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Protecting Their Pets. Protecting Your Practice.

Te c h n i c a l M o n o g r a p h

Ta b l e o f C o n t e n t s

Vectra 3D . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

TM

Dinotefuran . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Pyriproxyfen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Permethrin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Product Description and Dosing . . . . . . . . . . . . . . . . . . . . . 9 Patented Applicator . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 Product Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 Bloodhound Technology . . . . . . . . . . . . . . . . . . . . . . . . . 13

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Vectra 3D Flea (Ctenocephalides felis) Efficacy Studies . . . 14

Duration of Efficacy in 3 Groups of Dogs . . . . . . . . . . . . . . . . . . . . . . . . .14 Comparative Speed of Kill Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .16 Duration of Efficacy in Giant Breed Dogs . . . . . . . . . . . . . . . . . . . . . . . . .17

Vectra 3D Tick Efficacy Studies . . . . . . . . . . . . . . . . . . . . 19

Duration of Efficacy Against the Brown Dog Tick in Dogs 21 to 55 Pounds of Body Weight . . . . . . . . . . . . . . . . . . . . . . . . 19 Comparative Speed of Kill Study for the Brown Dog Tick . . . . . . . . . . . . 20 Duration of Efficacy Against the Brown Dog Tick in Giant Breed Dogs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 Comparative Duration of Efficacy Study ­ Brown Dog Tick . . . . . . . . . . . . 23 Duration of Efficacy Against the American Dog Tick in 2 Groups of Dogs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 Duration of Efficacy Against the Black-legged (Deer) Tick in Dogs 21 to 55 Pounds of Body Weight . . . . . . . . . . . . . . . . . . . . . . . . 25 Duration of Efficacy Against the Gulf Coast Tick in Dogs 21 to 55 Pounds of Body Weight . . . . . . . . . . . . . . . . . . . . . . . . 26

Vectra 3D Mosquito Efficacy Studies . . . . . . . . . . . . . . . . 28

Duration of Efficacy in Repelling, Killing and Reducing Feeding of 3 Mosquito Species in Dogs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

Vectra 3D Water Resistance Studies . . . . . . . . . . . . . . . . . 33

Duration and Efficacy Against Fleas and the Brown Dog Tick Following Repeated Immersion of Dogs in Water . . . . . . . . . . . . . . . . . . . 33 Duration and Efficacy Against Fleas and the Brown Dog Tick Following Bathing/Shampooing of Dogs . . . . . . . . . . . . . . . . . . . . . . . . . 35

Vectra 3D Safety Studies . . . . . . . . . . . . . . . . . . . . . . . . 38

Safety in Adult Dogs ­ Companion Animal Study . . . . . . . . . . . . . . . . . . 39 Safety in Puppies Overdose Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 National Clinical Trial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .41 How to Handle Adverse Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42 Human Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43

How to Contact Summit VetPharm . . . . . . . . . . . . . . . . . . 43

Product Insert . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44

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Vectra3D

TM

Vectra 3D is the first of a line of topical ectoparasiticides from Summit VetPharm . The Vectra line is based on the parasiticide, dinotefuran, a novel 3rd generation neonicotinoid and the insect growth regulator pyriproxyfen . Vectra 3D is a monthly topical flea, tick and mosquito parasiticide containing dinotefuran combined with the repellent acaricide/insecticide permethrin and the insect growth regulator (IGR) pyriproxyfen . Vectra 3D has the fastest onset of action of any available topical (EPA Reg . No . 83399-6) flea and tick product, and provides long-lasting protection against fleas, ticks and mosquitoes . Vectra 3D repels and kills 4 species of ticks (Rhipicephalus spp., Dermacentor variabilis, Ixodes spp ., Amblyomma maculatum); 3 species of mosquitoes (Culex spp ., Ochlerotatus spp ., Aedes spp .); and controls all stages of fleas (Ctenocephalides felis) . It provides long-lasting repellent, adulticidal and IGR activity for 30 days . The concentration of dinotefuran, permethrin and pyriproxyfen in each mL of Vectra is 50 mg/mL dinotefuran, 360 mg/mL permethrin and 4 .4 mg/mL pyriproxyfen or 4 .95% dinotefuran, 36 .08% permethrin and 0 .44% pyriproxyfen (by weight) .

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Dinotefuran

Name: Chemical Name: Chemical Formula: CAS Number: Activity: Molecular Structure: Dinotefuran (EZ)-(RS)-1-methyl-2-nitro-3-(tetrahydro-3 furylmethyl)guanidine C7H14N4O3 165252-70-0 Insecticide (nitroguanidine insecticide)

Dinotefuran is a water-soluble, quick-kill, nitroguanidine, neonicotinoid insecticide first discovered in 1993 by Mitsui Chemical .1 The compound was structured and synthesized with acetylcholine as the lead compound, making it different from other neonicotinoids that were based on nicotine .

ModeofAction

Dinotefuran is an insect synaptic poison . After application, this compound adheres to the skin surface and hair . Dinotefuran kills by contact . Ingestion by the insect is not necessary . Specifically, dinotefuran mimics the action of a neurotransmitter called acetylcholine . Acetylcholine normally activates a nerve impulse at the synapse but its effects are terminated very quickly . Dinotefuran binds to one of the same insect receptor sites as acetylcholine, and activates the nerve impulse . The binding is permanent; causing continuous nervous stimulation, which, in turn, results in tremors, uncoordinated movement, and death of the insect . Dinotefuran does not bind to the same sites as imidacloprid and other neonicotinoids, but at a unique site in the nerve synapse .2 Dinotefuran does not bind to mammalian acetylcholine receptor sites .

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SafetyofDinotefuran

Dinotefuran has an excellent safety profile . In laboratory animals, dinotefuran has low acute toxicity by the oral, dermal (skin), and inhalation routes . It is not a dermal sensitizer, causes a low level of skin irritation but is moderately irritating to the eye . Chronic high-dose oral exposure results in changes in the nervous system and the immune system in rabbits and rats . Nervous system toxicity is manifested with increased motor activity seen after repeated dosing; these findings are consistent with effects on the nicotinic cholinergic nervous system . No adverse effects in fetuses were seen in the developmental toxicity studies in rats or rabbits . (Table 1) Dinotefuran has been classified as, "Not likely to be carcinogenic to humans ." This classification is based on the lack of evidence in mice and rats . In studies conducted in rats, dinotefuran was found to have a chronic NOAEL of 127 mg/kg/day . In genotoxic studies dinotefuran tested negative, when evaluated by the Ames, chromosomal aberration and mouse micronucleus studies . Studies in other species suggest that dinotefuran is practically non-toxic to birds, fish and mammals .1,2,3 (Table 2) Table1.DinotefuranToxicityStudiesinLaboratoryAnimals.1,2 Acute oral LD50 Acute dermal LD50 Chronic NOAEL Skin sensitizer Eye irritation Oral teratogen Genotoxic Carcinogenic >2,000 mg/kg (rodent) >2,000 mg/kg (rodent) 127 mg/kg/day (rat) No (guinea pig) Moderate (rabbit) No (guinea pig, rabbit) No (Ames, chromosomal

aberration, mouse micronucleus)

No (rodent)

D i n o t e f u r a n o f f e r s a w i d e m a r g i n o f s a f e t y f o r c a n i n e p a t i e n t s , e v e n t h o s e a s y o u n g a s 7weeksofage.

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Table2.DinotefuranToxicityStudiesinDogs,Birds,Fish,MarineAnimals.3

Study Type

Acute Toxicity

Species

Dog

(Canis lupus familiaris)

Measure

NOAEL = 307 mg/kg/day (90 day oral) NOAEL = 20 mg/ kg/day (1 year oral) LD50 >2,000 mg/kg LC50 >5,000 ppm LC50 >1,301 ppm NOAEC = 5,270 ppm LC50 >99 .5 mg/L LC50 >99 .3 mg/L LC50 >99 .1 mg/L LC50 >968 .3 mg/L LC50 >109 mg/L LC50 >141 mg/L

Toxicity Category

Cat . IV

Chronic Toxicity Acute Toxicity Subacute Toxicity Subacute Toxicity Chronic Toxicity Acute Toxicity Acute Toxicity Acute Toxicity Acute Toxicity Acute Toxicity Acute Toxicity

Dog

(Canis lupus familiaris)

Japanese quail

(Coturnix japonica)

Practically non-toxic Practically non-toxic Slight­ practically nontoxic Practically non-toxic Practically non-toxic Practically non-toxic Practically non-toxic Practically non-toxic Practically non-toxic Practically non-toxic

Mallard duck

(Anas platyrhynchos)

Japanese quail

(Coturnix japonica)

Northern bobwhite quail

(Colinus virginianus)

Rainbow trout

(Oncorhynchus mykiss)

Bluegill sunfish

(Leopmis macrochirus)

Carp

(Cyprinus carpio)

Waterflea

(Daphnia magna)

Sheepshead Minnow

(Cyprinodon variegatus)

Eastern Oyster

(Crassostrea virginica)

LC50 ­ Median Lethal Concentration NOAEL ­ No Observed Adverse Effect Level NOAEC ­ No Observed Adverse Effect Concentration LD50 ­ Median Lethal Dose

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A comparison of toxicity measures between dinotefuran and other commonly used insecticides is found in Table 3 . The toxicology of dinotefuran compares well to other insecticides currently on the market when used as directed . Table3.ComparisonofToxicityMeasuresBetweenDinotefuranandOtherInsecticides CommonlyUsedonCompanionAnimals.1,2,4,5,6,7 Chronic NOAEL rat (mg/kg/day) 0 .02 No data available 5 .7 No data available 127 .0

Chemical

Oral LD50 rat (mg/kg) 92 >1,600 380-650 1,575-1,680 2,275-2,450

Dermal LD50 rat (mg/kg) 350 No data available >5,000 >2,000 >2,000

Rodent Carcinogen Yes No No No data available No

Fipronil Selamectin Imidacloprid Nitenpyram Dinotefuran

Dinotefuran in combination with pyriproxyfen and permethrin, the active ingredients in Vectra 3D, make it a unique combination that protects patients against all developmental stages of fleas, 4 species of ticks, and 3 species of mosquitoes .

