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Advocate : Performance meets convenience.

®

FA C T S A N D B E N E F I T S .

New

New

Flea

Larvae

Louse

Hookworm

Whipworm

Roundworm Angiostrongylus Heartworm

Otodectes

Sarcoptes

Demodex

And: Convenience meets care.

Treatment and prevention. Parasitic diseases in dogs and cats have become an integral component of veterinary practice and pet ownership. In addition, the zoonotic aspect of these parasites is just as important. Multiple parasites, one product. Advocate® combines excellent flea efficacy (imidacloprid) with sound protection against heartworm infestations, gastrointestinal worms as well as mites (moxidectin). It is "The Endectocide" with the broadest spectrum available. One spot-on application per month safeguards against a very large range of parasites in cats and dogs. It is the Companion Animal parasiticide with the most complete spectrum of indications! Advocate® does it. Advocate® is an ideal product offering heartworm prevention, flea treatment and prevention of flea infestations, control of biting lice1, 2 gastrointestinal worm control including several larval stages and French heartworm1, 2 treatment control of sarcoptic mange2, control of ear mites, treatment of Demodex mites2.

1 Registration obtained in Europe in August 2007. 2 in dogs

Advocate® is registered under the trademark Advantage Multi® in several countries such as the USA, Canada, New Zealand and Central America.

Unique formulation meets ongoing satisfaction.

T WO AC T I V E AGE N TS FOR MOR E OPPORT U NI T IE S. Advocate® is a combination of imidacloprid and moxidectin, designed for simple dermal application. Its spot-on formulation allows an easy and stress-free application for the pets and pet owners all year round. Advocate® allows you to replace multiple products due to its combination of two proven, highly efficient molecules:

1 1 3 3 5

2 4 2 4

Site of action of imidaclopr id on insect nerves

1 Vesicles of acetylcholine 2 Imidacloprid 3 Nicotinic receptors blocked open 4 Constant neuromuscular stimulation

Site of action of moxidec tin on neuronal membranes of worms and mites

1 Synaptic terminal of presynaptic neuron 2 Postsynaptic neuron 3 Synaptic vesicles releasing neurotransmitter 4 Glutamate-gated chloride channels 5 Open chloride ion channel after transmitter or moxidectin exposure at binding site

Application with Advocate®, the combination of imidacloprid and moxidectin.

Imidacloprid acts against fleas.

Imidacloprid acts as an agonist on the postsynaptic nicotinic acetylcholine receptors of motor neurones in insects. This causes an overstimulation of the nervous system, and ultimately kills the insect. (Following topical application, imidacloprid localises in the water-resistant lipid layer of the skin surface. Fleas do not need to bite an animal in order to be exposed to imidacloprid; rather, it is absorbed through the flea's non-sclerotised intersegmental membranes).

Moxidectin is effective in the prevention of heartworm infection and the treatment of gastrointestinal nematodes as well as several types of mites.

Moxidectin binds to receptors on neuronal membranes of nematodes and myoneural junctions of arthropods. The chloride ion influx lowers cell membrane resistance and causes a hyperpolarisation of the postsynaptic cells. This in turn makes neurotransmission more difficult and results in flaccid paralysis, death and/ or expulsion of the parasite.

Imidacloprid Moxidectin

Broad spectrum meets high efficacy.

L A S T I N G P R E V E N T I O N A N D E F F I C I E N T T R E AT M E N T. ec toparasite s

Protection against fleas with imidacloprid, the active ingredient of Advantage®. New claim: treatment of biting lice in dogs.1

Flea Louse

Advocate® provides up to 99.5% efficacy for ear mites in cats and 98.3% in dogs.2

Otodectes Sarcoptes Demodex

Treatment of sarcoptic mange as well as Demodex mites in dogs. Effective in preventing heartworm disease in dogs and cats.

endoparasite s

Heartworm prevention including larvae L3 / L4 Angiostrongylus 3

Treatment of A. vasorum in dogs.2

Hookworm adult + larvae

Roundworm adult + larvae

Whipworm

Broad spectrum treatment and control of intestinal parasites such as hookworms and roundworms, including all relevant larval stages as well as treatment of whipworms.

1 Registration obtained in Europe in August 2007. 2 Bayer internal research study, data on file. 3 Angiostrongylus vasorum (also known as French Heartworm)

Advocate® works spot-on, fast and against a broad range of parasites at the same time. Its application is as stressless for dogs and cats, puppies and kitten, as it is convenient for pet owners. To the veterinarian it means reliability and efficacy in his practice due to its combination of two proven, highly efficient molecules: imidacloprid and moxidectin.

1 minute

5 minutes

2 hours

6 hours

24 hours

Distribution of imidaclopr id after topical application

Imidacloprid is spread over the skin surface and throughout the hair coat of dogs and fur of cats within twelve hours after topical application. Due to the greater surface area of larger dogs, application at multiple spots maximizes the translocation and coverage of imidacloprid.

New claim

French heartworm therapy meets approved efficacy.

C L I N IC A L C A S E S O F A N GIO S T R O N G Y LO S I S B ECO M E M O R E PR E VA L E N T. Canine angiostrongylosis is an emerging disease with increasing numbers of diagnosed cases in dogs and other canids. It is caused by Angiostrongylus vasorum which belongs to the family of Angiostrongylidae. First discovered in France, it is also called French heartworm. Since its discovery A. vasorum has been found in many countries all over Europe, Africa and the Americas. This endoparasite has been recognised in endemic pockets in many countries with temperate climates. Recently the parasite has appeared in several new geographical areas and is becoming increasingly important in clinical practice.

