MIGLUSTAT GEN.ORPH 100mg capsules medication leaflet

Miglustat Gen.Orph 100 mg hard capsules

Each hard capsule contains 100 mg miglustat

For the full list of excipients, see section 6.1.

Hard capsule.

White opaque cap and body, hard gelatin capsules size 4 of about 14 mm length.

Miglustat Gen.Orph is indicated for the oral treatment of adult patients with mild to moderate type1 Gaucher disease. Miglustat Gen.Orph may be used only in the treatment of patients for whomenzyme replacement therapy is unsuitable (see sections 4.4 and 5.1).

Miglustat Gen.Orph is indicated for the treatment of progressive neurological manifestations in adultpatients and paediatric patients with Niemann-Pick type C disease (see sections 4.4, and 5.1).

Therapy should be directed by physicians who are knowledgeable in the management of Gaucherdisease or Niemann-Pick type C disease, as appropriate.

Dose 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 becauseof diarrhoea.

The efficacy of miglustat in children and adolescents aged 0-17 years with type 1 Gaucher disease hasnot been established. No data are available.

Dose in Niemann-Pick type C disease

Adult

The recommended dose for the treatment of adult patients with Niemann-Pick type C disease is 200mg three times a day.

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 asillustrated below:

Table 1. - Paediatric population

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 should be evaluated on a regular basis (seesection 4.4).

There is limited experience with the use of miglustat in Niemann-Pick type C disease patients underthe age of 4 years.

There is no experience with the use of miglustat in patients over the age of 70.

Pharmacokinetic data indicate increased systemic exposure to miglustat in patients with renalimpairment. 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 Gaucherdisease and at a dose of 200 mg twice daily (adjusted for body surface area in patients below the ageof 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 shouldcommence at a dose of 100 mg once daily in patients with type 1 Gaucher disease and at a dose of100 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).

Miglustat has not been evaluated in patients with hepatic impairment.

Oral use.

Miglustat Gen.Orph can be taken with or without food.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Tremor

Approximately 37% of patients in clinical studies in type 1 Gaucher disease, and 58% of patients in aclinical study in Niemann-Pick type C disease reported tremor on treatment. In type 1 Gaucherdisease, these tremors were described as an exaggerated physiological tremor of the hands. Tremorusually began within the first month of treatment, and in many cases resolved after 1 to 3 months ofcontinued treatment. Dose reduction may ameliorate the tremor, usually within days, butdiscontinuation of treatment may sometimes be required.

Gastrointestinal disturbances

Gastrointestinal events, mainly diarrhoea, have been observed in more than 80% of patients, either atthe outset of treatment or intermittently during treatment (see section 4.8). The mechanism is mostlikely inhibition of intestinal disaccharidases such as sucrase-isomaltase in the gastrointestinal tractleading to reduced absorption of dietary disaccharides. In clinical practice, miglustat-inducedgastrointestinal events have been observed to respond to individualised diet modification (for examplereduction of sucrose, lactose and other carbohydrate intake), to taking miglustat between meals, and/orto anti-diarrhoeal medicinal products such as loperamide. In some patients, temporary dose reductionmay be necessary. Patients with chronic diarrhoea or other persistent gastrointestinal events that do notrespond to these interventions should be investigated according to clinical practice. Miglustat has notbeen evaluated in patients with a history of significant gastrointestinal disease, including inflammatorybowel disease.

Cases of Crohn’s disease have been reported post-marketing in Niemann-Pick type C disease patientstreated with Miglustat Gen.Orph. Gastrointestinal disturbances are common adverse events of

Miglustat Gen.Orph. Therefore, in patients with chronic diarrhoea and/or abdominal pain that do notrespond to interventions or in the event of clinical worsening, the possibility of Crohn’s disease shouldbe considered.

Effects on spermatogenesis

Reliable contraceptive methods should be maintained while male patients are taking miglustat and for3 months following discontinuation. Miglustat should be discontinued and reliable contraception beused for the next 3 months before attempting to conceive (see sections 4.6 and 5.3). Studies in the rathave shown that miglustat adversely affects spermatogenesis and sperm parameters, and reducesfertility (see sections 4.6 and 5.3).

Due to limited experience, miglustat should be used with caution in patients with renal or hepaticimpairment. There is a close relationship between renal function and clearance of miglustat, andexposure 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 dosingrecommendations. Use of miglustat 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 intreatment-naive patients with type 1 Gaucher disease, there is no evidence of miglustat having anefficacy or safety advantage over ERT. ERT is the standard of care for patients who require treatmentfor type 1 Gaucher disease (see section 5.1). The efficacy and safety of miglustat has not beenspecifically 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 withoutconcurrent conditions such as vitamin B12 deficiency and monoclonal gammopathy. Peripheralneuropathy seems to be more common in patients with type 1 Gaucher disease compared to thegeneral population. All patients should undergo baseline and repeat neurological evaluation.

