4.1. Therapeutic indications

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).

4.2. Posology and method of administration

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

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

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.

4.3. Contraindications

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

• Contraindication to cipaglucosidase alfa.

4.4. Special warnings and precautions for use

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).

4.5. Interaction with other medicinal products and other forms of interaction

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.

4.6. Fertility, pregnancy, and lactation

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 in combination with cipaglucosidase alfa as well as with miglustat alone 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 of miglustat and excretion of 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.

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

In male rats, no effect on spermatogenesis was observed following administration of miglustat in combination with cipaglucosidase alfa or miglustat alone. However, preclinical data from a study in rats using another miglustat product have shown that miglustat adversely affects sperm parameters (motility and morphology), thereby reducing fertility (see section 5.3).

In female rats, increase in pre-implantation loss was noted with miglustat in combination with cipaglucosidase alfa and with miglustat alone (see section 5.3).

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

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 28.0 months.

Adverse reactions 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 of miglustat-treated patients

System organ class (SOC)

Frequency

Adverse reaction (preferred term)

Immune system disorders

Common

Anaphylactic reaction7

Uncommon

Hypersensitivity

Nervous system disorders

Very common

Headache

Common

Tremor, dysgeusia, paraesthesia

Uncommon

Balance disorder, migraine4

Cardiac disorders

Common

Tachycardia6

Common

Hypotension

Uncommon

Pallor

Respiratory, thoracic and mediastinal disorders

Common

Dyspnoea

Uncommon

Asthma

Gastrointestinal disorders

Common

Diarrhoea, nausea, abdominal pain1, flatulence, abdominal distension, vomiting, constipation†

Uncommon

Abdominal discomfort†, oesophageal spasm, oral pain

Skin and subcutaneous tissue disorder

Common

Urticaria3, rash2, pruritus, hyperhidrosis

Uncommon

Skin discolouration

Musculoskeletal and connective tissue disorders

Common

Muscle spasms, myalgia, arthralgia, muscular weakness

Uncommon

Flank pain, muscle fatigue, musculoskeletal stiffness

General disorders and administration site conditions

Common

Fatigue, pyrexia, chills, peripheral swelling

Uncommon

Asthenia, facial pain, feeling jittery†, non-cardiac chest pain

Investigations

Common

Blood pressure increased5

Uncommon

Lymphocyte count decreased, platelet count decreased†

† 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.

7 Anaphylaxis, anaphylactic reaction, and anaphylactoid reaction are grouped under anaphylactic reaction.

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:

Yellow Card Scheme

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

4.9. Overdose

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.