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L I F E C Y C L E A N D D E V E LO P M E N T S TAGE S O F A NG IOS T RO NG Y LUS VA SO RU M

A N G I O S T R O N G Y L O S I S : D I F F I C U LT D I A G N O S I S , E A S Y T R E AT M E N T. Angiostrongylosis is a crucial differential diagnosis in any dog with respiratory, bleeding, neurological or syncopal signs of unknown etiology. Coughing, dyspnoea, coagulopathy, weight loss, vomiting, abdominal pain, lumbar pain, heart failure, bleeding diathesis can be symptoms of angiostrongylosis. A precise diagnosis is difficult (Baermann technique) and often not performed. Due to these drawbacks the prevalence of Angiostrongylus seems to be underestimated. Advocate® was recently registered for treatment of Angiostrongylus vasorum in dogs in Europe. A recently published efficacy study showed an efficacy of 85.2 % for Advocate® and 91.3 % for fenbendazole, with no statistically significant difference between them. All dogs still positive on Baermann testing which then received a further dose of Advocate® were subsequently found to be Baermann negative, thus the efficacy in dogs receiving a second 1 dose of Advocate® was 100% and larval shedding was reduced in the remaining patients. The above mentioned study demonstrated that Advocate® is safe and yields an excellent prognosis for recovering from the infection. The application of Advocate® also leads to a significant improvement of the clinical signs.

5 4

4

Angiostrongylus vasorum male, posterior end

3

6

a

c

b

7

d

Angiostrongylus vasorum anterior end

Angiostrongylus vasorum is a metastrongylid nematode living in the pulmonary artery, mainly causing pulmonary and cardiac diseases ­ in rare cases even sudden death. Infections tend to be chronic (months to years). Dogs of any age can be infected. Clinical diseases are most common in younger dogs of less than 2 years of age. Advocate® is newly registered in Europe for the treatment of Angiostrongylus vasorum in dogs.

Coagulopathy, a common complication associated with Angiostrongylus vasorum infection.

8 e

f

1

1 Various snails act as an intermediate host. Infective larvae develop here (L3). 2 The fox is a natural host of Angiostrongylus vasorum, but dogs can be infected too.

3 Larvae (L3­L4­L5) migrate via the alimentary tract, abdominal lymph nodes, liver, venous system and right heart into the pulmonary artery. 4 Mature Angiostrongylus vasorum in the pulmonary artery (top female, bottom male).

5 Mature worms lay eggs which enter the lung via the bloodstream. 6 Tissue nodules a consisting of cellular infiltrate filled with larvae and eggs develop in the lung. Bronchiole b Arteriole c

7 Larvae (L1) develop inside the eggs in the capillaries d , hatch e and move into the alveolus f . They are transported up the airway to the larynx and then swallowed. 8 Larvae (L1) enter the ground through faeces.

1 Willesen JL, Kristensen AT, Jensen AL, Heine J, Koch J. Efficacy and safety of imidacloprid/ moxidectin spot-on solution and fenbendazole in the treatment of dogs naturally infected with Angiostrongylus vasorum. Veterinary Parasitology 147 (2007): P. 258­264.

therapy meets confidence.

Heartworm prevention meets high efficacy.

A R E L I A B L E S A F E G U A R D A G A I N S T O N E O F T H E B I G G E S T T H R E AT S . Heartworm disease is regarded as a serious and potentially life-threatening disease in dogs and cats caused by the adult stages of Dirofilaria immitis. Studies clearly confirm the efficacy of Advocate® for heartworm prevention in dogs, even when administered to dogs with 45-day-old heartworm larvae.1 Advocate® is higly effective in the prevention of heartworm disease in dogs and cats as shown in clinical trials.2

Evaluation of the heartworm prevention (Dirofilaria immitis) of Advocate® in cats

Heartworm Infection Days prior to treatment 30 Efficacy of Advocate® (%) 100

Dirofilaria immitis microfilaria

Dirofilaria immitis in the heart of a cat

100 L3 D. immitis larvae

experiment

McCall, TRS, Athens, USA. Efficacy of topically applied imidacloprid (10% w/v) + moxidectin (1% w/v) for the preventation of heartworm disease in cats. R&D efficacy heartworm Dirofilaria immitis cat.

Efficacy of Advocate® on 45 day old heartworm larvae (Dirofilaria immitis) in dogs

Heartworm Infection Days prior to treatment 45 Efficacy of Advocate® (%) 100

50 L3 D. immitis larvae

experiment

The dogs were examined for the presence of adult heartworms at day 164 post infection (day 119 post treatment). No adult heartworms were recovered from the Advocate® treated dogs. Bayer internal research studies, data on file.

Development stages of Dirofilaria immitis

Angiostrongylus vasorum*

1 A mosquito with infectious grabs (L3 approx. 1,2 mm) in its saliva infects the pet through the skin. 2 Pre-adult worms move within the tissue and bloodstream of venous vessels to the lungs. 4 Adult sexually mature female worms (25­30 cm) develop microfilaria (0.03 mm). 5 These microfilaria access the tissue through the arterial circulation. 6 A new mosquito contaminates itself with microfilaria.