TM

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Pyriproxyfen

Name: Chemical Name: Chemical Formula: CAS Number: Activity: Molecular Structure: Pyriproxyfen 4-phenoxyphenyl (RS)-2-(2-pyridyloxy)propyl ether C20H19NO3 95737-68-1 Insecticide (juvenile hormone mimic)

Pyriproxyfen

Pyriproxyfen is a second-generation insect growth regulator and acts to stop the flea life cycle by controlling the development of eggs, larvae and early (pharate) pupae . Pyriproxyfen is lipophilic and, after application, adheres to the animal's hair and skin, allowing it to maintain efficacy even when an animal becomes wet (e .g ., bathing or swimming) . Pyriproxyfen is long lasting and unlike other insect growth regulators, studies have demonstrated it is photostable and is not degraded by ultraviolet light .

ModeofAction

Pyriproxyfen is an insect growth hormone mimic . There are a number of insect growth hormones, one of which, Juvenile Hormone (JH), regulates the molting of insects from one stage to the other . High concentrations of JH prevent molting to the next stage . Normally in insects, an enzyme called JH esterase breaks down JH and, as the JH levels decrease, the insect molts from one stage to the other . Pyriproxyfen mimics the action of JH, killing flea eggs (ovicidal), flea larvae (larvacidal), early (pharate) pupae, and adult male and female fleas .8 Pyriproxyfen is not broken down by JH esterase, so any stages exposed to pyriproxyfen are unable to molt to the next stage and die .

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Permethrin

Name: Chemical Name: Chemical Formula: CAS Number: Activity: Molecular Structure: Permethrin 3-phenoxybenzyl (1RS,3RS;1RS,3SR)-3-(2, 2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate C21H20Cl2O3 52645-53-1 Insecticide/acaricide (pyrethroid ester)

Permethrin

Permethrin is a synthetic pyrethroid . Permethrin is a lipophilic, fast-acting adulticide and repellent against fleas, ticks and mosquitoes . It is very slowly degraded in ultraviolet light . After application, permethrin adheres to the animal where it persists . Along with its rapid knockdown effect, permethrin also has repellent properties against fleas, ticks and mosquitoes . Rapid killing in addition to prevention of attachment and feeding of these ectoparasites are important in the prevention of vector-borne diseases .

ModeofAction

Permethrin is an insect neurotoxin . During an insect nerve impulse, the voltage-gated sodium channel opens, causing stimulation of the nerve, and closes to terminate the nerve signal . Permethrin binds to this gate protein and prevents it from closing normally . This prolongs sodium ion permeability during the excitatory phase of the action potential thus causing repetitive activity in the sensory and motor pathways . This explains the tremors exhibited by poisoned insects . Insects lose control of their nervous system, are unable to produce coordinated movement, and die .

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Vectra 3D

TM

Product Description

Vectra 3D is a monthly topical flea, tick and mosquito parasiticide containing dinotefuran combined with the repellent acaricide/insecticide Permethrin and the insect growth regulator Pyriproxyfen. Vectra 3D repels and kills 4 species of ticks (Rhipicephalus spp., Dermacentor variabilis, Ixodes spp., Amblyomma maculatum); 3 species of mosquitoes (Culex spp., Ochlerotatus spp., Aedes spp.); and all stages of fleas (Ctenocephalides felis). It provides longlasting repellent, adulticidal and IGR activity for 30 days. The concentration of dinotefuran, permethrin and pyriproxyfen in each mL of Vectra 3D is 50 mg/mL dinotefuran, 360 mg/mL permethrin, and 4.4 mg/mL pyriproxyfen or 4.5% dinotefuran, 36.08% permethrin, and 0.44% pyriproxyfen (by weight). Vectra 3D is a clear yellow solution with minimal odor. Following application, Vectra 3D translocates over the body surface of the dog, adhering to the skin and hair for 30 days.

Dosing of Vectra 3D

The dosing ranges for Vectra 3D were calculated based on the surface area of dogs. Body surface area was viewed to be a more accurate measure since Vectra 3D is not absorbed, but adheres to the skin and hair. Dosage volumes and body-weight classes were formulated to maintain the mg/m2 dosage for each of the 3 actives within a narrow range. Table 4. A comparison of body-weight dosing (mg/lb) and body-surface dosing (mg/m2) for Vectra 3D.

Median

Package Size 2.5 ­ 20 lbs 21 ­ 55 lbs 56 ­ 5 lbs >5 lbs Body Weight (lbs) 11.25 38 75.5 123 Surface Area (m2) 0.2 0.67 1.06 1.46

Dosage Volume

mL 1.6 3.6 4.7 8.0

Dinotefuran

mg/lb 7.1 4.7 3.1 3.3 mg/m2 275. 268.7 221.7 274.0

Permethrin

mg/lb 51.2 34.1 22.4 23.4 mg/m2 186.2 134.3 156.2 172.6

Pyriproxyfen

mg/lb 0.63 0.42 0.27 0.2 mg/m2 24.3 23.6 1.5 24.1

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PatentedApplicator

Vectra 3D uses a unique, patented applicator that features an elongated tip to make it easy to apply to a dog's skin through the hair coat . The rounded tip minimizes risk of skin abrasions . The contoured applicator is easy to use, eliminates spillage and splashing, and has been clinically tested to ensure accurate dosing . With the one-piece applicator, there is no need to use scissors to open or remove a cap, making application fast and efficient and, at the same time, minimizing the potential of a choking hazard .

TM

HowtoApplyVectra3DProperly

1. 2.

Remove applicator from package .

The pet should be standing or in a comfortable position for easy application .

3.

Holding the applicator upright, place thumb and index finger around the applicator tip under the large disk . With the other hand, grasp the stem of applicator tip above the small disk .

4.

Press down firmly on small disk until both disks meet, piercing the seal .

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5.

Using the tip of the applicator, part the hair down to the level of the skin and slowly apply the product . Avoid superficial application to the animal's hair .

6.

Apply the product evenly along the dog's back, beginning between the shoulder blades and continuing in the order shown in the diagrams below, squeezing until the applicator tube is empty .

For dogs weighing 2 .5 to 20 lbs, apply the product to 1 spot, as shown in the diagram, onto the skin, squeezing the applicator tube until empty .

Do not get the product in dog's eyes or mouth

For dogs weighing 21 to 55 lbs OR for dogs weighing 56 to 95 lbs, apply the product evenly to 3 spots along the dog's back, beginning between the shoulder blades and continuing in the order shown in the diagram, squeezing the applicator tube until empty .

Do not get the product in dog's eyes or mouth

For dogs weighing over 95 lbs, apply the product evenly to 4 spots on the dog's back, beginning between the shoulder blades and continuing in the order shown in the diagram, squeezing the applicator tube until empty .

Do not get the product in dog's eyes or mouth

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ProductFeatures

Vectra 3D is a once-a-month topical treatment for use on dogs only against all flea life stages (adults, eggs, larvae and pupae), ticks and mosquitoes .

TM

· Kills and repels fleas .

96% lethal to adult fleas within 6 hours, 100% within 12 hours . Rapid flea kill lessens the possibility of flea allergy dermatitis . Prevents development of all flea stages for 1 month .

· Kills and repels the following ticks that can cause Lyme disease, Rocky Mountain Spotted fever, babesiosis, ehrlichiosis, and hepatozoonosis: Rhipicephalus sanguineus (Brown Dog tick), Ixodes scapularis and pacificus (Deer Tick and Western Black Legged Tick), Dermacentor variabilis (American Dog tick), and Amblyomma maculatum (Gulf Coast tick) . · Kills and repels 3 species of mosquitoes: Ochlerotatus spp ., Aedes spp ., and Culex spp . · Can be used on dogs as young as 7 weeks . · Remains effective after bathing or swimming . · Contains a potent, photostable IGR ­ pyriproxyfen . · Convenient topical treatment with patented applicator . · Pack sizes:

1 .6 mL for dogs and puppies older than 7 weeks and 2 .5-20 lbs . 3 .6 mL for dogs and puppies 21-55 lbs . 4 .7 mL for dogs 56-95 lbs . 8 .0 mL for dogs > 95 lbs .

