Anses – rapport annuelWhile pharmacovigilance mainly involves adverse effects related to...

Scientific EditionSeptember 2015

Veterinary Pharmacovigilance 2014 annual report of the French veterinary pharmacovigilance network

Annual Report

ANSES • annual report Veterinary pharmacovigilance - 2015 edition

French Agency for Veterinary Medicinal Products

VETERINARY PHARMACOVIGILANCE

2014 annual report of the

French veterinary

pharmacovigilance network

Fougères, September 2015

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Authors: French Agency for Food, Environmental and Occupational Health & Safety (ANSES) - French Agency for Veterinary Medicinal Products (ANMV)

Delphine BARBOT, Elisabeth BEGON, Luc CHARLES, Cédric COLMAR, Eric FRESNAY, Sylviane LAURENTIE, Jean-Pierre ORAND, Catherine SALLARD, Grégory VERDIER and Gwénaëlle VOISIN - ANSES-ANMV

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Contents Summary .......................................................................................................................................................... 4 INTRODUCTION ................................................................................................................................................ 7

I - INSPECTION OF VETERINARY PHARMACOVIGILANCE ACTIVITIES ................................................ 7

I - 1 The establishments concerned .........................................................................................................7

I - 2 Review of 2014 ..................................................................................................................................9

II - PHARMACOVIGILANCE DATA ................................................................................................. 16

II - 1 The reporters and reporting channels .......................................................................................... 16

II - 2 Change in the number of reports over the past 5 years ............................................................... 17

III - SERIOUS AND NON-SERIOUS CASES IN ANIMALS IN 2014 ....................................................... 19

III - 1 Breakdown of cases by species .................................................................................................... 19

III - 2 Breakdown of reported adverse events by species and therapeutic category ............................ 19

III - 3 Analysis of reported adverse events by therapeutic category of medicinal products used and by species ................................................................................................................................................... 21

III - 4 Breakdown of cases by type of information ................................................................................ 26

IV – SPECIFIC ACTIONS IN 2014 ................................................................................................... 31

IV – 1 Training of veterinarians ............................................................................................................. 31

IV – 2 Communication actions ............................................................................................................... 32

IV – 3 Actions with respect to the industrial sectors ............................................................................. 33

IV - 4 Under-reporting ........................................................................................................................... 34

IV - 5 Good pharmacovigilance practices .............................................................................................. 35

CONCLUSION .................................................................................................................................................. 36 ANNEX 1: The French veterinary pharmacovigilance system .......................................................................... 40 ANNEX 2: CHANGES TO MAs RELATED TO PHARMACOVIGILANCE REPORTED IN 2014 ................................. 42

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Summary

Veterinary medicinal products are only granted marketing authorisation (MA) if an assessment of data on their quality, safety and efficacy shows that the benefits associated with their use outweigh the risks. The various clinical trials undertaken as part of an MA application may reveal a number of adverse events that are likely to occur following the use of a medicinal product. However, since these trials are conducted in a limited number of animals under standardised conditions of use, the large-scale use of a medicinal product under real-life conditions once it has obtained an MA can further highlight adverse reactions to this medicinal product and reveal potential risk factors (species, breed, age, pre-existing conditions, etc.).

The objective of pharmacovigilance is to detect any emerging signs as early as possible, whether these are unexpected adverse events or expected adverse events whose frequency or severity is unexpected, and then to take appropriate risk control measures such as adding a precaution for use or withdrawing a product's marketing authorisation (MA).

The current scope of veterinary pharmacovigilance is very broad since it encompasses:

- the reporting of adverse events in animals after administration of a veterinary medicinal product or a medicinal product for human use in the framework of the 'cascade' approach,

- the reporting of adverse events in humans after exposure to a veterinary medicinal product,

- the collection of information about suspicions of lack of efficacy, - issues regarding withdrawal periods and residues, - environmental issues.

MA holders are obliged to establish a pharmacovigilance system that enables them to meet their different regulatory obligations, especially in terms of recording, communicating and assessing any adverse events. In France, the companies with this responsibility are pharmaceutical establishments authorised by ANSES-ANMV as veterinary medicinal product distributors, and are subject to regular controls by ANSES-ANMV inspectors. Review of the inspection mission in pharmacovigilance Currently, 59 establishments have the status of distributor, and in accordance with the Decisions made by the Director General of ANSES concerning frequency of inspections, 12 to 15 sites responsible for pharmacovigilance are inspected annually by the ANMV. This does not include any inspections related to specific events.

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The results of the 2014 inspections show that the pharmacovigilance systems in place are operational. The main areas for improvement concern the processes for organisation of the pharmacovigilance systems, the quality management process, risk management, management of adverse events and the regulatory obligations of the entity responsible for pharmacovigilance. Review of adverse events in animals in 2014 Between 2013 and 2014, the number of reports increased by 12.6%. In 2014, the ANMV recorded 3593 cases of adverse events in animals in its national database, 44% of which were considered serious. This number includes all reports submitted either directly to the authorities, i.e. to ANSES-ANMV and the Veterinary Pharmacovigilance Centre in Lyon, or electronically by MA holders to ANSES-ANMV. Around 90% of the reports submitted to the authorities were sent by veterinary practitioners. Animal owners and breeders submitted 7.4% of all reports. As in previous years, the vast majority of the adverse events reported in 2014 involved domestic carnivores, with 83.9% of reports involving dogs or cats. Cattle accounted for 8.1% of all reports. Other species accounted for less than 3% per species. The relative weight of the different therapeutic categories involved varied by species. In domestic carnivores, antiparasitics were the primary therapeutic category (34% for dogs and 55% for cats). In cattle, antimicrobials were the leading category (27%). Rather than particular risk profiles, the above figures reflect significantly higher exposure in these animal populations to certain types of products and/or greater responsiveness on the part of the reporters to events occurring in healthy animals. The breakdown between serious and non-serious cases varied depending on the therapeutic category: for ectoparasiticides and endoparasiticides, reports mostly concerned non-serious cases (70% and 65% respectively). In contrast, for vaccines and non-steroidal anti-inflammatory drugs, the reports primarily concerned serious cases (71% and 54% respectively).

Pharmacovigilance beyond the strict scope of adverse events While pharmacovigilance mainly involves adverse effects related to veterinary medicinal products in the strict sense, it also concerns suspicions of lack of efficacy, information about potential environmental risks and information about the validity of withdrawal periods for veterinary medicinal products. However, cases of adverse effects in animals are clearly dominant since they accounted for 91% of all reports. Suspicions of lack of efficacy accounted for 8% of all reports and other cases accounted for less than 1%. Adverse events resulting from uses not specified on the Summary of Product Characteristics (SPC) In a few cases defined by the regulations, a veterinary practitioner can prescribe the use of a medicinal product outside the terms of its MA (off-label use). Of the 3593 cases concerning animals

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that were reported in 2014, 1191 (33%) involved uses outside the terms defined in the marketing authorisations. The main species involved were cats (51% of reports) and dogs (36%). This breakdown by species is fully comparable to the results obtained in previous years. Key events in 2014 Promotion and communication As part of efforts to promote pharmacovigilance among veterinarians, ANSES-ANMV continued with various training activities in 2014. These were intended both for veterinary students and mandated veterinarians.

Another priority theme sought to show reporters that by reporting adverse events, they can help improve how the medicinal products are used. ANSES-ANMV has thus put in place different communication measures via the ANSES website, as well as press releases, participation in professional conventions and articles in specialised journals.

Specific actions have also been implemented by ANSES-ANMV to identify obstacles to reporting in the industrial production sectors. As part of this, a field survey was carried out among the various stakeholders in the pig and poultry sectors (farmers, technicians and veterinarians). Good pharmacovigilance practices In 2014, the Director General of ANSES signed a Decision on good pharmacovigilance practices. The goal is to supplement the regulatory principles defined in the French Public Health Code on the operation of establishments with obligations in the area of pharmacovigilance, by operational and technical specifications in this area. Conclusion The results of the 2014 assessment show that the total number of reports continues to increase steadily. In terms of breakdown by species and therapeutic category, the results are generally comparable to those obtained in previous years and confirm that the national system in place is fully capable of detecting new signals and thus supplementing the available knowledge on veterinary medicinal products.

In 2015, ANSES-ANMV will be investing considerable efforts in the upcoming debates on the reform of the EU veterinary pharmaceutical regulations. In fact, in the light of its experience and position at European level, the ANMV provided its own contribution during the consultation on the draft text published by the European Commission in September 2014, in order to ensure that the new reform is as efficient as possible. The pharmacovigilance department is also involved through the launch of an IT project covering both the reform of the national database of adverse events and the revision of the electronic submission website.