Shampooing and bathing 90 min after application does not reduce the effectiveness of Advocate® in the prevention of heartworm disease. The efficacy of Advocate® for heartworm prevention in dogs is not diminished when dogs are shampooed and rinsed with water 4 hours post treatment. Also swimming 60 min post treatment does not reduce efficacy.

1 Bayer internal research studies, data on file. 2 Arther RG, Bowman DD, McCall JW, Hansen O, Young DR. (2003) Feline Advantage Heart (Imidacloprid and Moxidectin) topical solution as monthly treatment for prevention of heartworm infection (Dirofilaria immitis) and control of fleas (Ctenocephalides felis) on cats. Parasitol. Res. 90: P. 136 ­138.

Worldwide distribution of hear t worm.

Endemic

Heartworm

*also known as French Heartworm

3 The adult worms (20­40 mm) move into the right pulmonary artery in the right-hand side of the heart.

Worm control meets your know-how.

W O R M S A R E A S E R I O U S T H R E AT. Worms, especially in their larval stages, can cause critical parasitic infestations in cats and dogs and are a threat to human health too. In light of the consequences of worm infestation, it is highly recommended that family cats and dogs are dewormed regularly. Advocate® allows control of a wide range of intestinal nematodes: roundworms, hookworms and whipworms, with only one application per month. Advocate® even helps to protect against immature larval stages (L4 stages) as well as pre-adult stages of gastrointestinal nematodes.

Dogs, as well as cats, heavily infected with adult Toxocara suffer from enteritis that can interfere with digestion and result in malabsorption of food. Ancylostoma caninum: Hookworms are regarded as nematodes that feed on both blood and intestinal mucosa.

Toxocara

Ancylostoma caninum

Uncinaria stenocephala

WHIPWORMS Trichuris vulpis is clinically significant for dogs worldwide, especially in warmer countries. Dogs of any age can be infected. It can result in diarrhoeic bloody, muscus-filled faeces and ultimately the dog becomes acutely ill. In clinical as well as multi-centered field studies1 Advocate® demonstrated an efficacy of up to 100% for the treatment of natural patent T. vulpis infections in dogs. The above-mentioned studies1 correspond well with a specific study1 in dogs naturally infected with whipworm. Here the efficacy of Advocate® was 97 % (see also table below).

1 Bayer internal research study, data on file.

ROUNDWORMS (ASC AR IDS) Toxocara canis is the most prevalent gastrointestinal nematode in dogs, and Toxocara cati in cats. They cause heavy infection, especially in puppies and kittens, and may be responsible for impaired growth and development. Young or adult dogs with mild infections are frequently asymptomatic or simply fail to gain weight. However, these animals remain important as a reservoir of infection, contaminating the environment and capable of passing the infection to human beings. Eggs can be found in the environment and on the pet's coat and remain infective in the soil for years. Toxocariasis is a serious human health risk, especially for children. In clinical as well as multi-centered field studies2 Advocate® demonstrated an efficacy of up to 100% for the treatment of natural patent T. canis infections in dogs, also against L4 and immature adult stages; an efficacy of up to 100% for the treatment of natural patent T. leonina infections in dogs; an efficacy of up to 100% for the treatment of T. cati in cats, also against L4 and against immature adults.

2 Hellmann K, Knoppe T, Radeloff I, Heine J. The anthelmintic efficacy and safety of a combination of imidacloprid and moxidectin spot-on in cats and dogs under field conditions in Europe. Parasitol Res (2003) 90: P. 142­143.

HOOK WORMS

Efficacy of Advocate® for treatment of patent infections of T. canis and T. leonina in dogs

Ascarid Geo. mean no.worms Advocate® T. canis Study 1 Study 2 T. leonina Study 1 Study 2 0.0 1.8 0.6 0.0 placebo 5.2 17.7 19.1 20.4 Efficacy of Advocate® (%) 100.0 97.0 97.0 100.0

Trichuris vulpis

Bayer internal research studies, data on file.

Efficacy of Advocate® against different developmental stages (L4 / immature adults) of T. canis in dogs

T. canis develop. stage Study 1 L4 Immature adults Study 2 L4 Immature adults Geo. mean worm counts at day 19 p.i.* Advocate® control 0.07 ­ 0.15 ­ 0.83 ­ 3.51 ­ Geo. mean worm counts at day 29 p.i. Efficacy of Advocate® (%)

Advocate®control day 20 day 29 0.2 0.0 0.0 0.15 13.8 0.93 3.27 12.6 91.6 ­ 97.6 ­ 98.6 100.0 99.0 99.0

Dogs can be infected with eggs of Trichuris vulpis and suffer from infections of the intestine.

Efficacy of Advocate® against natural whipworm (T. vulpis) infections in dogs

Whipworm T. vulpis Geo. mean worm counts Advocate® placebo 0.4 15.5 Efficacy of Advocate® (%) 97.0

Ancylostoma is more prevalent in warmer climates, while Uncinaria is well adapted to the temperate climates. Larvae are even able to survive over winter. A. caninum/A. tubaeforme cause anaemia in dogs/ cats of any age. Infections in puppies can cause diarrhoea, anorexia, lethargy and sudden death. Infective larvae ­ even of U. stenocephala in dogs ­ can cause pedal dermatitis. Experimental studies have shown daily blood intake from adult hookworms to be about 0.12 ml, the blood loss can lead to erythropenia, reduction of blood haemoglobin or decreased packed cell volumes. In humans, exposure to hookworm larvae may give rise to cutaneous larvae migrans (CLM). Hookworms generate a high risk of zoonotic transmission ­ due to its short life cycle and the risk of transmitting the larval stages to human beings. In clinical as well as multi-centred field studies3 Advocate® demonstrated an efficacy of up to 100% for the treatment of natural patent A. caninum and U. stenocephala infections in dogs, including L4 stages and immature adult stages; an efficacy of up to 100% for the treatment of A. tubaeforme and A. braziliense4 in cats, also against larval and immature adult stages of A. tubaeforme in experimentally infected cats.

