CMDh/223/2005
February 2012
Public Assessment Report
Scientific discussion
Solifenacin Portfarma5 mg
Pillola miksija b’rita or
Solifenacin Portfarma 5mg
Film-coated tablets
SolifenacinPortfarma 10 mg
Pillola miksija b’rita or
SolifenacinPortfarma
10mg Film –coated Tablets
Solifenacin Succinate
MT/H/0165/001-002/MR
Date: 5th March 2013
This module reflects the scientific discussion for the approval of Solifenacin 5mg tablets and
Solifenacin 10mg tablets. The procedure was finalised at 5th March 2013. For information on
changes after this date please refer to the module ‘update’
I.
INTRODUCTION
Based on the review of the data on quality, safety and efficacy data, the Member States have
granted a marketing authorisation for Solifenacin 5mg tablets and Solifenacin 10mg tablets,
from Portfarma ehf. Borgartúni 26 IS – 105 Reykjavík Iceland.
The product is indicated for:
•
Adults for symptomatic treatment of urge incontinence and/or increased urinary
frequency and urgency as may occur in patients with overactive bladder syndrome
A comprehensive description of the indications and posology is given in the SmPC.
The marketing authorisation has been granted pursuant to Article 10(1) of Directive
2001/83/EC.
The reference product for this application is Vesicare 5 mg (DK authorisation: 36386) and 10
mg (DK authorisation: 36387), film coated tablets, Astellas Pharma Ltd, are authorised in
Denmark since 2004-06-24.
For the RMS, the applicant has chosen Vesicare 5mg and 10 mg, film coated tablets,
Marketing authorisation holder: Astella Pharma Europe B.V Marketing authorisation
number(s): MA067/00801-2 as the Reference Medicinal Products.
The product is a prescription only medicine.
CMS: IS
II.
QUALITY ASPECTS
II.1
Introduction
Pharmaceutical form:
Film-coated tablets
Formulation:
The qualitative composition for both strengths of the drug product, are listed below in line
with the current product information:
Solifenacin Succinate 5 mg film-coated tablets
Solifenacin succinate 5mg (corresponding to 3.8 mg Solifenacin)
Tablet core:
Maize starch
Lactose monohydrate
Hypromellose (E464)
Magnesium stearate
Film Coating:
Hypromellose (E464)
Macrogol 8000/
Talc (E553b)
Titanium Dioxide (E171)
Iron Oxide Yellow (E172)
Solifenacin Succinate 10mg film-coated tablets
Solifenacin succinate 10mg (corresponding to 7.6 mg Solifenacin)
Tablet core:
Maize starch
Lactose monohydrate
Hypromellose (E464)
Magnesium stearate
Film Coating:
Hypromellose (E464)
Macrogol 8000/
Talc (E553b)
Titanium Dioxide (E171)
Iron Oxide Red (E172)
Container system:
The SmPC provides the following description of the container types and pack sizes:
Container:
The tablets are packed alternatively in PVC/PVDC-Aluminium blisters, PVC/ACLARAluminium blisters or OPA/Al/PVC/Aluminium blisters containing 10 tablets per blister.
The blisters are placed into a cardboard box.
Pack sizes in blisters:
10, 30 or 100 tablets (not all pack sizes may be marketed).
II.2
Drug Substance
INN:
The active substance is Solifenacin succinate
Chemical features and chemical class:
The Pharmacotherapeutic group of solifenacin succinate is classified under urinary
antispasmodics, ATC code: G04B D08.
Chemical name:
1(S)-Phenyl-1,2,3,4- tetrahydroisoquinoline-2-carboxylic
acid 3(R)-quinuclidinyl ester succinate
Structure
Structural formula:
Molecular Formula:
Molecular Weight:
C23H26N2O2.C4H6O4
480.55
Chirality:
Solifenacin Succinate molecule has two chiral centres leading to four possible
diastereoisomers.
Specifications:
The active substance Solifenacin Succinate is not described in the Ph. Eur. The ASMF procedure is
used.
The specifications were established based on ICH guidelines and Ph. Eur. general chapters.
Manufacture and control processes:
The manufacturing and control processes have been validated by the manufacturer and are
deemed to be acceptable.
Stability:
Stability studies according to the relevant EU/ICH stability guidelines have been submitted
and no significant changes in any parameters were observed. Based on stability results
submitted by the ASMF holder, a retest period of 3 years (when the active substance is stored
in tight, light resistant container) was granted.