®

· Utilizes Bloodhound Tracking Technology to ensure Vectra 3D is only available from licensed veterinarians .

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B l o o d h o u n d Te c h n o l o g y

®

Vectra 3D is protected with Summit VetPharm's Bloodhound Technology -- an innovative, proprietary track-and-trace system developed by Nutec Systems that ensures veterinary exclusivity of the product . Each package of Vectra 3D can be traced from the point of manufacture to veterinary purchase . Bloodhound Technology will allow Summit VetPharm to maintain the integrity of its products through a secure distribution channel, as well as guarding against counterfeiting . By securing our supply chain, Summit VetPharm is able to protect the veterinary professional, maintain authenticity of our products, and enhance the role of veterinarians in the lives of the animals they treat .

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Packaging

Vectra 3D is packaged in opaque laminated aluminum tubes with a unique, patented, resin dispensing applicator . Vectra 3D is available in 4 dosing sizes according to body weight: 2 .5-20 lbs ., 21-55 lbs ., 56-95 lbs ., and >95 lbs ., and is supplied in 3-dose and 6-dose packs .

Package

Dosage

Concentration

Weight/Age

For Dogs and Puppies 7 weeks or older 2 .5 ­ 20 lbs

Vectra 3D

(Teal Box and Applicator)

1 .6 mL

Vectra 3D

(Blue Box and Applicator)

3 .6 mL

4 .95% Dinotefuran 0 .44% Pyriproxyfen & 36 .08% Permethrin (by weight)

For Dogs and Puppies 21­ 55 lbs

Vectra 3D

(Purple Box and Applicator)

4 .7 mL

For Dogs 56 ­ 95 lbs

Vectra 3D

(Red Box and Applicator)

8 .0 mL

For Dogs >95 lbs

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V e c t r a 3 D F l e a ( C t e n o c e p h a l i d e s f e l i s ) EfficacyStudies

TM

D u r a t i o n o f E f f i c a c y o f V e c t r a 3 D A g a i n s t F l e a s (Ctenocephalides felis)in3GroupsofDogs. Studies#1715/1729/1730 Summary:

Three studies were conducted to evaluate the duration of efficacy of Vectra 3D against fleas on dogs . One study was conducted in dogs 11-20 pounds of body weight, the second in dogs 21-55 pounds of body weight, and the third in dogs >55 pounds of body weight . Vectra 3D showed ongoing high efficacy, maintaining a 92% or greater reduction in fleas throughout the 30-day period in all sizes of dog . Egg production was almost completely inhibited throughout the duration of the studies . Of the few eggs produced, greater than 98% failed to hatch, and none of the few larvae that hatched developed into adults . By killing fleas and preventing flea development for a minimum of 30 days Vectra 3D effectively breaks the flea life cycle .

StudyDesign:

In each study, 12 dogs were randomly assigned to 1 of 2 groups ­ a treatment group and a control group . The average weight of dogs was 14 .9 pounds (range: 12 .8­17 .9) in the 11-20 pound treatment group; 34 .0 pounds (range: 30 .0­41 .3) in the 21-55 pound treatment group; and 65 .7 pounds (range: 55 .3­78 .4) in the >55 pound treatment group . All dogs were infested with approximately 100 unfed cat fleas 1 day before treatment . On the day of treatment (day 0), dogs in the treatment groups were treated with Vectra 3D; dogs in the control group were treated with a placebo composed of the vehicle minus the active ingredients found in Vectra 3D . All dogs were treated according to label directions . For dogs in the 11-20 pound body weight group, dogs were combed and fleas counted 24 hours after infestation . To evaluate the duration of adulticidal activity, all dogs were infested every 7 days with 100 unfed fleas until day 29 after treatment . Flea counts were determined 24 hours after infestation . To measure flea egg production, all dogs were infested with 100 cat fleas on study days 3, 10, 17, 24, and 31 . Flea eggs were collected on study days 6, 13, 20, 27, and 34, and incubated to determine egg viability . For dogs in the 21-55 and >55 pound groups, dogs were combed and fleas counted 48 hours after infestation . To evaluate the duration of adulticidal activity, all dogs were infested every 7 days with 100 unfed fleas until day 29 after treatment . Flea counts were determined 24 hours after infestation . To measure flea egg production, all dogs were infested with 100 cat fleas on study days 2, 9, 16, 23 and 30 . Flea eggs were collected on study days 5, 12, 19, 26 and 33, and incubated to determine egg viability .

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Results:

The results of these studies are illustrated in Figures 1 and 2 . Vectra 3D persisted on the dogs, maintaining a 92% or greater reduction in fleas throughout the 30-day period . The Pyriproxyfen in Vectra 3D inhibited egg laying throughout the duration of the study . Of the few eggs produced, greater than 98% failed to hatch, and none of the few larvae that hatched developed into adults .

TM

Figure1.

Efficacy of Vectra 3DTM against the cat flea in dogs.

100 99.6 98.7 92.0 99.4 100 96.2 98.7 99.8 97.4 97.6 99.6 98.9 93.5 99.5 96.5

% Flea Reduction

80 60 40 20 0

1

2

9

16

23

30

Day of Study 11-20 lbs

Studies # 1715/1729/1730

21-55 lbs

>55 lbs

Figure2.

Efficacy of Vectra 3DTM on the hatchability of flea eggs.

% Reduction Flea Egg Hatch

100 80 60 40 20 0 98.7 100 100 100 100 100 100 100 100 100 99.2 100 100 99.5 100

5

6

12

13

19

20

26

27

33

34

Day of Study 11-20 lbs

Studies # 1715/1729/1730

21-55 lbs

>55 lbs

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V e c t r a 3 D S p e e d o f K i l l S t u d y f o r F l e a s (Ctenocephalides felis).

TM

Study#1736 Summary:

A study was conducted to evaluate the speed of kill for fleas of Vectra 3D on dogs 21-55 pounds of body weight . Flea counts were evaluated at 2, 6 and 12 hours after application of the product . Vectra 3D killed 96% of fleas in 6 hours . Rapid kill by Vectra 3D reduces the possibility of flea allergy dermatitis in flea allergic dogs .

StudyDesign:

In this study, 18 dogs were randomly divided into 4 groups: a central control group of 6 dogs; a Vectra 3D treatment group of 6 dogs; and two treatment groups of 3 dogs each for the competitve product treatment groups . One day prior to treatment, all dogs were infested with approximately 100 unfed fleas . Dogs in the control group had a mean body weight of 29 .4 pounds (range 24 .2-35 .8) and were treated with a placebo . Dogs in the Vectra 3D group had a mean body weight of 28 .0 pounds (range 24 .0-31 .6); dogs in the competitive A product group had a mean body weight of 27 .9 pounds (range 26 .2-30 .0); and dogs in the competitive B group had a mean body weight of 25 .1 pounds(range 21 .8-27 .2)* . All dogs were treated according to the manufacturers' instruction . At 2 and 6 hours after treatment all fleas were hand counted with finger combing .* The dogs were then combed at 12 hours, fleas counted and discarded .

Results:

The results are illustrated in Figure 3 . Vectra 3D demonstrated a rapid performance, killing 96% of fleas in 6 hours . 100% efficacy at 12 hours was demonstrated by Vectra 3D . Reduction of flea burden, as rapidly as possible, is important in flea allergic dogs . Figure3.

Efficacy of Vectra 3DTM against the cat flea in dogs 21 to 55 lbs of body weight.

95.9 100

100

% Flea Reduction

80 60 40 20 0 59.0

2

6

12

Hours post treatment

Study # 1736

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* Due to the small sample size of the competitor groups, statistical significance could not be demonstrated .

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D u r a t i o n o f E f f i c a c y o f V e c t r a 3 D A g a i n s t F l e a s (Ctenocephalides felis)inGiantBreedDogs.

TM

Study#1865 Summary:

A study was conducted to evaluate the duration of efficacy of Vectra 3D against fleas in giant breed dogs weighing between 89-132 pounds . Vectra 3D persisted on the dogs, maintaining a 99% or greater reduction in fleas throughout the 30-day period . The pyriproxyfen in Vectra 3D inhibited egg laying throughout the duration of the study . Vectra 3D was shown to be effective in breaking the flea cycle even in the largest size dogs .

StudyDesign:

Twelve mix-breed dogs were used in this study and randomly assigned to either a control group or a treatment group . Dogs in the control group had a mean body weight of 102 .2 pounds (range: 92 .5-106 .6) and were treated with a placebo . Dogs in the Vectra 3D group had a mean body weight of 94 .4 pounds (range: 90 .2-100 .8) and were treated with Vectra 3D according to label instructions . One day prior to treatment, all dogs were infested with approximately 100 unfed fleas . Forty-eight hours after treatment, dogs were combed and fleas counted (day 2) . To evaluate the duration of the killing effect, all dogs were infested every 7 days with 100 unfed fleas until day 29 after treatment . Flea counts were determined 24 hours after infestation . To measure flea egg production, dogs were infested with 100 cat fleas on study days 2, 9, 16, 23 and 30 . Flea eggs were collected on study days 5, 12, 19, 26 and 32, and incubated to determine egg viability .

