Miglustat Gen.Orph

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Miglustat Gen.Orph 100 mg hard capsules 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each capsule contains 100 mg miglustat 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Hard capsule. 
 
White opaque cap and body, hard gelatin capsules size 4 of about 14.0 mm length. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Miglustat Gen.Orph is indicated for the oral treatment of adult patients with mild to moderate type 1 
Gaucher disease. Miglustat Gen.Orph may be used only in the treatment of patients for whom enzyme 
replacement therapy is unsuitable (see sections 4.4 and 5.1). 
 
Miglustat Gen.Orph 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 Miglustat Gen.Orph 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. 
 



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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 Miglustat Gen.Orph should be evaluated on a regular basis 
(see section 4.4). 
 
There is limited experience with the use of Miglustat Gen.Orph in Niemann-Pick type C disease 
patients under the age of 4 years. 
 
Special populations 
 
Elderly 
There is no experience with the use of Miglustat Gen.Orph 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 
Miglustat Gen.Orph has not been evaluated in patients with hepatic impairment. 
 
Method of administration  
 
Miglustat Gen.Orph 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 



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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 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. 
 
Effects on spermatogenesis 
Male patients should maintain reliable contraceptive methods while taking Miglustat Gen.Orph. 
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 Miglustat Gen.Orph and maintain reliable contraceptive methods 
for a further 3 months. 
 
Special populations 
Due to limited experience, Miglustat Gen.Orph 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 Miglustat Gen.Orph 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 Miglustat Gen.Orph 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 Miglustat Gen.Orph. 



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Mild reductions in platelet counts without association to bleeding were observed in some patients with 
Niemann-Pick type C disease treated with miglustat. 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 Miglustat Gen.Orph; the benefit/risk balance should be re-assessed on an 
individual basis for continuation of therapy. 
 
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 reproductive toxicity, including dystocia (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. Miglustat Gen.Orph 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). Until further information is 
available, it is advised that before seeking to conceive, male patients should cease Miglustat Gen.Orph 
and maintain reliable contraceptive methods for 3 months thereafter. 
 
Contraceptive measures should be used by women of childbearing potential. Male patients should 
maintain reliable contraceptive methods while taking Miglustat Gen.Orph (see sections 4.4 and 5.3). 
 
4.7 Effects on ability to drive and use machines 
 
Miglustat Gen.Orph 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). 
 



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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 < 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. 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 Appendix V. 
 
4.9 Overdose 
 
Symptoms 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


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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. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: Other alimentary tract and metabolism products, ATC Code: A16AX06 
 
Type 1 Gaucher disease 
 
Gaucher disease is an inherited metabolic disorder caused by a failure to degrade glucosylceramide 
resulting in lysosomal storage of this material and widespread pathology. Miglustat is an inhibitor of 
glucosylceramide synthase, the enzyme responsible for the first step in the synthesis of most 
glycolipids. In vitro, glucosylceramide synthase is inhibited by miglustat with an IC50 of 20-37 μM. In 
addition, inhibitory action on a non-lysosomal glycosylceramidase has been demonstrated 
experimentally in vitro. The inhibitory action on glucosylceramide synthase forms the rationale for 
substrate reduction therapy in Gaucher disease. 
 
The pivotal trial of miglustat was conducted in patients unable or unwilling to receive 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 × 109/l 
were observed. Eighteen patients then continued to receive miglustat under an optional extended 
treatment protocol. Clinical benefit has been assessed at 24 and 36 months in 13 patients. After 3 years 
of continuous miglustat treatment, mean reductions in liver and spleen organ volume were 17.5% and 
29.6%, respectively. There was a mean increase of 22.2 × 109/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 imiglucerase, imiglucerase in 
combination with miglustat, or switch to miglustat. This study was conducted over a 6-month 
randomised comparison period followed by 18 months extension where all patients received miglustat 
monotherapy. In the first 6 months in patients who were switched to miglustat, 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 miglustat 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 
miglustat monotherapy (20 and 6 patients, respectively). No patient showed rapid deterioration of type 
1 Gaucher disease following the switch to miglustat monotherapy. 
 
A total daily dose of 300 mg miglustat 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. 
 
