Public Assessment Report - Medicines and … · Public Assessment Report Decentralised Procedure...

Public Assessment Report

Decentralised Procedure

ZOLEDRONIC ACID 5 MG/100 ML SOLUTION FOR INFUSION

(zoledronic acid)

Procedure No: UK/H/5586/001/DC

UK Licence No: PL 36390/0162

Cipla (EU) Limited

PAR Zoledronic Acid 5 mg / 100 ml Solution for Infusion UK/H/5586/001/DC

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LAY SUMMARY Zoledronic Acid 5 mg/100 ml Solution for Infusion

(zoledronic acid)

This is a summary of the public assessment report (PAR) for Zoledronic Acid 5 mg/100 ml Solution for

Infusion (PL 36390/0162). It explains how Zoledronic Acid 5 mg/100 ml Solution for Infusion 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 Zoledronic Acid 5 mg/100 ml Solution for Infusion.

For practical information about using Zoledronic Acid 5 mg/100 ml Solution for Infusion, patients

should read the Patient Information Leaflet or contact their doctor or pharmacist.

What is Zoledronic Acid 5 mg/100 ml Solution for Infusion and what is it used for?

Zoledronic Acid 5 mg/100 ml Solution for Infusion is a ‘generic medicine’. This means that Zoledronic

Acid 5 mg/100 ml Solution for Infusion is similar to a ‘reference medicine’ already authorised in the

European Union (EU) called Aclasta 5 mg/100 ml Solution for Infusion.

Zoledronic Acid 5 mg/100 ml Solution for Infusion is used to treat Paget’s disease of the bone in adults.

How does Zoledronic Acid 5 mg/100 ml Solution for Infusion work?

The active substance in Zoledronic Acid 5 mg/100 ml Solution for Infusion, zoledronic acid, belongs to

a group of medicines known as bisphosphates. This medicine is used in the treatment of Paget’s disease

of the bone in adults. Paget’s disease is a long-term disease where the normal process of bone growth

(remodelling) is altered, and bone remodelling is too rapid and new bone is formed in a disordered

fashion, causing the bones to be weaker than normal. Zoledronic acid works by returning the bone

remodelling process to normal, securing formation of normal bone, thus restoring strength to the bone.

How is Zoledronic Acid 5 mg/100 ml Solution for Infusion used?

Zoledronic Acid 5 mg/100 ml Solution for Infusion is administered into a vein by the doctor or nurse.

Zoledronic Acid 5 mg/100 ml Solution for Infusion is given as one infusion, lasting at least 15 minutes.

An additional infusion, given at least one year after the first one, can be considered if the disease comes

back. The doctor may advise that calcium and vitamin D supplements are taken at least for the first ten

days after being given this medicine.

This medicine is a prescription only medicine.

Please read Section 3 of the Patient Information Leaflet for detailed information on dosing

recommendations, the route of administration and the duration of treatment.

What benefits of Zoledronic Acid 5 mg/100 ml Solution for Infusion have been shown in studies?

No additional studies were needed as Zoledronic Acid 5 mg/100 ml Solution for Infusion as it is a

generic medicine that is given by infusion and contains the same active substance as the reference

medicine, Aclasta 5 mg/100 ml Solution for Infusion.

What are the possible side effects of Zoledronic Acid 5 mg/100 ml Solution for Infusion?

Because Zoledronic Acid 5 mg/100 ml Solution for Infusion is a generic medicine and contains the same

active substance as the reference medicine, its benefits and possible side effects are taken as being the

same as the reference medicine.


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For the full list of side effects, see the Patient Information Leaflet.

Why is Zoledronic Acid 5 mg/100 ml Solution for Infusion approved?

It was concluded that, in accordance with EU requirements, Zoledronic Acid 5 mg/100 ml Solution for

Infusion has been shown to have comparable quality and to be comparable to the reference medicine;

Aclasta 5 mg/100 ml Solution for Infusion. Therefore, it was decided that, as for Aclasta 5 mg/100 ml

Solution for Infusion, the benefits are greater than its risk and recommended that it can be approved for

use in the treatment of Paget’s disease of the bone in adults.

What measures are being taken to ensure the safe and effective use of Zoledronic Acid 5 mg/100

ml Solution for Infusion?

A risk management plan has been developed to ensure that Zoledronic Acid 5 mg/100 ml Solution for

Infusion is used as safely as possible. Based on this plan, safety information has been included in the

Summary of Product Characteristics and the Patient Information Leaflet for Zoledronic Acid 5 mg/100

ml Solution for Infusion, 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/healthcare professionals will be reviewed continuously as well.

