Product Name: Genta Equine 10% Solution for Injection

SCIENTIFIC DISCUSSION Product Name: Genta Equine 10% Solution for Injection MA Holder: Franklin Pharmaceuticals Ltd

I. INTRODUCTION

Genta Equine 10% Solution for Injection produced by Franklin Pharmaceuticals contains 100mg of gentamicin (as gentamicin sulphate) per ml. The product has been designed for use in horses to control severe bacterial infections sensitive to gentamicin, including Pseudomonas aeruginosa, Rhodococcus equi and Salmonella spp. The dose for adult horses is 6.6mg per kg bodyweight (3.3ml/50kg bodyweight), introduced by slow intravenous or intramuscular injection. In foals, Genta Equine is to be used at 7mg per kg bodyweight, (3.5ml per 50kg bodyweight), introduced as described for adult horses. Dosing may be repeated at twenty-four hour intervals, and higher or lower dosing may be used based on the results of therapeutic drug monitoring. To ensure correct dosage, bodyweight should be calculated as accurately as possible. Susceptibility testing of the target organism should be performed. If this is not possible, therapy should be based on local, (regional, farm level), epidemiological information with regard to the susceptibility of target bacteria. The product is not to be used in horses intended for human consumption, and horses must be declared as not intended for human consumption.

This application for a National Marketing Authorisation, was made with reference to a generic product, Gentaject 10% Solution for Injection, also produced by Franklin Pharmaceuticals. The application was made with regard to Article 13 (1) of Directive 2001/82/EC, as amended by Directive 2004/28/EC. Gentaject 10% Solution for Injection has been authorised in Ireland for more than 10 years. Exemption from bioequivalence studies was claimed under exemption article 4.c of the Guidelines for the Conduct of Bioequivalence Studies for Veterinary Medicinal Products, EMEA/CVMP/016/-corr-FINAL. Identical quantitative and qualitative composition was claimed, in addition to identical formulation and manufacturing processes.

II. QUALITY ASPECTS

Product Development and Composition

The product is bioequivalent to the reference product, Gentaject 10% Solution for Injection, therefore the manufacturing process is the same and is GMP compliant.

A test was performed to check the sterility of the product which entailed filling the glass vials used to hold the product with tryptone soya broth, known to encourage the growth of a variety of bacteria. The broth was placed in a pre-sterilised holding vessel for fifteen hours, and then poured into the glass vials and kept at approximately 30oC for two weeks. No bacterial growth was seen in the vials, and this was considered a satisfactory validation test.

Three production scale batches of 500 litres of product were produced and satisfactorily tested with regard to stability and effectiveness of filtration. The product was observed for bioburden prior to filtration, and for levels of the active ingredient and excipients at the beginning and end of the manufacturing process. pH levels, fill volume, product stability and environmental monitoring were all satisfactory. There are no intermediate products.

Page 1 of 5 SCIENTIFIC DISCUSSION Product Name: Genta Equine 10% Solution for Injection MA Holder: Franklin Pharmaceuticals Ltd

Active Substance

The active substance in Genta Equine 10% Solution for Injection is gentamicin (as gentamicin sulphate). This active substance is monographed in the European Pharmacopoeia (Ph. Eur) and is commonly employed for veterinary use. Gentamicin sulphate is bactericidal in its effect, acting on the bacterial ribosome, where protein synthesis is inhibited and translation of the genetic code is depleted. Transport of gentamicin appears to be linked to electron transport, oxidative phosphorylation and respiratory quinones in the cell membrane. Antibacterial activity is directed primarily against Gram-negative bacteria.

Other Substances

Excipients used in Genta Equine 10% Solution for Injection are sodium methyl parahydroxybenzoate and sodium propyl parahydroxybenzoate (preservatives), sodium metabisulphate (antioxidant), trisodium citrate (pH regulator), EDTA (chelating agent), citric acid monohydrate (pH regulator), and water for injection. All excipients are monographed in the Ph. Eur, and all are commonly used in veterinary medicines.

No class 1 residual solvents are present in any excipients. Where class 2 or class 3 solvents are present, these comply with the International Cooperation on Harmonisation of Technical Requirements for Registration of Veterinary Medicinal Products (VICH) limits.

Packaging Materials

Genta Equine 10% Solution for Injection is presented in 100ml volume, clear type II glass vials, sealed with a bromobutyl rubber bung and an aluminium overseal. The glass vials and bungs components comply with the Ph. Eur, and the aluminium seals are satisfactory.

The vials are sterilised by dry heat at approximately 280oC for seven minutes, and the rubber bungs and aluminium seals are sterilised by gamma irradiation at a minimum of 25 KiloGray (kGy). All procedures are considered satisfactory.

Manufacture of the Finished Product

Water for injection is placed in a mixing container, to which all excipients apart from citric acid are added. The ingredients are then mixed until a homogeneous solution is achieved. The active ingredient, gentamicin sulphate, is added to the mixing container, and the product is again mixed to homogeneity. The pH of the solution is tested, and adjustment made if necessary with citric acid. Remaining water for injection is added to bring the quantity of product up to the specified level, and a sample is then sent for analysis prior to being then filter sterilised and packaged. The final batch quantity is 500 litres.1

Finished Product Quality Control

The finished product is analysed for appearance, pH, relative density, fill volume, sterility and amounts of active substance and excipients. Where applicable, all analyses follow the requirements of the Ph. Eur. Data on batch analysis for four production scale batches were provided, these showed compliance with the proposed release specification. There was no requirement to test for endotoxins. Satisfactory data for the sterility method used were received.

