Bravecto Plus Spot-On For Cats

Bravecto® Spot-on Solution for Cats and Dogs

Qualitative and quantitative composition

Each ml contains 280 mg fluralaner.

Each pipette delivers:

For the full list of excipients, see 'Pharmaceutical particulars' section.

Pharmaceutical form

Spot on solution.

Clear colourless to yellow solution.

Clinical particulars

Target species:

Cats and Dogs.

Indications for use:

For the treatment of tick and flea infestations in cats and dogs.

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.

Dogs:

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

In both cats and dogs:

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).

Contraindications:

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

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.

Special precautions for use:

Cats:

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 veternary medicinal product should not be used on kitten less than 11 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.

Dogs:

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 2kg.

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

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

Operator warnings:

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 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. Contact may occur either directly, when handling the product, or when handling the treated animal. In order to avoid contact, disposable protective gloves provided with this product must be worn when handling and administering the product.

If skin contact does occur, wash the affected area immediately with soap and water. In some cases, soap and water is not sufficient to remove the product spilled on the fingers, therefore gloves must be used.

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.

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

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.

Hypersensitivity reactions to the product have been reported in a small number of people. The product should not be used by persons with a hypersensitivity to the active substance or to any of the excipients (see contraindications, section 4.3). 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.

Adverse Reactions:

Cats:

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 shorterly after administration were observed:

apathy/tremors/anorexia (0.9% of treated cats) or vomiting/hypersalivation (0.4% of treated cats).

Dogs:

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).

Cats and Dogs:

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).

Use during pregnancy or lactation:

Cats:

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.

Dogs:

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.

Interactions:

None known.

Fluralaner is highly bound to plasma proteins and might compete with other highly bound medicinal products such as non-steroidal and 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 or cats and routinely used veterinary medicinal products were observed.

Amounts to be administered and administration route:

For spot-on use.

Cats:

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

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 bodyweight.

Treatment Schedule:

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

Dogs:

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

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

Method of administration to dogs:

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 dorsalline from the shoulder to the base of the tail. Avoid the application of more than 1 ml of solution at any oen 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.

Overdose:

Cats:

No adverse reactions were observed following topical administration to kittens aged 11-13 weeks and weighing 1.2 - 1.5 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.

Dogs:

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 bodyweight) 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 bodyweight). No treatment-related clinical signs were observed.

Withdrawal periods:

Not applicable.

Pharmacological particulars

Pharmacotherapeutic group: Ectoparasiticides for systemic use.

ATCvet code: QP53B E02

Pharmacodynamic properties

Fluralaner is an acaricide and insecticide.

In cats:

In dogs:

In cats and dogs:

Fluralaner has a high potency against ticks and fleas by exposure via feeding, ie 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), phenylprazoles (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 and dogs have access.

Newly emerged fleas on a dog or cat are killed before viable eggs are produced. An in vitro study also demonstrated that very low concentrations of fluaralaner 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.

Pharmacokinetic particulars

Cats:

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 flurarlaner for the duration of the inter-dosing interval. Unchanged fluralaner is excreted in faeces and to a very low extent in urine.

Dogs:

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 conentrations 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 flurarlaner is excreted in faeces and to a very low extent in urine.

Pharmaceutical particulars

Excipients:

Dimethylacetamide, Glycofurol, Diethyltoluamide, Acetone

Major incompatibilities:

None known.

Shelf-life:

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

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.

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.

Not all pack sizes may be marketed.

Disposal:

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

Marketing Authorisation Holder (if different from distributor)

Intervet International B.V.

Marketing Authorisation Number

Bravecto Spot-On for Cats:

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

Bravecto Spot-On for Dogs:

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 1000 mg

EU/2/13/158/030-031 1400 mg

Date of the first authorisation or date of renewal

11/02/2014

Date of revision of the text

05/2018

Any other information

For animal treatment only. Keep out of the sight and reach of children.

Legal category

Bravecto® Plus spot-on solution for cats

Qualitative and quantitative composition

Active substance:

Each ml of solution contains 280 mg fluralaner and 14 mg moxidectin.

