Bravecto - summary of medicine characteristics

ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

• 1. NAME OF THE VETERINARY MEDICINAL PRODUCT

Bravecto 112.5 mg chewable tablets for very small dogs (2 – 4.5 kg)

Bravecto 250 mg chewable tablets for small dogs (>4.5 – 10 kg)

Bravecto 500 mg chewable tablets for medium-sized dogs (>10 – 20 kg)

Bravecto 1,000 mg chewable tablets for large dogs (>20 – 40 kg)

Bravecto 1,400 mg chewable tablets for very large dogs (>40 – 56 kg)

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Active substance:

Each chewable tablet contains:

Bravecto chewable tablets	Fluralaner (mg)
for very small dogs (2 – 4.5 kg)	112.5
for small dogs (>4.5 – 10 kg)	250
for medium-sized dogs (>10 – 20 kg)	500
for large dogs (>20 – 40 kg)	1,000
for very large dogs (>40 – 56 kg)	1,400

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Chewable tablet.

Light to dark brown tablet with a smooth or slightly rough surface and circular shape. Some marbling, speckles or both may be visible.

4. CLINICAL PARTICULARS4.1 Target species

Dogs

• 4.2 Indications for use, specifying the target species

For the treatment of tick and flea infestations in dogs.

This veterinary medicinal product is a systemic insecticide and acaricide that provides:

• – immediate and persistent flea (Ctenocephalides felis ) killing activity for 12 weeks,

• – immediate and persistent tick killing activity for 12 weeks for Ixodes ricinus, Dermacentor reticulatus and D. variabilis,

• – immediate and persistent tick killing activity for 8 weeks for Rhipicephalus sanguineus.

Fleas and ticks must attach to the host and commence feeding in order to be exposed to the active substance. The onset of effect is within 8 hours of attachment for fleas (C. felis ) and 12 hours of attachment for ticks (I. ricinus ).

The product can be used as part of a treatment strategy for the control of flea allergy dermatitis (FAD).

For the treatment of demodicosis caused by Demodex canis.

For the treatment of sarcoptic mange (Sarcoptes scabiei var. canis ) infestation.

4.3 Contraindications

Do not use in cases of hypersensitivity to the active substance or to any of the excipients.

• 4.4 Special warnings for each target species

Parasites need to start feeding on the host to become exposed to fluralaner; therefore the risk of the transmission of parasite borne diseases cannot be excluded.

• 4.5 Special precautions for use

Special precautions for use in animals

Use with caution in dogs with pre-existing epilepsy.

In the absence of available data, the veterinary medicinal product should not be used on puppies less than 8 weeks old and /or dogs weighing less than 2 kg.

The product should not be administered at intervals shorter than 8 weeks as the safety for shorter intervals has not been tested.

Special precautions to be taken by the person administering the veterinary medicinal product to animals

Keep the product in the original packaging until use, in order to prevent children from getting direct access to the product.

Hypersensitivity reactions in humans have been reported.

Do not eat, drink or smoke while handling the product.

Wash hands thoroughly with soap and water immediately after use of the product.

• 4.6 Adverse reactions (frequency and seriousness)

Mild and transient gastrointestinal effects such as diarrhoea, vomiting, inappetence, and drooling were commonly observed in clinical trials (1.6% of treated dogs).

Lethargy, muscle tremor, ataxia and convulsions have been reported very rarely in spontaneous reports.

Most reported adverse reactions were self-limiting and of short duration.

The frequency of adverse reactions is defined using the following convention:

• – very common (more than 1 in 10 animals treated displaying adverse reaction(s))

• – common (more than 1 but less than 10 animals in 100 animals treated)

• – uncommon (more than 1 but less than 10 animals in 1,000 animals treated)

• – rare (more than 1 but less than 10 animals in 10,000 animals treated)

• – very rare (less than 1 animal in 10,000 animals treated, including isolated reports).

• 4.7 Use during pregnancy, lactation or lay

The safety of the veterinary medicinal product in breeding, pregnant and lactating dogs has been demonstrated. Can be used in breeding, pregnant and lactating dogs.

