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Surveillance

Surveillance Pharmacovigilance

Suspected adverse events, 2012 l Increase in serious adverse events l Increase in reports involving products marketed under the Small Animal Exemption Scheme l  Decrease in injection site reactions These are some of the results from the surveillance work carried out by the pharmacovigilance unit at the Veterinary Medicines Directorate (VMD), as discussed by Giles Davis and colleagues

During 2012, the pharmacovigilance team at the VMD, which monitors reports of adverse events that have occurred within the UK, received a total of 4124 reports involving adverse events in animals. These reports were submitted by veterinary surgeons, marketing authorisation holders (MAHs), the general public and other organisations, such as the AHVLA. This is an increase of 369 (9.8 per cent) on the number of reports received during 2011. Fig 1 shows the primary source of reports received by the VMD. In 2012 MAHs (56 per cent) were the main source of reports received by the VMD, followed by veterinary surgeons (40 per cent). The remainder of the reports came directly from the general public, other government organisations, including one from Trading Standards, and from Suitably Qualified Persons or Agricultural Merchants. Fig 2 shows the number and source of serious reports received by the VMD. A serious event in an animal is defined as an adverse event which results in death, is life-threatening, results in persistent or significant disability or incapacity, or is a congenital anomaly or birth defect. In 2012, 1771 serious adverse events were reported to the VMD. This is an increase of 220 (14 per cent) on the number of reports received during 2011. As can be seen in Fig 2, the primary source of a serious report was the MAH (89 per cent), followed by veterinary surgeons (9 per cent) and the general public (1 per cent). The distribution by species of the 4124 of reports received by the VMD is given

Veterinary Record (2013) 173, 573-576 G. Davis, A. Rooney, S. Cooles, G. Evans, Suspected Adverse Reaction Surveillance Scheme, Veterinary Medicines Directorate, Woodham Lane, New Haw, Surrey KT15 3LS

in Table 1. This table compares the figures from 2012 with those from the previous four years. Certain aspects of reports recorded in the VMD’s pharmacovigilance database are used to identify groups with common features. A breakdown of the total number of reports received in 2012 according to these groups is presented in Table 2. In this table any one group excludes reports from all of the groups above it. Table 3 shows the number of adverse events to authorised veterinary medicines used according to manufacturers’ instructions classified according to therapeutic group and species.

Animal adverse events

There was an increase in the number of reports received in 2012 involving products marketed under the Small Animal Exemption Scheme (Veterinary Medicines Regulations 2013, Schedule 6). These products are exempt from the requirement to hold a marketing authorisation in order to improve the availability of veterinary medicines to certain minor species. In 2012, 47 reports were received compared to 37 reports received in 2011. In 2012, 28 reports

related to fish, nine to rabbits and 10 to other species (guinea pig, mouse, budgerigar, ferret, cat and hamster). The case involving a cat occurred after the application of a product containing permethrin. The VMD received 26 reports of injection site sarcomas in cats in 2012, a decrease of eight reports compared with the 34 reports received in 2011. Eighteen reports were associated with live viral vaccines, four with inactivated viral vaccines, three with vector vaccines and one with a mixed live bacterial and viral vaccine. A total of 312 reports involving use of authorised products contrary to the advice in their Summary of Product Characteristics (SPCs) were received during 2012. The largest proportion of these reports resulted from a failure to observe a warning or contraindication (67). Sixty-three cases resulted from overdosing and 50 occurred after use in a species not included in the SPC. In 35 cases the dose used was too low, while 25 cases occurred after use for an unauthorised indication. A further 72 cases were associated with other types of unauthorised use, that is, treatment programme not respected (31); unauthorised route of administration (20); and others,

Pharmacovigilance After a veterinary medicine is authorised and placed on the market, the company that produces and markets the product works closely with national regulatory agencies across the world, including the Veterinary Medicines Directorate in the UK, to monitor all reported suspected adverse events involving the medicine. The purpose of this process, which is known as pharmacovigilance, is to ensure that the balance between the benefits and risks of authorised medicines remains favourable. Pharmacovigilance covers all suspected adverse events that occur after the administration of a medicine, regardless of the strength of evidence as to their relationship with the medicine, or whether or not the medicine was used in accordance with its label or leaflet. The frequency with which adverse events occur can be calculated for a particular medicine. While this information is valuable, numerical data based on a voluntary reporting system are unlikely to reflect the full picture. Many adverse events are complicated by factors such as the health of the animal, or the concurrent use of other medicines. It is important to take into account the limitations of adverse event reporting and evaluation when interpreting pharmacovigilance data.

