Final Report. Project code: P.PSH.0653 Prepared by: Fiona Cotter Troy Laboratories Pty Ltd Date published: July 2014

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1 Final Report Project code: P.PSH.0653 Prepared by: Fiona Cotter Troy Laboratories Pty Ltd Date published: July 2014 PUBLISHED BY Meat & Livestock Australia Limited Locked Bag 991 NORTH SYDNEY NSW 2059 A GLP study to determine the safety of a meloxicam buccal formulation when applied at 1X, 3X and 5X the recommended dose rate of 0.5 mg/kg bodyweight in calves Meat & Livestock Australia acknowledges the matching funds provided by the Australian Government to support the research and development detailed in this publication. This publication is published by Meat & Livestock Australia Limited ABN (MLA). Care is taken to ensure the accuracy of the information contained in this publication. However MLA cannot accept responsibility for the accuracy or completeness of the information or opinions contained in the publication. You should make your own enquiries before making decisions concerning your interests. Reproduction in whole or in part of this publication is prohibited without prior written consent of MLA.

2 Contents 1. INTRODUCTION BACKGROUND OBJECTIVE METHODOLOGY STATISTICAL ANALYSIS RESULTS CONCLUSION: The study confirmed the safety of a meloxicam buccal formulation when applied at 1X, 3X and 5X the proposed dose rate of 0.5 mg/kg BW in calves Acknowledgments Troy Laboratories wishes to acknowledge the significant contributions of the following parties: Animal Phase and Animal Phase Study Report Veterinary Health Research Analytical Phase and Analytical Phase Report IDEXX Laboratories Study Consultant and Monitor Dr Merete Holm DVM Merete Holm Veterinary Consultancy Page 1 of 7

3 Abstract This study aimed to determine the safety of meloxicam at the proposed label dose rate of 0.5 mg/kg bodyweight and at elevated dose rates (3X and 5X the proposed label dose rate) in cattle following oral trans-mucosal (buccal) administration. Cattle 4 6 months of age were used for the study as these are the animals most likely to be treated with the test formulation during routine animal husbandry procedures. Confirmation of the IVP s safety at the label and elevated dose rates was made by comparison of detailed individual clinical examinations and observations; body weight changes; detailed haematological and biochemical parameters; gross pathology following sacrifice and post mortem in all trial cattle, histopathology of selected tissues following sacrifice and post mortem in some trial cattle. No adverse reactions were noted to any of the dose rates tested and no abnormal findings were identified from blood samples or pathology investigations. The study confirmed the safety of the proposed formulation when applied at 1X, 3X and 5X the proposed dose rate of 0.5 mg/kg bodyweight in calves. Page 2 of 7

4 Executive Summary There is widespread acknowledgement from beef producers, consumers, and industry and government bodies, that pain associated with surgical or non-surgical husbandry practices in cattle must be managed effectively. In Australia, meloxicam is registered as an injectable product for use in cattle and currently has a broad antipyretic, analgesic and anti-inflammatory claim. The use of this non-steroidal antiinflammatory drug (NSAID) therapy by parenteral administration is undesirable from an on-farm occupational health and safety risk minimisation perspective. For calves up to six, perhaps nine months of age, the preferred route of administration for meloxicam is oral trans mucosal (OTM) (or buccal) whereby the dose is applied into the sulcus between the molar teeth and the inside of the cheek. Previous studies have shown that meloxicam is readily absorbed in ruminants following buccal administration. Comparison of the bioavailability of oral and buccal meloxicam formulations administered to sheep showed that high serum levels of meloxicam were detected within 8 minutes of buccal dosing. These levels approximate reported therapeutic levels in other species. A buccal meloxicam formulation that could be readily administered by farm staff could be useful in improving the overall welfare of the farm animals. The aim of target animal safety studies is to provide information on the safety of an investigational veterinary product (IVP) in the intended species under the proposed conditions of use. Data from target animal safety studies is required by the APVMA for the registration of veterinary pharmaceutical products in Australia. Appropriate observations, physical examinations, clinical pathology tests (haematology, blood chemistry, urinalysis, faecal analysis, etc.), necropsy and histopathology should be conducted to identify possible adverse effects of the IVP 1. One margin of safety study was conducted with the proposed product ILIUM BUCCALGESIC OTM at 1X, 3X and 5X the recommended dose rate of 0.5 mg/kg BW. The study included clinical examinations and observations over 7 days, biochemistry and haematology, gross pathology and histopathology. No adverse reactions were noted to any of the dose rates tested and no abnormal findings were identified from blood samples or pathology investigations. The study confirmed the safety of the proposed formulation when applied at 1 times (1X), 3 times (3X) and 5 times (5X) the proposed dose rate of 0.5 mg/kg bodyweight in calves. Page 3 of 7