Efficacy of Advocate® against A. caninum and U. stenocephala in dogs

Hookworm Infection Geo. mean worm counts Advocate® placebo 0.0 0.0 221.3 45.3 Efficacy of Advocate® (%) 100 100

Study 1 U. stenocephala Study 2 A. caninum

natural* natural*

* Treatment group: n=8 dogs. Bayer internal research studies, data on file.

Efficacy of Advocate® against different developmental stages (L4 / immature adults) of A. caninum and U. stenocephala in dogs

Hookworm Geo. mean worm counts at day 12 p.i. Geo. mean worm counts at day 17 p.i. Efficacy of Advocate® (%)

A. caninum U. stenocephala

Advocate® placebo Advocate® placebo day 12 day 17 0 9.3 0 9.4 100.0 100.0 0 36.7 0 44.4 100.0 100.0

Bayer internal research study, data on file.

* Study 1: counts performed on day 19; Study 2: counts performed on day 20. Bayer internal research studies, data on file.

Efficacy of Advocate® against natural hookworm infections in cats

Hookworm A. tubaeforme* A. braziliense Geo. mean worm counts Advocate® placebo 0 0 2.32 19.9 Efficacy of Advocate® (%) 100.0 100.0

Treatment group: n=11 dogs. Bayer internal research study, data on file.

Efficacy of Advocate® against different developmental stages (L4 / immature adults) of T. cati in cats

T. cati develop. stage Geo. mean worm counts at day 19 p.i. (SD+ ) ­ 0 ­ 5.1 (3.7) ­ Geo. mean worm counts at day 29 p.i. (SD+ ) ­ Efficacy of Advocate® (%)

* Advocate® is registered for the treatment of Ancylostoma braziliense in Brazil. Treatment group: n=12 cats. Bayer internal research study, data on file.

Advocate® control Advocate® control day 19 day 29 L4 Immature adults 0.2 (0.01) 5.8 (7.3) 100.0 0.3 (0.02) 3.5 (5.3) ­ 97.0 91.0

Samson-Himmestjerna GV, Epe C, Schimmel A, Heine J. Larval and persistent efficacy of an imidacloprid and moxidectin topical formulation against endoparasites in cats and dogs. Parasitol Res (2003) 90: P. 114­115.

3 Hellmann K, Knoppe T, Radeloff I, Heine J. The anthelmintic efficacy and safety of a combination of imidacloprid and moxidectin spot-on in cats and dogs under field conditions in Europe. Parasitol Res (2003) 90: P. 142­143. 4 Advocate® is registered for the treatment of Ancylostoma braziliense in Brazil.

pet owners' well-being.

New claim

Lice control meets long lasting activity.

Biting lice1 (Trichodectes canis) specifically affect dogs. They rasp the surface of the skin and eat the debris. Lice spend their entire life on the host, all stages from the egg up to the adult occur in the dogs' fur. They are transmitted mainly by host to host interaction. Lice can be found on dogs throughout the world. In regions of the northern hemisphere they are regarded as common ectoparasites. They primarily occur on dogs kept under rough outdoor conditions. Dogs of any age may become infested. Large lice populations build up especially in young, old and unhealthy hosts where grooming is not effective. In addition to Australia and New Zealand, Advocate® is newly registered for lice control in dogs in Europe.1 An established population of biting lice can cause: intense pruritus associated with self-trauma; transfer of the tapeworm Dipylidium caninum.2, 3 Studies demonstrate that Advocate® offers a high level of lice control. A marked reduction of 89.9% one day after treatment and an overall efficacy of 99.7% at day 28 has been proven.4 The success of a single treatment for the strong indication of slowly developing biting lice is a strong hint for the long-term efficacy of Advocate®.4

1 Registration obtained in Europe in August 2007. 2 Jueco NL. Dipilydiasis. In: Steele, JH (ed), Handbook Series in Zoonoses, Section C: Parasitic Zoonose, 1982. 3 Wall R, Shearer D. Veterinary Entomology. Chapman & Hall, London, 1997. 4 Stanneck D, Doyle J, Ketzis J, Heine J, Fischer M. Efficacy of imidacloprid 10% and imidacloprid 10% plus moxidectin 2.5% against natural lice (Trichodectes canis) infestations in dogs. Parasitol Res, 2007, 101: P. 13­18.

N E W I N D I C AT I O N A P P R O V E D I N E U R O P E : B I T I N G L I C E O N D O G S .

