Zavecsa-h-435-psu -045 pi-en-clean

SUMMARY OF PRODUCT CHARACTERISTICS
NAME OF THE MEDICINAL PRODUCT

Zavesca 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 capsules with “OGT 918” printed in black on the cap and “100” printed in black on the body.
4.
CLINICAL PARTICULARS
Therapeutic indications

Zavesca is indicated for the oral treatment of adult patients with mild to moderate type 1 Gaucher
disease. Zavesca may be used only in the treatment of patients for whom enzyme replacement therapy
is unsuitable (see sections 4.4 and 5.1).
Zavesca 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 Zavesca 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. 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:
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
section 4.4).
There is limited experience with the use of Zavesca in Niemann-Pick type C disease patients under
the age of 4 years.
Special populations

Elderly
There is no experience with the use of Zavesca 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

Zavesca has not been evaluated in patients with hepatic impairment.
Method of administration
Zavesca 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. Special warnings and precautions for use
Tremor Approximately 37% of patients in clinical trials in type 1 Gaucher disease, and 58% of patients in a clinical trial in Niemann-Pick type C disease reported tremor on treatment. In type 1 Gaucher disease, these tremors were described as an exaggerated physiological tremor of the hands. Tremor usually began within the first month, 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 Zavesca between meals, and/or to anti-diarrhoeal medicinal products such as loperamide. In some patients, temporary dose reduction may be necessary. Patients with chronic diarrhoea or other persistent gastrointestinal events that do not respond to these interventions should be investigated according to clinical practice. Zavesca has not been evaluated in patients with a history of significant gastrointestinal disease, including inflammatory bowel disease. Effects on spermatogenesis Male patients should maintain reliable contraceptive methods while taking Zavesca. 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 Zavesca and maintain reliable contraceptive methods for a further 3 months. Special populations Due to limited experience, Zavesca should be used with caution in patients with renal or hepatic impairment. There is a close relationship between renal function and clearance of miglustat, and exposure to miglustat is markedly increased in patients with severe renal impairment (see section 5.2). At present, there is insufficient clinical experience in these patients to provide dosing recommendations. Use of Zavesca in patients with severe renal impairment (creatinine clearance < 30 ml/min/1.73 m2) is not recommended. Type 1 Gaucher disease Although no direct comparisons with Enzyme Replacement Therapy (ERT) have been performed in treatment-naive patients with type 1 Gaucher disease, there is no evidence of Zavesca having an efficacy or safety advantage over ERT. ERT is the standard of care for patients who require treatment for type 1 Gaucher disease (see section 5.1). The efficacy and safety of Zavesca has not been specifically evaluated in patients with severe Gaucher disease. Regular monitoring of vitamin B12 level is recommended because of the high prevalence of vitamin B12 deficiency in patients with type 1 Gaucher disease. Cases of peripheral neuropathy have been reported in patients treated with Zavesca with or without concurrent conditions such as vitamin B12 deficiency and monoclonal gammopathy. Peripheral neuropathy seems to be more common in patients with type 1 Gaucher disease compared to the general population. All patients should undergo baseline and repeat neurological evaluation. In patients with type 1 Gaucher disease, monitoring of platelet counts is recommended. Mild
reductions in platelet counts without association with bleeding were observed in patients with type 1
Gaucher disease who were switched from ERT to Zavesca.
Niemann-Pick type C disease
The benefit of treatment with Zavesca for neurological manifestations in patients with Niemann-Pick
type C disease should be evaluated on a regular basis, e.g. every 6 months; continuation of therapy
should be re-appraised after at least 1 year of treatment with Zavesca.
Mild reductions in platelet counts without association to bleeding were observed in some patients
with Niemann-Pick type C disease treated with Zavesca. In patients included in the clinical trial, 40%-
50% 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 Zavesca; 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 Zavesca 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 Zavesca 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. Zavesca 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 Zavesca 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 Zavesca (see sections 4.4 and 5.3). Effects on ability to drive and use machines

Zavesca has negligible influence on the ability to drive and use machines. Dizziness has been reported
as a common adverse reaction, and patients suffering from dizziness should not drive or use machines.
4.8
Undesirable effects
Summary of the safety profile The most common adverse reactions reported in clinical studies with Zavesca were diarrhoea, flatulence, abdominal pain, weight loss and tremor (see section 4.4). The most common serious adverse reaction reported with Zavesca treatment in clinical studies was peripheral neuropathy (see section 4.4). In 11 clinical trials in different indications 247 patients were treated with Zavesca 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 Metabolism and nutrition disorders Very common Peripheral neuropathy, ataxia, amnesia, paraesthesia, Nausea, vomiting, abdominal distension/discomfort, constipation, Musculoskeletal and connective tissue disorders Common General disorders and administration site reactions Common:
Description of selected adverse reactions
Weight loss has been reported in 55% of patients. The greatest prevalence was observed between 6
and 12 months.
Zavesca 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 Website:

4.9
Overdose

Symptoms
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 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 Zavesca 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 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 × 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 Zavesca, or switch to Zavesca. This study was conducted over a 6-month
randomised comparison period followed by 18 months extension 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.
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 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 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 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 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 t.i.d., 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 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, (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.
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 two-
fold 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).
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 tumour 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 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
List of excipients
Capsule contents Sodium starch glycollate, Povidone (K30), Magnesium stearate. Capsule shell Gelatin, Water, Titanium dioxide (E171). Printing ink
Black iron oxide (E172)
Shellac.
6.2
Incompatibilities

Not applicable.
6.3
Shelf life

5 years.
6.4
Special precautions for storage

Do not store above 30 °C.
6.5
Nature and contents of container

ACLAR/ALU blister strips supplied as a box of 4 blister strips, each blister strip containing
21 capsules providing a total of 84 capsules.
6.6
Special precautions for disposal

No special requirements for disposal.
7.
MARKETING AUTHORISATION HOLDER

Actelion Registration Ltd
Chiswick Tower, 13th Floor
389 Chiswick High Road
London W4 4AL
United Kingdom
8.
MARKETING AUTHORISATION NUMBER(S)

EU/1/02/238/001
9.
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 20 November 2002
Date of latest renewal: 20 November 2012
10.
DATE OF REVISION OF THE TEXT
November 2013 Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.

Source: http://www1.actelion.com.br/documents/corporate/smpc_pils/Zavesca_SmPC.pdf