Special Warning : אזהרת שימוש

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 individualized 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.

Cases of Crohn’s disease have been reported post-marketing in Niemann-Pick type C disease patients treated with Zavesca. Gastrointestinal disturbances are common adverse events of Zavesca. 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 Zavesca and for 3 months following discontinuation. Zavesca should be discontinued and reliable contraception be used for the next 3 months before attempting to conceive (see section 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, 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% 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 Zavesca; the benefit/risk balance should be re-assessed on an individual basis for continuation of therapy.


Important information about some of the ingredients of the medicine
Sodium
This medicinal product contains less than 1 mmol sodium (23 mg) per capsule, that is to say essentially 'sodium free'.

Effects on Driving

4.7 Effects on ability to drive and use machines
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.