4.8 Interaction with other medicinal products and other forms of interaction

Fluralaner is highly bound to plasma proteins and might compete with other highly bound active substances such as non-steroidal anti-inflammatory drugs (NSAIDs) and the coumarin derivative warfarin. Incubation of fluralaner in the presence of carprofen or warfarin in dog plasma at maximum expected plasma concentrations did not reduce the protein binding of fluralaner, carprofen or warfarin.

During clinical field testing, no interactions between Bravecto chewable tablets for dogs and routinely used veterinary medicinal products were observed.

• 4.9 Amounts to be administered and administration route

For oral use.

Bravecto should be administered in accordance with the following table (corresponding to a dose of 25 – 56 mg fluralaner/kg bodyweight within one weight band):

Bodyweight of dog (kg)	Strength and number of tablets to be administered
	Bravecto 112.5 mg	Bravecto 250 mg	Bravecto 500 mg	Bravecto 1,000 mg	Bravecto 1,400 mg
2 – 4.5	1
>4.5 – 10		1
>10 – 20			1
>20 – 40				1
>40 – 56					1

The chewable tablets should not be broken or divided.

For dogs above 56 kg body weight, use a combination of two tablets that most closely matches the bodyweight.

Method of administration

Administer Bravecto chewable tablets at or around the time of feeding.

Bravecto is a chewable tablet and is well accepted by most dogs. If the tablet is not taken up voluntarily by the dog it can also be given with food or directly into the mouth. The dog should be observed during administration to confirm that the tablet is swallowed.

Treatment schedule

For optimal control of flea infestation, the veterinary medicinal product should be administered at intervals of 12 weeks. For optimal control of tick infestation, the timing of retreatment depends on the tick species. See section 4.2.

For the treatment of Demodex canis mite infestations, a single dose of the product should be administered. As demodicosis is a multi-factorial disease, it is advisable to also treat any underlying disease appropriately.

For the treatment of sarcoptic mange infestations (Sarcoptes scabiei var. canis) , a single dose of the product should be administered. The need for and frequency of re-treatment should be in accordance with the advice of the prescribing veterinarian.

4.10 Overdose (symptoms, emergency procedures, antidotes), if necessary

No adverse reactions were observed following oral administration to puppies aged 8 – 9 weeks and weighing 2.0 – 3.6 kg treated with overdoses of up to 5 times the maximum recommended dose (56 mg, 168 mg and 280 mg fluralaner/kg body weight) on three occasions at shorter intervals than recommended (8-week intervals).

There were no findings on reproductive performance and no findings of concern on offspring viability when fluralaner was administered orally to Beagle dogs at overdoses of up to 3 times the maximum recommended dose (up to 168 mg/kg body weight of fluralaner).

The veterinary medicinal product was well tolerated in Collies with a deficient multidrug-resistance-protein 1 (MDR1 -/-) following single oral administration at 3 times the recommended dose (168 mg/kg body weight). No treatment-related clinical signs were observed.

• 4.11 Withdrawal period(s)

5. PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Ectoparasiticides for systemic use. ATCvet code: QP53BE02.

5.1 Pharmacodynamic properties

Fluralaner is an acaricide and insecticide. It is efficacious against ticks (Ixodes spp., Dermacentor spp. and Rhipicephalus sanguineus ), fleas (Ctenocephalides spp. ), Demodex canis mites and sarcoptic mange (Sarcoptes scabiei var. canis ) on the dog.

Fluralaner has a high potency against ticks and fleas by exposure via feeding, i.e. it is systemically active on target parasites.

Fluralaner is a potent inhibitor of parts of the arthropod nervous system by acting antagonistically on ligand-gated chloride channels (GABA-receptor and glutamate-receptor).

In molecular on-target studies on insect GABA receptors of flea and fly, fluralaner is not affected by dieldrin resistance.

In in vitro bio-assays, fluralaner is not affected by proven field resistances against amidines (tick), organophosphates (tick, mite), cyclodienes (tick, flea, fly), macrocyclic lactones (sea lice), phenylpyrazoles (tick, flea), benzophenyl ureas (tick), pyrethroids (tick, mite) and carbamates (mite).

The product contributes towards the control of the environmental flea populations in areas to which treated dogs have access.

Newly emerged fleas on a dog are killed before viable eggs are produced. An in vitro study also demonstrated that very low concentrations of fluralaner stop the production of viable eggs by fleas. The flea life cycle is broken due to the rapid onset of action and long lasting efficacy against adult fleas on the animal and the absence of viable egg production.

