T R E AT MEN T F OR P OULT RY MI T E INF E S TAT IONS IN CHICK ENS

T ECHNIC A L M A NUA L
BREAKTHROUGH
MITE CONTROL
Exzolt™, new from MSD Animal Health, wipes out over
99% of poultry mites (Poultry Red Mites and Northern
Fowl Mites), making it the most impactful and eff ective
solution for infestations. And because it’s simply
applied through your poultry drinking system,
there’s no special training or new equipment
needed, meaning one person can treat all your
birds faster than ever.

If you’re serious about keeping your birds and

your bottom line healthy, visit Exzolt.com

Exzolt.com
SAFER, SIMPLER, MORE EFFECTI
Exzolt provides 99%+ mite elimination in three simple steps. F
hen’s drinking water to eliminate live mites. Administration th
spraying and minimizes the potential of chemical exposure to
application to eradicate mite stages not susceptible to the firs

To maintain the fast and nearly complete elimination of mite p

bio-security measures, such as:

Avoiding entrance of poultry mites with the allocation of new he

Changing outer clothing per house and use specific tools per each

Cleaning and checking for poultry mite absence before being used

1 2

FIRST APPLICATION OF EXZOLT SECOND APPLICATION OF EXZOLT

THROUGH DRINKING SYSTEM KILLS EFFECTS OF TREATMENT TO KILL
BLOOD-FEEDING MITES ENTER THE BLOOD-FEEDING
 IVE MITE CONTROL
First, deliver the initial application through the
hrough the drinking water reduces stress caused by
o human workers. Seven days later, apply the second
st application.

populations that Exzolt provides, follow proper

en flocks

h barn

d in another house

MAINTAINS THE MAINTAIN PROPER BIOSECURITY

MITES AS THEY MEASURES TO ELIMINATE
G STAGES MITE REINFESTATION
TABLE OF CONTENTS
1. POULTRY MITES...................................................... 3
Poultry Red Mites
High Prevalence
Physiological Damage
Economic Damage
Poultry Red Mites as Vectors of Disease
Human Health Concerns
Control Attempts
Northern Fowl Mites
Life Cycle, Population Dynamics
Fowl Mite Impacts
Control Attempts
The New Approach
Mite Parasites Summary

2. PRODUCT PROFILE................................................. 15
Pharmacology, Mode of Action, Efficacy, Safety,
Fluralaner Chemical Properties
Label Information
Product Profile Summary

3. PHARMACOLOGY AND ACTIVITY.. ............................. 23

Pharmacokinetics
Pharmacodynamics and Activity
Resistance
Pharmacology and Activity Summary

4. SAFETY. . .............................................................. 31
Target Animal Safety – Laying Hens
Target Animal Safety – 3-Week-Old Chicks
Reproductive Safety
Withdrawal Period
Environmental Safety
Safety Summary

5. EFFICACY............................................................. 41
Efficacy Against Poultry Red Mites
Treatment Regimen Rationale
Dose-Determination Research
Dose-Confirmation Studies
Field Efficacy Study
Efficacy Against Northern Fowl Mites
In vitro Activity
Dose-Confirmation Study – Layers
Dose-Confirmation Study – Replacement Chickens
Field Efficacy Study – US
Natural Infestation Efficacy Study – Brazil
Efficacy Summary

6. USAGE GUIDELINES................................................ 59
Dose Calculation
Preparing Stock Solution and Dosing Birds
Considerations for Use of Dosing Pumps

7. SUMMARY.. ........................................................... 65

8. REFERENCES CITED............................................... 69

9. LABEL SUMMARY.................................................. 75
 SECTION ONE

POULTRY MITES
MITE PARASITES OF POULTRY
Though most health programs for chickens are focused on bacterial, viral, or coccidial threats,
production birds are also vulnerable to parasites that can live on or in their bodies. Cage housing
has greatly reduced the exposure of commercial layer flocks to internal nematode parasites and
their intermediate carriers (although recent trends to cage free and free range production is
causing some reversal of this trend), but the economic damage posed by external parasites has
historically lagged far behind in technological advancement.

POULTRY RED MITES

Poultry Red Mites (Dermanyssus gallinae, Figure 1-1) are common POULTRY RED MITES
skin parasites that are the most significant ectoparasite pest of Kingdom .... Animalia
laying hens worldwide and represent a severe threat to poultry Phylum ....... Arthropoda
Class ........... Arachnida
production in Europe.1 These extremely destructive nocturnal Subclass...... Acari
ectoparasites suck blood from host birds at night and then hide Order ......... Mesostigmata
Family......... Dermanyssidae
in the cracks, crevices, and litter of poultry houses when they are Genus.......... Dermanyssus
not feeding during the day.2 Adult mites measure about 1 mm Species........ D. gallinae

long, weigh about 76 μg (unfed) to 280 μg (after a blood meal),

and are red in color after feeding, but they appear black, grey,
or white without host blood in their system.3-6

HIGH PREVALENCE
Recent surveys have confirmed the extremely high
and increasing prevalence of infestations with
Poultry Red Mites in Europe. The average overall
infestation rate of European layer houses has been
estimated at 83%, with rates of 94% reported
for Germany, Belgium, and the Netherlands, and
67% to 90% for France, Spain, Italy, Poland, Sweden,
and the UK.7-9 Extrapolation of these estimates
suggests that about 300 million hens in Europe are
potentially suffering from mite infestations at
any particular point in time. Poultry Red Mites
are found
in all production types, from backyard
or organic farms to intensive, enriched cage or
Figure 1-1: Poultry Red Mites on a piece of straw at a free-range farm.. barn systems.10

5
 E X ZOLT.C OM

Though only very limited information has been published in the scientific literature regarding red mite
prevalence outside Europe, highly variable values have been reported for Africa, the Middle East, Asia, and
Latin America. Poultry Red Mites are known to co-exist with Northern Fowl Mites in Latin America and Asia.

POULTRY RED MITE LIFE CYCLE

Eggs

5x
12-24 hours 2-3 days

Blood
Feeding

Adults Larvae

2-3 days 1-2 days

Deutonymphs Protonymphs

Blood Feed- Blood Feed-

ing 1-2 days ing

Based on Sparagano, et al.10

Figure 1-2: The life cycle of the Poultry Red Mite, Dermanyssus gallinae. Aside from the egg, the Poultry Red Mites have 4 life cycle stages: larva, protonymph, deutonymph, and
adult. Larvae hatch with 6 legs and do not feed. After the first molt, both nymphal stages and adults have 8 legs. Protonymphs, deutonymphs, and adult females routinely feed on host
blood, but males only occasionally feed.1

6
PHYSIOLOGICAL DAMAGE
Infested chickens can develop anemia due to
repeated mite bites, with laying hens possibly losing
more than 3% of their blood volume every night.6 In
extreme cases, D. gallinae infestation burdens may
be so high that hens become severely anemic and
die from blood loss alone.11-12 A 10-fold increase
in hen mortality following severe infestation has
been reported.11

The direct mite life cycle can be as short as 7 days

(Figure 1-2), which allows for rapid growth of mite
populations. Heavy infestations of around 50,000
mites/hen in caged systems and up to 500,000 mites/
hen in severe cases have been reported.2 Typical mite
density ranges between 25,000 and 50,000 mites/
hen, levels that can induce aggressive feather-pecking
and cannibalistic behavior, changes in feed and water
intake, and decrease general condition.1,6,12,13 The
most severe infestations occur in the warm season,
from May to October.14

Mite bites are painful and induce skin irritation,

contributing to high stress levels in infested birds.
Increased self-grooming and head scratching both
day and night (characteristic symptoms of anxiety
that also contribute to decreased weight gain),
have been observed in artificially infested hens.12 Dermanyssus gallinae can also be involved in the
Mite infestation has been associated with a 1.5-fold transmission of numerous poultry pathogens,
increase in corticosterone blood levels and a 22% including zoonotic pathogens such as Salmonella
decrease in β-globulin levels, indicative of somatic enteritidis (responsible for one of the most
stress and immunosuppression. The adrenaline widespread zoonoses worldwide).13,18-20 Mites have
levels were also more than twice as high as in also been implicated as a vectors for numerous other
control animals, indicating psychogenic stress.17 poultry pathogens and avian influenza virus.10,21

In addition to experiencing anemia as well as

higher rates of mortality and disease susceptibility,
flocks infested with mites typically suffer eroded ECONOMIC DAMAGE
productivity as evidenced by:
Economic losses from poultry mite infestations
severely affect the productivity of the egg industry.
Decreased feed intake Consequences of red mite infestation in a layer
Decreased egg production operation include primarily a negative impact on
feed conversion ratio, a drop in egg production,
Decreased egg quality (shell thinning, spotting) an increase of downgraded eggs, and more
Decreased weight gain susceptibility to poultry diseases.1,6,22 In 2017, Van
Emous estimated that damage caused by mites in
Europe is about € 231 million. This value is almost
twice his 2005 estimation. This evaluation is based
on a current total cost of red mite infestation of
€0.60 per hen per year in the Netherlands.23

7
 E X ZOLT.C OM

A 2013-2014 FAO poultry census estimates the Salmonella gallinarum and enteritidis
number of layer chickens in the 17 largest egg-
Pasteurella multocida
producing countries in Europe to be 431 million. 24
Recently a large layer genetics supplier estimated Escherichia coli
that productivity losses can reach €0.57 per hen
Listeria monocytogenes
per year in case of moderate mite infestation
(range €0.27 for low infestation to €2.50 for high Mycoplasma synoviae
infestation). 25 The estimation of the evolution
Erysipelothrix rhusiopathiae
of direct treatment costs is complex due to the
changes in the acaricidal treatments arsenal Coxiella burnetti
available to the farmers for the past decades,
Nocardia brasiliensis
as described later in this review. However, the
same layer genetics supplier recently estimated Borrelia burgdorferi
the total cost of D. gallinae infestation to be up
Viral diseases such as Newcastle disease,
to €1 per laying hen per year, depending on the
St. Louis encephalitis, avian influenza,
housing system, the infestation intensity, and
Eastern, Western, and Venezuelan
the control methods used. 26 Based on the above
equine encephalitis1,8,18,19,21,27,28
recent poultry census data, 24 the updated average
infestation prevalence (83%7), and recent per bird
cost calculations, 26 we now estimate the current
cost of red mite infestation for the egg industry in HUMAN HEALTH CONCERNS
Europe to be about €200 million for productivity
Poultry Red Mite pests are of growing concern
losses and up to about €360 million for overall costs.
in human medicine as D. gallinae infestation is
increasingly responsible for human dermatological
lesions (gamasoidosis), particularly in people living
POULTRY RED MITES or working in close proximity to poultry.28 In fact, red
mites in poultry production buildings are recognized
AS VECTORS OF DISEASE as a significant occupational hazard to poultry
In addition to their effects on poultry production, workers.29,30 A recent survey reported an increasing
Poultry Red Mites can spread an array of diseases incidence of gamasoidosis worldwide and found
of humans and other animals.1,8,19 Many bacterial that the disease is underdiagnosed. 8 The survey
and viral pathogens that affect both humans showed that gamasoidosis severity is exacerbated
and animals and have been either isolated from by the persistence of mite infestation, treatment
red mites or had mite-vectored transmission failures, and the potential transmission of zoonotic
demonstrated in laboratory settings, including: diseases by the mites (such as Borrelia burgdorferi,
the cause of Lyme disease; Babesia spp.; Bartonella
spp.). Dermatitis related to D. gallinae has become
so substantial that workers in some countries have
to be paid 3-times the basic rate to work with D.
gallinae-infested birds.22

Dermanyssus gallinae
Adult Poultry Red Mite

8
 Although it may be applied in the presence
CONTROL ATTEMPTS of birds in an infested house, it should not be
Current methods for managing red mites lack sprayed directly onto the birds, thus decreasing
sufficient efficacy to keep infestations under its ability to reach mite refuges in crevices and
control in many poultry farms. 26 The parasites are cracks close to the birds.
difficult to control since they can be transferred
The product is restricted only to those cases
between flocks by crates, clothing, and wild birds,
where its use is unavoidable because the
and they can be difficult to detect unless birds are
infestation has become overwhelming.
examined at night when mites are feeding. 31

Simply removing the host from an area will not Users should wear special protective clothing
eliminate the mites, as deutonymphs and adults during treatment and cannot re-enter the treated
are known to resist desiccation and live as long house for at least 12 hours after treatment.
as 8 months without feeding.1,4 Furthermore,
recent European legislation (2012) banning use A 12-hour egg withdrawal period must be
of traditional cages for poultry birds (European observed after treatment (makes product
Council Directive 1999/74/EC) has favored the use unsuitable for use in large, intensive layer farms).
of housing systems incorporating more complex
Similar precautions apply for most other premise-
environments. While these animal welfare
spray/pesticide approaches to red mite control.
measures represent positive advancements for
Several acaricidal spray products are available in
poultry husbandry, such housing systems appear
some European countries for the treatment of the
to favor red mite proliferation and exacerbate
poultry house and equipment (not birds), mainly
infestation problems by providing mites more
for use during the unoccupied period between
hiding possibilities, thus enabling them to more
flocks. These products may contain pyrethroids
easily escape control measures. 22,26,32,33
(cypermethrin, permethrin, deltamethrin),
Chemical control of mites is often attempted, carbamates (bendiocarb), abamectin, and spinosad.
involving treatment/spraying of the local Most may only be applied in empty buildings; only
environment including walls, floors, roosts, nest a few (e.g., spinosad and cypermethrin) may be
boxes, and birds. Synthetic acaricides such as applied in the presence of birds in some countries.
organophosphates (dichlorvos, fenitrothion, However, some of these products have no approved
chlorpyrifos, diazinon), carbamates (carbaryl, recommended egg withdrawal time, thus posing
methomyl, propoxur), and pyrethroids a potential human food-safety risk. In addition,
(cyhalothrin) are the most common chemicals currently marketed acaricidal products have
used against mite infestations, though their only short residual activity, 34 which is a problem
efficacy is questionable. Many conventional mite since D. gallinae mites may not encounter treated
products have been withdrawn from European surfaces for several days post-application; and
markets or banned in the past few years because these products exert little or no activity on mite
they did not comply with European or national eggs, thus enabling regrowth of infestation burdens
regulatory requirements with regard to human in treated houses. The application of pesticides
consumer and user safety. to an entire poultry house also carries the risk of
feed contamination, and treatments often need to
Currently, the organophosphate phoxim is the be repeated at 2-week intervals. Thus, the use of
only veterinary medicinal product registered in chemical treatments involves the direct cost of the
Europe for the treatment of D. gallinae infestations pesticides used plus labor costs, worker protection
(since 2010). However, the product is not currently equipment, and the cost of maintaining the flock
licensed in the largest layer industry countries such through the egg and meat withdrawal times
as Germany, Poland, Spain, and the UK, where following treatment.
the prevalence of D. gallinae infestations exceeds
80%. Furthermore, strict precautions pertaining
to animal safety, user safety, and consumer safety
must be observed when using phoxim:

9
 E X ZOLT.C OM

Chemical treatments are also hampered by

resistance development to multiple acaricides1,35
THE UNMET NEED FOR A NEW MITE
due to selection of resistant mites that survive CONTROL OPTION
due to uneven spraying, especially inside crevices
In spite of many previous efforts, the development
and cracks resulting in exposure to sublethal
of more useful, effective, and innovative
concentrations.36 Resistance to organophosphates
treatments to keep Poultry Red Mite infestations
has been reported in the literature for several
under control remains in great demand. 26 This
decades36 and is now widespread. For instance, 10
unmet medical need has clearly been recognized
D. gallinae field isolates from German laying farms
by the scientific community, key opinion leader
were all resistant to the pyrethroid cyfluthrin and
groups, the layer industry, and government
90% to the organophosphate phoxim. 37
organizations. The absence of an effective
Because of the many problems associated with treatment is stated in most of the scientific
use of conventional chemicals and pesticides papers dealing with poultry mites and has been
for controlling Poultry Red Mites, several new officially recognized by the EU Commission, which
alternative solutions have been proposed or created and funds the COST Action FA 1404
developed in recent years, including essential (“Improving current understanding and research
oils, newer chemical pesticides (e.g., spinosad), for sustainable control of the Poultry Red Mite
predator mites, heat treatments, intermittent Dermanyssus gallinae,” COREMI32) to “rid laying
lighting programs, inert dusts (e.g., silica, hens of a common disease-spreading pest.”
diatomaceous earth), and even vaccines. 26 This 4-year project started in late 2014 involves
representatives from almost all EU countries,
Turkey, and Israel.