1 Due to a Variation Procedure to add a manufacturing site, the batch size increased to 2000 litres.

Page 2 of 5 SCIENTIFIC DISCUSSION Product Name: Genta Equine 10% Solution for Injection MA Holder: Franklin Pharmaceuticals Ltd

Stability of the Product

Active substance

Stability data for gentamicin were provided in accordance with VICH guidelines. Three batches of the active ingredient were stored for up to four years at 25oC/60% RH, and a further three batches were stored at 40oC/75% RH for three months. The batches stored were of production scale (500 litres), and the packaging was a smaller version of the packs to be marketed. In real time conditions, it was demonstrated that the active substance was generally stable, with a small increase in water content. However, under accelerated conditions, water content increased significantly. A retest period of four years, and storage below 25 oC was recommended.

Finished Product

Stability studies were performed on three production level batches, (stored in the packaging to be marketed), for up to twenty-four months at 25oC/60% RH. An additional study observed the same product parameters for up to six months at 40oC/75% RH. Description of methodology and subsequent validation were satisfactory.

In-Use

The pH of Genta Equine 10% Solution is maintained at between 3.0 and 4.5, conferring good stability on the product. Unopened, the product has a designated shelf life of two years and the in-use shelf life of the broached vial is 28 days. The product is to be protected from light.

CONCLUSIONS ON QUALITY

A declaration was made by the Marketing Authorisation Holder that no materials used in the manufacture of the product come under the scope of the transmissible spongiform encephalopathies (TSE) guidelines.

Descriptions of the manufacturing process and in-process controls were considered to be satisfactory. Process validation is generally satisfactory and covers the process parameters, aseptic manufacture and filter compatibility.

Information provided on the supplier of gentamicin is satisfactory and the active is supplied against a current certificate of suitability. Batch analysis data were all satisfactory, and all excipients are commonly used in veterinary products and have Ph. Eur monographs. Data provided for each excipient was satisfactory, as was all information provided concerning packaging materials.

III. SAFETY ASPECTS

Introduction

This Marketing Authorisation was granted in accordance with Article 13.1 of Directive 2001/82/EC, by demonstrating that Genta Equine is chemically equivalent to Gentaject 10% Solution for Injection, registered in Ireland under VPA 10976/2/1. The formulation and manufacturing process of the product is identical to the reference product, therefore, no pharmacological or toxicological data were required for bioequivalence tests.

Page 3 of 5 SCIENTIFIC DISCUSSION Product Name: Genta Equine 10% Solution for Injection MA Holder: Franklin Pharmaceuticals Ltd

The product is not to be used in pregnant horses, or in animals intended for human consumption. Genta Equine is not to be used in cases of known hypersensitivity to the active substance, or in cases of known renal impairment. The product should not be used for more than five days without biochemical confirmation of normal renal function, and is not to be used with other amino glycoside antibiotics. It should be noted that repeat injections may cause reactions at the site of injection.

Pharmacology

The application is in accordance with Article 13.1 of Directive 2001/82?ec as amended by Directive 2004/28/EC and therefore the applicant is not required to submit results of pharmacological and toxicological studies and clinical trials.

Toxicology

Residues

The product is only for use in horses not intended for human consumption, therefore no residues data was required.

Environmental Safety

A satisfactory Phase 1 Risk Assessment was provided. There will be minimal exposure of the environment to the product, (via slurry or manure), from only a small number of animals. This qualification falls under question 5 of the Phase 1 Guideline, (CVMP/VICH/592/98-final). Any unused product or waste material should be disposed of in accordance with national requirements.

CONCLUSIONS ON SAFETY AND RESIDUES

Conclusions on User Safety

There are no special precautions for user safety.

Conclusions on Consumer Safety

Not applicable.

Conclusions on Environmental Safety

Environmental safety is satisfactory.

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IV. CLINICAL ASPECTS Introduction

Bioequivalence is claimed with Gentaject 10% Solution for Injection, the product is therefore exempt with regard to the provision of data for pre-clinical and clinical trials.

Clinical Pharmacology

Pharmacodynamics

A basic description of the pharmacodynamics of gentamicin was provided. Refer to ‘Active Substance’ in this document.

Pharmacokinetics

A brief description of the action of gentamicin was provided which explained that the active substance is poorly absorbed from the gut, and so must be delivered parenterally for effective systemic action. Gentamicin is readily absorbed from intramuscular injection, reaching peak plasma concentrations at 0.5-2.0 hours after administration. Elimination is primarily by glomerular filtration, thus the product is rapidly excreted in the urine.

Tolerance in the Target Species

Resistance

Bioequivalence is claimed with Gentaject 10% Solution for Injection, therefore the claimed exemption from the need to provide resistance data was acceptable.

Clinical Efficacy

Bioequivalence is claimed with Gentaject 10% Solution for Injection, therefore the claimed exemption from the need to provide clinical data was acceptable.

CONCLUSIONS ON CLINICAL ASPECTS

PART V. OVERALL CONCLUSION ON THE PRODUCT

The data submitted in the dossier demonstrate that when the product is used in accordance with the Summary of Product Characteristics, the benefit risk profile for the target species is favourable and the quality and safety of the product for humans and the environment is acceptable.

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