescent and adult subjects.

Post-marketing 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 which is therefore categorized as not known. See Table 2.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine.
Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).
In case of overdose, general medical care is recommended. Headache and dizziness were the most common adverse reactions reported at doses of Galafold of up to 1250 mg and 2000 mg, respectively.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Various alimentary tract and metabolism products. ATC Code: A16AX14.
Fabry disease is a progressive X-linked lysosomal storage disorder that affects males and females. Fabry disease-causing mutations in the GLA gene result in a deficiency of the lysosomal enzyme α-galactosidase A (α-Gal A) that is required for glycosphingolipid substrate (e.g. GL-3, lyso-Gb3) metabolism. Reduced α-Gal A activity is, therefore, associated with the progressive accumulation of substrate in vulnerable organs and tissues, which leads to the morbidity and mortality associated with Fabry disease.

Mechanism of action.

Certain GLA mutations can result in the production of abnormally folded and unstable mutant forms of α-Gal A. Migalastat is a pharmacological chaperone that is designed to selectively and reversibly bind with high affinity to the active sites of certain mutant forms of α-Gal A, the genotypes of which are referred to as amenable mutations. Migalastat binding stabilizes these mutant forms of α-Gal A in the endoplasmic reticulum and facilitates their proper trafficking to lysosomes where dissociation of migalastat restores α-Gal A activity, leading to the catabolism of GL-3 and related substrates.
The GLA mutations amenable to treatment with Galafold are listed in Table 3.

Pharmacodynamic effects.

Treatment with Galafold in Phase 2 pharmacodynamic trials generally resulted in increases in endogenous α-Gal A activity in white blood cells (WBCs), as well as in skin and kidney for the majority of patients. In patients with amenable mutations, GL-3 levels tended to decrease in urine and in kidney interstitial capillaries.

Clinical trials.