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INTRODUCTION According to the WHO definition, pharmacovigilance means the "science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problem". The scope of veterinary pharmacovigilance encompasses:

- the reporting of adverse events in animals after administration of a veterinary medicinal product or a medicinal product for human use in the framework of the ‘cascade’ approach (Articles 10 and 11 of Directive 2001/82/EC ),

- the reporting of adverse events in humans after exposure to a veterinary medicinal product,

- the collection of information about suspicions of lack of efficacy, - issues regarding withdrawal periods and residues, - environmental issues.

MA holders are obliged to establish a pharmacovigilance system that enables them to meet their different regulatory obligations, especially in terms of recording, communicating and assessing any adverse events. In France, the companies with this responsibility are pharmaceutical establishments authorised by ANSES-ANMV as veterinary medicinal product distributors, and they are subject to regular controls by ANSES-ANMV inspectors.

I - INSPECTION OF VETERINARY PHARMACOVIGILANCE ACTIVITIES

ANSES-ANMV is responsible for enforcing application of the regulatory provisions in the field of veterinary pharmacovigilance.

This action mainly involves the inspection of veterinary pharmaceutical establishments engaged in pharmacovigilance activities.

I - 1 The establishments concerned Monitoring of unexpected adverse events or pharmacovigilance of veterinary medicinal products is carried out by the establishments responsible for placing the products on the market. The entity in charge of doing so is either the MA holder distributing its medicinal products in France from another country in the European Union, or an establishment based in France. In the latter case, the pharmaceutical company acquires the status of veterinary medicinal product distributor and must have an authorisation issued by ANSES-ANMV prior to acting as such. Alongside their pharmacovigilance activities, these companies are generally in charge of advertising, marketing, distribution, batch monitoring, claims and batch recalls, for which they are also inspected.

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Pharmacovigilance activities also involve establishments that: • prepare autovaccines, • hold a parallel import authorisation, • are responsible for the marketing of medicinal products subject to registration (homeopathic

medicines). There are therefore 59 establishments qualified with the status of distributor and subject to inspection by the ANMV. Among these, 19 organisations are also veterinary medicinal product manufacturers. In addition, there are four establishments producing autovaccines and three companies benefiting from a parallel import authorisation.

In accordance with the Decision of the Director General of ANSES1, relating to the adopted frequency of inspections, 12 to 15 sites responsible for pharmacovigilance are inspected every year by the ANMV. Planning takes into account the risk analyses formulated in view of the activities, which are revised after each inspection.

Inspection objectives and reference standards Since pharmacovigilance inspections began in 2004, the reference standards have changed:

• First inspection cycle (2004-2006): raising awareness of GMP2-GDP3, of Volume 94 , and of the French Public Health Code (CSP),

• Second inspection cycle (2007-2009): GMP-GDP-CSP-Vol. 9 and awareness of the new European guideline5,

• Third inspection cycle (2010-2013): GMP-GDP-CSP-Vol 9 - European guideline and awareness of Volume 9b,

• Fourth inspection cycle (2013-2016): GMP-GDP-CSP-Vol 9b6 and awareness of new GVPP7. The main aims of inspection are to:

• determine which personnel, resources, systems and facilities have been deployed by the entity responsible for placing the product on the market to meet the pharmacovigilance requirements,

• identify, record and report any nonconformities that may pose a risk to public health.

Type of inspection The term "pharmacovigilance inspection" comprises several types of inspection:

• Inspection of the entire pharmacovigilance system or inspection focused on pharmacovigilance for one product.

1 Decision of 17 September 2008 establishing the frequency of inspections of veterinary pharmaceutical establishments: 3 years maximum for distributors/manufacturers, 4 years for establishments that only distribute. 2 Good Laboratory Practices 3 Good Distribution Practices 4 EudraLex - Volume 9 Pharmacovigilance guidelines (2004) 5 EudraLex -Guidelines on Monitoring of Compliance with Pharmacovigilance Regulatory Obligations and Pharmacovigilance Inspections for Veterinary Medicinal Products. (2007) 6 EudraLex -Volume 9B - Guidelines on Pharmacovigilance for Medicinal Products for Veterinary Use (October 2011) 7 Decision No. 2014-01-31 of 5 March 2014 relating to good veterinary pharmacovigilance practices

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These inspections are planned in the framework of the national inspection programme managed by ANSES-ANMV, or at the request of the EMA for the European inspection programme.

Duration of inspections The duration of the pharmacovigilance inspections varies depending on:

• the type of inspection, • the size of the organisation responsible for placing the product on the market, the number

and type of veterinary medicinal products managed, • the composition of the inspection team (inspectors + experts).

When inspecting the systems set up by the entities responsible for placing the product on the market, inspectors may spend a quarter of their time on an overall assessment of how the pharmacovigilance activities are organised.

The pharmacovigilance inspections conducted at the request of the EMA take place over a longer period, lasting up to three days. In this case, the inspections are primarily focused on the pharmacovigilance system for one or more specific MAs.

Use of inspection results Each inspection is described in a report that, at the end of the adversarial process, enables the Director of the ANMV to rule on the level of compliance of the establishment’s activities according to the applicable standards. The statistical analysis of the data presented below focused on deviations identified in all the reports from 2014.

I - 2 Review of 2014

Quantitative data The ANMV conducted 16 pharmacovigilance inspections in 2014. In terms of planning, 13 establishment inspections were scheduled according to the regulatory frequency, one follow-up inspection took place earlier than scheduled for verification of the corrective action plan, and two pharmacovigilance inspections were carried out at the request of the EMA (related to MAs obtained according to centralised procedures). These 16 inspected sites included three new distributor sites and two establishments producing autovaccines. In 2014, 47 deviations were noted in the field of pharmacovigilance: none critical or requiring formal notice related to pharmacovigilance were issued during this period. The main unsatisfactory areas concerned organisation of the pharmacovigilance, the quality management and risk management process, management of adverse events and the regulatory obligations of the entity responsible for pharmacovigilance (RPhv).

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Figure 1: Classification of deviations noted during the pharmacovigilance inspections in 2014 Inspected pharmacovigilance process Number of deviations Process linked with PHV organisation 23

Contracts 11 Training 7

Delegation of key responsibilities 4 Interaction with affiliates 1

Process linked with regulatory duties of the RPhv 6 Responsibilities 4 Oversight of the PHV system 1 RPhv replacement 1

Process linked with quality and risk management 6 Self-inspection 3 Documentation - quality system elements/SOP 2 Corrective and preventive actions (CAPA) 1

Process linked with adverse event management 5 Management of adverse reactions 4 Management of other kinds of PHV reports 1

Process linked with surveillance 5 Literature search 2 Signal detection 2 Continuous benefit/risk assessment 1

Process linked with PHV data 2 Electronic data management 2

GENERAL TOTAL 47

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Figure 2: Frequency of deviations observed in 2014 by major pharmacovigilance process

Analysis, summary of the deficiencies noted and profile of the associated risks An assessment of all the deviations identified during 2014 helped identify the main risks related to the pharmacovigilance activities inspected in this period:

• The inspectors found shortcomings in the contractual arrangements relating to pharmacovigilance activities. These mainly relate to pharmacovigilance activities divided between two pharmaceutical companies responsible for placing the same product on the market (11 deviations). These inadequacies, mainly concerning formalisation of the respective responsibilities of each party involved and the way in which pharmacovigilance data are shared, may make it difficult for these establishments to meet their obligations with regard to pharmacovigilance. The diagnosis related to these observations shows a risk of breakdown of traceability and loss of data.

• An analysis of the deviations also revealed failures relating to the staff involved in the pharmacovigilance system. Firstly, deficiencies relating to shortcomings in establishment organisation charts, job descriptions and delegation of responsibilities (4 deviations) may

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prevent the head of pharmacovigilance from guaranteeing effective supervision of the distributor’s pharmacovigilance system. Secondly, the absence or inadequacy of the assessment of training provided to staff likely to be involved at different levels in the pharmacovigilance system (7 deviations) reflects a certain lack of proficiency in the process of acquisition and consolidation of knowledge and know-how that is essential to the implementation of veterinary pharmacovigilance within pharmaceutical companies. These deficiencies, taken together, give rise to a risk of failure to detect a deviation from a process.