Trichodectes canis adult

Trichodectes canis nymph

Efficacy of imidacloprid 10% /moxidectin 2.5% against Trichodectes canis on dogs

100 Geometric mean lice counts 90 80 60 50 40 30 20 10 0 -7 -3 1 2 7 14 study day 21 28 36

Treatment at day 1

Efficacy 89.9% 97.6% 99.1% 99.4% 99.2% 99.7% 99.9%

1

70

5

Louse

Life cycle of biting lice Trichodectes canis (egg to egg development period 3­5 weeks) 1 Adult louse 2 Egg 3 Nymph 1 4 Nymph 2 5 Nymph 3

Roundworm

Hookworm

Whipworm

Larvae

2

4

n = 10 dogs received imidacloprid 10% plus moxidectin 2.5% + 10 dogs served as an untreated control group Stanneck D, Doyle J, Ketzis J, Heine J, Fischer M. Efficacy of imidacloprid 10% and imidacloprid 10% plus moxidectin 2.5% against natural lice (Trichodectes canis) infestations in dogs. Parasitol Res, 2007, 101: P. 13­18.

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Mites treatment meets convenience.

Sarcoptes scabiei var. canis female Demodex canis

O N E T O T W O M O N T H LY A P P L I C AT I O N S W I L L D O . Mites such as Otodectes cynotis, Sarcoptes scabiei and Demodex canis are not just annoying to dogs and cats. When not treated immediately and properly Sarcoptes and Demodex mites can spread over the whole body and cause painful infections of the ear or even the whole of the skin. In most cases one spot-on application of Advocate® per month for a period of two months is a sufficient safeguard ­ in case of infection with ear mites a single application is sufficient.

1 1 Day 0 / initial treatment, clinical manifestation of generalised sarcoptic mange.

2 2 Day + 50, improvement after two consecutive treatments with Advocate®.

1 1 Day 0 / initial treatment, clinical manifestation of generalised canine demodicosis.

2 2 And improvement after monthly treatments with Advocate®.

Otodectes cynotis

EAR MITES Otodectes cynotis are the most common mange mites of dogs and cats in the world. It is estimated that 50% of external ear infections in dogs and 85% in cats involve Otodectes mites.1 They infect the outer ear canal of the pet. They should be treated with Advocate® at an early stage to prevent Otitis externa.

1 Veterinärmedizinische Parasitologie, Editor Thomas Schnieder, 6th Edition 2006, Chapter 5.4 by Kurt Pfister, page 543.

SA RCO P T IC M A NGE Sarcoptes scabiei are very contagious and occur in various host-specific subspecies, for example, in dogs Sarcoptes scabiei var. canis and can usually be taken care of with two simple applications. Sarcoptes mites cause highly contagious diseases: intense pruritus, alopecia, self-trauma, wrinkling and thickening of the skin. Studies2 showed that two treatments of Advocate®, applied 4 weeks apart, are highly effective against Sarcoptes scabiei in dogs and resulted in an almost complete resolution of the skin lesions typical of sarcoptic mange.

Efficacy of Advocate® Sarcoptes scabiei mites and associated clinical signs in dogs

Parameter 8.79 (28 cats) 1.79 (28 cats) 1.75 (4 cats) Number of dogs Percentage efficacy: proportion of dogs showing no Sarcoptes mites on day 56 (±2 days) 100.00 Advocate® 27

DEMODE X MITES Demodex canis causes the threatening demodicosis on dogs. But demodicosis can be also a multi-factorial disease and any underlying disease should be identified and treated appropriately. Demodex is often transmitted from the bitch to the nursing puppies. Advocate® helps to improve the clinical symptoms ­ such as skin irritation and infections ­ and kills mites within two to four applications. From the data obtained in the field study shown, it can be concluded that a single dose of Advocate® administered 2­4 times at 4 week intervals is efficacious and leads to an improvement of clinical symptoms.

Overall treatment success of Advocate® spot-on versus selamectin against Sarcoptes scabiei var. canis on naturally infected dogs

100 Overall treatment success (%) 90 80 70 60 50 40 30 20 10 0

6.7 7.1 66.7 66.7 92.9 100

Group 1 (n=15) selamectin Group 2 (n=14) imidacloprid/moxidectin (Advocate®, Bayer)

Efficacy of Advocate® against Otodectes cynotis in cats; mite counts and clinical cure

Parameter Number of cats Percentage efficacy: proportion of cats showing no ear mites After 28 ± 2 days 85.711 100.00

1

Clinical efficacy of Advocate® in reducing Demodex-induced skin lesions on dogs.

Mean Demodex-induced skin lesions (DSLS)1 Day 0 (pre-treatment) Day 28 Day 56 Day 84 Day 112 % of diseased body surface area (DBSA)2 Day 0 (pre-treatment) Day 28 Day 56 Scoring Advocate® treatment at 4 week interval 8.8 5.3 3.2 4.4 2.9 Scoring Advocate® treatment at 4 week interval 32.3 22.7 14.7 19.2 15.9 Scoring Milbemycin oxime treatment daily 8.4 4.7 2.2 2.3 3.1 Scoring Milbemycin oxime treatment daily 27.5 21.4 10.9 11.9 21.7

Advocate® 28

Day+22

Day+50

Day+64

Day 56 (±2 days)

Frequency of occurence (%)

1 O t i t i s e x te r na para sitica, debris in the ear canal of a cat with Otodectes cynotis infestation 2 And after successful treatment with Advocate®

Cumulative efficacy after 56 ± 2 days Mean Otodectes-included lesion score Day 0 Day 28 (±2 days)

Resolution of Sarcoptes scabiei var. canis skin lesions in dogs after treatment with imidacloprid/moxidectin or selamectin

100 90 80 70 60 50 40 30 20 10 0 Day+8 Day+22 Day+36 Day+50 Day+64

Group 1 (n=15) selamectin Group 2 (n=14) imidacloprid/moxidectin (Advocate®, Bayer) Lesions: Papules Crusts Hyperkeratosis

1 2

1 Significantly non-inferior to the positive control. 2 Sum of six clinical parameters each judged 0 (absent), 1 (mild), 2 (moderate), 3 (severe). Bayer internal research study, data on file.

