ZAVESCA Capsule, hard Ref.[9247] Active ingredients: Miglustat

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, and in many cases resolved during treatment after between 1 and 3 months. 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 Zavesca 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. Zavesca has not been evaluated in patients with a history of significant gastrointestinal disease, including inflammatory bowel disease.

Effects on spermatogenesis

Male patients should maintain reliable contraceptive methods while taking Zavesca. Studies in the rat have shown that miglustat adversely affects spermatogenesis and sperm parameters, and reduces fertility (see sections 4.6 and 5.3). Until further information is available, before seeking to conceive, male patients should cease Zavesca and maintain reliable contraceptive methods for a further 3 months.

Special populations

Due to limited experience, Zavesca 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 Zavesca 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 Zavesca 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 Zavesca 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 Zavesca 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 Zavesca.

Niemann-Pick type C disease

The benefit of treatment with Zavesca 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 Zavesca.

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

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 Zavesca; 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’.

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

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. Zavesca 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 child-bearing potential. Reliable contraceptive methods should be maintained while male patients are taking Zavesca and for 3 months following discontinuation (see sections 4.4 and 5.3).

Zavesca 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.

Summary of the safety profile

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

In 11 clinical trials in different indications 247 patients were treated with Zavesca 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 <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.

Description of selected adverse reactions

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

Zavesca 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 Appendix V.

Not applicable.