Results:

The results of these studies are illustrated in Figures 4 and 5 . Vectra 3D persisted on the dogs, maintaining a 99% or greater reduction in fleas throughout the 30-day period . The pyriproxyfen in Vectra 3D inhibited egg laying throughout the duration of the study . Of the few eggs collected from Vectra 3D treated dogs, all (100%) failed to hatch .

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Figure4. Efficacy of Vectra 3DTM against the cat flea in dogs 89 to 132 lbs body weight.

100 99.8 99.8 100 99.7 99.7

% Flea Reduction

80 60 40 20 0

2

9

16

23

30

Day of Study

Study # 1865

Figure5. Efficacy of Vectra 3DTM against the cat flea in dogs 89 to 132 lbs body weight.

100 100 100 100 100 100

% Reduction Flea Egg Hatch

80 60 40 20 0

5

12

19

26

32

Day of Study

Study # 1865

Vectra3D protectseven yourlargestpatientsfrom fleasfor1month.

TM

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Vectra3D TickEfficacyStudies

TM

D u r a t i o n o f E f f i c a c y o f V e c t r a 3 D A g a i n s t t h e B r o w n D o g T i c k ( R h i p i c e p h a l u s s a n g u i n e u s ) i n D o g s 21 t o 5 5 P o u n d s o f B o d y W e i g h t . Study#1715 Summary:

A study was conducted to evaluate the duration of efficacy of Vectra 3D against the Brown Dog tick (Rhipicephalus sanguineus) in dogs 21-55 pounds of body weight . Nine days after treatment, Vectra 3D maintained 95% or greater reduction in Brown Dog tick numbers throughout the 30-day period . Vectra 3D helps to prevent R. sanguineus attachment and minimizes exposure for a minimum of 1 month . Monthly application of Vectra 3D will provide maximum protection against the Brown Dog tick .

StudyDesign:

In this study, 12 dogs were randomly assigned to 1 of 2 groups: A treatment group and a control group . The average weight of dogs was 34 .0 pounds (range: 30 .0-41 .3) in the treatment group . All dogs were infested with approximately 75 adult R. sanguineus ticks 1 day before treatment . On the day of treatment (day 0), dogs in the treatment group were treated with Vectra 3D; dogs in the control group were treated with a placebo composed of the vehicle minus the active ingredients found in Vectra 3D . All dogs were treated according to label directions . Forty-eight hours after treatment, dogs were combed and ticks counted (day 2) . To evaluate the duration of the killing effect, all dogs were infested every 7 days with 75 adult R. sanguineus ticks until day 29 after treatment . Tick counts were determined 24 hours after infestation .

Results:

The results are illustrated in Figure 6 . Within 2 days after treatment, Vectra 3D reduced tick numbers by 83% . Nine days after treatment, Vectra 3D maintained 95 .8% or greater reduction in Brown Dog tick numbers throughout the 30-day period .

TheBrownDogtickisunusualamongticks inthefactthatitcancompleteitsentirelife cycleindoors.IntheUnitedStates,itfeedson dogsatallstagesofitsdevelopment.

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Figure6. Efficacy of Vectra 3DTM against the Brown Dog tick (Rhipicephalus sanguineus).

100 99.0 83.2 98.8 95.8 96.4

% Tick Reduction

80 60 40 20 0

2

9

16

23

30

Day of Study 21-55 lbs

Study # 1715

V e c t r a 3 D S p e e d o f K i l l S t u d y f o r t h e B r o w n D o g T i c k (Rhipicephalus sanguineus).

TM

Study#1736 Summary:

A study was conducted to evaluate the onset of flea activity after treatment of Vectra 3D on dogs 21-55 pounds of body weight . Brown Dog tick (Rhipicephalus sanguineus) counts were evaluated at 2, 6 and 12 hours after application of the products . Vectra 3D demonstrated a more rapid onset of effect, killing > 61% of ticks by 6 hours after application and >74% by 12 hours after application .

StudyDesign:

In this study, 18 dogs were randomly divided into 4 groups: A control group of 6 dogs; a Vectra 3D treatment group of 6 dogs; and 2 treatment groups of 3 dogs each for the competitive product groups . One day prior to treatment, all dogs were infested with 50 adult R. sanguineus ticks . Dogs in the control group had a mean body weight of 29 .4 pounds (range: 24 .2-35 .8) and were treated with a placebo . Dogs in the group had a mean body weight of 28 .0 pounds (range: 24 .0-31 .6); dogs in the competitive A group had a mean body weight of 27 .9 pounds (range: 26 .2-30 .0); and dogs in the competitive B group had a mean body weight of 25 .1 pounds (range: 21 .8-27 .2)* . All dogs were treated according to the manufacturers' instructions . At 2 and 6 hours after treatment, dogs were finger-combed and ticks hand counted . Live ticks remained on the dogs . The dogs were combed and ticks counted, 12 hours after treatment .

20

* Due to the small sample size of the competitor groups, statistical significance could not be demonstrated .

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Results:

The results are illustrated in Figure 7 . Vectra 3D demonstrated performance beginning at 2 hours post treatment, steadily improving at 6 hours and reaching 74 .2% kill in 12 hours .

TM

Figure7.

Efficacy of Vectra 3DTM against the Brown Dog tick (Rhipicephalus sanguineus) in dogs 21 to 55 lbs of body weight.

80 74.2 61.3

% Tick Reduction

60 40 20 0

30.3

2

6

12

Hours post treatment Vectra 3DTM

Study # 1736

D u r a t i o n o f E f f i c a c y o f V e c t r a 3 D A g a i n s t t h e B r o w n D o g T i c k ( R h i p i c e p h a l u s s a n g u i n e u s ) i n GiantBreedDogs.

TM

Study#1865 Summary:

A study was conducted to evaluate the duration of efficacy of Vectra 3D against the Brown Dog tick (Rhipicephalus sanguineus) in giant breed dogs weighing between 89-132 pounds . Nine days after treatment, tick numbers were reduced > 96% . Vectra 3D persisted on the dogs, maintaining this level of efficacy throughout the 30-day period . Vectra 3D was shown to be effective in controlling the Brown Dog tick, even in the largest size dogs .

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StudyDesign:

Twelve mix-breed dogs were used in this study and randomly assigned to either a control group or a treatment group . Dogs in the control group had a mean body weight of 102 .2 pounds (range: 92 .5-106 .6) and were treated with a placebo . Dogs in the Vectra 3D group had a mean body weight of 94 .4 pounds (range: 90 .2-100 .8) and were treated with Vectra 3D according to label instructions . One day prior to treatment, all dogs were infested with 50 adult R. sanguineus ticks . Forty-eight hours after treatment, dogs were combed and ticks counted (day 2) . To evaluate the duration of the killing effect, all dogs were infested every 7 days with 50 adult R. sanguineus ticks until day 29 after treatment . Tick counts were determined 24 hours after infestation .

TM

Results:

The results of this study are illustrated in Figure 8 . Nine days after treatment, tick numbers were reduced > 96% . Vectra 3D persisted on the dogs, maintaining this level of efficacy throughout the 30-day period . Figure8. Efficacy of Vectra 3DTM against the Brown Dog tick (Rhipicephalus sanguineus).

100 96.8 97.8 99.4 99.0

% Tick Reduction

80 60 40 20 0 62.1

2

9

16

23

30

Day of Study

Study # 1865

Within9days,BrownDogtick numberswerereducedby>96% ongiantbreeddogs(Figure8).

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Vectra3D ComparativeDurationofEfficacyStudy­ BrownDogTick(Rhipicephalus sanguineus) .

TM

Study#SVP07016 Summary:

A study was conducted to compare the duration of efficacy of Vectra 3D and K9 Advantix against the Brown Dog tick in dogs 21-55 pounds of body weight . Within 9 days of treatment, reduction of ticks was > 97% . No statistically significant difference in performance was noted between Vectra 3D and K9 Advantix .

StudyDesign:

In this study, 18 dogs were randomly assigned to either a control group or to 1 of 2 treatment groups . Dogs in the Vectra 3D group had a mean body weight of 29 .9 pounds (range: 22 .6-33 .1); and dogs in the K9 Advantix group had a mean body weight of 38 .8 pounds (range: 32 .3-44 .7) . One day prior to treatment, all dogs were infested with approximately 50 unfed Brown Dog ticks . Dogs in the control group were treated with a placebo . Dogs in the treated groups were treated with Vectra 3D or K9 Advantix according to label instruction (day 0) . Forty-eight hours after treatment, dogs were combed and ticks counted (day 2) . To evaluate the duration of the killing effect, all dogs were infested every 7 days with 50 Brown Dog ticks until day 29 after treatment . Tick counts were determined 24 hours after infestation .

Results:

The results of this study are illustrated in Figure 9 . Within 9 days of treatment, reduction of ticks was >97% . The performance of Vectra 3D was equivalent to that of K9 Advantix throughout the duration of the study . Figure9. Comparative Efficacy of Vectra 3DTM against the Brown Dog tick (Rhipicephalus sanguineus) in dogs 21 to 55 lbs body weight.

