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PUBLIC ASSESSMENT REPORT
of the Medicines Evaluation Board
in the Netherlands
Tacrolimus Lambda 0.5 mg and 1 mg capsules, hard
Lambda Therapeutics Limited, United Kingdom
tacrolimus (as monohydrate)
This assessment report is published by the MEB pursuant Article 21 (3) and (4) of Directive 2001/83/EC. The report
comments on the registration dossier that was submitted to the MEB and its fellow –organisations in all concerned EU
member states.
It reflects the scientific conclusion reached by the MEB and all concerned member states at the end of the evaluation
process and provides a summary of the grounds for approval of a marketing authorisation.
This report is intended for all those involved with the safe and proper use of the medicinal product, i.e. healthcare
professionals, patients and their family and carers. Some knowledge of medicines and diseases is expected of the
latter category as the language in this report may be difficult for laymen to understand.
This assessment report shall be updated by a following addendum whenever new information becomes available.
General information on the Public Assessment Reports can be found on the website of the MEB.
To the best of the MEB’s knowledge, this report does not contain any information that should not have been made
available to the public. The MAH has checked this report for the absence of any confidential information.
EU-procedure number: NL/H/1335/001-002/DC
Registration number in the Netherlands: RVG 102531-102532
15 November 2010
Pharmacotherapeutic group:
ATC code:
Route of administration:
Therapeutic indication:
Prescription status:
Date of authorisation in NL:
Concerned Member States:
Application type/legal basis:
immunosuppressants; calcineurin inhibitors
L04AD02
oral
prophylaxis of transplant rejection in liver, kidney or heart
allograft recipients; allograft rejection resistant to treatment with
other immunosuppressive medicinal products.
prescription only
4 November 2010
Decentralised procedure with AT, CZ, DE, DK, FI, FR, HU, NO,
PL, SE, SK
Directive 2001/83/EC, Article 10(1)
For product information for healthcare professionals and users, including information on pack sizes and
presentations, see Summary of Product Characteristics (SPC), package leaflet and labelling.
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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 Tacrolimus Lambda 0.5 mg and 1 mg capsules, hard from Lambda Therapeutics Limited.
The date of authorisation was on 4 November 2010 in the Netherlands. The MAH withdrew the application
for the 5 mg strength in all member states (see II.3 Clinical aspects).
The product is indicated for:
• prophylaxis of transplant rejection in liver, kidney or heart allograft recipients.
• treatment of allograft rejection resistant to treatment with other immunosuppressive medicinal
products.
A comprehensive description of the indications and posology is given in the SPC.
Tacrolimus belongs to the pharmacotherapeutic group of macrolide immunosuppressants, and to the
subgroup of calcineurin inhibitors. At the molecular level, the effects of tacrolimus appear to be mediated
by binding to a cytosolic protein (FKBP12) which is responsible for the intracellular accumulation of the
compound. The FKBP12-tacrolimus complex specifically and competitively binds to and inhibits
calcineurin, leading to a calcium-dependent inhibition of T-cell signal transduction pathways, thereby
preventing transcription of a discrete set of lymphokine genes.
Tacrolimus is a potent immunosuppressive agent and has proven activity in both in vitro and in vivo
experiments. In particular, tacrolimus inhibits the formation of cytotoxic lymphocytes, which are mainly
responsible for graft rejection. Tacrolimus suppresses T-cell activation and T-helper-cell dependent B-cell
proliferation, as well as the formation of lymphokines (such as interleukins-2, -3, and γ-interferon) and the
expression of the interleukin-2 receptor.
This decentralised procedure concerns a generic application claiming essential similarity with the
innovator products Prograft 0.5 mg, 1 mg and 5 mg capsules (NL License RVG 22236 and 18107
respectively) which have been registered in the Netherlands by Astellas Pharma B.V. since 1996 (1 mg)
and 1998 (0.5 mg). In addition, reference is made to Prograft authorisations in the individual member
states (reference product).
The marketing authorisation is granted based on article 10(1) of Directive 2001/83/EC.