II.3
Medicinal Product
Pharmaceutical development, Manufacture of the product and product specification:
The development of the product has been described, the choice of excipients is justified and
their functions explained. Excipients common to pharmaceutical manufacture have been
selected and each is described in the European Pharmacopoeia, with the exception of the
excipients iron oxide yellow and iron oxide red found in the film-coating which are described
in the United States Pharmacopoeia - National Formulary. The reference products used in the
two bioequivalence studies are Vesicare 5mg, film-coated tablets and Vesicare 10mg, filmcoated tablets respectively from the UK market (marketing authorisation holder: Astellas
Pharma Ltd., U.K.; marketing authorisation numbers: PL 00166/0197 and PL 00166/0198
respectively).
Comparative dissolution data between the test product and reference product has also been
provided. The bio batch was 10% of the maximum intended production batch size and was the
same formulation and specification as that proposed for marketing. Validations of the
analytical methods have been presented. Batch analysis has been performed on three batches
of each strength (including the bio batch). The finished product specifications were
established based on ICH guidelines and Ph. Eur. general chapters
Stability of the product:
The stability studies on the products in the containers proposed for marketing (three different
blister pack types) have been undertaken on three batches of each strength (including the biobatch). An 18 months shelf life (with no special storage conditions) has been granted for two
blister pack types (PVC/PVDC-Aluminium blister and OPA/Al/PVC/Aluminium blister), and
a 15 months shelf life (with a special storage condition to store below 30°C) has been granted
for the third blister pack type (PVC/ACLAR-Aluminium blister) in accordance with the
relevant EU/ICH stability guidelines
III.
NON-CLINICAL ASPECTS
III.1
Introduction
The pharmacological, pharmacokinetic and toxicological properties of solifenacin are well
known. As solifenacin is a well known active substance, no further studies are required and
the applicant has provided none. An overview based on a literature review is thus appropriate.
The non-clinical overview is dated June 2010. The applicant has not provided additional
studies and further studies are not required. Overview based on literature review is, thus,
appropriate. The overview cites 31 references from the published literature which are dated
from 1976 to 2009.
The non-clinical overview on the pre-clinical pharmacology, pharmacokinetics and
toxicology is adequate.
III.2
Pharmacology
Mechanism of action
Solifenacin is a competitive, specific cholinergic-receptor antagonist.
Pharmacodynamic effects
The urinary bladder is innervated by parasympathetic cholinergic nerves. Acetylcholine
contracts the detrusor smooth muscle through muscarinic receptors of which the M3 subtype
is predominantly involved. In vitro and in vivo pharmacological studies indicate that
solifenacin is a competitive inhibitor of the muscarinic M3 subtype receptor. In addition,
solifenacin showed to be a specific antagonist for muscarinic receptors by displaying low or
no affinity for various other receptors and ion channels tested.
Clinical efficacy and safety
Treatment with solifenacin in doses of 5 mg and 10 mg daily was studied in several doubleblind, randomised, controlled clinical trials in men and women with overactive bladder.
As shown in the table below, both the 5 mg and 10 mg doses of solifenacin produced
statistically significant improvements in the primary and secondary endpoints compared with
placebo. Efficacy was observed within one week of starting treatment and stabilised over a
period of 12 weeks. A long-term open- label study demonstrated that efficacy was maintained
for at least 12 months. After 12 weeks of treatment, approximately 50% of patients suffering
from incontinence before treatment were free of incontinence episodes, and in addition 35%
of patients achieved a micturition frequency of less than 8 micturitions per day. Treatment of
the symptoms of overactive bladder also results in a benefit on a number of Quality of Life
measures, such as general health perception, incontinence impact, role limitations, physical
limitations, social limitations, emotions, symptom severity, severity measures and
sleep/energy.
Results (pooled data) of four controlled Phase 3 studies with a treatment duration of 12 weeks
Placebo
Solifenacin Solifenacin
5 mg o.d.
10 mg o.d.
Tolterodine
2 mg b.i.d.
