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Public Assessment Report
Decentralised Procedure
Ganciclovir 500 mg powder for solution for infusion
Procedure No: UK/H/5148/001/DC
UK Licence No: PL 28176/0139
Strides Arcolab International Limited
Ganciclovir 500 mg powder for solution for infusion
UK/H/5148/001/DC
LAY SUMMARY
Ganciclovir 500 mg powder for solution for infusion
(ganciclovir sodium)
This is a summary of the public assessment report (PAR) for Ganciclovir 500 mg powder for
solution for infusion (PL 28176/0139; UK/H/5148/001/DC). It explains how Ganciclovir 500
mg powder for 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
Ganciclovir 500 mg powder for solution for infusion.
For practical information about using Ganciclovir 500 mg powder for solution for infusion,
patients should read the patient information leaflet (PIL) or contact their doctor or
pharmacist.
What is Ganciclovir 500 mg powder for solution for infusion and what is it used for?
Ganciclovir 500 mg powder for solution for infusion is a ‘generic medicine’. This means that
it is similar to a ‘reference medicine’, already authorised in the European Union (EU) called
Cymevene powder for solution for infusion.
In patients with acquired immunodeficiency syndrome (AIDS) Ganciclovir 500 mg powder
for solution for infusion is used to treat infections caused by a virus called cytomegalovirus
(CMV). This medicine is also used to prevent CMV infection after an organ transplant.
How does Ganciclovir 500 mg powder for solution for infusion work?
Ganciclovir 500 mg powder for solution for infusion contains the active substance
ganciclovir (as ganciclovir sodium), which belongs to a group of medicines called ‘antivirals’. This active substance works by inhibiting enzymes that allow the virus to replicate.
How is Ganciclovir 500 mg powder for solution for infusion used?
Before Ganciclovir powder for solution for infusion can be used it must be dissolved in a
sterile infusion liquid. Usually this is done in a pharmacy or a hospital. A doctor or nurse will
administer this dissolved sterile solution into the patient’s vein through a small tube (a
process called ‘intravenous infusion’). This medicine will be given to the patient gradually,
over the course of an hour. The dose, determined by the doctor, will vary from one patient to
another, and will depend on the patient’s age, weight, how well their kidneys are working,
and what the medicine is treating.
Ganciclovir powder for solution for infusion can only be obtained with a prescription.
How has Ganciclovir 500 mg powder for solution for infusion been studied?
No additional studies were needed as Ganciclovir 500 mg powder for solution for infusion is
a generic medicine that is given by infusion and contains the same active substance as the
reference medicine, Cymevene powder for solution for infusion.
What are the possible side effects of Ganciclovir 500 mg powder for solution for
infusion?
Because Ganciclovir 500 mg powder for solution for infusion is a generic medicine, its
benefits and possible side effects are taken as being the same as those of the reference
medicine.
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For further information, please see the patient information leaflet.
Why is Ganciclovir 500 mg powder for solution for infusion approved?
It was concluded that, in accordance with EU requirements, Ganciclovir 500 mg powder for
solution for infusion has been shown to have comparable quality and be comparable to
Cymevene powder for solution for infusion. Therefore, the view was that, as for Cymevene
powder for solution for infusion, the benefits outweigh the identified risks.
What measures are being taken to ensure the safe and effective use of Ganciclovir 500
mg powder for solution for infusion?
A risk management plan has been developed to ensure that Ganciclovir 500 mg powder for
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 Ganciclovir 500 mg powder for 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 and healthcare professionals will be monitored and reviewed continuously as well.
Other information about Ganciclovir 500 mg powder for solution for infusion
Austria, France and the UK agreed to grant a marketing authorisation to Strides Arcolab for
Ganciclovir 500 mg powder for solution for infusion on 04 August 2014. The marketing
authorisation in the UK was granted on 08 September 2014.
The full PAR for Ganciclovir 500 mg powder for solution for infusion follows this summary.
For more information about treatment with Ganciclovir 500 mg powder for solution for
infusion, read the PIL or contact your doctor or pharmacist.