Other information about Zoledronic Acid 5 mg/100 ml Solution for Infusion

Austria, Belgium, Bulgaria, Croatia, the Czech Republic, Germany, Denmark, Finland, France,

Hungary, Ireland, Italy, Luxembourg, the Netherlands, Norway, Portugal, Spain, Slovakia, Slovenia,

Sweden and the United Kingdom (UK) agreed to grant a Marketing Authorisation for Zoledronic Acid 5

mg/100 ml Solution for Infusion on 27 July 2014. Following a subsequent national phase, a Marketing

Authorisation was granted in the UK on 21 August 2014.

The full PAR for Zoledronic Acid 5 mg/100 ml Solution for Infusion follows this summary. For more

information about treatment with Zoledronic Acid 5 mg/100 ml Solution for Infusion, read the Patient

Information Leaflet or contact your doctor or pharmacist.

This summary was last updated in October 2014.


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TABLE OF CONTENTS

Module 1: Information about initial procedure Page 5

Module 2: Summary of Product Characteristics Page 6

Module 3: Patient Information Leaflet Page 7

Module 4: Labelling Page 8

Module 5: Scientific discussion during initial procedure Page 11

I Introduction

II About the product

III Scientific overview and discussion

III.1 Quality aspects

III.2 Non-clinical aspects

III.3 Clinical aspects

IV Overall conclusion and benefit-risk assessment

Module 6: Steps taken after initial procedure Page 17


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Module 1

Information about initial procedure

Product Name

Zoledronic Acid 5 mg/100 ml Solution for Infusion

Type of Application

Generic, Article 10(1)

Active Substances

Zoledronic acid

Form

Solution for infusion

Strength

5 mg/100 ml

MA Holder

Cipla (EU) Limited

Hillbrow House, Hillbrow Road,

Esher, Surrey, KT10 9NW,

United Kingdom

Reference Member State (RMS)

UK

Concerned Member States

(CMS)

Austria, Belgium, Bulgaria, Croatia, the Czech

Republic, Germany, Denmark, Finland, France,

Hungary, Ireland, Italy, Luxembourg, the Netherlands,

Norway, Portugal, Spain, Slovakia, Slovenia, Sweden

Procedure Number

UK/H/5586/001/DC

Timetable

Day 210 – 27 July 2014


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Module 2

Summary of Product Characteristics

In accordance with Directive 2010/84/EU the Summary of Product Characteristics (SmPC) for products

that have been granted Marketing Authorisations at a national level are available on the MHRA website.


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Module 3

Patient Information Leaflet

In accordance with Directive 2010/84/EU the Patient Information Leaflet for products that are granted

Marketing Authorisations at a national level are available on the MHRA website.


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Module 4

Labelling


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Module 5

Scientific discussion during initial procedure

I INTRODUCTION

Based on the review of the data on quality, safety and efficacy, the Member States considered that the

application for Zoledronic Acid 5 mg/100 ml Solution for Infusion (PL 36390/0162;

UK/H/5586/001/DC) could be approved. The application was submitted via the Decentralised

Procedure, with the UK as Reference Member State (RMS), and Austria, Belgium, Bulgaria, Croatia, the

Czech Republic, Germany, Denmark, Finland, France, Hungary, Ireland, Italy, Luxembourg, the

Netherlands, Norway, Portugal, Spain, Slovakia, Slovenia, Sweden as Concerned Member States

(CMS).

The application was submitted under Article 10(1) of Directive 2001/83/EC, as amended, claiming to be

a generic medicinal product of the reference medicinal product; Aclasta 5mg/100 ml Solution for

Infusion. Aclasta 5 mg/100 ml Solution for Infusion was granted a Marketing Authorised on 15 April

2005 to Novartis Europharm Limited via the centralised procedure (EU/1/05/308/001-002). The

originator product is Zometa 4 mg powder and solvent for Solution for Infusion (Novartis Europharm

Limited), which was initially, granted a marketing authorisation in the EU, via the Centralised

Procedure, on 20 March 2001.

Zoledronic Acid 5 mg/100 ml Solution for Infusion is a prescription-only medicine (legal classification

POM), used in the treatment of Paget's disease of the bone in adults. The product is a solution for

infusion and contains the active substance zoledronic acid (as monohydrate).

Zoledronic acid belongs to the class of nitrogen-containing bisphosphonates and acts primarily on bone.

It is an inhibitor of osteoclast-mediated bone resorption. The selective action of bisphosphonates on

bone is based on their high affinity for mineralised bone.

The main molecular target of zoledronic acid in the osteoclast is the enzyme farnesyl pyrophosphate

synthase. The long duration of action of zoledronic acid is attributable to its high binding affinity for the

active site of farnesyl pyrophosphate (FPP) synthase and its strong binding affinity to bone mineral.

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

on being a generic medicinal product of the reference product that has been licensed for over 10 years.