11.9
1.4
(12%)
1138
12.1
2.3
(19%)
552
<0.001
11.9
2.7
(23%)
1158
<0.001
12.1
1.9
(16%)
250
0.004
6.3
2.0
(32%)
1124
5.9
2.9
(49%)
548
<0.001
6.2
3.4
(55%)
1151
<0.001
5.4
2.1
(39%)
250
0.031
2.9
1.1
(38%)
781
2.6
1.5
(58%)
314
<0.001
2.9
1.8
(62%)
778
<0.001
2.3
1.1
(48%)
157
0.009
1.8
0.4
(22%)
1005
2.0
0.6
(30%)
494
0.025
1.8
0.6
(33%)
1035
<0.001
1.9
0.5
(26%)
232
0.199
166 ml
9 ml
(5%)
1135
146 ml
32 ml
(21%)
552
163 ml
43 ml
(26%)
1156
147 ml
24 ml
(16%)
250
No. of micturitions/24 h
Mean baseline
Mean reduction from baseline
% change from baseline
n
p-value*
No. of urgency episodes/24 h
Mean baseline
Mean reduction from baseline
% change from baseline
n
p-value*
No. of incontinence episodes/24 h
Mean baseline
Mean reduction from baseline
% change from baseline
n
p-value*
No. of nocturia episodes/24 h
Mean baseline
Mean reduction from baseline
% change from baseline
n
p-value*
Volume voided/micturition
Mean baseline
Mean increase from baseline
% change from baseline
n
p-value*
<0.001
<0.001
<0.001
2.8
1.3
(46%)
236
<0.001
2.7
1.3
(48%)
242
<0.001
2.7
1.0
(37%)
250
0.010
No. of pads/24 h
Mean baseline
Mean reduction from baseline
% change from baseline
n
p-value*
3.0
0.8
(27%)
238
Note: In 4 of the pivotal studies, solifenacin film-coated tablets of 10 mg and placebo were
used. In 2 out of the 4 studies also solifenacin film-coated tablets 5 mg were used and one of
the studies included tolterodine 2 mg bid.
Not all parameters and treatment groups were evaluated in each individual study. Therefore,
the numbers of patients listed may deviate per parameter and treatment group.
* P-value for the pair-wise comparison to placebo
III.3
Pharmacokinetics
The applicant has submitted two bioequivalence studies, dated July 2010, performed under
fasting conditions. Both studies were randomised, single dose, open label, two treatment, two
period, two sequence, crossover bioavailability studies on Solifenacin Portfarma 5mg and 10
mg tablets (Test) and Vesicare® 5mg and 10 mg tablets (Reference).
Both studies were undertaken in February/March 2010 in Canada. Both studies were
conducted in accordance with good clinical practice with an adequate design.
The submitted fasting bioequivalence study with Solifenacin Portfarms 5 mg tablets indicates
bioequivalence with Vesicare® 5mg tablets, Astellas Pharma Ltd., U.K. The 90% confidence
intervals (CI) of the Test/Reference ratios of geometric means for AUC0-72 and Cmax were
calculated based on the least square means. The Test/Reference ratio of geometric means and
the corresponding 90% confidence interval for the AUC0-72 and Cmax parameters contained
within the acceptance range of 80.00-125.00%.
The submitted fasting bioequivalence study with Solifenacin Porfarma10 mg tablets indicates
bioequivalence with Vesicare® 10mg tablets, Astellas Pharma Ltd., U.K. The 90%
confidence intervals (CI) of the Test/Reference ratios of geometric means for AUC0-72 and
Cmax were calculated based on the least square means. The Test/Reference ratio of geometric
means and the corresponding 90% confidence interval for the AUC0-72 and Cmax parameters
contained within the acceptance range of 80.00-125.00%.
Plasma pre-dose concentrations levels of solifenacin were below the limit of quantification for
the two periods of the trial.
Based on the findings of both studies (fasting) both Test and Reference formulations have
been shown to meet the bioequivalence criteria of 80% - 125% under fasting conditions.
III.4
Toxicology
Non-clinical data reveal no special hazard for humans based on conventional studies of safety
pharmacology, repeated dose toxicity, fertility, embryofetal development, genotoxicity, and
carcinogenic potential. In the pre- and postnatal development study in mice, solifenacin
treatment of the mother during lactation caused dose-dependent lower postpartum survival
rate, decreased pup weight and slower physical development at clinically relevant levels.
III.5
Ecotoxicity/environmental risk assessment (ERA)
Since Solifenacin 5mg tablets and Solifenacin 10mg tablets are intended for generic
substitution, this will not lead to an increased exposure to the environment. An environmental
risk assessment is therefore not deemed necessary.
III.6
Discussion on the non-clinical aspects
This application is made under reference to Article 10(1) of Directive 2001/83/EC as
amended Abridged applications avoid the need for repetitive tests on animals and humans.