• Lastly, the inspectors noted some shortcomings in the management of adverse events (4 deviations concerning severity, causality, reporting, etc.). These shortcomings are likely to create a risk of failure in the safety or efficacy profile of the medicinal product as assessed and authorised.

Changes since 2009 Since 2009, the number of inspections has remained stable except for 2013, for which a higher number of inspections was carried out in connection with the training of an inspector.

Figure 3: Changes in pharmacovigilance inspections carried out by ANSES-ANMV over the period 2009-2014

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Figure 4: Number of deviations identified by ANSES-ANMV over the period 2009-2014

Despite variations in the proportions for each category, the ranking of the types of deviations has been constant in recent years.

Figure 5: Distribution of the deviations identified by ANSES-ANMV over the period 2009-2014 by major category

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European and international activities The inspection unit has a representative on the European Pharmacovigilance Inspectors Working Group set up by the EMA. With its significant experience of inspection in pharmacovigilance, ANSES-ANMV has been a driving force for proposals and led the European WG in the definition of inspection reference standards in the veterinary field. The group’s main task is to harmonise and coordinate activities related to pharmacovigilance and inspection at EU level. Each member is involved in the preparation of guidelines and procedures for inspection and pharmacovigilance, and plays a key role in developing collaborative projects within the EU. At the same time, the EMA draws on the inspection unit's expertise to carry out pharmacovigilance inspections of MA holders based in France or Europe for products authorised via the centralised procedure. In 2008 the ANMV also joined the Pharmaceutical Inspection Cooperation Scheme (PIC/S), an international organisation of 46 authorities whose main objectives are to develop recommendations for good practice in the pharmaceutical field. The PIC/S, which has extended its mandate and sphere of competence to good pharmacovigilance practice and good clinical practice, created an ad-hoc working group in 2014 in which the ANMV participates.

Outlook for 2015 For 2015, the main objectives for pharmacovigilance inspections are to ensure compliance with the frequency of inspections, to assess compliance with Volume 9B and with the French good veterinary pharmacovigilance practice guidelines published in 2014, and to implement inspections at the request of the CVMP.

In connection with the results from the analysis of the risks identified during the 2014 inspections, inspections of the pharmacovigilance systems in 2015 will endeavour to focus special attention on the following points:

1. Risk of breakdown of traceability and loss of data through incomplete or absent contracts (Focal point in 2014 maintained for 2015):

• Description of responsibilities and respective contacts identified, • Deadlines set for reporting adverse events, and verifying compliance with these

deadlines, • What happens to the data if the planned contract is breached;

2. Failure to detect a deviation from a process through a deficient quality management system: • Staff training, • Organisational procedures, job descriptions and organisation chart;

3. Failure in the safety or efficacy profile of the medicinal product through poor management of adverse events:

• Procedures for assessing adverse events (criteria of severity, causality, expected/unexpected nature, VeDDRA coding, etc.),

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• Procedures for reporting adverse events.

Lastly, the 2015 inspection programme will target: • specific problems at on the request of the ANMV's pharmacovigilance department; • specific veterinary drugs at the request of the MA department, in particular related to MAs

accompanied by risk management plans.

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II - PHARMACOVIGILANCE DATA

II - 1 The reporters and reporting channels The typology of reporters in 2014 was very similar to that observed in previous years: veterinarians were responsible for the majority of reports made in France (89.3% by private veterinarians and 3.2% via veterinary schools in 2014).

These reports are sent either to the authorities, i.e. ANSES-ANMV and the Veterinary Pharmacovigilance Centre in Lyon (CPVL), or to the pharmaceutical companies concerned: the MA holders.

All the reports transmitted either to the CPVL or directly to ANSES-ANMV are recorded in the national veterinary pharmacovigilance database.

Regarding the reports sent to the MA holders, they have a regulatory requirement to transmit reports of all serious cases occurring in France to ANSES-ANMV, by electronic means, within 15 days. However, at present, the requirement to promptly transmit reports does not apply to non-serious cases. Nevertheless, these non-serious cases are also saved and analysed by the MA holders, although they are only brought to the attention of ANSES-ANMV when the MA holders submit their periodic safety update reports (PSURs). These PSURs provide a summary of all the cases (serious and non-serious cases collected and analysed by the MA holder) and are transmitted according to a schedule defined by the regulations. Thus, non-serious cases may only be brought to the attention of ANSES-ANMV as much as three years after they occur.

For the purposes of this document, for reports transmitted by MA holders, only those transmitted electronically have been taken into account.

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In 2014, 69% of the reports recorded in the national database had been sent directly to the authorities (see graph below). This breakdown between authorities and MA holders is comparable to that observed in 2013 (73.7%). However, compared to previous years, an increase in reports sent directly to ANSES-ANMV, as well as those collected by the MA holders, should be noted.

II - 2 Change in the number of reports over the past 5 years The graph below shows the increase in the number of reports taking into account the reports recorded each year, apart from bluetongue reports, which represented an epiphenomenon recorded between 2008 and 2010 (see the veterinary pharmacovigilance annual reports from 2011 to 2013).

The data correspond to the number of reports of adverse events occurring in animals following administration of a veterinary medicinal product or a medicinal product for human use in the framework of the "cascade" approach.

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The total number of reports continues to increase steadily. Since 2010, this increase has been 40%, and 12.6% compared to last year. This increase relates to both serious and non-serious cases.

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III - SERIOUS AND NON-SERIOUS CASES IN ANIMALS IN 2014

Between 2013 and 2014, the number of spontaneous reports concerning animals increased by 12.6%. On the other hand, the breakdown between serious and non-serious cases was practically identical over these two years (43.9% of serious cases in 2013, compared with 44.9% in 2014).

III - 1 Breakdown of cases by species As in 2013, the vast majority of the adverse events reported in 2014 involved domestic carnivores, with 83.8% of reports involving dogs or cats. Cattle accounted for 8.1% of all reports. Other species accounted for less than 3% per species each time.

III - 2 Breakdown of reported adverse events by species and therapeutic category A single report may concern several medicinal products and each medicinal product belongs to a specific therapeutic category. This explains why, in 2014, 4682 medicinal products were mentioned in the 3593 reports collected for animals. A breakdown of adverse events by species and therapeutic category(ies) for the medicinal products mentioned in these reports is given below.

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Dogs Cats CattleHorses/ Donkeys

Sheep Goats Pigs Rabbits PoultryExotic pets/

WildlifeOther Total

Ectoparasiticides 519 568 11 4 0 1 0 0 0 19 34 1156Endoparasiticides 267 325 79 15 10 4 2 2 5 10 0 719Antimicrobials 143 90 102 15 2 6 2 3 9 12 0 384Anti-inflammatories (NSAIDs) 135 42 22 11 1 2 0 0 0 1 0 214Vaccines 471 204 79 29 13 9 45 6 10 32 1 899Nervous system/Anaesthetics 234 146 20 33 2 0 2 0 0 5 0 442Digestive tract 73 52 22 3 0 0 0 0 1 4 0 155Hormones 71 30 3 4 0 0 0 0 0 1 0 109Genital and reproductive organs 81 12 25 0 0 1 0 0 0 0 0 119Cardiovascular and circulatory system 76 72 3 0 0 1 0 0 0 1 0 153Dermatology 36 19 2 2 0 0 0 0 0 1 0 60Other 180 76 10 1 0 0 5 0 0 0 0 272Total 2286 1636 378 117 28 24 56 11 25 86 35 4682

Reports involving rabbits were divided between cases occurring in industrial facilities ("rabbits" column) and cases occurring in domestic rabbits ("exotic pets" column). The main therapeutic categories mentioned in the pharmacovigilance reports are listed in the table above. Regarding the drugs grouped in the "other" category, they overwhelmingly relate to ear drops and ointments, eye drops, immunomodulatory products or vitamins. It should be noted that since certain types of medicinal products are frequently used in combination (e.g. anaesthetics and certain vaccines), the total percentages for their categories are considerably increased. In terms of breakdown between serious and non-serious cases, the graph below shows that for ectoparasiticides, 70% of reports were classified as non-serious. The main clinical signs reported were primarily of three types:

- Gastrointestinal (vomiting, anorexia, hypersalivation, diarrhoea, etc.), especially in the event of accidental ingestion of the product, usually by licking;

- Neurological (tremors, lethargy, hyperactivity, mydriasis, etc.) related to their mechanism of action;

- Local reactions at the application site (erythema, pruritus, depilation, etc.) in the event of intolerance to the product in some animals.