An open-label, non comparative, 2-year study enrolled 42 patients with type 1 Gaucher disease, who 
had received a minimum of 3 years of ERT and who fulfilled criteria of stable disease for at least 
2 years. The patients were switched to monotherapy with miglustat 100 mg t.i.d. Liver volume 
(primary efficacy variable) was unchanged from baseline to the end of treatment. Six patients had 



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miglustat treatment prematurely discontinued for potential disease worsening, as defined in the study. 
Thirteen patients discontinued treatment due to an adverse event. Small mean reductions in 
haemoglobin [–0.95 g/dL (95% CI: –1.38, –0.53)] and platelet count [-44.1 × 109/L (95% CI: –57.6, –
30.7)] were observed between baseline and end of study. Twenty-one patients completed 24 months of 
miglustat treatment. Of these, 18 patients at baseline were within established therapeutic goals for liver 
and spleen volume, haemoglobin levels, and platelet counts, and 16 patients remained within all these 
therapeutic goals at Month 24. 
 
Bone manifestations of type 1 Gaucher disease were evaluated in 3 open-label clinical studies in 
patients treated with miglustat 100 mg t.i.d. 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 
 
Niemann-Pick type C disease is a very rare, invariably progressive and eventually fatal 
neurodegenerative disorder characterised by impaired intracellular lipid trafficking. The neurological 
manifestations are considered secondary to the abnormal accumulation of glycosphingolipids in 
neuronal and glial cells. 
 
Data to support safety and efficacy of miglustat 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 substudy 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 miglustat for more than 3 years. The survey 
included a case series of 66 patients treated with miglustat 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 miglustat in adult patients was 200 mg t.i.d., and was 
adjusted according to body surface area in paediatric patients. 
 
Overall the data show that treatment with miglustat can reduce the progression of clinically relevant 
neurological symptoms in patients with Niemann-Pick type C disease. 
 
The benefit of treatment with Miglustat Gen.Orph 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 Miglustat Gen.Orph, (see 
section 4.4). 
 
5.2 Pharmacokinetic properties 
 
Pharmacokinetic parameters of miglustat were assessed in healthy subjects, in a small number of 
patients with type 1 Gaucher disease, Fabry disease, HIV-infected patients, and in adults, adolescents 
and children with Niemann-Pick type C disease or type 3 Gaucher disease. 
 
The kinetics of miglustat appear to be dose linear and time independent. In healthy subjects miglustat 
is rapidly absorbed. Maximum plasma concentrations are reached about 2 hours after dose. Absolute 
bioavailability has not been determined. Concomitant administration of food decreases the rate of 
absorption (Cmax was decreased by 36% and tmax delayed 2 hours), but has no statistically significant 
effect on the extent of absorption of miglustat (AUC decreased by 14%). 
 
The apparent volume of distribution of miglustat is 83 l. Miglustat does not bind to plasma proteins. 
Miglustat is mainly eliminated by renal excretion, with urinary recovery of unchanged drug 
accounting for 70-80% of the dose. Apparent oral clearance (CL/F) is 230 ± 39 ml/min. The average 
half-life is 6–7 hours. 



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Following administration of a single dose of 100 mg 14C-miglustat to healthy volunteers, 83% of the 
radioactivity was recovered in urine and 12% in faeces. Several metabolites were identified in urine 
and faeces. The most abundant metabolite in urine was miglustat glucuronide accounting for 5% of the 
dose. The terminal half-life of radioactivity in plasma was 150 h suggesting the presence of one or 
more metabolites with very long half-life. The metabolite accounting for this has not been identified, 
but may accumulate and reach concentrations exceeding those of miglustat at steady state. 
 
The pharmacokinetics of miglustat is similar in adult type 1 Gaucher disease patients and Niemann-
Pick type C disease patients when compared to healthy subjects. 
 