• 5.2 Pharmacoki­netic particulars

Following oral administration, fluralaner is readily absorbed reaching maximum plasma concentrations within 1 day. Food enhances the absorption. Fluralaner is systemically distributed and reaches the highest concentrations in fat, followed by liver, kidney and muscle. The prolonged persistence and slow elimination from plasma (t1/2 = 12 days) and the lack of extensive metabolism provide effective concentrations of fluralaner for the duration of the inter-dosing interval. Individual variation in Cmax and t1/2 was observed. The major route of elimination is the excretion of unchanged fluralaner in faeces (~90% of the dose). Renal clearance is the minor route of elimination.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Pork liver flavour

Sucrose

Maize starch

Sodium lauryl sulfate

Disodium embonate monohydrate

Magnesium stearate

Aspartame

Glycerol

Soya-bean oil

Macrogol 3350

6.2 Major incompatibilities

None known.

6.3 Shelf life

Shelf life of the veterinary medicinal product as packaged for sale: 2 years.

6.4. Special precautions for storage

This veterinary medicinal product does not require any special storage conditions.

• 6.5 Nature and composition of immediate packaging

Cardboard box with 1 aluminium foil blister sealed with PET aluminium foil lid stock containing 1, 2 or 4 chewable tablets.

Not all pack sizes may be marketed.

• 6.6 Special precautions for the disposal of unused veterinary medicinal product or waste materials derived from the use of such products

Any unused veterinary medicinal product or waste materials derived from such veterinary medicinal products should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

Intervet International B. V.

Wim de Korverstraat 35

5831 AN Boxmeer

The Netherlands

8. MARKETING AUTHORISATION NUMBER(S)

EU/2/13/158/001–015

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 11/02/2014

Date of last renewal: 05/02/2019

10. DATE OF REVISION OF THE TEXT

{MM/YYYY}

Detailed information on this veterinary medicinal product is available on the website of the European

Medicines Agency.

PROHIBITION OF SALE, SUPPLY AND/OR USE

• 1. NAME OF THE VETERINARY MEDICINAL PRODUCT

Bravecto 112.5 mg spot-on solution for very small dogs (2 – 4.5 kg)

Bravecto 250 mg spot-on solution for small dogs (>4.5 – 10 kg)

Bravecto 500 mg spot-on solution for medium-sized dogs (>10 – 20 kg)

Bravecto 1,000 mg spot-on solution for large dogs (>20 – 40 kg)

Bravecto 1,400 mg spot-on solution for very large dogs (>40 – 56 kg)

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Active substance:

Each ml contains 280 mg fluralaner.

Each pipette delivers:

	Pipette content (ml)	Fluralaner (mg)
for very small dogs 2 – 4.5 kg	0.4	112.5
for small dogs >4.5 – 10 kg	0.89	250
for medium-sized dogs >10 – 20 kg	1.79	500
for large dogs >20 – 40 kg	3.57	1,000
for very large dogs >40 – 56 kg	5.0	1,400

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Spot-on-solution.

Clear colourless to yellow solution.

4. CLINICAL PARTICULARS4.1 Target species

Dogs.

• 4.2 Indications for use, specifying the target species

For the treatment of tick and flea infestations in dogs.

This veterinary medicinal product is a systemic insecticide and acaricide that provides:

• – immediate and persistent flea (Ctenocephalides felis and Ctenocephalides canis ) killing activity for 12 weeks, and

• – immediate and persistent tick (Ixodes ricinus, Rhipicephalus sanguineus and Dermacentor reticulatus ) killing activity for 12 weeks.

Fleas and ticks must attach to the host and commence feeding in order to be exposed to the active substance.

The product can be used as part of a treatment strategy for the control of flea allergy dermatitis (FAD).

For the treatment of demodicosis caused by Demodex canis.

For the treatment of sarcoptic mange (Sarcoptes scabiei var. canis ) infestation.

4.3 Contraindications

Do not use in cases of hypersensitivity to the active substance or to any of the excipients.

• 4.4 Special warnings for each target species

Parasites need to start feeding on the host to become exposed to fluralaner; therefore the risk of the transmission of parasite borne diseases cannot be excluded.

• 4.5 Special precautions for use

Special precautions for use in animals

Care should be taken to avoid contact with the eyes of the animal.