This summary was last updated in November 2014.
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TABLE OF CONTENTS
Module 1: Information about the 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
Page 12
1 Introduction
2 Quality aspects
3 Non-clinical aspects
4 Clinical aspects
5 Overall conclusions
Module 6
Steps taken after initial procedure
Page 19
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Ganciclovir 500 mg powder for solution for infusion
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Module 1
Information about the initial procedure
Product Name
Ganciclovir 500 mg powder for solution for infusion
Type of Application
Generic, Article 10(1)
Active Substances
Ganciclovir (as gancicolvir sodium)
Form
Powder for solution for infusion
Strength
500 mg
MA Holder
Strides Arcolab International Limited,
Unit 4, Metro Centre,
Tolpits Lane,
Watford, Hertfordshire,
WD18 9SS,
United Kingdom.
Reference Member State (RMS)
UK
Concerned Member States (CMS)
Austria and France
Procedure Number
UK/H/5148/001/DC
Timetable
End of procedure (Day 208) – 04 August 2014
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Module 2
Summary of Product Characteristics
The current approved UK version of the Summary of Product Characteristics (SmPC) for this
product is available on the MHRA website.
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Module 3
Patient Information Leaflet
The current approved UK version of the Patient Information Leaflet (PIL) for this product is
available on the MHRA website.
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Module 4
Labelling
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9
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10
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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 Ganciclovir 500 mg powder for solution for infusion (PL 28176/0139;
UK/H/5148/001/DC) could be approved. This application was submitted via the
Decentralised Procedure, with the UK as Reference Member State (RMS), and Austria and
France as Concerned Member States (CMS).
This is a prescription-only medicine (POM) used in the treatment of cytomegalovirus (CMV)
infection during acquired immunodeficiency syndrome (AIDS), particularly retinal,
gastrointestinal (colitis, oesophagitis), lung and brain infections. This medicine is also used in
the prevention of CMV infection after organ transplant, specifically in:
-
-
treatment of the following visceral disorders in patients with bone marrow and organ
transplants: pneumonia, colitis and other digestive tract disorders, retinitis
early treatment, exclusively, in patients with allogeneic bone marrow transplants:
initiation of therapy must be considered upon evidence of CMV viral excretion
(viraemia, virus isolation in bronchoalveolar lavage fluid), as these factors are
predictive for the onset of severe pulmonary involvement.
prophylactic treatment after organ transplants with increased risk of symptomatic
CMV infection due to intensive immunosuppressive treatment, if the recipient is
already immunised against CMV (presence of anti-CMV antibodies in serum prior to
transplantation), especially in heart transplantation.
This marketing authorisation has been granted pursuant to Article 10(1) of Directive
2001/83/EC, as amended, claiming to be a generic medicinal product of Cymevene powder
for solution for infusion, which was granted a licence in Belgium to N.V. Roche S.A. on 30
June 1988. The equivalent medicinal product marketed in the UK is Cymevene powder for
infusion (PL 00286/0100), which was granted a marketing authorisation to Syntex
Pharmaceuticals Limited on 15 June 1998. Following a subsequent change of ownership,
granted on 31 May 1996, the current marketing authorisation holder for this UK reference
product is Roche Products Limited, (PL 00031/0465).
This medicinal product contains the active substance ganciclovir (as ganciclovir sodium). In
CMV-infected cells ganciclovir is phosphorylated by a viral protein kinase and then various
cellular kinases to produce ganciclovir triphosphate. This phosphorylated form of the active
substance acts in two ways to reduce viral DNA synthesis: (i) competitively inhibiting
incorporation of deoxyguanosine triphosphate into viral DNA by DNA polymerase and, (ii)
termination, or very limited elongation, of viral DNA by incorporation of ganciclovir
triphosphate into the viral DNA.
No new non-clinical studies were performed, which is acceptable given that the application
was based on being a generic medicinal product of a reference product that has been in
clinical use for over 10 years.