Paediatric population 
 
Pharmacokinetic data were obtained in paediatric patients with type 3 Gaucher disease aged 3 to 15 
years, and patients with Niemann-Pick type C disease aged 5–16 years. Dosing in children at 200 mg 
t.i.d. adjusted for body surface area resulted in Cmax and AUCτ values which were approximately 
twofold those attained after 100 mg t.i.d. in type 1 Gaucher disease patients, consistent with the dose-
linear pharmacokinetics of miglustat. At steady state, the concentration of miglustat in cerebrospinal 
fluid of six type 3 Gaucher disease patients was 31.4–67.2% of that in plasma. 
 
Limited data in patients with Fabry disease and impaired renal function showed that CL/F decreases 
with decreasing renal function. While the numbers of subjects with mild and moderate renal 
impairment were very small, the data suggest an approximate decrease in CL/F of 40% and 60% 
respectively, in mild and moderate renal impairment (see section 4.2). Data in severe renal impairment 
are limited to two patients with creatinine clearance in the range 18 – 29 ml/min and cannot be 
extrapolated below this range. These data suggest a decrease in CL/F by at least 70% in patients with 
severe renal impairment. 
 
Over the range of data available, no significant relationships or trends were noted between miglustat 
pharmacokinetic parameters and demographic variables (age, BMI, gender or race). 
 
There are no pharmacokinetic data available in patients with liver impairment or in the elderly 
(> 70 years). 
 
5.3 Preclinical safety data 
 
The main effects common to all species were weight loss and diarrhoea, and, at higher doses, damage 
to the gastrointestinal mucosa (erosions and ulceration). Further effects seen in animals at doses that 
result in exposure levels similar to or moderately higher than the clinical exposure level were: changes 
in lymphoid organs in all species tested, transaminase changes, vacuolation of thyroid and pancreas, 
cataracts, nephropathy and myocardial changes in rats. These findings were considered to be 
secondary to debilitation. 
 
Administration of miglustat to male and female Sprague-Dawley rats by oral gavage for 2 years at 
dose levels of 30, 60 and 180 mg/kg/day resulted in an increased incidence of testicular interstitial cell 
(Leydig cell) hyperplasia and adenomas in male rats at all dose levels. The systemic exposure at the 
lowest dose was below or comparable to that observed in humans (based on AUC0-∞) at the 
recommended human dose. A No Observed Effect Level (NOEL) was not established and the effect 
was not dose dependent. There was no drug-related increase in tumor incidence in male or female rats 
in any other organ. Mechanistic studies revealed a rat specific mechanism which is considered to be of 
low relevance for humans. 
 
Administration of miglustat to male and female CD1 mice by oral gavage at dose levels of 210, 420 
and 840/500 mg/kg/day (dose reduction after half a year) for 2 years resulted in an increased incidence 
of inflammatory and hyperplastic lesions in the large intestine in both sexes. Based on mg/kg/day and 
corrected for differences in faecal excretion, the doses corresponded to 8, 16 and 33/19 times the 
highest recommended human dose (200 mg t.i.d.). Carcinomas in the large intestine occurred 



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occasionally at all doses with a statistically significant increase in the high dose group. A relevance of 
these findings to humans cannot be excluded. There was no drug-related increase in tumour incidence 
in any other organ. 
 
Miglustat did not show any potential for mutagenic or clastogenic effects in the standard battery of 
genotoxicity tests. 
 
Repeated-dose toxicity studies in rats showed effects on the seminiferous epithelium of the testes. 
Other studies revealed changes in sperm parameters (motility and morphology) consistent with an 
observed reduction in fertility. These effects occurred at exposure levels similar to those in patients, 
but showed reversibility. Miglustat affected embryo/foetal survival in rats and rabbits, dystocia was 
reported, post-implantation losses were increased, and an increased incidence of vascular anomalies 
occurred in rabbits. These effects may be partly related to maternal toxicity. 
 
Changes in lactation were observed in female rats in a 1-year study. The mechanism for this effect is 
unknown. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Capsule contents 
Sodium starch glycolate (Type A), 
Povidone (K30), 
Magnesium stearate. 
 
Capsule shell 
Gelatin, 
Titanium dioxide (E171). 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
3 years.  
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 
6.5 Nature and contents of container  
 
Polyamide/aluminium/PVC/Aluminium blister supplied as a box of 12 blisters, each blister containing 
7 capsules providing a total of 84 capsules. 
 
