PAR Alendronic Acid/Cholecalciferol 70 mg/2800 IU and 70 mg/5600 IU tablets UK/H/6228/001-2/DC 1 Public Assessment Report Decentralised Procedure Alendronic Acid/Cholecalciferol 70 mg/2800 IU tablets Alendronic acid/Cholecalciferol 70 mg/5600 IU tablets (Alendronic acid and cholecalciferol) Procedure No: UK/H/6228/001-2/DC UK Licence No: PL 33561/0008-9 DOC GENERICI SRL
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PAR Alendronic Acid/Cholecalciferol 70 mg/2800 IU and 70 mg/5600 IU tablets UK/H/6228/001-2/DC
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Public Assessment Report
Decentralised Procedure
Alendronic Acid/Cholecalciferol 70 mg/2800 IU tablets
Alendronic acid/Cholecalciferol 70 mg/5600 IU tablets
(Alendronic acid and cholecalciferol)
Procedure No: UK/H/6228/001-2/DC
UK Licence No: PL 33561/0008-9
DOC GENERICI SRL
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LAY SUMMARY Alendronic Acid/Cholecalciferol 70 mg/2800 IU tablets
Alendronic acid/Cholecalciferol 70 mg/5600 IU tablets
(Alendronic acid and cholecalciferol)
This is a summary of the Public Assessment Report (PAR) for Alendronic Acid/Cholecalciferol 70
mg/2800 IU and 70 mg/5600 IU tablets (PL 33561/0008-9; UK/H/6228/01-2/DC). It explains how
Alendronic Acid/Cholecalciferol 70 mg/2800 IU and 70 mg/5600 IU tablets were assessed and their
authorisation recommended, as well as the conditions of use. It is not intended to provide practical
advice on how to use Alendronic Acid/Cholecalciferol 70 mg/2800 IU and 70 mg/5600 IU tablets.
These medicinal products will be referred to as Alendronic Acid/Cholecalciferol Tablets in the
remainder of the lay summary for ease of reading.
For practical information about using Alendronic Acid/Cholecalciferol Tablets, patients should read the
package leaflet or contact their doctor or pharmacist.
What are Alendronic Acid/Cholecalciferol Tablets and what are they used for?
Alendronic Acid/Cholecalciferol Tablets are ‘generic medicines’. This means that these products are
similar to ‘reference medicines’, already authorised in the EU called Fosavance 70 mg/2800 IU Tablets
(EU/1/05/310/001-004) and Fosavance 70 mg/5600 IU tablets (EU/1/05/310/006-008).
Alendronic Acid/Cholecalciferol Tablets are used to treat osteoporosis (thining of the bone) in patients
who are at risk of vitamin D insufficiency. This medicine is also used to reduce the risk of spine and hip
fractures in women after menopause.
How do Alendronic Acid/Cholecalciferol Tablets work?
Alendronic acid/Cholecalciferol tablets contain two active ingredients, alendronic acid (commonly
called alendronate) and cholecalciferol known as vitamin D3.
Alendronate belongs to a group of non-hormonal medicines called bisphosphonates. Alendronate
prevents the loss of bone that occurs in women after they have been through the menopause, and helps to
rebuild bone. Vitamin D3 helps the body to absorb calcium and enhances bone formation.
How are Alendronic Acid/Cholecalciferol Tablets used?
Alendronic Acid/Cholecalciferol Tablets are taken by mouth. The whole tablet should be swallowed
with a full glass of water (not less than 200 ml). The tablets must not be crushed or chewed. Patients
must wait at least 30 minutes before taking their first food, drink or other medicine of the day.
The recommended dose of Alendronic Acid/Cholecalciferol Tablet is once a week.
Alendronic Acid/Cholecalciferol Tablets can only be obtained on prescription from a doctor.
For further information on how Alendronic Acid/Cholecalciferol Tablets are used, please see the
Summaries of Product Characteristics and package leaflet available on the MHRA website.
How have Alendronic Acid/Cholecalciferol Tablets been studied?
Because Alendronic Acid/Cholecalciferol Tablets are generic medicines, studies in patients have been
limited to tests to determine that they are bioequivalent to the reference medicines, Fosavance 70
mg/2800 IU and 70 mg/5600 IU tablets. Two medicines are bioequivalent when they produce the same
levels of the active substance in the body.
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What are the benefits and risks of Alendronic Acid/Cholecalciferol Tablets?
Because Alendronic Acid/Cholecalciferol Tablets are generic medicines, and are bioequivalent to the
reference medicines, Fosavance 70 mg/2800 IU and 70 mg/5600 IU tablets, their benefits and risks are
taken as being the same as the reference medicines.
Why are Alendronic Acid/Cholecalciferol Tablets approved?