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Number of reports received

Surveillance

2400 2200 2000 1800 1600 1400

■ Veterinary surgeon ■ Marketing authorisation holder ■ General public ■ Farmer ■ AHVLA ■ Suitably Qualified Person

1200 1000 800 600 400 200 0

■ Veterinary surgeon 2008 2009 2010 ■ Marketing authorisation holder Year ■ General public ■ Farmer FIG 1: Sources of reports to the VMD, 2008 to 2012 ■ AHVLA ■ Suitably Qualified Person

2011

2012

Number of reports received

1600

1400 1200 1000 800 600 400 200 0

2008

2009

20010

2011

2012

Year

FIG 2: Sources of serious reports to the VMD, 2008 to 2012 (key as for Fig 1)

such as failure to monitor blood parameters, incorrect or accidental application or administration, and use of expired product. The species breakdown for these 312 reports can be seen in Fig 3. Of the 312 cases resulting from use of authorised products contrary to the advice in their SPCs, 128 (41 per cent) occurred in dogs, with 100 (32 per cent) occurring in cats. In 2012 there were 16 reports of adverse reactions in cats resulting from the unauthorised use of canine ‘spot-on’ products containing permethrin, a decrease on the 27 reports received in 2011. The number of reports received involving human medicines used in animals under the prescribing cascade decreased slightly from 35 reports in 2011 to 33 reports in 2012. The products reported were metronidazole tablets, tetracosactide, ranitidine, terbutaline, bupivacaine, dorzolamide, hypurin protamine zinc, amantadine, ioversol, hydroxyzine, tramadol, cefuroxime, itraconazole, amlodipine and amoxicillin/ clavulanate intravenous infusion. Of the 33 reports received, 12 related to the use of Co-amoxiclav Powder for Solution for Injection or Infusion, containing amoxicillin 574 | Veterinary Record | December 14, 2013

sodium and potassium clavulanate. All 12 reports involve hypersensitivity reactions following use. A letter highlighting this issue was published in Veterinary Record in October 2011 (Dyer 2011).

During 2012, 18 reports were received relating to products imported using a Special Import Certificate (SIC), compared to only 11 such reports in 2011. Of the 18 reports, five related to pharmaceuticals and 13 to immunological products, including vaccines and allergen immunotherapy products. There was an increase in the number of lack of efficacy and safety reports received involving rabbit vaccines. Suspected lack of efficacy report numbers increased from 22 in 2011 to 46 reports in 2012; 86 per cent of the reports described signs of suspected myxomatosis after vaccination in 2012 compared with 90 per cent in 2011. The increase in numbers reported may be due to increased environmental challenge from wild type myxoma virus or increased awareness of adverse event reporting. Safety report numbers increased from 75 in 2011 to 102 in 2012. The most commonly reported clinical sign in 2012 was death following vaccination, included in 68.8 per cent of reports (53.3 per cent in 2011). Injection site reactions were the second most commonly reported clinical sign included in 37.3 per cent of reports in 2012 which is a decrease from 2011 where 76.0 per cent of reports involved injection site reactions. The reason for these changes in reaction patterns is not currently known as no specific brand or batch is responsible. Indeed, this could just be an artefact of reporting, but the VMD will continue to monitor the situation in conjunction with other European agencies. There was little change in the number of reports received involving anaphylaxis following vaccination of dogs with vaccines containing canine parvovirus, adenovirus, distemper virus, parainfluenza virus and Leptospira species. Ninety-seven reports were received in 2012 compared to 93 reports in 2011.

