Opfolda 65 mg hard capsules

Each hard capsule contains 65 mg of miglustat.

For the full list of excipients, see section 6.1

Hard capsule

Size 2 hard capsule (6.35x18.0 mm) with a grey opaque cap and white opaque body with “AT2221” printed in black on the body, containing white to off-white powder.

Opfolda (miglustat) is an enzyme stabiliser of cipaglucosidase alfa long-term enzyme replacement therapy in adults with late-onset Pompe disease (acid α-glucosidase [GAA] deficiency).

Treatment should be supervised by a physician experienced in the management of patients with Pompe disease or other inherited metabolic or neuromuscular diseases.

Miglustat 65 mg hard capsules must be used in combination with cipaglucosidase alfa. The summary of product characteristics (SmPC) for cipaglucosidase alfa should be consulted before taking miglustat.

Posology

The recommended dose is to be taken every other week in adults aged 18 years and older and is based on body weight:

• For patients weighing ≥ 50 kg, the recommended dose is 260 mg (4 capsules of 65 mg).

• For patients weighing ≥ 40 kg to < 50 kg, the recommended dose is 195 mg (3 capsules of 65 mg).

Miglustat 65 mg hard capsules should be taken orally approximately 1 hour but no more than 3 hours before the start of the cipaglucosidase alfa infusion.

Figure 1. Dose timeline

Patient response to treatment should be routinely evaluated based on a comprehensive evaluation of all clinical manifestations of the disease. In case of an insufficient response or intolerable safety risks, discontinuation of miglustat 65 mg hard capsules in combination with cipaglucosidase alfa treatment should be considered. Both medicinal products should either be continued or discontinued.

Missed dose

If the miglustat dose is missed, treatment should occur as soon as possible. If it is not taken, do not start the cipaglucosidase alfa infusion. Cipaglucosidase alfa infusion can start 1 hour after miglustat is taken.

Special populations

Renal and hepatic impairment

The safety and efficacy of miglustat in combination with cipaglucosidase alfa therapy have not been evaluated in patients with renal and/or hepatic impairment. When administering every other week, increased plasma miglustat exposure as a result of moderate or severe renal or hepatic impairment is not expected to appreciably impact cipaglucosidase alfa exposures and is not anticipated to affect efficacy and safety of cipaglucosidase alfa in a clinically meaningful manner. No dose adjustment is required in patients with renal or hepatic impairment.

Elderly

There is limited experience with the use of miglustat in combination with cipaglucosidase alfa therapy in patients above the age of 65 years old. There is no dose adjustment required in elderly patients.

Paediatric population

The safety and efficacy of miglustat in combination with cipaglucosidase alfa therapy in paediatric patients less than 18 years old have not yet been established. No data are available.

Method of administration

Miglustat is for oral use.

Miglustat 65 mg hard capsule has a crimp to prevent opening the capsule shells, and should be swallowed whole and taken on an empty stomach.

Patients should fast 2 hours before and 2 hours after taking miglustat 65 mg hard capsules, see section 5.2. During this 4-hour fasting period, water, fat-free (skimmed) cow's milk, and tea or coffee with no cream, sugars, or sweeteners can be consumed. The patient can resume normal eating and drinking 2 hours after taking miglustat.

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

• Contraindication to cipaglucosidase alfa.

Miglustat 65 mg hard capsules must be used in combination with cipaglucosidase alfa. Because of this, the summary of product characteristics (SmPC) for cipaglucosidase alfa should be consulted in relation to its safety profile before taking miglustat.

Adverse drug reactions may occur upon the use of miglustat in combination with cipaglucosidase alfa, see section 4.8.

No interaction studies have been performed related to the use of miglustat.

Food interaction

Miglustat is known to have a direct effect on the enzymatic function of major disaccharidases of the intestinal epithelium. Specifically, miglustat inhibits disaccharidases with alpha-glycosidic linkages including sucrase, maltase, and isomaltase. The strength of potential interactions can immediately interfere with digestive activity of sucrose, maltose and isomaltose leading to maldigestion, osmotic influx of water, increased fermentation, and production of irritating metabolites. Patients should fast for 2 hours before and for 2 hours after taking miglustat.