For endoparasiticides, 65% of reports were classified as non-serious. As above, the main associated symptoms were neurological (ataxia, lethargy, tremors, etc.) and/or gastrointestinal disorders (vomiting, diarrhoea, anorexia, hypersalivation, etc.). In contrast, for vaccines, 71% of recorded cases were serious. They mainly concerned post-vaccination febrile reactions (lethargy, hyperthermia, etc.) and/or hypersensitivity (allergic oedema, vomiting, diarrhoea). Several cases of anaphylactic reactions led to the death of the animals. Similarly, for non-steroidal anti-inflammatory drugs (NSAIDs), 54% of cases were serious. They mainly concerned gastrointestinal disorders (vomiting, gastro-duodenal ulceration), kidney and liver disorders, as well as some cases of anaphylaxis.

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Lastly, for antimicrobials, 49% of reports were serious. Again, the main signs described were hypersensitivity reactions (vomiting, respiratory disorders, ulcers, tremors, etc.), with several cases of mortality.

This breakdown by therapeutic category is fully comparable to that observed in 2013.

Concerning autovaccines, which in France are included in the scope of pharmacovigilance in the same way as other drugs, three reports were recorded in 2014, all describing local inflammation following accidental injections in humans.

III - 3 Analysis of reported adverse events by therapeutic category of medicinal products used and by species

III.3.a - Dogs In 2014, in dogs, the collected reports were mainly related to ectoparasiticides (23%), vaccines (21%) and endoparasiticides (12%). The other therapeutic categories each accounted for 10% or less of reports.

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Regarding the breakdown between serious and non-serious cases, 59% of reports related to non-serious cases.

For this species, 76.7% of cases relating to ectoparasiticides were classified as non-serious. For the other therapeutic categories, the observed breakdown between serious and non-serious cases was very similar to that obtained for all species combined.

In terms of clinical profile, the described effects were mostly consistent with the general analysis presented above by therapeutic categories: gastrointestinal (vomiting, hypersalivation, diarrhoea, etc.) and nervous symptoms (tremor, ataxia, hyperactivity, etc.) for antiparasitics, and febrile (lethargy, hyperthermia, anorexia, etc.) and/or hypersensitivity reactions for vaccines. Local reactions at the administration site were also described fairly regularly for products for external use (ectoparasiticides) or vaccines (inflammation at the injection site, itching).


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III.3.b - Cats In cats, ectoparasiticides accounted for 35% of reports and endoparasiticides 20%. Vaccines were involved in 12% of cases. As with dogs, the other therapeutic categories each accounted for 10% or less of reports.

35%

20%5%

3%

12%

9%

3%

2%

1%

4%

1%

5%

Cats

Ectoparasiticides

Endoparasiticides

Antibiotics

Anti-inflammatory drugs (NSAIDs)

Vaccines

Nervous system/Anaesthetics

Digestive tract

Hormones

Genital and reproductive organs

Cardiovascular and circulatory system

Dermatology

Other

The breakdown between serious and non-serious cases by therapeutic category was quite similar to that observed for other species, except for the category of ectoparasiticides, for which 36.6% of cases were serious in this species.


Concerning the clinical profile of the reported adverse events, it is quite consistent with the general trend described in the previous paragraphs. However, all cases combined, the symptomatology of the cases involving ectoparasiticides proves significantly more serious, mainly because of the cases involving permethrin (whose typical toxic effects in cats primarily include severe tremors and convulsions, which can lead to the death of the animal). Leaving aside these specific cases, the profile of the cases associated with other antiparasitics appears quite similar to that described in dogs, essentially neurological signs (lethargy, ataxia, mild tremors) and gastrointestinal disorders in the event of ingestion (vomiting, anorexia, diarrhoea).

Apart from the specific situations mentioned above, the clinical profile of the other cases remains fairly conventional, depending on the therapeutic categories concerned: nervous and gastrointestinal

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signs for antiparasitics (as well as local reactions at the application site for external formulations), and febrile and anaphylactic reactions (and inflammatory reactions at the injection site), essentially for vaccines.

III.3.c Cattle For cattle, vaccines accounted for 21% of all reports. Endoparasiticides were mentioned in 21% of reports and antimicrobials in 27%.

Within the antimicrobials category, approximately 30% of the products involved were beta-lactams (including 12% cephalosporins), which are also the most widely used antimicrobials in cattle (see the ANSES report "Sales survey of veterinary medicinal products containing antimicrobials in France in 2014"). Macrolides followed, with 11% of antimicrobials involved, while quinolones accounted for just under 7%.

In cattle, the reports relate mainly to serious cases (78%). However, given the requirements of livestock production systems, the problems (especially adverse events) likely to be encountered with veterinary drugs are only generally reported – to veterinarians and therefore to the competent authorities – when the zootechnical and/or financial consequences are significant. Thus, reports mainly concern only serious cases.

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Due to the reporting of mainly serious cases in cattle – compared to domestic carnivores – and the significantly different profile of the products used (with a very high preponderance of internal antiparasitics over external formulations), the clinical profile of the adverse events reported also varies. Indeed, while the nature of the clinical signs associated with the different therapeutic categories is consistent with the general trend, their relative weight is modified. Thus, since vaccines are among the most frequently cited products, the main symptoms described concern anaphylactic reactions (and more rarely febrile events). Moreover, these hypersensitivity reactions are not specific and may also occur with other products such as antimicrobials (also mentioned more here than in dogs and cats). Cases of reproductive disorders (including abortion) are also proportionally more frequent than in pets, whether they relate to (suspected) direct effects of products or the consequences of other mechanisms (especially severe fever or hypersensitivity reactions). Lastly, because of the specific nature of livestock production in terms of epidemiological context, treatment methods and performance monitoring, the respective share of suspected cases of lack of efficacy is much higher in cattle, compared to other species (particularly domestic species). These cases are analysed in the next chapter.


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III - 4 Breakdown of cases by type of information Adverse events typically reported include adverse reactions to veterinary medicinal products in the strict sense, suspicions of lack of efficacy, information on potential environmental risks and information on the validity of withdrawal periods for veterinary medicinal products. The following table shows how the cases reported in 2014 were broken down into these various categories.

Adverse reactions in animals 3283 Lack of efficacy 302 Residue issues 8 Environmental issues 0

As in previous years, cases of adverse reactions in animals made up a clear majority (91%).

Suspicions of lack of efficacy accounted for 8.4% of all reports and other cases accounted for less than 1%. However, since these reports most often related to non-serious cases, they were normally submitted to ANSES-ANMV by MA holders in PSURs and not immediately as the cases occurred.

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Suspicions of lack of efficacy

With 302 reports compared with 179, the number of reports of lack of efficacy increased in 2014, which could testify to greater awareness among veterinarians and farmers of this component of pharmacovigilance, as a result of the communication and training measures implemented in recent years.

41%

20%

17%

4%

5%

2%2%

2%

5%2%

Breakdown by species of cases of lack of efficacy

Dogs

Cattle

Cats

Sheep

Exotic pets

Rabbits

Goats

Horses/Donkeys

Pigs

Poultry

The species most represented in reports concerning lack of efficacy were, as in 2013, dogs (41%), cattle (20%) and cats (17%). Like the previous year, cattle formed a large share in this sub-category compared to the total number of cases by species (where cattle accounted for less than 10% of the total). Compared to last year, there was an increase in reports of lack of efficacy for different therapeutic categories, especially vaccines and reproductive medicines (the share of "other" medicinal products was also increased artificially by a series of reports following a clinical trial and involving a product that is not authorised in France and not classified).

27


0

20

40

60

80

100

120

140

160

180

200

220

Breakdown of cases of lack of efficiency by therapeutic category2013-2014 comparison

2013

2014

The vast majority of cases of lack of efficacy related to vaccines, with 52% in dogs, 70% in cats and 47% in cattle. Very often, the suspected lack of efficacy was based on the occurrence of disease in the vaccinated animals, whereas some products are only intended to provide partial protection against certain diseases.

Moreover, the vaccine protocols (number of injections to perform, precise timetable, minimum age of animals, etc.) necessary to achieve effective immunity may not always be strictly followed (in particular when the disease occurs before the end of primary vaccination). Assessing these cases is quite complex and requires consideration of multiple factors, and most of the time the actual conditions of use of vaccines (failure to follow protocols, pre-existing infections at vaccination, etc.) mean that no conclusions can be drawn about a possible failure in the products.