TABLE 1: Number of reports received by the Veterinary Medicines Directorate in 2012, classified by species and compared with the years 2008 to 2011 Species

2012

2011

Number of reports in 2010

2009

2008

Total

Dog Cat Horse Cattle Sheep Pig Rabbit Pigeon Turkey Chicken Pheasant Other birds Guinea pig Ferret Goat Donkey Rat Mouse Fish Other Total

1767 1027 158 550 332 15 169 4 1 22 1 3 6 4 3 1 2 2 45 12 4124

1615 962 205 495 251 16 126 2 0 8 0 8 6 3 14 0 8 1 24 11 3755

1463 882 136 639 256 10 145 3 0 11 1 2 6 2 1 2 1 1 28 5 3594

1261 850 92 486 254 18 126 2 0 7 1 6 3 4 7 1 2 1 22 8 3151

1307 926 90 389 237 24 136 2 1 5 0 7 9 4 8 0 2 2 9 18 3176

7413 4647 681 2559 1330 83 702 13 2 53 3 26 30 17 33 4 15 7 128 54 17,800

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Surveillance

ake

ret

Sn

Fer

at

en

Go

ick

Pig

nt

h

Ro

Ch

4124

de

it

Fis

bb

Ra

rse

Ho

eep

ttle

Do

g

299 1 2303

50 40 30 20 10 0 Ca

28 88 50 210 810 312

t

23

Unidentified products Unauthorised or non-medicinal products Human or imported medicines Unlikely to be related to the product Reports with insufficient information Use of product not according to manufacturer’s instructions Suspected lack of expected efficacy Withdrawal period (residues) issue Suspected adverse reactions to authorised veterinary medicines used according to manufacturers’ instructions Total

Sh

Total

Reports from studies

Number of reports

Group

130 120 110 100 90 80 70 60

Ca

TABLE 2: Breakdown of the total number of reports received in 2012 into groups with common features

Species

FIG 3: Distribution by species of reports of unauthorised use in 2012

An increase in the number of reports of bovine neonatal pancytopenia in calves following historic use of bovine viral diarrhoea vaccination in dams was noted with 233 reports recorded in 2012 compared to 170 in 2011. This somewhat surprising result may be due to increased awareness of the condition itself and its suspected link with vaccination with a product whose marketing authorisation was suspended in 2010 or due to increased awareness of the importance of adverse event reporting in general.

Human adverse events

The VMD received 160 reports of human adverse events due to accidental or occupational exposure to veterinary medicines in 2012, which represents an increase of 30 per cent compared to the

figure for 2011 (123). The majority of reports (86.9 per cent) were received from MAHs, while 11.9 per cent were reported by veterinary surgeons or veterinary nurses, 0.6 per cent by patients and 0.6 per cent by retailers. As was the case in 2011, seven of the reactions were considered to be serious as they required hospital in-patient care. Of the 160 reports, 66 involved injectable vaccines and pharmaceutical products. Of these, 64 (98.5 per cent) were associated with minor needlestick injuries and one (1.5 per cent) involved accidental self-injection necessitating hospital treatment, which is a decrease on the five cases requiring such attention in 2011. Of the remainder, 65 reports were related to ectoparasiticides and endectocides

such as companion animal sprays and ‘spot-on’ products and large animal ‘pour-on’ products, while nine reports involved other veterinary medicines (such as anthelmintics, anti-inflammatories, hormones and ectoparasiticides) marketed in tablet form and four reports involved antiinflammatories and antimicrobials marketed as oral solutions. Five reports involved vaccines for nasal administration; two involved ectoparasiticidal collars and two involved inhalation anaesthetics. Regarding products without UK marketing authorisations, five reports involved imported veterinary medicines and two involved medicines sold under the Small Animal Exemption Scheme. There were also six related cases involving the

TABLE 3: Analysis of 2303 reports of suspected adverse events to authorised products, used in accordance with the Summary of Product Characteristics, received by the Veterinary Medicines Directorate during 2012 Therapeutic group Anthelmintic Antihormone agent Anti-inflammatory Antineoplastic agent Antiemetic Antimicrobial Antimicrobial intramammary Antiprotozoal Antiseptic Cardiovascular Ectoparasiticide Endectocide Gastrointestinal antiemetic Herbal Hormone Inactivated vaccine Insect growth regulator Live vaccine Mineral Mixed vaccine Neurological NSAID Prostaglandin Replacement agent Respiratory Teat seal Vector vaccine Total