It was concluded that, in accordance with EU requirements, Alendronic Acid/Cholecalciferol Tablets
have been shown to have comparable quality and to be bioequivalent to Fosavance 70 mg/2800 IU and
70 mg/5600 IU tablets. Therefore, the view was that, as for Fosavance 70 mg/2800 IU and 70 mg/5600
IU tablets, the benefits outweigh the identified risks.
What measures are being taken to ensure the safe and effective use of Alendronic
Acid/Cholecalciferol Tablets?
A risk management plan has been developed to ensure that Alendronic Acid/Cholecalciferol Tablets are
used as safely as possible. Based on this plan, safety information has been included in the Summaries of
Product Characteristics (SmPC) and the package leaflet for Alendronic Acid/Cholecalciferol Tablets,
including the appropriate precautions to be followed by healthcare professionals and patients.
Known side effects are continuously monitored. Furthermore new safety signals reported by patients and
healthcare professionals will be monitored and reviewed continuously as well.
Other information about Alendronic Acid/Cholecalciferol Tablets
Italy and the UK agreed to grant Marketing Authorisations for Alendronic Acid/Cholecalciferol Tablets
on 24 February 2017. Marketing Authorisations was granted in the UK on 24 March 2017.
The full PAR for Alendronic Acid/Cholecalciferol Tablets follows this summary.
This summary was last updated in May 2017.
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TABLE OF CONTENTS
I Introduction Page 5
II Quality aspects Page 7
III Non-clinical aspects Page 9
IV Clinical aspects Page 9
V User consultation Page 20
VI Overall conclusion, benefit/risk assessment and Page 20
recommendation
Table of content of the PAR update for MRP and DCP Page 28
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I INTRODUCTION Based on the review of the data on quality, safety and efficacy the Member States considered that the
applications for Alendronic Acid/Cholecalciferol 70 mg/2800 IU and 70 mg/5600 IU tablets (PL
33561/0008-9; UK/H/6228/01-2/DC), are approvable. Alendronic Acid/Cholecalciferol 70 mg/2800 IU
and 70 mg/5600 IU tablets are prescription only medicines (POM), indicated:
70 mg/ 2800 IU strength
- For the treatment of postmenopausal osteoporosis in women at risk of vitamin D insufficiency.
Alendronic Acid/Cholecalciferol reduces the risk of vertebral and hip fractures.
70 mg/ 5600 IU strength
- For the treatment of postmenopausal osteoporosis in women who are not receiving vitamin D
supplementation and are at risk of vitamin D insufficiency. Alendronic acid/Cholecalciferol
reduces the risk of vertebral and hip fractures.
The applications were submitted using the Decentralised Procedure (DCP), with the UK as Reference
Member State (RMS), and Italy as Concerned Member State (CMS). The applications were submitted
under Article 10(1) of Directive 2001/83/EC, as amended, as generic applications. The applicant has
cross-referred to Fosavance 70 mg/2800 IU Tablets (EU/1/05/310/001-004) and Fosavance 70 mg/5600
IU tablets (EU/1/05/310/006-008) authorised to Merck Sharp & Dohme Ltd since 24 August 2005 via a
centralised procedure.
Alendronate sodium is a bisphosphonate that inhibits osteoclastic bone resorption with no direct effect
on bone formation. Preclinical studies have shown preferential localisation of alendronate to sites of
active resorption. Activity of osteoclasts is inhibited, but recruitment or attachment of osteoclasts is not
affected. The bone formed during treatment with alendronate is of normal quality.
Vitamin D3 is produced in the skin by conversion of 7-dehydrocholesterol to vitamin D3 by ultraviolet
light. In the absence of adequate sunlight exposure, vitamin D3 is an essential dietary nutrient. Vitamin
D3 is converted to 25-hydroxyvitamin D3 in the liver, and stored until needed. Conversion to the active
calcium-mobilizing hormone 1,25-dihydroxyvitamin D3 (calcitriol) in the kidney is tightly regulated.
The principal action of 1,25-dihydroxyvitamin D3 is to increase intestinal absorption of both calcium and
phosphate as well as regulate serum calcium, renal calcium and phosphate excretion, bone formation and
bone resorption.
Vitamin D3 is required for normal bone formation. Vitamin D insufficiency develops when both sunlight
exposure and dietary intake are inadequate. Insufficiency is associated with negative calcium balance,
bone loss, and increased risk of skeletal fracture. In severe cases, deficiency results in secondary
hyperparathyroidism, hypophosphataemia, proximal muscle weakness and osteomalacia, further
increasing the risk of falls and fractures in osteoporotic individuals. Supplemental vitamin D reduces
these risks and their consequences.
Osteoporosis is defined as bone mineral density (BMD) of the spine or hip 2.5 standard deviations (SD)
below the mean value of a normal young population or as a previous fragility fracture, irrespective of
BMD.
No new non-clinical studies were conducted, which is acceptable given that the applications were based
on being generic medicinal products of originator products that have been licensed for over 10 years.