NORTHERN FOWL MITES16

The Northern Fowl Mite (Ornithonyssus sylviarum, Figure 1-3) NORTHERN FOWL MITES
is another mite species that poses a severe threat to poultry
Kingdom .... Animalia
production, particularly in North America, Brazil, China, and Phylum ....... Arthropoda
Class ........... Arachnida
Australia. Fowl mites are the most common and damaging
Subclass...... Acari
ecto-parasite of poultry in the US, though Poultry Red Mites Order ......... Mesostigmata
Family......... Macronyssidae
(D. gallinae) can also afflict US flocks. Fowl mites also occur
Genus.......... Ornithonyssus
in Europe and may pose an emerging threat but are not Species........ O. sylviarum

comparable there to the damage caused by Poultry Red Mites

(the reasons for this disparity are unclear).

Fowl mites are closely related to Poultry Red Mites and induce similar consequences in terms
of animal welfare and production losses. Like Poultry Red Mites, O. sylviarum is considered a
“dermanyssoid” mite but is placed in a different taxonomic family (Macronyssidae rather than
the Dermanyssidae). Though originally a nest-parasite of wild birds, these obligate blood-

10
feeding mites have become common ectoparasites of domestic birds, causing direct damage
to poultry and decreased economic output. Severe infestations and economic damage occur
primarily in layer hens (chickens) or breeders (chickens or turkeys), which are raised for
longer periods of time than other poultry types (such as broilers) and thus allow high mite
populations to develop and be maintained.

NORTHERN FOWL MITE LIFE CYCLE

Eggs

24-48 hours < 24 hours

Adults Larvae

Blood Feeding

< 24 hours ~ 1 day

Deutonymphs Protonymphs

Blood Feeding
1-2 days

Entire Northern Fowl Mite

life cycle exists on bird.
Figure 1-3: The life cycle of the Northern Fowl Mite, Ornithonyssus sylviarum. Aside from the egg, fowl mites have 4 life-cycle stages: larva, protonymph, deutonymph, and adult.
Larvae hatch with 6 legs and do not feed. After the first molt, both nymphal stages and adults have 8 legs. Only protonymphs and adult females feed on host blood. All stages remain on the
chicken (unlike daily exodus of red mites off the bird). Eggs mature to adults in as few as 5 days.

11
 E X ZOLT.C OM

LIFE CYCLE, POPULATION DYNAMICS

Populations of Northern Fowl Mites are
predominated by females (4:1 ratio), and even
unfertilized eggs can produce male off spring
available for future mating. Thus, introduction of a
single unmated female, even if immature, may be
able to trigger infestation of a new host.

A major difference between Northern Fowl

Mites and Poultry Red Mites is that the entire
O. sylviarum life cycle is completed on birds.
Thus, chickens are infested with all O. sylviarum
development stages (Figure 1-4), with the mites
perpetually residing on host feathers (usually in
Figure 1-4: Photomicrograph of Northern Fowl Mite adult female, Ornithonyssus the vent area) and migrating to the skin surface
sylviarum (100×).16 (Used with permission.) where only protonymphs and adults feed on blood
(no daily exodus off the bird as with red mites). In
addition, adult O. sylviarum are generally smaller
(~0.6 mm) than D. gallinae adults (~1-1.5 mm).

The direct fowl mite life cycle requires 5 to 12 days

to complete (Figure 1-5). Because the life cycle can
be as short as 5 days under optimal conditions,
rapid growth of mite populations can occur. Fowl
mite eggs are laid primarily onto feathers of
the vent region just anterior to the cloaca of an
infested chicken, offering an optimum feather
structure and microclimate favored by mites. Fowl
mites are able to survive off a host for periods of
1 to 3 weeks. Protonymphs survive much better
than adults, and survival of both stages improves
at lower temperature and higher humidity.
Figure 1-5: Photomicrograph of life stages of the Northern Fowl Mite: egg (e),
Large numbers of fowl mites are readily visible on
egg with developing larva (e-l), larvae (l), protonymph (p), and adult female.16 (Used
infested birds, with feathers typically appearing
with permission.)
“dirty” because of the collection of mites, cast
skins, eggs, and mite feces (Figure 1-6). Dense
clusters of these components and matted feathers
“glued” together by mite debris can create a semi-
porous microhabitat that may be quite thick.

Northern Fowl Mites easily spread among caged

hens and exhibit rapid and steady population
growth when introduced to naïve chickens. On a
flock basis, fowl mite infestations grow steadily for
4 to 10 weeks after introduction, while populations
on individual birds usually peak 3 to 6 weeks post-
introduction. Low mite levels then persist for the
remainder of the bird’s life, and this decline in mite
population is likely due to bird immune responses.
However, older hens may experience moderate
mite ‘relapses’ at intervals of about 5 to 6 weeks.
Figure 1-6: Northern Fowl Mites (primarily adults) blood-feeding at the base of an
infested vent feather (arrow indicates area of concentrated mite feeding).

12
 populations increased. All of these negative
impacts may also be related to mite-induced
immune responses.

Like Poultry Red Mites, Northern Fowl Mites can

also cause irritation to human workers. As mite
populations expand and become very dense, mites
may be seen on eggs (Figure 1-7), equipment, and
poultry workers. In fact, visually monitoring of
fowl mite numbers on eggs has been proposed
as a relatively quick and easy monitoring method,
though less exact than directly checking hens.

Unlike Poultry Red Mites, Northern Fowl Mites

to date have not been implicated as important
Figure 1-7: Adult Northern Fowl Mites on a chicken egg. Mites may be visible pathogen vectors (perhaps due to less research
on eggs when populations are dense and may be used as a monitoring tool to gauge conducted compared to red mites). However,
relative mite populations. they may serve as a minor mechanical vector of
western equine encephalitis and may play a role as
a reservoir for poultry pathogens between flocks
In severe cases, mite numbers can well exceed (especially if mites are ingested directly by birds
50,000 and sometimes even 100,000 mites per while grooming).16
bird. At such high infestation levels, mites can
cause up to 6% blood loss per day per hen. 38 Mite
populations vary substantially among birds of the CONTROL ATTEMPTS
same age and strain, with some of this variation
under genetic control. Successful integrated pest management programs
for poultry should focus first on preventative
measures and then, if infestation occurs, strive to
NORTHERN FOWL MITE IMPACTS keep the population below economic thresholds.
Once Northern Fowl Mites are established in
Blood-feeding by Northern Fowl Mites can a facility they can be very difficult to eliminate
cause skin irritation and inflammation (immune and may become a predictable problem in
activation), anemia (up to 6% blood loss/day), and subsequent flocks. Conventional control attempts
sometimes even death. Lesions associated with are similar to those used for Poultry Red Mites,
mite feeding have been identified as an animal such as chemical methods (e.g., pesticide
welfare concern. The parasites are most damaging sprays) and a variety of alternative strategies
early in a new flock during the first egg-production discussed earlier (and other alternatives, like dust
cycle, when young hens are immunologically naïve bags and encouragement of dust bathing and
to mites. grooming behaviors). However, control efficiency
is threatened by mite resistance to a shrinking
Resulting economic impacts due to fowl mite arsenal of acaricidal compound classes, especially
infestations include decreased egg production for the synthetic pyrethroids, but also against
and feed conversion efficiency. One 2009 study carbamates and organophosphates.40
reported profit reductions of $0.07 to $0.10/hen
over only a 10-week peak mite-infestation period, Applications of materials intended for Poultry
which basically eroded all the expected profit Red Mite control are typically off-host (applied to
margin at that time. 39 The damage appeared to mite resting areas, facility, etc.) while products for
depend on infestation level, as low rates (≤ 100 Northern Fowl Mites somehow need to be applied
mites/bird) were not as economically damaging on the bird for effective control, thus complicating
to egg production. Degradation of standard both practicality and host safety. On most large-
measures of egg quality (e.g., Haugh units, scale production operations in the US, Northern
albumen height, egg weight, egg specific gravity) Fowl Mites are typically managed by spraying
have also been documented over time as mite chemical pesticides at high pressure directly

13
 E X ZOLT.C OM

onto birds, with the spray directed upwards from exposure are increasing, organic production is
underneath hanging ‘battery’ cages (pesticides increasing (which disallows most pesticides), and
are most effective when applied to feathers in poultry housing is changing.
the vent region where mites gather). However, the
US industry is gradually transitioning away from
using small wire battery cages for egg production THE NEW APPROACH
and switching instead to larger ‘enriched’ cages or
cage-free housing. Effective spraying of birds with The development and approval of Exzolt (fluralaner)
pesticides is more difficult in these systems and solution for use in drinking water now offers an
thus severely limits some methods for mite control. innovative new approach for comprehensive
management of Poultry Red Mites and Northern Fowl
Clearly, an urgent need exists to develop new Mites in chickens. As discussed in the following pages,
or alternative control methods for fowl mites novel Exzolt provides a unique combination of potent
because the number of available synthetic control efficacy, user convenience, and bird safety in a ready-
agents is decreasing, concerns about pesticide to-use aqueous solution for water administration.

MITE PARASITES SUMMARY

External mite parasites are a costly global problem for poultry production, with an
estimated 83% average overall infestation rate for European layer houses.

Poultry Red Mites (Dermanyssus gallinae) are the primary mite threat in Europe,
while Northern Fowl Mites (Ornithonyssus sylviarum) predominate in other regions
such as the US and Latin America.

The approximate total cost of Poultry Red Mite infestations and overall costs totals
€360 million in Europe, and the parasites can spread a diversity of bacterial and
viral diseases of humans and other animals.

Poultry Red Mites can spread a diversity of bacterial and viral diseases of humans
and other animals.

Current methods for managing Poultry Red Mites lack sufficient efficacy to keep
infestations under control at many poultry farms, and often pose safety threats
for both birds and humans.

The development of more useful, effective, and innovative treatments to

control mite infestations has been an unmet medical need recognized by
the scientific community, key opinion leader groups, the layer industry, and
governmental authorities.

14
 SECTION TWO

PRODUCT PROFILE
PRODUCT PROFILE
Exzolt is a unique parasiticide for chickens that provides potent efficacy against Poultry Red
Mites and Northern Fowl Mites via a convenient oral solution dosage form for administration
in the drinking water. Fluralaner (carbamoyl-benzamide-phenyl-isoxazoline), the active
ingredient of Exzolt, is a member of the novel antiparasitic compound class of isoxazoline-
substituted benzamide derivatives. It is a racemic mixture of S- and R-enantiomers, with the
S-enantiomer expressing activity (equal amounts of left- and right-handed enantiomers of the
chiral molecule). Exzolt is a 1% fluralaner aqueous solution (10 mg/mL) intended for treatment
and control of Poultry Red Mite (D. gallinae) and Northern Fowl Mite (O. sylviarum) infestation
in chickens (pullets, breeders, and layers) when administered orally via drinking water twice
(7 days apart) at a dose of 0.5 mg fluralaner per kg body weight (BW) (equivalent to 0.05 mL
Exzolt/kg BW).

Fluralaner is a compound from a new chemical class and is the first isoxazoline approved for
use in poultry. This development is notable because very few new pharmaceutical molecules
have been licensed over the past few years for use in poultry in Europe. In fact, the high
economic pressures and low margins inherent to egg and chicken meat production typically
mean the poultry industry can “afford” only older compounds or agents widely used in the
crop or premise-protection domain. In contrast, fluralaner has never been used in agriculture,
and therefore represents a truly new and innovative treatment for poultry.

PHARMACOLOGY MODE OF ACTION

After oral administration, fluralaner is absorbed Once ingested by a mite feeding on a treated
rapidly from the medicated drinking water, reaching chicken, fluralaner acts as a potent inhibitor
maximum plasma concentrations 36 hours after the of parts of the arthropod nervous system by
first administration and 12 hours after the second acting antagonistically on ligand-gated chloride
one, following start of administration via medicated channels (GABA-receptor and glutamate-
drinking water. The bioavailability is high, with receptor). The compound has demonstrated high
approximately 91% of the dose absorbed following activity on various heterologous GABA-receptors
oral administration. Fluralaner is highly bound to (Rhipicephalus microplus, Ctenocephalides felis,
protein. Fluralaner is widely distributed throughout Drosophila melanogaster), but shows no activity
the body, with the highest concentrations reported on the tested mammalian GABA-receptor.41
in the liver and skin/fat. No significant metabolites Research also showed that the fluralaner activity
are observed in chickens, and fluralaner is mainly was not affected by the dieldrin resistance (RDL)
eliminated via the hepatic route. The apparent using the RDL-GABA-receptor variants from C. felis
elimination half-life is approximately 5 days and D. melanogaster (these RDL-GABA-receptor
following oral administration. variants exhibit resistance against dieldrin and

17
 E X ZOLT.C OM

partly against fipronil). In vitro bio-assays have BENEFITS OF EXZOLT

shown that fluralaner is effective against parasites
having proven field resistance, including Dose rate: 0.5 mg fluralaner/kg BW
organophosphates (tick, mite), pyrethroids (tick, mite), administered twice, 7 days apart
and carbamates (mite).42 POTENT EFFICACY:
Induces a rapid and massive decrease
in mite populations in a chicken house.
FAST, POTENT EFFICACY Treats the bird, not just the environment.

Treatment of the host with Exzolt (instead of Fast start of kill (within 4 hours for
Poultry Red Mite), with prolonged
treating the host environment) is an innovative
duration in birds spanning 2 mite
approach to targeting mite parasites that live on life cycles.
the premises and spend only 30 to 90 minutes/
High bioavailability, systemic distribution
day on the host.6 Convenient treatment of
in poultry.
poultry with Exzolt via the drinking water causes
effective levels of the acaricide to be systemically Active against mites resistant to
classical acaricides.
distributed within all birds, ready to kill mites
whenever parasites extract a blood meal from
WATER TREATMENT:
their hosts. Efficacy against D. gallinae begins
within 4 hours after exposure of mites to treated Treats all birds, unlike hit-and-
chickens, and any mites feeding on treated miss spraying.
chickens for at least 2 weeks after the first Exzolt More convenient and cost-effective
administration will be killed. In addition, non- than sprays.
blood-feeding stages (eggs, larvae) are killed as Uniform dosing accuracy.
soon as they develop into hematophagous forms,
1 treatment—2 administrations,
and egg production by female mites is stopped. 1 week apart.
Thus, the mite life cycle is disrupted due to the
Ready-to-use solution for simple dilution,
rapid onset of fluralaner activity, the very high
with no sedimentation or clogging.
mite-killing efficacy (duration of at least 2 mite
life cycles), and the absence of egg production Flexible; easy to tailor treatment to
bird management programs (feeding,
from female mites exposed to treated chickens. housing, etc.).
Exzolt also contributes toward long-term control
of mite populations in a poultry house when used Reduced labor compared to sprays.
in conjunction with implementation of proper Re-sealable, multiple-entry container
biosecurity measures. with an in-use shelf-life of 1 year.