100 97.1 100 90.2 99.7 99.6 100 97.5 99.0

% Tick Reduction

80 60 40 20 0 54.5 53.6

2

9

16

23

30

Day of Study Vectra 3DTM

Study # SVP07016

K9 Advantix®

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D u r a t i o n o f E f f i c a c y o f V e c t r a 3 D A g a i n s t t h e A m e r i c a n D o g T i c k ( D e r m a c e n t o r v a r i a b i l i s ) i n 2GroupsofDogs.

TM

Studies#1729/1730 Summary:

Two studies were conducted to determine the duration of efficacy of Vectra 3D against the American Dog tick (Dermacentor variabilis) in 2 groups of dogs: Those 11-20 pounds of body weight and those > 55 pounds of body weight . Nine days after treatment, Vectra 3D achieved 97 .5% and 87 .1% respectively, in the reduction of American Dog tick numbers . Vectra 3D helps to prevent D. variabilis attachment and minimizes exposure for a minimum of 1 month . Monthly application of Vectra 3D will provide maximum protection against the American Dog tick .

StudyDesign:

In each study, 12 dogs were randomly assigned to 1 of 2 groups: A treatment group and a control group . The average weight of dogs was 14 .9 pounds (range: 12 .8-17 .9) in the 11-20 pound treatment group; and 65 .7 pounds (range: 55 .3-78 .4) in the > 55 pound treatment group . All dogs were infested with 50 adult D. variabilis ticks 1 day before treatment . On the day of treatment (day 0), dogs in the treatment groups were treated with Vectra 3D; dogs in the control group were treated with a placebo composed of the solvents found in Vectra 3D . All dogs were treated according to label directions . Fortyeight hours after treatment, dogs were combed and ticks counted (day 2) . To evaluate the duration of the killing effect, all dogs were infested every 7 days with 50 adult D. variabilis ticks until day 29 after treatment . Tick counts were determined 24 hours after infestation .

TheAmericanDogtick isavectorofRocky MountainSpottedfever,ehrlichiosisandtularemia.

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Results:

The results are illustrated in Figure 10 . Nine days after treatment, Vectra 3D maintained 82% or greater reduction in American Dog tick numbers for dogs 11-20 pounds body weight, and 87% or greater for dogs > 55 pounds body weight through the duration of the study .

TM

Figure10. Efficacy of Vectra 3DTM against the American Dog tick (Demacentor variabilis).

100 97.5 87.1 76.7 97.5 96.8 82.0 96.1 91.7 95.7

% Tick Reduction

80 60 40 20 0

42.5

2

9

16

23

30

Day of Study 11-20 lbs

Studies # 1729/1730

>55 lbs

D u r a t i o n o f E f f i c a c y o f V e c t r a 3 D A g a i n s t t h e B l a c k - l e g g e d ( D e e r ) T i c k ( I x o d e s s c a p u l a r i s ) i n D o g s 21 t o 55 P o u n d s o f B o d y W e i g h t . Study# 1751 Summary:

A study was conducted to evaluate the duration of efficacy of Vectra 3D against the Black-legged (Deer) tick (Ixodes scapularis) in dogs 21-55 pounds of body weight . Vectra 3D was > 96% effective in killing Black-legged ticks after 24 hours exposure, and 100% effective after 48 hours exposure . This efficacy persisted throughout the 30-day study period . Rapid tick kill by Vectra 3D reduces the possibility of I. scapularis transmitted diseases in dogs . Monthly application of Vectra 3D will provide maximum protection against the Black-legged tick . Black-legged tick nymphs were used in this study, due to their aggressive feeding habits and high potential for carrying Lyme disease .

StudyDesign:

In this study, 12 dogs were randomly assigned to either a control group or a treatment group . Dogs in the control group had a mean body weight of 35 .6 pounds (range: 28 .4-49 .4) and were treated with a placebo; dogs in the treatment group

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had a mean body weight of 31 .7 pounds (range: 29 .0-35 .6) and were treated according to label directions with Vectra 3D . At 2, 9, 16, 23 and 30 days after treatment, hair samples were removed from each dog . Each dog's hair samples were placed in an individual Petri dish . Each Petri dish was then infested with 10 Black-legged tick nymphs, and live tick counts were conducted 24 and 48 hours later .

TM

Results:

The results are illustrated in Figure 11 . Vectra 3D was > 96% effective in killing Black-legged ticks after 24 hours exposure to the hair, and 100% effective after 48 hours exposure to hair . This efficacy persisted throughout the 30-day study period . Figure11. Efficacy of Vectra 3DTM against the Black-legged tick (Ixodes sapularis) in dogs 21 to 55 lbs body weight.

100 100 100 97.9 100 96.5 100 100 100 100 100

% Tick Reduction

80 60 40 20 0

2

9

16

23

30

Day of Study 24 Hours Exposure

Study # 1751

48 Hours Exposure

D u r a t i o n o f E f f i c a c y o f V e c t r a 3 D A g a i n s t t h e G u l f C o a s t T i c k ( A m b l y o m m a m a c u l a t u m ) i n D o g s 21 t o 55 P o u n d s o f B o d y W e i g h t .

TM

Study#1778 Summary:

A study was conducted to evaluate the duration of efficacy of Vectra 3D against the Gulf Coast tick (Amblyomma maculatum) in dogs 21-55 pounds of body weight . Vectra 3D was > 80% effective in killing Gulf Coast ticks beginning as early as 2 days after treatment and continuing throughout the duration of the study . Vectra 3D helps to prevent A. maculatum attachment and minimizes exposure for a minimum of 1 month . Monthly application of Vectra 3D will provide maximum protection against the Gulf Coast tick .

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StudyDesign:

In this study, 12 dogs were randomly assigned to either a control group or a treatment group . Dogs in the control group had a mean body weight of 30 .6 pounds (range: 23 .6-35 .8) and were treated with a placebo; dogs in the treatment group had a mean body weight of 33 .5 pounds (range: 22 .2-43 .2) . One day prior to treatment, dogs were infested with 50 adult A. maculatum ticks . On the day of treatment (day 0), dogs in the treatment group were treated with Vectra 3D; dogs in the control group were treated with a placebo composed of the vehicle minus the active ingredients found in Vectra 3D . All dogs were treated according to label directions . Forty-eight hours after treatment (day 2), dogs were combed and ticks counted . To evaluate the duration of the killing effect, all dogs were infested every 7 days with 50 adult A. maculatum ticks until day 29 after treatment . Tick counts were determined 24 hours after infestation .

TM

Results:

The results are illustrated in Figure 12 . Vectra 3D was > 80% effective in killing Gulf Coast tick beginning as early as 2 days after treatment and continuing throughout the duration of the study . Figure12. Efficacy of Vectra 3DTM against the Gulf Coast tick (Amblyomma maculatum) in dogs 21 to 55 lbs body weight.

100 85.3 96.7 81.8 93.6 94.7

% Tick Reduction

80 60 40 20 0

2

9

16

23

30

Day of Study

Study # 1778

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Vectra3D MosquitoEfficacyStudies

TM

D u r a t i o n o f E f f i c a c y o f V e c t r a 3 D i n R e p e l l i n g , K i l l i n g a n d R e d u c i n g F e e d i n g o f 3 M o s q u i t o S p e c i e s ( O c h l e r o t a t u s t r i s e r i a t u s , A e d e s a e g y p t i , andCulex pipiens quinquefasciatus)inDogs. Studies#1737/1762/1763 Summary:

Three studies were conducted to evaluate the efficacy of Vectra 3D against 3 representative species of mosquitoes found in the United States . Vectra 3D both reduced the number of mosquito landings and/or increased mosquito mortality, causing an overall decrease in mosquito feeding during the 30-day study period .

StudyDesign:

The efficacy of Vectra 3D against mosquitoes was examined in 3 studies using 3 mosquito species: Ochlerotatus triseriatus; Aedes aegypti; and Culex pipiens quinquefasciatus . In each of the 3 studies, repellency, prevention of feeding, and ability to kill was examined for each mosquito species . Ochlerotatus triseriatus: Twelve dogs were divided into control and treatment groups . Dogs in the control group had a mean body weight of 30 .4 pounds (range: 27 .5-32 .3) and were treated with a placebo . Dogs in the treatment group had a mean body weight of 30 .5 pounds (range: 26 .833 .0) and were treated with Vectra 3D according to label directions . On the day after treatment, all dogs were exposed to 100 unfed female O. triseriatas mosquitoes, and the number of landings (an indirect measure of repellency), the number of mosquitoes feeding, and mosquito mortality were measured . To evaluate the duration of the effect, dogs were re-exposed to mosquitoes weekly thereafter until the end of the study (day 30) . Aedes aegypti: Twelve dogs were divided into control and treatment groups . Dogs in the control group had a mean body weight of 27 .0 pounds (range: 22 .4-30 .8) and were treated with a placebo . Dogs in the treatment group had a mean body weight of 27 .7 pounds (range: 24 .6-34 .0) and were treated with Vectra 3D according to label directions . On the day after treatment, all dogs were exposed to 100 unfed female A. aegypti mosquitoes, and the number of landings (an indirect measure of repellency), the number of mosquitoes feeding, and mosquito mortality were measured . To evaluate the duration of the effect, dogs were reexposed to mosquitoes weekly thereafter until the end of the study (day 36) . Culex pipiens quinquefasciatus: Twelve dogs were divided into control and treatment groups . Dogs in the control group had a mean body weight of 32 .4 pounds (range: 27 .9-39 .2) and were treated with a placebo . Dogs in the treatment group had a mean body weight of 31 .6 pounds (range: 24 .7-37 .0) and were treated with Vectra 3D according to label directions . On the day after treatment, all dogs were exposed to 100 unfed C. pipiens quinquefaciatus female mosquitoes, and the number of landings (an indirect measure of repellency), the number of mosquitoes feeding, and mosquito mortality were measured . To evaluate the duration of the effect, dogs were re-exposed to mosquitoes weekly thereafter until the end of the study (day 30) .

