Download Public Assessment Report Scientific discussion AlendroSteo Kit 70

Public Assessment Report
Scientific discussion
AlendroSteo Kit 70 mg + 1000 mg/800 I.E.
tablets + chewable tablets
alendronic acid, calcium carbonate
and colecalciferol
NL/H/2972/001/DC
Date: 23 July 2014
This module reflects the scientific discussion for the approval of AlendroSteo Kit 70
mg + 1000 mg/800 I.E. tablets + chewable tablets. The procedure was finalised on 12
March 2014. For information on changes after this date please refer to the module
‘Update’.
This report includes a summary, on pages 7-9.
I.
INTRODUCTION
Based on the review of the quality, safety and efficacy data, the Member States have granted a
marketing authorisation for AlendroSteo Kit 70 mg + 1000 mg/800 I.E. tablets + chewable tablets, from
Takeda Belgium.
The product is indicated for the treatment of postmenopausal osteoporosis, in patients who are at risk
of a vitamin D and/or calcium deficiency. AlendroSteo Kit 70 mg +1000 mg/800 IU reduces the risk of
vertebral and hip fractures.
A comprehensive description of the indications and posology is given in the SmPC.
AlendroSteo Kit contains 3 active substances: alendronic acid (as sodium alendronate), calcium
carbonate and colecalciferol (vitamin D3).
This decentralised procedure concerns a generic application claiming essential similarity with the
originator product marketed as Alendromed Kit. This reference product has been registered in the
Netherlands by Takeda Belgium since 14 November 2012 by means of a decentralised procedure
(NL/H/2563/001) in accordance with Article 10a in Directive 2001/83/EC, well-established use.
The marketing authorisation for the generic AlendroSteo Kit has been granted pursuant to Article 10(1)
of Directive 2001/83/EC.
The concerned member states (CMS) involved in this procedure were Belgium and Luxembourg.
The MAH claims similarity to the originator/reference product Alendromed Kit, which is also a product
from Takeda Belgium.
To bridge the current application to the reference product, a biowaiver has been submitted, indicating
that the product at issue and the reference product are identical in qualitative and quantitative
composition. The active pharmaceutical ingredient used, the manufacturing process and
manufacturing site for the finished dosage form are the same. A bioavailability study is therefore not
required to demonstrate bioequivalence, and none is provided in this application. These generic
products can be used instead of the reference products.
II.
QUALITY ASPECTS
II.1
Introduction
AlendroSteo Kit is a combination package of two medicinal products: alendronic acid 70 mg tablets
and calcium/vitamin D3 1000 mg/800 IU chewable tablets.
The alendronic acid 70 mg tablets contain 76.188 mg sodium alendronate corresponding to 70 mg
alendronic acid. They are a white to off-white, round tablets, debossed with “A” on one side and “4” on
the other side. The diameter of the tablets is about 11 mm.
The excipients are mannitol (E421), croscarmellose sodium, magnesium stearate, talc, and colloidal
anhydrous silica.
Calcium/vitamin D3 1000 mg/800 I.E. are round, white, uncoated and convex chewable tablets, with a
flavour of lemon. They may have small specks. The diameter of the tablets is about 18 mm.
The excipients are xylitol, lemon flavour granulate, povidone, magnesium stearate and sucralose.
Components of the lemon flavour granulate are lemon flavour, isomalt and mono- and diglycerides of
fatty acid.
A week package (PVC/PE/PVdC/Auminium blister) contains one tablet of Alendratol 70 mg (for one
day per week) and six chewable tablets containing calcium carbonate equivalent to 1000 mg
calcium/colecalciferol 880 IU (for 6 days per week).
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II.2
Drug Substances
The product concerns a combined packaging of two products already registered in the Netherlands,
and contains 3 active substances: alendronate sodium trihydrate, calcium carbonate and colecalciferol
(vitamin D3). All drug substances are well known and described in the European Pharmacopoeia
(Ph.Eur.).
The Active Substance Master File (ASMF) procedure is used for the active substance alendronic acid.
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.
The CEP procedure is used for the active substances calcium carbonate and colecalciferol. Under the
official Certification Procedures of the EDQM of the Council of Europe, manufacturers or suppliers of
substances for pharmaceutical use can apply for a certificate of suitability concerning the control of the