Available data indicate that Exzolt is more SAFETY ASSURED:

effective than traditional spray products for Zero egg withdrawal time for layers.
rapidly and dramatically decreasing building
Not stressful for hens, safe for breeders,
infestation burdens. Furthermore, regrowth of
no harm on egg production, hatchability,
mite populations takes longer than with spray or progeny.
treatments, indicating that more mites are
Broad safety margin.
eliminated by systemic treatment with Exzolt.
Avoids exposure of house workers
and birds to toxic chemical sprays.

SAFE FOR CHICKENS AND PEOPLE

Fluralaner offers high selectivity for arthropods like poultry mites, and the formulated product has a large safety
margin demonstrated in chickens. Unlike spraying, water-borne Exzolt is not stressful for hens and minimizes the
potential for exposure of chemicals by human workers. Furthermore, Exzolt has a zero-day withdrawal period for
eggs and is safe for layers, which is essential for large poultry units. Treatment compliance is also enhanced by
convenient administration of the ready-to-use solution in drinking water, greatly reducing the workload for house
workers compared to spraying (e.g., removing birds and/or eggs, repeat applications, quarantines, less safety
equipment, application license requirements, fewer safety precautions, etc.).

18
NOVEL,
REVOLUTIONARY EXZOLT
Exzolt provides poultry producers a revolutionary new option
for managing Poultry Red Mites and Northern Fowl Mites that
is that is effective, safe, convenient, and cost-effective, thus
helping chickens maintain optimal productivity performance
unhindered by profit-suppressing ectoparasites. Exzolt sets
a new standard for management of mites and represents an
excellent therapeutic component of comprehensive health
programs aimed at optimizing overall performance of pullets,
breeders, and layers.

Determine the duration of time (between 4 and

EXZOLT LABEL INFORMATION 24 hours) over which to administer the medicated
water on the treatment day. This period of time
INGREDIENTS must be long enough to allow all the birds to
Exzolt contains 10 mg fluralaner per mL of solution receive the required dose. Estimate how much
for use in drinking water for chickens. Excipient water birds will consume during treatment based
ingredients include α-tocopherol, diethylene on the previous day’s water consumption. The
glycol monoethyl ether, and polysorbate 80. It is product should be added to a volume of water that
a light yellow to dark yellow solution for use in the chickens will consume in one day. No other
drinking water. source of drinking water should be available during
the medication period.

INDICATIONS Calculate the volume of product needed based on

Treatment and control of Poultry Red Mite the total weight of all birds in the house to be treated.
(Dermanyssus gallinae) and Northern Fowl Mite To ensure administration of the correct dose, the
(Ornithonyssus sylviarum) infestation in pullets, body weight should be determined as accurately as
breeders, and layer hens. (Note: not approved for possible and an accurate measuring device should
Northern Fowl Mites in the EU.) be used for measuring the calculated volume of the
product to be administered.

DOSAGE AND ADMINISTR ATION The required amount of product on each treatment
For use in drinking water. day is calculated from the total BW (kg) of the
entire group of chickens to be treated, using the
Dose: 0.5 mg fluralaner per kg BW (equivalent to following formula:
0.05 mL Exzolt) administered twice, 7 days apart. The volume of product (mL)/treatment day = Total
complete course of treatment must be administered estimated BW (kg) of chickens to be treated X 0.05 mL
for a full therapeutic effect. If another course of
treatment is indicated, the interval between two Therefore 500 mL of product treats 10,000 kg
courses of treatment should be at least 3 months. body weight (e.g., 5,000 chickens of 2 kg body weight
each) per day of treatment administration.

Follow instructions on the full package leaflet to

prepare medicated water.

19
 E X ZOLT.C OM

FLURALANER CHEMICAL PROPERTIES

GENERIC NAME: Fluralaner

CHEMICAL NAME: (±)-4-[5(RS)-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-

dihydroisoxazol- 3-yl]-2-methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino) ethyl]
benzamide

MOLECULAR FORMULA: C 22H17Cl2F 6N 3O3

MOLECULAR WEIGHT: 556.3

PHARMACOTHERAPEUTIC Ectoparasiticides
GROUP: for systemic use

ATCVET CODE: QP53BE02

F3C O N
Cl O
H
N
N CF3
H
Cl CH3 O

WITHDR AWAL PERIODS breeding chickens were treated at 3-times the

Eggs: zero (0) days recommended dose for 2-times the recommended
Meat and offal: 13 days duration of treatment.

CONTR AINDICATIONS, ADVERSE ANIMAL PRECAUTIONS

REACTIONS, INTER ACTIONS Strict biosecurity measures at house and farm level
None known. should be implemented to prevent re-infestation of
treated houses. To ensure long term control of the
In the absence of compatibility studies, mite populations in a treated house, it is essential
Exzolt must not be mixed with other veterinary to treat any other infested poultry in houses in
medicinal products. proximity to the treated one.

SAFET Y, OVERDOSE USER PRECAUTIONS

Safety has been demonstrated in layers and The veterinary medical product may be slightly
breeders, and product can be used during lay. irritating to skin and/or eyes. Avoid contact with skin,
eyes and mucous membranes. Do not eat, drink
No adverse reactions/effects observed following or smoke while handling the product. Wash hands
treatment of 3-week old chickens, adult chickens, and contacted skin with soap and water after use
or laying hens (egg production) dosed at up to of the product. In case of eye contact, immediately
5-times the recommended dose for 3-times the rinse thoroughly with water. If the product is spilled,
recommended duration of treatment. No adverse remove any affected clothes.
effects on reproductive performance when

20
PACK AGING/STOR AGE/EXPIR ATION
Packaged in 1-L and 4-L bottles (HDPE) closed
with an aluminum foil seal and a child-resistant
polypropylene screw cap.

Do not store above 30o C.

Shelf life as packaged: 3 years

Shelf life after opening the immediate packaging:

12 months

Shelf life of medicated drinking water: 24 hours

PRODUCT PROFILE SUMMARY

Exzolt (fluralaner) represents a completely new approach for comprehensive
management of Poultry Red Mites and Northern Fowl Mites in chickens by
systemically treating host birds (via drinking water) instead of treating the
animal facilities.

Fluralaner is a potent inhibitor of parts of the arthropod nervous system and

acts antagonistically on ligand-gated chloride channels (GABA-receptor and
glutamate-receptor).

Treatment with Exzolt provides fast, convenient, and potent acaricidal efficacy,
with proven safety for chickens and the users of the product.

Exzolt is approved for treatment of Poultry Red Mite (Dermanyssus gallinae) and
Northern Fowl Mite (Ornithonyssus sylviarum) infestation in pullets, breeders, and
layers when provided in drinking water at 0.5 mg fluralaner/kg BW, administered
twice 7 days apart.

Exzolt has a zero-day withdrawal for chicken eggs and a 14-day withdrawal
period for meat and offal, with no contraindications, known adverse effects,
or known interactions.

21
 E X ZOLT.C OM

NOTES

22
 SECTION THREE

PHARMACOLOGY
AND ACTIVITY
PHARMACOLOGY AND ACTIVITY
Because orally administered fluralaner reaches target ectoparasites via the gastrointestinal tract
and the bloodstream, a review of the pharmacologic behavior of fluralaner within chickens is
relevant. Several studies documented the pharmacokinetics and pharmacodynamics/activity of
fluralaner in support of product indications. As mentioned earlier, fluralaner is a racemic mixture
of S- and R-enantiomers (equal amounts of left- and right-handed enantiomers of the chiral
molecule), with the S-enantiomer expressing acaricidal activity.

Comprehensive studies examined the label recommendations and fluralaner pharmacokinetic profile of Exzolt.

25
 E X ZOLT.C OM

PHARMACOKINETICS
Research investigated the pharmacokinetic RESULTS
profile of fluralaner in chickens after intravenous Fluralaner was quickly absorbed (Figure 3-1) and
administration of 0.5 mg/kg BW and after oral concentrations peaked at the 1.5-day time-point
administration by gavage at 0.25, 0.5, and 1 mg/ after the first administration and 0.5 day after
kg BW (4 treatment groups, 45 laying hens/ the second administration, with Cmax of 323.7
treatment).43 Blood samples were collected pre- ng/mL and 355.1 ng/mL after the respective first
treatment and at 17 post-treatment time-points (5 and second administrations, indicating slight
minutes through 35 days). Fluralaner displayed a accumulation. Concentrations of fluralaner then
slow elimination profile (T1/2 of about 5 days after decreased gradually. The AUC was 1297 ng*day/
intravenous administration), dose linearity, and mL (day 0-7) and 2388 ng*day/mL (day 7-infinity).
91% oral bioavailability. Fluralaner is highly bound Notably, the 2-administration fluralaner plasma
(~100%) to plasma proteins.44 profile covered the time-period needed for
completion of 2 consecutive mite life cycles,
The pivotal pharmacokinetic study examined use a fundamental concept used for selecting the
of Exzolt according to label recommendations and dose regimen with the intent of imposing lengthy
assessment of the fluralaner pharmacokinetic disruption of mite population dynamics.
profile after oral administration via drinking water.44

CONCLUSIONS
STUDY DESIGN
Fluralaner oral bioavailability is high and drug
55 healthy laying hens were treated with was rapidly absorbed after oral administration
2 single administrations of Exzolt (2-times in drinking water at 0.5 mg/kg BW twice at 7-day
0.5 mg fluralaner/kg BW) at 7-day intervals. intervals, and slight accumulation occurred in
blood, consistent with a rhythm of administration
Blood samples were collected from hens designed to maintain therapeutic efficacy between
pre-treatment and at 20 time-points from administrations. Appropriate levels were achieved
6 hours until 21 days post-treatment and maintained in blood plasma for targeting of
(4 sample-times/hen). blood-feeding mites.

Plasma was analyzed for fluralaner concentration

using a validated HPLC-MS/MS chiral method.

Plasma fluralaner concentration (log10 - ng/mL)

1000
Total fluralaner
S-enantiomer (active)

100

2 mite life cycles or more

10

1
0 Exzolt 7 14 21
Treatments

Figure 3-1: Fluralaner plasma concentration; time profile after Exzolt administration in chickens at 0.5 mg/kg BW in drinking water, twice at a 7-day interval.

26
 STUDY DESIGN
PHARMACODYNAMICS AND ACTIVITY
16 laying hens (~ 20 weeks of age) were randomly
In preliminary research regarding fluralaner allocated to 2 groups of 8 hens housed in 2
pharmacodynamics and activity, fluralaner separate pens. One group was treated on days
demonstrated a prominent feeding activity against 0 and 7 with Exzolt at the recommended dose of
Dermanyssus gallinae compared to a less potent 0.5 mg fluralaner/kg BW while the second group
contact activity, which is appropriate for an orally remained unmedicated (controls).
administered drug with a systemic mode of
action (Figure 3-2). 43 Another study evaluated the Six hens of each group were artificially infested
susceptibility of nymph and adult mites to fluralaner, with unfed D. gallinae (mainly adults) on multiple
using an immersion test.43 Fluralaner was highly active occasions between days 1 and 26. After each
in vitro against both nymph (LC90=0.38 ppm) and adult infestation, a sample of engorged mites were
(LC90 =0.52 ppm) mite stages. collected from each infested hen, incubated, and
assessed for mortality after 4, 8, 12, and 24 hours.

100 For the reproductive portion of the study, tubes

containing mite eggs, surviving mites, or both
80 were incubated for 8 additional days. Counts of
Mortality %

dead adult male and female mites, mite eggs,

60 larvae, and nymphs were performed daily.

40 The primary reproduction parameter was the

control of nymphal development (i.e., control of
20 the capability to finally reproduce into nymphs
as the first blood-sucking development stage).
0 10000 1000 100 10 1 0,1 0,01 0,001 1E-4 1E-5 1E-6 1E-7 The conversion from each mite stage to the next
Percent mortality of D. gallinae after 3 different was also determined, including the number of
in vitro exposure tests to fluralaner eggs laid per incubated female (fertility) and
hatchability rate.
Filter paper test Immersion test Feeding test

Figure 3-2: Percent mortality of D. gallinae after exposure

to different fluralaner concentrations in 3 different tests.

The primary pharmacodynamic study of interest

evaluated the speed of kill and the impact of
treatment on reproductive capacity of mites after
feeding on Exzolt-treated hens.45

27
 E X ZOLT.C OM

RESULTS The oral administration of Exzolt was well tolerated

Outcomes for the speed-of-kill portion of the in all hens, with no treatment-related adverse
study (Figure 3-3) indicate that the mortality of reactions observed in treated birds.
mites infested on day 1 was 100% by 4 hours post-
infestation while the mortality of mites infested on CONCLUSIONS
day 5 was 98.7% at 4 hours and 100% at 8 hours.
The treatment of hens with Exzolt led to profound
After the second oral Exzolt treatment of hens on
and fast mite mortality for at least 15 days.
day 7, mortality of mites infested on day 8 was again
Furthermore, the demonstrated fast onset of
100% at 4 hours, and at day 12 near complete mite
action resulted in an immediate interruption of the
mortality (98.7-100%) was still observed within just
reproduction of the affected female mites prior to
4 hours of mites feeding on treated hens. Notably,
the lethal effect. Even 12 or 15 days after the second
100% mortality was observed within 24 hours
Exzolt treatment (days 19 and 22), the medication
for all mite infestations through day 15, without
still demonstrated major impacts on the ability of
any oviposition. These impressive outcomes are
surviving females to produce the next parasitic mite
related to the fact that mites feed on birds for a
generation (nymph emergence). Ongoing mortality
very short time (30-90 minutes), absorbing a high
of incubated mites combined with a reduction of laid
amount of fluralaner during this period. By day 19,
eggs are the main factors responsible for reduced
mite mortality 24 hours post-infestation was 74.8%
reproduction of the mites (nymph emergence).
and the oviposition (eggs laid within 24 hours) was
Molting processes of the mite progeny were not
reduced 82.2% vs controls.
notably impacted by fluralaner.
Nymph emergence (an indicator of reproductive
success) was completely inhibited in treated hens
through day 15, and reduction was still 90.8% at
day 19 vs controls (Figure 3-4). Fertility of surviving
females (control of eggs laid) was impaired mainly for
mites infested on day 19 (48.1% reduction, Figure 3-4).

Mite mortality in Exzolt group (% reduction vs controls) Reduction in Exzolt group (% reduction vs controls)

100 100
100 Nymphs produced
99.3
100
100

100

100

100
98.7

98.7

90.8 per incubated female

95.2

80 80
Eggs laid per
82.6

live female mite

74.8

60 60

40 40 48.1

20
31.1

24.2
20
15.9 15.2
3.3

15.2

0 10.6
0 Day 1 Day 5 Day 8 Day 12 Day 15 Day 19
Days 1-15* Day 19 Day 22 Day 26
Study day (Exzolt treatment on days 0 and 7)
Hours after artificial mite infestation:
Figure 3-4: Impact of Exzolt on reproductive capacity of surviving female mites (percent
4 hours 8 hours 12 hours 24 hours reduction vs controls). *Egg value could not be calculated before day 19 because the dead
females did not lay eggs before death.
Study day (Exzolt treatment on days 0 and 7)

Figure 3-3: Impact of Exzolt on mite mortality (percent reduction vs controls).