Mean Sarcoptes-induced skin lesion scores (SSLS)2 Day 0 Day 28 (±2 days) Day 56 (±2 days) Mean percentage diseased body surface area (DBSA)2 Day 0 Day 28 (±2 days) Day 56 (±2 days) 24.74 (27 dogs) 8.22 (27 dogs) 1.52 (27 dogs) 9.59 (27 dogs) 2.22 (27 dogs) 1.00 (27 dogs)

Efficacy of Advocate® against Otodectes cynotis as a single treatment in dogs in comparison to two treatments four weeks apart

Treatment day Mites counts at day 28 p.i. Mites counts at day 56 p.i. Efficacy of Advocate® (%)

Day 84 Day 112

1 Sum of seven parameters each judged 0 (absent, 1 (mild), 2 (moderate) or 3 (severe). 2 Extent of area covered by Demodex-induced skin lesions. Bayer internal research study, data on file.

Advocate® control Advocate® control day 28 day 56 0 28 1.3 ­ 74.9 ­ ­ 0.3 ­ 17.0 98.0 ­ ­ 98.3

Bayer internal research study, data on file.

1 Sum of seven clinical parameters each judged 0 (absent), 1 (mild), 2 (moderate), 3 (severe). 2 Extent of the lesions. Bayer internal research study, data on file.

2 Fourie LJ, Du Rand C, Heine J. Evaluation of the efficacy of imidacloprid 10% / moxidectin 2.5% spot-on against Sarcoptes scabiei var. canis on dogs. Parasitol Res, 2003, 90: P. 135­136. Bayer internal research study, data on file.

meets spot-on application.

Flea control meets high speed.

V E R Y H I G H F L E A E F F I C A C Y D U E T O H I G H LY E F F E C T I V E I M I D A C L O P R I D .

Ctenocephalides felis adult

Clinical signs of FAD in a cat infested with Ctenocephalides felis.

Fleas are recognised as a major cause of skin disease in dogs and cats. However, they also act as the intermediate host for the tapeworm D. caninum and other zoonotic parasites as well. Advocate® is registered for flea control in companion animals throughout the world. Studies1 demonstrate that Advocate® offers a high level of flea control. Fleas do not have to bite; they are killed following direct contact with imidacloprid. The target ectoparasites include various species of fleas (Ctenocephalides spp.) as well as biting lice2 (Trichodectes canis) and sucking lice3 (Linognathus setosus). Diseases caused or mediated by fleas include: flea bite dermatitis, flea bite hypersensitivity or flea allergy dermatitis (FAD); transfer of Dipylidium caninum, Bartonella henselae and Mycoplasma haemofelis. Control of the surroundings as well. In addition to rapid and potent adulticidal activity against fleas present on dogs and cats, Advocate® has been shown to have significant flea larval activity, both in laboratory studies4 as well as in simulated home environments. Flea larvae are killed after contact with a pet treated with imidacloprid. This is important as immature stages present in the pets' surroundings are a reservoir of reinfestation.

1 a) Bayer internal research studies, data on file. b) Arther RG, Bowman DD, McCall JW, Hansen O, Young DR (2003) Feline Advantage Heart (Imidacloprid and Moxidectin) topical solution as monthly treatment for prevention of heartworm infection (Dirofilaria immitis) and control of fleas (Ctenocephalides felis) on cats. c) Rust MK, Hinkle NC, Waggoner M, Mencke N, Hansen O, Vaughn MB. The influence of imidacloprid on adult cat flea feeding. Suppl Compend Cont Educ Pract Vet, 2001, 23(4A): P. 18­21. 2 Registration in Europe, Australia and New Zealand. 3 Registration for sucking lice in Australia and New Zealand. 4 Mehlhorn H, Mencke N, Hansen O. Effects of imidacloprid on adult and larval stages of the flea Ctenocephalides felis after in vivo and in vitro application: a light- and electron-microscopy study. Parasitol Res, 1999, 85: P. 625­637.

Efficacy (geometric mean %) of Advocate® against fleas on cats and dogs

100 Percentage of flea reduction (%) 90 80 70 60 50 40 30 20 10 0 Day 1 Day 7 Day 14 Day 21 Day 28

Conclusion: Moxidectin did not interfere with the activity of imidacloprid to kill fleas in the combination formulation. Arther RG, Bowman DD, McCall JW, Hansen O, Young DR. Advantage Multi (imidacloprid + moxidectin) Topical Solution as monthly treatment for prevention of heartworm infection (Dirofilaria immitis) and control of fleas (Ctenocephalides felis) on cats. Parasitol Res.2003, 90:S137­S139. Bayer internal research studies, data on file. Cat Dog Cat Dog Cat Dog Cat Dog Cat Dog 100 99.8 98.9 100 98.9 99.5 97.3 99.1 97.9 97.7

1

Life cycle of Ctenocephalides felis adult egg larva emerging from egg 4 larva 5 pupa

1 2

5

3

Otodectes

Sarcoptes

Demodex

Flea

2

4

3

The smallest patients meet great reliability.

