Zavesca®
(miglustat) Abbreviated Prescribing
Information (PI). For further prescribing information, please refer to the Zavesca Summary of Product Characteristics (SmPC). Presentation: Miglustat 100mg hard capsules. Four blister sheets with 21 capsules per sheet and 84 capsules per pack. MAH Number: EU1/02/238/001. Indications / Uses: The oral treatment of mild to moderate type 1 Gaucher disease for adult patients in whom enzyme replacement therapy is unsuitable. Zavesca is indicated for the treatment of progressive neurological manifestations in adult patients and paediatric patients with Niemann-Pick type C disease. Dosage and Administration: Therapy should be conducted under the supervision of a physician. Zavesca can be taken with or without food. Dosage in type 1 Gaucher disease: Adults: Recommended starting dose is 100 mg three times a day. The presence of diarrhoea or side effects such as tremor may necessitate temporary dose reduction. Hepatic Impairment: Zavesca has not been evaluated in patients with hepatic impairment. Renal Impairment: Zavesca should be used with caution in patients with renal impairment. Use in patients with severe renal disease is not recommended. Children, Adolescents and Elderly: There is no experience with the use of Zavesca in patients with type 1 Gaucher disease under the age of 18 or over 70 years. Dosage in Niemann-Pick type C disease: The recommended dose for the treatment of adult and adolescent patients 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. Temporary dose reduction may be necessary in some patients because of diarrhoea. The benefit to the patient of treatment with Zavesca should be evaluated on a regular basis (see Warning and Precautions). There is limited experience with the use of Zavesca in Niemann-Pick type C disease patients under the age of 4 years. Contraindications: Hypersensibility to miglustat or any of the excipients. Warnings and Precautions: The safety and efficacy of Zavesca has not been specifically evaluated in patients with severe Gaucher disease. In clinical trials, approximately 38% of patients with type 1 Gaucher disease, and 58% of patients with Niemann- Pick type C disease reported tremor on treatment. Dose reduction may ameliorate the tremor but cessation of treatment may be required. Regular monitoring of vitamin B12 levels is recommended because of the high prevalence of vitamin B12 deficiency in this population. Cases of peripheral neuropathy have been reported in Zavesca-treated patients 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 evaluations with re-assessment of risk/benefit in those who develop symptoms. Patients with chronic diarrhoea or other persistent gastrointestinal events that do not respond to diet modification, to taking Zavesca away from meals, and/or to anti-diarrhoeal medicinal products such as loperamide 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. Males and females of childbearing potential should use effective contraception during treatment and men for three months after. 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. Reduced growth has been reported in some paediatric patients with Niemann-Pick type C disease. 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. 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. Interactions: When Zavesca is combined with Cerezyme, limited data suggests decreased exposure to miglustat (14% reduction in AUC) and limited or no effects on Cerezyme. Pregnancy and Lactation: Zavesca should not be used during pregnancy or during breastfeeding. Male patients should maintain reliable contraceptive methods while taking Zavesca and for 3 months after finishing treatment. Undesirable Effects: In nine clinical trials in five different indications 206 patients were treated with Zavesca at dosages of 50-200 mg three times a day for an average duration of 2.2 years. Of these patients, 90 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. Very common effects were: weight loss, tremor, diarrhoea, flatulence and abdominal pain. Common effects were: thrombocytopenia, anorexia, decreased appetite, insomnia, less libido, peripheral neuropathy, headache, paraesthesia, dizziness, ataxia, hypoaesthesia, nausea,
