rivastigmin

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Public Assessment Report
Scientific discussion
Rivamylan
4.6 mg /24 hours and 9.5 mg /24 hours,
transdermal patches
(rivastigmine)
NL/H/2958/001-002/DC
Date: 30 March 2015
This module reflects the scientific discussion for the approval of Rivamylan,
transdermal patches 4.6 and 9.5 mg / 24 hour. The procedure was finalised at 24
October 2014. For information on changes after this date please refer to the module
‘Update’.
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INTRODUCTION
Based on the review of the quality, safety and efficacy data, the Member States have granted a
marketing authorisation for Rivamylan, transdermal patches 4.6 mg/24 hours and 9.5 mg/24 hours,
from Mylan B.V.
The product is indicated for symptomatic treatment of mild to moderately severe Alzheimer's
dementia.
A comprehensive description of the indications and posology is given in the SmPC.
This decentralised procedure concerns a generic application claiming essential similarity with the
innovator products Exelon 4.6 mg/24 hours and 9.5 mg/24 hours transdermal patches which have
been registered through the centralised procedure (EMEA/H/C/169/X/38) by Novartis Europharm Ltd.
since July 2007. This pharmaceutical form was authorised as a line extension to the original Exelon
dossier of 1.5 mg capsules tablets which have been registered through the centralised procedure
(EU/1/98/066) by Novartis Europharm Ltd. since 1998.
Rivastigmine is an acetyl- and butyrylcholinesterase inhibitor of the carbamate type, thought to
facilitate cholinergic neurotransmission by slowing the degradation of acetylcholine released by
functionally intact cholinergic neurones. Thus, rivastigmine may have an ameliorative effect on
cholinergic-mediated cognitive deficits in dementia associated with Alzheimer’s disease and
Parkinson’s disease.
The concerned member states (CMS) involved in this procedure were Belgium, Denmark, Finland,
France, Germany, Greece, Italy, Liechtenstein, Norway, Poland, Portugal, Slovenia, Spain, Sweden,
and the United Kingdom.
The marketing authorisation has been granted pursuant to Article 10(1) of Directive 2001/83/EC.
II.
QUALITY ASPECTS
II.1
Introduction
Rivamylan 4.6 mg/24 hour is a transdermal patch of 5 cm2 containing 9 mg rivastigmine, of which 4.6
mg is released over a 24 hour period.
Rivamylan 9.5 mg/24 hour is a transdermal patch of 10 cm2 containing 18 mg rivastigmine, of which
9.5 mg is released over a 24 hour period.
Each round transdermal patch consists of a pigmented peach-coloured backing film randomly printed
with “Rivamylan 4.6 mg /24 hours” or “Rivamylan 9.5 mg / 24 hours” in brown ink, a solid matrix drug
reservoir layer, a translucent adhesive skin contact layer and a clear to slightly hazy oversized release
liner that is slit and has small dimples surrounding the patch. Each patch also has a clear to slightly
hazy oversized underlay.
The transdermal patches are packed individually in heat-sealed child resistant sachets made of
polyethylene terephthalate (PET), white low-density polyethylene (WLDPE), aluminium foil and
polyacrylonitrile laminated material.
The excipients are:
Backing film with imprint: polyethylene/polyester film
Medicinal product matrix: acrylic adhesive and poly(butylmethacrylate, methylacrylate)
Adhesive matrix: dimethicone, silicone adhesive
Release liner: fluoropolymer coated polyester film.
II.2
Drug Substance
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The active substance is rivastigmine, an established active substance described in the European
Pharmacopoeia (Ph.Eur.). Rivastigmine is a colourless to yellow or very slightly brown coloured
viscous liquid, which is miscible in water and organic solvents. A single stereoisomer (the S-isomer) is
used. The rivastigmine transdermal system cannot be affected by polymorphism or particle size of the
active substance, as rivastigmine in a liquid state is completely miscible and dissolved throughout the
manufacturing process.