6.6 Special precautions for disposal  
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Gen.Orph 



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185 Bureaux de la Colline 
92213 Saint Cloud Cedex 
France 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/17/1232/001 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 10 november 2017 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 
 
 



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ANNEX II 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE  

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION 

 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 

 



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A.  MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 

Name and address of the manufacturer responsible for batch release 

Delpharm Reims 
10 rue Colonnel Charbonneaux 
51100 Reims 
France 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product 
Characteristics, section 4.2). 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION  

• Periodic safety update reports  
 

The requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent updates published on the European medicines web-portal. 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT 

• Risk Management Plan (RMP) 
 

The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 
agreed RMP presented in Module 1.8.2 of the marketing authorisation and any agreed subsequent 
updates of the RMP. 

An updated RMP should be submitted: 

• At the request of the European Medicines Agency; 

• Whenever the risk management system is modified, especially as the result of new 
information being received that may lead to a significant change to the benefit/risk profile or 
as the result of an important (pharmacovigilance or risk minimisation) milestone being 
reached.  

 

 

 
 
 
 
 

 
 
 
 
 



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ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



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A. LABELLING 



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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Miglustat Gen.Orph 100 mg hard capsules 
 
miglustat 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each capsule contains 100 mg miglustat 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Hard capsule. 
84 capsules 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 



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Gen.Orph 
185 Bureaux de la Colline 
92213 Saint Cloud Cedex 
France 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/17/1232/001 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Miglustat Gen.Orph 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
 PC: {number}  
SN: {number}  
NN: {number} 



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MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTERS  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Miglustat Gen.Orph 100 mg hard capsules 
 
miglustat 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Gen.Orph (logo) 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
 



19 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



20 

Package leaflet: Information for the user 
 

Miglustat Gen.Orph 100 mg hard capsules 
miglustat 

 
Read all of this leaflet carefully before you start taking this medicine because it contains 

important information for you. 
- Keep this leaflet. You may need to read it again.  
- If you have any further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.  
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What Miglustat Gen.Orph is and what it is used for  
2. What you need to know before you take Miglustat Gen.Orph 
3. How to take Miglustat Gen.Orph 
4. Possible side effects  
5. How to store Miglustat Gen.Orph 
6. Contents of the pack and other information 
 
 
1. What Miglustat Gen.Orph is and what it is used for 
 
Miglustat Gen.Orph contains the active substance miglustat which belongs to a group of medicines 
that affect metabolism. It is used to treat two conditions: 
 
• Miglustat Gen.Orph is used to treat mild to moderate type 1 Gaucher disease in adults. 
 
In type 1 Gaucher disease, a substance called glucosylceramide is not removed from your body. It 
starts to build up in certain cells of the body’s immune system. This can result in liver and spleen 
enlargement, changes in the blood and bone disease. 
 
The usual treatment for type 1 Gaucher disease is enzyme replacement therapy. Miglustat Gen.Orph is 
only used when a patient is considered unsuitable for treatment with enzyme replacement therapy. 
 
• Miglustat Gen.Orph is also used to treat progressive neurological symptoms in Niemann-

Pick type C disease in adults and in children. 
 
If you have Niemann-Pick type C disease, fats such as glycosphingolipids build up in the cells of your 
brain. This can result in disturbances in neurological functions such as slow eye movements, balance, 
swallowing, and memory, and in seizures. 
 
Miglustat Gen.Orph works by inhibiting the enzyme called ‘glucosylceramide synthase’ which is 
responsible for the first step in the synthesis of most glycosphingolipids. 
 
 
2. What you need to know before you take Miglustat Gen.Orph  
 
Do not take Miglustat Gen.Orph 
- if you are allergic to miglustat or any of the other ingredients of this medicine  

(listed in section 6) 
 
Warnings and precautions  
Talk to your doctor or pharmacist before taking Miglustat Gen.Orph 



21 

- if you suffer from kidney disease 
- if you suffer from liver disease 
 
Your doctor will perform the following tests before treatment and during treatment with Miglustat 
Gen.Orph: 
- an examination to check the nerves in your arms and legs 
- measurement of vitamin B12 levels 
-  monitoring growth if you are a child or adolescent with Niemann-Pick type C disease 
- monitoring of blood platelet counts 
 
The reason for these tests is that some patients have had tingling or numbness in the hands and feet, or 
a decrease in body weight, while taking Miglustat Gen.Orph. The tests will help the doctor decide 
whether these effects are due to your disease or other existing conditions, or due to side effects of 
Miglustat Gen.Orph (see section 4 for further details). 
 