Besides vaccines, the other categories of veterinary drugs mainly involved in a suspected lack of efficacy were antiparasitics: ectoparasiticides in domestic carnivores (respectively 11% of cases of lack of efficacy reported in cats and 6% in dogs) and endoparasiticides in cattle (8%). However, as with vaccines, it is generally difficult to reach any conclusion about a possible lack of efficacy of the drug used, because several other factors, including infestation pressure in the animal environment, are also involved. In addition, in cattle in particular, antimicrobials are also involved in 22% of cases of suspected lack of efficacy.

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In domestic carnivores, the other therapeutic categories involved in the suspicions of lack of efficacy were:

- anaesthetics and sedatives (especially regarding unsatisfactory results of anaesthetic protocols),

- reproductive medicines, and in particular those intended to induce abortions.

Issues of residues

Like last year, cases involving suspicions of veterinary drug residues in milk were reported. In this regard, eight reports were submitted to ANSES-ANMV in 2014, all involving milk samples declared "positive" for inhibitors under the official method for testing for antimicrobial residues in milk. However, in most of these cases, quantification or identification of the incriminated compounds was unavailable.

Depending on test sensitivity, some compounds can be detected at a level below the MRL (Maximum Residue Limit), others above it and the majority around it.

To use these positive results to call into question the withdrawal periods for the drugs concerned, it is necessary to ensure that the inhibitor detected is indeed the suspected compound and that the drug involved was used in accordance with its SPC. In these cases, only a specific quantitative analysis of residues in the affected milk samples and the identification of a residue level above the MRL after the withdrawal period has elapsed can characterise a problem with the withdrawal period that justifies a case for pharmacovigilance. Based on the data submitted in the reports, it is not presently possible to draw any conclusions regarding the presence of veterinary drug residues, due to the use of qualitative multiresidue testing that is unable to define either the levels or nature of the residues found in the samples. Therefore, all of these reports have been classified in category ‘O’. It should be noted however that this type of report is important: even though their individual case assessments do not appear satisfactory, they can serve as alerts to the appearance of new potential problems.

It should also be noted that, independently of pharmacovigilance, the public authorities implement a plan for the monitoring and control of veterinary drug residues in the food chain every year.

Environmental problems

In 2014, no cases of adverse effect on the environment were reported. The results from the previous years show that, apart from possible accidents (in particular wild animals consuming the carcasses of euthanised animals), the veterinary pharmacovigilance system cannot be used to identify possible environmental problems.

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Off-label use

The French Public Health Code (Article L.5143-4) defines the conditions under which a veterinary practitioner can prescribe the use of a medicinal product outside the scope of its authorisation. Of the 3593 animal cases reported in 2014, 1191 (approximately 33% of reports) involved uses outside the terms defined in the marketing authorisations. However, this number is probably underestimated, since apart from obvious cases, such as a target species not provided for in the MA, and in the absence of a formal mention of off-label use, adverse events are by default considered to have occurred following administration within the framework of a medicinal product's authorisation.

The main species involved were cats (51% of reports), dogs (36%) and cattle (4%). This breakdown by species is quite comparable to the results obtained in 2013, with respectively 48%, 38% and 4% in these three species. It may also be noted that 3.8% of off-label reports related to Exotic pets/Wildlife (5.8% in 2013). This result is not surprising since few veterinary drugs are authorised in these minority species. These reports related mainly to pet rabbits and ferrets.

51,4%

36%

3,9%3,8%

2,1%

0,8%1%

0% 0,1%

0,3% 0,3%

Breakdown of cases of off-label use by species

Cats

Dogs

Cattle

Exotic pets/Wildlife

Horses/Donkeys

Sheep

Goats

Pigs

Poultry

Rabbits (farmed)

Other

The marked predominance of feline species in these figures is partly due to the many cases (240) reported following off-label use in cats of permethrin-based antiparasitics intended for dogs. If the corresponding data are excluded, the adverse events reported in cats fall to second place (39%) behind dogs (45%).

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Antiparasitics are still implicated in the vast majority (about two thirds) of off-label uses reported in cats: they mainly concern overdoses, use in cats of products intended for dogs and/or administration errors (ingestion of products intended for dermal application). These trends are also seen in dogs, where again antiparasitics alone account for 40% of the reported cases of off-label uses, with very similar descriptions: mainly dosing errors, the use in dogs of products intended for other species (usually cattle or horses) and the ingestion (accidental by the animal or following an administration error) of drugs for external use. In cattle, the respective share of ectoparasiticides (4%) and endoparasiticides (13%) was similar to that of antimicrobials (22%). Overall, reports involving off-label use essentially concerned dosing errors and non-compliance with the products' therapeutic indications and/or routes of administration. IV – SPECIFIC ACTIONS IN 2014

IV – 1 Training of veterinarians As part of efforts to promote pharmacovigilance to veterinarians, ANSES-ANMV continued its training activities in 2014, for both veterinary students and mandated veterinarians.

Initial training Two lectures on pharmacovigilance intended for fifth-year students were held at ONIRIS (Nantes Veterinary School); the first in June in the framework of inter-school teaching in caprine medicine with students from Nantes and Maisons-Alfort, and the second in October for students specialising in canine and/or equine medicine.

In November, a meeting was held between clinicians and interns at the Maisons-Alfort Veterinary School and ANSES-ANMV to raise awareness about pharmacovigilance and consider actions that could be implemented in their school for students.

Lastly, in December 2014, an expert from ANSES-ANMV participated as a member of the jury in the defence of a thesis on the promotion of pharmacovigilance and the analysis of the veterinary pharmacovigilance system in academia.

Continuous training In 2014, ANSES-ANMV continued its partnership with the ENSV and the SNGTV as part of organisation of the training module for mandated veterinarians entitled "Antimicrobial resistance-Pharmacovigilance". In all, 359 veterinarians were trained in 2014, through 31 sessions.

The "Antimicrobial resistance-Pharmacovigilance" module ranks first among the various continuous training courses proposed by the ENSV, in terms of number of veterinarians trained.

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IV – 2 Communication actions Conventions ANSES-ANMV had a stand at the 2014 National Meeting of the SNGTV, which took place in Reims from 21 to 23 May. The aim was to meet veterinarian attendees in order to discuss pharmacovigilance with them and answer their questions. A poster presenting the French pharmacovigilance system as well as an information pamphlet on pharmacovigilance in France were produced for the occasion. This pamphlet (see Annex 1), whose aim was to summarise the main provisions that each veterinarian should know and implement, was made available on the booth, and was also distributed via the veterinary trade press (La Dépêche Vétérinaire and La Semaine Vétérinaire).

On the occasion of the congress of the French Association of Veterinarians for Pets, two communications were presented by the Pharmacovigilance Department. The theme of the first presentation was "The use of dissociative anaesthetics in the Sphynx breed of cats". The corresponding press release – "Use of dissociative anaesthetics in the Sphynx breed of cats: protocols without specific contraindication in healthy animals" – is available on the ANSES website. The second communication was a presentation of the preliminary results of a 5-year retrospective study of adverse events involving NSAIDs administered orally to dogs. The adverse effects of NSAIDs are well-known: digestive intolerance, inhibition of platelet aggregation (increased bleeding time), nephrotoxicity, embryotoxicity and skin reactions of immune origin. Depending on their more or less selective mode of action on cyclooxygenases used to transform arachidonic acid into prostaglandins (mixed inhibitors of cox-1 and cox-2, preferential inhibitors of cox-2 or selective inhibitors of cox-2), the different compounds are considered to present these adverse effects with varying frequencies and more or less serious consequences. The purpose of this study was to improve understanding of the respective effects of the different classes of NSAIDs (Coxibs and other NSAIDs) and to validate or disprove the hypothesis of a difference in tolerance. The final results of this study will be published in a specialised veterinary journal. Press Releases ANSES ANMV published two press releases, one intended for the general public and the other for veterinarians.

Treatment of lice in children Following recent reports of the use of veterinary medications to treat head lice in children, ANSES reminded the public that antiparasitic, insecticide and acaricide treatments intended for pets should never be used on humans, especially children (the full press release is available from the ANSES website).

PEXION® Due to suspicions of lack of efficacy reported following the use of PEXION®, ANSES-ANMV brought veterinarians' attention to the prescription conditions for this medicinal product.

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IV – 3 Actions with respect to the industrial sectors Given the low rate of reporting in the production-animal sectors, specific actions have been undertaken by ANSES-ANMV to identify obstacles to reporting and raise awareness among the veterinarians concerned.