The Active Substance Master File (ASMF) procedure is used for the active substance. The main
objective of the ASMF procedure, commonly known as the European Drug Master File (EDMF)
procedure, is to allow valuable confidential intellectual property or ‘know-how’ of the manufacturer of
the active substance (ASM) to be protected, while at the same time allowing the applicant or
marketing authorisation holder (MAH) to take full responsibility for the medicinal product, the quality
and quality control of the active substance. Competent Authorities/EMA thus have access to the
complete information that is necessary to evaluate the suitability of the use of the active substance in
the medicinal product.
Manufacturing process
The manufacturing process of the ASMF holder has been described. The route of synthesis is
adequately characterised.
Quality control of drug substance
The MAH applies the same drug substance specifications as the ASMF holder, which is in line with the
Ph.Eur. monograph for rivastigmine, however with two tighter limits for solvents. Description and
validation have been provided for the in-house methods used. Results of batch analysis have been
provided for eight production-scale batches.
Stability of drug substance
Stability data on the active substance have been provided in accordance with applicable European
guidelines demonstrating the stability of the active substance. The drug substance was stored under
accelerated and long term conditions. Based on the data submitted, a retest period could be granted
of 12 months when stored at 5ºC ± 3ºC.
II.3
Medicinal Product
Pharmaceutical development
The development of the product has been described, the choice of excipients is justified and their
functions explained. Both strengths are manufactured from the same bulk laminate. With reference to
use in other products, the several materials of the patch layers are not considered novel excipients.
Adequate specifications have been provided for these materials. Robustness of the patch at
conditions allowed according to the SmPC of the proposed and reference product (bathing, hot
weather), have been substantiated with results of in-use studies. Additionally it has been
demonstrated that the direction of peeling off of the release liner does not affect the peel force and
does not result in an increased risk of curling or adhesion problems with the patch. The MAH chose to
use an acrylic adhesive which is equivalent to the one used in the reference product, but without an
anti-oxidant.
The quantitative composition of the two strengths is dose-proportional. Data on the comparison of the
dissolution profiles of both strengths have been provided. The drug release of the higher strength of
9.5 mg/24 hours used in the bioequivalence studies has been compared with the 4.6 mg/24 hours
strength in phosphate buffer pH 6.8, 0.1N HCl and acetate buffer pH 4.5. Results were also provided
of the comparison of the dissolution of the proposed products and their reference products, which
were satisfactory.
Manufacturing process
The manufacturing process has been adequately described according to relevant European
guidelines. Validation results have been provided for six pilot-scale batches, including the biobatches.
As the process is a non-standard manufacturing process, only this pilot-scale is at this moment
acceptable as production scale.
Control of excipients
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All the ingredients are either described in a pharmacopoeia or are purchased from an established
commercial supplier, to an agreed specification, whose suitability has been established over many
years of commercial supply to the pharmaceutical industry. These specifications are based on
information provided by the respective suppliers and include a suitable, specific test for identification.
The specifications and analytical methods are provided together with Certificates of Analysis.
These specifications are acceptable. The printing ink never comes in contact with the adhesive matrix
of the product and therefore does not come in contact with the skin when the patient wears the
transdermal system.
Quality control of drug product
The drug product specification is adequately drawn up. The descriptions and validations are
appropriate.
Satisfactory validation data for the analytical methods have been provided.
Batch analytical data for six batches from the proposed production site have been provided,
demonstrating compliance with the specification.
Stability of drug product
Stability data have been provided on three batches of each strength stored at 25°C/60% RH (up to 24
months), 30°C/65% RH (12 months) and 40°C/75% RH (6 months). The conditions used in the
stability studies are according to the ICH stability guideline. The test methods are stability indicating. A
photostability study showed that the product is sensitive to light.
Based on the stability data submitted, the following proposed shelf-life and storage conditions are
approved: 2 years, in PET-LDPE-Al-polyacrylonitril (PAN) sachets. Do not store above 25ºC. Keep the
transdermal patch in the sachet until use.
Specific measures concerning the prevention of the transmission of animal spongiform encephalopathies
There are no substances of ruminant animal origin present in the product nor have any been used in
the manufacturing of this product, so a theoretical risk of transmitting TSE can be excluded.