Do not use directly on skin lesions.

Do not wash or allow the dog to become immersed in water or swim in water courses within 3 days after treatment.

In the absence of available data, this veterinary medicinal product should not be used on puppies less than 8 weeks old and /or dogs weighing less than 2 kg.

The product should not be administered at intervals shorter than 8 weeks as the safety at shorter intervals has not been tested.

This product is for topical use and should not be administered orally.

Special precautions to be taken by the person administering the veterinary medicinal product to animals

Contact with the product should be avoided and disposable protective gloves obtained with this product at the point of sale must be worn when handling the product for the following reasons: Hypersensitivity reactions have been reported in a small number of people, which can potentially be serious.

Persons with a hypersensitivity to fluralaner or to any of the excipients should avoid any exposure to the product.

The product binds to skin and may also bind to surfaces after spillage of the product. Skin rashes, tingling or numbness have been reported in a small number of individuals after skin contact.

If skin contact does occur, wash the affected area immediately with soap and water. In some cases, soap and water are not sufficient to remove the product spilled on the fingers.

Contact with the product may also occur when handling the treated animal.

Make sure that your animal’s appli­cation site is no longer noticeable before resuming contact with the site of application. This includes cuddling the animal and sharing a bed with the animal. It takes up to 48 hours for the application site to become dry but it will be noticeable for longer.

If skin reactions occur, consult a physician and show them the product packaging.

People with a sensitive skin or known allergy in general e.g. to other veterinary medicinal products of this type should handle the veterinary medicinal product as well as treated animals with caution.

This product can cause eye irritation. In case of contact with the eyes, immediately rinse thoroughly with water.

This product is harmful after ingestion. Keep the product in the original packaging until use, in order to prevent children from getting direct access to the product. A used pipette should immediately be disposed of. In case of accidental ingestion, seek medical advice and show the package leaflet or the label to the physician.

The product is highly flammable. Keep away from heat, sparks, open flame or other sources of ignition.In case of spillage onto, for example table or floor surfaces, remove excess product using paper tissue and clean the area with detergent.

• 4.6 Adverse reactions (frequency and seriousness)

Mild and transient skin reactions such as erythema or alopecia at the application site were commonly observed in clinical trials (1.2% of treated dogs).

Emesis, lethargy and anorexia have been reported very rarely in spontaneous reports after the use of this product.

The frequency of adverse reactions is defined using the following convention:

• – very common (more than 1 in 10 animals treated displaying adverse reaction(s))

• – common (more than 1 but less than 10 animals in 100 animals treated)

• – uncommon (more than 1 but less than 10 animals in 1,000 animals treated)

• – rare (more than 1 but less than 10 animals in 10,000 animals treated)

• – very rare (less than 1 animal in 10,000 animals treated, including isolated reports).

• 4.7 Use during pregnancy, lactation or lay

The safety of the veterinary medicinal product in breeding, pregnant and lactating dogs has been demonstrated. Can be used in breeding, pregnant and lactating dogs.

4.8 Interaction with other medicinal products and other forms of interaction

None known.

Fluralaner is highly bound to plasma proteins and might compete with other highly bound active substances such as non-steroidal anti-inflammatory drugs (NSAIDs) and the coumarin derivative warfarin. Incubation of fluralaner in the presence of carprofen or warfarin in dog plasma at maximum expected plasma concentrations did not reduce the protein binding of fluralaner, carprofen or warfarin. During laboratory and clinical field testing, no interactions between Bravecto spot-on solution for dogs and routinely used veterinary medicinal products were observed.

• 4.9 Amounts to be administered and administration route

For spot-on use.

Bravecto should be administered in accordance with the following table (corresponding to a dose of 25 – 56 mg fluralaner/kg body weight):

Body weight of dog (kg)	Strength and number of pipettes to be administered
	Bravecto 112.5 mg	Bravecto 250 mg	Bravecto 500 mg	Bravecto 1,000 mg	Bravecto 1,400 mg
2 – 4.5	1
>4.5 – 10		1
>10 – 20			1
>20 – 40				1
>40 – 56					1

For dogs above 56 kg body weight, use a combination of two pipettes that most closely matches the body weight.