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Results:

The efficacy of Vectra 3D against Ochlerotatus triseriatus is illustrated in Figure 13 . Vectra 3D had a moderate repellent effect in preventing the landing of the female mosquitoes and Vectra 3D caused high mortality with approximately 94% of mosquitoes killed . This resulted in a reduction of feeding of over 97% for female O. triseriatus mosquitoes .

TM

The results for Aedes aegypti are illustrated in Figure 14 . Vectra 3D had little repellent effect in preventing the landing of mosquitoes, but caused high mortality with approximately 90% of mosquitoes killed . This resulted in a reduction of feeding of over 83% A. aegypti mosquitoes . The lack of repellency allowed the mosquitoes to land and begin feeding, but once there was contact, the mortality was high . The results for Culex pipiens quinquefasciatus are illustrated in Figure 15 . Vectra 3D had a high-repellent effect in preventing the landing of the female mosquitoes resulting in a 100% reduction of feeding . A 50-86% mortality was seen in C. pipiens quinquefasciatus mosquitoes . This lower rate is probably due to the high-repellency effect of Vectra 3D . Mosquitoes that do not land cannot come into contact with the insecticide .

Mosquitoes are a source of irritation for many dogs and a confirmed vector of disease, which is why protection against this parasite is so important . Testing of Vectra 3D confirms that mosquito behaviorlanding, feeding and mortality- are altered in these 3 species of mosquitoes tested after treatment with Vectra 3D .

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M o s q u i t o E f f i c a c y T r i a l D a t a

Figure13. Efficacy of Vectra 3DTM against Ochlerotatus triseriatus in dogs 21 to 55 lbs body weight.

100

% Reduction in Landings

80 60 40 20 0 53.1 35.9 32.4 63.4

68.4

1

8

15

23

30

Days post treatment

100

98.4

99.2

99.2

97.9

100

% Reduction in Feeding

80 60 40 20 0

1

8

15

23

30

Days post treatment

100

96.4

96.1

94.9

94.8

96.1

% Mortality

80 60 40 20 0

1

8

15

23

30

Days post treatment

Study # 1763

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M o s q u i t o E f f i c a c y T r i a l D a t a

Figure14. Efficacy of Vectra 3DTM against Aedes aegypti in dogs 21 to 55 lbs body weight.

100

% Reduction in Landings

80 60 40 20 0 20.6 5.9 0 0 0 23.9

1

7

14

21

28

36

Days post treatment

100

87.3

92.8

88.5

% Reduction in Feeding

80 60 40 20 0

86.2

83.6

90.1

1

7

14

21

28

36

Days post treatment

100

90.1

98.5

97.1

91.0

94.7

92.7

% Mortality

80 60 40 20 0

1

7

14

21

28

36

Days post treatment

Study # 1737

Vectra3Dsignificantlyreducesmosquitofeeding in3species­upto100%.(Figures13,14,15).

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M o s q u i t o E f f i c a c y T r i a l D a t a

Figure15. Efficacy of Vectra 3DTM against Culex pipiens quinquefasciatus in dogs 21 to 55 lbs body weight.

100

% Reduction in Landings

80 60 40 20 0

72.5

82.0

77.0

88.3

81.6

1

8

15

22

29

Days post treatment

100

100

100

100

100

100

% Reduction in Feeding

80 60 40 20 0

1

8

15

22

29

Days post treatment

100

% Mortality

80 60 40 20 0

75.9

86.2

81.1 49.6

75.6

1

8

15

22

29

Days post treatment

Study # 1762

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Vectra3D WaterResistanceStudies

TM

D u r a t i o n a n d E f f i c a c y o f V e c t r a 3 D A g a i n s t F l e a s a n d t h e B r o w n D o g T i c k ( R h i p i c e p h a l u s s a n g u i n e u s ) Fo ll o w i n g Re p e a t e d Im m e r s i o n o f D o g s i n Wa t e r. Study#1734 Summary:

The ability of Vectra 3D to withstand water and bathing was examined in a number of studies . This study was to simulate rain exposure or swimming . Weekly water immersion had little effect on the ability of Vectra 3D to reduce the number of fleas and Brown Dog ticks . The numbers of both fleas and ticks were reduced by > 90% for both immersed and nonimmersed dogs throughout the duration of the study . Occasional swimming or rain exposure should not have an effect on the efficacy of Vectra 3D against fleas and ticks .

StudyDesign:

In this study, 18 dogs were randomly assigned to a control and 2 treatment groups . One day prior to treatment, all dogs were infested with approximately 100 unfed fleas and 75 unfed Brown Dog ticks . Dogs in the control group had a mean body weight of 35 .6 pounds (range: 21 .6-52 .2) and were treated with a placebo . Dogs in the first treatment group had a mean body weight of 37 .4 pounds (range: 31 .2-42 .6); and in the second treatment group had a mean body weight of 34 .6 pounds (range: 20 .6-49 .3) . Dogs in both treatment groups were treated with Vectra 3D according to label recommendations . Fleas and ticks were counted 2 days after treatment (day 2) . Dogs in the control group and 1 of the treated groups were then immersed in water for 60 seconds and then allowed to drip dry on study days 5, 12, 19 and 26 after treatment . Dogs were re-infested with fleas and ticks weekly and counted 1 day later .

Water immersion has little effect on the efficacy of Vectra 3D against fleas and Brown Dog ticks .

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Results:

Results of this study are illustrated in Figures 16 and 17 . Weekly water immersion had little effect on the ability of Vectra 3D to reduce the number of fleas and Brown Dog ticks . The numbers of both fleas and ticks were reduced by > 90% for both immersed and nonimmersed dogs throughout the duration of the study .

TM

Figure16. Efficacy of Vectra 3DTM against the cat flea in dogs 21 to 55 lbs of body weight with weekly immersion in water.

100 97.0 100 99.7 100 99.8 99.3 94.2 99.3 93.7 99.0

% Flea Reduction

80 60 40 20 0

2

9

16

23

30

Day of Study Immersed

Study # 1734

Not Immersed

Figure17.

Efficacy of Vectra 3DTM against the Brown Dog tick (Rhipicephalus sanguineus) in dogs 21 to 55 lbs of body weight with weekly immersion in water.

100 95.1 100 100 99.5 93.1 99.3 97.3 95.8 93.2

% Tick Reduction

80 60 47.9 40 20 0

2

9

16

23

30

Day of Study Shampooed

Study # 1734

Not Shampooed

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D u r a t i o n a n d E f f i c a c y o f V e c t r a 3 D A g a i n s t F l e a s a n d t h e B r o w n D o g T i c k ( R h i p i c e p h a l u s s a n g u i n e u s ) FollowingBathing / ShampooingofDogs.

TM

Study#1728 Summary:

This study was to evaluate the efficacy of Vectra 3D following bathing and shampooing . As many of the commonly used topical ectoparasiticides, shampooing did have an effect on the ability of Vectra 3D to reduce the number of fleas with the reduction in flea counts decreased to 73-85% . Shampooing had no effect on the efficacy of Vectra 3D in preventing flea hatch, larval development or the reduction of Brown Dog ticks . The numbers of ticks were reduced by > 90% for both shampooed and non-shampooed dogs throughout the duration of the study .

StudyDesign:

In this study, 18 dogs were randomly assigned to a control and 2 treatment groups . One day prior to treatment, all dogs were infested with approximately 100 unfed fleas and 50 unfed Brown Dog ticks . Dogs in the control group had a mean body weight of 29 .6 pounds (range: 24 .9-41 .8) and were treated with a placebo . Dogs in the first treatment group had a mean body weight of 31 .8 pounds (range: 22 .6-40 .8); and in the second treatment group had a mean body weight of 32 .9 pounds (range: 27 .6-37 .7) . Dogs in the control group were treated with a placebo . Dogs in the treatment groups were treated with Vectra 3D according to label instructions . Fleas and ticks were counted 2 days after treatment (day 2) . Dogs were re-infested with fleas and ticks weekly thereafter and counted 1 day later . Dogs in the control group and 1 of the treated groups were shampooed on day 14 after treatment . The shampoo was permitted to remain on the dogs for 5 to 10 minutes . To measure flea egg production, dogs were infested with 100 cat fleas on study days 2, 9, 16, 23 and 30 . Flea eggs were collected on study days 6, 13, 20, 27 and 34, and incubated to determine egg viability .