28
RESISTANCE
The development of resistance by mites to control agents is an ongoing concern, as with most all medicinal or
chemical interventions used for animal health (e.g., antimicrobials, anthelmintics, insecticides, etc.). However,
because fluralaner is a new agent recently introduced in veterinary medicine, resistance has not shown to be a
concern and none has been detected. Isoxazolines like fluralaner act at previously unrecognized activity sites
without cross-resistance to other chemotypes, and effects differ between insects and mammals so toxicity is
selective.46 In vitro bioassays have indicated that fluralaner offers efficacy against parasites with known field
resistance to various chemical classes, including organophosphates (tick, mite), pyrethroids (tick, mite), and
carbamates (mite).

During dose confirmation and field studies conducted in support of Exzolt approval, 12 Poultry Red Mite
isolates were collected in 2014 and 2015 from 12 chicken houses in France, Germany, and Spain. The
collected isolates were tested for in vitro acaricide sensitivity to fluralaner (11 isolates) and several other
acaricides (not all tested for each isolate), with the following outcomes for various agents:47

Fluralaner: Isolates were highly susceptible Additional in vitro research found that pyrethroid-
to fluralaner with LC90 < 15.63 ppm. resistant Northern Fowl Mites were also extremely
sensitive to fluralaner.48 The test isolate was
Phoxim: Demonstrated variable sensitivity resistant to pyrethroids (permethrin, deltamethrin)
as 6 of 11 isolates had LC90 greater than the despite not being exposed to acaricides for at least
recommended concentration for chicken houses 10 years. Still, the LC99 for fluralaner against adult
(2,000 ppm). The average LC90 for the 11 recent fowl mites was achieved at only 8.09 ppm (study
isolates was 3 dilutions higher than an older details presented in Efficacy section).
isolate collected in 2011.
The Exzolt dosage regimen (2 administrations
Deltamethrin: 3 of 3 isolates tested had LC90 seven days apart) was designed to ensure effective
exceeding the recommended concentration treatment and elimination of all mite development
for chicken houses (250 ppm). stages from the flock, which limits resistance
development. In addition, research45 showed that
Propoxur: 2 of 2 isolates tested had
female Poultry Red Mites dying after a blood
LC90 > 1,000 ppm.
meal from a fluralaner-treated hen were unable
Spinosad: 1 of 11 isolates tested had LC90 to lay any eggs, suggesting that the development
(> 4000 ppm) higher than the highest of less sensitive mite stages from eggs is unlikely.
recommended concentration in the field Correct use of Exzolt according to label directions
(4000 ppm). cannot be overemphasized, such as providing
the full approved dose regimen (2 consecutive
administrations 7 days apart), estimating bird
weights as closely as possible, etc.

29
 E X ZOLT.C OM

PHARMACOLOGY AND ACTIVITY SUMMARY

After oral administration, fluralaner is rapidly absorbed, reaching maximum concentrations
in plasma within 36 hours after first administration and within 12 hours after second
administration following start of administration via medicated drinking water.

The bioavailability is high, approximately 91% of the dose. Fluralaner is highly bound
to protein. The apparent elimination half-life is approximately 5 days following
oral administration.

Fluralaner is a very potent acaricide, acting extremely fast (within 4 hours) and for at
least 15 days when administered to chickens by the recommended Exzolt dosage regimen.

Exzolt significantly impairs reproduction of D. gallinae. During the first 15 days post-
treatment, all mites died within 24 hours without laying any eggs, and after 19 days,
mite reproduction was still seriously limited due to a remaining killing effect on female
mites combined with a reduction of their oviposition, thus limiting development of any
less sensitive mite stages from eggs.

No resistance for fluralaner has been detected in field isolates, and fluralaner was
active in vitro against mite isolates that were resistant to other acaricides.

The Exzolt treatment regimen (2 administrations 7 days apart) provides acaricidal activity
for a duration sufficient to break 2 consecutive mite life stages, thus providing a complete
elimination of mite population in the building and thus limiting development of resistance.

30
SECTION FOUR

SAFETY
SAFETY
A comprehensive safety program was conducted to demonstrate the safety of Exzolt for
chickens. One study investigated safety in laying hens, the primary production class for Exzolt,
while another study evaluated safety in young 3-week-old chicks. A reproductive safety study
was also conducted, evaluating safety in both treated breeder birds and their eggs/progeny.
Outcomes obtained in these studies support the safety of Exzolt in pullets, breeders, and layers,
per label indications.

TARGET ANIMAL SAFETY – LAYING HENS

STUDY DESIGN
A pivotal study was designed to evaluate the safety of Exzolt treatment via drinking water when administered
at 0 (control), 1-, 3-, or 5-times the recommended dose (0, 0.5, 1.5, or 2.5 mg fluralaner/kg BW, respectively)
for 3-times the recommended frequency (6 treatments instead of 2), for a total overall dosage up to 15-times
the recommended dose (Figure 4-1).49

120 laying hens at peak egg production (~28 weeks of age; under high physiological stress related to intensive
egg production) were randomly allocated to 4 treatment groups of 30 birds.

The 3 treated groups were offered tap water medicated with Exzolt as described in Figure 4-1 on 6
occasions (days 0, 1, 2, 7, 8, 9) while control group birds received non-medicated water. (As a result, the
total net doses of fluralaner administered were 3-, 9-, or 15-times the recommended total dose.)

Clinical health was monitored throughout the 35-day study, and feed and water intake were recorded.
Egg production was assessed daily for each treatment group, and eggs from 10 randomly pre-selected
birds in each group were evaluated for typical quality parameters. Hematology and clinical chemistry
parameters were measured pre-treatment and at multiple time-points.

Eight birds per group were euthanized on days 10 and 28 for complete gross necropsy, and complete
histopathological examination was performed on organs from the control and the highest dose (5X) group.

Data collections were performed by personnel blinded to treatment.

CONTROL 0 mg/kg/d (unmedicated water)

1X DOSE 0.5 mg/kg/d (recommended dose rate) = 3 mg/kg total dose (3X)

3X DOSE 1.5 mg/kg/d (3X recommended dose rate) = 9 mg/kg total dose (9X)

5X DOSE 2.5 mg/kg/d (5X recommended dose rate) = 15 mg/kg total dose (15X)
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 35
Exzolt Treatments Exzolt Treatments

Figure 4-1: Experiment design of target animal safety study for laying hens.

33
 E X ZOLT.C OM

RESULTS
Evaluations of the massive quantity of collected data revealed no clinically significant or relevant differences
for any safety or toxicological parameters between the control group and all medicated groups, including birds
treated at the 5X dose rate. Furthermore, no statistically significant differences between groups were detected
for egg production, the number of abnormal eggs, or egg quality characteristics.

Water intake was similar between all treatment groups, indicating that normal palatability was maintained
for drinking water medicated with Exzolt.

CONCLUSIONS
This target animal safety study demonstrated that Exzolt is well tolerated and normally palatable in laying hens,
even when grossly overdosed at up to 5-times the recommended dose rate for 3-times the recommended
frequency. Use of Exzolt at the recommended daily dose rate of 0.5 mg/kg BW twice at a 7-day interval clearly
offers a wide margin of safety for laying hens and does not impact rates of water consumption.

TARGET ANIMAL SAFETY – 3-WEEK-OLD CHICKS

STUDY DESIGN
A similar pivotal study involving young chickens evaluated the safety Exzolt treatment via drinking water when
administered at 0 (control), 1, 3, or 5-times the recommended dose (0, 0.5, 1.5, or 2.5 mg fluralaner/kg BW,
respectively) for 3-times the recommended frequency (6 treatments instead of 2), for a total overall dosage up
to 15-times the recommended dose (Figure 4-2).43

320 broiler male and female chicks (3 weeks of age at start of dosing) were randomly allocated to 4 treatment
groups of 80 birds.

The 3 treated groups were offered tap water medicated with Exzolt as described in Figure 4-2 on 6 occasions
at weekly intervals (days 0, 7, 14, 21, 28, 35) while control group birds received non-medicated water. (As a
result, the total net doses of fluralaner administered were 3X, 9X, or 15X the recommended total dose.)

Clinical health was monitored throughout the 54-day study, feed and water intakes were recorded, and
pen body weights were obtained weekly. Hematology and clinical chemistry parameters were measured
pre-treatment and at multiple time-points.

Ten birds per group were euthanized on days 36 and 54 for complete gross necropsy, and complete
histopathological examination was performed on organs from the control and the highest dose (5X) group.

Data collections were performed by personnel blinded to treatment.

CONTROL 0 mg/kg/d (unmedicated water)

1X DOSE 0.5 mg/kg/d (recommended dose rate) = 3 mg/kg total dose (3X)

3X DOSE 1.5 mg/kg/d (3X recommended dose rate) = 9 mg/kg total dose (9X)

5X DOSE 2.5 mg/kg/d (5X recommended dose rate) = 15 mg/kg total dose (15X)
0 7 14 21 28 35 42 49 54

Exzolt Treatments

Figure 4-2: Experiment design of target animal safety study for 3-week-old chicks.

34
RESULTS
No clinically significant or relevant differences for any safety or toxicological parameters were detected between
the control group and all medicated groups, including birds treated at the 5-times dose rate. The mortality
rate per pen was similar for all groups, and treatments had no effect on BW or rates of feed consumption by
chicks. Thus, use of Exzolt even at such extreme levels was not associated with any clinical, gross, or microscopic
findings, productivity not measured.

Water intake was similar between all treatment groups, indicating that normal palatability was maintained
for drinking water medicated with Exzolt.

CONCLUSIONS
This target animal safety study demonstrated that Exzolt is well tolerated and normally palatable in chicks and
growing chickens, even when grossly overdosed at up to 5-times the recommended dose rate for 3-times the
recommended frequency (6 occasions at 7-day intervals). Use of Exzolt at the recommended daily dose rate
of 0.5 mg/kg BW twice at a 7-day interval clearly offers a wide margin of safety for growing chickens and does
not impact water consumption. Consequently, there is no age restriction for Exzolt use in chickens.

REPRODUCTIVE SAFETY
STUDY DESIGN
A pivotal study assessed the reproductive safety of Exzolt when administered via drinking water to layer breeders
(Bovans brown) at their time of peak egg production (31 weeks of age). 50

Exzolt was purposefully overdosed at 1.5 mg/kg BW/day, a dose rate 3-times the recommended dose rate of
0.5 mg/kg (Figure 4-3). In addition, treatment was administered weekly for 4 consecutive weeks, 2-times the
recommended frequency (2 treatments a week apart). As a result, the total net dose of fluralaner administered
was 6 mg/kg BW, 6-times the recommended total dose.

432 layer breeders (384 females, 48 males) were randomly assigned to 16 pens holding 3 males and 24
females per pen. Birds in 8 pens received Exzolt treatment while birds in the other 8 pens served as non-
medicated controls.

The treatment period extended for at least

1 estrous cycle in females, complete egg 0 mg/kg/d
CONTROL
(unmedicated water)
formation, and spermatogenic cycle in
the males. Thus, the treatment duration
ensured that eggs collected for hatching
during the last week of the treatment = 6 mg/kg
1.5 mg/kg/d total dose
3X DOSE
period were generated from ovum and (3X recommended dose rate) (6X)
sperm exposed to a dose in excess (3-times)
of the recommended Exzolt dose. 0 7 14 21 28

All eggs produced 1 week prior to the Exzolt Treatments

treatment period and during the last week
Figure 4-3: Experiment design of reproductive safety study for layer breeders.
of the treatment period were incubated.
Chicks were evaluated at hatching,
unhatched eggs were necropsied, and
some hatchlings were monitored for 14
days to evaluate their viability. Some adult
birds were necropsied at the end of the
treatment period and histopathological
evaluations were performed on the
reproductive tract.

35
 E X ZOLT.C OM

RESULTS
No adverse impact of treatment with Exzolt was detected in regard to adult pen weight, egg production,
egg weight, egg fertility, chick hatchability, chick viability, and day 14 chick weight. Furthermore, gross and
microscopic examinations revealed no tissue alterations or changes in weights of reproductive organs
attributable to Exzolt administration.

Water intake was similar between all treatment groups, indicating that normal palatability was maintained
for drinking water medicated with Exzolt.

CONCLUSIONS
This reproductive safety study conducted in layer breeders demonstrated that Exzolt has no adverse effect on
overall reproductive performance, even when overdosed at 3-times the recommended dose rate for 2-times the
recommended frequency. Use of Exzolt at the recommended daily dose rate of 0.5 mg/kg BW twice at a 7-day
interval clearly offers a wide margin of safety for breeder chickens and does not impact water consumption.

WITHDRAWAL PERIOD ENVIRONMENTAL SAFETY

Multiple radiolabeled metabolism studies and tissue- Exzolt is a Veterinary Medicinal Product. As such,
depletion studies were conducted to determine the the environmental safety has been scrupulously
tissue residue profile for Exzolt. As a result of this evaluated as part of the approval process, according
extensive body of research, the maximum residue to the most recent EU and global regulatory
limits (MRL) for fluralaner have been established in guidelines. The evaluation followed a regulatory
various countries and regions. Using appropriate Risk Assessment process based on EU agricultural
statistical methodology, a withdrawal period of 14 practices that considers all environmental
days after last administration of Exzolt was computed compartments (soil, groundwater and surface
for meat and offal, but notably, NO withdrawal period water), all relevant exposure pathways, and all
(0 days) is required for eggs. relevant organisms that are potentially at risk.

Eggs from layers medicated with Exzolt can be

immediately consumed by humans after the
first Exzolt administration. Use of Exzolt poses
absolutely no loss of egg value or income, whether
for human consumption or for hatch. This lack of
an egg withdrawal period represents a tremendous
advantage for Exzolt compared to competitive mite
control strategies (e.g., phoxim, or Byemite ®).

36
SAFETY SUMMARY
Two target animal safety studies demonstrated that Exzolt was well tolerated and
palatable in both very young birds as well as adult hens under high physiological stress
related to intensive egg production, even when dosed at 5 times the recommended
dose for 3 times the recommended duration of treatment (no adverse impacts on
health, egg production, or growth performance).

A reproductive safety study demonstrated that Exzolt is well tolerated in breeder

chickens, even at 6-times the intended total dosage (no adverse effects on fertility,
hatchability, chick viability, or overall reproductive performance).

Use of Exzolt at the recommended daily dose rate of 0.5 mg/kg BW twice at a 7-day
interval clearly offers a wide margin of safety for all classes of pullets, breeders, and
layers and has no impact on water consumption.

Eggs from hens treated with Exzolt are not harmful to consumers and NO withdrawal
period is necessary before collection of eggs for human consumption (even on the day
of administrations or between administration days). A withdrawal period of 14 days after
last administration of Exzolt is required for human consumption of meat and offal.

37
 E X ZOLT.C OM

NOTES

38
BREAKTHROUGH
Welfare
 SECTION FIVE

EFFICACY
EFFICACY
The recommended treatment regimen for Exzolt (0.5 mg/kg BW twice at a 7-day interval) was
identified as a result of a comprehensive dose-determination program that evaluated multiple
doses and durations using artificial infestations of Poultry Red Mites under experimental
conditions. Clinical data demonstrating the efficacy of Exzolt against natural Poultry Red
Mite infestations in layers, breeders, and pullets was subsequently generated from 4 studies:

Three EU-based dose-confirmation studies were designed to confirm under field conditions
the dose and frequency of treatment with Exzolt that was needed for efficacy against natural
infections with D. gallinae. Because the earlier dose-determination studies showed that the
frequency of treatment is also relevant for efficacy, the dose-confirmation studies focused on
2 treatments at a 7-day interval.

An extensive 9-site field study assessed the efficacy of Exzolt against Poultry Red Mites
for chickens reared under commercial production conditions.

Research also investigated the activity and efficacy of Exzolt against Northern Fowl Mites
(O. sylviarum) when used at the same dose regimen as that used for Poultry Red Mites.
An in vitro study confirmed the susceptibility of Northern Fowl Mites to fluralaner, and
1 dose-confirmation study, 1 field efficacy study, and 1 natural infestation efficacy study
documented the efficacy and duration of the 2-dose Exzolt regimen against Northern Fowl
Mite infestations in chickens.