Sector survey by students During the first half of 2014, a field survey was carried out among the various stakeholders in the pig and poultry sectors (farmers, technicians and veterinarians), in conjunction with the pharmacovigilance department, by a group of students from the Institut Polytechnique La Salle Beauvais to identify the obstacles and incentives to pharmacovigilance reporting in these sectors. The purpose of pharmacovigilance and the results of this survey were presented in Rennes during lectures given by ANSES at the SPACE trade show. Indeed, reports of adverse events in farmed animals come predominantly from the cattle sector. The other sectors account for only 3% of reports. Furthermore, even if some reports may be submitted by farmers and technicians, the veterinarians themselves are generally behind them.

The objective of the study was firstly to find out whether the farmers and technicians in the pig and poultry sectors were familiar with pharmacovigilance, and secondly to study the reasons for the under-reporting inherent in these two sectors. In order to respond to these questions, semi-structured interviews were conducted with farmers, technicians and veterinarians in these sectors. Thematic and typological analyses were performed at the end of the interview phase. Even though the study involved a limited number of people, the results show that in both sectors, the farmers and technicians do not feel concerned by the reporting system and that, in their view, it is up to the veterinarians to do the reporting. This view is shared by the veterinarians themselves. Furthermore, these results confirmed the relevance of the awareness-raising and communication measures carried out by ANSES-ANMV over the past few years with veterinarians, as well as the specific actions undertaken with these sectors and presented below.

Development of a reporting form adapted to collective treatment Treatments in organised livestock farming generally concern an entire group of animals, and when an adverse event occurs it often concerns several animals. The current reporting form is well suited to individual treatment but makes data entry more complicated for the reporter when a group of animals is concerned. A study was conducted by the pharmacovigilance department in partnership with the correspondent/sentinel veterinarians for the rabbit, poultry and pig sectors at the French National Society of Veterinary Technical Groups (SNGTV) in order to propose a reporting form more suitable for collective treatment. This work resulted, in March 2014, in a draft reporting form being distributed to veterinarians specialising in these production sectors for several months of field testing before its final validation and online availability.

Definition of serious cases in organised production sectors According to the regulations, veterinary and health professionals are required to report serious adverse events, mainly those resulting in death or that may be life-threatening. This definition from the French Public Health Code applies clearly to an individual medicine, but less so to a collective

33


medicine where the veterinarian is alerted more by an increase in the mortality rate or a degradation of zootechnical performance. A study initiated in autumn 2014 with the correspondent/sentinel veterinarians for the rabbit, poultry and pig sectors at the SNGTV is under way to define in each sector the alert thresholds above which an event should be regarded as serious and therefore notifiable.

Request for enhanced surveillance of a vaccine In an announcement specifically addressed to veterinarians specialising in poultry medicine via their representative associations, ANSES-ANMV drew their attention to the change in composition of the CEVAC LANDAVAX SC® and CEVAC LANDAVAX NEO® vaccines, which are inactivated vaccines against pasteurellosis in mulard ducks, manufactured by CEVA SANTE ANIMALE. Following industrial production constraints, the level of bacterial endotoxin in these two vaccines was increased. Even though studies carried out by the manufacturer in support of this change did not reveal any safety problem, veterinarians were asked, as a precautionary measure, to be especially vigilant regarding the state and zootechnical results of animals vaccinated with these products, and to report any adverse event observed to the ANMV. Since this announcement, no reports of adverse events have been recorded in the national database for these vaccines.

IV - 4 Under-reporting Under-reporting is a reality that prevents pharmacovigilance from fully carrying out its role. To assess this phenomenon, a prospective study was carried out with around thirty voluntary veterinarians who were asked to systematically report, over a one-year period, all adverse events about which they were aware. They were recruited following a call for applications via the "pharmacovigilance correspondents" of the various commissions of the SNGTV for dissemination to their respective members. The voluntary veterinarians undertook to report throughout 2014 all cases falling within the scope of pharmacovigilance about which they were aware. To cover the different types of practice and the different animal species, veterinarians practising one of the following predominant activities were included in the study: canine (dogs and cats), mixed (cattle, small ruminants, dogs and cats), equine (horses), swine (pigs) and poultry (chickens, turkeys and other poultry, and/or rabbits). As the study called on volunteers, no minimum number of veterinarians was set by type of activity. A meeting to present the protocol and the harmonisation of collection procedures was organised in December 2013 by ANSES-ANMV, with a representative from each voluntary veterinary organisation.

In the context of this study, an average of 4.96 adverse events per veterinarian was reported for pets and an average of 2.06 for livestock, which is around 9 times greater than the average annual number calculated on the basis of reports received for a year and the number of veterinarians in France (Figure from the Veterinary Association Higher Council). The full results of this study will be published in the Bulletin of the veterinary technical groups (GTV).

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IV - 5 Good pharmacovigilance practices Following the publication in early 2014 of a Decision of the Director General of ANSES regarding good pharmacovigilance practices, on 16 October 2014, ANSES-ANMV held a seminar on veterinary pharmacovigilance at ANSES's premises in Maisons-Alfort.

The event brought together more than a hundred people, mainly representatives from the pharmaceutical industry. Employees from the pharmacovigilance department and the inspection unit of the ANMV presented and detailed the different chapters of this Decision.

Good pharmacovigilance practices primarily concern pharmaceutical companies with marketing authorisations for veterinary medicinal products. However, the provisions of these good practices are also applicable to the holders of all categories of specific administrative authorisations for veterinary medicinal products: veterinary autovaccines, veterinary homeopathic drugs subject to registration, or parallel import authorisations.

After presenting a review of the pharmacovigilance inspections carried out by ANSES-ANMV, the various chapters of this Decision were successively presented and explained:

• Chapter I: Roles and responsibilities in terms of veterinary pharmacovigilance; • Chapter II: Requirements for the pharmacovigilance systems, monitoring of compliance and

pharmacovigilance inspections; • Chapter III: Reporting of adverse events; • Chapter IV: Periodic Safety Update Reports (PSURs); • Chapter V: Overall assessment of pharmacovigilance data and regulatory measures related to

safety; • Chapter VI: Communication to the public relating to medicinal products for veterinary use.

Given the review of the inspections, particular attention was paid to the various categories of contractual arrangements.

Lastly, the specific provisions laid down for establishments authorised to prepare autovaccines were summarised.

All these presentations are available from the ANSES website.

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CONCLUSION

Provision of updated, validated information on veterinary medicinal products The assessment process taking place prior to granting the marketing authorisation of a medicinal products helps to define its conditions of use in terms of destination species, therapeutic indication(s), treatment regimen, withdrawal period, contraindication(s), precaution(s) for use, etc.: all these features are outlined in the summary of product characteristics (SPC), appended to the marketing authorisation. The information mentioned in the SPC is validated by ANSES-ANMV or by the European Commission, and is repeated on the labelling and/or instructions that accompany all medicinal products. The SPCs for the 2975 veterinary medicinal products that are today authorised in France can be consulted on the ANSES website (http://www.ircp.anmv.anses.fr/). The corresponding "Index of veterinary medicinal products authorised in France" tool has been improved and can now be used not only to view the SPC of any medicinal product but also to carry out various types of simple searches (for example search for all medicinal products containing a particular active substance, all medicines of the same pharmaceutical form, etc.) but also to conduct searches for each of the sections of the SPC. The results of these enquiries can also be exported in order to facilitate their analysis. This information on veterinary medicinal products available via the ANSES website is continuously reviewed, thus allowing any person to obtain validated up-to-date information. In addition, new MAs as well as changes to MAs having an impact on the use of the medicinal product are also covered in a monthly publication. Changes to the SPC relating to pharmacovigilance data are mentioned in these monthly publications. In fact, thanks to the reporting of adverse events, predominantly by veterinarians, knowledge about the adverse effects of medicinal products can be improved and brought to everyone’s attention. The large-scale use of medicinal products can make it possible to identify an adverse event not mentioned in the SPC, or one that is mentioned there but whose frequency or severity is unexpected, as well as to take the appropriate measures, which can range from modification of the SPC to suspension of the MA. In this regard, in 2014, 26 drugs had their MAs modified (see Annex 2). These modifications mainly concern the SPC section relating to "Adverse reactions" (e.g. KARSIVAN®, LOXICOM®, the EQUIP® vaccines) but may also relate to other sections such as the "Special warnings" (e.g. SUPRELORIN®) or information in the event of overdose (e.g. HISTACALMINE®). These changes resulted from an analysis of the spontaneous reports as well as data from the literature. The results of the 2014 assessment show that the total number of reports continues to increase steadily. The results, in terms of breakdown by species and by therapeutic category, are generally comparable to those obtained in previous years and confirm that the national system in place is fully capable of detecting new signs and thus supplementing the available knowledge on veterinary medicinal products.

