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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

anhydrous, magnesium stearate (E572), butyl hydroxytoluene (E321) and pregelatinized starch (maize).

Appropriate justification for the inclusion of each excipient has been provided.

All excipients used comply with their respective European Pharmacopoeia monographs. Satisfactory

Certificates of Analysis have been provided for all excipients showing compliance with their proposed

specifications.

The only excipients used that contain material of animal or human origin are lactose anhydrous and

gelatin. The applicant has provided a declaration that the milk used in the production of lactose

monohydrate is sourced from healthy animals under the same conditions as required for human

consumption. In addition, the supplier has confirmed that no ruminant material other than calf rennet is

used during the production of lactose monohydrate. Satisfactory documentation has also been provided

by the gelatin supplier/s stating that the gelatin they provide complies with the criteria described in the

current version of the monograph ‘Products with risk of transmitting agents of animal spongiform

encephalopathies’. Confirmation has been given that the magnesium stearate used in the tablets is of

vegetable origin.

The finished products are packaged in aluminium/aluminium blisters in cartons containing 2, 4, 6, 12

tablets (70 mg/2800 IU) and 4 tablets (70 mg/5600 IU tablets). Not all pack sizes may be marketed.

Satisfactory specifications and Certificates of Analysis have been provided for all packaging

components. All primary packaging complies with the current European regulations concerning

materials in contact with food.

II.2 Drug Substances

(1) Sodium alendronate trihydrate

rINN: Sodium alendronate trihydrate

Structure:

Molecular formula: C4H12NNaO7P2. 3H2O

Molecular weight: 325.1 g/mol

Appearance: Sodium alendronate trihydrate is a white or almost white crystalline powder.

Solubility: Soluble in water, practically insoluble in methanol and in methylene chloride.

Sodium alendronate trihydrate is the subject of a European Pharmacopoeia monograph.

All aspects of the manufacture and control of the active substance, sodium alendronate trihydrate, are

covered by European Directorate for the Quality of Medicines and Healthcare (EDQM) Certificates of

Suitability.

https://www.pharmacopoeia.com/bp-2016/v3/monographs/images/large/sodium_alendronate_trihydrate_cf1564-b.png?date=2016-04-01


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(2) Cholecalciferol

INN: Cholecalciferol

Chemical name(s): (5Z,7E)-9,10-secocolesta-5,7,10(19)-trien-3β-ol

Structure:

Molecular formula: C27H44O

Molecular weight: 384.6 g/mol

Appearance: White or almost white crystals powder.

Solubility: Practically insoluble in water, freely soluble in ethanol (96 per cent), soluble in

trimethylpentane and saturated fats.

Cholecalciferol is the subject of a European Pharmacopoeia monograph.

All aspects of the manufacture and control of the active substance, cholecalciferol, are covered by

European Directorate for the Quality of Medicines and Healthcare (EDQM) Certificates of

Suitability.

II.3 Medicinal Product

Pharmaceutical Development The objective of the development programme was to formulate safe, efficacious tablets that are generic

products to the reference products Fosavance 70 mg/2800 IU and 70 mg/5600 IU tablets (Merck Sharp

& Dohme Ltd).

Comparative in vitro dissolution profiles have been provided for the proposed and originator products.

Manufacture of the products

Satisfactory batch formulae have been provided for the manufacture of the products, along with an

appropriate account of the manufacturing processes. A validation report for commercial scale batches

has been provided. The process validation data provided is satisfactory.

Finished Product Specification

The finished product specifications proposed are acceptable. The test methods have been described that

have been adequately validated. Batch data have been provided that comply with the release

specification. Certificates of Analysis have been provided for all working standards used.

Stability of the Products

Finished product stability studies were performed in accordance with current guidelines on batches of

finished product in the packaging proposed for marketing. The data from these studies support a

shelf-life of 18 months with storage conditions ‘Store in the original blister in order to protect from

moisture and light’ and ‘Do not store above 25°C’.

.


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Suitable post approval stability commitments have been provided to continue stability testing on batches

of finished product.

II.4 Discussion on chemical, pharmaceutical and biological aspects

The grant of Marketing Authorisations is recommended.

III Non-Clinical Aspects III.1 Introduction

As the pharmacodynamic, pharmacokinetic and toxicological properties of alendronic acid and

cholecalciferol are well-known, no new non-clinical studies are required and none have been provided.

An overview based on the literature review is, thus, appropriate.

The Applicant’s non-clinical expert report has been written by an appropriately qualified person and is

satisfactory, providing an appropriate review of the relevant non-clinical pharmacology,

pharmacokinetics and toxicology.