vomiting, abdominal distension/discomfort, constipation, dyspepsia, muscle spasms, fatigue, asthenia and nerve conduction studies abnormal. Zavesca has been studied in indications where certain events reported as adverse drug reactions, such as neurological symptoms/signs and thrombocytopenia could also be due to the underlying condition. Isolated cases of cognitive dysfunction have been reported during clinical trials of Zavesca in type 1 Gaucher disease. A causal relationship to Zavesca has not been established. Effects on availability to drive and use machines: Patients suffering from dizziness should not drive or operate machinery. Overdosage: No acute symptoms of overdose have been identified. Zavesca 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. Pharmacodynamic properties: Type 1 Gaucher disease: The pivotal trial of Zavesca was conducted in patients unsuitable for ERT. Reasons for not receiving ERT included the burden of intravenous infusions and difficulties in venous access. Twenty eight patients with mild to moderate type 1 Gaucher disease were enrolled in this 12-month non comparative study, and 22 patients completed the study. At 12 months, there was a mean reduction in liver organ volume of 12.1% and a mean reduction in spleen volume of 19.0%. A mean increase in haemoglobin concentration of 0.26 g/dl and a mean platelet count increase of 8.29 x 109/l were observed. Eighteen patients then continued to receive Zavesca under an optional extended treatment protocol. Clinical benefit has been assessed at 24 and 36 months in 13 patients. After 3 years of continuous Zavesca treatment, mean reductions in liver and spleen organ volume were 17.5% and 29.6%, respectively. There was a mean increase of 22.2 x109/l in platelet count, and a mean increase of 0.95 g/dl in haemoglobin concentration. A second open, controlled study randomised 36 patients who had received a minimum of 2 years of treatment with ERT, into three treatment groups: continuation with Cerezyme, Cerezyme in combination with Zavesca, or switch to Zavesca. This study was conducted over a 6 month randomised comparison period followed by an extension of 18 months where all patients received Zavesca monotherapy. In the first 6 months in patients who were switched to Zavesca, liver and spleen organ volumes and haemoglobin levels were unchanged. In some patients there were reductions in platelet count and increases in chitotriosidase activity-indicating that Zavesca monotherapy may not maintain the same control of disease activity in all patients. 29 patients continued in the extension period. When compared to the measurements at 6 months, disease control was unchanged after 18 and 24 months of Zavesca monotherapy (20 and 6 patients, respectively). No patient showed rapid deterioration of type 1 Gaucher disease following the switch to Zavesca monotherapy. A total daily dose of 300 mg Zavesca administered in three divided doses was used in the above two studies. An additional monotherapy study was performed in 18 patients at a total daily dose of 150 mg, and results indicate reduced efficacy compared to a total daily dose of 300 mg. Bone manifestations of type 1 Gaucher disease were evaluated in 3 open-label clinical studies in patients treated with miglustat 100 mg three times a day for up to 2 years (n = 72). In a pooled analysis of uncontrolled data, bone mineral density Z-scores at the lumbar spine and femoral neck increased by more than 0.1 units from baseline in 27 (57%) and 28 (65%) of the patients with longitudinal bone density measurements. There were no events of bone crisis, avascular necrosis or fracture during the treatment period. Niemann-Pick type C disease: Data to support safety and efficacy of Zavesca in Niemann-Pick type C disease come from a prospective open-label clinical trial and a retrospective survey. The clinical trial included 29 adult and juvenile patients in a 12-month controlled period, followed by extension therapy for an average total duration of 3.9 years and up to 5.6 years. In addition 12 paediatric patients were enrolled in an uncontrolled sub-study for an overall average duration of 3.1 years and up to 4.4 years. Among the 41 patients enrolled in the trial 14 patients were treated with Zavesca for more than 3 years. The survey included a case series of 66 patients treated with Zavesca outside of the clinical trial for a mean duration of 1.5 years. Both data sets included paediatric, adolescent and adult patients with an age range of 1 year to 43 years. The usual dose of Zavesca in adult patients was 200 mg three times a day, and was adjusted according to body surface area in paediatric patients. Overall the data show that treatment with Zavesca can reduce the progression of clinically relevant neurological symptoms in patients with Niemann-Pick type C disease. The benefit of treatment with Zavesca on the neurological manifestations of 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 (see section Warning and Precautions). Legal classification: Subject to restricted medical prescription MAH Holder: Actelion Registration Ltd., BSI Building 13th Floor, 389 Chiswick High Road, London W4 4AL, UK. Date of last revision: April 2009.
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Population-based Studies on the Clinical Progression of Motor and Non-motor Features in Parkinson’s Disease
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Thomas Geeraerts, David K Menon and Dan Benhamou
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