With the exception of two bioequivalence studies, no new clinical data were provided with these
applications. A pilot and pivotal bioequivalence studies were submitted to support the applications
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comparing the applicant’s test product Alendronic acid/Choleclaciferol 70 mg/5600 IU tablet with the
reference product Fosavance 70 mg/5600 IU tablets (Merck Sharp & Dohme Ltd) in healthy adult
human volunteers, under fasting conditions. The bioequivalence studies were conducted in line with
current Good Clinical Practice (GCP).
A summary of the pharmacovigilance system and a detailed risk management plan have been provided
with these applications and these are satisfactory.
The RMS has been assured that acceptable standards of Good Manufacturing Practice are in place for
this product type at all sites responsible for the manufacture, assembly and batch release of these
products.
For manufacturing sites within the Community, the RMS has accepted copies of current manufacturing
authorisations issued by inspection services of the competent authorities as certification that acceptable
standards of GMP are in place at those sites.
All Member States agreed to grant Marketing Authorisations for the above products at the end of the
procedure (Day 194 – 24 February 2017). After a subsequent national phase, the UK granted Marketing
Authorisations (PL 33561/0008-0009) for these products on 24 March 2017.
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II QUALITY ASPECTS II.1 Introduction
The finished products are tablets, containing 70 mg alendronic acid as alendronate sodium trihydrate,
and 70 micrograms (2800 IU) cholecalciferol (vitamin D3) or 140 micrograms (5600 IU) cholecalciferol
(vitamin D3), as active ingredients. The excipients present are microcrystalline cellulose (E460), lactose
anhydrous, medium chain triglycerides, gelatin, croscarmellose sodium, sucrose, silica, colloidal
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
PAR Alendronic Acid/Cholecalciferol 70 mg/2800 IU and 70 mg/5600 IU tablets UK/H/6228/001-2/DC
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
The 90% confidence intervals of the test/reference ratio for ln-transformed AUC0-t and Cmax for
alendronic acid and cholecalciferol, lie within the acceptable limits of 80.00% to 125.00%, in line with
the ‘Guideline on the Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev 1/Corr**). Thus,
the data support the claim that the Applicant’s test products are bioequivalent to the reference products.
Satisfactory justification is provided for a bio-waiver for the applicant’s lower strength tablets. As
Alendronic Acid/Cholecalciferol 70 mg/2800 IU and 70 mg/5600 IU tablets meet the criteria specified in
the “Guideline on the Investigation of Bioequivalence” (CPMP/EWP/QWP/1401/98 Rev 1/Corr**), the
results and conclusions of the bioequivalence studies for the 70 mg/5600 IU formulation can be
extrapolated to the other strength, i.e. 70 mg/2800 IU tablets.
IV.3 Pharmacodynamics
No new pharmacodynamics data were submitted and none were required for applications of this type.
IV.4 Clinical efficacy
No new efficacy data were submitted and none were required for applications of this type.
IV.5 Clinical safety
No new clinical safety data are required for these applications and none have been submitted.
IV.6 Risk Management Plan (RMP) and Pharmacovigilance system
The Marketing Authorisation Holder (MAH) has submitted an RMP, 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 Alendronic
Acid/Cholecalciferol 70 mg/2800 IU and 70 mg/5600 IU tablets.
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A summary of safety concerns and planned risk minimisation activities, as approved in the RMP,
is listed below:
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Routine pharmacovigilance and routine risk minimisation are proposed for all safety concerns.
IV.7 Discussion on the clinical aspects
The grant of Marketing Authorisations is recommended.
V User consultation User testing of the package leaflet has been accepted, based on bridging reports provided by the
applicant making reference to the user-testing of the PIL for Fosavance 70 mg/2800 IU and 70 mg/5600
IU tablets (Merck Sharp & Dohme Ltd). The products are from the same therapeutic class and have
similar indications. A critical analysis demonstrated that the key messages for safe and effective use for
both leaflets were similar. The justification on the rationale for bridging is accepted.
IV OVERALL CONCLUSION AND BENEFIT-RISK ASSESSMENT AND
RECOMMENDATION
The quality of the products is acceptable, and no new non-clinical or clinical concerns have been
identified. The data provided by the applicant showed that the products are bioequivalent to the
authorised reference products. Extensive clinical experience with alendronic acid and cholecalciferol is
considered to have demonstrated the therapeutic value of the compounds. The benefit-risk assessment is,
therefore, considered to be positive.
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Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and labelling
In accordance with Directive 2010/84/EU the Summaries of Product Characteristics (SmPCs) and
Patient Information Leaflets (PILs) for products that are granted Marketing Authorisations at a national
level are available on the MHRA website.
The approved labelling for Alendronic Acid/Cholecalciferol 70 mg/2800 IU and 70 mg/5600 IU
tablets is presented below:
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Table of content of the PAR update for MRP and DCP
Steps taken after the initial procedure with an influence on the Public Assessment Report (Type II