If you have diarrhoea, your doctor may ask you to change your diet to reduce your lactose and 
carbohydrate intake such as sucrose (cane sugar), or not to take Miglustat Gen.Orph together with 
food, or to temporarily reduce your dose. In some cases the doctor may prescribe anti-diarrhoeal 
medicines such as loperamide. If your diarrhoea does not respond to these measures, or if you have 
any other abdominal complaint, consult your doctor. In such case, your doctor may decide to conduct 
further investigations. 
 
Male patients should use reliable birth control methods during their treatment with Miglustat 
Gen.Orph, and for 3  months after finishing treatment. 
 
Children and adolescents 
Do not give this medicine to children and adolescents (below 18 years old) with type 1 Gaucher 
disease because it is not known if it works in this disease. 
 
Other medicines and Miglustat Gen.Orph 
Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other 
medicines. 
 
Tell your doctor if you are taking medicines containing imiglucerase, which are sometimes used at the 
same time as Miglustat Gen.Orph. They may lower the amount of Miglustat Gen.Orph in your body. 
 
Pregnancy, breast-feeding and fertility 
You should  not take Miglustat Gen.Orph if you are pregnant or thinking of becoming pregnant. Your 
doctor can give you more information. You must use effective birth control while taking Miglustat 
Gen.Orph. Do not breastfeed while you are taking Miglustat Gen.Orph. 
 
Male patients should use reliable birth control methods during their treatment with Miglustat 
Gen.Orph, and for 3 months after finishing treatment. 
 
If you are pregnant, breast feeding, think you may be pregnant or planning to have a baby, ask your 
doctor or pharmacist for advice before taking this medicine. 
 
Driving and using machines 
Miglustat Gen.Orph may make you feel dizzy. Do not drive or use any tools or machines if you feel 
dizzy. 
 
 
3. How to take Miglustat Gen.Orph 
 
Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 
if you are not sure. 
 



22 

• For type 1 Gaucher disease: for adults, the usual dose is one capsule (100 mg) three times a day 
(morning, afternoon and evening). This means a daily maximum of three capsules (300 mg). 

 
• For Niemann-Pick type C disease: For adults and adolescents (over 12 years old), the usual dose 

is two capsules (200 mg) three times a day (morning, afternoon and evening). This means a daily 
maximum of six capsules (600 mg). 

 
For children less than 12 years old, your doctor will adjust the dose for Niemann-Pick type C disease. 
 
If you have a problem with your kidneys you may receive a lower starting dose. Your doctor may 
reduce your dose, e.g., to one capsule (100 mg) once or twice a day, if you suffer from diarrhoea when 
taking Miglustat Gen.Orph (see section 4). Your doctor will tell you how long your treatment will last. 
 
Miglustat Gen.Orph can be taken with or without food. You should swallow the whole capsule with a 
glass of water. 
 
If you take more Miglustat Gen.Orph than you should 
If you take more capsules than you were told to, consult your doctor immediately. Miglustat has been 
used in clinical trials at doses ten times higher than the recommended dose: this caused decreases in 
white blood cells and other side effects similar to those described in section 4. 
 
If you forget to take Miglustat Gen.Orph 
Take the next capsule at the usual time. Do not take a double dose to make up for a forgotten dose. 
 
If you stop taking Miglustat Gen.Orph 
Don’t stop taking Miglustat Gen.Orph without talking to your doctor. 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Most serious side effects: 
Some patients have had tingling or numbness in the hands and feet (seen commonly). They could 
be signs of peripheral neuropathy, due to side effects of Miglustat Gen.Orph or they could be due to 
existing conditions. Your doctor will perform some tests before and during treatment with Miglustat 
Gen.Orph to assess this (see section 2). 
 