Results:

Results of this study are illustrated in Figures 18, 19, 20 and 21 . Shampooing did have an effect on the ability of Vectra 3D to reduce the number of fleas . Following shampooing, the reduction of adult flea counts decreased to 82 .7% at day 16 and 73 .7% on day 30 . Data on egg hatch and larval development demonstrated no difference between shampooed and non-shampooed dogs . Shampooing had no effect on the reduction of Brown Dog ticks . The numbers of ticks were reduced by > 90% for both the control and test animals throughout the study duration .

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Figure18. Efficacy of Vectra 3DTM against the cat flea in dogs 21 to 55 lbs of body weight with shampooing on Day 14.

100 92.5 95.7 100 98.9 82.7 100 85.8 73.7 100 99.7

% Flea Reduction

80 60 40 20 0

2

9

16

23

30

Day of Study Shampooed

Study # 1728

Not Shampooed

Figure19. Efficacy of Vectra 3DTM against flea hatchability in dogs 21 to 55 lbs of body weight with shampooing on Day 14.

100 100 100 100 100 99.7 100 100 100 100 100

% Reduction of Flea Egg Hatch

80 60 40 20 0

6

13

20

27

34

Day of Study Shampooed

Study # 1728

Not Shampooed

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B a t h i n g / S h a m p o o i n g T r i a l D a t a

Figure20. Efficacy of Vectra 3DTM against flea larvae development in dogs 21 to 55 lbs of body weight with shampooing on Day 14.

100 100 100 100 100 100 100 100 100 100 100

% Reduction of Flea Larvae Development

80 60 40 20 0

5

12

19

26

33

Day of Study Shampooed

Study # 1728

Not Shampooed

Figure21. Efficacy of Vectra 3DTM against the Brown Dog tick (Rhipicephalus sanguineus) in dogs 21 to 55 lbs of body weight.

100 96.3 97.6 98.5 90.0 98.0 99.3 96.1 99.2

% Tick Reduction

80 60 40 20 0 18.5 58.3

2

9

16

23

30

Day of Study Shampooed

Study # 1728

Not Shampooed

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Vectra3D SafetyStudies

TM

Vectra 3D was shown to be safe when used as directed on adult dogs and puppies as young as 7 weeks and weighing as little as 2 .5 pounds . Toxicology values for laboratory animals for the 3 components of Vectra 3D are shown in Table 5 . Table5.AcuteToxicityStudiesforthe3ActiveComponentsofVectra3D. Measure Acute oral LD50 Acute dermal LD50 Chronic NOAEL Skin sensitizer Eye irritation Oral teratogen Genotoxic Dinotefuran > 2,000 mg/kg

(rodent)

Permethrin 3,580 mg/kg

(rodent)

Pyriproxyfen > 5,000 mg/kg

(rodent)

> 2,000 mg/kg

(rodent)

> 4,000 mg/kg

(rabbit)

> 2,000 mg/kg

(rodent)

127 mg/kg/day

(rat)

25 mg/kg/day

(rat)

16 mg/kg/day

(rat)

(guinea pig) (rabbit) (guinea pig, rabbit) (Ames, chromosomal aberration, mouse micronucleus) (rodent)

No

(guinea pig) (rabbit) (rat) (Ames, chromosomal aberration, mouse micronucleus) (rat)

No

(guinea pig)

No

Slight No

Slight No No

Minimal

(rabbit)

(rat, rabbit) (Ames, chromosomal aberration, mouse micronucleus) (rat)

No No

No

Carcinogenic

No

Yes

No

Acute Toxicity Studies were conducted for Vectra 3D in laboratory animals . The results of these studies are found in Table 6 . Vectra 3D showed minimal toxicity in laboratory animals . Table6.AcuteToxicityStudiesforVectra3DinLaboratoryAnimals Acute oral LD50 Acute dermal LD50 Skin sensitizer Eye irritation > 5,000 mg/kg (rodent) > 5,000 mg/kg (rodent) No (guinea pig) Moderate (rabbit)

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S a f e t y o f V e c t r a 3 D i n A d u l t D o g s ­ C o m p a n i o n AnimalSafetyStudy

TM

Study#1749 Summary:

The safety of Vectra 3D was evaluated in an overdose study using adult beagle dogs . No detrimental effects were noted in any dogs . Vectra 3D was well tolerated, both locally and systemically in adult dogs .

StudyDesign:

In this study, 48 healthy adult dogs were randomly assigned to 4 groups, each containing 6 male and 6 female dogs . The weight of the dogs ranged from 22-48 pounds . The 4 groups were treated in the following manner: · Group 1 dogs were the control group and treated with a placebo; · Group 2 dogs were treated with 1 time the normal dose of Vectra 3D; · Group 3 dogs were treated with 3 times the normal dose of Vectra 3D; · Group 4 dogs were treated with 5 times the normal dose of Vectra 3D . Following treatment, dogs were evaluated hourly for 6 hours after treatment and twice daily for the following 14 days . The following physical and clinical measures were measured during the study: Body weight, food consumption, blood parameters, and clinical evaluations .

Results:

Dogs in all treatment groups ate normally and maintained weight throughout the duration of the study . No clinically important abnormalities were noted in blood cell counts or in blood chemistries . No clinically important abnormalities or clinical signs were recorded in any dog throughout the duration of the study .

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Safety of Vectra 3D in Puppies ­ Companion Animal Safety Study

TM

Study # 1851 Summary:

The safety of Vectra 3D was evaluated in an overdose study using 7-8-week-old beagle puppies. Vectra 3D was demonstrated to be safe in puppies as young as 7 weeks of age.

Study Design:

In this study, 48 healthy puppies (23 males and 25 females) 49-62 days of age were randomly assigned to 4 groups. Groups 1, 2 and 4 each contained 6 male and 6 female puppies. Group 3 contained 5 male and 7 female puppies. The weight of the puppies ranged from 1.9-6.4 pounds. The 4 groups were treated in the following manner: · Group 1 puppies were the control group and treated with a placebo; · Group 2 puppies were treated with 1 time the normal dose of Vectra 3D; · Group 3 puppies were treated with 3 times the normal dose of Vectra 3D; · Group 4 puppies were treated with 5 times the normal dose of Vectra 3D. Following treatment, puppies were evaluated hourly for 6 hours after treatment and twice daily for the following 14 days. The following physical and clinical measures were measured during the study: Body weight, food consumption, blood parameters, and clinical evaluations.

Results:

Puppies in all treatment groups ate normally and gained weight throughout the duration of the study. No significant differences in weight gain were seen between the control and treatment groups. No clinically significant abnormalities were noted in blood cell counts or in blood chemistries. No abnormal clinical signs were recorded in any puppy throughout the duration of the study.

40

No detrimental effects were noted in dogs or puppies even at 5 times the normal dose of Vectra 3D.

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Vectra 3D

TM

i n a N a t i o n a l C l i n i c a l Tr i a l

Figure 22.

Applicator Assessment - Very Easy

90 80 70

Percentage

Study # SVP0719

A national clinical trial using Vectra 3D was conducted during July / August, 2007 in 23 veterinary hospitals / clinics located in 11 states. There were 233 dogs enrolled; 197 were treated with Vectra 3D and 36 were treated with K9 Advantix as a reference control. The veterinarians were asked to evaluate the applicator, instructions and formula appearance on the dogs. (Figure 22) The owners did not know which treatment the pet cats received. Owners evaluated the treatment site, appearance and animal acceptance of the treatment at 24 hours and 30 days post treatment during a telephone interview. (Figure 23) Figure 23.

24 Hour Behavior/Well-Being/Habits

60 50 40 30 20 10 0

Opening Applicator Instructions Vectra 3D

TM

Illustration K9 Advantix

®

Ease of Use

Study # SVP0719

24 Hour Appearance

30 Day Behavior/Well-Being/Habits

1.0%

7.1%

2.0%

99.0%

Normal

92.9%

Normal

98.0%

Normal

Vectra 3DTM

Abnormal

Vectra 3DTM

Abnormal

Vectra 3DTM

Abnormal

5.6%

11.1%

2.8%

94.4%

Normal Abnormal

88.9%

Normal

97.2%

Normal Abnormal

Abnormal

K9 Advantix®

K9 Advantix®

K9 Advantix®

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HowtoHandleAdverseReactionstoVectra3D Whattodoifthereisareaction:

TM

If used appropriately, the likelihood of a reaction in any treated dog is extremely rare . If an unexpected sign does occur within 24-48 hours of treatment, it is recommended to bathe the dog with a liquid hand dish detergent (Dawn® or Palmolive®) . Bathing with a liquid hand dish detergent will remove most of the product . Follow with symptomatic and supportive treatment . Please call Summit VetPharm for further advice directly or indirectly .