In patients with type 1 Gaucher disease, monitoring of platelet counts is recommended. Mildreductions in platelet counts without association with bleeding were observed in patients with type1 Gaucher disease who were switched from ERT to miglustat.

Niemann-Pick type C disease

The benefit of treatment with miglustat for neurological manifestations in patients with Niemann-Picktype C disease should be evaluated on a regular basis, e.g. every 6 months; continuation of therapyshould be re-appraised after at least 1 year of treatment with miglustat.

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 study, 40%-50% had platelet counts below the lower limit of normal at baseline. Monitoring of platelet counts isrecommended in these patients.

Reduced growth in the paediatric population

Reduced growth has been reported in some paediatric patients with Niemann-Pick type C disease inthe early phase of treatment with miglustat where the initial reduced weight gain may be accompaniedor followed by reduced height gain. Growth should be monitored in paediatric and adolescent patientsduring treatment with miglustat; the benefit/risk balance should be re-assessed on an individual basisfor continuation of therapy.

This medicinal product contains less than 1 mmol sodium (23 mg) per hard capsule, that is to sayessentially 'sodium-free'.

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

There are no adequate data from the use of miglustat in pregnant women. Studies in animals haveshown maternal and embryo-foetal toxicity, including decreased embryo-foetal survival (see section5.3). The potential risk for humans is unknown. Miglustat crosses the placenta and should not be usedduring pregnancy.

It is not known if miglustat is secreted in breast milk. Miglustat Gen.Orph should not be taken duringbreast-feeding.

Studies in the rat have shown that miglustat adversely affects sperm parameters (motility andmorphology) thereby reducing fertility (see sections 4.4 and 5.3).

Contraceptive measures should be used by women of childbearing potential. Reliable contraceptivemethods should be maintained while male patients are taking Miglustat Gen.Orph and for 3 monthsfollowing discontinuation (see sections 4.4 and 5.3).

Miglustat has negligible influence on the ability to drive and use machines. Dizziness has beenreported as a common adverse reaction, and patients suffering from dizziness should not drive or usemachines.

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 seriousadverse reaction reported with miglustat treatment in clinical studies was peripheral neuropathy (seesection 4.4).

In 11 clinical studies in different indications 247 patients were treated with miglustat at doses of50-200 mg three times a day (t.i.d.) for an average duration of 2.1 years. Of these patients, 132 hadtype 1 Gaucher disease, and 40 had Niemann-Pick type C disease. Adverse reactions were generally ofmild to moderate severity and occurred with similar frequency across indications and doses tested.

Adverse reactions from clinical studies and spontaneous reporting, occurring in > 1% of patients, arelisted in the table below by system organ class and frequency (very common: ≥ 1/10, common:≥ 1/100 to < 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.

Table 2. - Tabulated list of adverse reactions

System Organ Class (SOC) Frequency Adverse reaction

Blood and lymphatic system Common Thrombocytopeniadisorders

Metabolism and nutrition Very common Weight loss, decreased appetitedisorders

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, abdominaldistension/discomfort, constipation,dyspepsia

Musculoskeletal and connective Common Muscle spasms, muscle weaknesstissue disorder

General disorders and Common Fatigue, asthenia, chills and malaiseadministration site reactions

Investigations Common Nerve conduction studies abnormal

Weight loss has been reported in 55% of patients. The greatest prevalence was observed between6 and 12 months.

Miglustat has been studied in indications where certain events reported as adverse reactions, such asneurological and neuropsychological symptoms/signs, cognitive dysfunction and thrombocytopeniacould also be due to the underlying conditions.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

No acute symptoms of overdose have been identified. Miglustat has been administered at doses of upto 3000 mg/day for up to six months in HIV positive patients during clinical studies. Adverse eventsobserved included granulocytopenia, dizziness and paraesthesia. Leukopenia and neutropenia havealso been observed in a similar group of patients receiving 800 mg/day or higher dose.

In case of overdose general medical care is recommended.