II.4
Discussion on chemical, pharmaceutical and biological aspects
Based on the submitted dossier, the member states consider that Rivamylan, transdermal patches 4.6
mg/24 hours and 9.5 mg/ 24 hours have a proven chemical-pharmaceutical quality. Sufficient controls
have been laid down for the active substance and finished product.
The following post-approval commitment was made:
The requirements for dissolution and cold flow will be re-evaluated when additional batch and stability
results are available.
III.
III.1
NON-CLINICAL ASPECTS
Ecotoxicity/environmental risk assessment (ERA)
Since Rivamylan is 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.2
Discussion on the non-clinical aspects
This product is a generic formulation of Exelon 4.6 mg/24 hours and 9.5 mg/24 hours transdermal
patches which is available on the European market. Reference is made to the preclinical data
obtained with the innovator product. A non-clinical overview on the pharmacology, pharmacokinetics
and toxicology has been provided, which is based on up-to-date and adequate scientific literature. The
overview justifies why there is no need to generate additional non-clinical pharmacology,
pharmacokinetics and toxicology data. Therefore, the member states agreed that no further nonclinical studies are required.
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CLINICAL ASPECTS
Introduction
Rivastigmine is a well-known active substance with established efficacy and tolerability.
A clinical overview has been provided, which is based on scientific literature. The overview justifies
why there is no need to generate additional clinical data. Therefore, the member states agreed that no
further clinical studies are required.
For this generic application, the MAH has submitted six studies:
•
a single dose and a multiple dose bioequivalence study with the 9.5mg/24h transdermal patch
in healthy volunteers to compare pharmacokinetics.
two reports on single dose adhesion of the test and reference transdermal patches 4.6 mg/24h
and 9.5 mg/24h in healthy volunteers.
two reports on comparative irritation/sensitization studies of the test and reference
transdermal patches 4.6 mg/24h and 9.5 mg/24h in healthy volunteers.
•
•
The studies are discussed below.
IV.2
Pharmacokinetics
The MAH conducted two bioequivalence studies, a single dose and a multiple dose study, in which the
pharmacokinetic profile of the test product Rivamylan, transdermal patches 9.5 mg/ 24 hour (Mylan
B.V., the Netherlands) is compared with the pharmacokinetic profile of the reference product Exelon
9.5 mg/24 hour transdermal patches (Novartis Europharm Ltd., Ireland)
The choice of the reference product in the bioequivalence study is justified. The formula and
preparation of the bioequivalence batch is identical to the formula proposed for marketing.
Biowaiver
A biowaiver is for the 4.6 mg/24h (9 mg/patch) transdermal patch is accepted because of the following
argumentation:
 The qualitative composition of the two strengths is the same.
 The quantitative composition of the two strengths is dose-proportional.
 Both strengths are manufactured in the same site with the same manufacturing process.
 Both strengths demonstrate the same degree of local irritation, adhesiveness to the skin,
phototoxicity (phototoxic potential), sensitization and similar adverse events profile compared to
the reference product.
 There is an acceptable in vitro release test.
 The pharmacokinetics of rivastigmine is more than dose-proportional.
Bioequivalence study I: single dose study
Design
A single-dose, randomised, two-period, two-treatment, crossover bioequivalence study was carried out
under fasted conditions in 40 healthy male and female subjects, aged 18-64 years. As secondary
objectives, adhesion and irritation were also assessed.
Each subject received a single 9.5 mg/24 h patch of one of the 2 rivastigmine formulations applied on
clean, dry skin of the upper chest after an overnight fast of at least 10 hours. Subjects had an overlay
applied over the patch at the time of application in order to test for adhesion. The patch was worn for a
period of 24 hours. There were two dosing periods, separated by a washout period of a minimum of
six days.
Blood samples were collected at 120 minutes prior to patch application and at 2, 4, 6, 7, 8, 9, 10, 11,
12, 13, 14, 15, 16, 17, 18, 20, 24, 27, 30, 33 and 36 hours after application of the products.