No new clinical data have been submitted and none are required for this type of application.
A bioequivalence study was not necessary to support this application for a parenteral product,
containing the same active substance as the reference product.
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The RMS has been assured that acceptable standards of Good Manufacturing Practice (GMP)
are in place for these product types at all sites responsible for the manufacture and assembly
of this product.
For manufacturing sites within the Community, the RMS has accepted copies of current
manufacturer authorisations issued by inspection services of the competent authorities as
certification that acceptable standards of GMP are in place at those sites.
For a manufacturing site outside the Community, the RMS has requested a copy of an in date
manufacturing authorisation issued by the inspection services of an EU competent authority.
A summary of the pharmacovigilance system and Risk Management Plan (RMP) have been
provided with this application and is satisfactory.
The RMS and CMS considered that the application could be approved at the end of
procedure (Day 208) on 04 August 2014. After a subsequent national phase, a licence was
granted in the UK on 08 September 2014.
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Ganciclovir 500 mg powder for solution for infusion
II.
UK/H/5148/001/DC
ABOUT THE PRODUCT
Name of the product in the Reference Member State
Name(s) of the active substance(s) (INN)
Pharmacotherapeutic classification
(ATC code)
Pharmaceutical form and strength(s)
Reference numbers for the Mutual Recognition
Procedure
Reference Member State
Member States concerned
Marketing Authorisation Number(s)
Name and address of the authorisation holder
Ganciclovir 500 mg powder for solution for
infusion
Ganciclovir
Anti-infectives for systemic use, antivirals
for systemic use, direct acting antivirals,
nucleosides and nucleotides excluding
reverse transcriptase inhibitors.
(J05AB06)
Powder for solution for infusion
UK/H/5148/001/DC
United Kingdom
Austria and France
PL 28176/0139
Strides Arcolab International Limited
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III
SCIENTIFIC OVERVIEW AND DISCUSSION
III.1 QUALITY ASPECTS
DRUG SUBSTANCE
rINN:
Chemical names:
Ganciclovir
2-amino-1,9-dihydro-9-[[2-hydroxy-1-hydroxymethyl)ethoxy]methyl]6H-purin-6-one,
2-amino-9-[2-hydroxymethyl)ethoxymethyl]-9H-purin-6(1H)-one, 9[[2-hydroxy-1-(hydroxymethyl)ethoxy]methyl]guanine,
And,
9-[1,3-dihydroxy-2-propoxy)methyl]guanine.
Structure:
Molecular formula:
Molecular weight:
Appearance:
Solubility:
C9H13N5O4
255.24 g/mol
a white or off white crystalline powder
slightly soluble in water, practically insoluble in organic solvents, and
soluble in diluted solution of hydroxides and acids
Ganciclovir is the subject of a European Pharmacopoeia monograph.
All aspects of the manufacture and control of the active substance, ganciclovir, are covered
by a European Directorate for the Quality of Medicines and Healthcare (EDQM) Certificate
of Suitability.
DRUG PRODUCT
Other Ingredients
Other ingredients consist of the pharmaceutical excipients sodium hydroxide and water for
injections. Appropriate justification for the inclusion of each excipient has been provided.
All excipients comply with their respective European Pharmacopoeia (and other)
monographs. Certificates of Analysis have been provided for all excipients, showing
compliance with the proposed 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 finished product equivalent
to that of the reference product, Cymevene powder for solution for infusion.
Suitable pharmaceutical development data have been provided for this application.
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Manufacturing Process
A satisfactory batch formula has been provided for the manufacture of the finished product,
together with an appropriate account of the manufacturing process. The manufacturing
process has been validated with industrial-scale batches that have shown satisfactory results.
Control of the Finished Product
The finished product specification is acceptable. Test methods have been described that have
been adequately validated. Batch data have been provided and comply with the release
specification. Certificates of Analysis have been provided for all working standards used.
Container-Closure System
The product is individually packaged in 10 ml Type 1 glass vials, sealed with grey
bromobutyl rubber closures and flip-off aluminium seals. The vials are placed in a cardboard
carton, in pack sizes of 1, 5 or 25 vials.