If you do get any of these effects, please seek medical advice from your doctor as soon as 
possible. 
 
If you get a slight tremor, usually trembling hands, seek medical advice from your doctor as soon 
as possible. The tremor often disappears without needing to stop the treatment. Sometimes your doctor 
will need to reduce the dose or stop Miglustat Gen.Orph treatment to stop the tremor. 
 
Very common effects may affect more than 1 in 10 people. 
The most common side effects are diarrhoea, flatulence (wind),  abdominal (stomach) pain, weight loss 
and decreased appetite. 
 
If you do lose some weight when you start treatment with Miglustat Gen.Orph don’t worry. People 
usually stop losing weight as treatment goes on. 
 
Common effects may affect up to 1 in 10 people. 
Common side effects of treatment include headache, dizziness, paraesthesia (tingling or numbness), 
abnormal coordination, hypoaesthesia (reduced sensation to touch), dyspepsia (heartburn), nausea 
(feeling sick), constipation and vomiting, swelling or discomfort in the abdomen (stomach) and 



23 

thrombocytopenia (reduced levels of blood platelets). The neurological symptoms and 
thrombocytopenia could be due to the underlying disease. 
 
Other possible side effects are muscular spasms or weakness, fatigue, chills and malaise, depression, 
difficulty sleeping, forgetfulness and less libido. 
 
Most patients get one or more of these side effects, usually at the start of treatment or at intervals 
during treatment. Most cases are mild and disappear quite quickly. If any of these side effects cause 
problems, consult your doctor. He or she may reduce the dose of Miglustat Gen.Orph or recommend 
other medicines to help control side effects. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine. 
 
 
5. How to store Miglustat Gen.Orph 
 
Keep this medicine out of the sight and reach of children. 
 
Do not take this medicine after the expiry date which is stated on the carton after ‘EXP’. The expiry 
date refers to the last day of that month. 
 
This medicine does not require any special storage conditions. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Miglustat Gen.Orph contains  
- The active substance is miglustat 100 mg. 
- The other ingredients are sodium starch glycolate (type A), povidone (K30), magnesium 

stearate, gelatin, titanium dioxide (E171).  
 
What Miglustat Gen.Orph looks like and contents of the pack 
Miglustat Gen.Orph 100 mg hard capsules are white opaque cap and body, hard gelatin capsules 
size 4 of 14.0 mm length. 
Box of 12 blisters, each blister containing 7 capsules providing a total of 84 capsules. 
 
Marketing Authorisation Holder  
Gen.Orph 
185 Bureaux de la Colline 
92213 Saint Cloud Cedex 
France 
 
Manufacturer 
Delpharm Reims 
10 rue Colonel Charbonneaux 
51100 Reims 
France 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder. 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


24 

België/Belgique/Belgien  
Gen.Orph  
Tél/Tel: +33 (0)1 47 71 04 50 
e-mail: contact@gen-orph.com 
 

Lietuva  
Gen.Orph 
Tel: +33 (0)1 47 71 04 50 
e-mail: contact@gen-orph.com 
 

България  
Диакомерс ЕООД 
Тел.: +359 2 807 50 00 
Е-mail: diacommerce@diacommerce.bg 
 

Luxembourg/Luxemburg  
Gen.Orph 
Tél/Tel.: +33 (0)1 47 71 04 50 
email: contact@gen-orph.com 
 

Česká republika  
Gen. Orph 
Tel: +33 (0)1 47 71 04 50 
e-mail: contact@gen-orph.com 

Magyarország  
Gen.Orph 
Tel.: +33 (0)1 47 71 04 50 
e-mail: contact@gen-orph.com 
 

Danmark  
Gen.Orph 
Tlf: +46 (0)8 21 54 45 
e-mail: pharmacovigilance.SE@propharmagroup.com 
 

Malta  
Gen.Orph 
Tel: +33 (0)1 47 71 04 50 
e-mail: contact@gen-orph.com 

Deutschland  
Gen.Orph 
Tel: +49 30 8560687897 
email: pharmacovigilance.DE@propharmagroup.com 
 