EFFICACY VS. POULTRY RED MITES (D. GALLINAE)

feeding stage (hematophagous protonymphs)
TREATMENT REGIMEN RATIONALE normally occurs within 3 to 5 days (Figure 1-2), and a
The objective of dose-determination studies was blood meal is required for further development of
to select a treatment regimen (dose, number of protonymphs to deutonymphs and adults, and also
administrations, and administration interval) that for production of mite eggs. Therefore, the target
provides efficacy (killing activity) against Poultry efficacy duration (~15 days) ensures that all non-
Red Mites that feed on Exzolt-treated chickens. The blood-feeding mite development stages present at
duration of efficacy was intended to cover a period the time of first Exzolt administration will eventually
that is needed for the completion of 2 consecutive ingest fluralaner once they develop into a blood-
mite life cycles, an efficacy duration of at least 15 feeding stage.
days. Mite development from egg to the first blood-

43
 E X ZOLT.C OM

EFFICACY CRITERIA
DOSE-DETERMINATION RESEARCH
Efficacy assessment was based on percent of mite
In preliminary research, a regimen dosing Exzolt at mortality for treated birds as compared to the
0.5 mg/kg BW twice at a 7-day interval was identified negative controls, and the duration of high efficacy.
as the most effective method for the treatment
of induced red mite infestations on hens.43 This
RESULTS
regimen provided sufficient mite-killing efficacy
against D. gallinae for at least 15 days and was thus All 3 Exzolt treatment groups experienced high
able to span the targeted 2 mite life cycles. Other mite mortality and inhibition (most 100%) for 1
single-dose treatments, even those of higher drug to 5 days after each dose, while only 2.7% mite
concentration, did not provide persistent efficacy for mortality was observed in controls. The low-dose
15 days. group (B, 0.25 mg/kg) did not provide suitable
efficacy for 15 days. In contrast, Group C birds (0.5
A second study evaluated only 2-dose regimens mg/kg) demonstrated consistent 100% efficacy
where Exzolt was administered at a 7-day interval against red mites, providing complete mortality
at 0, 0.25, 0.5, or 1.0 mg/kg BW to hens artificially for 15 days (Figure 5-1). The high-dose group (D,
challenged with red mites.43 1.0 mg/kg) did not show a significant additional
benefit to justify the greater dose.

ANIMALS
CONCLUSIONS
32 laying hens
22 weeks of age The Exzolt dosage regimen of 0.5 mg fluralaner/kg
BW twice at a 7-day interval achieved 100% mite-
killing efficacy for at least 15 days, thus meeting
STUDY DESIGN the target efficacy duration spanning 2 mite
development cycles.
A controlled, randomized dose-determination
study. On day -12, hens were allocated
to 4 treatment groups according to BW, Mite mortality (%)
8 birds group.
100
Exzolt treatments were administered via
drinking water (first dose=day 0) as follows: 80
2 mite life cycles or more
– Group A: untreated control group 60

– Group B: 0.25 mg fluralaner/kg BW/day 40

twice 7 days apart
20
– Group C: 0.5 mg fluralaner/kg BW/day
twice 7 days apart 0 0 7 14 21 28
Exzolt
Treatments
– Group D: 1.0 mg fluralaner/kg BW/day Day of study
twice 7 days apart Figure 5-1: Mite mortality (D. gallinae; assessed 24 hours after each artificial
infestation) experienced by hens administered Exzolt at 0.5 mg fluralaner/kg BW twice 7 days
apart (Group C).
Each hen was artificially infested with
D. gallinae every 3 to 4 days until day 26.

The numbers of dead, damaged, and live

mites were counted 24 hours after each mite
infestation to allow for determination of
acaricidal effect.

Mite mortality and inhibition were calculated

for each treatment group at each time-point.

44
 STUDY DESIGN
DOSE-CONFIRMATION STUDIES
Three controlled, single-site dose-confirmation
Three studies were conducted to confirm the studies. Each study involved a qualifying
efficacy of the Exzolt dosage regimen found effective commercial laying hen farm (in Germany, France,
in previous dose-determination studies (0.5 mg or Spain) with 2 comparable houses naturally
fluralaner/kg BW in drinking water twice at a 7-day infested with Poultry Red Mites (no recent
interval). The 3 studies, conducted under a common acaricide treatment).
protocol at commercial laying farms of different sizes
in Germany, France, and Spain, evaluated Exzolt The 2 houses at each of the 3 enrolled farms were
dose efficacy for treating natural infestations of as similar as possible with regard to size, breed,
Poultry Red Mites (D. gallinae)(Table 5-1).43 Unlike the and age of chickens; feed/water distribution
previous dose-determination studies that directly systems; and housing system (Table 5-1).
evaluated efficacy by killing mites feeding on treated
Mite infestation levels of each house were
animals, these dose-confirmation studies assessed
assessed using mite traps, with farm eligibility
the effect of treatment on the reduction of the mite
confirmed if mite counts averaged > 100 in
population in the house.
each house. Field isolates of study mites were
confirmed to be susceptible to fluralaner using a
ANIMALS contact in vitro test (LC90 < 15.63 ppm).
Over 166,600 laying hens On day 0 at each farm, birds in 1 house were
46-58 weeks of age treated with Exzolt (0.5 mg/kg BW/day twice 7
days apart) and the remaining house was left
untreated (controls). Houses with the highest mite
infestations were selected for Exzolt treatment,
for animal welfare reasons. Treatment was
administered either using a medication tank or
a dosing pump.

STUDY A STUDY B STUDY C

COUNTRY Germany France Spain

PRODUCTION T YPE Laying hens Laying hens Laying hens

HYBRID/BREEDS Lohmann Brown Hy-Line Brown Lohmann LSL

NO. CHICKENS/HOUSE 2715 (E) 32,467 (E) 54,947 (E)

ON DAY 0 2700 (C) 18,851 (C) 54,987 (C)

START MONTH May October March

53 wk (E)
AGE ON DAY 0 46 wk 58 wk
54 wk (C)
STUDY DUR ATION ~ 4 months ~ 3 months ~ 6 months

MEAN INITIAL MITE COUNTS/

2250 (E) 1610 (E) 1313 (E)
TR AP/HOUSE (BASELINE, ALL
751 (C) 367 (C) 1194 (C)
MITE STAGES AT DAY -1)

DRINKING WATER SYSTEM Tank Dosing pump Dosing pump

HOUSING SYSTEM Barn + free-range Enriched cages Enriched cages

E=Exzolt-treated house; C=control house Table 5-1: Description of 3 Exzolt dose-confirmation studies.

45
 E X ZOLT.C OM

Additional mite traps were placed at the As expected, Exzolt efficacy against larval non-
same locations on day -1 (baseline infestation blood-feeding stages of mites (Figure 5-3) increased
level) and at multiple time-points thereafter. more slowly than efficacy against nymphs and/
Traps were removed after 24 hours for mite or adults. However, as larval stages progressed
differentiation and counting. to later blood-feeding forms, Exzolt efficacy was
more consistently detected, with more than 95%
Data were also collected regarding adverse efficacy confirmed by day 6 (before the second
events and the number of dead chickens, laid administration). Thereafter, mite counts for larvae,
eggs, and downgraded eggs (study B) per house. nymphs, and adults were similar.

Personnel involved in the assessment of efficacy Favorable impacts of effective mite control were also
and safety criteria were blinded to treatment observed for several production parameters (Figure
group assignments. 5-4). For each parameter, the difference between
the Exzolt group and controls was calculated pre-
EFFICACY CRITERIA treatment (week -1) and post-treatment (from first
treatment through study conclusion). Mortality
Efficacy assessment was based on the percentage
remained very low in both houses of each study.
reduction of mites (mobile stages, i.e., larvae,
Overall, birds treated with Exzolt experienced an
nymphs, adults) in the treated house at each post-
increase in the laying rate (0.9-1.9%) and a decrease
treatment time-point compared to the control house.
in the percentage of downgraded eggs in study
Production parameters were descriptively analyzed.
B (3.4% more normal eggs). These productivity
benefits reflect the successful and prolonged relief
RESULTS of ectoparasite burdens by Exzolt, which thus
Study A was concluded after 4 months because allowed for better productivity in these field studies.
mite counts decreased spontaneously in the control
No adverse events related to the use of Exzolt were
group. Study B was concluded at the end of the
reported during the studies.
scheduled production cycle of the hens, after about
3 months. Study C extended about 6 months, until
regrowth of the mite population in the treated CONCLUSIONS
house reached 50% of the baseline count. However, Dose-confirmation studies demonstrated that Exzolt
the birds in the control house received treatment consistently provided high efficacy against Poultry
with another product at week 11 (day 77) to ensure Red Mites when administered at 0.5 mg fluralaner/
appropriate animal welfare. Analyses of water kg BW given twice 7 days apart via drinking water.
samples from all 3 studies confirmed that actual Treated birds also demonstrated excellent tolerance
fluralaner concentrations were generally close to of Exzolt, with no treatment-related adverse
target levels. effects observed. Under commercial production
conditions in these studies, the 2-dose Exzolt
The efficacy of Exzolt against all mite stages
regimen successfully controlled mite infestations
compared to controls is summarized in Figure 5-2.
for extended periods far exceeding the 2 weeks
For all studies, efficacy resulting from the complete
of effective blood concentrations. This extended
2-dose regimen exceeded 95% by day 6 and 99%
period of efficacy was due to the ability of Exzolt
by day 14, achieving 100% at several time-points.
to interrupt mite life cycles and, thus, massively
Efficacy remained high through the end of the
decrease mite populations of the houses.
production cycle in study B (3 months) and for
17 and 19 weeks in studies A and C, respectively.

46
 Exzolt reduction of mite population FIELD EFFICACY STUDY
(% reduction vs controls) An extensive, multi-site field study was conducted
in the Germany, France, and Spain to evaluate
100 the efficacy of Exzolt (0.5 mg fluralaner/kg BW in
98 drinking water twice at a 7-day interval) for treating
96 natural infestations of Poultry Red Mites (D. gallinae)
at a variety of commercial poultry farms.43 The
94
study was conducted at 9 sites involving 5 layer
92 farms, 2 breeder farms, and 2 replacement chicken
90 (pullet) farms (Table 5-2), using a protocol similar
Study A Study B Study C to the previous dose-confirmation studies. The
88
farms covered all relevant chicken production types
86 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 (layers, breeders, pullets), various housing systems
Exzolt (barn, barn with free-range, enriched cages), various
Treatments Week of study
drinking water systems (dosing pump, medication
Figure 5-2: Percentage of Exzolt reduction of mite population vs controls in dose- tank, gravity tank) and drinking water compositions,
confirmation studies (sum of larvae, nymphs, adults; weeks after first Exzolt administration).
and different climatic conditions.

Exzolt reduction of mite larvae

ANIMALS
(% reduction vs controls)
Over 524,000 chickens:
100 99.7 100
97.8 98.5
94.6
80 441,100 layers
72.8 22-63 weeks of age
60

40
65,600 breeders
20 25.4 34-41 weeks of age
21.4
n/a
0
Day 2 Day 4 Day 7 18,100 pullets
Study A Study B Study C 11-13 weeks of age

Figure 5-3: Percentage of Exzolt reduction of non-bloodsucking mite larvae 24 hours

after trap placement (on days 1, 3, 6) vs controls in dose-confirmation studies (days after first
Exzolt treatment).
STUDY DESIGN
Field efficacy study at 9 sites, controlled and
Exzolt improvement (%) partially blinded. Each site was a qualifying
commercial chicken farm (5 in Germany, 3 in
3.5 France, 1 in Spain) with 2 comparable houses
3.4 naturally infested with Poultry Red Mites (no
3.0
recent acaricide treatment). Sites were enrolled
2.5 between mid May and late July, at the peak of
2.0 mite season.
1.9
1.5
The 2 houses at each of the 9 sites (550-100,000
1.0 birds/house) were as similar as possible with
0.9 0.9
0.5 regard to size, breed and age of chickens, feed/
n/a n/a water distribution systems, housing system,
0
Laying rate Normal-grade eggs climate control, and cleaning system (Table 5-2).
Study A Study B Study C

Figure 5-4: Productivity improvements of Exzolt group vs controls for average laying
rate and percent of normal (non-downgraded) eggs over time; post-treatment change vs
pre-treatment (treated house - control house).

47
 E X ZOLT.C OM

Mite infestation levels of each house were Data were also collected regarding the number
assessed using mite traps. Field isolates of of dead chickens and laid eggs, and 2 flocks
study mites were confirmed to be susceptible were observed for adverse events. Rates of
to fluralaner using a contact in vitro test incubation, fertility, and hatchability were
(LC90 < 15.63 ppm for 7/9 isolates, and recorded for the 2 breeder farms.
15.63-31.25 ppm for the other 2 isolates).
Personnel involved in the assessment of efficacy
On day 0 at each farm, birds in 1 house were and safety criteria were blinded to treatment
treated with Exzolt (0.5 mg/kg BW/day twice 7 group assignments.
days apart) and the remaining house was left
untreated (controls). Houses with the highest The control house at 3 sites (L1, L3, L5) had to
mite infestations were usually selected for be treated for mites during the study due to
Exzolt treatment, for animal welfare reasons. an unacceptable mite burden (animal welfare).
After treatment at site L3, mite counts for efficacy
Additional mite traps were placed at the same assessment were still available and > 95% through
locations on day -1 (baseline infestation level) the end of the production cycle at day 238.
and at multiple time-points thereafter.
Traps were removed after 24 hours for mite
differentiation and counting.

SITE L1 SITE L2 SITE L3 SITE L4 SITE L5 SITE B1 SITE B2 SITE P1 SITE P2

COUNTRY Germany Germany France France Spain Germany France Germany Germany

PRODUCTION
TYPE
Layer Layer Layer Layer Layer Breeder Breeder Pullet Pullet

Ross PM3J
Dekalb ISA Novo Lohmann (hens) Tetra Tetra
HYBRID/BREEDS ISA Brown Ross 308
White Brown Brown Brown RJ344 Brown Browna
(cocks)

NO. CHICKENS/ 4600 (E)

2000 550 56,000 62,000 100,000 24,000 8800 3000
HOUSE ON DAY 0 7500 (C)

54 wk (E) 22 wk (E) 35 wk (E)

AGE ON DAY 0 40 wk 40 wk 36 wk 41 wk 13 wk 11 wk
63 wk (C) 27 wk (C) 34 wk (C)

MEAN INITIAL
MITE COUNTS/
TRAP/HOUSE 568 (E) 2138 (E) 2244 (E) 196 (E) 680 (E) 1148 (E) 8279 (E) 430 (E) 1074 (E)
(BASELINE, ALL 409 (C) 1673 (C) 758 (C) 162 (C) 829 (C) 521 (C) 1841 (C) 997 (C) 347 (C)
MITE STAGES AT
DAY -1)

DRINKING WATER Dosing Gravity Dosing Dosing Dosing Dosing Dosing Medication Medication
SYSTEM pump tank pump pump pump pump pump tank tank

Barn + Enriched Enriched Enriched

HOUSING SYSTEM Barn Barn Barn Barn Barn
free-range cages cages cages

Poor (same Poor (same

HOUSE Good Good Good Good
building; building; Good Good Good
(TREATMENT (same (same (same (same
non- non- (separate (separate (separate
GROUP) building; building; building; building;
SEPAR ATION hermetic hermetic buildings) buildings) buildings)
corridor) corridor) corridor) corridor)
door) door)

a
E=Exzolt-treated house C=control house also Harco Black, Koenigsberger Blue, and Sussex Table 5-2: Description of 9-site Exzolt field study.

48
EFFICACY CRITERIA Mortality was low at most of the farms and
Efficacy assessment was based on the percentage comparable between the study groups before and
reduction of mites (larvae, nymphs, adults) in after treatment. However, the acaricidal efficacy
the treated house at each post-treatment time- of Exzolt and resulting relief from mite infestation
point compared to the control house. Production positively impacted the laying rate at 6 of the 7
parameters were descriptively analyzed. layer or breeder farms, with a relative increase
ranging from 0.9% to 12.6% (Figure 5-7). The sole
RESULTS site with reduced post-treatment lay rate (B1) had
The efficacy of Exzolt (against all mite stages) a known history of reduced performance in the
compared to controls is summarized in Figure 5-5. house selected for treatment relative to the house
The onset of efficacy was very fast, with an overall used as a control. In regard to breeder performance,
average mite reduction of 46.6% observed after increased fertility and hatchability rates (2.8% and
the first night following the day of initial treatment 1.7%, respectively) were observed at the B2 site, but
(day 0; trap placed and mites collected for 24 hours). no improvements were detected at the other B1
Efficacy was already 97.6% on day 3, achieved >97% breeder farm (site houses not fully comparable for
by day 6, and persisted at that level for a lengthy these parameters).
period of time depending on the farm (100% efficacy
No adverse events related to the use of Exzolt were
at day 14 after the second Exzolt dose in 7/9 farms).
reported during the study.
A similar degree of fast and high onset of mite
control efficacy was observed in all production types
(layers, breeders, pullets) and housing systems. CONCLUSIONS
The field study confirmed the high efficacy and
The duration of mite population control following
excellent safety of Exzolt when administered in the
the 2-dose Exzolt regimen was assessed at the
drinking water (0.5 mg fluralaner/kg BW twice 7 days
house level using a threshold of 90% reduction vs
apart). Under commercial production conditions at 9
non-medicated controls (Figure 5-6). The duration
diverse layer, breeder, or pullet farms, Exzolt provided
of mite control was long and variable (2-8 months)
fast and persistent reductions in mite counts and
and did not depend on the production type or the
positively impacted production parameters (rates of
drinking water system, but was impacted by the
lay, fertility, hatchability). The 2-dose Exzolt regimen
duration of the remaining time until the end of
successfully controlled natural mite infestations for
the chicken production cycle and on the level of
extended periods, far exceeding the time of actual
house separation of the compared groups. At 6 sites
drug administration (e.g., up to 34 weeks, or nearly
(L3, L4, B1, B2, P1, P2), no decrease of efficacy was
8 months, at 1 layer farm).
observed until the end of the study (6 to 34 weeks;
the 6-week efficacy of the pullet sites reflected the
short remaining production cycle and shipment/
removal of the birds). Three sites (L1, L2, L5) Exzolt reduction of mite population
experienced a regrowth of the mite population (% reduction vs controls)
in the treated group after 8 to 18 weeks.
100
100

100
99.9
99.8
99.4

99.4
99.2

99.2
98.9
97.7

97.6
95.7

Regarding house separation, the presence of 2

rooms close to each other under 1 roof, separated 80
by a wall but connected by an incompletely
60
hermetic door, allowed faster mite regrowth in
52.6

the treated house (in about 2 months) at sites 40

46.6
42.2

L1 and L2 than that observed at farms with

36.1

appropriately separated houses or rooms. 20

Under real field conditions, the 2 houses would
be treated at the same time. In 4 of the 5 layer 0
Exzolt Treatment Exzolt Treatment
and breeder farms with an appropriate separation Day 0 Day 3 Day 6 Day 14
Layers Breeders Pullets All
between the study groups (sites L3, L4, B1, B2), (n=5) (n=2) (n=2) (n=9)

the mite population was controlled until the end Figure 5-5: Percentage of Exzolt efficacy against mites vs controls at 9 sites of field
of the production cycle (16-34 weeks). efficacy study (larvae, nymphs, adults; days after first Exzolt treatment).

49
 E X ZOLT.C OM

Duration of Exzolt reduction of mite population

Exzolt lay rate change (%)
(weeks > 90% reduction vs controls)
Layers Breeders Pullets
L1 9
15
Poor separation from controls, Layers Breeders All
L2 non‑hermetic door between rooms
8 12 12.6
L3 34

L4 24
9
Site

L5 18 6
5.7 5.7
B1 16

B2 20
3 0.9 1.1
3.7
2.0
P1 6 0
Pullets shipped from farm on day 42 -2.2
P2 6
-3
0 5 10 15 20 25 30 35 L1 L2 L3 L4 L5 B1 B2 All

Weeks after first Exzolt treatment Site

Figure 5-6: Duration (weeks) of mite population control provided by Exzolt at each Figure 5-7: Lay rate improvements of Exzolt group vs controls; post-treatment change
study site (last sample date with mite reduction > 90% vs controls). vs pre-treatment (treated house – control house). (At site L2, hens of the treated group were
9 weeks younger than those of the control group, likely accounting for some of the large
difference at this site.)

EFFICACY VS. NORTHERN FOWL MITES (O. SYLVIARUM)

Packets were then re-sealed and held for
IN VITRO ACTIVITY an additional 72 hours after which emerged
A study was conducted to determine the in vitro immature stages were counted to determine
mortality of Northern Fowl Mites exposed to egg hatch or larval-protonymph survival.
different acaricides (including fluralaner) and to
LC50 and LC99 values were calculated for adult
assess impacts on mite egg production, hatch, and
mortality (probit analysis).
immature survival. 48

RESULTS
STUDY DESIGN
Mortality outcomes summarized in Table 5-3
30 adult female fowl mites were placed in
indicated that the LC99 for fluralaner against adult
each of a series of filter paper packets treated
mites was achieved at only 8.09 ppm. No other
with different concentrations of fluralaner,
tested acaricides demonstrated this degree of
phoxim, spinosad, propoxur, deltamethrin, or
mite susceptibility. Oviposition was reduced by
permethrin.
fluralaner at concentrations higher than 100 ppm,
After 48 hours of continuous exposure, the while phoxim required 1500 ppm, spinosad 2000
packets were opened and mite mortality was ppm, deltamethrin 1000 ppm, and propoxur
assessed by counting and removal of dead and 100 ppm to reduce egg production. Permethrin
live mites, and eggs already deposited by the had no effect on egg production. None of the
mites were counted. acaricides reduced egg hatch or seriously impeded
development to the nymph stage.

50
CONCLUSIONS STUDY DESIGN
Northern Fowl Mites (O. sylviarum) appear to be A controlled, randomized dose-confirmation
similarly sensitive to fluralaner as Poultry Red study. Hens originating from an infested flock
Mites (D. gallinae). In this study, O. sylviarum mites were distributed in 12 pens (11 birds/pen); 3
were found to be extremely sensitive to fluralaner, pens were then allocated according to vent
even though the test isolate was resistant to mite-count densities to either of 4 treatment
pyrethroids (permethrin, deltamethrin) despite groups.
not being exposed to acaricides for at least 10
years. Reduction of egg production was obtained Exzolt treatments were administered via
with fluralaner concentrations higher than lethal drinking water (first dose=day 0) as follows:
concentrations, but the drug had no further
effects on reproduction in this study. – Group A: untreated control group
– Group B: 0.25 mg fluralaner/kg BW/day twice
ACARIDE LC 50 (PPM) LC 99 (PPM) 7 days apart

FLUR AL ANER 2.95 8.09 – Group C: 0.5 mg fluralaner/kg BW/day twice 7

days apart
PHOXIM 420 750
– Group D: 1.0 mg fluralaner/kg BW/day twice 7
days apart
SPINOSAD 1587 3123

PROPOXUR 86 181 6 hens in each pen were treated by gavage and

5 were left untreated to maintain an infestation
challenge (permanent mite re-infestation).
DELTAMETHRIN > 1000 > 1000
Pre-treatment mite counts ranged from 10
to 288/hen.
PERMETHRIN > 1000 > 1000
Mite counts were performed using 2 feathers
Table 5-3: In vitro susceptibility of adult Northern Fowl Mites (O. sylviarum) to around the vent area taken from a randomly
fluralaner and other acaricides. selected hen in each pen. Counts were
conducted on days -1, 1, 2, 6, 8, 12, 15, 19, 22,
and 26.
DOSE CONFIRMATION STUDY – LAYERS
EFFICACY CRITERIA
A study was conducted in the US to confirm
that the Exzolt dosage regimen selected for D. Efficacy assessment was based on the percent
gallinae in chickens (0.5 mg fluralaner/kg BW reduction of mites on treated hens vs.
twice at a 7-day interval) was also relevant for untreated controls.
treating infestations of Northern Fowl Mites
(O. sylviarum). 51 In this study, the efficacy of oral RESULTS
fluralaner was evaluated at 3 dosing regimens in
All 3 Exzolt treatment groups experienced high
layers infested with O. sylviarum.
efficacy (>90%) through day 19 or 22, and mite
counts were significantly (P ≤ 0.013) reduced
ANIMALS vs controls through day 22. The efficacy of the
132 layer hens recommended Exzolt dose appears in Figure 5-8.
32 weeks of age

51
 E X ZOLT.C OM

CONCLUSIONS
DOSE-CONFIRMATION STUDY –
The recommended Exzolt dosage regimen of 0.5
mg fluralaner/kg BW twice at a 7-day interval
REPLACEMENT CHICKENS
achieved 98% efficacy against Northern Fowl Another US study was conducted to confirm the
Mites for at least 15 days, covering at least 2 mite fowl mite efficacy of the Exzolt dosage regimen
life cycles. Exzolt provided an efficacy profile found effective in the previous dose-confirmation
against O. sylviarum similar to that provided for D. study (0.5 mg fluralaner/kg BW in drinking
gallinae, even under a ‘worst case’ test scenario water twice at a 7-day interval). Conducted at a
involving permanent re-infestation of treated university research facility, the trial evaluated
birds due to the continuous presence of untreated Exzolt dose efficacy for treating infestations of
mite-source hens in the same pen. (Under typical Northern Fowl Mites (O. sylviarum) in replacement
field conditions, all birds of a same flock would chickens. 38
be treated, thus potentially allowing for total
eradication of the mite population.)
ANIMALS
132 layer hens
Exzolt efficacy against Northern fowl mites
(% reduction vs. controls) 32 weeks of age

100

80
STUDY DESIGN
A controlled, single-site dose-confirmation
60 study. Birds were housed in a small-scale
2 mite life cycles or more
poultry house at a major Western US university.
40
Birds were obtained as uninfested birds and
following a brief acclimation period in the study
20
cages were infested with Northern Fowl Mites.
0
0
Exzolt
7 14 21 28 Healthy birds with established mite infestation
Treatments Day of study were ranked by mite counts on day -8 and
Figure 5-8: Efficacy of Exzolt (0.5 mg fluralaner/kg BW twice 7 days apart) for reducing
randomly assigned to 32 cages (4 birds/cage
counts of Northern Fowl Mites (O. sylviarum) vs. controls, under conditions with permanent each) with 16 cages assigned to each of 2
re-infestation. treatment groups.

On day 0, birds in 1 group were treated with

Exzolt efficacy against Northern fowl mites Exzolt (0.5 mg/kg BW/day twice 7 days apart)
(% reduction vs. controls) via the drinking water while the other group
100
remained untreated (controls). Exzolt dosage
was based on cage bird weights determined on
80 days -1 and 6.

60 Mite vent counts were performed on days -7,

2 mite life cycles or more 2, 8, 14, 19, and 28. Adequacy of infestation
40 criteria set in the protocol specified that
controls be infested with at least ≥ 25 mites
20
per individual bird and average ≥50 mites per
group. The criteria were met by most control
0
0 7 14 21 28 birds, with average mite counts ranging from
Exzolt
Treatments Day of study 127 to 226 between days 2 and 28.
Figure 5-9: Efficacy of Exzolt (0.5 mg fluralaner/kg BW twice 7 days apart) for reducing
counts of Northern Fowl Mites (O. sylviarum) vs. controls in a dose-confirmation study. EFFICACY CRITERIA
Efficacy assessment was based on the percent
reduction of mites on treated birds vs.
untreated controls.

52
RESULTS On day 0, birds in 1 group were treated with
The efficacy of Exzolt compared to controls is Exzolt (0.5 mg/kg BW/day twice 7 days apart)
summarized in Figure 5-9. Early onset of action using a dosing pump system while the other
was noted as mite vent counts were significantly group remained untreated (controls). Exzolt
reduced 99.6% in the Exzolt group beginning at dosage was based on cage bird weights
day 2 (P < 0.001). Similarly, significant 100% mite determined on day -1 and water consumption
count reductions (P < 0.001) were observed on measured on days -4 and -3.
every subsequent sample day, even at 4 weeks
Mite vent counts were performed on days -5,
after initiation of treatment. No adverse events
2, 8, 14, 19, and 28. Adequacy of infestation
related to the use of Exzolt were observed.
criteria set in the protocol specified that at least
1 bird from 60 of 80 sampled control cages had
CONCLUSIONS a mite count ≥ 25 mites per individual bird. The
This dose-confirmation study verified that Exzolt criteria were met at each counting day.
provided high (100%) efficacy against Northern
Fowl Mite infestations of replacement chickens EFFICACY CRITERIA
when administered at 0.5 mg fluralaner/kg BW
Efficacy assessment was based on the percent
given twice 7 days apart via drinking water.
reduction of mites on treated birds vs.
Treated birds also demonstrated excellent
untreated controls.
tolerance of Exzolt, with no treatment-related
adverse effects observed. The Exzolt dose regimen
successfully met (and far exceeded) the target RESULTS
efficacy duration spanning 2 development cycles The efficacy of Exzolt compared to controls is
for Northern Fowl Mites. summarized in Figure 5-10. Exzolt provided
early onset of action as mite vent counts were
significantly reduced 99.5% beginning at day 2.
FIELD EFFICACY STUDY – US Mite count reductions of 100% were achieved on
every subsequent sample day, even at 4 weeks
A field study was conducted in a US university after initiation of treatment. No adverse events
facility to evaluate the efficacy of Exzolt (0.5 mg related to the use of Exzolt were observed.
fluralaner/kg BW in drinking water twice at a
7-day interval) for treating natural infestations
of Northern Fowl Mites (O. sylviarum) in layer CONCLUSIONS
chickens derived from a commercial poultry farm This US field efficacy study demonstrated that Exzolt
in California. 43 provided high (100%) efficacy against Northern
Fowl Mite infestations of commercial chickens when
administered at 0.5 mg fluralaner/kg BW given
ANIMALS twice 7 days apart via drinking water. Treated birds
800 commercial White Leghorn chickens also showed excellent tolerance of Exzolt, with
(Hy-Line W36), 16 weeks of age. no treatment-related adverse effects observed.
The Exzolt dose regimen successfully met (and far
exceeded) the target efficacy duration spanning
2 development cycles for Northern Fowl Mites.
STUDY DESIGN
A controlled, single-site field efficacy study.
Commercial layer chickens were obtained
as uninfested birds and following a brief
acclimation period became naturally infested
with Northern Fowl Mites.

800 healthy birds with established mite

infestation were randomly placed into 400
cages (2/cage) on day -6. Cages were then
randomly assigned to either of 2 treatment
groups (400 cages/group).

53
 E X ZOLT.C OM

Mite vent counts were performed on days 2, 8,

Exzolt efficacy against Northern Fowl Mites
(% reduction vs. controls) 14, 19, and 28.