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 foodstuff.
Stability of the product
Finished product stability studies were performed in accordance with current guidelines on
batches of finished product in the packaging proposed for marketing. Based on the results, a
shelf life of 2 years has been approved for the unopened product, with no special storage
conditions.
Chemical and physical in-use stability has been demonstrated for the reconstituted and
diluted product of 12 hours at 25 °C, and 24 hours at 25 °C and 2-8 °C, respectively. From a
microbiological point of view the diluted product should be used immediately. If not used
immediately, in-use storage times and conditions prior to use are the responsibility of the
user.
Suitable post approval stability commitments have been provided to continue stability testing
on batches of finished product.
Bioequivalence/Bioavailability
A bioequivalence study was not necessary to support this type of application for a parenteral
product.
Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and
Labels
The SmPC, PIL and labels are satisfactory from a pharmaceutical perspective.
A package 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)
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The quality overall summary has been written by an appropriately qualified person and is a
suitable summary of the pharmaceutical aspects of the dossier.
Conclusion
The grant of a marketing authorisation is recommended.
III.2 NON-CLINICAL ASPECTS
As the pharmacodynamic, pharmacokinetic and toxicological properties of ganciclovir are
well-known, no new non-clinical data have been submitted and none are required.
The applicant’s non-clinical overview has been written by an appropriately qualified person
and is satisfactory, providing an appropriate review of the relevant non-clinical
pharmacology, pharmacokinetics and toxicology.
Suitable justification has been provided for non-submission of an Environmental Risk
Assessment. As the application is for a generic version of an already authorised product, it is
not expected that environmental exposure will increase following approval of the marketing
authorisation for the proposed product.
The grant of a marketing authorisation is recommended.
III.3 CLINICAL ASPECTS
CLINICAL PHARMACOLOGY
The clinical pharmacology of ganciclovir sodium is well-known. No new clinical
pharmacology data have been provided and none are required for this type of application. A
bioequivalence study was not provided and is not necessary to support this application for a
parenteral product, in accordance with CPMP guidelines (CPMP/EWP/QWP/1401/98 Rev.
1/Corr**, Guideline on the Investigation of Bioequivalence).
EFFICACY
No new efficacy data have been submitted and none are required for this type of application.
The clinical efficacy of ganciclovir sodium is well-established.
SAFETY
No new safety data have been submitted with this application and none are required. No new
or unexpected safety concerns arose from this application. The safety profile of ganciclovir
sodium is well-known.
CLINICAL EXPERT REPORT
A clinical expert report has been written by a suitably qualified person and is satisfactory.
SUMMARY OF PRODUCT CHARACTERISTICS (SmPC), PATIENT
INFORMATION LEAFLET (PIL) AND LABELLING
The SmPC, PIL and labels are acceptable from a clinical perspective. The SmPC is consistent with
that for the reference product. The PIL is consistent with the details in the SmPC and in line with
current guidance. The labelling is in line with current guidance.
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.
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The applicant has provided an acceptable Risk Management Plan (RMP). Routine risk
minimisation is provided through the Summary of Product Characteristics and the Patient
Information Leaflet and this is sufficient.
APPLICATION FORM
The MAA form is acceptable from a clinical perspective.
MEDICAL CONCLUSION
The grant of a marketing authorisation is recommended for this application.
IV
OVERALL CONCLUSION AND BENEFIT/RISK ASSESSMENT
QUALITY
The important quality characteristics of Ganciclovir 500 mg powder for 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
No new clinical data were submitted and none were required for an application of this type.
No bioequivalence studies were submitted or required for this application for a parenteral
product.
BENEFIT/RISK ASSESSMENT
The quality of the product is acceptable and no new non-clinical safety concerns have been
identified. Ganciclovir sodium is a well-known active substance. Extensive clinical
experience with ganciclovir sodium is considered to have demonstrates the therapeutic value
of the compound. The benefit/risk balance 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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