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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
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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PAR Zoledronic Acid 5 mg / 100 ml Solution for Infusion
UK/H/5586/001/DC
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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PAR Zoledronic Acid 5 mg / 100 ml Solution for Infusion
UK/H/5586/001/DC
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
II
III
III.1
III.2
III.3
IV
Introduction
About the product
Scientific overview and discussion
Quality aspects
Non-clinical aspects
Clinical aspects
Overall conclusion and benefit-risk assessment
Module 6: Steps taken after initial procedure
Page 17
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PAR Zoledronic Acid 5 mg / 100 ml Solution for Infusion
UK/H/5586/001/DC
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)
Procedure Number
Austria, Belgium, Bulgaria, Croatia, the Czech
Republic, Germany, Denmark, Finland, France,
Hungary, Ireland, Italy, Luxembourg, the Netherlands,
Norway, Portugal, Spain, Slovakia, Slovenia, Sweden
UK/H/5586/001/DC
Timetable
Day 210 – 27 July 2014
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PAR Zoledronic Acid 5 mg / 100 ml Solution for Infusion
UK/H/5586/001/DC
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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PAR Zoledronic Acid 5 mg / 100 ml Solution for Infusion
UK/H/5586/001/DC
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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PAR Zoledronic Acid 5 mg / 100 ml Solution for Infusion
UK/H/5586/001/DC
Module 4
Labelling
8
PAR Zoledronic Acid 5 mg / 100 ml Solution for Infusion
UK/H/5586/001/DC
9
PAR Zoledronic Acid 5 mg / 100 ml Solution for Infusion
UK/H/5586/001/DC
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PAR Zoledronic Acid 5 mg / 100 ml Solution for Infusion
UK/H/5586/001/DC
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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PAR Zoledronic Acid 5 mg / 100 ml Solution for Infusion
II.
UK/H/5586/001/DC
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)
Pharmacotherapeutic classification
(ATC code)
Pharmaceutical form and strength(s)
Zoledronic acid
Drugs for treatment of bone diseases,
bisphosphonates (M05BA08)
Solution for infusion 5 mg/ 100 ml
Reference numbers for the Decentralised
Procedure
Reference Member State
Member States concerned
UK/H/5586/001/DC
Marketing Authorisation Number(s)
Name and address of the authorisation holder
UK
Austria, Belgium, Bulgaria, Croatia, the
Czech Republic, Germany, Denmark,
Finland, France, Hungary, Ireland, Italy,
Luxembourg, the Netherlands, Norway,
Portugal, Spain, Slovakia, Slovenia,
Sweden
PL 36390/0162
Cipla (EU) Limited
Hillbrow House, Hillbrow Road,
Esher, Surrey, KT10 9NW,
United Kingdom.
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PAR Zoledronic Acid 5 mg / 100 ml Solution for Infusion
UK/H/5586/001/DC
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:
Molecular weight:
Appearance:
Solubility:
C5H10N2O7P2.H2O
290.11
White to off white powder (white crystalline powder)
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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PAR Zoledronic Acid 5 mg / 100 ml Solution for Infusion
UK/H/5586/001/DC
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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PAR Zoledronic Acid 5 mg / 100 ml Solution for Infusion
UK/H/5586/001/DC
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 physicochemical characteristics between Zoledronic Acid 5 mg/100 ml Solution for Infusion and its respective
reference product.
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PAR Zoledronic Acid 5 mg / 100 ml Solution for Infusion
UK/H/5586/001/DC
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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PAR Zoledronic Acid 5 mg / 100 ml Solution for Infusion
UK/H/5586/001/DC
Module 6
STEPS TAKEN AFTER INITIAL PROCEDURE - SUMMARY
Date
submitted
Application
type
Scope
Outcome
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