ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Zavesca 100 mg hard capsules.
2.
Each capsule contains 100 mg miglustat.
For a full list of excipients, see section 6.1.
3.
Hard capsule.
White capsules with “OGT 918” printed in black on the cap and “100” printed in black on the body.
4.
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).
Therapy should be directed by physicians who are knowledgeable in the management of Gaucher
disease or Niemann-Pick type C disease, as appropriate.
Zavesca can be taken with or without food.
Dosage in type 1 Gaucher disease
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.
There is no experience with the use of Zavesca in patients with type 1 Gaucher disease under the age
of 18. The use of Zavesca is therefore not recommended in children or adolescents with type 1
Gaucher disease. There is no experience with the use of Zavesca in patients over the age of 70.
Dosage in Niemann-Pick type C disease
The recommended dose for the treatment of adult and adolescent patients with Niemann-Pick type C
disease is 200 mg three times a day.
Dosing in patients under the age of 12 years should be adjusted on the basis of body surface area as
illustrated below:
2
Body surface area (m
2
)
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 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.
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 m
2
, 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 m
2
, 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 m
2
)
is not recommended (see sections 4.4 and 5.2).
Hepatic Impairment
Zavesca has not been evaluated in patients with hepatic impairment.
Hypersensitivity to the active substance or to any of the excipients.
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.
Approximately 38% 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.
Regular monitoring of vitamin B
12
level is recommended because of the high prevalence of
vitamin B
12
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
B
B
12
deficiency and monoclonal gammopathy.
Peripheral
3
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. Patients
who develop symptoms such as numbness and tingling should have a careful re-assessment of
risk-benefit.
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 probably
inhibition of disaccharidases in the gastrointestinal tract. The majority of cases are mild and are
expected to resolve spontaneously on therapy. In clinical practice, diarrhoea has been observed to
respond to diet modification (reduction of lactose and other carbohydrate intake), to taking Zavesca
away from 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.
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.
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 of 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 m
2
)
is not recommended.
Niemann-Pick type C disease
The benefit of treatment with Zavesca for neurological manifestations in patients with Niemann-Pick
type C disease should be evaluated on a regular basis, e.g. every 6 months; continuation of therapy
should be re-appraised after at least 1 year of treatment with Zavesca.
Reduced growth has been reported in some paediatric patients with Niemann-Pick type C disease 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.
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.
Limited data suggest that co-administration of Zavesca and Cerezyme in patients with type 1 Gaucher
disease may
result in decreased exposure to miglustat (approximate reductions of 22% in C
max
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 Cerezyme.
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).
4
The potential risk for humans is unknown. Miglustat crosses the placenta and should not be used
during pregnancy. Contraceptive measures should be used by women of childbearing potential.
It is not known if miglustat is secreted in breast milk. Zavesca should not be used during
breast-feeding.
Male patients should maintain reliable contraceptive methods while taking Zavesca and for 3 months
after finishing treatment (see sections 4.4 and 5.3)
No studies on the effects of Zavesca on the ability to drive or use machines have been performed.
However, dizziness has been reported as a very common adverse event, and patients suffering from
dizziness should not drive or operate machinery.
In nine clinical trials in different indications 206 patients were treated with Zavesca at dosages of 50-
200 mg t.i.d. for an average duration of 2.2 years. Of these patients, 90 had type 1 Gaucher disease,
and 40 had Niemann-Pick type C disease. Adverse reactions were generally of mild to moderate
severity and occurred with similar frequency across indications and dosages tested. The most common
adverse reactions were gastrointestinal, with diarrhoea and other abdominal complaints, and weight
loss.
Adverse drug reactions, defined as treatment-emergent adverse events reported as related to treatment
by the investigator and occurring in >1% of patients, are listed in the table below by body system and
frequency (very common: ≥ 1/10, common: ≥ 1/100 < 1/10). 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
Common
Anorexia, decreased appetite
Psychiatric disorders
Common
Insomnia, libido decreased
Nervous System Disorders
Very common
Tremor,
Common
Peripheral neuropathy, headache, paraesthesia, dizziness,
Gastrointestinal Disorders
Very common
Nausea, vomiting, abdominal distension/discomfort, constipation,
dyspepsia
Musculoskeletal and connective tissue disorders
Common
Muscle spasms
General disorders and administration site reactions
Common:
Fatigue, asthenia
Investigations
5
ataxia, hypoaesthesia
Common
Diarrhoea, flatulence, abdominal pain
Common
Nerve conduction studies abnormal,
Weight loss has been observed in approximately 60% of patients. The greatest effect was at
12 months, with a mean weight loss of 6–7% of body weight, with a subsequent tendency for
increase in weight towards the baseline value.