Contraception in females

Reliable contraceptive measures must be used by women of childbearing potential during treatment with miglustat in combination with cipaglucosidase alfa, and for 4 weeks after discontinuing treatment, see section 5.3. The medicinal product is not recommended in women of childbearing potential not using reliable contraception.

Pregnancy

There are no clinical data from the use of miglustat in combination with cipaglucosidase alfa in pregnant women. Miglustat crosses the placenta. Animal studies with miglustat alone as well as in combination with cipaglucosidase alfa have shown reproductive toxicity, see section 5.3. Miglustat in combination with cipaglucosidase alfa therapy is not recommended during pregnancy.

Breast-feeding

It is not known if miglustat and cipaglucosidase alfa are secreted in human breast milk, see section 5.3. Available pharmacodynamic/toxicological data in animals have shown secretion/excretion of miglustat and cipaglucosidase alfa in milk. A risk to new-borns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from miglustat in combination with cipaglucosidase alfa therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

There are no clinical data on the effects of miglustat in combination with cipaglucosidase alfa therapy on fertility.

In 7 healthy adult men who received miglustat 100 mg, orally, twice daily for 6 weeks, no effects on sperm concentration, motility, or morphology were seen.

In a preclinical study conducted in male rats, no effect on spermatogenesis was observed following administration of miglustat in combination with cipaglucosidase alfa or miglustat alone. However, previous preclinical data in rats exposed to miglustat alone have shown adverse effects on sperm parameters (motility and morphology), and reduced fertility, see section 5.3.

In female rats, significant increases in pre-implantation loss were noted with miglustat in combination with cipaglucosidase alfa and with miglustat alone, see section 5.3.

Miglustat has no or negligible influence on the ability to drive or to use machines.

Summary of the safety profile

The most commonly reported adverse reaction only attributable to miglustat 65 mg was constipation (1.3%).

Tabulated list of adverse reactions

The assessment of adverse reactions was informed by subjects treated with miglustat in combination with cipaglucosidase alfa therapy from the pooled safety analysis across the 3 clinical trials. The total mean duration of exposure was 17.2 months.

Adverse reactions from the clinical trials are listed by MedDRA system organ class in Table 1.

The corresponding frequency categories are defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10 000 to < 1/1000), very rare (< 1/10 000), and not known (cannot be estimated from available data).

Table 1: Summary of adverse reactions from clinical trials with miglustat-treated subjects

† Reported with miglustat only

¹ Abdominal pain, abdominal pain upper, and abdominal pain lower are grouped under abdominal pain.

² Rash and rash erythematous are grouped under rash.

³ Urticaria, urticaria rash, and mechanical urticaria are grouped under urticaria.

⁴ Migraine and migraine with aura are grouped under migraine.

⁵ Hypertension and blood pressure increased are grouped under blood pressure increased.

⁶ Tachycardia and sinus tachycardia are grouped under tachycardia.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

United Kingdom

Yellow Card Scheme

Website: at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

Symptoms

Leukopenia, granulocytopenia, neutropenia, dizziness, and paraesthesia have been observed in human immunodeficiency virus (HIV) patients receiving miglustat at a dosage of 800 mg/day or higher.

Management

In the event of an overdose, supportive medical care should be provided immediately. Full blood counts should be monitored for reduced white cells.

Pharmacotherapeutic group: Other alimentary tract and metabolism products, various alimentary track and metabolism products. ATC Code: A16AX06

Mechanism of action

Miglustat is a pharmacokinetic enzyme stabiliser of cipaglucosidase alfa.

Miglustat binds selectively with cipaglucosidase alfa in the blood during infusion; thereby stabilising the conformation of cipaglucosidase alfa and minimising the loss of enzyme activity while in circulation. This selective binding between cipaglucosidase alfa and miglustat is transient with disassociation occurring in the lysosome. Miglustat alone has no effect on glycogen reduction.

Paediatric population

The Medicines and Healthcare products Regulatory Agency has deferred the obligation to submit the results of studies with Opfolda in one or more subsets of the paediatric population in the treatment of glycogen storage disease Type II (Pompe disease) (see section 4.2 for information on paediatric use).