S A F E I N P U P P I E S A N D K I TT E N S . Studies were conducted in puppies and kittens to evaluate the safety of repeated dermal application of Imidacloprid. Treatment was tolerated in all groups without serious side effects1, even at the highest dosage. Even overdosages as high as 20 and 24 times the recommended label dosage in puppies and kittens, respectively, did not cause adverse effects.1 Dermal aspects: No adverse clinical signs or significant effects in cat and dog studies2. Advocate® is well tolerated at up to 10 times the maximum recommended dermal application rate.

1 a) Krämer F, Mencke N. Imidacloprid. In: Flea Biology and Control. Springer-Verlag, Berlin, Germany, 2001, p. 90­92. b) Paul AJ, Hutchens DE, Forkins LD, Borgstrom M. Dermal safety study with imidacloprid/ moxidectin topical solution in the ivermectin-sensitive collie. Veterinary Parasitology 2004, 121:285­291. 2 Cats of 4­5 months of age and dogs of 7­8 months of age were treated.

G O O D TO K N OW. Results in dogs with patent heartworm infection: No adverse effects were recorded in any of the heartworm-positive dogs treated with Advocate®, even at doses up to five times the recommended dose rate. Treatment of heartworm-positive dogs is safe. It is recommended to test dogs for heartworm infection prior to treatment. Results in ivermectin-sensitive breeds: No clinical abnormalities or adverse reactions. Harmless application up to five times the maximum recommended dose to Collies. Oral ingestion tolerance: Serious side effects were not encountered. Oral ingestion after dermal overdosing is potentially harmful to kittens. Pet owners should be instructed to employ dermal application only.

M O R E A D VA N TA G E S O F A D V O C AT E ® . Brief contact of the animal with water on one or two occasions between monthly treatments is unlikely to significantly reduce the efficacy of the product. Simple-to-use spot-on application. Monthly flea and nematode treatment aids in protecting pets and families against potentially zoonotic diseases, including Toxocariasis.

Advocate® and water exposure

Treatment group

1 2 3 4

Time of water exposure (after treatment)

1 hour 4 hours & at 7, 14, 21, 28 days 4 hours 24 hours

Type of water exposure

simulated swimming or rain simulated swimming or rain bathed/ shampooed bathed/ shampooed

Efficacy (% heartworm prevention)

100 100 100 100

Bayer internal research study, data on file.

Advocate : All-rounder meets specialist.

S U M M A R I S E D F E AT U R E S F O R D O G S . S U M M A R I S E D F E AT U R E S F O R C AT S .

®

Registered Indications worldwide

Advocate® Stronghold® Program® Plus Advantage Multi® Revolution Sentinel

Registered Indications worldwide

Advocate® Stronghold® Advantage Multi® Revolution

Flea Hookworm adult Hookworm larvae Roundworm adult Roundworm larvae Whipworm adult Heartworm Angiostrongylus vasorum1, 2 Otodectes

3

· · · · · ·

1

Prevention strategy: One single dosage applied spot-on protects dogs against common ecto- and endoparasites including larval stages. Applicable for puppies from the age of 7 weeks on. Suitable for breeds with high sensitivity to Ivermectin. Stable efficacy after short contact with water (1­2 times per month). High efficacy and fast activity of Advocate® are confirmed by numerous clinical studies4. Advocate® combines very high comfort for the dog and easy application for the pet owner.

· · · · · ·

Flea Hookworm adult Hookworm larvae Roundworm adult Roundworm larvae Heartworm

· · ·

1

Prevention strategy: Just one dosage per month applied spot-on protects cats against most ectoparasites and endoparasites including larval stages. Applicable for kittens from the age of 9 weeks on. High efficacy and fast activity of Advocate® are confirmed by numerous clinical studies6. Advocate® offers treatment and prevention of lots of important parasites in cats and dogs. Advocate® is ideal for prevention and therapy. Advocate® ­ The Endectocide which stops worms, fleas, heartworm and several mites in one.

2

2

3

Otodectes

Louse

4

· · ·

3

4

5

Sarcoptes3 Demodex3 Louse5

5

6

6 a) Rust MK, Hinkle NC, Waggoner M, Mencke N, Hansen O, Vaughn MB. The influence of imidacloprid on adult cat flea feeding. Suppl Compend Cont Educ Pract Vet, 2001, 23(4A): P. 18­21. b) Arther RG, Bowman DD, McCall JW, Hansen O, Young DR. (2003) Feline Advantage Heart (Imidacloprid and Moxidectin) topical solution as monthly treatment for prevention of heartworm infection (Dirofilaria immitis) and control of fleas (Ctenocephalides felis) on cats. c) Fourie LJ, Kok DJ, Heine J (2003) Evaluation of the efficacy of an imidacloprid 10%/moxidectin 1% spot-on against Otodectes cynotis in cats. Parasitol Res 90: P. 112­113. d) Hellmann K, Knoppe T, Radeloff I, Heine J. The anthelmintic efficacy and the safety of a combination of imidacloprid and moxidectin spot-on in cats and dogs under field conditions in Europe. Parasitol Res (2003) 90: P. 142­143. e) Samson-Himmestjerna GV, Epe C, Schimmel A, Heine J. Larvicidal and persistent efficacy of an imidacloprid and moxidectin topical formulation against endoparasites in cats and dogs. Parasitol Res (2003) 90: P. 114­115.