Adhesion of the patch was assessed based on a 12-point scale at the end of the dosing period. Acute
dermal irritation was assessed 30 to 45 minutes following patch removal based on a scoring scale.
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The design of the study is acceptable. The start and the duration of the sampling are sufficient to
measure pharmacokinetic parameters considering the tmax and half-life (10-16 h and 3-4 h,
respectively) of rivastigmine.
Analytical/statistical methods
The analytical method has been adequately validated and is considered acceptable for analysis of the
plasma samples. The methods used in this study for the pharmacokinetic calculations and statistical
evaluation are considered acceptable.
Results
Seven subjects discontinued due to the following reasons: a greater than 15% lift of patch (3, as
specified in the protocol), adverse event (2), personal reason (1) and did not report for check-in (1).
The remaining 33 periods completed both periods of the study and were included in the analysis.
Table 1.
Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD, tmax
(median, range)) of rivastigmine under fasted conditions.
Treatment
N=33
Test
AUC0-t
AUC0-∞
Cmax
tmax
ng.h/ml
ng.h/ml
ng/ml
h
t1/2
h
177.9 ± 35
179 ± 35
9.9 ± 40
10
7-20
2.3 ± 20
Reference
167.2 ± 38
168.3 ± 38
9.4 ± 41
2.3 ± 18
*Ratio (90%
CI)
1.07
(1.03-1.11)
1.07
(1.03-1.11)
1.06
(1.01-1.12)
10
7-20
-
-
AUC0-∞ area under the plasma concentration-time curve from time zero to infinity
AUC0-t area under the plasma concentration-time curve from time zero to t hours
Cmax
maximum plasma concentration
tmax
time for maximum concentration
t1/2
half-life
*ln-transformed values
Conclusion
The 90% confidence intervals calculated for AUC0-t, AUC0-∞ and Cmax are in agreement with those
calculated by the MAH and are within the bioequivalence acceptance range of 0.80–1.25. Based on
the pharmacokinetic parameters of rivastigmine, it can be concluded that the Rivamylan, transdermal
patches 9.5 mg/ 24 hour is comparable with the pharmacokinetic profile of the reference product
Exelon 9.5 mg/24 hour transdermal patches under fasted conditions with respect to rate and extent of
absorption, and fulfil the bioequivalence requirements outlined in the relevant CHMP Note for
Guidance.
The reasons for withdrawal are acceptable, in particular, the withdrawal of the 3 subjects due to a
greater than 15% lift of patch is acceptable as this was pre-defined in the protocol. It is noted that all
the 3 subjects discontinued due to a greater than 15% lift of patch received the reference product.
Bioequivalence study II: multiple dose study
Design
A multiple-dose, randomised, two-period, two-treatment, crossover bioequivalence study was carried
out under steady-state conditions in 67 healthy male and female subjects, aged 18-74 years. As
secondary objectives, adhesion and irritation were also assessed. Each subject received three
consecutive 9.5 mg/24 h patches of one of the 2 rivastigmine formulations applied on clean, dry skin of
the upper chest, applied every 24 hours. Subjects had an overlay applied over the patch at the time of
application in order to test for adhesion. A light breakfast was served prior to the first patch application.
There were two dosing periods, separated by a washout period of a minimum of six days. Subjects
were housed at least 12 hours prior to dosing until 25 hours after last patch application.
Blood samples were collected on day three at 120 minutes prior to patch application and at 2, 4, 6, 8,
10, 12, 14, 16, 18, 20, 22 and 24 hours post-dose. Adhesion of the patch was assessed based on a
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12-point scale at the end of the dosing period. Acute dermal irritation was assessed 30 to 45 minutes
following patch removal based on a scoring scale.
The design of the study is acceptable. Assuming a ratio between 90%-110% and an intra-subject
variability of 20%, a minimum of 37 subjects were required to conclude bioequivalence with
approximately 80% power. To account for subject withdrawal and dropouts 48 subjects were originally
randomized and dosed. An additional group of 20 subjects was added via protocol amendment due to
an unanticipated drop-out rate in Period 1 of the study because of less than 85% adhesion throughout
the rest of the study in 14 subjects. The overlay which was applied in order to ensure adhesion over
the entire wear period caused irritation that precluded re-application of the overlay; therefore the
overlay was not applied in the second group of subjects.