HowtotreataVectra3Dapplicationtoacat:

Vectra 3D contains permethrin and should only be used on dogs, and never used on cats . Exposures in cats can be harmful due to their unique physiology and inability to metabolize certain compounds, if not appropriately treated . Cats may be exposed if the product is accidentally applied directly to them, or through direct ingestion (e .g ., the cat grooms the wet product off of the dog) . Signs of a Vectra 3D toxicosis in the cat can include: tremors, drooling, lack of appetite, vomiting, diarrhea, incoordination, hyperactivity, disorientation, vocalization, depression, difficulty breathing and seizures . Death is possible .

IfacatisaccidentallyadministeredVectra3D,orifitisexposedtoVectra3Dfrom atreateddogandsignsareevident,thefollowingisrecommended:

1 . If administered directly to a cat, bathe the cat with a liquid hand dish detergent (Dawn or Palmolive) to remove any residual product . Dry the cat well and maintain body temperature . 2 . Cats accidentally administered or indirectly exposed to a treated dog: control tremors with METHOCARBAMOL injectable administered intravenously . The dose is 25-100 mg/lb of body weight, half the dose should be administered rapidly IV . Stop, see how much the cat has relaxed, and give the remainder as needed . Do not exceed 150 mg/lb . 3 . DO NOT ADMINISTER ATROPINE . 4 . Control hyper- or hypothermia . Cats may have hyperthermia initially due to tremors/seizures, but can become hypothermic if sedated with anticonvulsants and bathed . Hypothermia may worsen the signs of a permethrin toxicosis . 5 . Place cat on fluids, maintain hydration and nutrition . 6 . Recovery is usually within 24-72 hours . 7 . Call Summit VetPharm at 1-800-999-0297 to report .

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HumanExposuretoVectra3D

T M

FirstAid

If in the eyes: Hold eye open and rinse slowly and gently with water for 15 to 20 minutes . Remove contact lenses, if present, after the first 5 minutes, then continue rinsing . Call a poison control center or doctor for treatment advice . If swallowed: Call a poison control center or doctor immediately for treatment advice . Have the person sip a glass of water if able to swallow . Do not induce vomiting unless told to do so by a poison control center or doctor . Do not give anything to an unconscious person . If on the skin: Take off contaminated clothing . Rinse skin immediately with plenty of water for 15 to 20 minutes . Call a poison control center, doctor or 1-800-999-0297 (or 1-888-426-4435 after 6 pm EST) immediately for treatment advice . Have the product container or label with you when calling a poison control center or doctor or going for treatment . You may contact 1-800-999-0297 (or 1-888-426-4435 after 6 pm EST) for emergency medical treatment information .

HowtogetaMaterialSafetyDataSheet(MSDS)

A downloadable copy of the Vectra 3D MSDS is available on our Website at http://summitvetpharm . com . You may also contact us by phone, fax, or e-mail to obtain a copy of the MSDS .

H o w t o C o n t a c t S u m m i t V e t P h a r m

If you have a question, want to place an order, or would like to discuss a case, please feel free to contact us through the following: Address: Summit VetPharm, 400 Kelby Street, Fort Lee, NJ 07024 USA Phone: (800) 999-0297 (US only) Fax: (877) 777-5138 · (201) 363-8639 Website: summitvetpharm .com

1 Wakita T, Yasui N, Yamada E, and Kishi D . Development of a novel insecticide, dinotefuran . J. Pestic. Sci., 30: 122-123, 2005 . 2 Tomizawa M, and Casida JE . Neonicotinoid insect toxicology: Mechanisms of Selective Action . Annu. Rev. Pharmacol. Toxicol. 45:247-268, 2005 . 3 Dinotefuran Fact Sheet . United States Environmental Protection Agency, Office of Prevention, Pesticides and Toxic Substances . Washington, DC . 4 Kidd H, James DR, editors . The Agrochemicals Handbook, 3rd Edition . Cambridge, UK: Royal Society of Chemistry Information Services; 1991 . 5 Pesticide residues in food ­ Fipronil (1997) . Report of the joint meeting of the FAO Panel of Experts on Pesticide Residues in Food and the Environment, and the WHO Core Assessment Group on Pesticide Residues, Lyons, France, 22 Sept ­ 1 October, 1997 . Food and Agriculture Organization of the United Nations . Rome; 1998 . FAO Plant Production and Protection Paper No . 145 . ® 6 Pfizer Inc . MSDS for Revolution, May 11, 2004 . 7 Physical and Theoretical Chemistry Laboratory, Oxford University . Safety (MSDS) data for nitenpyram . Updated May 4, 2006 . 8 Miller RJ, Broce AB, Dryden MW & Hopkins T . Susceptibility to Insect Growth Regulators and Cuticle Deposition of the Cat Flea (Siphonaptwere: Pulicidae) as a Function of Age, J. Med Entomol 36: 780-787, 1999 . 9 Marsella, R . 1999, Advances in flea Control . Veterinary Clinics of North America: Small Animal Practice . Vol 29, No 6 . 1407-1424 . *Vectra 3D is not indicated for the prevention of heartworm disease in dogs . K9 Advantix is a registered trademark of Bayer . Frontline is a registered trademark of Merial . Revolution is a registered trademark of Pfizer, Inc . Dawn is a registered trademark of Proctor & Gamble . Palmolive is a registered trademark of Colgate­Palmolive Company . Vectra 3D and Bloodhound are trademarks of Summit VetPharm LLC .

©2007 Summit VetPharm LLC

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Vectra 3DTM for dogs and puppies 2.5 to 20 lbs, over 7 weeks of age Vectra 3DTM for dogs and puppies 21 to 55 lbs, over 7 weeks of age Vectra 3DTM for dogs 56 to 95 lbs Vectra 3DTM for dogs over 95 lbs Repels and kills fleas, ticks, and mosquitoes for one month Protects against 4 types of ticks Rhipicephalus , Dermacentor variabilis, Ixodes , Amblyomma maculatum 3 types of mosquitoes Culex , Ochlerotatus , Aedes , and all stages of fleas Kills fleas in 6 hours Kills the vectors that may cause Lyme disease, Rocky Mountain Spotted fever, babesiosis, ehrlichiosis, bartonellosis, hepatozoonosis, and heartworm disease Easy, spot-on topical application Remains effective after bathing and swimming Performance guaranteed or your money back Only available from licensed veterinarians Using the patented applicator, Vectra 3DTM is specially designed to spread naturally over the dog's body, providing effective control of fleas, ticks, and mosquitoes for one month ACTIVE INGREDIENTS: Dinotefuran . . . . . . . . . . . . . . . .4.95% Pyriproxyfen . . . . . . . . . . . . . . .0.44% Permethrin . . . . . . . . . . . . . . .36.08% OTHER INGREDIENTS . . . . . .58.53% TOTAL . . . . . . . . . . . . . . . . . .100.00%

KEEP OUT OF REACH OF CHILDREN

See directions for use, precautionary statements, first aid, and ingredients. FOR ADDITIONAL INFORMATION, CONTACT US AT 1-800-999-0297 READ ENTIRE LABEL BEFORE EACH USE USE ONLY ON DOGS OR PUPPIES OVER 7 WEEKS OLD

WARNING:

PRECAUTIONARY STATEMENTS

HAZARDS TO HUMANS AND DOMESTIC ANIMALS For external use on dogs only. Do not use this product on cats. Use only on dogs and puppies over 7 weeks old (1.6 mL and 3.6 mL sizes) WARNING: Causes substantial but temporary eye injury. Harmful if swallowed. Do not get in eyes or on clothing. Wash thoroughly with soap and water after handling and before eating, drinking, chewing gum, or using tobacco products. Do not use this product on debilitated, aged, medicated, pregnant or nursing animals, or animals known to be sensitive to pesticide products without first consulting a veterinarian. Sensitivity, such as slight transitory redness of the skin at the site of application, may occur after using ANY pesticide product for pets. If signs of sensitivity occur, bathe your pet with mild soap or shampoo and rinse with large amounts of water. If signs of individual animal sensitivity occur and persist, contact your veterinarian. Have the product container or label with you when calling your veterinarian for advice. DO NOT USE ON CATS. Due to their unique physiology and inability to metabolize certain compounds, this product must not be used on cats. If applied to a cat, or ingested by a cat that actively grooms a recently treated dog, this product may have serious harmful effects. If this occurs, contact your veterinarian immediately. FIRST AID If in eyes: Hold eye open and rinse slowly and gently with water for 15­20 minutes. Remove contact lenses, if present, after the first 5 minutes, then continue rinsing. Call a poison control center or doctor for treatment advice. If swallowed: Call a poison control center or doctor immediately for treatment advice. Have person sip a glass of water if able to swallow. Do not induce vomiting unless told to do so by a poison control center or doctor. Do not give anything to an unconscious person. If on skin: Take off contaminated clothing. Rinse skin immediately with plenty of water for 15­20 minutes. Call a poison control center, doctor, or 1-888-426-4435 immediately for treatment advice. Have the product container or label with you when calling a poison control center or doctor or going for treatment. You may contact 1-888-426-4435 for emergency medical treatment information.

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Summit VetPharm 400 Kelby Street Fort Lee, NJ 07024 USA Phone: (800) 999-0297 (US only) Fax: (877) 777-5138 · (201) 363-8639 Website: www.summitvetpharm.com

©2008 Summit VetPharm LLC V3D-019-08

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