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 1 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. 2 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. 3 Vancomycin 500 mg and 1000 mg Powder for concentrate for solution for infusion UK/H/5402/001-02/DC 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 Page 15 4 Vancomycin 500 mg and 1000 mg Powder for concentrate for solution for infusion UK/H/5402/001-02/DC 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. 5 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). 6 Vancomycin 500 mg and 1000 mg Powder for concentrate for solution for infusion UK/H/5402/001-02/DC 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 7 Vancomycin 500 mg and 1000 mg Powder for concentrate for solution for infusion UK/H/5402/001-02/DC 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. 8 Vancomycin 500 mg and 1000 mg Powder for concentrate for solution for infusion UK/H/5402/001-02/DC 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 9 Vancomycin 500 mg and 1000 mg Powder for concentrate for solution for infusion UK/H/5402/001-02/DC Summary table of risk minimisation measures 10 Vancomycin 500 mg and 1000 mg Powder for concentrate for solution for infusion UK/H/5402/001-02/DC 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 11 Vancomycin 500 mg and 1000 mg Powder for concentrate for solution for infusion UK/H/5402/001-02/DC 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. 12 Vancomycin 500 mg and 1000 mg Powder for concentrate for solution for infusion UK/H/5402/001-02/DC 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: 13 Vancomycin 500 mg and 1000 mg Powder for concentrate for solution for infusion UK/H/5402/001-02/DC 14 UK/H/5402/001-02/DC 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
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