4.1. Therapeutic indications

Yargesa is indicated for the oral treatment of adult patients with mild to moderate type 1 Gaucher disease. Yargesa may be used only in the treatment of patients for whom enzyme replacement therapy is unsuitable (see sections 4.4 and 5.1).

Yargesa is indicated for the treatment of progressive neurological manifestations in adult patients and paediatric patients with Niemann-Pick type C disease (see sections 4.4, and 5.1).

4.2. Posology and method of administration

Therapy should be directed by physicians who are knowledgeable in the management of Gaucher disease or Niemann-Pick type C disease, as appropriate.

Posology

Dosage in type 1 Gaucher disease

Adult

The recommended starting dose for the treatment of adult patients with Type 1 Gaucher disease is 100 mg three times a day.

Temporary dose reduction to 100 mg once or twice a day may be necessary in some patients because of diarrhoea.

Paediatric population

The efficacy of Yargesa in children and adolescents aged 0-17 years with type 1 Gaucher disease has not been established. No data are available.

Dosage in Niemann-Pick type C disease Adult

The recommended dose for the treatment of adult patients with Niemann-Pick type C disease is 200 mg three times a day.

Paediatric population

The recommended dose for the treatment of adolescent patients (12 years of age and above) with Niemann- Pick type C disease is 200 mg three times a day.

Dosing in patients under the age of 12 years should be adjusted on the basis of body surface area as illustrated below:

Body surface area (m2)

Recommended dose

> 1.25

200 mg three times a day

> 0.88 - 1.25

200 mg twice a day

> 0.73 - 0.88

100 mg three times a day

> 0.47 - 0.73

100 mg twice a day

≤ 0.47

100 mg once a day

Temporary dose reduction may be necessary in some patients because of diarrhoea. The benefit to the patient of treatment with Yargesa should be evaluated on a regular basis (see section 4.4). There is limited experience with the use of Yargesa in Niemann-Pick type C disease patients under the age of 4 years.

Special populations

Elderly

There is no experience with the use of Yargesa in patients over the age of 70.

Renal Impairment

Pharmacokinetic data indicate increased systemic exposure to miglustat in patients with renal impairment. In patients with an adjusted creatinine clearance of 50–70 mL/min/1.73 m2, administration should commence at a dose of 100 mg twice daily in patients with type 1 Gaucher disease and at a dose of 200 mg twice daily (adjusted for body surface area in patients below the age of 12) in patients with Niemann-Pick type C disease.

In patients with an adjusted creatinine clearance of 30–50 mL/min/1.73 m2, administration should commence at a dose of 100 mg once daily in patients with type 1 Gaucher disease and at a dose of 100 mg twice daily (adjusted for body surface area in patients below the age of 12) in patients with Niemann-Pick type C disease. Use in patients with severe renal impairment (creatinine clearance < 30 mL/min/1.73 m2) is not recommended (see sections 4.4 and 5.2).

Hepatic Impairment

Yargesa has not been evaluated in patients with hepatic impairment.

Method of Administration

Yargesa can be taken with or without food.

4.3. Contraindications

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

4.4. Special warnings and precautions for use

Tremor

Approximately 37% of patients in clinical trials in type 1 Gaucher disease, and 58% of patients in a clinical trial in Niemann-Pick type C disease reported tremor on treatment. In type 1 Gaucher disease, these tremors were described as an exaggerated physiological tremor of the hands. Tremor usually began within the first month of treatment, and in many cases resolved after 1 to 3 months of continued treatment. Dose reduction may ameliorate the tremor, usually within days, but discontinuation of treatment may sometimes be required.

Gastrointestinal disturbances

Gastrointestinal events, mainly diarrhoea, have been observed in more than 80% of patients, either at the outset of treatment or intermittently during treatment (see section 4.8). The mechanism is most likely inhibition of intestinal disaccharidases such as sucrase-isomaltase in the gastrointestinal tract leading to reduced absorption of dietary disaccharides. In clinical practice, miglustat-induced gastrointestinal events have been observed to respond to individualised diet modification (for example reduction of sucrose, lactose and other carbohydrate intake), to taking miglustat between meals, and/or to anti-diarrhoeal medicinal products such as loperamide. In some patients, temporary dose reduction may be necessary. Patients with chronic diarrhoea or other persistent gastrointestinal events that do not respond to these interventions should be investigated according to clinical practice. Miglustat has not been evaluated in patients with a history of significant gastrointestinal disease, including inflammatory bowel disease.

Cases of Crohn's disease have been reported post-marketing in Niemann-Pick type C disease patients treated with Yargesa. Gastrointestinal disturbances are common adverse events of Yargesa. Therefore, in patients with chronic diarrhoea and/or abdominal pain that do not respond to interventions or in the event of clinical worsening, the possibility of Crohn's disease should be considered.

Effects on spermatogenesis

Reliable contraceptive methods should be maintained while male patients are taking Yargesa and for 3 months following discontinuation.Yargesa should be discontinued and reliable contraception be used for the next 3 months before attempting to conceive (see sections 4.6 and 5.3). Studies in the rat have shown that miglustat adversely affects spermatogenesis and sperm parameters, and reduces fertility (see sections 4.6 and 5.3)..

Special populations

Due to limited experience, Yargesa should be used with caution in patients with renal or hepatic impairment. There is a close relationship between renal function and clearance of miglustat, and exposure to miglustat is markedly increased in patients with severe renal impairment (see section 5.2). At present, there is insufficient clinical experience in these patients to provide dosing recommendations. Use of Yargesa in patients with severe renal impairment (creatinine clearance < 30 mL/min/1.73 m2) is not recommended.

