Vancomycin 500 mg and 1000 mg Powder for concentrate for

Vancomycin 500 mg and 1000 mg Powder for concentrate for solution for infusion
UK/H/5402/001-02/DC
Public Assessment Report
Decentralised Procedure
Vancomycin 500 mg and 1000 mg Powder for concentrate
for solution for infusion
(vancomycin hydrochloride)
Procedure No: UK/H/5402/001-02/DC
UK Licence No: PL 41734/0002-0003
Pharma Regulatory Solutions Ltd
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Vancomycin 500 mg and 1000 mg Powder for concentrate for solution for infusion
UK/H/5402/001-02/DC
LAY SUMMARY
Vancomycin 500 mg and 1000 mg Powder for concentrate for solution for infusion
(vancomycin hydrochloride)
This is a summary of the Public Assessment Report (PAR) for Vancomycin 500 mg and 1000 mg
Powder for concentrate for solution for infusion (PL 41734/0002-0003; UK/H/5402/001-02/DC). It
explains how the applications for Vancomycin 500 mg and 1000 mg Powder for concentrate for solution
for infusion were assessed and their authorisations recommended, as well as the conditions of use. It is
not intended to provide practical advice on how to use Vancomycin 500 mg and 1000 mg Powder for
concentrate for solution for infusion.
For practical information about using Vancomycin 500 mg and 1000 mg Powder for concentrate for
solution for infusion, patients should read the package leaflet or contact their doctor or pharmacist.
What are Vancomycin 500 mg and 1000 mg Powder for concentrate for solution for infusion and
what are they used for?
Vancomycin 500 mg and 1000 mg Powder for concentrate for solution for infusion are “generic
medicines”. This means that Vancomycin 500 mg and 1000 mg Powder for concentrate for solution for
infusion are similar to a ‘reference medicine’ already authorised in the UK called Vancocin 500 mg
and 1000 mg Powder for solution for infusion and oral solution (Flynn Pharma Limited; PL
13621/0033).
Vancomycin 500 mg and 1000 mg Powder for concentrate for solution for infusion are used for the
treatment of serious infections caused by certain bacteria, such as infections of the bones, lung
infections, skin and muscle (soft tissue) infection, infection of the valves or lining of the heart.
How do Vancomycin 500 mg and 1000 mg Powder for concentrate for solution for infusion work?
Vancomycin 500 mg and 1000 mg Powder for concentrate for solution for infusion contain the active
ingredient vancomycin, which is an antibiotic. Antibiotics help the body fight infections. Vancomycin
works by eliminating certain bacteria that cause infections.
How are Vancomycin 500 mg and 1000 mg Powder for concentrate for solution for infusion used?
Vancomycin 500 mg and 1000 mg Powder for concentrate for solution for infusion are given by a
healthcare professional. These medicines are given into a vein, usually in the arm, slowly over at least
one hour. A doctor will decide at which rate and for how long these medicines are given, depending on
the patient’s age, weight, kidney functions and the severity of the infection.
The usual dose in adults and children above 12 years is 2000 mg daily in two or four doses (500 mg
every 6 hours or 1000 mg every 12 hours) or will be calculated depending on the body weight.
The dosage in children from one month to 12 years is 10 mg/kg per dose given every six hours (total
daily dosage 40 mg/kg of body weight). Each dose is administered over a period of at least 60 minutes.
The dosages will be calculated depending on the body weight.
A starting dose of 15 mg/kg, followed by 10 mg/kg every 12 hours for newborn infants (full-term) 0-7
days of age and a dose of 15 mg/kg, followed by 10mg/kg every 8 hours for infants aged 7-30 days are
recommended. Each dose is administered over 60 minutes.
These medicinal products can only be obtained with a prescription from a doctor.
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Vancomycin 500 mg and 1000 mg Powder for concentrate for solution for infusion
UK/H/5402/001-02/DC
For further information on how Vancomycin 500 mg and 1000 mg Powder for concentrate for solution
for infusion are used, please see the Summaries of Product Characteristics or the package leaflet
available on the MHRA website.
What are the benefits and risks of Vancomycin 500 mg and 1000 mg Powder for concentrate for
solution for infusion?
As Vancomycin 500 mg and 1000 mg Powder for concentrate for solution for infusion are generic
medicines and are comparable to the reference medicine, Vancocin 500 mg and 1000 mg Powder for
solution for infusion and oral solution (Flynn Pharma Limited; PL 13621/0033), their benefits and risks
are taken as being the same as those of Vancocin 500 mg and 1000 mg Powder for solution for infusion
and oral solution (Flynn Pharma Limited; PL 13621/0033).