an
Z
as neurological symptoms/signs and thrombocytopenia could also be due to the underlying conditions.
avesca has been studied in indications where certain events reported as adverse drug reactions, such
Is
Gaucher disease. A causal relationship to Zavesca has not been established.
olated cases of cognitive dysfunction have been reported during clinical trials of Zavesca in type 1
4
N
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 hav
also been observed in a similar group of patients receiving 800 mg/day or higher dose.
o acute symptoms
of overdose have been identified. Zavesca has been administered at doses of up to
e
5
5
. Pharmacodynamic properties
P
harmacotherapeutic group: Other alimentary tract and metabolism products, ATC Code: A16AX06
T
to the rarity of the disease it has not been possible to obtain complete information on this medicinal
product. The European Medicines Agency (EMA) will review any new information, which may
become available every year and this SPC will be updated as necessary.
his medicinal product has been authorised under “Exceptional Circumstances”. This means that due
T
ype 1 Gaucher disease
G
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 IC
50
of 20-3
addition, inhibitory action on a non-lysosomal glycosylceramidase has been demonstrated
experimentally
in vitro.
The inhibitory action on glucosylceramide synthase forms the ratio
substrate reduction therapy in Gaucher disease.
aucher disease is an inherited metabolic disorder caused by a failure to degrade glucosylceramide
7 µM. In
nale for
T
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 × 10
9
/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
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 × 10
9
/l in platelet count, and a mean increase
of 0.95 g/dl in haemoglobin concentration.
he pivotal trial of Zavesca was conducted in pa
tients unable or unwilling to receive ERT. Reasons
years
A
treatm
second open, controlled study randomised 36 patient
s who had received a minimum of 2 years of
ent with ERT, into three treatment groups: continuation with Cerezyme, Cerezyme in
6
1
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
monotherapy. In the first 6 months in patients who were switched to Zavesca, liver and splee
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. Whe
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.
Zavesca
n organ
n
doses was used in the above two
tudies. An additional monotherapy study was performed in 18 patients at a total daily dose of 150 mg,
s
and results indicate reduced efficacy compared to a total daily dose of 300 mg.
Bone manifestations of type 1 Gaucher disease were evaluated in 3 open-label c
p
uncontrolled data, bone mineral density Z-scores at the lumbar spine and femoral neck increased b
more than 0.1 units from baseline in 27 (57%) and 28 (65%) of the patients with longitudinal b
density measurements. There were no events of bone crisis, avascular necrosis or fracture during the
treatment period.
y
one
Niemann-Pick typ
e C disease
Niemann-Pick type C disease i
n
manifestations are considered secondary to the abnormal accumulation of glycosphingol
neuronal and glial cells.
Data to support safety an
p
juvenile patients in a 12-month controlled period, followed by extension therapy for an averag
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 su
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 w
adjusted according to body surface area in paediatric patients.
rvey
as
he progression of clinically relevant
eurological symptoms in patients with Niemann-Pick type C diseas
e
.
The benefit of treatment with Zavesca for neurological manifestations i
ty
should be re-appraised after at least 1 year of treatment with Zavesca, (see section 4.4).
5.2 Pharmacokinetic properties
Pharmacokinetic parameters of miglusta
p
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 h
is
bioavailability has not been determined. Concomitant administration of food decreases the rate of
absorption (C
max
was decreased by 36% and t
max
delayed 2 hours), but has no statistically significant
effect on the extent of absorption of miglustat (AUC decreased by 14%).