6

also known as French Heartworm Registration for A.vasorum in Europe only In the US, Advantage Multi Dog is not approved for Otodectes, Sarcoptes nor Demodex mites. a) Arther RG, Bowman DD, McCall JW, Hansen O, Young DR. (2003) Feline Advantage Heart (Imidacloprid and Moxidectin) topical solution as monthly treatment for prevention of heartworm infection (Dirofilaria immitis) and control of fleas (Ctenocephalides felis) on cats. b) Fourie LJ, Kok DJ, Heine J (2003) Evaluation of the efficacy of an imidacloprid 10%/moxidectin 2.5% spot-on against Sarcoptes scabiei var canis on dogs. Parasitol Res, 2003, 90: P. 135­136. c) Hellmann K, Knoppe T, Radeloff I, Heine J. The anthelmintic efficacy and the safety of a combination of imidacloprid and moxidectin spot-on in cats and dogs under field conditions in Europe. Parasitol Res (2003) 90: P. 142­143. d) Samson-Himmestjerna GV, Epe C, Schimmel A, Heine J. Larvicidal and persistent efficacy of an imidacloprid and moxidectin topical formulation against endoparasites in cats and dogs. Parasitol Res (2003) 90: P. 114­115. 5 Registration for lice in Europe, Australia and New Zealand.

1 2 3 4

The range of multiparasite control

Meet Advocate .

®

Advocate® Spot-on solution for cats and dogs. Composition: Advocate® for cats contains 10% imidacloprid and 1.0% moxidectin. 1 tube for cats up to 4 kg body weight contains 0.4 ml solution, containing 40 mg imidacloprid and 4.0 mg moxidectin. 1 tube for cats over 4 up to 8 kg body weight contains 0.8 ml solution, containing 80 mg imidacloprid and 8.0 mg moxidectin. Advocate® for dogs contains 10% imidacloprid and 2.5% moxidectin. One tube for dogs up to 4 kg body weight contains 0.4 ml solution, containing 40 mg imidacloprid and 10 mg moxidection. One tube for dogs over 4 up to 10 kg body weight contains 1.0 ml solution, containing 100 mg imidacloprid and 25 mg moxidectin. 1 tube for dogs over 10 up to 25 kg body weight contains 2.5 ml solution, containing 250 mg imidacloprid and 62.5 mg moxidectin. 1 tube for dogs over 25 up to 40 kg weight contains 4.0 ml solution, containing 400 mg imidacloprid and 100 mg moxidectin. 0.1% butylhydroxytoluene is added as antioxidant to all presentations. Indications for use: for dogs suffering from, or at risk from, mixed parasitic infections: for the treatment and prevention of flea infestation (Ctenocephalides felis), treatment of biting lice (Trichodectes canis), treatment of ear mite infestation (Otodectes cynotis), sarcoptic mange (caused by Sarcoptes scabiei var. canis), demodicosis (caused by Demodex canis), prevention of heartworm disease (L3 and L4 larvae of Dirofilaria immitis), treatment of Angiostrongylus vasorum, and treatment of infections with gastrointestinal nematodes (L4 larvae, immature adults and adults of Toxocara canis, Ancylostoma caninum and Uncinaria stenocephala, adults of Toxascaris leonina and Trichuris vulpis). For cats suffering from, or at risk from, mixed parasitic infections: for the treatment and prevention of flea infestation (Ctenocephalides felis), treatment of ear mite infestation (Otodectes cynotis), prevention of heartworm disease (L3 and L4 larvae of Dirofilaria immitis) and treatment of infections with gastrointestinal nematodes (L4 larvae, immature adults and adults of Toxocara cati and Ancylostoma tubaeforme). The product can be used as part of a treatment strategy for flea allergy dermatitis (FAD). Contra-indications: Do not use in puppies under 7 weeks of age and kittens under 9 weeks of age. Treatment of animals weighing less than 1 kg should be based on a risk-benefit assessment. There is limited experience on the use of the product in sick and debilitated animals, thus the product should only be used based on a risk-benefit assessment for these animals. Undesirable effects: On rare occasions reaction in dogs may include transient skin sensitivity (including pruritus, alopecia and erythema at the application site) or lethargy. Poisoning following inadvertent oral uptake in dogs is unlikely but may occur in very rare cases. In this event, neurological signs such as tremor and lethargy can occur. Treatment should be symptomatic under veterinary medical attention. There is no known specific antidote. Special warnings for target species: Care should be taken that the content of the tube or the applied dose does not come into contact with the eyes or mouth of the recipient and/or other animals. Do not allow recently treated animals to groom each other. As with any product containing macrocyclic lactones, oral uptake by Collies, Old English Sheepdogs and related breeds or crossbreeds should be prevented. Withdrawal period: Not applicable. Marketing Authorisation Holder: Bayer HealthCare AG, Animal Health, D 51368 Leverkusen, Germany, www.animalhealth.bayerhealthcare.com

www.advocate-spot-on.com

Advocate® is registered under the trademark Advantage Multi® in several countries such as the USA, Canada, New Zealand and Central America.

Information

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