Why is Vancomycin 500 mg and 1000 mg Powder for concentrate for solution for infusion
approved?
No new or unexpected safety concerns arose from these applications. It was, therefore, concluded that
the benefits of Vancomycin 500 mg and 1000 mg Powder for concentrate for solution for infusion
outweigh the risks; and the grant of Marketing Authorisations was recommended.
What measures are being taken to ensure the safe and effective use of Vancomycin 500 mg and
1000 mg Powder for concentrate for solution for infusion?
A risk management plan has been developed to ensure that Vancomycin 500 mg and 1000 mg Powder
for concentrate for solution for infusion are used as safely as possible. Based on this plan, safety
information has been included in the Summaries of Product Characteristics and the package leaflet for
Vancomycin 500 mg and 1000 mg Powder for concentrate for solution for infusion, including the
appropriate precautions to be followed by healthcare professionals and patients.
Other information about Vancomycin 500 mg and 1000 mg Powder for concentrate for solution
for infusion
Austria, Belgium, Bulgaria, Czech Republic, Denmark, Finland, Germany, Greece, Hungary, Iceland,
Italy, Lithuania, Latvia, Luxembourg, Norway, Poland, Portugal, Republic of Estonia, Republic of
Ireland, Romania, Slovak Republic, Slovenia, Spain, Sweden, The Netherlands and the UK agreed to
grant Marketing Authorisations for Vancomycin 500 mg and 1000 mg Powder for concentrate for
solution for infusion on 23rd December 2014. Marketing Authorisations were granted in the UK on 19th
January 2015.
The full PAR for Vancomycin 500 mg and 1000 mg Powder for concentrate for solution for infusion
follows this summary. For more information about treatment with Vancomycin 500 mg and 1000 mg
Powder for concentrate for solution for infusion, read the package leaflet or contact your doctor or
pharmacist.
This summary was last updated in March 2015.
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Vancomycin 500 mg and 1000 mg Powder for concentrate for solution for infusion
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TABLE OF CONTENTS
I
II
III
IV
V
VI
Introduction
Quality aspects
Non-clinical aspects
Clinical aspects
User consultation
Overall conclusion, benefit/risk assessment and
recommendation
Page 5
Page 6
Page 8
Page 8
Page 11
Page 12
Table of content of the PAR update for MRP and DCP
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I
INTRODUCTION
Based on the review of the data on quality, safety and efficacy, the Reference Member State (RMS) and
Concerned Member States (CMSs) considered that the applications for Vancomycin 500 mg and 1000
mg Powder for concentrate for solution for infusion (PL 41734/0002-0003; UK/H/5402/001-02/DC)
indicated in the following severe infections caused by gram-positive bacteria susceptible to vancomycin
which cannot be treated or failed to respond or are resistant to other antibiotics such as penicillins and
cephalosporins, are approvable.
-
endocarditis
infections of the bones (osteomyelitis)
pneumonia
soft tissue infections
Where appropriate, vancomycin should be co-administered with other antibacterial agents. This
particularly applies to the treatment of endocarditis. Vancomycin may be used for the perioperative
prophylaxis against bacterial endocarditis, in patients at high risk of developing bacterial endocarditis
when they undergo major surgical procedures (e.g., cardiac and vascular procedures, etc) and are unable
to receive a suitable beta-lactam antibacterial agent.
These applications were submitted according to Article 10(1) of Directive 2001/83/EC, as amended. The
applicant has cross-referred to Vancocin 500 mg and 1000 mg Powder for solution for infusion and
oral solution which was originally authorised to Eli Lilly and Company Limited (PL 00006/5076R) on
18th April 1990. This reference licence underwent a change of ownership procedure to the current
Marketing Authorisation Holder, Flynn Pharma Limited (PL 13621/0033) on 26th May 2006.
With UK as the RMS in these Decentralised Procedures (UK/H/5402/001-02/DC), Pharma Regulatory
Solutions Ltd, applied for the Marketing Authorisations for Vancomycin 500 mg and 1000 mg Powder
for concentrate for solution for infusion in Austria, Belgium, Bulgaria, Czech Republic, Denmark,
Finland, Germany, Greece, Hungary, Iceland, Italy, Lithuania, Latvia, Luxembourg, Norway, Poland,
Portugal, Republic of Estonia, Republic of Ireland, Romania, Slovak Republic, Slovenia, Spain, Sweden
and The Netherlands.
Vancomycin is a tricyclic glycopeptide antibiotic that inhibits the synthesis of the cell wall in sensitive
bacteria by binding with high affinity to the D-alanyl-D-alanine terminus of cell wall precursor units.