Analytical/statistical methods
The analytical method has been adequately validated and is considered acceptable for analysis of the
plasma samples. The methods used in this study for the pharmacokinetic calculations and statistical
evaluation are considered acceptable.
Results
Twenty-five subjects discontinued due to the following reasons: a greater than 15% lift of patch (18, as
specified in the protocol), adverse event (6), and personal reasons (1). The remaining 33 subjects
completed both periods of the study. Steady-state was achieved after 3 patch applications (3 days).
Table 2. Pharmacokinetic parameters in steady-state (non-transformed values; arithmetic mean ± SD)
Treatment
N=33
Test
Reference
*Ratio
(90% CI)
AUC
Cmax
Cmin
PTF%
AUC
Cmax,ss
Cmin,ss
ng/ml/h
ng/ml
ng/ml
PTF%
%
183.1± 41
10.9 ± 50
4.7 ± 36
77 ± 35
164.4± 46
9.9 ± 57
4.1 ± 33
76 ± 36
1.14
(1.08–1.20)
1.14
(1.07–1.22)
1.15
(1.08 – 1.22)
area under the plasma concentration-time curve over the dosing interval
maximum plasma concentration
minimum plasma concentration
fluctuation index
Conclusion
The 90% confidence intervals calculated for AUC, Cmin,ss and Cmax,ss are within the 0.80 – 1.25
range. Based on the pharmacokinetic parameters of rivastigmine, it can be concluded that the
pharmacokinetic profile of Rivamylan, transdermal patches 9.5 mg/24 hour is comparable with that of
the reference product Exelon 9.5 mg/24 hour transdermal patches under steady-state conditions with
respect to rate and extent of absorption, and fulfil the bioequivalence requirements outlined in the
relevant CHMP Note for Guidance.
Fourteen (14) subjects were discontinued due to greater than 15% patch lift during Period 1. After a
discussion about the application techniques after completion of the Group 1, Period 1 dosing, only four
(4) of the additional subjects had less than 85% adhesion throughout the rest of the study. Generally,
patches maintained good skin contact throughout the wear period with proper application techniques.
Overall conclusion on bioequivalence studies:
It has been sufficiently shown that Rivamylan 9.5 mg/24 hours transdermal patch is
pharmacokinetically bioequivalent compared to the reference product Exelon Patch 9.5 mg/24 hours
under both fasted and steady-state conditions.
The MEB has been assured that the bioequivalence studies have been conducted in accordance with
acceptable standards of Good Clinical Practice (GCP, see Directive 2005/28/EC) and Good
Laboratory Practice (GLP, see Directives 2004/9/EC and 2004/10/EC).
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Adhesion studies
Two studies were performed in which the adhesion of the test product Rivamylan, transdermal
patches 4.6 mg/24 hour and 9.5 mg/24 hour was compared with the adhesion of the reference product
Exelon 4.6 mg/24 hour and 9.5 mg/24 hour transdermal patches (Novartis Europharm Ltd., Ireland).
As a secondary objective, acute irritation was assessed.
Design
The two studies were irritation evaluator-blinded, randomized, single dose, one-period, two-group
parallel design. Thirty-six male and female volunteers (18 years or older) were included in each study.
In the first study (study I), the subjects wore one patch of the 4.6 mg/24 hour strength of the test
product and one patch of the 4.6 mg/24 hour strength of the reference product simultaneously on the
left and right side of the upper chest for 24 hours in a randomized fashion. In the other study (study II)
either a test or a reference patch of the 9.5 mg/24 hour strength was worn for 24 hours in a
randomized fashion.
Adhesion assessments were performed at 4, 8, 12, 16, 20 and 24 hours (±10 minutes) after patch
application by trained clinical staff utilizing a 12-point scale. A score of ‘100’ indicated 100% adhered
to the skin, while a score of ‘0’ indicated the transdermal system was completely detached from the
skin. The design of the study and the methods used are acceptable.