The pharmacological, pharmacokinetic and toxicological properties of solifenacin are well
known. As solifenacin is a well known active substance, no further studies are required and
the applicant has provided none. An overview based on a literature review is thus appropriate.
IV.
CLINICAL ASPECTS
IV.1
Introduction
To support the application, the applicant has submitted 2 bioequivalence studies:
•
BIOEQUIVALENCE STUDY 1: A Single-Dose, Randomized, Open-Label,
Crossover, Pivotal, Comparative Bioavailability Study of Solifenacin Succinate 5
mg Film-Coated Tablets (Helm AG, Germany) and Vesicare® 5 mg Film-Coated
Tablets (Astellas Pharma Ltd., U.K.) in Healthy Male and Female Volunteers
under Fasting Conditions.
•
BIOEQUIVALENCE STUDY 2: A Single-Dose, Randomized, Open-Label,
Crossover, Pivotal, Comparative Bioavailability Study of Solifenacin Succinate 10
mg Film-Coated Tablets (Helm AG, Germany) and Vesicare® 10 mg Film-Coated
Tablets (Astellas Pharma Ltd., U.K.) in Healthy Male and Female Volunteers
under Fasting Conditions.
Given that this is an Article 10(1) application, the submission of clinical studies in the form of
BE studies alone is acceptable. The reference medicinal products used for the Biostudies are
Vesicare 5 mg, film coated tablets, Astellas Pharma Ltd., U.K, PL 00166/0197 and Vesicare
10 mg, film coated tablets, Astellas Pharma Ltd., U.K PL 00166/0198.
Since the formulations of Solifenacin Portfarma 5mg and 10 mg film-coated tablets are not
proportional, the applicant’s choice of conducting two BE studies, one using the 5mg strength
and one using the 10 mg strength is justified. Both studies are conducted in the fasting state.
IV.2
Pharmacokinetics
Bioequivalence studies
Summary of assessment bioequivalence studies.
Table 1.
Pharmacokinetic parameters (arithmetic mean ± SD, tmax median)
For Solifenacin 5mg (n=27)
Treatment
AUC0-72
(n=25 /
pg/ml/h
26)
Test
313312.1±10495
7.2
Reference
306526.9±10900
0.0
(93.89 - 106.92)
*Ratio (90% CI)
AUC0-∞
Cmax
xg/ml/h
ng/ml
tmax
(n=27/27)
h
-
8279.74±1942.21
5.50
-
8234.45±2038.70
6
-
(96.46 - 105.81)
-
AUC0-t
Area under the plasma concentration curve from administration to last observed
concentration at time t.
AUC0-72h can be reported instead of AUC0-t, in studies with sampling period of
72 h, and where the concentration
at 72 h is quantifiable. Only for immediate release products
AUC0-∞
Area under the plasma concentration curve extrapolated to infinite time.
AUC0-∞ does not need to be reported when AUC0-72h is reported instead of
AUC0-t
Cmax Maximum plasma concentration
tmax
Time until Cmax is reached
*ln-transformed values
Table 2. Pharmacokinetic parameters (arithmetic mean ± SD, tmax median)
For Solifenacin 10mg (n=28)
Treatment
AUC0-72
pg/ml/h
Test
Reference
*Ratio (90% CI)
AUC0-∞
(n=28 /
xg/ml/h
26)
491803.80±
108775.5
506201.25±
121608.1
(94.73 - 103.11) -
Cmax
ng/ml
tmax
(n=28/28)
h
13866.28±1942.
21
14041.74±2038.
70
(94.89 - 102.49) -
6.00
5.50
AUC0-t
Area under the plasma concentration curve from administration to last observed
concentration at time t.
AUC0-72h can be reported instead of AUC0-t, in studies with sampling period of
72 h, and where the concentration
at 72 h is quantifiable. Only for immediate release products
AUC0-∞
Area under the plasma concentration curve extrapolated to infinite time.
AUC0-∞ does not need to be reported when AUC0-72h is reported instead of
AUC0-t
Cmax Maximum plasma concentration
tmax
Time until Cmax is reached
*ln-transformed values
Conclusion on bioequivalence studies:
Based on the submitted bioequivalence studies Solifenacin 5mg and 10mg film-coated is
considered bioequivalent with the reference medicinal products used for the Biostudies:
Vesicare 5 mg, film coated tablets, Astellas Pharma Ltd., U.K, PL 00166/0197 and Vesicare
10 mg, film coated tablets, Astellas Pharma Ltd., U.K PL 00166/0198.