Nederland  
Gen.Orph 
Tel: +33 (0)1 47 71 04 50 
e-mail : contact@gen-orph.com 
 

Eesti  
Gen.Orph 
Tel: +33 (0)1 47 71 04 50 
email: contact@gen-orph.com 
 

Norge  
Gen.Orph 
Tlf: +46 (0)8 21 54 45 
e-mail: pharmacovigilance.SE@propharmagroup.com 
 

Ελλάδα  
Gen.Orph 
Τηλ: +33 (0)1 47 71 04 50 
email: contact@gen-orph.com 
 

Österreich  
Gen.Orph 
Tel : +33 (0)1 47 71 04 50 
e-mail : contact@gen-orph.com 
 

España  
Pharma International S.A. 
Tel: +34 915 635 856 
e-mail: farmacovigilancia@pharmaintl.net 
 

Polska  
Gen.Orph 
Tel.: +33 (0)1 47 71 04 50 
e-mail: contact@gen-orph.com 
 

France  
Gen.Orph 
Tél.: +33 (0)1 47 71 04 50 
e-mail : contact@gen-orph.com 
 

Portugal  
PharSolution Pharmaceutical Consulting, Lda.  
Tel: +351 21 464 32 25 
e-mail: pharmacovigilance@pharsolution.com 
 

Hrvatska  
Gen.Orph 
Tel: +33 (0)1 47 71 04 50 
e-mail: contact@gen-orph.com 
 
 

România  
Gen.Orph 
Tel: +33 (0)1 47 71 04 50 
e-mail: contact@gen-orph.com 

Ireland  
Gen.Orph 
Tel : +33 (0)1 47 71 04 50 
email: contact@gen-orph.com 
 

Slovenija  
Gen.Orph 
Tel: +33 (0)1 47 71 04 50 
email: contact@gen-orph.com 
 

mailto:contact@gen-orph.com
mailto:diacommerce@diacommerce.bg
mailto:contact@gen-orph.com
mailto:pharmacovigilance.SE@propharmagroup.com
mailto:contact@gen-orph.com
mailto:pharmacovigilance.DE@propharmagroup.com
mailto:contact@gen-orph.com
mailto:pharmacovigilance.SE@propharmagroup.com
mailto:contact@gen-orph.com
mailto:contact@gen-orph.com
mailto:pharmacovigilance@pharsolution.com
mailto:contact@gen-orph.com
mailto:contact@gen-orph.com
mailto:contact@genorph.com


25 

Ísland  
Gen.Orph 
Sími: +33 (0)1 47 71 04 50 
e-mail : contact@gen-orph.com 
 

Slovenská republika  
Gen.Orph 
Tel: +33 (0)1 47 71 04 50 
email: contact@gen-orph.com 
 

Italia  
Biovalley Investments Partner S.r.l. 
Tel: +39 040 899 2219 
e.mail: info@biovalleyinvestmentspartner.it 
 

Suomi/Finland  
Gen.Orph 
Puh/Tel : +46 (0)8 21 54 45 
e-mail: pharmacovigilance.SE@propharmagroup.com 
 

Κύπρος  
Gen.Orph 
Τηλ: +33 (0)1 47 71 04 50 
email: contact@gen-orph.com 
 

Sverige  
Gen.Orph 
Tel: +46 (0)8 21 54 45 
e-mail : pharmacovigilance.SE@propharmagroup.com 
 

Latvija  
Gen.Orph 
Tel: +33 (0)1 47 71 04 50 
e-mail : contact@gen-orph.com 

United Kingdom  
Gen.Orph 
Tel: +33 (0)1 47 71 04 50 
email: contact@gen-orph.com 
 

 
 
This leaflet was last revised in {month YYYY}. 
 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. There are also links to other websites about rare diseases and treatments.  
 
 

mailto:contact@gen-orph.com
mailto:info@biovalleyinvestmentspartner.it
mailto:pharmacovigilance.SE@propharmagroup.com
mailto:contact@gen-orph.com
mailto:pharmacovigilance.SE@propharmagroup.com
mailto:contact@gen-orph.com
mailto:contact@gen-orph.com

	SUMMARY OF PRODUCT CHARACTERISTICS
	A.  MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION 
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET