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Research Article - (2021) Volume 0, Issue 0

Updated Summary on Use and Safety of Flea and Tick Preventives for Animals

W Jean Dodds1*and Jon P Kimball2

1 Department of Path Biological, University of Wisconsin-Madison, California, USA

2 Department of Orthopaedic Surgery, University of North Carolina at Chapel Hill School of Medicine, North Carolina, USA

*Corresponding Author:
W Jean Dodds
Department of Pathbiological,
University of Wisconsin-Madison,
California,
USA
E-mail: pwjeandodds@gmail.com

Received Date: June 16, 2021; Accepted Date: June 30, 2021; Published Date: July 07, 2021

Citation: Dodds WJ, Kimball JP (2021) Updated Summary on Use and Safety of Flea and Tick Preventives for Animals. J Vet Med Surg Vol.5 No.S2:005.

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Abstract

Objective: Although the development of novel, potent flea and tick preventives began more than 20 years ago, with collars, spot-on topical, and tablets/chews, adverse events associated with their use have recently escalated since these reactions report were reviewed. Adverse events are believed to be grossly underreported, and 3 Class Action lawsuits have been filed in North America.

Materials and methods: The present report updates the previously published Jake Survey conducted in 2018 and published in 2020, to include US Food and Drug Administration (FDA) and Environmental Protection Agency (EPA) adverse events. Along with European Medicines Agency (EMA) data through spring 2021.

Conclusion: Updated results from the USA and European Union indicate a notable increase in the number of particularly serious adverse events reported for the flea and tick preventives including seizures, behavioural aggression, and death. The actual number of adverse incidents is likely much higher than those reported to regulatory agencies.

Keywords

Preventives; Isooxazoline; Parasiticides; Environmental protection agency

Introduction

Unlike the Food and Drug Administration (FDA) which regulates parasiticides, such as the isooxazoline compounds, the Environmental Protection Agency (EPA) regulates pesticides like the imidacloprid+flumethrin collar. This difference in regulatory authority in the USA has caused confusion among veterinarians and companion animal owners. In contrast, the European Medicines Agency (EMA) regulates all these categories of products [1-3].

Current Class Action lawsuits include one in Quebec and a second in New Jersey involving fluralaner (Bravecto®) and related compounds, due to the incidence of serious AR (Adverse Reactions) including death, that have a duration of treatment lasting from one to 3 months. A third Class Action lawsuit was filed in March 2021 against the imidacloprid+flumethrin product (Seresto Collar®). The collar was introduced in 2012, and is touted to last for 8 months.

The present manuscript provides updated data on these parasite and pesticide products through April 17, 2021, as available from the Food and Drug Administration (FDA), Environmental Protection Agency (EPA) and European Medicines and Agency (EMA) websites and published literature [1-5].

Materials and Methods

The websites for the Food and Drug Administration (FDA) (www.open.fda.gov; API, animal and veterinary endpoints), Environmental Protection Agency (EPA) (www.epa.gov, pesticides, incident-report), and European Medicines and Agency (EMA) (www.ema.europa.eu, pharmacovigilance, incident report) were searched for adverse events reported through April, 2021. These drugs were introduced to the commercial veterinary market from as early as 1996 (ivermectin; HeartGard®, Ivomec®) and to as recently as 2020 for fluralaner+moxidectin (Bravecto Plus®), and for sarolaner+moxidectin+pyrantel+pamoate (Simparica Trio®).

The number of adverse reports was highest for spinosad+milbemycin+oxime (TriFexis®) (200,941) followed by afoxalaner+milbemycin+oxime (NexGard Spectra®) (190,802). The smallest reported number was for the more recently introduced lotilaner (Credelio®, 2018) at 3.302. With regard to the number of reported deaths, the largest number was for sar olaner+moxidectin+pyrantel+pamoate (Simparica Trio®) at 6,717 (approved in 2020), followed closely by spinosad+milbemycin+o xime(TriFexis®) with 6,662 (approved in 2011) and ivermectin+py rantel+pamoate+praziquantel (Iverhart Max®, approved in 2018) at 6,207.

Results

Table 1 lists the Food and Drug Administration (FDA) fluralaner incident reports by species and number of cases. The vast majority of reports involved dogs (86%) with cats accounting for 13%, and 1.5% involving humans.