IV.3
Pharmacodynamics
No new studies have been performed and none is required for this type of application.
IV.4
Clinical efficacy
No new studies have been performed and none is required for this type of application.
IV.5
Clinical safety
The bioequivalence studies have raised no new or unexpected safety concerns.
IV.6
Discussion on the clinical aspects
This is a decentralised application, submitted under Directive 2001/83/EC Article 10 (1)
generic application for the marketing authorisation of Solifenacin 5mg and 10mg film-coated
tablets.
Solifenacin has been developed for the symptomatic treatment of urge incontinence and/or
increased urinary frequency and urgency as may occur in patients with overactive bladder
syndrome.
The clinical overview report refers 50 publications up to year 2009.
Given that this is an Article 10(1) application, the submission of clinical studies in the form of
BE studies alone is acceptable. The reference medicinal products used for the Biostudies are
Vesicare 5 mg, film coated tablets, Astellas Pharma Ltd., U.K, PL 00166/0197 and Vesicare
10 mg, film coated tablets, Astellas Pharma Ltd., U.K PL 00166/0198. Since the formulations
of Solifenacin Portfarma5mg and 10 mg film-coated tablets are not proportional, the
applicant’s choice of conducting two BE studies, one using the 5mg strength and one using
the 10 mg strength is justified. Both studies are conducted in the fasting state.
V.
OVERALL
CONCLUSION,
BENEFIT/RISK
ASSESSMENT
AND
RECOMMENDATION
Based on the review of the data on quality, safety and efficacy, the RMS/CMSs considered
that the application for:
Solifenacin Portfarma 5mg tablets and Solifenacin Portfarma10mg tablets, in the treatment of:
•
adults for symptomatic treatment of urge incontinence and/or increased urinary
frequency and urgency as may occur in patients with overactive bladder syndrome
was approvable given that the applicant has committed to perform a number of post
authorisation follow-up measures to be reported back to the Member States within predefined
timeframes.
Follow-up measures:
Quality
1. The stability studies of the pilot batches will be continued and completed as described
in module 3.2.P.8.1 in order to firmly establish the shelf life of the product.
Furthermore, the applicant commits that the first three production batches will be
placed on long term stability studies through the proposed shelf life and on accelerated
studies for 6 months according to current ICH stability guidelines.
2. The applicant commits that the process validation will be carried out for a
commercial batch size for both strengths on the first three production-scale batches
and that the Certificates of analyses for these three production scale batches will be
provided.
User consultation
The package leaflet has been evaluated via a user consultation study in accordance with the
requirements of Articles 59(3) and 61(1) of Directive 2001/83/EC. The language used for the
purpose of user testing the PIL was English.
The results show that the package leaflet meets the criteria for readability as set out in the
Guideline on the readability of the label and package leaflet of medicinal products for human
use.
Public Assessment Report
Update
Scientific discussion
Solifenacin Portfarma5 mg
Pillola miksija b’rita or
Solifenacin Portfarma 5mg
Film-coated tablets
SolifenacinPortfarma 10 mg
Pillola miksija b’rita or
SolifenacinPortfarma
10mg Film –coated Tablets
Solifenacin Succinate
This module reflects the procedural steps and scientific information after the finalisation of the
initial procedure.
Scope
Procedure number
The scope of the variation was to submit an EU RMP as MT/H/0165/00
per post-approval commitment for Solifenacin 1-002/II/002
Portfarma, together with SmPC in line with
recommendations of the submitted RMP.
The RMP submitted by the MAH is acceptable to the
RMS. The benefit:risk of Solifenacin Portfarma is
positive. No additional risk minimisation measures are
being proposed by the MAH in addition to routine
pharmacovigilance.
The safety profile of solifenacin can be considered to be
well
established
and
no
product
specific
pharmacovigilance issues were identified, pre- or postauthorization, which are not adequately covered by the
current SmPC. The RMS agrees with the applicant that
routine pharmacovigilance is sufficient to address any
safety concerns identified to maintain a positive risk:
benefit profile.
The proposed SmPC and PL are acceptable to the RMS,
since the SmPCs are being aligned to the reference
product’s core safety profile.
Product Information
affected
Date of start of the
procedure
Date of end of
procedure
Approval/
non approval
Assessment report
attached
SmPC and PL
17/07/2013
1/11/2013
Approved
N