7
A total daily dose of 300 mg Zavesca administered in three divided
linical studies in
atients treated with miglustat 100 mg t.i.d. for up to 2 years (n = 72). In a pooled analysis of
s a very rare, invariably progressive and eventually fatal
eurodegenerative disorder characterised by impaired intracellular lipid trafficking. The neurological
ipids in
d efficacy of Zavesca in Niemann-Pick type C disease
come from a
rospective open-label clinical trial and a retrospective survey. The clinical trial included 29 adult and
e total
Overall the data show that treatment with Zavesca can reduce t
n
n patients with Niemann-Pick
pe C disease should be evaluated on a regular basis, e.g. every 6 months; continuation of therapy
t were assessed in healthy subjects, in a small number of
atients with type 1 Gaucher disease, Fabry disease, HIV-infected patients, and in adults, adolescents
ealthy subjects miglustat
rapidly absorbed. Maximum plasma concentrations are reached about 2 hours after dose. Absolute
M
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.
on of a single dose of 100 mg C-miglustat to healthy volunteers, 83% of the
dioactivity was recovered in urine and 12% in faeces. Several metabolites were identified in urine
14
ra
and faeces. The most abundant metabolite in urine was miglustat glucuronide accounting for 5% of th
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.
e
The pharmacokinetics of miglustat is similar in adult type 1 Gaucher disease patients and
N
obtained in paediatric patients with type 3 Gaucher disease aged 3 to 15 years, and patients
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 C
max
and AUC
τ
values which were approximately two-fold those attained
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.
after
Limited data in patients with Fabry disease and impa
w
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 im
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.
pairment
ilable, no significant relationships or trends were noted between miglustat
harmacokinetic parameters and demographic variables (age, BMI, gender or race).
There are no pharmacokinetic data available in patients with liver impairment or in
(>
the elderly
5.3 Preclin
ical safety data
The ain effects common to al
to
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 miglusta
d
(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 AUC
0-∞
) 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
rats in any other organ. Mechanistic studies revealed a rat specific mechanism which is considered to
be of low relevance for humans.
female
le and female CD1 mice by oral gavage at dose levels of 210, 420
nd 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
8
The apparent volume of distribution of miglustat is 83 l. Miglustat does not bind to plasma proteins.
iglustat is mainly eliminated by renal excretion, with urinary recovery of unchanged drug
Following administrati
iemann-Pick type C disease patients when compared to healthy subjects. Pharmacokinetic data were
with
ired renal function showed that
CL/F decreases
ith decreasing renal function. While the numbers of subjects with mild and
moderate renal
Over the range of data ava
p
70 years).
m l species were weight loss and diarrhoea, and, at higher doses, damage
the gastrointestinal mucosa (erosions and ulceration). Further effects seen in animals at doses that
t to male and female Sprague-Dawley rats by oral gavage for 2 years at
ose levels of 30, 60 and 180 mg/kg/day resulted in an increased incidence of testicular interstitial cell
Administration of miglustat to ma
a
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 incide
in any other organ.
nce
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 revea
o
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.
led changes in sperm parameters (motility and morphology) consistent with an
bserved reduction in fertility. These effects occurred at exposure levels similar to those in patients,
Changes in lactation were observed in female rats in a 1-year study. The mechanism for this effect is
unknown.
6.
PHA
RMACEUTICAL PARTICULARS
6
.1 List of excipients
C
apsule contents:
Sodium starch glycollate,
P
Magnesium stearate
ovidone (K30),
.
Capsule shell:
Gelatin,
Water,
e (E171).
Printing
ink:
Black iron oxide (E172)
S
hellac.
6.2 Incompatibilities
N
ot applicable.
6
.3 Shelf life
3
years.
6
.4 Special precautions for storage
D
o not store above 30 °C.
6
.5 Nature and contents of container
A
21 c sules providing a total of 84 capsule
CLAR/ALU blister strips supplied as a box of 4 blister strips, each blister strip containing
ap
s.
6.6 Special precautions for disposal
9
Titanium dioxid
No special requirements.
7.
MARKETING AU
THORISATION HOLDER
A
BSI Building 13
th
Floor
3
London W4 4AL
United Kingdom
ctelion Registration Ltd
89 Chiswick High Road
8.
MARKETI
NG AUTHORISATION NUMBER(S)
E
U/1/02/238/001
9.
DATE OF F
IRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
2
0 November 2002
2
0 November 2007
10. DATE OF RE
VISION OF THE TEXT
10
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
C.
11
A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer responsible for batch release
Actelion Pharmaceuticals Deutschland GmbH
Basler Strasse 63-65
79100 Freiburg
Germany
B. CONDITIONS OF THE MARKETING AUTHORISATION
•
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
Characteristics, section 4.2)
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable.