.
Parasiticide drug Species Number of FDA reports
Fluralaner (Bravecto®) Dog 38,619
Fluralaner (Bravecto®) Cat 5,818
Fluralaner (Bravecto®) Human 674
Fluralaner (Bravecto®) Wolf 3
Fluralaner (Bravecto®) Bobcat 2
Fluralaner (Bravecto®) Tiger 2
Fluralaner (Bravecto®) Doormouse 1
Fluralaner (Bravecto®) Fox 1
Total=45,118    

Table 1: FDA (Food and drug administration) records animal and veterinary api endpoints, May 24, 2021.

The official data for all parasiticides used in the U.S. retrieved from the Food and Drug Administration (FDA) through April 17, 2021 included 16 brand name drugs and a total of 1,577,958 Adverse Reactions (AR) with 60,909 deaths (Table 2).

Data (USA) from FDA of reported adverse reactions and deaths after administration of flea, tick and heartworm treatments-updated 4/17/2021
Brand name Active ingredient Introduced to market Adverse reactions Deaths*
Bravecto fluralaner 2014 43,602 1,533
Bravetco plus fluralaner+moxidectin 2019-2020 77,459 4,753
Comfortis spinosad 2012 1,62,354 4.816
Trifexis spinosad+milbemycin+oxime 2011 2,00,941 6,662
Credelio lotilaner 2018 3,302 95
Revolution selamectin 2000 19,552 1,980
Revolution plus selamectin+sarolaner 2019 31,605 2,346
Nexgard afoxolaner 2013 36,340 1,086
Nexgard Spectra afoxolaner+milbemycin+oxime 2014 1,90,802 5,998
Simparica sarolaner 2016 14,153 432
Simparica trio sarolaner+moxidectin+pyrantel+pamoate 2020 1,40,646 6,717
Heartgard, Ivomec ivermectin 1996 94,798 4,103
Heartgard Plus, Triheart ivermectin+pyrantel+pamoate 2003 1,05,139 5,332
Iverhart Max ivermectin+pyrantel+pamoate+praziquanel 2018 1,29,815 6,207
Interceptor milbemyxin+oxime 2013 1,54,190 3,911
Interceptor Plus, Milbemax milbemyxin+oxime+praziquantel 2,01,02,015 1,72,860 4,938
Totals:     15,77,958 60,909

Table 2: Summary of Food and Drug Administration (FDA) reported adverse events and deaths through April 2021 (USA only) TriFexis® (spinosad+milbemycin oxime) and Comfortis® (spinosad), both spinosads, generated notable adverse reactions in the Food and Drug Administration (FDA) report of April 17, 2021 in Table 2.

Pesticide drug Domestic animal species Number of EPA reports
Imidacloprid+flumethrin (Seresto Collar®) Degree of adverse effect 75,000 since 2012
Imidacloprid+flumethrin (Seresto Collar®) Minor 21, 439
Imidacloprid+flumethrin (Seresto Collar®) Moderate 7, 743
Imidacloprid+flumethrin (Seresto Collar®) Major 3,767
Imidacloprid+flumethrin (Seresto Collar®) Fatality 1, 698
Imidacloprid+flumethrin (Seresto Collar®) Human 907

Table 3: EPA Office of pesticide programs incident data system, June 16, 2020.

These drugs were introduced to the commercial veterinary market from as early as 1996 (ivermectin; HeartGard®, Ivomec®) and to as recently as 2020 for fluralaner+moxidectin (Bravecto Plus®), and for sarolaner+moxidectin+pyrantel+pamoate (Simparica Trio®).

The number of adverse reports was highest for spinosad+milbemycin+oxime (TriFexis®) (200,941) followed by afoxalaner+milbemycin+oxime (NexGard Spectra®) (190,802). The smallest reported number was for the more recently introduced lotilaner (Credelio®, 2018) at 3.302. With regard to the number of reported deaths, the largest number was for sarolaner+mox idectin+pyrantel+pamoate (Simparica Trio®) at 6,717 (approved in 2020), followed closely by spinosad+milbemycin+oxime(TriFe xis®) with 6,662 (approved in 2011) and ivermectin+pyrantel+pa moate+praziquantel (Iverhart Max®, approved in 2018) at 6,207 (Table 2).

It is estimated that only 1% of adverse events are actually reported, and counterfeit flea and tick products have started to flood the commercial pet market [2,3,6].