Promotion and communication

36

http://www.ircp.anmv.anses.fr/


One of the priorities for ANSES-ANMV in the last few years has been to improve the veterinary pharmacovigilance system and in particular to encourage potential reporters to notify any adverse events about which they are aware. Since the reporters are overwhelmingly veterinarians, most of the promotion and communication actions carried out focused on this professional category. Different complementary themes have thus been developed:

- Training of veterinarians In order to improve their knowledge of the veterinary pharmacovigilance system, ANSES-ANMV offers training to veterinarians, whether initial training in veterinary schools or continuous training through courses organised for mandated veterinarians by the ENSV and the SNGTV.

- Communication actions The best way to motivate reporters is to show them that the reports they submit are indeed useful and enable the use of medicinal products to be improved. For this reason, in addition to the "Letters of information on medicines" published each month on its website, ANSES-ANMV issues press releases on specific drugs or categories of drugs and also takes part in various professional conventions. Furthermore, in order to assess under-reporting in veterinary medicine, a prospective study was carried out throughout 2014 with voluntary veterinarians covering different types of practice and different animal species. The results show that the average number of reports submitted by these veterinarians is nine times higher than the average annual number calculated on the basis of reports received for a year and the number of veterinarians practising in France. The full results of the study will be published in late 2015 in the Bulletin of the veterinary technical groups (GTV). Actions with respect to the industrial sectors Given the low rate of reporting in these sectors, specific actions have been taken by ANSES-ANMV to identify obstacles to reporting. In this context a field survey was carried out, in conjunction with the pharmacovigilance department, by a group of students from the Institut Polytechnique La Salle Beauvais among the various stakeholders in the pig and poultry sectors (farmers, technicians and veterinarians) to identify the obstacles and incentives to pharmacovigilance reporting in these sectors. The results were presented at SPACE 2014 during talks organised by ANSES. They show that in both sectors studied, the farmers and technicians do not feel concerned by the reporting system and consider that it is up to the veterinarians to do the reporting. This view is shared by the veterinarians themselves. These results furthermore confirmed the expectations of these veterinarians particularly in terms of communication by ANSES-ANMV and also regarding adapting the reporting form to collective treatment. This work on revising the reporting template was conducted in partnership with veterinarians of the SNGTV. This new template will be made available to veterinarians when the electronic submission website has been overhauled (see below). In addition to this adaptation of the reporting template, discussions began in late 2014 on the definition of serious cases in the organised production sectors. Pharmacovigilance inspections

37


ANSES-ANMV oversees the implementation of the national veterinary pharmacovigilance system, but all MA holders are obliged to establish a pharmacovigilance system that enables them to meet their different regulatory obligations, especially in terms of recording, communicating and assessing any adverse events. In France, the companies with this responsibility are pharmaceutical establishments authorised by ANSES-ANMV as veterinary medicinal product distributors. As such, they are also inspected regularly by ANSES-ANMV inspectors. The results of the 2014 inspections show that the pharmacovigilance systems in place are operational. The main areas for improvement concern the processes for organisation of the pharmacovigilance systems, the quality management process, risk management, management of adverse events and the regulatory obligations of the entity responsible for pharmacovigilance. The publication of good pharmacovigilance practices On 5 March 2014, a Decision on good pharmacovigilance practices was signed by the Director General of ANSES. The aim of this Decision is to supplement the regulatory principles on the operation of establishments with obligations in the area of pharmacovigilance, by operational and technical specifications in this area. These provisions primarily concern pharmaceutical companies with marketing authorisations for veterinary medicinal products. However, they are also applicable to the holders of all categories of specific administrative authorisations for veterinary medicinal products: veterinary autovaccines, veterinary homeopathic drugs subject to registration, or parallel import authorisations. In order to clarify the content of these good practices to the manufacturers concerned, ANSES-ANMV organised a seminar in October where it detailed the various chapters of this Decision.

2015 programme In 2015, ANSES-ANMV will be investing considerable efforts in the upcoming debates on the reform of the EU veterinary pharmaceutical regulations. The draft revision of the European regulations on veterinary medicinal products, expected for several years now, was published by the European Commission in September 2014. This proposal is based on:

- A new regulation that will replace Directive 2001/82/EC on the Community code relating to veterinary medicinal products,

- An amendment to Regulation (EC) 726/2004 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency.

The last revision of the texts relating to veterinary medicinal products dates back to 2004 (Directive 2004/28/EC). In 2008, the ANMV launched a debate on the achievements of this 2004 reform and on avenues of improvement, by organising a European symposium on the opportunities for improvement in the framework of the French Presidency of the Council of the European Union. It is clear that the motives behind this revision and the objectives set at the time have not all been achieved in this proposal. Difficulties remain and new themes have emerged (antimicrobial resistance, new technologies). With its significant experience and its status at the European level, the ANMV will make its contribution during the negotiations on this new regulation and the forthcoming parliamentary discussions to ensure that the new reform is as efficient as possible.

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Finally, in 2015 work will begin on the IT project to reform the national database on adverse events. This project (VIGIE) is being accompanied by a revision of the current website for electronic submission of adverse events. It is expected to be operational in late 2016. This new database will firstly help ease the administrative burden by saving time when recording and submitting adverse events, and secondly will implement automated alerts and a signal detection tool. The goal of VIGIE is to help improve the surveillance of these adverse events. The revision of the electronic submission website will aim to respond to the expectations expressed by veterinarians by facilitating reporting. This tool will therefore make it possible to save the profile of reporters, will interface with the veterinary medicinal products database, and will also offer different fields depending on whether the report relates to an individual or a collective treatment.

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ANNEX 1: THE FRENCH VETERINARY PHARMACOVIGILANCE SYSTEM

40


41


ANNEX 2: CHANGES TO MAs RELATED TO PHARMACOVIGILANCE

REPORTED IN 2014 This table summarises the changes to MAs that were reported in 2014 as well as the wording of the

corresponding sections (additions and/or rewordings are indicated in bold).

Name of medicinal product

MA holder Section modified Wording of the section amended

KARSIVAN 50

KARSIVAN 100 INTERVET Adverse

reactions

Vomiting has been observed on rare occasions, especially at the start of treatment.

In very rare cases, allergic reactions (for example: urticaria) may occur and may require discontinuation of treatment. Lethargy has been observed in very rare cases. Cardiac hyperstimulation and cerebral symptoms (including convulsions) have been observed. In such cases, the animals must receive symptomatic treatment.

HISTACALMINE VIRBAC Adverse reactions

Very rare cases of neurological signs (hyperaesthesia, tremor, mydriasis, hyperactivity), digestive signs (vomiting, diarrhoea, hypersalivation) or lethargy have been reported.

HISTACALMINE VIRBAC Overdose

The literature states that the active substances contained in Histacalmine, which belongs to the first-generation of antihistamines, present anticholinergic effects expressed as dryness of the oral mucosa, pupillary dilation and tachycardia. The most common adverse reactions at high doses include hyperactivity, irritability and seizures.

ACTIVYL SPOT-ON SOLUTION

INTERVET INTERNATIONAL

Adverse reactions

A brief period of hypersalivation may occasionally occur if the animal licks the application site immediately after treatment. This is not a sign of intoxication and disappears within some minutes without treatment. Correct application (see section 4.9) will minimise licking of the application site.

Transitory scratching or hair loss at the application site may occur. These effects will usually resolve without treatment.

The application of the veterinary medicinal product may produce a local, temporary oily appearance or hair clumping at the application site. A dry white residue may also be observed. This is normal and will generally resolve within a couple of days after administration. These changes do not affect the safety or efficacy of the veterinary medicinal product.

In rare cases of licking the product, gastrointestinal signs (for example, vomiting, anorexia) or reversible neurological signs (for example, incoordination, tremor, ataxia, mydriasis) have been observed in cats.

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STARTVAC LABORATORIOS HIPRA

Adverse reactions

Very rare adverse reactions: - Slight to moderate transient local reactions may occur after the administration of one dose of vaccine. They would mainly be swelling (up to 5 cm2 on average) which disappears within 1 or 2 weeks at most. In some cases, there may also be pain at the inoculation site that spontaneously subsides in a maximum of 4 days. - A mean transient increase in body temperature of about 1°C, in some cows up to 2°C, may occur in the first 24 hours after injection.