100
EFFICACY CRITERIA
80 Efficacy assessment was based on the percent
reduction of mites on treated birds vs.
60
2 mite life cycles or more untreated controls.
40

RESULTS
20
The efficacy of Exzolt compared to controls is
0
summarized in Figure 5-11. Early onset of action
0
Exzolt
7 14 21 28 was noted as mite vent counts were significantly
Treatments Day of study reduced 94% in the Exzolt group beginning at day
Figure 5-10: Efficacy of Exzolt (0.5 mg fluralaner/kg BW twice 7 days apart) for reducing 2 (P < 0.01). Furthermore, significant 100% mite
counts of Northern Fowl Mites (O. sylviarum) vs. controls in a US field efficacy study. count reductions (P < 0.01) were observed on
every subsequent sample day, even at 4 weeks
after initiation of treatment. No adverse events
NATURAL INFESTATION EFFICACY related to the use of Exzolt were observed.
STUDY – BRAZIL
CONCLUSIONS
Another field study was conducted in Brazil to
evaluate the efficacy of Exzolt (0.5 mg fluralaner/ This natural infestation efficacy study verified
kg BW in drinking water twice at a 7-day interval) that Exzolt provided high (100%) efficacy against
for treating natural infestations of Northern Northern Fowl Mite infestations of laying hens
Fowl Mites (O. sylviarum) in laying hens from a when administered at 0.5 mg fluralaner/kg BW
commercial poultry farm. 52 given twice 7 days apart via drinking water.
Treated birds also demonstrated excellent
tolerance of Exzolt, with no treatment-related
ANIMALS adverse effects observed. The Exzolt dose regimen
60 commercial laying hens. successfully met (and far exceeded) the target
efficacy duration spanning 2 development cycles
for Northern Fowl Mites.

STUDY DESIGN Exzolt efficacy against Northern Fowl Mites

A controlled, single-site natural infestation (% reduction vs. controls)
efficacy study. Chickens were naturally infested 100
with Northern Fowl Mites.
80
60 healthy birds with established mite
infestation were randomly assigned to 2 60
2 mite life cycles or more
treatment groups (30/group), with homogeneity
of mite infestation confirmed on day -7. Groups 40

were housed in different barns to avoid cross-

20
infestation, with each barn holding 3 pens, 10
birds/pen.
0
0 7 14 21 28
Exzolt
On day 0, birds in 1 group were treated with Treatments Day of study
Exzolt (0.5 mg/kg BW/day twice 7 days apart)
via the drinking water while the other group Figure 5-11: Efficacy of Exzolt (0.5 mg fluralaner/kg BW twice 7 days apart) for reducing
counts of Northern Fowl Mites (O. sylviarum) vs. controls in a Brazilian natural infestation
remained untreated (controls). Exzolt dosage efficacy study.
was based on total bird weight per pen and
average daily water consumption measured
for each pen on days -3 to -2.

54
EFFICACY SUMMARY
The Poultry Red Mite efficacy of Exzolt administered in the drinking water of chickens at
the recommended dosage regimen of 0.5 mg fluralaner/kg BW twice 7 days apart was
evaluated in multiple studies, including a dose-determination study using artificial Poultry
Red Mite infestation as well as several dose-confirmation studies and a 9-site field-
efficacy study conducted under natural infestation conditions.

Total or near-total elimination of Poultry Red Mite populations in the treated houses was
quickly achieved in all layer, breeder, and/or pullet houses treated.

This effect was maintained for a duration largely exceeding the duration of effective blood
concentrations required to kill mites feeding on the treated birds.

Northern Fowl Mites were found to be extremely sensitive to fluralaner in vitro. Two
dose-confirmation studies verified Exzolt efficacy against fowl mites using the same
dose regimen as for Poultry Red Mites. Furthermore, 2 field efficacy studies
demonstrated fast Exzolt efficacy in reducing Northern Fowl Mite infestations within
2 days of treatment initiation, and 100% efficacy that extended for at least 4 weeks
after initiation of treatment.

In several studies, positive impacts on productivity (e.g., laying rate, fertility, etc.) were
observed for treated birds, likely due to the ability of Exzolt to massively decrease the
mite population of the house.

Exzolt clearly offers potent, consistent, convenient, and safe efficacy against Poultry Red
Mites and Northern Fowl Mites and thus helps prevent the significant adverse economic
consequences of inadequately controlled mite infestation.

55
 E X ZOLT.C OM

NOTES

56
BREAKTHROUGH
PRODUCTION
 SECTION SIX

USAGE GUIDELINES
USAGE GUIDELINES
DOSE CALCULATION PREPARING STOCK SOLUTION
The dose for Exzolt is 0.5 mg fluralaner per kg BW AND DOSING BIRDS
per day (equivalent to 0.05 mL Exzolt) administered
The instructions below need to be followed in the
twice, 7 days apart. The full course of therapy must
order described to prepare the medicated water.
be administered for full therapeutic effect.
Check the water system to ensure it works
First, determine the time period (in hours) needed
properly and is free of leaks; also ensure that
to administer the product on the treatment day.
water is available to all nipple or bell drinkers.
This period must allow all birds to receive the
required dose. Estimate how much water birds will For each day of treatment, medicated water
consume during treatment based on their water must be freshly prepared.
consumption during the same period the day
before start of treatment.
– Mix the required volume of Exzolt into a large
Next, calculate the needed volume of Exzolt, based medication tank or with additional water
on the total weight of the bird group to be treated. to create a stock solution to be dosed by
To ensure administration of the correct dose, proportioner or dosing pump. Always add
body weight should be determined as accurately product and water simultaneously in order
as possible and a sufficiently accurate measuring to avoid foaming. It is important to rinse
device should be used. The required amount of the container used to measure the required
Exzolt on each treatment day should be calculated product volume during the filling phase in order
from the total body weight (kg) of the entire group of to ensure that the complete dose is emptied
chickens to be treated, using the following formula: into the medication tank or the stock solution
and that no residues remain in the measuring
volume of product (mL)/treatment day = Total body device. Stir the stock solution or the content of
weight (kg) of chickens to be treated × 0.05 mL the medication tank gently until the medicated
water is homogeneous, and connect the
Examples: medication tank or the proportioner or dosing
TOTAL BODY WEIGHT OF AMOUNT OF EX ZOLT PER pump to the drinking water system.
CHICKENS TO BE TREATED TREATMENT DAY (ML /DAY )

40,000 kg 2000 mL (2 L) Make sure the dosing pump is properly set

to deliver the medicated water during the
160,000 kg 8000 mL (8 L) predetermined treatment period (hours per day).

(1 L of Exzolt fully treats 10,000 kg body weight Prime the drinker lines with medicated water and
across the 2 doses – e.g., 5000 chickens weighing check to see when medicated water has reached
2 kg body weight each will use a total of 1 L of Exzolt, the end of the line. This procedure should be
or 0.5 L per treatment day × 2 treatment days.) repeated on each day of administration.

61
 E X ZOLT.C OM

CONSIDERATIONS FOR USE OF DOSING PUMPS

Dosing pumps offer very interesting possibilities in
therapeutics, allowing prompt action in targeting the
treatment of a room, a pen, or a batch of animals, and
the flexibility to alter the medication, or even adjust
the dose, during a course of treatment. The use of
dosing pumps for administering medications requires
adherence to Good Practice standards to maximize
the accuracy of dosing, which reduces the overuse of
medications, limits the risk of developing resistance,
and eases conformity with withdrawal times and
maximum residue limits in meat, offal, and eggs.

The distribution of drugs via drinking water using

dosing pumps requires a homogeneous active
ingredient which dissolves or mixes well, reliable
equipment, and a well-regulated water flow at the
level of the drinkers. It is absolutely essential to check
the flow of water through the drinkers, the cleanliness
of the tank, the state of the dosing pump, and the
valves governing the distribution of the water to each
room or pen. Regular servicing of pumps is crucial for
the accuracy of dosing. This also means systematic
cleaning and rinsing of the equipment after each use
and a yearly maintenance program. Adhere to Good Practice standards when administering Exzolt through dosage pumps.

62
BREAKTHROUGH
APPLICATION
SECTION SEVEN

SUMMARY
SUMMARY
Exzolt represents an innovative, completely new approach for comprehensive management of
Poultry Red Mites and Northern Fowl Mites in chickens, providing systemic acaricidal activity
within the bird instead of relying on external contact with a pesticide. Only Exzolt offers a
unique combination of features and benefits that, together, distinguish the product as a major
advance for optimizing the health and productivity of layers, breeders, and pullets threatened by
external mite parasites.

Contains fluralaner, a potent yet safe acaricide Highly active against mite strains resistant
from a new chemical class, the first isoxazoline to classical acaricides.
approved for use in poultry.
Ideal for layers due to zero egg withdrawal period.
Induces a rapid and massive decrease in mite
populations in a chicken house, often with No adverse impacts on egg production,
more than 99% efficacy. hatchability, or chick survival of breeders
(in fact, positive impacts often observed).
Fast kill starts within hours of administration,
and the 2 administrations a week apart span Safe and well tolerated in all classes of chickens,
2 mite life cycles, thus disrupting mite with a very wide margin of safety.
population dynamics.
Avoids exposure of house workers and birds to
Convenient treatment in the drinking water at a toxic sprays.
low dose of 0.5 mg/kg BW/day, repeated 1 week
Short 13-day withdrawal for meat or offal.
later, allowing uniform and accurate dosing
compared to other control methods. Fulfills a critical unmet need for overall animal
health and welfare in several regions including
Ready-to-use aqueous solution (1% fluralaner,
Latin America, Africa, Middle East and Asia etc.
10 mg/mL) for simple dilution, with no
sedimentation, clogging, or spoilage. High product quality and research-based
technical support from MSD Animal Health.
Treats the bird, not just the surroundings. Much
more effective, safe, targeted, and convenient
than mite sprays.

67
 E X ZOLT.C OM

68
 SECTION EIGHT

REFERENCES
REFERENCES CITED
1
Chauve C. The Poultry Red Mite Dermanyssus gallinae (De Geer, 1778): current situation and future prospects
for control. Vet Parasitol 1998; 79:239-245.

2
Pickworth CL, Morishita TY. Common external parasites in poultry: lice and mites. Ohio State University
Extension Fact Sheet.

3
Roberts V. Diseases of farmyard poultry part 4 - External and internal parasites of chickens. National Animal
Disease Information Service. 2014. http://www.nadis.org.uk/bulletins/diseases-of-farmyard-poultry/part-4-
external-and-internal-parasites-of-chickens.aspx (accessed August 2016).

4
Carter E, Gillett-Kaufman JL. Chicken mite (other common names: Poultry Red Mite, roost mite) Dermanyssus
gallinae (De Geer) (Arachnida: Acari: Dermanyssidae). Document EENY611, UF/IFAS Extension, Gainesville, FL.
December 2014. http://edis.ifas.ufl.edu/in1070 (accessed August 2016).

5
Hoy MA. Agricultural acarology: introduction to integrated mite management. CRC Press, Boca Raton, FL,
2011. p 325-327.

6
Van Emous R. Wage war against the red mite! Poultry Int 2005; 44:26-33.

7
Mul M. Fact sheet: the Poultry Red Mite, Dermanyssus gallinae (De Geer, 1778) A small pest that packs a big
punch. Wageningen UR, 2013.

8
George DR, Finn RD, Graham KM, Mul MF, Maurer V, Moro CV, Sparagano O. Should the Poultry Red Mite
Dermanyssus gallinae be of wider concern for veterinary and medical science? Parasites & Vectors 2015; 8:178.

9
Guy, JH, Khajavi M, Hlalel MM, Sparagano O. Red mite (Dermanyssus gallinae) prevalence in laying units in
Northern England. Br Poultry Sci 2004; 45: 5-6.

Sparagano OAE, George DR, Harrington DWJ, Giangaspero A. Significance and control of the Poultry Red
10

Mite Dermanyssus gallinae. Annu Rev Entomol 2014; 59:447-466.

11
Cosoroaba I. Massive Dermanyssus gallinae invasion in battery-husbandry raised fowls. Revue Méd Vét
2001; 152:89-96.

Kilpinen O. How to obtain a blood meal without being eaten by a host: the case of Poultry Red Mite,
12

Dermanyssus gallinae. Physiol Entomology 2005; 30:232-240.

13
Mul M. Control methods for Dermanyssus gallinae in systems for laying hens: results of an international
seminar. World Poult Sci J 2009; 65:589-599.

14
Arends JJ. External parasites and poultry pests. In Diseases of Poultry, 11th edition, Ed JM Saif, 2003.
p 905-930.

15
Axtell R. Poultry integrated pest management: status and future. Integrated Pest Management Rev 1999;
4:53-73.

Murillo AC, Mullens BA. A review of the biology, ecology, and control of the northern fowl mite,
16

Ornithonyssus sylviarum (Acari: Macronyssidae). Vet Parasitol 2017; 246:30-37.

71
 E X ZOLT.C OM

17
Kowalski A, Sokol R. Influence of Dermanyssus gallinae (Poultry Red Mite) invasion on the plasma levels of
corticosterone, catecholamines and proteins in layer hens. Polish J Vet Sci 2005; 12:231-235.

Valiente Moro C, Chauve C, Zenner L. Experimental infection of Salmonella Enteritidis by the Poultry Red
18

Mite, Dermanyssus gallinae. Vet Parasitol 2007; 146:329-336.

19
Valiente Moro C, de Luna CJ, Tod A, Guy JH, Sparagano OAE, Zenner L. The Poultry Red Mite (Dermanyssus
gallinae): a potential vector of pathogenic agents. Exp Appl Acarol 2009; 48:93-104.

20
Valiente Moro C, Fravalo P, Amelot M, Chauve C, Salvat G, Zenner L. Experimental studies on the potential
role of the Poultry Red Mite Dermanyssus gallinae, as a vector of Salmonella serotype Enteritidis. Trends in
Acarology: Pro 12th Int Cong 2010; p 521-525.

21
Sommer D, Heffels-Redmann U, Köhler K, Lierz M, Kaleta EF. Role of the Poultry Red Mite (Demanyssus
gallinae) in the transmission of avian influenza A virus. Tierärztliche Praxis Grosstiere 2016; 1:47-54.

Sparagano O, Pavlicevic A, Murano T, Camarda A, Sahibi H, Kilpinen O, Mul M, van Emous R, le Bouquin S,
22

Hoel K, Cafiero MA. Prevalence and key figures for the Poultry Red Mite Dermanyssus gallinae infections in
poultry farm systems. Exp Appl Acarol 2009; 48:3-10.

23
Van Emous R. Verwachtte schade bloedluis 21 miljoen euro. Pluimveeweb.nl. 2017. https://www.
pluimveeweb.nl/artikelen/2017/01/schade-bloedluis-21-miljoen-euro/ (accessed 13 September 2016).

24
FAOSTAT. Food and Agriculture Organization of the United Nations. 2016. http://www.fao.org/faostat/
en/#home (accessed 18 August 2016).

Mozafar F. 2014. Die rote vogelmilbe, eine grosse herausforderung für eierproduzenten. Frühjahrveranstaltung;
25

Deutchen Vereinigung für Geflügelwissenschaft. Leipzig, 11-12 März 2014.

26
Mozafar F, Tierzucht L. Tackling red mite in laying hens remains a challenge. World Poultry - Health. Jul 2,
2014. http://www.worldpoultry.net/Health/Articles/2014/7/Tackling-red-mite-in-laying-hens-remains-a-
challenge-1438417W/ (accessed August 2016).

27
De Luna CJ, Arkle S, Harrington D, George DR, Guy JH, Sparagano O. The Poultry Red Mite Dermanussus
gallinae as a potential carrier of vector-borne diseases. Ann NY Acad Sci 2008; 1149:255-258.