Table 3 shows The U.S. House Subcommittee on Economic and Consumer Policy called for Elanco Animal Health to “immediately institute a temporary recall of all Seresto® flea and tick collars, following reports that the collars may have killed thousands of pets and may have caused injuries to many more pets as well [6]. Some clinical veterinarians, veterinary internal medicine, dermatology and toxicology specialists continue to defend the safety of this type of product. The reported adverse reactions for Seresto® collars included 11,510 moderate to major in severity, as well as 1,698 deaths (Table 3).

A summary of the reported results obtained from two sources, the Food and Drug Administration (FDA) and Project Jake Survey Is shown in Table 4. Serious Adverse Reactions (AR) associated with neurotoxicity included those for death, seizures/convulsions, and shaking/tremors/ataxia.

FDA serious adverse events reports
Events reported Jan 2013-Sept 2017 Number and percent of sample population displaying reaction
Overall (N=32,374) Fluralaner (N=16,896) Afoxolaner (N=14,116) Sarolaner (N=1,361)
Death 801 2.47% 416 2.50% 341 2.40% 44 3.20%
Seizure 1,728 5.34% 468 2.80% 981 6.90% 279 20.50%
Shaking/Tremors/Ataxia 2,223 6.87% 600 3.60% 1,063 7.50% 560 41.10%
Jake survey serious adverse events results
Events/symptoms aug 2018 Overall (N=1,070) Fluralaner (N=791) Afoxolaner (N=235) Sarolaner (N=44)
N % N % N % N %
Death 147 13.74%% 117 14.79% 28 11.91% 2 4.55%
Seizures/Conclusions 147 13.74%% 117 14.79% 28 11.91% 2 11.14%
Shaking/Tremors/Ataxia 493 43.2%% 271 34.3%% 178 75.7%% 13 29.6%%

Table 4: Summary comparison of serious adverse events for fda and project Jake survey.

The cumulative increase in serious Adverse Reactions (AR) for the three isoxazolines reported by the European Medicines Agency (EMA) from 2019 to 2021 is shown in Table 5. Results were highest for the European Medicines Agency (EMA) reports, and lowest for the Food and Drug Administration (FDA) reports; those from the Project Jake Survey were displayed to be in between the other two sets of data but closer to those of the European Medicines Agency (EMA). These European Medicines Agency (EMA) cumulative reports through April 2021 paralleled those of our earlier published reporting period through 2017 and 2018 [1].

Table 5 shows the increase in serious neurotoxic Adverse Reactions (AR) for the three isoxazolines reported by the European Medicines Agency (EMA) from 2019 to 2021 is shown in Table 5. The overall numbers that involved death and seizures for the January 2013 to April 2021 time frame increased proportionately, as expected if these events had resulted from the pathological effects of the chemical compounds in the products. The cumulative deaths reported to April 2021 ranged from a high of 2,627 (24%) for fluralaner (Bravecto®) to 726 (2.8%) for afoxolaner (NexGard®) and 412 (12.7%) for sarolaner (Simparica®). The cumulative reported seizures ranged from 1,933 (60%) for sarolaner (Simparica®) to 1518 (5.8%) for afoxolaner (NexGard®) (Table 5).

EMA adverse event data increase for fluralaner, afoxolaner and sarolaner
EMA serious adverse events results
Events reported Jan 2013-Jan Percent of sample population displaying reaction
Overall (N=32,991) Fluralaner (N=10,172) Afoxolaner (N=20,902) Sarolaner (N=1,917)
Death 3,186 9.66% 2,408 23.70% 528 2.53% 250 13.04%
Seizure 4,002 12.13% 1,860 18.30% 1,087 46.69% 1,055 55.10%
EMA serious adverse events results
Events reported Jan 2013-Apr 2021 Percent of sample population displaying reaction
Overall (N=40669) Fluralaner (N=11097) Afoxolaner (N=26330) Sarolaner (N=3242)
Death 3,765 9.26% 2,627 23.67% 726 2.76% 412 12.71%
Seizure 5,753 14.15% 2,302 20.74% 1,518 5.77% 1,933 59.62%
FDA serious adverse events reports

Table 5: EMA (European Medicines Agency) adverse event data increases for fluralaner, afoxolaner and sarolaner.

Additionally, an in-depth review has recently been published about the widespread use of fipronil pesticide, which shows neurological effects affecting emotional and cognitive behaviors in mammals, including dogs and cats [5].

Discussion

The results shown here document that the adverse events reported in the U.S. and European Union are continuing to increase as these products and new ‘spot-ons’, collars, topicals, and internal flea and tick parasiticides and pesticides continue to be used.