The clinical efficacy and safety of Galafold have been evaluated in two Phase 3 pivotal trials and two open-label extension trials. All patients received the recommended dosage of 123 mg Galafold every other day.
The first Phase 3 trial (ATTRACT) was an 18-month, randomised open-label active comparator trial that evaluated the efficacy and safety of Galafold compared to enzyme replacement therapy (ERT) (agalsidase beta, agalsidase alfa) in 52 male and female patients with Fabry disease who were receiving ERT prior to trial entry and who have amenable mutations (ERT-experienced trial). The study was structured in two periods. During the first period (18 months) ERT-experienced patients were randomised to switch from ERT to migalastat or continue with ERT. The second period was an optional 12-month open-label extension (OLE) in which all subjects received migalastat.
The second Phase 3 trial (FACETS) was a 6-month randomised double-blind placebo-controlled trial (through Month 6) with an 18-month open-label period to evaluate the efficacy and safety of Galafold in 50 male and female patients with Fabry disease who were naive to ERT, or had previously been on ERT and had stopped for at least 6 months, and who have amenable mutations (ERT-naive trial).
The first OLE trial (AT1001-041) included patients from Phase 2 and Phase 3 studies and has completed. The mean extent of exposure to the marketed dose of Galafold 123 mg QOD in patients completing study AT1001-041 was 3.57 (± 1.23) years (n = 85). The maximum exposure was 5.6 years.
The second OLE trial (AT1001-042) included patients that either transferred from OLE study AT1001-041 or directly from Phase 3 study ATTRACT. The mean (SD) and median extent of exposure to the marketed dose of Galafold 123 mg QOD in patients in this study was 32.3 (± 12.3) months and 36.75 months (n = 82), respectively. The maximum exposure was 51.9 months.
Renal function. In the ERT-experienced trial, renal function remained stable for up to 18 months of treatment with Galafold. Mean annualised rate of change in eGFRCKD-EPI was -0.40 mL/min/1.73 m2 (95% CI: -2.272, 1.478) in the Galafold group compared to -1.03 mL/min/1.73 m2 (95% CI: -3.636, 1.575) in the ERT group.
In the ERT-naive trial and open-label extension, renal function remained stable for 3 years of treatment with Galafold. After an average of 36 months of treatment, the mean annualised rate of change in eGFRCKD-EPI was -0.81 mL/min/1.73 m2 (95% CI: -2.00, 0.37). No clinically significant differences were observed during the initial 6-month placebo-controlled period.
Data for the annualized rate of change for eGFRCKD-EPI was pooled for ERT-naive subjects and ERT-experienced subjects with amenable mutations and is partly derived from the uncontrolled, open-label extension studies. Whilst acknowledging the study limitations, these results are consistent with stabilisation of renal function up to 8.6 years in annualized rate of change. After a mean duration of 5.2 years, ERT-naive patients had a mean annualized rate of change from baseline of -1.71 mL/min/1.73 m2 (CI: -2.83, -0.60; n = 47) with a median of -1.06 mL/min/1.73 m2. After a mean duration of 4.3 years, ERT-experienced patients had a mean annualized rate of change from baseline of -1.78 mL/min/1.73 m2 (CI: -3.76, 0.20; n = 49) with a median of -1.21 mL/min/1.73 m2.
Left ventricular mass index (LVMi). In the ERT-experienced trial, following 18 months of treatment with migalastat there was a statistically significant decrease in LVMi (p < 0.05). The baseline values were 95.3 g/m2 for the Galafold arm and 92.9 g/m2 for the ERT arm and the mean change from baseline in LVMi at Month 18 was -6.6 (95% CI: -11.0, -2.1 n = 31) for migalastat and -2.0 (95% CI: [-11.0, 7.0 n = 13) for ERT (Figure 1).
In the ERT-naive trial, Galafold resulted in a statistically significant decrease in LVMi for all patients with amenable mutations (p < 0.05); the mean change from baseline in LVMi from Month 18 to 24 was -7.7 (95% CI: -15.4, -0.01; n = 27). After follow up in the open-label extension, the mean change from baseline in LVMi from Month 30 to 36 was -17.0 (95% CI: -26.2, -7.9; n = 15) (p < 0.05). The mean change from baseline in LVMi from Month 18 to 24 in patients with left ventricular hypertrophy at baseline (females with baseline LVMi > 95 g/m2 or males with baseline LVMi > 115 g/m2) was -18.6 (95% CI: -38.2, 1.0; n = 8). After follow up in the open-label extension, the mean change from baseline in LVMi in patients with left ventricular hypertrophy at baseline from Month 30 to 36 was -30.0 (95% CI: -57.9, -2.2; n = 4). No clinically significant differences in LVMi were observed during the initial 6-month placebo-controlled period.
These results demonstrate that Galafold leads to improvements in cardiac hypertrophy, which is a major risk factor for cardiac complications in Fabry disease.
Data for the mean change in LVMi was pooled for ERT-naive subjects and ERT-experienced subjects with amenable mutations and is partly derived from the uncontrolled, open-label extension studies. Whilst acknowledging the study limitations and small sample size in this analysis, the mean change in LVMi from AT1001-042 baseline was 1.2 g/m2 (95% CI: -5.3, 7.7; n = 15) and -5.6 g/m2 (95% CI: -28.5, 17.2; n = 4) respectively, and the median change in LVMi from AT1001-042 baseline was 0.41 g/m2 and 1.02 g/m2 respectively, for patients treated with Galafold for an average of 2.4 and 2.9 years (up to 4.0 and 4.3 years, respectively).
Disease substrate. In the ERT-naive trial, Galafold showed statistically significant reductions in plasma lyso-Gb3 concentrations and kidney interstitial capillary GL-3 inclusions in patients with amenable mutations. Patients randomised to Galafold in Stage 1 demonstrated statistically significant greater reduction (± SEM) in mean interstitial capillary GL-3 deposition (-0.25 ± 0.10; -39%) at Month 6 compared to placebo (+0.07 ± 0.13; +14%) (p = 0.008). Patients randomised to placebo in Stage 1 and switched to Galafold at Month 6 (Stage 2) also demonstrated statistically significant decreases in interstitial capillary GL-3 inclusions at Month 12 (-0.33 ± 0.15; -58%) (p = 0.014). Qualitative reductions in GL-3 levels were observed in multiple renal cell types: podocytes, mesangial cells, and glomerular endothelial cells, respectively, over 12 months of treatment with Galafold.
In the ERT-experienced trial, plasma lyso-Gb3 levels remained low and stable for up to 18 months in patients with amenable mutations switched from ERT to Galafold, and in patients remaining on ERT.
Composite clinical outcomes. In the ERT-experienced trial, analysis of a composite clinical outcome composed of renal, cardiac, and cerebrovascular events, or death, the frequency of events observed in the Galafold treatment group was 29% and was 44% in the ERT group (Table 4).
Patient-reported outcome - gastrointestinal symptoms rating scale. In the ERT-naive trial, analyses of the Gastrointestinal Symptoms Rating Scale demonstrated that treatment with Galafold was associated with statistically significant (p < 0.05) improvements versus placebo from baseline to Month 6 in the diarrhoea domain, and in the reflux domain for patients with symptoms at baseline. During the open-label extension, statistically significant (p < 0.05) improvements from baseline were observed in the diarrhoea and indigestion domains, with a trend of improvement in the constipation domain.

