Elsevier

The Veterinary Journal

Volume 206, Issue 2, November 2015, Pages 183-190
The Veterinary Journal

An analysis of the relative frequencies of reported adverse events associated with NSAID administration in dogs and cats in the United Kingdom

https://doi.org/10.1016/j.tvjl.2015.07.025Get rights and content

Highlights

  • The Veterinary Medicines Directorate collates data regarding adverse events.

  • Frequencies of adverse events related to NSAIDs in cats and dogs were analysed.

  • The most common adverse events were emesis, death, anorexia, lethargy, and diarrhoea.

  • Frequencies of reported adverse events were similar between cats and dogs.

  • Times since authorisation and frequency of event reports were negatively correlated.

Abstract

This study aimed to analyse UK pharmacovigilance data to quantify adverse events (AEs) associated with the non-steroidal anti-inflammatory drug (NSAID) molecules found in veterinary medicines authorised for use in dogs and cats. It was hypothesised that the frequency of AEs would be lower when associated with cyclo-oxygenase-2 selective (coxib), compared to non-selective (non-coxib) NSAIDs. The UK Veterinary Medicines Directorate (VMD) supplied frequencies of AEs derived from Periodic Safety Update Reports subdivided by formulation and species for each NSAID molecule.

Frequencies of AEs were similar between species. The five most reported AEs were emesis, death, anorexia, lethargy, and diarrhoea. Reported frequency of emesis, renal insufficiency and death was higher with injectable compared to oral NSAIDs (P = 0.043). Reported frequency of emesis, lethargy and death was higher with coxib, compared to non-coxib NSAIDs (P = 0.029). Median (range) interval since authorisation was shorter for coxibs at 5 (2.5–9) years compared to non-coxibs at 15 (12–25) years. A negative correlation between time elapsed since authorisation and the frequency of AEs was identified (rs = −0.11 to −0.94). Higher frequency of reported AEs with injectable NSAIDs may be related to perioperative administration. The AE frequency associated with coxib and non-coxib NSAIDs may be confounded by changes in reporting habits over time.

This study highlights the value of interrogating passive surveillance data to identify low frequency AEs and the need to facilitate improvement in recording and collecting AEs in small animal practice.

Introduction

Prescription of non-steroidal anti-inflammatory drugs (NSAIDs) to dogs and cats is commonplace for perioperative analgesia (Farnworth et al, 2014, Hunt et al, 2015) and management of painful inflammatory conditions such as osteoarthritis (Sanderson et al, 2009, Sparkes et al, 2010). Concern exists amongst veterinary surgeons (Capner et al, 1999, Hugonnard et al, 2004) and pet owners1, 2 about potential adverse effects (AEs) of NSAIDs in pet animals.

An AE is defined by the International Cooperation on Harmonisation of Technical Requirements for Registration of Veterinary Medicinal Products (VICH) as ‘any observation in animals, whether or not considered to be product-related, that is unfavourable and unintended and that occurs after use of a Veterinary Medicinal Product (VMP) (off-label and on-label uses)’. Most NSAID AEs are mild and self-limiting (Forsyth et al, 1998, Leong, Chan, 2006), although serious AEs, defined by the VICH as ‘an event which results in death, is life-threatening, results in persistent or significant disability/incapacity, or a congenital anomaly or birth defect’, coincident with NSAID administration are reported (Duerr, 2004, Enberg et al, 2006).

It has been proposed that selective cyclo-oxygenase 2 (COX-2) inhibitors decrease NSAID AEs (Simmons et al., 2004). Increased tolerability of COX-2 selective (coxib), compared to non-selective (non-coxib), NSAIDs in dogs (Wooten et al, 2009, Reymond et al, 2012) or cats (Kamata et al, 2012, Sano et al, 2012) has, however, not been reported.

Recently, two reviews of NSAID AEs in dogs have been published. Monteiro-Steagall et al. (2013) concluded that ‘most studies were not appropriately designed to determine the safety of NSAIDs, and involved a healthy non-geriatric population of research dogs’, whilst Innes et al. (2010) commented that ‘robust data on the safety of long-term NSAID use are lacking in large numbers of dogs’. No published studies address the frequency of NSAID AEs in cats. Randomised controlled clinical studies are powered to investigate the efficacy of a drug, and are unlikely to generate valid estimates of the incidence of rare AEs (Tramèr et al., 2000). Moreover, reporting of AEs within clinical trials may not always be complete (Edwards et al., 1999).

The UK Veterinary Medicines Directorate (VMD) administers a passive AE surveillance programme and summary reports are published regularly (Dyer et al, 2011, Dyer et al, 2012). Marketing Authorisation Holders (MAHs) submit Periodic Safety Update Reports (PSURs) to the VMD and these incorporate instances of non-serious AEs that have been reported to the MAH, but may not have generated an AE report to the VMD.