Analytical/statistical methods
The analytical method has been adequately validated and is considered acceptable for analysis of the
adhesion scores. The methods used in this study for the adhesion calculations and statistical
evaluation are considered acceptable.
Results
In studies I and II there were two and one drop-outs, respectively. Results are shown in tables 3 and 4
below.
Table 3. Adhesion results study I (4.6 mg/24 hour patches)
Hour
4
8
12
16
20
24
Cumulative mean
Arithmetic mean (%CV) test
product
99.12 (2.90)
95.00 (3.89)
95.15 (2.42)
95.15 (3.29)
92.35 (6.70)
91.91 (14.05)
94.78 (3.92)
Arithmetic mean (%CV)
reference product
97.35 (4.05)
92.06 (7.22)
92.50 (5.68)
90.88 (12.15)
90.59 (9.87)
90.74 (7.93)
92.35 (6.21)
Table 4. Adhesion results study II (9.5 mg/24 hour patches)
Hour
4
8
12
16
20
24
Cumulative mean
Arithmetic mean (%CV) test
product
95.00 (4.42)
93.89 (3.44)
92.78 (5.91)
90.56 (10.18)
83.89 (13.49)
77.22 (26.49)
88.89 (7.95)
Arithmetic mean (%CV)
reference product
93.82 (3.54)
92.65 (8.12)
92.06 (6.39)
90.88 (5.58)
92.06 (8.38)
87.94 (14.36)
91.57 (6.76)
Conclusion
The patch adhesion assessment results showed that Rivamylan transdermal patches (4.6mg/24h and
9.5mg/24 h) are non-inferior to the corresponding innovator Exelon transdermal patches with respect
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to adhesion. However, these results should be seen in the context that the adhesion assessments of
the studies were not blinded.
IV.4
Local irritation and sensitization studies
Two studies were performed to compare the cumulative irritation and sensitization potential of
Rivamylan 4.6 mg/24 hours and 9.5 mg/24 hours with the reference product Exelon in healthy
volunteers.
Irritation and sensitization study I
Design
This was an open-label, multiple-dose, randomized application site, two-treatment, one-period human
dermal safety study investigating the cumulative irritation of the test and reference product after
repetitive placement of each topical patch treatment to the same skin site.
Thirty-six male and female volunteers (18 years or older) were included in the study.
Each subject received a 2.0 cm2 die-cut of Rivamylan 4.6 mg/24 hours and Exelon 4.6 mg/24 hours
transdermal patch applied on the right or left side of the upper chest according to the randomization
scheme. Subjects wore each treatment for 24 hours. Patches were reapplied to the same skin site
every 24 hours for 21 consecutive days (for a total of 21 patch applications per treatment). Patch
adhesion was assessed within one hour after each patch removal by trained clinical staff. Irritation was
assessed using an 8-point scale. If a subject developed an irritation score of 3 or greater, the subject
did not have any further patches of that treatment applied during the study. The other treatment
applications continued as scheduled.
Statistical analysis
The primary assessment parameter was the mean cumulative irritation, which was defined for each
subject as the sum of all 21 individual irritation scores obtained at 0.5 hours after patch removal
divided by 21. Subjects must have had 16 valid irritation scores recorded to be included in the
analysis. For any missing score, the previous score was carried forward.
The analytical method has been adequately validated and is considered acceptable for analysis of the
adhesion scores. The methods used in this study for the adhesion calculations and statistical
evaluation are considered acceptable.
Results
Four subjects were discontinued due to limiting irritation. Data from those subjects were included in
the analysis as per protocol. For two subjects irritation data could not be verified, therefore the
analysis was conducted with data from 34 subjects.
Conclusion
The statistical results of the cumulative irritation scores showed that Rivamylan transdermal patches
(4.6mg/24h and 9.5mg/24 h) are non-inferior to their corresponding innovator Exelon transdermal
patches, with respect to irritation.