28
George. Of mites and men: should the Poultry Red Mite Dermanyssus gallinae be of wider concern for medical
science? 1st COST Conference and Management Committee meeting. 28-29 May 2015, Foggia, p 27-28.

29
Cafiero MA, Camarda A, Circella E, Santagada G, Schino G, Lomuto M. Pseudoscabies caused by Dermanyssus
gallinae in Italian city dwellers: a new setting for an old dermatitis. J Eur Acad Dermatol Venereol 2008; 22:1382-1383.

30
Cafiero MA, Galante D, Camarda A, Giangaspero A, Sparagano O. Why dermanyssosis should be listed as
an occupational hazard. Occup Environ Med 2011; 68:628.

Northern fowl mite management. The Poultry site. October, 2013. http://www.thepoultrysite.com/articles/2947/
31

northern-fowl-mite-management/ (accessed August 2016).

32
COREMI. Memorandum of understanding for the implementation of a European Concerted Research
Action designated as COST Action FA1404: improving current understanding and research for sustainable
control of the Poultry Red Mite Dermanyssus gallinae (COREMI), COST 036/14. May 2014. http://w3.cost.eu/
fileadmin/domain_files/FA/Action_FA1404/mou/FA1404-e.pdf (accessed August 2016).

72
33
Chirico J, Tauson D. Traps containing acaricides for the control of Dermanyssus gallinae. Vet Parasitol 2002;
110:109-116.

34
Mul M. Validation of an automated mite counter for Dermanyssus gallinae in experimental laying hen cages.
Exp Appl Acarol 2015; 66:589-603.

35
Nordenfors H, Höglund J, Tauson R, Chirico J. Effect of permethrin impregnated plastic strips on Dermanyssus
gallinae in loose-housing systems for laying hens. Vet Parasitol 2001; 102:121-131.

36
Abbas RZ, Colwell DD, Iqbal Z, Khan A. Acaricidal drug resistance in Poultry Red Mite (Dermanyssus
gallinae) and approaches to its management. World’s Poultry Sci J 2014; 70:113-124.

37
Liebisch A, Liebisch G. Biologie, schäden und bekämpfung beim befall durch die rote vogelmilbe (Dermanyssus
gallinae). Lohmann Information 2003; 4:1-7.

38
DeLoach JR, DeVaney JA. Northern fowl mite ingests large quantities of blood from white leghorn hens. J Med
Entomol 1981; 18:374-377.

39
Mullens BA, Owen JP, Kuney DR, Szijj CE, Klingler KA. Temporal changes in distribution, prevalence and
intensity of northern fowl mite (Ornithonyssus sylviarum) parasitism in commercial caged laying hens, with
a comprehensive economic analysis of parasite impact. Vet Parasitol 2009; 160:116-133.

40
Mullens BA, Velten RK, Hinkle NC, Kuney DR, Szijj CE. Acaricide resistance in northern fowl mite
(Ornithonyssus sylviarum) populations on caged layer operations in southern California. Poultry Sci 2004;
83:365-374.

41
Gassel M, Wolf C, Noack S, Williams H, Ilg T. The novel isoxazoline ectoparasiticide fluralaner: selective
inhibition of arthropod γ-aminobutyric acid- and L-glutamate-gated chloride channels and insecticidal/
acaricidal activity. Insect Biochem Molec Biol 2014; 45:111-124.

42
European Public Assessment Report (EPAR) for Exzolt. European Medicines Agency. http://www.ema.
europa.eu/ema/index.jsp?curl=pages/medicines/landing/vet_epar_search.jsp&mid=WC0b01ac058008d7a8

43
Data on file. MSD Animal Health.

44
European public MRL assessment report (EPMAR), Fluralaner (poultry), European Medicines Agency.

45
Brauneis MD, Zoller H, Williams H, Zschiesche E, Heckeroth AR. The acaricidal speed of kill of orally
administered fluralaner against Poultry Red Mites (Dermanyssus gallinae) on laying hens and its impact on
mite reproduction. Parasites & Vectors 2017; 10:594.

46
Casida JE. Golden age of RyR and GABA-R diamide and isoxazoline insecticides: common genesis, serendipity,
surprises, selectivity, and safety. Chem Res Toxicol 2015; 28:560-566.

47
Thomas E, Zoller H, Heckeroth AR, Liebisch G, Flochlay Sigognault A. Comparative in vitro susceptibility of
Dermanyssus gallinae field isolates to fluralaner, phoxim, spinosad, deltamethrin and propoxur. Proc WVPA
2017 Congress. Edinburgh, September 2017.

48
Mullens BA, Murillo AC, Zoller H, Heckeroth AR, Jirjis F, Flochlay-Sigognault A. Comparative in vitro
evaluation of contact activity of fluralaner, spinosad, phoxim, propoxur, permethrin and deltamethrin
against the northern fowl mite, Ornithonyssus sylviarum. Parasites & Vectors 2017; 10:358.

49
Prohaczik A., Menge M, Huyghe. B, Flochlay-Sigognault A. and Le Traon G. Safety of fluralaner oral solution, a
novel systemic antiparasitic treatment for chickens, in laying hens after oral administration via drinking water.
Accepted for publication Parasites & Vectors 2017.

73
 E X ZOLT.C OM

50
Huyghe B, Le Traon G, Flochlay-Sigognault A. Safety of fluralaner oral solution, a novel systemic Poultry
Red Mite treatment, for chicken breeders’ reproductive performances. Accepted for publication Parasite and
Vectors. 2017.

51
Hinkle NC, Jirjis F, Szewczyk E, Sun F, Flochlay-Sigognault A. Efficacy and safety assessment of a water-
soluble formulation of fluralaner for treatment of natural Ornithonyssus sylviarum infestations in laying
hens. Parasites & Vectors 2018; 11:99.

52
Jirjis F, Vettorato L, Chiummo R, Szewczyk E, Flochlay Sigognault A. Efficacy and safety of fluralaner
administered orally against northern fowl mite (Ornithonyssus sylviarum) infestations in layers. Amer Assoc
Avian Path, Indianapolis, July 2017.

74
 SECTION NINE

LABEL SUMMARY
SUMMARY OF PRODUCT CHARACTERISTICS
(NON EU SPC)
• Too frequent and repeated use of acaricides
1. NAME OF THE VETERINARY from the same class, over an extended period
MEDICINAL PRODUCT of time.
Exzolt 10 mg/ml solution for use in drinking water • Underdosing, which may be due to
for chickens underestimation of body weight,
misadministration of the product, or lack of
calibration of the volume measuring device.
2. QUALITATIVE AND
QUANTITATIVE COMPOSITION 4.5 SPECIAL PRECAUTIONS FOR USE

Special precautions for use in animals

Active substance:
Strict biosecurity measures at house and farm level
Each ml contains 10 mg fluralaner.
should be implemented to prevent re-infestation of
For a full list of excipients, see section 6.1. treated houses. To ensure long term control of the
mite populations in a treated house, it is essential
to treat any other infested poultry house in
3. PHARMACEUTICAL FORM proximity to the treated one.

Light yellow to yellowish-brown solution for use in Special precautions to be taken by the person
drinking water. administering the veterinary medicinal product
to animals
The colour of Exzolt may change slightly over
The veterinary medical product may be slightly
time due to the presence of the antioxidant
irritating to skin and/or eyes.
(α-tocopherol).
Avoid contact with skin, eyes and
mucous membranes.
4. CLINICAL PARTICULARS Do not eat, drink or smoke while handling the product.

4.1 TARGET SPECIES Wash hands and contacted skin with soap and water
after use of the product.
Chickens.
In case of eye contact, immediately rinse thoroughly
4.2 INDICATIONS FOR USE, SPECIFYING THE with water.
TARGET SPECIES Remove clothes affected by the spillage.
Treatment and control of Poultry Red Mite
(Dermanyssus gallinae) or Northern Fowl Mite 4.6 ADVERSE REACTIONS (FREQUENCY
(Ornithonyssus sylviarum) infestation in pullets, AND SERIOUSNESS)
breeders and layer hens.
None known.

4.3 CONTR AINDICATIONS

4.7 USE DURING PREGNANCY, LACTATION
None. OR LAY
The safety of the veterinary medicinal product has
4.4 SPECIAL WARNINGS been demonstrated in layers and breeders. The
Care should be taken to avoid the following product can be used during lay.
practices because they increase the risk of
In clinical field studies in layer hens, it was shown
development of resistance and could ultimately
that treatment of mite infestation was usually
result in ineffective therapy:
associated with an increased laying rate.

77
 E X ZOLT.C OM

4.8 INTER ACTION WITH OTHER MEDICINAL simultaneously in order to avoid foaming.
PRODUCTS AND OTHER FORMS OF It is important to rinse the container used
INTER ACTION to measure the required product volume
None known. In clinical field trials, no interaction during the filling phase in order to ensure
was observed with accompanying routine that the complete dose is emptied into the
treatment such as vaccination, deworming or medication tank or the stock solution and
supplementing with nutritional additives. that no residues remain in the measuring
device. Stir the stock solution or the content
of the medication tank gently until the
4.9 AMOUNTS TO BE ADMINISTERED AND
medicated water is homogeneous. Connect
ADMINISTR ATION ROUTE
the medication tank or the proportioner or
For use in drinking water. dosing pump to the drinking water system.
The dose is 0.5 mg fluralaner per kg body weight • Make sure the dosing pump is properly set
(equivalent to 0.05 ml Exzolt) administered twice, to deliver the medicated water during the
7 days apart. The full course of therapy must be predetermined treatment period (hours per
administered for a full therapeutic effect. day).
Determine the time period (between 3 and • Prime the drinker lines with medicated water and
24 hours) to administer the treatment on each check to see when medicated water has reached
treatment day. This period of time must allow all the end of the line. This procedure should be
birds to receive the required dose. Estimate how repeated on each day of administration.
much water birds will consume during treatment
based on the previous day’s water consumption. After each treatment administration, fill the stock
solution container with clean (unmedicated) water
Calculate the volume of Exzolt needed based on to rinse the water lines.
the total weight of the bird group to be treated. To
ensure administration of the correct dose, body
4.10 OVERDOSE (SYMPTOMS, EMERGENCY
weight should be determined as accurately as
PROCEDURES, ANTIDOTES), IF NECESSARY
possible and an accurate measuring device should
be used for measuring the calculated volume of the No adverse reactions were observed following the
product to be administered. treatment of 3-week old and adult chickens dosed
with up to 5 times the recommended dose for 3
The required volume of product for each treatment times the recommended duration of treatment.
day is calculated from the total body weight (kg) of
the entire group of chickens to be treated: No negative effects on egg production was
observed when layer hens were treated with up
ml product/treatment day = Total body weight to 5 times the recommended dose for 3 times the
(kg) of chickens to be treated x 0.05 ml recommended duration of treatment.
500 ml of Exzolt treats 10,000 kg body weight (e.g., There were no adverse effects on reproductive
5,000 chickens of 2 kg body weight each) per day of performance when breeding chickens were treated
treatment administration. at 3 times the recommended dose for 2 times the
The instructions below need to be followed, in the recommended duration of treatment.
order described, to prepare the medicated water:
4.11 WITHDR AWAL PERIOD(S)
• Check the water system to ensure it works
properly and is free of leaks; also ensure that Meat and offal: 13 days.
water is available to all nipple or bell drinkers. Eggs: zero days.
• For each day of treatment, medicated water must
be freshly prepared.
−− Mix the required volume of Exzolt into a
large medication tank or with additional
water to create a stock solution. The solution
should be dosed by proportioner or dosing
pump. Always add product and water

78
 mite), cyclodienes (tick, flea, fly), macrocyclic
5. PHARMACOLOGICAL PROPERTIES lactones (sea lice), phenylpyrazoles (tick, flea),
Pharmacotherapeutic group: Ectoparasiticides for benzophenyl ureas (tick), pyrethroids (tick, mite) and
systemic use. carbamates (mite).

ATCvet code: QP53BE02.

5.2 PHARMACOKINETIC PARTICULARS
After oral administration, fluralaner is absorbed
5.1 PHARMACODYNAMIC PROPERTIES
rapidly, reaching maximum plasma concentrations
Fluralaner is an acaricide and an insecticide. It 36 hours after the first dosing and 12 hours after
is efficacious against poultry mites, including the second dosing following start of administration
Dermanyssus gallinae (Poultry Red Mite) and via medicated drinking water. The bioavailability
Ornithonyssus sylviarum (Northern Fowl Mites). is high, with approximately 90% of the dose
Fluralaner has a high potency against mites, mostly absorbed following oral administration. Fluralaner
by exposure via feeding, i.e. it is systemically active is highly bound to protein. Fluralaner is widely
on target parasites. distributed throughout the body, with the highest
Fluralaner is a potent inhibitor of parts of the concentrations reported in the liver and skin/
arthropod nervous system by acting antagonistically fat. No significant metabolites are observed in
on ligand-gated chloride channels (GABA-receptor chickens, and fluralaner is mainly eliminated via the
and glutamate-receptor). In molecular on-target hepatic route. The apparent elimination half-life is
studies on insect gamma-aminobutyric acid (GABA) approximately 4 days following oral administration.
receptors of flea and fly, fluralaner is not affected by
dieldrin resistance.
The onset of activity against Dermanyssus gallinae
6. PHARMACEUTICAL PARTICULARS
is within four hours of mites starting to feed on
6.1 LIST OF EXCIPIENTS
treated chickens.
α-tocopherol
All mites feeding on treated chickens are killed
for at least two weeks after the first Exzolt Diethylene glycol monoethyl ether
administration. Fluralaner stops the production of Polysorbate 80
eggs by female mites.
The mite life cycle is broken due to the rapid onset 6.2 INCOMPATIBILITIES
of activity of fluralaner, to the very high efficacy In the absence of compatibility studies, this
in killing mites feeding on treated chickens for a veterinary medicinal product must not be mixed
duration of at least two mite life cycles, and to with other veterinary medicinal products.
the absence of egg production from female mites
exposed to treated chickens.
6.3 SHELF LIFE
Exzolt contributes towards the long term control Shelf life of the veterinary medicinal product as
of the mite populations in the poultry house. In packaged for sale: 3 years
clinical field studies, it was shown that treatment
quickly eliminated Dermanyssus gallinae populations Shelf life after first opening the immediate
in treated houses, and that parasite population packaging: 1 year
regrowth was controlled when proper biosecurity Shelf life of the medicated drinking water:
measures were implemented. 24 hours
In vitro bio-assays show that fluralaner is effective
against parasites having proven field resistance, 6.4. SPECIAL PRECAUTIONS FOR STOR AGE
including amidines (tick), organophosphates (tick, Do not store above 30°C.

79
 E X ZOLT.C OM

6.5 NATURE AND COMPOSITION OF IMMEDIATE

PACK AGING
HDPE bottle closed with an aluminum foil seal and
a child-resistant polypropylene screw cap.
Pack sizes: bottles of 1 litre or 4 litres.
Not all pack sizes may be marketed.

6.6 SPECIAL PRECAUTIONS FOR THE DISPOSAL

OF UNUSED VETERINARY MEDICINAL PRODUCT
OR WASTE MATERIALS DERIVED FROM THE USE
OF SUCH PRODUCTS
Exzolt should not enter water courses as this may
be dangerous for aquatic invertebrates.
Any unused veterinary medicinal product or waste
materials derived from such veterinary medicinal
products should be disposed of in accordance with
local requirements.

80
NOTES

81
 E X ZOLT.C OM

NOTES

82
2017 Intervet International B.V., also known as MSD Animal Health. All Rights Reserved.
GL/XZP/0318/0003
T R E AT MEN T F OR P OULT RY MI T E INF E S TAT IONS IN CHICK ENS T ECHNIC A L M A NUA L