This type of application refers to information that is contained in the pharmacological-toxicological and
clinical part of the dossier of the authorisation of the reference product. A reference product is a medicinal
product authorised and marketed on the basis of a full dossier, i.e. including chemical, biological,
pharmaceutical, pharmacological-toxicological and clinical data. This information is not fully available in
the public domain. Authorisations for generic products are therefore linked to the ‘original’ authorised
medicinal product, which is legally allowed once the data protection time of the dossier of the reference
product has expired. For this kind of application, it has to be demonstrated that the pharmacokinetic profile
of the product is similar to the pharmacokinetic profile of the reference product. To this end the MAH has
submitted a bioequivalence study in which the pharmacokinetic profile of the product is compared with the
pharmacokinetic profile of the reference product Prograft 0.5 mg capsules, registered in Germany. A
bioequivalence study is the widely accepted means of demonstrating that difference of use of different
excipients and different methods of manufacture have no influence on efficacy and safety. These generic
products can be used instead of their reference product.
No new pre-clinical and clinical studies were conducted, which is acceptable for this abridged application.
No scientific advice has been given to the MAH with respect to these products and no paediatric
development programme has been submitted, as this is not required for generic medicinal products.
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SCIENTIFIC OVERVIEW AND DISCUSSION
Quality aspects
Compliance with Good Manufacturing Practice
The MEB has been assured that acceptable standards of GMP (see Directive 2003/94/EC) are in place for
these product types at all sites responsible for the manufacturing of the active substance as well as for the
manufacturing and assembly of this product prior to granting its national authorisation.
Active substance
The active substance is tacrolimus, an established active substance, however not described in the
European Pharmacopoeia (Ph.Eur.*) or any other pharmacopoeia. The active substance is a white to offwhite powder, which is insoluble in water, soluble in methanol, ethanol, acetone, ethyl acetate, chloroform
and diethyl ether and sparingly soluble in hexane and petroleum ether. Tacrolimus contains one water
molecule as a water of crystallisation. It does not display polymorphism. Information on isomerism of
tacrolimus has been included in the dossier.
The Active Substance Master File (ASMF) procedure is used for both suppliers of 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 both manufacturers consists of a fermentation process followed by
extraction and purification. Detailed information on the manufacturing process and on potential impurities
has been included in the restricted part of the DMFs.
Quality control of drug substance
The specifications, provided separately for both manufacturers, are acceptable in view of the route of
synthesis and the various European guidelines. The proposed limits for impurities are justified. Batch
analytical data demonstrating compliance with the drug substance specification have been provided for
tacrolimus monohydrate from both manufacturers.
Stability of drug substance
For drug substance from one supplier, stability data have been provided for three supportive batches
stored at 25ºC/60% RH (36 months) and 40ºC/75% RH (6 months), and three full-scale commercial
batches stored at 25ºC/60% RH (24 months) and 40ºC/75% RH (6 months). The batches were stored in
packaging material used for commercial supply. Both the supportive and commercial batches remain
stable at long term conditions; no significant changes or specific trends were observed. A re-test period for
the drug substance of 36 months is acceptable, when stored in the original container in order to protect
from light.
For drug substance from the other manufacturer, stability data have been provided for six batches stored
at 25ºC/60% RH (24 months) and 40ºC/75% RH (6 months). No trends or out of specification results were
observed during stability studies. The proposed re-test period of 24 months is acceptable for the drug
substance from this supplier, if stored in the original container in order to protect from light.
* Ph.Eur. is an official handbook (pharmacopoeia) in which methods of analysis with specifications for
substances are laid down by the authorities of the EU.
Medicinal Product
Composition
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Tacrolimus Lambda 0.5 mg is a light yellow/light yellow hard gelatin capsule, size "5" imprinted with “TCR”
on cap & “0.5” on body containing white to off white granular powder.
Tacrolimus Lambda 1 mg is a white/white hard gelatin capsule, size "5" imprinted with “TCR” on cap & “1”
on body containing white to off white granular powder.
The hard capsules are packed in Alu/Alu blisters.
The excipients are:
Capsule content – lactose monohydrate, croscarmellose sodium (E468), hypromellose (E464),
magnesium stearate (E572).
Capsule shell – gelatin, titanium dioxide (E171), iron oxide yellow (E172) (0.5 mg only), sodium lauryl
sulphate.
Printing ink – shellac, propylene glycol, potassium hydroxide, black iron oxide (E172).
The contents of the 0.5 and 1 mg capsules have nearly the same composition; the contents of the
excipients showed a minor difference to compensate the difference in active substance. Both strengths
contain less than 5% of active substance. Differences in the ratio between tacrolimus and excipients were
sufficiently explained by the MAH.