Irritation and sensitization study II
Design
This was an open-label, multiple-dose, randomized application site, three-treatment, three phase, oneperiod human dermal safety study investigating the cumulative irritation and contact sensitization
potential of the test and reference product after repetitive placement of each topical patch treatment to
the same skin site. Rivamylan 4.6 mg/24 hours was compared to two different formulations of Exelon
4.6 mg/24 hours (USA and UK). Only the results regarding the relevant, European formulation are
discussed here.
Two hundred and thirty-seven male and female volunteers (18 years or older) were included in the
study.
Each subject received a 2.0 cm2 die-cut of Rivamylan 4.6 mg/24 hours and Exelon 4.6 mg/24 hours
transdermal patch applied on the right or left side of the upper chest according to the randomization
scheme. The first group of 75 subjects had an overlay applied over each treatment patch at the time of
application in order to insure adhesion over the entire wear period, but because this caused irritation
that precluded re-application of the overlay, the overlay was not applied in the remaining subjects.
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Subjects wore each treatment for 24 hours. Patches were reapplied to the same skin site every 24
hours for 21 consecutive days (for a total of 21 patch applications per treatment), followed by a 14-day
rest phase and a subsequent 48-hour challenge phase, followed by a 3-day observation and irritation
evaluation. In the event that a subject was potentially sensitized, the challenge phase was repeated
during a re-challenge phase between 4 to 8 weeks after the conclusion of the challenge phase. Only
the sites that had sensitization reactions were re-challenged.
Patch adhesion was assessed within one hour after each patch removal by trained clinical staff.
Irritation was assessed using an 8-point scale. If a subject developed an irritation score of 3 or greater,
the subject did not have any further patches of that treatment applied during the study. The other
treatment application continued as scheduled.
If a subject developed an irritation score of 3 or greater, the subject did not have any further patches
applied to the same application site during the induction phase of the study. In this case, any reapplications for induction were made at a designated alternate site and appropriately documented and
diagrammed. All other treatment applications continued as scheduled.
During the induction phase, irritation assessments were performed 30 to 45 minutes after each patch
was removed. During the challenge phase, irritation assessments occurred at study hours 0.5, 24, 48,
and 72 hours after removal of the patch. Patch adhesion was assessed within one hour prior to patch
removal during the induction and challenge phases. Subjects remained at the clinical site until
completion of all scheduled study procedures at a given time, but were then allowed to leave and
return as needed.
Interpretation of a potential sensitization reaction was based on combined dermal response/other
effects score of at least 2 at the last challenge phase evaluation and was generally a higher score than
what was observed in the induction phase. This reaction is distinguished from an irritation reaction,
which would be anticipated to subside after patch removal.
Statistical analysis
The primary assessment parameter was the mean cumulative irritation, which was defined for each
subject as the sum of all 21 individual irritation scores obtained at 0.5 hours after patch removal
divided by 21. Subjects must have had 16 valid irritation scores recorded to be included in the
analysis. For any missing score, the previous score was carried forward.
The analytical method has been adequately validated and is considered acceptable for analysis of the
adhesion scores. The methods used in this study for the adhesion calculations and statistical
evaluation are considered acceptable.
Results
Thirty-one subjects dropped out of the study for the following reasons: adverse event (6), protocol
deviations (8), withdrawal of consent (17). 206 subjects completed the study for at least one treatment.
For both the test and reference products, 15 subjects had sensitization scores that would indicate a
sensitization reaction.
For Rivamylan 19 subjects were potentially considered sensitized after the challenge phase, 18
subjects returned for the re-Challenge Phase, 14 were confirmed to have sensitization and four 4 were
deemed not to be sensitizers; one (1) subject was not re-challenged.
For the Exelon patch 18 subjects were potentially considered sensitized after the challenge phase, 15
subjects returned for the re- challenge phase, 13 were confirmed to have sensitization, and 2 were
deemed not to be sensitizers; 3 subjects were not re-challenged. The results of the sensitization
scores showed that Rivamylan transdermal patches 9.5mg/24 h are comparable to Exelon
transdermal patches 9.5mg/24 h (sensitized subjects: 7% and 6.5%, respectively) with respect to
sensitization.