Dog 29 54 70 1 5 77 0 0 1 13 154 55 5 1 7 71 0 259 0 173 38 128 0 0 0 0 0 1141

Cat 39 91 11 0 0 15 0 0 0 6 123 46 2 0 0 58 5 170 0 22 28 19 0 0 1 0 45 681

Horse 0 0 3 0 0 5 0 0 0 0 3 12 0 0 0 44 0 10 0 33 6 5 0 0 0 0 0 121

Cattle 1 0 0 0 0 19 2 1 0 0 2 33 0 0 3 191 0 4 3 1 0 6 1 2 0 1 0 270

Sheep

Pig

Rabbit

Rodent

Fish

Bird

Donkey

3 0 0 0 0 1 0 0 0 0 6 8 0 0 0 6 0 4 2 0 0 0 0 0 0 0 0 30

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 1

0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 12 0 32 0 0 0 0 0 0 0 0 0 45

0 0 0 0 0 3 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 3

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 6 0 0 0 0 0 0 0 0 0 0 0 6

0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 2

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 1

Bee 0 0 0 0 0 0 0 0 0 0 2 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2

Total 72 145 84 1 5 121 2 1 1 19 291 154 7 1 10 390 5 479 5 229 73 158 1 2 1 1 45 2303

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Surveillance TABLE 4: Incidence of adverse events in cats involving permethrin spot-on products authorised for use in dogs Ratio of number of cats Ratio of number of reacting to number cat deaths to number Year of dog doses sold of dog doses sold 2006 2007 2008 2009 2010 2011 2012

 1:48,386  1:65,101  1:79,156  1:75,654 1:107,098 1:118,865 1:161,690

1:416,124 1:269,084 1:474,933 1:216,359 1:589,040 1:301,736 1:287,450

use of a surgical disinfectant which is not a veterinary medicine. However, the VMD still welcomes all such reports. All human adverse events were considered by Veterinary Products Committee (VPC). Further information on the work and findings of the VPC can be found in its annual reports, which are available at www.vmd.defra.gov.uk/vpc

Environmental adverse events

The VMD receives reports of adverse events in the environment which involve the possible use of veterinary medicinal products from the Environment Agency, the Scottish Environment Protection Agency, the Northern Ireland Environment Agency and the Wildlife Incident Investigation Scheme (WIIS). Reports may also be received from MAHs and the general public.

576 | Veterinary Record | December 14, 2013

In 2012 three environmental incident reports attributed to veterinary medicines were presented to the VMD compared with three in 2011 and seven reports in 2010. The level of reporting of adverse effects in the environment continues to be low and all were made by WIIS. One of the adverse events involved the suspected poisoning of a red kite. One red kite was found dead and fenthion residue was detected in the gizzard. Illegal use was suspected. Fenthion has not been authorised as a veterinary medicine since 1999, but is used as an agricultural insecticide so it is unlikely that this incident was the result of veterinary medicinal use. Two of the adverse events involved bees, and in both cases fipronil was implicated. However, since this molecule is used as an agricultural pesticide as well as in veterinary medicines, it was considered unlikely that these events were the result of veterinary use. In the first event, a new beekeeper who had been given a swarm of bees discovered many deaths within two days of a spray

application of fungicides to a field of wheat. Laboratory analysis confirmed residues of the fungicide prothioconazole as well as the insecticide fipronil. Fungicides are not usually toxic to honeybees therefore the results were consistent with pesticide poisoning following exposure to fipronil. In the second adverse event, one of four honeybee swarms died within hours after transportation in a car boot to new premises. Laboratory analysis again detected residues of fipronil. The beekeeper owned dogs that were treated for fleas, but the fact that the dogs did not travel in the car boot contributed to the conclusion being made that veterinary use of fipronil was not responsible.

Conclusion

The pharmacovigilance reporting system in the UK continues to provide an example to many countries of practical and effective arrangements for collecting information about adverse events in animals and humans following exposure to veterinary medicines. The importance of the part played by the practising veterinary surgeon in ensuring the success of the system cannot be overestimated, and the VMD thanks all those who enlarged and enriched its knowledge of adverse events during 2012.

Reference

Dyer, F. (2011) Co-amoxiclav powder for solution for injection or infusion. Veterinary Record 169, 450

doi: 10.1136/vr.f7381

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Suspected adverse events, 2012 G. Davis, A. Rooney, S. Cooles and G. Evans Veterinary Record 2013 173: 573-576

doi: 10.1136/vr.f7381 Updated information and services can be found at: http://veterinaryrecord.bmj.com/content/173/23/573

These include:

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Suspected adverse events, 2012.

Increase in serious adverse events; Increase in reports involving products marketed under the Small Animal Exemption Scheme; Decrease in injection sit...
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