Under-reporting of AEs is likely. Dean et al. (2013) found that the number of reports of feline injection site sarcomas to the VMD in 2007 was fewer than the number identified during a period of active surveillance for the condition. However, the data collated by the VMD represent the most comprehensive record of AEs available for NSAIDs, and was therefore considered appropriate for this analysis. It is recognised that whilst passive surveillance schemes are subject to reporting biases (Wallenstein, Fife, 2001, Hartnell, Wilson, 2004), their value lies in the comparison of the frequency of AEs associated with products which would be expected to be subject to similar biases; and in the identification of ‘signal’ data of low frequency or unanticipated AEs (Williams, 2012).

The aim of this study was to investigate the reported relative frequencies of adverse events (AEs) associated with NSAIDs in dogs and cats. We hypothesised that coxibs would be associated with fewer gastrointestinal AEs, compared to non-coxibs.

Section snippets

Terminology

We considered that the NSAIDs available comprised individual molecules (e.g. carprofen, meloxicam, robenacoxib), which were formulated by MAHs into authorised preparations, which could be injectable or oral formulations.

The VMD supplied cumulative frequencies of AEs, calculated since the date of marketing authorisation (MA) of each molecule (Table 1) and classified in a spreadsheet file (Excel 2007, Microsoft) according to terms for clinical signs given in the European Medicines Agency's

Results

In total, encompassing all molecules, there were 2231 AE reports related to oral administration of NSAIDs in dogs, resulting from approximately 748,000,000 doses given. In cats, 190 AE reports resulted from approximately 60,000,000 administered doses of oral NSAIDs. For injectable NSAIDs, 952 reports were received for cats and dogs, resulting from approximately 46,500,000 doses. The annual number of AE reports, encompassing all drug classes, is shown in Table 4 (G. Davis, personal

Discussion

These data represent the most complete assessment possible of AE reports following NSAID administration in companion species in the UK. Pain management, which may include NSAID prescription, represents a significant contribution of the veterinary profession to animal welfare (Lascelles and Main, 2002). Knowledge of the frequency of reported NSAID AEs contributes to the ability of prescribers to balance benefits with risks of treatment, and informs discussions with animal owners. Until more

Conflict of interest statement

Elanco Animal Health funded the research post of James Hunt but played no role in the study design, in the collection, analysis and interpretation of data, or in the manuscript writing or submission for publication. None of the authors has any other financial or personal relationships that could inappropriately influence or bias the content of the paper.

Acknowledgements

With thanks to Sue Cooles and the Pharmacovigilance Unit of the VMD. The Centre for Evidence-based Veterinary Medicine is supported by an unrestrictive grant from Elanco Animal Health and The University of Nottingham. Initial results were presented as an abstract at the Association of Veterinary Anaesthetists Spring Meeting, 24–25 April 2014, Nottingham, UK.

References (41)

  • C.A. Capner et al.

    Current British veterinary attitudes to perioperative analgesia for dogs

    Veterinary Record

    (1999)
  • P. Chhabra et al.

    Adverse event reporting patterns of newly approved drugs in the USA in 2006: An analysis of FDA adverse event reporting system data

    Drug Safety

    (2013)
  • S.R. Cox et al.

    Population pharmacokinetics of mavacoxib in osteoarthritic dogs

    Journal of Veterinary Pharmacology and Therapeutics

    (2011)
  • R.S. Dean et al.

    The incidence of feline injection site sarcomas in the United Kingdom

    BMC Veterinary Research

    (2013)
  • F. Duerr

    Challenging diagnosis – icterus associated with a single perforating duodenal ulcer after long-term nonsteroidal anti-inflammatory drug administration in a dog

    The Canadian Veterinary Journal

    (2004)
  • F. Dyer et al.

    Suspected adverse events, 2010

    Veterinary Record

    (2011)
  • F. Dyer et al.

    Suspected adverse events, 2011

    Veterinary Record

    (2012)
  • T.B. Enberg et al.

    Gastrointestinal perforation in five dogs associated with the administration of meloxicam

    Journal of Veterinary Emergency and Critical Care

    (2006)
  • M. Farnworth et al.

    Veterinary provision of analgesia for domestic cats (Felis catus) undergoing gonadectomy: A comparison of samples from New Zealand, Australia and the United Kingdom

    New Zealand Veterinary Journal

    (2014)
  • A.P. Fletcher

    Spontaneous adverse drug reaction reporting vs event monitoring: A comparison

    Journal of the Royal Society of Medicine

    (1991)
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