The drug is bactericidal for dividing microorganisms.
No new non-clinical or clinical studies were conducted, which is acceptable given that this is a generic
application of an originator product that has been in clinical use for over 10 years.
A bioequivalence study was not necessary to support these applications for parenteral products,
containing the same active substance as the reference product.
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 manufacturer
authorisations issued by inspection services of the competent authorities as certification that acceptable
standards of GMP are in place at those sites.
All involved Member States agreed to grant Marketing Authorisations for the above products at the end
of the procedure (Day 210 – 23rd December 2014). After a subsequent national phase, the UK granted
Marketing Authorisations (PL 41734/0002-0003) for these products on 19th January 2015.
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Vancomycin 500 mg and 1000 mg Powder for concentrate for solution for infusion
II
UK/H/5402/001-02/DC
QUALITY ASPECTS
II.1 Introduction
The submitted documentation concerning the proposed products is of sufficient quality and meets the
current EU regulatory requirements.
The quality overall summary has been written by an appropriately qualified person and is a suitable
summary of the pharmaceutical aspects of the dossier.
Each Vancomycin 500 mg and 1000 mg Powder for concentrate for solution for infusion contains 500
mg and 1000 mg vancomycin as vancomycin hydrochloride, respectively (equivalent to 500,000 IU and
1000,000 IU).
These products do not contain any pharmaceutical excipients.
The finished product is supplied in a colourless type 1 glass vial with a chlorobutyl type 1 silicone
coated stopper and a grey aluminium/polypropylene flip-off cap (500 mg formulation) and a green
aluminium/polypropylene flip-off cap, in a pack size of 1 vial. Not all pack sizes may be marketed.
Satisfactory specifications and Certificates of Analysis for the primary packaging materials have been
provided. All primary packaging complies with current European regulations concerning materials in
contact with foodstuff.
II.2 DRUG SUBSTANCE
Vancomycin hydrochloride
INN:
Vancomycin hydrochloride
Chemical Name:
The monohydrochloride of (3S, 6R, 7R, 22R, 23S, 26S, as, 36R, 38aR)-3(2- amino- 2oxoethyl)-44-[[2-0-(3-amino-2,3,6-trideoxy- 3- C- methyl-aL- lyxo- hexopyranosyl)-pD-glucopyranosyl]oxy-10,19-dichloro7,22,28,30,32- pentahydroxy-6-[(2R)-4-methyl-2(methylamino)pentanoyI]-amino]2, 5, 24, 38, 39-pentaoxo 2,3,4,5,6,7,23,24,25,26,36,37,38,38a-tetradecahydro-22H-8, II: 18, 21dietheno-23, 36- (iminomethano)- 13, 16: 31, 35-dimetheno- lH, 13H- [1,
6, 9] oxadiazacyc1ohexadecino [4, 5- m] [10,
2,16]benzoxadiazacyclotetracosine-26- carboxylic acid (Vancomycin B).
Molecular formula:
Structure:
C66H75Cl2N9O24.HCl
Molecular mass:
Appearance:
Solubility:
1486
White or almost white hygroscopic powder
Freely soluble in water and slightly soluble in ethanol (96 per cent).
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Vancomycin 500 mg and 1000 mg Powder for concentrate for solution for infusion
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Vancomycin hydrochloride is the subject of a European Pharmacopoeia monograph.
All aspects of the manufacture and control of the active substance, vancomycin hydrochloride, are
covered by a European Directorate for the Quality of Medicines and Healthcare (EDQM) Certificate of
Suitability.
Appropriate stability data have been generated supporting a suitable retest period when stored in the
proposed packaging.
II.3 MEDICINAL PRODUCT
Pharmaceutical Development
The objective of the pharmaceutical development programme was to obtain stable products containing
vancomycin hydrochloride which could be considered as generic medicinal products of Vancocin 500
mg and 1000 mg Powder for solution for infusion and oral solution (Flynn Pharma Limited).
Suitable pharmaceutical development data have been provided for these applications.
Comparative impurity 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 process. The manufacturing process has been validated and
has shown satisfactory results. Process validation data on commercial batches have been provided. The
results are satisfactory.
Finished Product Specifications
The finished product specifications are satisfactory. The test methods have been described and validated
adequately. Batch data have been provided that comply with the release specifications. Certificates of
Analysis have been provided for any working standards used.
Stability of the products
Finished product stability studies have been conducted in accordance with current guidelines and in the
packaging proposed for marketing.