•
OTHER CONDITIONS
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in
the Pharmacovigilance Plan, as agreed in version 6 of the Risk Management Plan (RMP), dated 3
December 2009, presented in Module 1.8.2. of the Marketing Authorisation and any subsequent
updates of the RMP agreed by the CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the
updated RMP should be submitted at the same time as the next Periodic Safety Update Report
(PSUR).
In addition, an updated RMP should be submitted
•
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
•
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being
reached
•
At the request of the EMA
The MAH will continue to submit yearly PSURs unless otherwise specified by the CHMP.
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, as described in version 5,
26 November 2009, presented in Module 1.8.1. of the Marketing Authorisation application, is in place
and functioning before and whilst the product is on the market.
C. SPECIFIC OBLIGATIONS TO BE FULFILLED BY THE MARKETING
AUTHORISATION HOLDER
The Marketing Authorisation Holder shall complete the following programme of studies within the
specified time frame, the results of which shall form the basis of the annual reassessment of the
benefit/risk profile.
12
Clinical aspects:
1.
Actelion commits to continue the comprehensive Zavesca Post-Marketing Surveillance Plan
(PMSP) in the EU, which will educate prescribers on the appropriate use of Zavesca and
actively solicit safety information from as many patients as possible who receive Zavesca, in
order to supplement the PSURs.
The PMSP, as previously submitted to and agreed by CHMP will continue to be implemented
prior to launch of Zavesca in each Member State.
Summary safety information gathered will be provided alongside the Annual
Re-assessment/PSURs.
2.
Actelion will conduct an open-label study to provide safety and efficacy data for patients
switched from Enzyme Replacement Therapy (ERT) to Zavesca. This study is referenced as
OGT 918-011.
Progress updates will be provided alongside the Annual Re-assessment/PSURs.
The final study report will be provided to the CHMP upon completion.
3.
Actelion will conduct a natural history observational study of 100 patients with type 1 Gaucher
disease taking the Scientific Advice provided in November 2003 into consideration. The study
will be conducted in conjunction with the European Working Group for Gaucher disease
(EWGGD). This study will aim to enhance the knowledge of the neurological aspects of type 1
Gaucher disease. Longitudinal data will then be gathered on the patient cohort over a 2-year
period. This study is referenced as OGT 918-018.
Progress updates will be provided alongside the Annual Re -assessment/PSURs.
The final study report will be provided to the CHMP upon completion.
13
ANNEX III
LABELLING AND PACKAGE LEAFLET
14
A. LABELLING
15
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE
PACKAGING
OUTER CARTON
1.
Zavesca 100 mg hard capsules
Miglustat
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each capsule contains 100 mg miglustat
3.
LIST OF EXCIPIENTS
4.
84 capsules
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP MM/YYYY
9.
SPECIAL STORAGE CONDITIONS
Do not store above 30°C.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
16
Actelion Registration Ltd
BSI Building 13
th
Floor
389 Chiswick High Road
London W4 4AL
United Kingdom
EU/1/02/238/001
13. BATCH NUMBER
Batch {number}
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Zavesca
17
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
1.
Zavesca 100 mg hard capsules
Miglustat
2.
Actelion Registration Ltd
3.
EXPIRY DATE
EXP MM/YYYY
4.
BATCH NUMBER
Batch {number}
5.
OTHER
18
B. PACKAGE LEAFLET
19
PACKAGE LEAFLET: INFORMATION FOR THE USER
Zavesca 100 mg hard capsules
Miglustat
Read all of this leaflet carefully before you start taking this medicine.
-
Keep this leaflet. You may need to read it again.
-
If you have any further questions, please ask your doctor or pharmacist.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet
:
1.
What Zavesca is and what it is used for
2.
Before you take Zavesca
3.
How to take Zavesca
4.
Possible side effects
5.
How to store Zavesca
6.
Further information
1.
WHAT ZAVESCA IS AND WHAT IT IS USED FOR
Zavesca belongs to a group of medicines that affect metabolism. It is used to treat two conditions:
•
Zavesca is used to treat mild to moderate type 1 Gaucher disease.
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. Zavesca is only used
when a patient is considered unsuitable for treatment with enzyme replacement therapy.
•
Zavesca is also used to treat progressive neurological symptoms in Niemann-Pick type C
disease.
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 eye movements, balance,
swallowing, and memory, and in seizures.