Pharmaceutical development
The development of the product has been described, the choice of excipients is justified and their
functions explained. Appropriate development studies have been performed. Tacrolimus capsules have
been manufactured using the same excipients as that of the innovator products. The contents of the 0.5
and 1 mg capsules have the same qualitative composition. Differences in quantitative composition are
necessary to keep the ratio Tacrolimus:hypromellose constant. A bioequivalence study has been
conducted with tacrolimus 0.5 mg capsules and the reference product Prograf 0.5 mg, sourced from the
German market. The use of the German reference product is acceptable. Comparative dissolution studies
have been performed in three different media with the developed product and the innovator products used
for bioequivalence studies as well as for the innovator products sourced from the Dutch market. The
dissolution profiles of the innovator product and proposed product comparable. Comparative dissolution
between the different strengths of the proposed product has also been demonstrated in three different
media.
Manufacturing process
The manufacturing process consists of preparation of common granules for tacrolimus capsules by wet
granulation, followed by sizing, blending, encapsulation and packaging.
Process validation data on the product has been presented for three pilot-scale batches of common
granules, and two pilot-scale finished product batches per strength. The MAH committed to conduct
process validation on the first three commercial-scale batches.
Control of excipients
All excipients comply with the specifications of the respective Ph.Eur. monographs. These specifications
are acceptable.
Quality control of drug product
The product specification includes tests for description, identification, identification of colourants on
capsule shell, average weight of capsule, disintegration time, dissolution, uniformity of dosage units,
related substances, content of tautomers, assay, ethanol content and microbial contamination. The
specification has been adequately justified. The release and shelf life specifications are identical, except
for total impurities. The analytical methods have been adequately described and validated.
Batch analytical data from the proposed production site have been provided on three pilot-scale batches
per strength, demonstrating compliance with the release specification. Results for three consecutive fullscale batches will be provided when available.
Stability of drug product
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Stability data on the product has been provided three pilot-scale batches per strength stored at
25°C/60%RH (24 months) and at 30°C/65%RH (12 months). The batches were stored in packaging
proposed for commercial supply (Alu/Alu blister packs) and bulk packaging. The conditions used in the
stability studies are according to the ICH stability guideline. All batches included in the stability program
have been manufactured according to the same formulation and a similar manufacturing process as
proposed for marketing.
No out of specification results or significant changes have been observed for the parameters tested after
storage at long term and intermediate storage conditions. Based upon the currently available stability
data, a shelf life of 24 months was granted, if stored in Alu-Alu blister packs below 25°C. The product
should be stored in the original package in order to protect from moisture. The results of photostability
sutdies indicate that the product is stable with respect to light.
A storage period of 6 months for bulk capsules in polypropylene containers is acceptable. Compliance
with the guideline on declaration of storage conditions has been confirmed.
Specific measures concerning the prevention of the transmission of animal spongiform encephalopathies
Gelatin is the only excipient of animal origin. Compliance with the Note for Guidance on Minimising the
Risk of Transmitting Animal Spongiform Encephalopathy Agents via medicinal products has been
satisfactorily demonstrated.
II.2
Non-clinical aspects
This product is a generic formulation of Prograft, which is available on the European market. No new
preclinical data have been submitted, and therefore the application has not undergone preclinical
assessment. This is acceptable for this type of application.
Environmental risk assessment
The product is intended as a substitute for other identical products on the market. The approval of this
product will not result in an increase in the total quantity of tacrolimus released into the environment. It
does not contain any component, which results in an additional hazard to the environment during storage,
distribution, use and disposal.
II.3
Clinical aspects
Tacrolimus is a well-known active substance with established efficacy and tolerability.
For this generic application, the MAH has submitted a bioequivalence study in which the pharmacokinetic
profile of the test product Tacrolimus Lambda 0.5 mg (Lambda Therapeutics Limited, UK) is compared
with the pharmacokinetic profile of the reference product Prograft 0.5 mg capsules (Astellas Ireland Co.
Ltd., Germany).
The choice of the reference product
The choice of the reference product in the bioequivalence study has been justified by comparison of
dissolution results and compositions of reference products in different member states.
The formula and preparation of the bioequivalence batch is identical to the formula proposed for
marketing.
Design
A single-dose, randomised, two-period, two-treatment, two-sequence, crossover bioequivalence study
was carried out under fasted conditions in 40 healthy, non-smoking male subjects, aged 19-41 years.