5 1. INTRODUCTION This report summarises the GLP target animal safety study conducted to determine the safety of a meloxicam buccal formulation when applied at 1X, 3X and 5X the recommended dose rate of 0.5 mg/kg bodyweight in calves. The study was commissioned by Troy Laboratories Pty Ltd. 2. BACKGROUND Various forms of surgical husbandry procedures are necessary in cattle under good animal husbandry practices. Animal welfare, in particular pain management, following surgical husbandry procedures has evolved into a political issue that could impact the Australian meat industry. Meloxicam is registered for use in cattle and pigs in Australia as an anti-inflammatory, analgesic and antipyretic agent. The registered administration methodology is either via intravenous (IV) or subcutaneous (SC) injection. Administration of meloxicam by injection requires user skill and care for optimal drug uptake. Buccal application is an easy and efficient route of administration, designed to increase the compliance by the cattle producer when considering the use of a non-steroidal anti-inflammatory drug (NSAID) in connection with potentially painful livestock management and/or surgical procedures for the welfare of the calves. Buccal administration of specifically formulated medications can result in rapid absorption. Previously conducted feasibility studies compared the bioavailability of oral and buccal meloxicam formulations administered to sheep. Results showed that high serum levels of meloxicam were detected within 8 minutes of buccal dosing. These levels approximate reported therapeutic levels in other species. It was proposed that administering meloxicam to cattle via the buccal cavity could provide easy, quick, effective and safe pain management and inflammation control for cattle following surgical husbandry procedures such as castration and disbudding. Meloxicam is an oxicam derivative and a NSAID, with anti-inflammatory, antipyretic and analgesic properties. Unlike traditional non-selective NSAIDs, meloxicam preferentially inhibits the activity of cyclooxygenase-2 (COX-2), resulting in a decreased conversion of arachidonic acid into prostaglandin precursors. The resulting decrease in prostaglandin synthesis is responsible for the therapeutic effects of meloxicam. 2 Before a veterinary chemical product can be legally supplied, sold, or used in Australia it must be registered by the Australian Pesticides and Veterinary Medicines Page 4 of 7

6 Authority (APVMA). Various studies to support safety and efficacy, and to determine the pharmacokinetic/metabolic profile and residue depletion profile of meloxicam were required for registration of a product for use in cattle in Australia. The aim of target animal safety studies is to provide information on the safety of an investigational veterinary product (IVP) in the intended species under the proposed conditions of use. Ref. 1 VICH GL 43 (Target Animal Safety) Pharmaceuticals July 2008 Ref OBJECTIVE The objective of this pivotal study was to confirm the safety of an investigational veterinary product (IVP) Ilium Meloxicam Buccal when applied at 1X, 3X and 5X the proposed dose of 0.5 mg/kg bodyweight in calves. 4. METHODOLOGY Thirty-two beef weaner calves 4 to 6 months of age, equal numbers of male castrate and female calves were used in the study. The calves were sorted by sex and then ranked by descending order of bodyweight, sequentially blocked into fours and randomly allocated from each block into 4 groups of 8 cattle each. Detailed individual clinical examinations were performed on all trial animals. Blood samples were collected for pre-treatment baseline haematology and biochemistry. On Days -3, -2 and -1 the calves were observed in a group setting for clinical baseline behaviour. One animal was deemed abnormal on Day -1 and substituted with a spare calf. On Day 0 the trial cattle were weighed and the weights recorded. Cattle in Groups 2 to 4 were treated with the test formulation, buccal meloxicam 10 mg/ml, according to individual bodyweight at 1X, 3X or 5X the recommended label dose of 0.5 mg/kg bodyweight. Individual doses of the IVP were applied orally into the sulcus between the molar teeth and the inside of the cheek. The administration was buccal with delivery and retention on the cheek mucosa. The left cheek sulcus was preferentially used. Volumes in excess of 20 ml were applied to the right cheek sulcus i.e. the first 20 ml was applied to the left cheek sulcus and any volume thereafter was applied to the right cheek sulcus. The side(s) used was recorded for each animal. Group 1 animals were retained as placebo treated controls receiving 1X of the formulation without active. As both the placebo and drug formulations were blue this ensured blinding of post-treatment observations by the attending veterinarian. Page 5 of 7