Method of administration

Step 1: Immediately before use, open the sachet and remove the pipette. Put on gloves. The pipette should be held by the base or by the upper rigid portion below the cap in an upright position (tip up) for opening it. The cap should be rotated clockwise or counter clockwise one full turn. The cap will stay on the pipette; it is not possible to remove it. The pipette is open and ready for application when the breaking of the seal is felt.

Step 2 : The dog should be standing or lying with its back horizontal during application. Place the pipette tip vertically against the skin between the shoulder blades of the dog.

Step 3: Squeeze the pipette gently and apply the entire contents directly to the dog’s skin in one (when volume is small) or several spots along the dog’s dorsal line from the shoulder to the base of the tail. Avoid the application of more than 1 ml of solution at any one spot as it could cause some of the solution to run or drip off the dog.

Treatment schedule

For optimal control of tick and flea infestation, the product should be administered at intervals of 12 weeks.

For the treatment of Demodex canis mite infestations, a single dose of the product should be applied. As demodicosis is a multi-factorial disease, it is advisable to also treat any underlying disease appropriately.

For the treatment of sarcoptic mange infestations (Sarcoptes scabiei var. canis ), a single dose of the product should be applied. The need for and frequency of re-treatment should be in accordance with the advice of the prescribing veterinarian.

4.10 Overdose (symptoms, emergency procedures, antidotes), if necessary

No adverse reactions were observed following topical administration to puppies aged 8 – 9 weeks and weighing 2.0 – 3.7 kg treated with overdoses of up to 5 times the maximum recommended dose (56 mg, 168 mg and 280 mg fluralaner/kg body weight) on three occasions at shorter intervals than recommended (8-week intervals).

There were no findings on reproductive performance and no findings of concern on offspring viability when fluralaner was administered orally to Beagle dogs at overdoses of up to 3 times the maximum recommended dose (up to 168 mg/kg body weight of fluralaner).

Fluralaner was well tolerated in Collies with a deficient multidrug-resistance-protein 1 (MDR1 -/-) following single oral administration at 3 times the maximum recommended dose (168 mg/kg body weight). No treatment-related clinical signs were observed.

• 4.11 Withdrawal period(s)

Not applicable.

5. PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Ectoparasiticides for systemic use.

ATCvet code: QP53B E02.

5.1 Pharmacodynamic properties

Fluralaner is an acaricide and insecticide. It is efficacious against ticks (Ixodes spp., Dermacentor spp. and Rhipicephalus sanguineus ), fleas (Ctenocephalides spp. ), Demodex canis mites and sarcoptic mange (Sarcoptes scabiei var. canis ) on the dog.

The onset of efficacy is within 8 hours for fleas (C. felis ) and 12 hours for ticks (I. ricinus ).

Fluralaner has a high potency against ticks and fleas by exposure via feeding, i.e. it is systemically active on target parasites.

Fluralaner is a potent inhibitor of parts of the arthropod nervous system by acting antagonistically on ligand-gated chloride channels (GABA-receptor and glutamate-receptor).

In molecular on-target studies on insect GABA receptors of flea and fly, fluralaner is not affected by dieldrin resistance.

In in vitro bio-assays, fluralaner is not affected by proven field resistances against amidines (tick), organophosphates (tick, mite), cyclodienes (tick, flea, fly), macrocyclic lactones (sea lice), phenylpyrazoles (tick, flea), benzophenyl ureas (tick), pyrethroids (tick, mite) and carbamates (mite).

The product contributes towards the control of the environmental flea populations in areas to which treated dogs have access.

Newly emerged fleas on a dog are killed before viable eggs are produced. An in vitro study also demonstrated that very low concentrations of fluralaner stop the production of viable eggs by fleas. The flea life cycle is broken due to the rapid onset of action and long lasting efficacy against adult fleas on the animal and the absence of viable egg production.

• 5.2 Pharmacoki­netic particulars

Fluralaner is readily absorbed from the topical administration site into the hair, skin and subjacent tissues, from where it is slowly absorbed into the vascular system. A plateau is seen in plasma between 7 and 63 days post administration, after which concentrations decline slowly. The prolonged persistence and slow elimination from plasma (t1/2 = 21 days) and the lack of extensive metabolism provide effective concentrations of fluralaner for the duration of the inter-dosing interval. Unchanged fluralaner is excreted in feces and to a very low extent in urine.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Dimethylacetamide

Glycofurol

Diethyltoluamide (DEET)

Acetone

6.2 Major incompatibilities

None known.