Zavesca works by inhibiting the enzyme called ‘glucosylceramide synthase’ which is responsible for
the first step in the synthesis of most glycosphingolipids.
2.
BEFORE YOU TAKE ZAVESCA
Do not take Zavesca
-
if you are allergic (hypersensitive) to miglustat or any of the other ingredients of Zavesca. If this
applies to you,
tell your doctor. Don’t take Zavesca.
Take special care with Zavesca
-
if you suffer from kidney disease
-
if you suffer from liver disease
If any of these apply to you, tell your doctor before you take Zavesca.
20
Your doctor will perform the following tests before treatment and during treatment with Zavesca:
-
an examination to check the nerves in your arms and legs
-
monitoring growth if you are a child or adolescent with Niemann-Pick type C disease
-
monitoring of blood platelet counts if you are a patient with Niemann-Pick type C disease
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 Zavesca. 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 Zavesca (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, or not to take Zavesca 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 Zavesca, and for
3 months after finishing treatment.
Using other medicines
Talk to your doctor if you are using Cerezyme, or other medicines containing imiglucerase, which are
sometimes used at the same time as Zavesca. They may lower the amount of Zavesca in your body.
Please tell your doctor or pharmacist if you are using, or have recently used, any other medicines,
including medicines obtained without prescription.
Taking Zavesca with food and drink
Zavesca can be taken with or without food. You should swallow the whole capsule with a glass of
water.
Pregnancy and breast-feeding
You should not use Zavesca if you are pregnant or thinking of becoming pregnant. Your doctor can
give you more information. You must use effective birth control while using Zavesca. Do not breast-
feed while you are using Zavesca.
Male patients should use reliable birth control methods during their treatment with Zavesca, and for
3 months after finishing treatment.
Ask your doctor or pharmacist for advice before taking any medicine.
Driving and using machines
Zavesca may make you feel dizzy. Do not drive or use any tools or machines if you feel dizzy.
3.
HOW TO TAKE ZAVESCA
Always take Zavesca exactly as your doctor has told you. You should check with your doctor or
pharmacist if you are not sure about any of the instructions.
•
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, 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).
If you are
less than 12 years old
, your doctor will adjust your dose for Niemann-Pick type C disease.
21
-
measurement of vitamin B
12
levels
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 Zavesca (see section 4). Your doctor will tell you how long your treatment will last.
To remove the capsule:
1. Separate at perforations
2. Peel back paper at arrows
3. Push product through foil
The Zavesca capsule should be swallowed whole with water.
If you take more Zavesca than you should
If you take more capsules than you were told to, consult your doctor immediately. Zavesca 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 Zavesca
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 Zavesca
Don’t stop taking Zavesca 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, Zavesca can cause side effects, although not everybody gets them.
Very common effects
–
likely to affect more than 1 in 10 people
The most common side effects are weight loss, tremor, diarrhoea, flatulence (wind), abdominal
(stomach) pain.
Common effects –
likely to affect less than 1 in 10 people and more than 1 in 100 people
Common side effects of treatment include anorexia
(lack of appetite), decreased appetite, headache,
dizziness, peripheral neuropathy, 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 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, difficulty sleeping
,
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 Zavesca or recommend other
medicines to help control side effects.
22
Some patients
have had tingling or numbness in the hands and feet.
They could be signs of
peripheral neuropathy, due to side effects of Zavesca or they could be due to existing conditions. Your
doctor will perform some tests before and during treatment with Zavesca to assess this (see section 2).
If you do get any of these effects, please report them to your doctor as soon as possible
.
If you do lose some weight
when you start treatment with Zavesca don’t worry. People usually stop
losing weight as treatment goes on.
If you
get
a
slight tremor
, usually
trembling hands, report
it to 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 Zavesca treatment to stop the tremor.
If any of the side effects gets serious
, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
For storage and other information, please turn over.
5.
HOW TO STORE ZAVESCA
Keep out of the reach and sight of children.
Do not use Zavesca after the expiry date stated on the carton.
Store below 30 °C.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist
how to dispose of medicines no longer required. These measures will help to protect the
environment.
6.
FURTHER INFORMATION
What Zavesca contains
The active substance
is miglustat 100 mg.
Other ingredients in the capsule are:
Sodium starch glycollate,
Povidone (K30),
Magnesium stearate.