Each subject received a single dose (0.5 mg) of one of the 2 tacrolimus formulations. The tablet was orally
administered with 240 ml water after an overnight fast of 10 hours. There were 2 dosing periods,
separated by a washout period of 20 days.
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Blood samples were collected pre-dose and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.5,
4, 4.5, 5, 6, 7, 8, 12, 16, 24, 30, 36, 48 and 72 hour after administration of the products.
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
Two subjects did not show up for period 2; two other subjectswere withdrawn on medical grounds prior
and after period 2, respectively, not related to the treatment. Thirty-six subjects completed the study and
were eligible for pharmacokinetic analysis.
Table 1.
Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD, tmax
(median, range)) of tacrolimus under fasted conditions
Treatment
N=36
Test
ng.h/ml
ng.h/ml
ng/ml
h
h
33.6 ± 20.7
Not calculated
4.64 ± 2.22
1.25
(0.75-2.25)
Not calculated
Reference
34.0 ± 22.2
Not calculated
4.08 ± 1.90
Not calculated
*Ratio (90%
CI)
0.98
(0.92-1.06)
Not calculated
1.12
(1.03-1.21)
1.5
(0.75-2.5)
-
18.5
Not calculated
20.2
-
-
CV (%)
AUC0-72h
AUC0-∞
Cmax
tmax
t1/2
-
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
In December 2009, the CHMP decided that tacrolimus should be considered a Narrow Therapeutic Index
drug in the sense indicated in the NfG on Bioequivalence and Bioavailability (and the new BE Guideline).
It was decided that for tacrolimus generics, the acceptance criterion for AUC should be narrowed to 0.901.11. The acceptance range for Cmax could remain 0.80-1.25.
The 90% confidence intervals calculated for AUC0-72 and Cmax are in agreement with those calculated by
the MAH and are within the bioequivalence acceptance range of 0.90-1.11 and 0.80-1.25, respectively.
Based on the pharmacokinetic parameters of tacrolimus under fasted conditions, it can be concluded that
Tacrolimus Lambda 0.5 mg and Prograft 0.5 mg capsules are bioequivalent with respect to rate and
extent of absorption, and fulfil the bioequivalence requirements outlined in the relevant CHMP Note for
Guidance.
The advice is to administer the capsules on an empty stomach or at least 1 hour before or 2 to 3 hours
after a meal, to achieve maximal absorption. Therefore a food interaction study is not deemed to be
necessary.
Extrapolation to 1 mg capsules
A biowaiver was requested for the 1 mg strength, based on the provided data for the 0.5 mg strength. This
biowaiver was granted, since:
• Based on literature, tacrolimus pharmacokinetics appears reasonably linear between a 0.5 mg and 5
mg dose.
• The 0.5 and 1 mg strengths are manufactured by the same manufacturer and manufacturing process.
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The contents of the 0.5 and 1 mg capsules have nearly the same composition. Both strengths contain
less than 5% of active substance. Differences in the ratio between tacrolimus and excipients were
justified: the ratio of tacrolimus:hypromellose is kept constant in order to optimize absorption of
tacrolimus. The difference in croscarmellose is considered insignificant, as is the difference in the
amount of filler lactose, necessary because of the above-mentioned differences in hypromellose and
croscarmellose.
Comparable dissolution between the 0.5 and 1.0 mg strength has been demonstrated at different pH
values.
The MEB has been assured that the bioequivalence study has 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).
Withdrawal of 5 mg strength
The initial application included an additional 5 mg capsule. A bioequivalence study was performed with
Tacrolimus Lambda 5 mg, but failed to demonstrate bioequivalence applying the acceptance criteria of
0.90-1.11 (the point estimate (90%) for AUC0-72h was 98.4 (91.51 – 105.9) and for Cmax 111.5 (103.0 –
120.8)). Therefore, the MAH chose to withdraw the application for the 5 mg capsule.
Risk management plan
Tacrolimus was first approved in 1993, and there is now more than 10 years post-authorisation
experience with the active substance. The safety profile of tacrolimus can be considered to be well
established and no product specific pharmacovigilance issues were identified pre- or post authorisation
which are not adequately covered by the current SPC. Additional risk minimisation activities have not
been identified for the reference medicinal product. The MAH has a pharmacovigilance system at their
disposal, which is based on the current European legislation. Routine pharmacovigilance activities are
sufficient to identify actual or potential risks and a detailed European Risk Management Plan is not
necessary for this product.