Patient reported outcome - short form-36 (SF-36v2).

After 24 months of treatment with migalastat in the ERT naive patients study and 18 months of treatment in ERT experienced patients study, no significant changes from baseline were observed in SF-36v2.

Patient reported outcome - brief pain inventory (BPI).

Patient's pain scales remained stable when switched from ERT to Galafold.
Paediatric population. In Study AT1001-020, a 1-year, Phase 3b, open-label, uncontrolled, multicenter study, the safety, PK, pharmacodynamic (PD), and efficacy of migalastat treatment was evaluated in 21 adolescent subjects (12 to < 18 years of age and weighing ≥ 45 kg) with Fabry disease and who have amenable mutations of the gene encoding α-galactosidase A (GLA). Subjects were either naive to enzyme replacement therapy (ERT) or had stopped ERT at least 14 days before screening. The mean number of years since diagnosis of Fabry disease was 9.6 (± 4.25) years and the median years since diagnosis of Fabry disease was 10.70 years (range: 1.6 to 16.9 years) (n = 22; 21 actually dosed with migalastat).
The overall mean (SD) and median (range) change from baseline in eGFR was -1.6 (15.4) mL/min/1.73 m2 and 0.0 (-21, 45) mL/min/1.73 m2 (n = 19), respectively. The overall mean (SD) and median (range) change from baseline for LVMi was -3.9 (13.5) g/m2 and -4.3 (-29.9, 15.3) g/m2 (n = 18), respectively. LVMi decreased in 10 subjects and increased in 8 subjects, but all subjects remained within normal limits at 12 months. Baseline plasma lyso-Gb3 median (range) was 4.49 (0.4, 78.8) nanogram/mL and the overall median (range) change from baseline in plasma lyso-Gb3 was 0.18 (-65.4, 115.8) (n = 19). A reduction in plasma lyso-Gb3 from baseline was observed in ERT-naive subjects (median [range] -2.23 [-65.4, 0.1] nanogram/mL, n = 9) and levels remained generally stable in ERT-experienced subjects (median [range] 0.54 [0.2, 115.8] nanogram/mL, n = 10). There were no notable changes in patient reported outcomes. The efficacy results presented in these subjects may reflect factors other than treatment with migalastat hydrochloride.

5.2 Pharmacokinetic Properties

Absorption.

The absolute bioavailability (AUC) for a single oral 150 mg migalastat hydrochloride dose was approximately 75%. Following a single oral dose of 150 mg migalastat hydrochloride solution, the time to peak plasma concentration was approximately 3 hours. Plasma migalastat exposure (AUC0-∞) and mean peak migalastat plasma concentration (Cmax) demonstrated dose-proportional increases at migalastat oral doses from 50 mg to 1250 mg.
Migalastat hydrochloride administered with a high-fat meal, or 1 hour before a high-fat or light meal, or 1 hour after a light meal, resulted in significant reductions of 37% to 42% in mean total migalastat exposure (AUC0-∞) and reductions of 15% to 40% in mean peak migalastat plasma concentration (Cmax) compared with the fasting state.
A single dose, 6-way crossover pharmacokinetic study was conducted in 20 healthy subjects. Compared to the intake of a single dose of migalastat with water, co-administration of approximately 190 mg caffeine reduced the mean migalastat AUC0-∞ by 55% and Cmax by 60%. The rate of absorption (tmax) of migalastat was not affected by administration of caffeine in comparison to water, nor was any effect observed when migalastat was taken with natural (sucrose) or artificial (aspartame or acesulfame K) sweeteners.

Distribution.

In healthy volunteers, the volume of distribution (Vz/F) of migalastat following ascending single oral doses (25 to 675 mg migalastat HCl) ranged from 77 to 133 L, indicating that it is well distributed into tissues and greater than total body water (42 L). There was no detectable plasma protein binding following administration of [14C]-migalastat hydrochloride in the concentration range between 1 and 100 microM.

Biotransformation.

Based upon in vivo data, migalastat is a substrate for UGT, being a minor elimination pathway. Migalastat is not a substrate for P-glycoprotein (P-gP) in vitro, and it is considered unlikely that migalastat would be subject to drug-drug interactions with cytochrome P450s. A pharmacokinetic trial in healthy male volunteers with 150 mg [14C]-migalastat hydrochloride revealed that 99% of the radiolabelled dose recovered in plasma was comprised of unchanged migalastat (77%) and 3 dehydrogenated O-glucuronide-conjugated metabolites, M1 to M3 (13%). Approximately 9% of the total radioactivity was unassigned.