As per Guideline on the Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev. 1/ Corr **)

no bioequivalence studies or any other new clinical studies are required for this application.

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 the product.

The RMS and CMS’s considered that this application could be approved at the end of procedure (Day

210) on 27 July 2014. Following a subsequent national phase, a Marketing Authorisation was granted in

the UK on 21 August 2014.


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II. ABOUT THE PRODUCT

Name of the product in the Reference Member

State

Zoledronic Acid 5 mg/100 ml Solution

for Infusion.

Name(s) of the active substance(s) (INN) Zoledronic acid

Pharmacotherapeutic classification

(ATC code)

Drugs for treatment of bone diseases,

bisphosphonates (M05BA08)

Pharmaceutical form and strength(s) Solution for infusion 5 mg/ 100 ml

Reference numbers for the Decentralised

Procedure

UK/H/5586/001/DC

Reference Member State UK

Member States concerned Austria, Belgium, Bulgaria, Croatia, the

Czech Republic, Germany, Denmark,

Finland, France, Hungary, Ireland, Italy,

Luxembourg, the Netherlands, Norway,

Portugal, Spain, Slovakia, Slovenia,

Sweden

Marketing Authorisation Number(s)

PL 36390/0162

Name and address of the authorisation holder Cipla (EU) Limited

Hillbrow House, Hillbrow Road,

Esher, Surrey, KT10 9NW,

United Kingdom.


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III SCIENTIFIC OVERVIEW AND DISCUSSION

III.1 QUALITY ASPECTS

S. Active substance – Zoledronic Acid

rINN: Zoledronic Acid

Chemical name: (1-Hydroxy-2-imidazol-1-yl-phosphonoethyl) phosphonic acid

monohydrate

or

[l -hydroxy-2-(1 H-imidazol- 1 -yl) ethylidene]bisphosphonic acid

monohydrate

Structure:

Molecular formula: C5H10N2O7P2.H2O Molecular weight: 290.11

Appearance: White to off white powder (white crystalline powder)

Solubility: Sparingly soluble in 2M Sodium Hydroxide

Synthesis of the active substance from the designated starting material has been adequately described,

and appropriate in-process controls and intermediate specifications are applied. Satisfactory

specification tests are in place for all starting materials and reagents, and these are supported by relevant

certificates of analysis.

Appropriate proof-of-structure data has been supplied for the active pharmaceutical ingredient. All

potential known impurities have been identified and characterised.

Appropriate specifications are provided for the active substance zoledronic acid, with suitable test

methods and limits. The methods of testing and limits for residual solvents are in compliance with

current guidelines. Batch analysis data are provided and comply with the proposed specifications.

Suitable certificates of analysis have been provided for all reference standards used.


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Satisfactory specifications have been provided for all packaging used for storing the active substance,

zoledronic acid. The primary packaging has been shown to comply with current legislation concerning

materials in contact with foodstuff.

Appropriate stability data have been generated showing the active substance to be physically and

chemically stable. A suitable retest period has been set based on stability data submitted for the active

substance stored in the proposed packaging.

P. Medicinal Product

Other Ingredients

Other ingredients consist of the pharmaceutical excipients, as follows:

Mannitol (E421), sodium citrate (E331), water for injections and nitrogen gas.

All excipients, with the exception of nitrogen gas, comply with their respective European

Pharmacopoeia monographs. The nitrogen gas conforms to its in-house specifications.

None of the excipients are sourced from animal or human origin. No genetically modified organisms

(GMO) have been used in the preparation of this product.

Pharmaceutical Development

The objective of the development programme was to formulate a globally acceptable, stable solution for

infusion that could be considered a generic medicinal product of the reference product, Aclasta 5

mg/100 ml Solution for (Novartis Europharma Limited).

A satisfactory account of the pharmaceutical development has been provided.

Pharmaceutical equivalence has been demonstrated based on the comparability of the physico-chemical

characteristics of this product versus the respective reference product.

Manufacturing Process

A satisfactory batch formula has been provided for the manufacture of the product, along with an

appropriate account of the manufacturing process. Suitable in-process controls are in place to ensure the

quality of the finished product.

Process validation has been carried out on three commercial-scale batches of the finished product. The

results are satisfactory.

Finished Product Specification

The finished product specification proposed is acceptable. Test methods have been described and have

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

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

Container-Closure System

The finished product is supplied in transparent plastic (cyclo olefinic polymer) bottle closed with a

fluoro-polymer coated chlorobutyl rubber stopper and an aluminium/polypropylene cap with a flip

component.

Zoledronic Acid 5 mg / 100 ml Solution for Infusion is supplied in packs containing one bottle as unit

pack or in multi-packs comprising 5 packs, each containing 1 bottle.

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

components.