III.2 Pharmacology

Not applicable for this product type. Refer to section ‘III.1; Introduction’ detailed above.

III.3 Pharmacokinetics


III.4 Toxicology


III.5 Ecotoxicity/environmental risk assessment (ERA)

Since these products are intended for generic substitution, their use will not lead to an increased

exposure to the environment. An environmental risk assessment is therefore not deemed necessary.

III.6 Discussion on the non-clinical aspects

No new non-clinical studies were conducted, which is acceptable given that the applications were based

on being generic medicinal products of the originator products that have been licensed for over 10 years.

There are no objections to the approval of these applications from a non-clinical viewpoint.

IV Clinical Aspects IV.1 Introduction

The clinical pharmacology of alendronic acid and cholecalciferol is well-known. With the exception of

data from the bioequivalence studies detailed below, no new pharmacodynamics or pharmacokinetic

data are provided or are required for this type of applications.

The Applicant submitted two bioequivalence studies in support of these applications in order to

demonstrate bioequivalence with the reference product.

No new efficacy or safety studies have been performed and none are required for this type of

applications. A comprehensive review of the published literature has been provided by the Applicant,

citing the well-established clinical pharmacology, efficacy and safety of alendronic acid and

cholecalciferol.


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Based on the data provided, Alendronic Acid/Cholecalciferol 70 mg/5600 IU tablets can be considered

bioequivalent to Fosavance 70 mg/5600 IU tablets (Merck Sharp & Dohme Ltd). This conclusion also

applies to Alendronic Acid/Cholecalciferol 70 mg/2800 IU Tablets.

IV.2 Pharmacokinetics

In support of these applications, the Applicant submitted two bioequivalence studies, pilot and pivotal.

Pilot bioequivalence study

This is an open-label, randomised, two treatment, two sequence, two period, single oral dose

crossover bioequivalence study comparing the pharmacokinetics of the Applicant’s test product

Alendronic Acid/Cholecalciferol 70 mg/5600 IU tablets versus the reference product, Fosavance 70

mg/5600 IU tablets (Merck Sharp & Dohme Ltd) in healthy adult human volunteers under fasting

conditions.

Blood samples were collected for the measurement of the analytes alendronate and cholecalciferol in

human plasma.

The bioequivalence criteria were met for cholecalciferol, but not for alendronate. This is acceptable for a

pilot study, which is likely to be under-powered.

Pivotal bioequivalence study

This is an open-label, balanced, randomised, two treatment, two sequence, two period, single oral

dose crossover bioequivalence study comparing the pharmacokinetics of the Applicant’s test

product Alendronic Acid/Cholecalciferol 70 mg/5600 IU tablets versus the reference product,

Fosavance 70 mg/5600 IU tablets (Merck Sharp & Dohme Ltd) in healthy adult human volunteers

under fasting conditions.

Blood samples were collected before dosing and up to and including 96 hours after each administration.

The washout period between the treatment phases was 14 days. The pharmacokinetic results are

presented below:

Table 1 Alendronate pharmacokinetic parameters (non-transformed values; arithmetic

mean ± SD, tmax median, range)

*ln-transformed values

Treatment AUC0-t

ng/ml/h

AUC0-∞

ng/ml/h

Cmax

ng/ml

tmax

h Test

173.28 + 94.99 184.48 + 100.26 61.43 + 36.98 1.00 (0.50 – 2.50)

Reference

175.72 + 99.29 187.29 + 105.19 60.84 + 36.75 1.00 (0.50 – 2.00)

*Ratio (90% CI)

101.8

(94.07 – 110.16)

101.9

(94.28 – 110.23)

103.8

(95.23 – 113.14)

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


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Table 2 Cholecalciferol (baseline corrected) pharmacokinetic parameters (non-transformed

values; arithmetic mean ± SD, tmax median, range)

Treatment AUC0-t

ng/ml/h

AUC0-∞

ng/ml/h

Cmax

ng/ml

tmax

h Test

375.71 + 133.56 420.27 + 154.43 10.50 + 3.44 11.00 (8.00 – 18.00)

Reference

392.30 + 133.81 439.00 + 159.14 11.06 + 3.29 10.00 (7.00 – 18.00)

*Ratio (90% CI)

97.2

(91.00 – 103.87)

96.2

(90.00 – 102.78)

95.1

(90.30 – 100.11)

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

variations, PSURs, commitments)

Scope Procedure

number

Product

information

affected

Date of

start of the

procedure

Date of end

of

procedure

Approval/

non

approval

Assessment

report

attached

Y/N

(version)

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