Elimination.

A pharmacokinetic trial in healthy male volunteers with 150 mg [14C]-migalastat hydrochloride revealed that approximately 77% of the radiolabelled dose was recovered in urine 55% of the dose was excreted as unchanged migalastat, 4% as M1 to M3 and 5% was from unassigned components, for a total of 64%. The remaining 5% represents metabolites below quantifiable concentrations. Approximately 20% of the total radiolabelled dose was excreted in faeces, with unchanged migalastat being the only measured component.
Following ascending single oral doses (25 to 675 mg migalastat hydrochloride), no trends were found for clearance, CL/F. At the 150-mg dose, CL/F was approximately 11 to 14 L/hr. Following administration of the same doses, the mean elimination half-life (t1/2) ranged from approximately 3 to 5 hours.

Special populations.

Renal impairment.

Galafold has not been studied in patients with Fabry disease who have a GFR less than 30 mL/min/1.73 m2. In a single dose study with Galafold in non-Fabry subjects with varying degrees of renal insufficiency, exposures were increased by 4.3-fold in subjects with severe renal impairment (GFR < 30 mL/min/1.73 m2).

Hepatic impairment.

No studies have been carried out in subjects with impaired hepatic function. From the metabolism and excretion pathways, it is not expected that a decreased hepatic function may affect the pharmacokinetics of migalastat.

Elderly (> 65 years).

Clinical studies of Galafold included small number of patients aged 65 and over. The effect of age was evaluated in a population pharmacokinetic analysis on plasma migalastat clearance in the ERT-naive study population. The difference in clearance between Fabry patients ≥ 65 years and those < 65 years was 20%, which was not considered clinically significant.

Paediatric population.

The pharmacokinetics of migalastat were characterised in 20 adolescent subjects (12 to < 18 years and weighing ≥ 45 kg) with Fabry disease who received the same dosage regimen as adults (123 mg migalastat capsule every other day) in an open-label phase 3b trial (AT1001-020).
Assessment of bioequivalence of exposure was simulated in adolescent subjects (12 to < 18 years and weighing ≥ 45 kg) and receiving migalastat 123 mg once every other day compared to adults receiving the same dosing regimen. Model derived AUCtau in adolescent subjects (12 to < 18 years) were similar to adult exposures.
No dosage adjustment is required for adolescents 12 to < 18 years of age and weighing ≥ 45 kg.

Gender.

The pharmacokinetic characteristics of migalastat were not significantly different between females and males in either healthy volunteers or in patients with Fabry disease.

5.3 Preclinical Safety Data

Genotoxicity.

Migalastat hydrochloride was not genotoxic in a bacterial mutation assay, a forward mutation test and a rat micronucleus test.

Carcinogenicity.

In a rat 104-week carcinogenicity study, there was an increased incidence of pancreatic islet cell adenomas in males at a dose level 19-fold higher than the exposure (AUC) at the clinically efficacious dose. This is a common spontaneous tumour in ad libitum-fed male rats. In the absence of similar findings in females, no findings in the genotoxicity studies or in the carcinogenicity study with Tg.rasH2 mice (at 27 times the AUC exposure expected clinically), and no pre-neoplastic pancreatic findings in the rodents or monkeys, this observation in male rats is not considered related to treatment and its relevance to humans is unknown.

6 Pharmaceutical Particulars

6.1 List of Excipients

Galafold hard capsules contain the following inactive ingredients: pregelatinised maize starch and magnesium stearate. The capsule shells are made of gelatin and contain the following colouring agents: titanium dioxide (E171) and indigo carmine (E132). The capsules are marked with printing ink (2328), containing shellac (E904), iron oxide black (E172) and potassium hydroxide.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store in the original package in order to protect from moisture. Store below 30°C.

6.5 Nature and Contents of Container

PVC/ PCTFE/ PVC/Al blister.
Pack size of 14 capsules.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.


Australian Approved Name (AAN): migalastat hydrochloride.
Molecular formula: C6H13NO4.HCl.
Molecular weight: 199.63 (hydrochloride salt); 163.17 (free base).
Chemical name: (+)-(2R, 3S, 4R, 5S)-2-(hydroxymethyl)-piperidine-3,4,5-triol, hydrochloride.
Migalastat hydrochloride is a white to pale brown powder, freely soluble between pH 1.2 and pH 7.5 in aqueous media. The pKa is 7.47 ± 0.01.

CAS number.

75172-81-5.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription only medicine.

Summary Table of Changes