6.3 Shelf life

Shelf life of the veterinary medicinal product as packaged for sale:

Bravecto 112.5 mg spot-on solution: 2 years

Bravecto 250 mg / 500 mg / 1,000 mg / 1,400 mg spot-on solution: 3 years

6.4. Special precautions for storage

This veterinary medicinal product does not require any special temperature storage conditions. The pipettes should be kept in the outer packaging to prevent solvent loss or moisture uptake. The sachets should only be opened immediately prior to use.

• 6.5 Nature and composition of immediate packaging

Unit dose pipette made of laminated aluminium/poly­propylene foil closed with an HDPE cap and packed in a laminated aluminium foil sachet. Each carton box contains 1 or 2 pipettes and a pair of gloves per pipette.

Not all pack sizes may be marketed.

• 6.6 Special precautions for the disposal of unused veterinary medicinal product or waste

materials derived from the use of such products

Any unused veterinary medicinal product or waste materials derived from such veterinary medicinal product should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

Intervet International B. V.

Wim de Korverstraat 35

5831 AN Boxmeer

The Netherlands

8. MARKETING AUTHORISATION NUMBER(S)

EU/2/13/158/016–017   112.5 mg

EU/2/13/158/020–021   250 mg

EU/2/13/158/024–025   500 mg

EU/2/13/158/028–029   1,000 mg

EU/2/13/158/030–031   1,400 mg

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 11/02/2014

Date of last renewal: 05/02/2019

10. DATE OF REVISION OF THE TEXT

{MM/YYYY}

Detailed information on this veterinary medicinal product is available on the website of the European

Medicines Agency.

PROHIBITION OF SALE, SUPPLY AND/OR USE

Not applicable.

• 1. NAME OF THE VETERINARY MEDICINAL PRODUCT

Bravecto 112.5 mg spot-on solution for small cats (1.2 – 2.8 kg)

Bravecto 250 mg spot-on solution for medium-sized cats (>2.8 – 6.25 kg)

Bravecto 500 mg spot-on solution for large cats (>6.25 – 12.5 kg)

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Active substance:

Each ml contains 280 mg fluralaner.

Each pipette delivers:

	Pipette content (ml)	Fluralaner (mg)
for small cats 1.2 – 2.8 kg	0.4	112.5
for medium-sized cats >2.8 – 6.25 kg	0.89	250
for large cats >6.25 – 12.5 kg	1.79	500

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Spot-on-solution.

Clear colourless to yellow solution.

4. CLINICAL PARTICULARS4.1 Target species

Cats.

• 4.2 Indications for use, specifying the target species

For the treatment of tick and flea infestations in cats.

This veterinary medicinal product is a systemic insecticide and acaricide that provides immediate and persistent flea (Ctenocephalides felis ) and tick (Ixodes ricinus) killing activity for 12 weeks.

Fleas and ticks must attach to the host and commence feeding in order to be exposed to the active substance.

The product can be used as part of a treatment strategy for the control of flea allergy dermatitis (FAD).

For the treatment of infestations with ear mites (Otodectes cynotis ).

4.3 Contraindications

Do not use in cases of hypersensitivity to the active substance or to any of the excipients.

• 4.4 Special warnings for each target species

Parasites need to start feeding on the host to become exposed to fluralaner; therefore the risk of the transmission of parasite borne diseases cannot be excluded.

• 4.5 Special precautions for use

Special precautions for use in animals

Care should be taken to avoid contact with the eyes of the animal. Do not use directly on skin lesions.

In the absence of available data, this veterinary medicinal product should not be used on kittens less than 9 weeks old and /or cats weighing less than 1.2 kg.

The product should not be administered at intervals shorter than 8 weeks as the safety at shorter intervals has not been tested.

This product is for topical use and should not be administered orally.

Do not allow recently treated animals to groom each other.

Special precautions to be taken by the person administering the veterinary medicinal product to animals

Contact with the product should be avoided and disposable protective gloves obtained with this product at the point of sale must be worn when handling the product for the following reasons: Hypersensitivity reactions have been reported in a small number of people, which can potentially be serious.

Persons with a hypersensitivity to fluralaner or to any of the excipients should avoid any exposure to the product.