Other ingredients in the capsule shell are:
Gelatin,
Water,
Titanium dioxide (E171).
Other ingredients in the Printing ink are:
Black iron oxide (E172)
Shellac.
What Zavesca looks like and contents of the pack
Zavesca is a white 100 mg capsule with “OGT 918” printed in black on the cap and “100” printed in
black on the body.
23
Box of 4 blister strips, each blister strip containing 21 capsules providing a total of 84 capsules.
Marketing Authorisation Holder:
Actelion Registration Ltd
BSI Building 13
th
Floor
389 Chiswick High Road
London W4 4AL
United Kingdom
Manufacturer responsible for batch release:
Actelion Pharmaceuticals Deutschland GmbH
Basler Strasse 63–65
79100 Freiburg
Germany
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder.
België/Belgique/Belgien
Actelion Pharmaceuticals Belgium N.V.
Tél/Tel: +32-(0)15 284 777
Luxembourg/Luxemburg
Actelion Pharmaceuticals Belgium N.V.
Tél/Tel: +32-(0)15 284 777
България
Actelion Pharmaceuticals Ltd
Teл.: +420-2 3413 8150
Magyarország
Actelion Pharmaceuticals Ltd
Tel: +420-2 3413 8150
Česká republika
Actelion Pharmaceuticals CZ, s.r.o.
Tel: +420-2 3413 8150
Malta
Actelion Pharmaceuticals Ltd
Tel: +420-2 3413 8150
Danmark
Actelion Pharmaceuticals Sverige AB
Tlf: +46-(0)8 544 982 50
Nederland
Actelion Pharmaceuticals Nederland B.V.
Tel: +31-(0)348 435950
Deutschland
Actelion Pharmaceuticals Deutschland GmbH
Tel: +49-(0)761 45 64 0
Norge
Actelion Pharmaceuticals Sverige AB
Tlf: +46-(0)8 544 982 50
Eesti
Nycomed SEFA AS
Tel: +372 6112 569
Österreich
Actelion Pharmaceuticals Austria GmbH
Tel: +43-(0)1 505 4527
Ελλάδα
Actelion Pharmaceuticals Eλλάς Α.Ε.
Τηλ: +30 210 675 25 00
Polska
Actelion Pharma Polska Sp. z o.o.
Tel: +48 (0) 500 145 920
España
Actelion Pharmaceuticals España S.L.
Tel: +34 93 253 10 64
Portugal
Actelion Pharmaceuticals Portugal Lda.
Tel: +351 21 358 6120
France
Actelion Pharmaceuticals France SAS
Tél: +33-(0)1 58 62 32 32
România
Geneva Romfarm Internacional
Tel: + 40 (021) 231 3561
24
Ireland
Actelion Pharmaceuticals UK Ltd
Tel: +353 1890 771 648
Slovenija
Medis d.o.o.
Tel: +386-(0)1 589 69 00
Ísland
Actelion Pharmaceuticals Sverige AB
Sími: +46-(0)8 544 982 50
Slovenská republika
Actelion Pharmaceuticals SK, s.r.o.
Tel: +420 2 3413 8150
Italia
Actelion Pharmaceuticals Italia S.r.l.
Tel: +39 0542 64 87 40
Suomi/Finland
Actelion Pharmaceuticals Sverige AB
Puh/Tel: +46-(0)8 544 982 50
Κύπρος
Actelion Pharmaceuticals Eλλάς Α.Ε.
Τηλ: +30 210 675 25 00
Sverige
Actelion Pharmaceuticals Sverige AB
Tel: +46-(0)8 544 982 50
Latvija
Nycomed Latvija
Tel: +371 784 0082
United Kingdom
Actelion Pharmaceuticals UK Ltd
Tel: +44-(0)845 075 0555
Lietuva
Nycomed atstovybė
Tel: +370 5210 9070
This leaflet was last approved in:
This medicine has been authorised under “Exceptional Circumstances”. This means that because of the
rarity of this disease it has been impossible to get complete information on this medicine. The
European Medicines Agency (EMA) will review any new information on the medicine every year and
this leaflet will be updated as necessary.
Detailed information on this medicine is available on the European Medicines Agency (EMA)
website: http://www.ema.europa.eu. There are also links to other websites about rare diseases and
treatments.
25
Source: European Medicines Agency
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