When examining the Food and Drug Administration (FDA), Adverse Reactions (AR) reports for active ingredients of a common class, the data in Table 2 show that spinosad containing treatments (Comfortis® and Trifexis®) resulted in a combined 363,295 AR reports with 11,478 deaths, followed by afoxolaner treatments (Nexgard® and Nexgard Spectra®) with 227,142 reports containing 7,084 deaths; sarolaner treatments (Simparica® and Simparica Trio®) with 154,799 reports and 7,149 deaths; and fluralaner formulations (Bravecto® and Bravecto Plus®) with 121,061 reports and 6,286 deaths. It is also noted that recently Food and Drug Administration (FDA) approved (2020) multi-compound formulations (Bravecto Plus® and Simparica Trio®) had markedly increased numbers of Adverse Reactions (AR) reports and deaths in a short period of post-marketing reporting when compared to the original product formulations. Since 2018, lotilaner (Credelio®) has had 3,302 reports with 95 deaths: noticeably fewer incident reports than for 2020 approved Bravecto Plus® or Simparica Trio®. Similarly, apparent ‘improved’ product formulation releases for Interceptor Plus® (2015), Iverhart Max® (2018), and Revolution Plus® (2019) have all shown moderate to marked increases in adverse reaction reports and deaths when compared to their respective earlier formulations.

It is also noteworthy that of the 45,118 Food and Drug Administration (FDA) Adverse Reactions (AR) reports by species in Table 1, 674 were for humans, whereas the Environmental Protection Agency (EPA) Office of Pesticide Programs Incident Data System Table 3 showed 907 human AR (Adverse Reactions) reports; indicative of human exposure/toxicity at a level that is significant enough to warrant submission of a human event record for a pet product.

What is particularly disconcerting, especially now that additional adverse events are required to be listed on the product labels and inserts, is the fact that treating veterinarians continue to prescribe them despite these new warnings and the moderate to marked increases in Adverse Reactions (AR) reports [7-14].

Pet caregivers are rarely informed about these side effects and so may only find out about them from pet magazines, news media reports, and on-line accounts [12,13]. Further backlash against revealing these adverse effects have come not only from industry employed veterinarians and scientists but also from private practitioners, and specialist veterinarians. Some veterinarians working for companies manufacturing these products have asserted that they regularly use them on their own pets.

The first author of this report frequently encounters dog owning clients that are referred for holistic alternative care of pets exhibiting the classical adverse effects seen from using these parasiticides or pesticides. Prescribed by their local veterinary clinics. This misleading situation parallels that of local veterinarians and veterinary cardiologists that still tell clients to avoid grain-free pet foods as they cause Dilated Cardiomyopathy (DCM) shown in Table 6. The more recent peer-reviewed published data to refute these original large pet food producer claims has either been ignored or discounted, or proponents are unaware of them [15-17].

Events reported jan 2013-Sept 2017 Number and percent of sample population displaying reaction
Overall (N=32,374) Fluralaner (N=16,896) Afoxolaner (N=14,116) Sarolaner (N=1,361)
Death 801 2.47% 416 2.50% 341 2.40% 44 3.20%
Seizure 1,728 5.34% 468 2.80% 981 6.90% 279 20.50%
Shaking/Tremors/Ataxia 2,223 6.87% 600 3.60% 1,063 7.50% 560 41.10%
Jake survey serious adverse events results
Events/symptoms aug 2018 Overall (N=1,070) Fluralaner (N=791) Afoxolaner (N=235) Sarolaner (N=44)
N % N % N % N %
Death 147 13.74%% 117 14.79% 28 11.91% 2 4.55%
Seizures/Convulsions 147 13.74%% 117 14.79% 28 11.91% 2 11.14%
Shaking/Tremors/Ataxia 493 43.2%% 271 34.3%% 178 75.7%% 13 29.6%%

Table 6: Number and percenft off sampfle popuflafion dfispflayfing reacfion.

The co-authors of the present report also have encountered denials or ignorance of this latest information. The question remains about the motivation or reasons for professional veterinary colleagues and their teaching institutions to fail to relay or be aware of these updates.

Conclusion

Updated results from the USA and European Union indicate a noteworthy increase in the number of reported adverse events from the flea and tick preventives and collars beyond what was originally on the product labels, including seizures, behavioural aggression, and death. The actual number of adverse incidents is likely much higher than is reported. The veterinary profession has been less than forthcoming in informing their clients about these potential serious side effects.

References