Based on the results, a shelf-life of 2 years as packaged for sale with storage conditions “Store below
25°C” and “Keep the vial in the outer carton in order to protect from light.” have been set. These are
satisfactory.
Reconstituted concentrate:
The reconstituted concentrate should be further diluted immediately after reconstitution.
Diluted product:
From a microbiological point of view, the product should be used immediately.
II.4 Discussion on chemical, pharmaceutical and biological aspects
The grant of Marketing Authorisations is recommended
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III
NON-CLINICAL ASPECTS
III.1 Introduction
The pharmacodynamic, pharmacokinetic and toxicological properties of vancomycin hydrochloride are
well known. No new non-clinical data have been submitted for these applications and none are required.
The applicant has provided an overview based on published literature. The 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.
III.2 Pharmacology
Not applicable, see Section III.1 Introduction, above.
III.3 Pharmacokinetics
Not applicable, see Section III.1 Introduction, above.
III.4 Toxicology
Not applicable, see Section III.1 Introduction, above.
III.5 Ecotoxicity/Environmental Risk Assessment (ERA)
Suitable justification has been provided for non-submission of an Environmental Risk Assessment. As
these products are intended for generic substitution with a product that is already marketed, no increase
in environmental exposure to vancomycin hydrochloride is anticipated. Thus, the justification for
non-submission of an Environmental Risk Assessment is accepted.
III.6 Discussion of the non-clinical aspects
There are no objections to the approval of these products from a non-clinical point of view.
IV.
CLINICAL ASPECTS
IV.1 Introduction
The applications for Vancomycin 500 mg and 1000 mg Powder for concentrate for solution for infusion
(PL 41734/0002-0003; UK/H/5402/001-02/DC) were submitted under Article 10(1) of Directive
2001/83/EC, as amended, as generic applications cross-referring to Vancocin 500 mg and 1000 mg
Powder for solution for infusion and oral solution (Flynn Pharma Limited).
In accordance with the Note for Guidance on the investigation of bioavailability and bioequivalence
(CPMP/EWP/QWP/1401/98 Rev.1/Corr**), a bioequivalence study is not required if the test product is
a solution containing the same active substance as the reference product. As these products are solution
at the time of administration, no bioequivalence studies have been submitted and none are required.
IV.1 Pharmacokinetics
The clinical pharmacokinetic properties of vancomycin hydrochloride are well-known. No new
pharmacokinetic data are provided or required for these applications.
IV.2 Pharmacodynamics
The clinical pharmacodynamics properties of vancomycin hydrochloride are well-known. No new
pharmacodynamic data were submitted and none are required for applications of this type.
IV.3 Clinical Efficacy
The clinical efficacy of vancomycin hydrochloride is well-known. No new efficacy data are presented or
are required for applications of this type.
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IV.4 Clinical Safety
No new safety data have been submitted with these applications and none are required. No new or
unexpected safety concerns arose from these applications. Vancomycin hydrochloride has a
well-established safety profile and an acceptable level of safety in the proposed indications.
IV.5 Risk Management Plan
The Marketing Authorisation Holder (MAH) has submitted a risk management plan, 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 Vancomycin 500
mg and 1000 mg Powder for concentrate for solution for infusion.
Summary table of Safety concerns
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Summary table of risk minimisation measures
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No additional risk minimisation activities were required beyond those included in the product
information.
IV.6 Discussion of 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 Vancomycin 500 mg and 1 g Powder for
Solution for infusion (UK/H/5411/001-02/DC). The products are from the same therapeutic class and
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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.
VI.
OVERALL CONCLUSION AND BENEFIT/RISK ASSESSMENT AND
RECOMMENDATION
The quality of the products is acceptable and no new non-clinical or clinical safety concerns have been
identified. The qualitative and quantitative assessment supports the claim that the applicant’s
Vancomycin 500 mg and 1000 mg Powder for concentrate for solution for infusion are generic versions
of the reference product, Vancocin 500 mg and 1000 mg Powder for solution for infusion and oral
solution (Flynn Pharma Limited). Extensive clinical experience with vancomycin hydrochloride is
considered to have demonstrated the therapeutic value of the active substance. The benefit: risk ratio is
considered to be positive.
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Vancomycin 500 mg and 1000 mg Powder for concentrate for solution for infusion
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Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and Labels
The SmPCs, PIL and labelling are satisfactory and, where appropriate, in line with current guidance.
In accordance with Directive 2010/84/EU, the current version of the SmPCs and PIL are available on the
MHRA website. The current labelling are presented below:
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Vancomycin 500 mg and 1000 mg Powder for concentrate for solution for infusion
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)
15