Absorption

The rate of absorption (t_max) of miglustat was approximately 2 to 3 hours. At the clinical dose, 260 mg, plasma miglustat attained a C_max of approximately 3000 ng/mL and an AUC_0-∞ of approximately 25,000 ng h/mL.

Effect of food

A significant food effect was observed and resulted in a decreased C_max by 36% and delayed absorption by approximately 2 hours, see section 4.2.

Metabolism

Miglustat is largely unmetabolised with < 5% of a radiolabeled dose recovered as glucuronides.

Elimination

The terminal elimination half-life was approximately 6 hours for miglustat. Oral clearance was approximately 10.5 L/h and terminal phase volume of distribution was approximately 90 L.

Linearity

Miglustat demonstrated dose proportional kinetics.

Special populations

Gender, elderly, and race/ethnicity

Based on pooled population pharmacokinetic analysis, gender, age (18 to 74 years), and race/ethnicity did not have clinically meaningful effect on the exposure to miglustat in combination with cipaglucosidase alfa.

Hepatic impairment

The pharmacokinetics of miglustat in combination with cipaglucosidase alfa therapy have not been evaluated in patients with hepatic impairment.

Renal impairment

The AUC_0-24hr of miglustat increased by 21%, 32%, and 41% in patients with mild (creatinine clearance [CLcr] 60 to 89 mL/minute, estimated by Cockcroft-Gault), moderate (CLcr 30 to 59 mL/minute), and severe (CLcr 15 to 29 mL/minute) renal impairment, respectively, compared to patients with normal renal function. The effect of end stage renal disease on the pharmacokinetics of miglustat is unknown.

Nonclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, single and repeated dose toxicity, genotoxicity, and mutagenicity.

Carcinomas in the large intestine of mice occurred occasionally following oral treatment with miglustat at 210, 420 and 840/500 mg/kg/day for a period of 2 years. These doses correspond to 8, 16, and 33/19 times a human dose of 200 mg three times per day. The relevance of these findings to humans taking miglustat is unknown at the substantially lower studied doses at 195 to 260 mg every other week for Pompe disease.

Reproductive and developmental toxicology

In a Segment I study in rats, there was no effect of miglustat in combination with cipaglucosidase alfa therapy or miglustat alone on spermatogenesis.

In another miglustat product study in rats, miglustat administered orally at doses of 60 mg/kg/day and above resulted in seminiferous tubule and testicular atrophy/degeneration. Decreased spermatogenesis with altered sperm morphology and motility and decreased fertility were observed in rats orally dosed with miglustat 20 mg/kg/day oral gavage 14 days prior to mating with doses at exposures less than the human therapeutic systemic exposure based on body surface area comparisons (mg/m²). Decreased spermatogenesis was reversible in rats following 6 weeks of active substance withdrawal.

In a segment I fertility and early embryonic development study in rats, pre-implantation loss was observed in the female fertility component of the study in both miglustat alone (60 mg/kg) and the combination treatment group (cipaglucosidase alfa 400 mg/kg with oral miglustat 60 mg/kg) and was considered miglustat-related.

Capsule contents

Pregelatinised starch (maize)

Magnesium stearate (E470b)

Microcrystalline cellulose (E460i)

Sucralose (E955)

Colloidal silicon dioxide

Capsule shell

Gelatin

Titanium dioxide (E171)

Black iron oxide (E172)

Edible printing ink

Black iron oxide (E172)

Potassium hydroxide (E525)

Propylene glycol (E1520)

Shellac (E904)

Strong ammonia solution (E527)

Not applicable.

3 years

This medicinal product does not require any special storage conditions.

40 mL high density polyethylene (HDPE) bottle with 33 mm white child resistant polypropylene cap with label. Bottle opening is sealed with an induction sealed foil liner.

Bottles of 4 and 24 capsules.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Amicus Therapeutics UK Limited

One Globeside

Fieldhouse Lane

Marlow, Buckinghamshire

SL7 1HZ

PLGB 25823/0004

08/08/2023

08/08/2023