Type 1 Gaucher disease

Although no direct comparisons with Enzyme Replacement Therapy (ERT) have been performed in treatment-naive patients with type 1 Gaucher disease, there is no evidence of miglustat having an efficacy or safety advantage over ERT. ERT is the standard of care for patients who require treatment for type 1 Gaucher disease (see section 5.1). The efficacy and safety of miglustat has not been specifically evaluated in patients with severe Gaucher disease.

Regular monitoring of vitamin B12 level is recommended because of the high prevalence of vitamin B12 deficiency in patients with type 1 Gaucher disease.

Cases of peripheral neuropathy have been reported in patients treated with miglustat with or without concurrent conditions such as vitamin B12 deficiency and monoclonal gammopathy. Peripheral neuropathy seems to be more common in patients with type 1 Gaucher disease compared to the general population. All patients should undergo baseline and repeat neurological evaluation.

In patients with type 1 Gaucher disease, monitoring of platelet counts is recommended. Mild reductions in platelet counts without association with bleeding were observed in patients with type 1 Gaucher disease who were switched from ERT to miglustat.

Niemann-Pick type C disease

The benefit of treatment with Yargesa for neurological manifestations in patients with Niemann-Pick type C disease should be evaluated on a regular basis, e.g. every 6 months; continuation of therapy should be re- appraised after at least 1 year of treatment with Yargesa.

Mild reductions in platelet counts without association to bleeding were observed in some patients with Niemann-Pick type C disease treated with Yargesa. In patients included in the clinical trial, 40%-50% had platelet counts below the lower limit of normal at baseline. Monitoring of platelet counts is recommended in these patients.

Reduced growth in the paediatric population

Reduced growth has been reported in some paediatric patients with Niemann-Pick type C disease in the early phase of treatment with miglustat where the initial reduced weight gain may be accompanied or followed by reduced height gain. Growth should be monitored in paediatric and adolescent patients during treatment with Yargesa; the benefit/risk balance should be re-assessed on an individual basis for continuation of therapy.

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per capsule, that is to say essentially 'sodium-free'.

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

Limited data suggest that co-administration of miglustat and enzyme replacement with imiglucerase in patients with type 1 Gaucher disease may result in decreased exposure to miglustat (approximate reductions of 22% in Cmax and 14% in AUC were observed in a small parallel-group study). This study also indicated that miglustat has no or limited effect on the pharmacokinetics of imiglucerase.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no adequate data from the use of miglustat in pregnant women. Studies in animals have shown maternal and embryo-foetal toxicity, including decreased embryo-foetal survival (see section 5.3). The potential risk for humans is unknown.

Miglustat crosses the placenta and should not be used during pregnancy.

Breast-feeding

It is not known if miglustat is secreted in breast milk. Yargesa should not be taken during breast-feeding.

Fertility

Studies in the rat have shown that miglustat adversely affects sperm parameters (motility and morphology) thereby reducing fertility (see sections 4.4 and 5.3).

Contraception in males and females

Contraceptive measures should be used by women of childbearing potential. Reliable contraceptive methods should be maintained while male patients are taking Yargesa and for 3 months following discontinuation (see sections 4.4 and 5.3).

4.7. Effects on ability to drive and use machines

Yargesa has negligible influence on the ability to drive and use machines. Dizziness has been reported as a common adverse reaction, and patients suffering from dizziness should not drive or use machines.

4.8. Undesirable effects

Summary of the safety profile

The most common adverse reactions reported in clinical studies with miglustat were diarrhoea, flatulence, abdominal pain, weight loss and tremor (see section 4.4). The most common serious adverse reaction reported with miglustat treatment in clinical studies was peripheral neuropathy (see section 4.4).

In 11 clinical trials in different indications 247 patients were treated with miglustat at dosages of 50-200 mg t.i.d. for an average duration of 2.1 years. Of these patients, 132 had type 1 Gaucher disease, and 40 had Niemann-Pick type C disease. Adverse reactions were generally of mild to moderate severity and occurred with similar frequency across indications and dosages tested.

Tabulated list of adverse reactions

Adverse reactions from clinical trials and spontaneous reporting, occurring in >1% of patients, are listed in the table below by system organ class and frequency (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). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Blood and lymphatic system disorders

Common

Thrombocytopenia

Metabolism and nutrition disorders

Very common

Weight loss, decreased appetite

Psychiatric disorders

Common

Depression, insomnia, libido decreased

Nervous system disorders

Very common

Tremor,

Common

Peripheral neuropathy, ataxia, amnesia, paraesthesia, hypoaesthesia, headache, dizziness

Gastrointestinal disorders

Very common

Diarrhoea, flatulence, abdominal pain

Common

Nausea, vomiting, abdominal distension/discomfort, constipation, dyspepsia

Musculoskeletal and connective tissue disorders

Common

Muscle spasms, muscle weakness

General disorders and administration site reactions

Common

Fatigue, asthenia, chills and malaise

Investigations

Common

Nerve conduction studies abnormal

Description of selected adverse reactions

Weight loss has been reported in 55% of patients using miglustat. The greatest prevalence was observed between 6 and 12 months.

Miglustat has been studied in indications where certain events reported as adverse reactions, such as neurological and neuropsychological symptoms/signs, cognitive dysfunction and thrombocytopenia could also be due to the underlying conditions.

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 the national reporting system listed in Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

4.9. Overdose

Symptoms

No acute symptoms of overdose have been identified. Miglustat has been administered at doses of up to 3000 mg/day for up to six months in HIV positive patients during clinical trials. Adverse events observed included granulocytopenia, dizziness and paraesthesia. Leukopenia and neutropenia have also been observed in a similar group of patients receiving 800 mg/day or higher dose.

Management

In case of overdose general medical care is recommended.