The product binds to skin and may also bind to surfaces after spillage of the product. Skin rashes, tingling or numbness have been reported in a small number of individuals after skin contact.

If skin contact does occur, wash the affected area immediately with soap and water. In some cases, soap and water are not sufficient to remove the product spilled on the fingers.

Contact with the product may also occur when handling the treated animal.

Make sure that your animal’s appli­cation site is no longer noticeable before resuming contact with the site of application. This includes cuddling the animal and sharing a bed with the animal. It takes up to 48 hours for the application site to become dry but it will be noticeable for longer.

If skin reactions occur, consult a physician and show them the product packaging.

People with a sensitive skin or known allergy in general e.g. to other veterinary medicinal products of this type should handle the veterinary medicinal product as well as treated animals with caution.

This product can cause eye irritation. In case of contact with the eyes, immediately rinse thoroughly with water.

This product is harmful after ingestion. Keep the product in the original packaging until use, in order to prevent children from getting direct access to the product. A used pipette should immediately be disposed of. In case of accidental ingestion, seek medical advice and show the package leaflet or the label to the physician.

The product is highly flammable. Keep away from heat, sparks, open flame or other sources of ignition.In case of spillage onto, for example table or floor surfaces, remove excess product using paper tissue and clean the area with detergent.

• 4.6 Adverse reactions (frequency and seriousness)

Mild and transient skin reactions at the application site, such as erythema and pruritus or alopecia were commonly observed in clinical trials (2.2% of treated cats).

The following other signs shortly after administration were uncommonly observed: apathy/tremor­s/anorexia (0.9% of treated cats) or vomiting/hyper­salivation (0.4% of treated cats).

Convulsions have been reported very rarely based on post marketing safety experience (pharmacovigi­lance).

The frequency of adverse reactions is defined using the following convention:

• – very common (more than 1 in 10 animals treated displaying adverse reaction(s))

• – common (more than 1 but less than 10 animals in 100 animals treated)

• – uncommon (more than 1 but less than 10 animals in 1,000 animals treated)

• – rare (more than 1 but less than 10 animals in 10,000 animals treated)

• – very rare (less than 1 animal in 10,000 animals treated, including isolated reports)

• 4.7 Use during pregnancy, lactation or lay

The safety of the veterinary medicinal product has not been established during pregnancy and lactation. Use only accordingly to the benefit/risk assessment by the responsible veterinarian.

4.8 Interaction with other medicinal products and other forms of interaction

None known.

Fluralaner is highly bound to plasma proteins and might compete with other highly bound active substances such as non-steroidal anti-inflammatory drugs (NSAIDs) and the coumarin derivative warfarin. Incubation of fluralaner in the presence of carprofen or warfarin in dog plasma at maximum expected plasma concentrations did not reduce the protein binding of fluralaner, carprofen or warfarin. During laboratory and clinical field testing, no interactions between Bravecto spot-on solution for cats and routinely used veterinary medicinal products were observed.

• 4.9 Amounts to be administered and administration route

For spot-on use.

Bravecto should be administered in accordance with the following table (corresponding to a dose of 40 – 94 mg fluralaner/kg body weight):

Body weight of cat (kg)	Strength and number of pipettes to be administered
	Bravecto 112.5 mg	Bravecto 250 mg	Bravecto 500 mg
1.2 – 2.8	1
>2.8 – 6.25		1
>6.25 – 12.5			1

For cats above 12.5 kg body weight, use a combination of two pipettes that most closely matches the body weight.

Method of administration

Step 1: Immediately before use, open the sachet and remove the pipette. Put on gloves. The pipette should be held by the base or by the upper rigid portion below the cap in an upright position (tip up) for opening it. The twist-and-use cap should be rotated clockwise or counter clockwise one full turn. The cap will stay on the pipette; it is not possible to remove it. The pipette is open and ready for application when the breaking of the seal is felt.

Step 2 : The cat should be standing or lying with its back horizontal for easy application. Place the pipette tip on the base of the skull of the cat.

Step 3: Squeeze the pipette gently and apply the entire contents directly to the cat’s skin. The product should be applied on cats up to 6.25 kg body weight in one spot at the base of the skull and in two spots on cats greater than 6.25 kg body weight.