7 Animals were observed in a group setting at approximately 1 and 3 hours post treatment mid-point. Detailed individual clinical examinations were performed at approximately 5 hours post treatment mid-point. A veterinarian performed detailed individual clinical examinations on Days 1, 2, 3, 7 and 14 post-treatment. Clinical observations (confined to observations of gait, mental attitude and other gross signs) were performed on the calves in a group setting on Days 4, 5, 6, 8, 9, 10, 11, 12 and 13 post-treatment. Any animals showing abnormal clinical signs during these observations were to be examined in detail. Individual blood samples were collected on Days 3, 7 and 14 post-treatment and were forwarded to the designated laboratory for assessment of a range of biochemical and haematological parameters. The trial animals were weighed on Days -4 and 0 pre-treatment and Days 3, 7 and 14 post-treatment. The calves were grazing one paddock as a single group during the study. Three cattle were sacrificed from each of Groups 1, 2, 3, and 4 (selected on ascending tag numbers) on Days 15, 16 and 17 post-treatment; necropsy and gross pathology examinations were conducted and organs weighed as appropriate. Selected tissue samples (kidney, liver, duodenum, jejunum, ileum, abomasum and treatment site (left cheek sulcus) were collected and placed in 10% formalin and forwarded to the designated laboratory for histopathology evaluation. Safety assessment was based on comparison of treated and untreated group clinical signs and haematological and biochemical parameters, trends within groups pre and post-treatment, and gross- and histopathology. 5. STATISTICAL ANALYSIS Data was forwarded by the analytical laboratory as a Microsoft Excel spread sheet. Marker parameters in regard to bovine health were analysed for significant differences between groups by One-Way Analysis of Variance using a commercial software package. Data that were not normally distributed (as determined by Levene s Test of equal variances) were assessed for significant differences using the equivalent non-parametric test (Kruskal-Wallis analysis of variance). Pairwise comparison of means indicated significant or non-significant differences between group means at α = RESULTS General health Page 6 of 7

8 The trial animals were assessed at each clinical examination/observation time point for their general demeanour and overall health. No abnormal visual clinical findings were observed within the groups during the course of the study. Body temperature, heart rate and respiration Results from each individual detailed clinical examination showed that no statistically significant differences were found between Groups 2, 3 and 4 (test formulation at 1X, 3X and 5X respectively) and Group 1 (Control) in relation to body temperature, heart rate and respiration during the study. Bodyweights The calves were weighed before and after treatment and no statistically significant differences were found between Groups 2, 3 and 4 (test formulation at 1X, 3X and 5X respectively) and Group 1 (Control) in relation to bodyweight and bodyweight changes during the study. Haematology/Biochemistry Group arithmetic mean values obtained for the biochemical and haematological parameters and changes within each group over time were calculated. No statistically significant differences were found between Groups 2, 3 and 4 (test formulation at 1X, 3X and 5X respectively) and Group 1 (Control) in relation to the key haematological and biochemical parameters measured during the trial. Gross Pathology Necropsy findings were essentially unremarkable. Gross pathological changes of an incidental nature were identified in three of the twenty-four animals sacrificed. All of these were deemed unrelated to test item treatment. Histopathology Mild histological changes were identified in all of the organs examined, namely liver, kidney, abomasum, small intestine (duodenum, jejunum, ileum) and cheek sulcus. These findings were consistent across Groups 1, 3 and 4 (untreated control group, 3X and 5X respectively) indicating that they are unrelated to treatment. 7. CONCLUSION: The study confirmed the safety of a meloxicam buccal formulation when applied at 1X, 3X and 5X the proposed dose rate of 0.5 mg/kg BW in calves. Page 7 of 7