Product information
SPC
To harmonise the different nationally approved SPCs, Prograft capsules underwent a company-initiated
Article 30 referral in 2006 and then was converted into the SPC of the MRP product (IE/H/0165/001-002003/MR). The SPC proposed for Tacrolimus Lambda is in line with the SPC for Prograft.
Readability test
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 test consisted of two rounds with 10 participants
each. The questions covered the following areas sufficiently: traceability, comprehensibility and
applicability. A satisfactory test outcome for the method outlined above is when 90% of literate adults are
able to find the information requested within the PIL, of whom 90% can show they understand it, i.e. each
and every question must be answered correctly by at least 81% of the participants.
Scores were very high in both test rounds. Therefore, no revisions were condidered necessary.
The readability test has been sufficiently performed.
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OVERALL CONCLUSION AND BENEFIT-RISK ASSESSMENT
Tacrolimus Lambda 0.5 mg and 1 mg capsules, hard have a proven chemical-pharmaceutical quality and
are generic forms of Prograft 0.5 mg and 1 mg capsules. Prograft is a well-known medicinal product with
an established favourable efficacy and safety profile.
Bioequivalence has been shown to be in compliance with the requirements of European guidance
documents.
The initial application included an additional 5 mg capsule. A bioequivalence study was performed with
Tacrolimus Lambda 5 mg, but failed to demonstrate bioequivalence applying the narrowed acceptance
criteria. Therefore, the MAH chose to withdraw the application for the 5 mg capsule.
The MAH has provided written confirmation that systems and services are in place to ensure compliance
with their pharmacovigilance obligations.
The SPC is consistent with that of the reference product. The SPC, package leaflet and labelling are in the
agreed templates.
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 concerned member states, on the basis of the data submitted, considered that essential
similarity has been demonstrated for Tacrolimus Lambda 0.5 mg and 1 mg capsules, hard with the
reference product, and have therefore granted a marketing authorisation. The decentralised procedure
was finished on 4 August 2010. Tacrolimus Lambda 0.5 mg and 1 mg capsules were authorised in the
Netherlands on 4 November 2010.
A European harmonised birth date has been allocated (2 April 1993) and subsequently the first data lock
point for tacrolimus is March 2011. The first PSUR will cover the period to March 2011, after which the
PSUR submission cycle is 6 months.
The date for the first renewal will be: 5 August 2015.
The following post-approval commitments have been made during the procedure:
Quality - active substance
- The MAH committed to provide validation data and batch analysis results of three consecutive fullscale batches.
Quality - medicinal product
- The MAH committed to provide the results of the long term stability studies (throughout the proposed
shelf life) and on intermediate stability studies (for 12 months) of 3 full-scale production batches.
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List of abbreviations
ASMF
ATC
AUC
BP
CEP
CHMP
CI
Cmax
CMD(h)
CV
EDMF
EDQM
EU
GCP
GLP
GMP
ICH
MAH
MEB
OTC
PAR
Ph.Eur.
PIL
PSUR
SD
SPC
t½
tmax
TSE
USP
Active Substance Master File
Anatomical Therapeutic Chemical classification
Area Under the Curve
British Pharmacopoeia
Certificate of Suitability to the monographs of the European Pharmacopoeia
Committee for Medicinal Products for Human Use
Confidence Interval
Maximum plasma concentration
Coordination group for Mutual recognition and Decentralised procedure for
human medicinal products
Coefficient of Variation
European Drug Master File
European Directorate for the Quality of Medicines
European Union
Good Clinical Practice
Good Laboratory Practice
Good Manufacturing Practice
International Conference of Harmonisation
Marketing Authorisation Holder
Medicines Evaluation Board in the Netherlands
Over The Counter (to be supplied without prescription)
Public Assessment Report
European Pharmacopoeia
Package Leaflet
Periodic Safety Update Report
Standard Deviation
Summary of Product Characteristics
Half-life
Time for maximum concentration
Transmissible Spongiform Encephalopathy
Pharmacopoeia in the United States
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STEPS TAKEN AFTER THE FINALISATION OF THE INITIAL PROCEDURE - SUMMARY
Scope
Procedure
number
Type of
modification
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Date of start
of the
procedure
Date of
end of the
procedure
Approval/
non
approval
Assessment
report
attached
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