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Stability of the product

Stability studies were performed, in accordance with current guidelines on batches of finished product

manufactured by the finished product manufacturer and packed in the packaging proposed for

marketing. The results from these studies support a shelf-life of 24 months for the unopened vials. This

medicinal product does not require any special storage conditions

Bioequivalence/bioavailability

A bioequivalence study is not required for an application of this type as per Guideline on the

Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev. 1/ Corr **). Therapeutic equivalence

has been demonstrated successfully through the comparable physico-chemical characteristics between

Zoledronic Acid 5 mg/100 ml Solution for Infusion and the respective reference product.

Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and Labels The SmPC, PIL and labels are acceptable from a pharmaceutical perspective.

A Patient Information Leaflet has been submitted to the MHRA along with results of consultations with

target patient groups (“user testing”), in accordance with Article 59 of Council Directive 2001/83/EC, as

amended. The results indicate that the package leaflet is well-structured and organised, easy to

understand and written in a comprehensive manner. The test shows that the patients/users are able to act

upon the information that it contains.

Marketing Authorisation Application (MAA) form

The MAA form is satisfactory from a pharmaceutical perspective.

Quality Overall Summary (Expert report)

The pharmaceutical expert report has been written by an appropriately qualified person and is a suitable

summary of the pharmaceutical dossier.

Conclusion

The grant of a Marketing Authorisation is recommended.

III.2 NON-CLINICAL ASPECTS

As the pharmacodynamic, pharmacokinetic and toxicological properties of zoledronic acid are

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

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

satisfactory, providing an appropriate review of the product’s pharmacology and toxicology.

Suitable justification has been provided for the non-submission of an Environmental Risk Assessment.

As this product is intended for generic substitution with products that are currently marketed, no

increase in environmental burden is expected.

There are no objections to the approval of this product from a non-clinical viewpoint.

III.3 CLINICAL ASPECTS

Pharmacokinetics and Pharmacodynamics

As per Guideline on the Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev. 1/ Corr **)

no new pharmacokinetic/pharmacodynamic data have been submitted with this application and none are

required. Therapeutic equivalence has been demonstrated successfully through the comparable physico-

chemical characteristics between Zoledronic Acid 5 mg/100 ml Solution for Infusion and its respective

reference product.


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Efficacy

No new data on efficacy have been submitted and none are required for an application of this type.

Safety

No new safety data were submitted and none were required. No new or unexpected safety issues arose

from this application.

SmPC, PIL and Labels

The SmPC, PIL and labels are acceptable from a clinical perspective.

Pharmacovigilance System and Risk Management Plan

The Pharmacovigilance System, as described by the applicant, fulfils the requirements and provides

adequate evidence that the applicant has the services of a qualified person responsible for

pharmacovigilance, and has the necessary means for the notification of any adverse reaction suspected

of occurring either in the Community or in a third country.

A risk management plan has been developed to ensure that Zoledronic Acid 5 mg/100 ml Solution for

Infusion is used as safely as possible. Based on this plan, safety information has been included in the

Summary of Product Characteristics and the Patient Information Leaflet for Zoledronic Acid 5 mg/100

ml Solution for Infusion, including the appropriate precautions to be followed by healthcare

professionals and patients.

Clinical Expert Report

The clinical expert report has been written by an appropriately qualified physician and is a suitable

summary of the clinical aspects of the dossier.

Conclusion

The grant of a Marketing Authorisation is recommended.

IV OVERALL CONCLUSION AND BENEFIT-RISK ASSESSMENT

QUALITY

The important quality characteristics of Zoledronic Acid 5 mg/100 ml Solution for Infusion are

well-defined and controlled. The specifications and batch analytical results indicate consistency from

batch to batch. There are no outstanding quality issues that would have a negative impact on the

benefit-risk balance.

NON-CLINICAL

No new non-clinical data were submitted and none are required for an application of this type.

CLINICAL

Therapeutic equivalence has been demonstrated successfully through the comparable physico-chemical

characteristics between Zoledronic Acid 5 mg / 100 ml Solution for Infusion and its respective reference

product. No new or unexpected safety concerns arose from this application.

The SmPC, PIL and labels are satisfactory and consistent with those for the reference product.

BENEFIT-RISK ASSESSMENT

The quality of the product is acceptable, and no new non-clinical or clinical safety concerns have been

identified. Therapeutic equivalence has been demonstrated between the applicant’s product and the

respective reference product. Extensive clinical experience with zoledronic acid is considered to have

demonstrated the therapeutic value of the compound. The benefit-risk assessment is, therefore,

considered to be positive.


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Module 6

STEPS TAKEN AFTER INITIAL PROCEDURE - SUMMARY

Date

submitted

Application

type

Scope Outcome

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