chemical purity and microbiological quality of their substance according to the corresponding specific
monograph, or the evaluation of reduction of Transmissible Spongiform Encephalopathy (TSE) risk,
according to the general monograph, or both. This procedure is meant to ensure that the quality of
substances is guaranteed and that these substances comply with the European Pharmacopoeia.
Details on the active substances of the Alendratol 70 mg tablets and Calci-Chew D3 chewable tablets
are present in the authorised dossiers of the respective drug products and were not assessed as part
of this procedure.
II.3
Medicinal Product
Pharmaceutical development
The pharmaceutical development of the individual drug products was assessed and authorized as part
of the registration procedure for the respective drug products. No additional developmental data are
deemed necessary for the generic combination pack.
Manufacturing process
The manufacturing process of the individual drug products as performed by their respective suppliers
has been assessed and authorized as part of the registration of the respective drug products. For the
proposed product the different tablets are supplied in bulk and are packed in a combination pack. No
process validation data are needed.
Control of excipients
The quality of the excipients was assessed and authorized as part of the registration procedure for the
individual drug products. No additional excipients are included for the combination pack.
Quality control of drug product
The product specifications and analytical procedures for the individual drug products were assessed
and authorized as part of the registration procedure for the respective drug products. No additional
specifications are proposed or needed for the generic combination pack.
Stability of drug product
No stability data are provided for the combination package. The drug products are packed in a
PVC/PE/PVdC-Al blister. Each blister contains one tablet of alendronate 70 mg (day 1) combined with
6 tablets of Calci-Chew D3 1000 mg/800 I.E. (day 2-7). The PVC/PE/PVdC-Aluminium blisters used in
the combination pack are exactly the same as used for the Calci-Chew D3 chewable tablets. The
proposed blister materials are not similar to that of the blister pack authorised for the existing
alendronic acid 70 mg tablets but at least equal to the blister material used for the alendronate 70 mg
tablet in respect to their respective properties. The proposed shelf-life of 24 months and storage
conditions ‘Do not store above 25°C’, ‘Store in the original package in order to protect from moisture’
and ‘Keep blisters in the outer carton in order to protect from light’ are justified as they are stricter than
the conditions registered for the different drug products.
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Specific measures concerning the prevention of the transmission of animal spongiform encephalopathies
The risk of transmitting TSE has been assessed and authorised as part of the registration procedures
of the individual drug products. No additional data is provided or required.
II.4
Discussion on chemical, pharmaceutical and biological aspects
Based on the submitted dossier, the member states consider that AlendroSteo Kit 70 mg + 1000
mg/800 I.E. tablets + chewable tablets has a proven chemical-pharmaceutical quality. Sufficient
controls have been laid down for the active substance and finished product.
The following post-approval commitments were made:
- The MAH commits to place the first three production-scale batches of the combined pack into
the formal stability studies and will submit the results of these studies as soon as available.
III.
III.1
NON-CLINICAL ASPECTS
Ecotoxicity/environmental risk assessment (ERA)
Since AlendroSteo Kit 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 Alendromed Kit, which is available on the European market.
Reference is made tot 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-todate 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 non-clinical studies are required.
IV.
IV.1
CLINICAL ASPECTS
Introduction
Alendronic acid, calcium carbonate and colecalciferol are well-known active substances 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 not performed a bioequivalence study. This is not required,
as the reference product and the product applied for are exactly the same products.
IV.2
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 AlendroSteo Kit.
Summary table of safety concerns as approved in RMP
Important identified risks