Pharmacotherapeutic group: Other alimentary tract and metabolism products, various alimentary tractand metabolism products, ATC Code: A16AX06

Type 1 Gaucher disease

Gaucher disease is an inherited metabolic disorder caused by a failure to degrade glucosylceramideresulting in lysosomal storage of this material and widespread pathology. Miglustat is an inhibitor ofglucosylceramide synthase, the enzyme responsible for the first step in the synthesis of mostglycolipids. In vitro, glucosylceramide synthase is inhibited by miglustat with an IC50 of 20-37 μM. Inaddition, inhibitory action on a non-lysosomal glycosylceramidase has been demonstratedexperimentally in vitro. The inhibitory action on glucosylceramide synthase forms the rationale forsubstrate reduction therapy in Gaucher disease.

The pivotal study of miglustat was conducted in patients unable or unwilling to receive ERT. Reasonsfor 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-monthnon-comparative study, and 22 patients completed the study. At 12 months, there was a meanreduction in liver organ volume of 12.1% and a mean reduction in spleen volume of 19.0%. A meanincrease in haemoglobin concentration of 0.26 g/dL and a mean platelet count increase of 8.29 × 109/Lwere observed. Eighteen patients then continued to receive miglustat under an optional extendedtreatment protocol. Clinical benefit has been assessed at 24 and 36 months in 13 patients. After 3 yearsof continuous miglustat treatment, mean reductions in liver and spleen organ volume were 17.5% and29.6%, respectively. There was a mean increase of 22.2 × 109/L in platelet count, and a mean increaseof 0.95 g/dL in haemoglobin concentration.

A second open, controlled study randomised 36 patients who had received a minimum of 2 years oftreatment with ERT, into three treatment groups: continuation with imiglucerase, imiglucerase incombination with miglustat, or switch to miglustat. This study was conducted over a 6-monthrandomised comparison period followed by 18 months extension where all patients received miglustatmonotherapy. In the first 6 months in patients who were switched to miglustat, liver and spleen organvolumes and haemoglobin levels were unchanged. In some patients there were reductions in plateletcount and increases in chitotriosidase activity indicating that miglustat monotherapy may not maintainthe same control of disease activity in all patients. 29 patients continued in the extension period. Whencompared to the measurements at 6 months, disease control was unchanged after 18 and 24 months ofmiglustat monotherapy (20 and 6 patients, respectively). No patient showed rapid deterioration of type1 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 twostudies. 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, whohad received a minimum of 3 years of ERT and who fulfilled criteria of stable disease for at least2 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 hadmiglustat treatment prematurely discontinued for potential disease worsening, as defined in the study.

Thirteen patients discontinued treatment due to an adverse event. Small mean reductions inhaemoglobin [-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 ofmiglustat treatment. Of these, 18 patients at baseline were within established therapeutic goals for liverand spleen volume, haemoglobin levels, and platelet counts, and 16 patients remained within all thesetherapeutic goals at Month 24.

Bone manifestations of type 1 Gaucher disease were evaluated in 3 open-label clinical studies inpatients treated with miglustat 100 mg t.i.d. for up to 2 years (n = 72). In a pooled analysis ofuncontrolled data, bone mineral density Z-scores at the lumbar spine and femoral neck increased bymore than 0.1 units from baseline in 27 (57%) and 28 (65%) of the patients with longitudinal bonedensity measurements. There were no events of bone crisis, avascular necrosis or fracture during thetreatment period.

Niemann-Pick type C disease

Niemann-Pick type C disease is a very rare, invariably progressive and eventually fatalneurodegenerative disorder characterised by impaired intracellular lipid trafficking. The neurologicalmanifestations are considered secondary to the abnormal accumulation of glycosphingolipids inneuronal and glial cells.

Data to support safety and efficacy of miglustat in Niemann-Pick type C disease come from aprospective open-label clinical study and a retrospective survey. The clinical study included 29 adultand juvenile patients in a 12-month controlled period, followed by extension therapy for an averagetotal duration of 3.9 years and up to 5.6 years. In addition 12 paediatric patients were enrolled in anuncontrolled substudy for an overall average duration of 3.1 years and up to 4.4 years. Among the41 patients enrolled in the study 14 patients were treated with miglustat for more than 3 years. Thesurvey included a case series of 66 patients treated with miglustat outside of the clinical study for amean duration of 1.5 years. Both data sets included paediatric, adolescent and adult patients with anage range of 1 year to 43 years. The usual dose of miglustat in adult patients was 200 mg t.i.d., andwas adjusted according to body surface area in paediatric patients.

Overall the data show that treatment with miglustat can reduce the progression of clinically relevantneurological symptoms in patients with Niemann-Pick type C disease.

The benefit of treatment with miglustat for neurological manifestations in patients with Niemann-Picktype C disease should be evaluated on a regular basis, e.g. every 6 months; continuation of therapyshould be re-appraised after at least 1 year of treatment with miglustat, (see section 4.4).

