Some of the views expressed in the following notes on newly approved products should be regarded as preliminary, as there may have been limited published data at the time of publication, and little experience in Australia of their safety or efficacy. However, the Editorial Executive Committee believes that comments made in good faith at an early stage may still be of value. Before new drugs are prescribed, the Committee believes it is important that more detailed information is obtained from the manufacturer's approved product information, a drug information centre or some other appropriate source.

Zavesca (Actelion)
100 mg capsules
Approved indication: type I Gaucher disease and Niemann-Pick disease type C
Australian Medicines Handbook Appendix A

Miglustat is indicated for people with mild to moderate type I Gaucher disease, and for progressive neurological manifestations in adults and children with Niemann-Pick type C disease. These are both rare inherited disorders which result in the build-up of glycosphingolipids in the body.

Miglustat is a synthetic analogue of D-glucose and is a competitive inhibitor of glucosylceramide synthase, an enzyme involved in the synthesis of most glycosphingolipids.

Treatment with miglustat aims to reduce the production of glycosphingolipids. Type I Gaucher disease is caused by a deficiency in betaglucocerebrosidase an enzyme which breaks down the glycosphingolipid glucocerebroside. This lipid builds up in macrophages found primarily in the liver, spleen and bone marrow. Clinical features of this disease include hepatomegaly, splenomegaly, anaemia, thrombocytopenia and bone lesions.

Regular intravenous infusion of recombinant glucocerebroside (see Aust Prescr 1999;22:95-8) is the mainstay of treatment and benefits most patients with type I Gaucher disease. Miglustat is an oral option for people who cannot have enzyme therapy.

The safety and efficacy of miglustat has been assessed in several open-label studies.1-4 In the main trial of 28 patients, treatment with oral miglustat 100 mg three times a day reduced mean liver size by 12% (CI R 7.8-16.4) and mean spleen size by 19% (CI 14.3-23.7) after 12 months. (Seven patients had had a previous splenectomy.) Nine of the 22 patients who completed treatment had anaemia (<115 g/L) at baseline. After 12 months, haemoglobin had increased by more than 5 g/L in five of these people. Of the 21 patients who could be assessed for platelet count, four had an increase of at least 15 x 109/L platelets. Glycolipid biosynthesis assessed by measuring surface expression of Gm1 on leucocytes - was found to have decreased by an average of 38.5% over 12 months in a sample of five patients. Plasma chitotriosidase activity - a measure of stored lipids - had also decreased by the end of the trial.1 The benefits of miglustat were maintained for up to three years in an extension of the trial.2 Similar effects on the liver and spleen were observed in the other open-label trials.2-4

The most frequent adverse event during the trial was diarrhoea (79% of patients). Six patients dropped out two of these were because of gastrointestinal problems. Two patients were withdrawn because of paraesthesiae which were confirmed to be peripheral neuropathy.1 Other common adverse events reported in the open-label trials included weight loss, tremor, flatulence and abdominal pain.2-4

Dose reduction or discontinuation may be required for tremor. Peripheral neuropathy may be related to vitamin B12 deficiency, which is common in type I Gaucher disease, so regular monitoring of vitamin B12 as well as neurological evaluation is recommended.

Niemann-Pick type C disease is an incurable progressive disease that leads to premature death. Impaired transport of lipids within cells causes some fatty acids including glycosphingolipids to accumulate in tissues and organs, particularly the brain. This can lead to supranuclear gaze palsy, ataxia, problems with speech and swallowing, dystonia, seizures, dementia, psychiatric problems and gelastic cataplexy.S

Until now, treatment for this disease has mainly been supportive. As miglustat can cross the blood-brain barrier, its efficacy has been assessed in Niemann-Pick type C disease. In a randomised controlled 12-month trial, oral miglustat 200 mg given three times a day was compared to standard care (drug treatment and physical, speech and occupational therapy) in a 2:1 ratio in 28 patients aged 12 years or older. In addition, 12 children aged under 12 years enrolled in the trial were all given miglustat (dose was adjusted according to body surface area). Most of the participants had severe clinical manifestations at baseline and were allowed to continue their medications which included analgesics, antibiotics, antidiarrhoea drugs, sedatives and hypnotics, antiepileptics and drugs to treat dystonia.5

The main measure of efficacy in the trial was the speed of horizontal eye movements between fixed points. After a year of treatment, improvements were observed in patients given miglustat, but this was not significantly different to results seen in patients given standard care alone. Improvements in the ability to swallow and in intellectual performance (mini-mental status examination) were also seen in older patients (>12 years old) given miglustat compared to those who received standard care.5 Open-label extensions of this study (up to three years) reported that patients' neurological symptoms did not progress while taking miglustat.6,7

A retrospective observational study analysed physician questionnaires about ambulation, manipulation, language and swallowing in patients who had been taking miglustat for an average of 1.5 years. Overall, 74.5% (49/65) of patients had reduced disease progression or stabilisation of neurological symptoms.8

Adverse events in Niemann-Pick disease were similar to those seen in type I Gaucher disease, with diarrhoea being the most common (85% of patients). Weight loss (63%), tremor (46%) and flatulence (44%) were also frequently reported. Severe adverse events included severe confusional state and salivary hypersecretion, severe dehydration and respiratory syncytical virus infection. These were thought to be unrelated to miglustat. Three people were withdrawn from the trial because of an adverse event one because of insomnia and confusional state, one due to diarrhoea related to Crohn's disease and one from lethargy, impaired memory and depression (in a child).5

As weight loss was commonly reported with miglustat, growth rate should be monitored in children and adolescents taking miglustat. Reductions in platelet counts have occurred with miglustat in Niemann-Pick disease so blood counts should be monitored. Dizziness was a common adverse effect and patients should not drive if they experience this. The benefit of miglustat in Niemann-Pick disease should be reviewed at six-month intervals.

To reduce gastrointestinal effects such as diarrhoea, miglustat should not be taken with food. After a 100 mg dose, maximum plasma concentrations are reached after approximately two hours. Its half-life is about 6-7 hours so steady-state concentrations are predicted to be reached after 1.5-2 days. Miglustat is excreted mainly by the kidneys so dose adjustment may be necessary with milder renal impairment. It is not recommended in severe renal impairment.

Miglustat showed modest efficacy in mild to moderate type I Gaucher disease and Niemann-Pick disease, although numbers of patients in the trials were small. It has been approved as an orphan drug in Australia and is only available through the Life Saving Drugs Program.

R confidence interval

S sudden weakness or collapse associated with strong emotion, particularly laughter

manufacturer provided only the product information

The Transparency Score () is explained in New drugs: transparency', Vol 37 No 1, Aust Prescr 2014;37:27.

Notes on references

At the time the comment was prepared, information about this drug was available on the web site of the Food and Drug Administration in the USA (

At the time the comment was prepared, a scientific discussion about this drug was available on the website of the European Medicines Agency (

At the time the comment was prepared, information about this drug was available on the website of the Therapeutic Goods Administration (

Correction - June 2010
Spelling corrected to recombinant glucocerebrosidase.