Osteonecrosis of the jaw

Atypical femoral fractures

Oesophageal toxicity
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
Gastritis, gastric ulcer, duodenitis

Hypersensitivity and skin reactions
including Stevens-Johnson syndrome
(SJS) and toxic epidermal necrolysis
(TEN)
-----
Important potential risks
Important missing information
IV.3
Discussion on the clinical aspects
For this authorisation, reference is made to the clinical studies and experience with the innovator
product Alendromed Kit. No new clinical studies were conducted. The MAH indicated that the product
is identical to the reference product. Therefore a bioequivalence study is not required.
Risk management is adequately addressed. This generic medicinal product can be used instead of the
reference product.
V.
USER CONSULTATION
A bridging report has been submitted to bridge between the package leaflet (PL) for AlendroSteo Kit
(daughter PL) and the PL for another combination pack containing alendronic acid, calcium carbonate
and colecalciferol (parent PL). The bridging is acceptable, based on the fact that the products contain
the same active substances and have the same indications. Furthermore, since both MAHs belong to
the same mother company, the same lay-out will be used.
VI.
OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND
RECOMMENDATION
AlendroSteo Kit 70 mg + 1000 mg/800 I.E. tablets + chewable tablets has a proven chemicalpharmaceutical quality and is a generic form of Alendromed Kit 70 mg + 1000 mg/800 I.E. tablets +
chewable tablets. Alendromed Kit is a well-known medicinal product with an established favourable
efficacy and safety profile.
A bioequivalence study was not deemed necessary, as the product at issue and the reference product
are identical in qualitative and quantitative composition and manufacturing process.
The SmPC is in line with the SmPC of the reference product Alendromed. The SmPC, 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 member states, on the basis of the data submitted, considered that essential
similarity has been demonstrated for AlendroSteo Kit 70 mg + 1000 mg/800 I.E. tablets + chewable
tablets with the reference product, and have therefore granted a marketing authorisation. The
decentralised procedure was finalised with a positive outcome on 12 March 2014.
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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
Summary Public Assessment Report
Generics
AlendroSteo Kit 70 mg + 1000 mg/800 I.E.
tablets + chewable tablets
(alendronic acid, calcium and vitamin D3)
NL/H/2972/001/DC
Date: 23 July 2014
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Summary Public Assessment Report
Generics
AlendroSteo Kit 70 mg + 1000 mg/800 I.E. tablets + chewable tablets
Active substances: alendronic acid, calcium and vitamin D3
This is a summary of the public assessment report (PAR) for AlendroSteo Kit. It explains how this
medicine was assessed and its authorisation recommended as well as its conditions of use. It is not
intended to provide practical advice on how to use AlendroSteo Kit.
For practical information about using this medicine, patients should read the package leaflet or contact
their doctor or pharmacist.
What is AlendroSteo Kit and what is it used for?
AlendroSteo Kit 70 mg + 1000 mg/800 I.E. is a ‘generic medicine’. This means that it is similar to a
‘reference medicine’ already authorised in the European Union (EU) called Alendromed Kit 70 mg +
1000 mg/800 I.E.
The combination pack AlendroSteo Kit is prescribed for the treatment of osteoporosis, in patients who
also have a calcium and vitamin D deficiency or who have a high risk for such a deficiency.
A treatment with the combination package AlendroSteo does not only prevent bone loss, it also helps
to rebuild bone that is lost. Therefore the risk of spine and hip fractures is reduced.
How is this medicine used?
The medicine can only be obtained with a prescription.
AlendroSteo is a weekly combination therapy. One blister should be used each week. A blister
contains 1 alendronic acid 70 mg tablet and 6 chewable tablets containing calcium as well as Vitamin
D3. On the back of the blister is mentioned when to take which tablet.
The treatment is started with taking 1 tablet alendronic acid 70 mg on day 1. For the next 6 days one
should take 1 chewable tablet calcium/vitamin D3 a day.
On day 8 this sequence starts again with a new blister strip. Therefore, a new blister strip is started on
the same day of each week.
How does this medicine work?
Alendronic acid belongs to a group of medicines called bisphosphonates. This active substance
prevents the loss of bone, and therewith reduces the risk of spine and hip fractures.
The other tablet contains calcium and vitamin D3, which both are important substances in bone
formation. These tablets are used in the prevention and treatment of calcium and vitamin D deficiency,
and as a supplement to specific treatment of osteoporosis. Sufficient intake of calcium and vitamin D
strengthens the bone.
How has this medicine been studied?
The two individual drug products were already authorized as part of the registration procedure for the
respective drug products. Therefore no bioequivalence studies were needed as the composition of
AlendroSteo is identical to that of the reference medicine.
What are the benefits and risks of this medicine?
Because AlendroSteo is identical to the reference medicine, its benefits and risks are taken as being
the same as the reference medicine.
Why is this medicine approved?
It was concluded that, in accordance with EU requirements, AlendroSteo Kit tablets and chewable
tablets have been shown to have comparable quality and the same composition as Alendromed.
Therefore, the view was that, as for Alendromed, the benefit outweighs the identified risk.
What measures are being taken to ensure the safe and effective use of this medicine?
A risk management plan has been developed to ensure that this medicine is used as safely as
possible. Based on this plan, safety information has been included in the summary of product
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characteristics and the package leaflet for AlendroSteo Kit, including the appropriate precautions to be
followed by healthcare professionals and patients.
Other information about this medicine
In the Netherlands, the marketing authorisation for AlendroSteo Kit 70 mg + 1000 mg/800 I.E. tablets
+ chewable tablets was granted on 7 May 2014.
The full PAR for this medicine can be found on the website http://mri.medagencies.org/Human. For
more information about treatment with AlendroSteo Kit, read the package leaflet
(http://mri.medagencies.org/download/NL_H_2972_001_FinalPL.pdf) or contact your doctor or
pharmacist.
This summary was last updated in July 2014.
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