Safety
No new safety issues were identified. Except for the last study the safety profile of the two products in
all the other studies appeared to be comparable.
Conclusion
The statistical results of the cumulative irritation scores showed that Rivamylan transdermal patches
(4.6mg/24h and 9.5mg/24 h) are non-inferior to their corresponding innovator Exelon transdermal
patches, with respect to irritation and sensitization.
10/13
C
IV.5
B
G
M
E
B
Risk Management Plan
The MAH has submitted a risk management plan, in accordance with the requirements of Directive
2001/83/EC as amended, describing the pharmacovigilance activities and interventions designed to
identify, characterise, prevent or minimise risks relating to Rivamylan transdermal patches 4.6mg/24h
and 9.5mg/24 h.
- Summary of Safety Concerns and Planned Risk Minimisation Activities as approved in RMP
Important identified risks
•Gastrointestinal symptoms (nausea,
vomiting and diarrhoea)
• Worsening of motor symptoms
associated with Parkinson’s disease
• Pancreatitis
• Cardiac arrhythmias
• Exacerbation of asthma and COPD
• Application site skin reactions and
irritations
• Hypertension
• Gastrointestinal ulceration, haemorrhage
and perforation
• Seizures
• Hallucinations
• Syncope and loss of consciousness
• Medication misuse
• Medication errors
• Dehydration
• Liver disorders
• Severe skin reactions (bullous reactions)
Important potential risks
• Myocardial infarction
• Cerebrovascular accident
• Pulmonary infections
• Death
• Acute renal failure
• none
Important missing information
The MAH should follow, where appropriate, the risk minimization activities of the innovator. The MAH
committed to submit educational material, the final version of which should be agreed by the National
Competent Authorities of each member state, before marketing.
IV.6
Discussion on the clinical aspects
For this authorisation, reference is made to the clinical studies and experience with the innovator
product Exelon transdermal patches. No new clinical studies were conducted. The MAH demonstrated
through studies that the pharmacokinetic profile of the product is similar to the pharmacokinetic profile
of this reference product, and that adhesion, irritation, and sensitization are non-inferior. Risk
management is adequately addressed. This generic medicinal product can be used instead of the
reference product.
V.
USER CONSULTATION
A user consultation with target patient groups on the package leaflet (PL) has been performed on the
basis of a bridging report making reference to the PL of the centrally authorised reference product
Exelon transdermal patches. Furthermore, the layout and design of the Rivastigmine PL is in line with
the house style of the MAH: reference is made to user tests of other products to confirm that the leaflet
design allows information to be easily located by the user. The bridging report has been found
acceptable.
11/13
C
VI.
B
G
M
E
B
OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND
RECOMMENDATION
Rivamylan, transdermal patches 4.6 and 9.5 mg/ 24 hour has a proven chemical-pharmaceutical
quality and is a generic form of Exelon 4.6 and 9.5 mg/24 hour transdermal patches. Exelon 4.6 and
9.5 mg/24 hour transdermal patches are a well-known medicinal products with an established
favourable efficacy and safety profile.
Bioequivalence has been shown to be in compliance with the requirements of European guidance
documents. Non-inferiority to the innovator has been demonstrated for adhesion, irritation, and
sensitization in a number of studies.
The Board followed the advice of the assessors.
There was no discussion in the CMD(h). Agreement between member states was reached during a
written procedure. The member states, on the basis of the data submitted, considered that essential
similarity has been demonstrated for Rivamylan, transdermal patches 4.6 and 9.5 mg/ 24 hour with
the reference product, and have therefore granted a marketing authorisation. The decentralised
procedure was finalised with a positive outcome on 24 October 2014.
12/13
C
B
G
M
E
B
STEPS TAKEN AFTER THE FINALISATION OF THE INITIAL PROCEDURE - SUMMARY
Scope
Procedure
number
Type of
modification
13/13
Date of start
of the
procedure
Date of
end of the
procedure
Approval/
non
approval
Assessment
report
attached