Treatment schedule

For optimal control of tick and flea infestation, the product should be administered at intervals of 12 weeks.

For the treatment of ear mite infestations (Otodectes cynotis) , a single dose of the product should be applied. A further veterinary examination 28 days after treatment is recommended as some animals may require further treatment with an alternative product.

4.10 Overdose (symptoms, emergency procedures, antidotes), if necessary

No adverse reactions were observed following topical administration to kittens aged 9 – 13 weeks and weighing 0.9 – 1.9 kg treated with overdoses of up to 5 times the maximum recommended dose (93 mg, 279 mg and 465 mg fluralaner/kg body weight) on three occasions at shorter intervals than recommended (8-week intervals).

Oral uptake of the product at the maximum recommended dose of 93 mg fluralaner/kg body weight was well tolerated in cats, apart from some self-limiting salivation and coughing or vomiting immediately after administration.

• 4.11 Withdrawal period(s)

Not applicable.

5. PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Ectoparasiticides for systemic use

ATCvet code: QP53B E02

5.1 Pharmacodynamic properties

Fluralaner is an acaricide and insecticide. It is efficacious against ticks (Ixodes spp.), fleas (Ctenocephalides spp. ) and ear mites (Otodectes cynotis ) on the cat.

The onset of efficacy is within 12 hours for fleas (C. felis ) and within 48 hours for ticks (I. ricinus ).

Fluralaner has a high potency against ticks and fleas by exposure via feeding, i.e. it is systemically active on target parasites.

Fluralaner is a potent inhibitor of parts of the arthropod nervous system by acting antagonistically on ligand-gated chloride channels (GABA-receptor and glutamate-receptor).

In molecular on-target studies on insect GABA receptors of flea and fly, fluralaner is not affected by dieldrin resistance.

In in vitro bio-assays, fluralaner is not affected by proven field resistances against amidines (tick), organophosphates (tick, mite), cyclodienes (tick, flea, fly), macrocyclic lactones (sea lice), phenylpyrazoles (tick, flea), benzophenyl ureas (tick), pyrethroids (tick, mite) and carbamates (mite).

The product contributes towards the control of the environmental flea populations in areas to which treated cats have access.

Newly emerged fleas on a cat are killed before viable eggs are produced. An in vitro study also demonstrated that very low concentrations of fluralaner stop the production of viable eggs by fleas. The flea life cycle is broken due to the rapid onset of action and long lasting efficacy against adult fleas on the animal and the absence of viable egg production.

• 5.2 Pharmacoki­netic particulars

Fluralaner is readily systemically absorbed from the topical administration site, reaching maximum concentrations in plasma between 3 and 21 days after administration. The prolonged persistence and slow elimination from plasma (t1/2 = 12 days) and the lack of extensive metabolism provide effective concentrations of fluralaner for the duration of the inter-dosing interval. Unchanged fluralaner is excreted in feces and to a very low extent in urine.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Dimethylacetamide

Glycofurol

Diethyltoluamide (DEET)

Acetone

6.2 Major incompatibilities

None known.

6.3 Shelf life

Shelf life of the veterinary medicinal product as packaged for sale:

Bravecto 112.5 mg spot-on solution: 2 years

Bravecto 250 mg / 500 mg spot-on solution: 3 years

6.4. Special precautions for storage

This veterinary medicinal product does not require any special temperature storage conditions. The pipettes should be kept in the outer packaging to prevent solvent loss or moisture uptake. The sachets should only be opened immediateley prior to use.

• 6.5 Nature and composition of immediate packaging

Unit dose pipette made of laminated aluminium/poly­propylene foil closed with an HDPE cap and packed in a laminated aluminium foil sachet. Each carton box contains 1 or 2 pipettes and a pair of gloves per pipette.

Not all pack sizes may be marketed.

• 6.6 Special precautions for the disposal of unused veterinary medicinal product or waste materials derived from the use of such products

7. MARKETING AUTHORISATION HOLDER

Intervet International B. V.

Wim de Korverstraat 35

5831 AN Boxmeer

The Netherlands

8. MARKETING AUTHORISATION NUMBER(S)

EU/2/13/158/018–019   112.5 mg

EU/2/13/158/022–023   250 mg

EU/2/13/158/026–027   500 mg

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 11/02/2014

Date of last renewal: 05/02/2019