- Anaphylactic-type reactions may occur in some sensitive animals, which might be life-threatening. Under these circumstances, appropriate and rapid symptomatic treatment should be administered.

CANAURAL DECHRA

VETERINARY PRODUCTS

Adverse reactions

Like any active product, this medicinal product may, in some animals, cause more or less impairing effects: allergic reactions/hypersensitivity.

On very rare occasions and primarily in geriatric animals, use of auricular preparations may be associated with hearing impairment which may be either transient or

prolonged.

LOXICOM 0.5 MG/ML ORAL SUSPENSION

FOR CATS

NORBROOK LABORATORIES

Adverse reactions

Typical adverse reactions of NSAIDs such as loss of appetite, vomiting, diarrhoea, faecal occult blood, apathy and renal failure have occasionally been reported. In very rare cases, elevated liver enzymes have been reported.

These adverse reactions occur generally within the first week of treatment and are in most cases transient and disappear following termination of the treatment, but in

very rare cases may be serious or fatal.


FOR DOGS

NORBROOK LABORATORIES Adverse

reactions

Typical adverse reactions of NSAIDs such as loss of appetite, vomiting, diarrhoea, faecal occult blood, apathy and renal failure have occasionally been reported. In very rare cases, haemorrhagic diarrhoea, haematemesis, gastrointestinal ulceration and elevated liver enzymes have been reported.

These adverse reactions occur generally within the first week of treatment and are in most cases transient and disappear following termination of the treatment, but in

very rare cases may be serious or fatal.


FOR DOGS

LOXICOM 1 MG CHEWABLE TABLETS

FOR DOGS

LOXICOM 2.5 MG CHEWABLE TABLETS

FOR DOGS

43




LOXICOM 5 MG/ML SOLUTION FOR INJECTION FOR

DOGS AND CATS NORBROOK

LABORATORIES Adverse reactions

Typical adverse reactions of NSAIDs such as loss of appetite, vomiting, diarrhoea, faecal occult blood, apathy and renal failure have occasionally been reported. In very rare cases, elevated liver enzymes have been reported. In dogs, in very rare cases, bloody diarrhoea, haematemesis and gastrointestinal ulceration have been reported. In dogs, these adverse events generally occur during the first week of treatment, are in most cases transient and disappear following termination of the treatment, but in very rare cases may be serious or fatal.

In very rare cases, anaphylactoid reactions may occur and will require symptomatic treatment.

NOBIVAC MYXO-RHD INTERVET INTERNATIONAL

Adverse reactions

A transient temperature increase of 1-2°C can occur. A small non-painful swelling (maximum 2 cm diameter) at the injection site is commonly observed within the first two weeks after vaccination. The swelling will resolve completely by 3 weeks after vaccination. In pet rabbits, in very rare cases, local reactions at the injection site such as necrosis, scabs, crusts or hair loss may occur. In very rare cases, serious hypersensitivity reactions, which may be fatal, may occur after vaccination. In very rare cases, the appearance of mild clinical signs of myxomatosis may occur within 3 weeks of vaccination. Recent or latent infection with field myxoma virus seems to play a role in this to a certain extent.

EQUILIS STREPE LYOPHILISATE FOR SUSPENSION FOR INJECTION, FOR

HORSES

INTERVET INTERNATIONAL

Adverse reactions

After vaccination, a diffusely swollen reaction, which may be warm or painful, develops at the injection site within 4 hours. The reaction is maximal at 2-3 days post vaccination, with a maximum area of 3 cm by 8 cm. This swelling resolves completely within 3 weeks and normally has no effect on the appetite of the vaccinated animal and causes no apparent discomfort. The vaccine organism may establish a small suppurative inflammation locally at the injection site, leading to a disruption of the overlaying lip mucosa and subsequent discharge of fluid and inflammatory cells. A slight cloudy discharge commonly occurs from the mucosal injection site at 3 or 4 days post vaccination. Slight enlargements, which may be transiently painful, of the retropharyngeal and mandibular lymph nodes, may occur for a few days after vaccination.

ASCATENE TABLETS VETO-CENTRE Adverse reactions

In very rare cases, treatment may induce vomiting, neurological disorders (ataxia, tremor, prostration, etc.)

as well as systemic disorders (lethargy, depression, weakness, apathy, etc.).

PORCILIS AR-T DF INTERVET INTERNATIONAL

Adverse reactions

A mean transient increase in body temperature of 1.5°C, in some sows up to 3°C, which could lead to an abortion, can generally be measured on the day of vaccination or the following day. Reduced activity and lack of appetite on the day of vaccination very commonly occurs and/or a transient swelling (max. 10 cm) for up to 2 weeks may arise at the site of injection.

In very rare cases, other immediate hypersensitivity reactions, e.g. vomiting, dyspnoea and shock, may occur.

44




CEVAC LANDAVAX NEO

CEVA SANTE ANIMALE

Adverse reactions

A local reaction, in the form of palpable swelling at the site of injection, was observed in 31% of birds, following the complete vaccination programme of birds vaccinated at 3 weeks of age. This swelling can reach a maximum area of 10 cm2, but tends to resolve gradually. It persists for at least 5 weeks in 17% of birds. This reaction requires no special treatment. In the field, transient post-immunisation apathy may occur. After vaccination at 1 day of age followed by repetition at 14 days of age, a local reaction at the site of injection can be observed in 35% of birds. This reaction may reach 8.4 cm2.

During vaccination at the age of one day, delayed growth may be observed in birds that are seronegative at the

time of vaccination.

SUPRELORIN 4.7 MG IMPLANT FOR DOGS VIRBAC Special

warnings

[…] With respect to testosterone levels (an established surrogate marker of fertility), during clinical trials more than 80% of dogs administered one or more implants, returned to normal plasma testosterone levels (≥ 0.4 ng/ml) within 12 months of implantation. Ninety-eight percent of dogs returned to normal plasma testosterone levels within 18 months of implantation. However, data demonstrating the complete reversibility of clinical effects (reduced testicular size, reduced ejaculation volume, reduced sperm count and reduced libido) including fertility after 6 months, or repeated implantation, are limited. In very rare cases (< 0.01%) the temporary infertility may last more than 18 months. […]

VERSICAN DHPPI/L3R LYOPHILISATE AND

SOLVENT FOR SUSPENSION FOR

INJECTION FOR DOGS

ZOETIS FRANCE Adverse reactions

Following subcutaneous administration to dogs, swelling may occur at the injection site and reach a maximum diameter of 5 cm. These reactions generally disappear after 10 days, and may on rare occasions be sensitive to palpation for up to 3 days after vaccination.

In rare cases, hypersensitivity reactions may occur. If such a reaction occurs, appropriate treatment must be

administered without delay. VERSICAN DHPPI/L3 LYOPHILISATE AND

SOLVENT FOR SUSPENSION FOR

INJECTION FOR DOGS

PANOLOG EAR OINTMENT

NOVARTIS SANTE ANIMALE

Adverse reactions

In very rare cases, local inflammation or deafness has been reported.

Sensitivity to neomycin may occur. A cross-allergy with other aminoglycoside antibiotics may also be observed. Allergic reactions to nystatin may be observed in rare

cases. EQUIP FT

ZOETIS FRANCE Adverse reactions

Hypersensitivity reactions may occur in very rare cases. In the event of an allergic or anaphylactic reaction, immediate treatment should be given with a soluble glucocorticoid intravenously or adrenaline intramuscularly.

Systemic (hyperthermia, apathy) and local (swelling, pain, and even abscess at the site of injection, muscle

stiffness) reactions may be observed in very rare cases.

EQUIP F

EQUIP T

45




VECOXAN ORAL SUSPENSION 2.5

MG/ML LILLY FRANCE Adverse reactions

In very rare cases, adverse events involving gastrointestinal disorders (such as diarrhoea, with possible presence of blood), lethargy and/or neurological disorders (agitation, recumbency, paresis, etc.) have been reported.

Some treated animals may show signs of clinical disease (diarrhoea), even though oocyst excretion is reduced to a

very low level. DICLAZURIL ELANCO

2.5 MG/ML ORAL SUSPENSION

46

French Agency for Food,Environmental and Occupational Health & Safety14 rue Pierre et Marie Curie94701 Maisons-Alfort Cedexwww.anses.frwww.anses .fr / @ Anses_fr

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Anses – rapport annuelWhile pharmacovigilance mainly involves adverse effects related to...

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