Pharmacokinetic parameters of miglustat were assessed in healthy subjects, in a small number ofpatients with type 1 Gaucher disease, Fabry disease, HIV-infected patients, and in adults, adolescentsand 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 miglustatis rapidly absorbed. Maximum plasma concentrations are reached about 2 hours after dose. Absolutebioavailability has not been determined. Concomitant administration of food decreases the rate ofabsorption (Cmax was decreased by 36% and tmax delayed 2 hours), but has no statistically significanteffect 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 activesubstance 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.

Following administration of a single dose of 100 mg 14C-miglustat to healthy volunteers, 83% of theradioactivity was recovered in urine and 12% in faeces. Several metabolites were identified in urineand faeces. The most abundant metabolite in urine was miglustat glucuronide accounting for 5% of thedose. The terminal half-life of radioactivity in plasma was 150 h suggesting the presence of one ormore 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.

Pharmacokinetic data were obtained in paediatric patients with type 3 Gaucher disease aged 3 to15 years, and patients with Niemann-Pick type C disease aged 5-16 years. Dosing in children at200 mg t.i.d. adjusted for body surface area resulted in Cmax and AUCτ values which wereapproximately twofold those attained after 100 mg t.i.d. in type 1 Gaucher disease patients, consistentwith the dose-linear pharmacokinetics of miglustat. At steady state, the concentration of miglustat incerebrospinal 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 decreaseswith decreasing renal function. While the numbers of subjects with mild and moderate renalimpairment 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 impairmentare limited to two patients with creatinine clearance in the range 18 - 29 mL/min and cannot beextrapolated below this range. These data suggest a decrease in CL/F by at least 70% in patients withsevere renal impairment.

Over the range of data available, no significant relationships or trends were noted between miglustatpharmacokinetic 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).

The main effects common to all species were weight loss and diarrhoea, and, at higher doses, damageto the gastrointestinal mucosa (erosions and ulceration). Further effects seen in animals at doses thatresult in exposure levels similar to or moderately higher than the clinical exposure level were: changesin 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 besecondary to debilitation.

Administration of miglustat to male and female Sprague-Dawley rats by oral gavage for 2 years atdose 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 thelowest dose was below or comparable to that observed in humans (based on AUC0-∞) at therecommended human dose. A No Observed Effect Level (NOEL) was not established and the effectwas not dose dependent. There was no drug-related increase in tumor incidence in male or female ratsin any other organ. Mechanistic studies revealed a rat specific mechanism which is considered to be oflow relevance for humans.

Administration of miglustat to male and female CD1 mice by oral gavage at dose levels of 210, 420and 840/500 mg/kg/day (dose reduction after half a year) for 2 years resulted in an increased incidenceof inflammatory and hyperplastic lesions in the large intestine in both sexes. Based on mg/kg/day andcorrected for differences in faecal excretion, the doses corresponded to 8, 16 and 33/19 times thehighest recommended human dose (200 mg t.i.d.). Carcinomas in the large intestine occurredoccasionally at all doses with a statistically significant increase in the high dose group. A relevance ofthese findings to humans cannot be excluded. There was no drug-related increase in tumour incidencein any other organ.

Miglustat did not show any potential for mutagenic or clastogenic effects in the standard battery ofgenotoxicity tests.

Repeated-dose toxicity studies in rats showed seminiferous tubule degeneration and atrophy. Otherstudies revealed changes in sperm parameters (sperm concentration, motility and morphology)consistent with an observed reduction in fertility. These effects occurred at dose levels adjusted forbody surface area similar to those in patients, but showed reversibility. Miglustat decreasedembryo/foetal survival in rats and rabbits. Prolonged parturition was reported, post-implantation losseswere increased, and an increased incidence of vascular anomalies occurred in rabbits. These effectsmay be partly related to maternal toxicity.

Changes in lactation were observed in female rats in a 1-year study. The mechanism for this effect isunknown.

Sodium starch glycolate (Type A)

Povidone (K30)

Magnesium stearate

Gelatin

Titanium dioxide (E171)

Not applicable.

3 years.

This medicinal product does not require any special storage conditions.

Polyamide/aluminium/PVC/Aluminium blister containing 7 (perforated unit dose) or 7 (non-perforated) capsules.

Pack size of 84 hard capsules in non-perforated blisters.

Pack size of 84x1 hard capsules in perforated unit dose blisters

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Gen.Orph185 Bureaux de la Colline92213 Saint Cloud Cedex

France

EU/1/17/1232/001

EU/1/17/1232/002

Date of first authorisation: 10 november 2017

Date of latest renewal: 19 September 2022

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.