Each pipette delivers:BRAVECTO PLUS spot-on solutionPipette content (ml)Fluralaner (mg)Moxidectin (mg)for small cats 1.2 – 2.8 kg0.4112.55.6for medium-sized cats >2.8 – 6.25 kg0.8925012.5for large cats >6.25 – 12.5 kg1.7950025

BRAVECTO PLUS spot-on solution

for small cats 1.2 – 2.8 kg

for medium-sized cats >2.8 – 6.25 kg

for large cats >6.25 – 12.5 kg

Excipient(s):

Butylhydroxytoluene 1.07 mg/ml

For the full list of excipients, see section “Pharmaceutical particulars”.

Pharmaceutical form

Spot-on solution.

Clear colourless to yellow solution.

Clinical particulars

Target Species:

Cats.

Indications for use:

For cats with, or at risk from, mixed parasitic infestations by ticks or fleas and ear mites, gastrointestinal nematodes or heartworm. The veterinary medicinal product is exclusively indicated when use against ticks or fleas and one or more of the other target parasites is indicated at the same time.

For the treatment of tick and flea infestations in cats providing 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 flea allergy dermatitis (FAD).

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

For the treatment of infections with intestinal roundworm (4th stage larvae, immature adults and adults of Toxocara cati) and hookworm (4th stage larvae, immature adults and adults of Ancylostoma tubaeforme).

For the prevention of heartworm disease caused by Dirofilaria immitis for 8 weeks.

Contra-indications:

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

Special warnings for each target species:

Ticks and fleas 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.

Cats in areas endemic for heartworm (or those which have travelled to endemic areas) may be infected with adult heartworms. No therapeutic effect against adult Dirofilaria immitis has been established. It is therefore recommended, in accordance with good veterinary practice, that animals of 6 months of age or older and living in areas where a vector exists, should be tested for existing adult heartworm infections before application of the veterinary medicinal product for the prevention of heartworm disease.

For the prevention of heartworm disease in cats that are only temporarily in endemic areas, the product should be applied before the first expected exposure to mosquitoes. The period between treatment and return from the endemic areas should not exceed 60 days.

For the treatment of infections with ear mites (Otodectes cynotis) or the gastrointestinal nematodes T. cati and A. tubaeforme, the need for, and the frequency of, re-treatment as well as the choice of the treatment (monosubstance or combination product) should be evaluated by the prescribing veterinarian.

Parasite resistance to any particular class of anthelmintic may develop following frequent, repeated use of an anthelmintic of that class under specific circumstances. The use of this veterinary medicinal product should be based on the assessment of each individual case and on local epidemiological information about the current susceptibility of the target species in order to limit the possibility of a future selection for resistance. Parasite control is recommended throughout the period of potential infestation risk.

Avoid frequent swimming or shampooing the animal because the maintenance of effectiveness of the product in these cases has not been tested.

Special precautions for use:

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, treatment of kittens less than 9 weeks of age and cats less than 1.2 kg bodyweight is not recommended.

Treatment of male breeding animals is not recommended.

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

Oral uptake of the product at the maximum recommended dose of 93 mg fluralaner + 4.65 mg moxidectin/kg body weight induced some self-limiting salivation or single incidences of vomiting immediately after administration.

It is important to apply the dose as indicated to prevent the animal from licking and ingesting the product.

Do not allow recently treated animals to groom each other.

Do not allow treated animals to come into contact with untreated animals until the application site is dry.

Operator warnings:

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 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. Contact may occur either directly, when handling the product, or when handling the treated animal. In order to avoid contact, disposable protective gloves obtained with this product at the point of sale must be worn when handling and administering the product.

If skin contact does occur, wash the affected area immediately with soap and water. In some cases, soap and water is not sufficient to remove the product spilled on the fingers, therefore gloves must be used.

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.

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

Hypersensitivity reactions to another veterinary medicinal product containing fluralaner and the same excipients as Bravecto Plus have been reported in a small number of people. The product should not be used by persons with a hypersensitivity to the active substance or to any of the excipients (see contraindications, section 4.3). 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.

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.

Adverse Reactions:

Mild and transient skin reactions at the application site (alopecia, flaking skin and pruritus) were commonly observed in clinical trials.

The following other adverse reactions were uncommonly observed in clinical trials shortly after administration: dyspnoea after licking the application site, hypersalivation, emesis, haematemesis, diarrhoea, lethargy, pyrexia, tachypnoea, mydriasis.

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)

Use during pregnancy or lactation:

The safety of the veterinary medicinal product has not been established in pregnant or lactating animals and therefore use in such animals is not recommended.

Interactions:

Macrocyclic lactones including moxidectin have been shown to be substrates for p-glycoprotein. Therefore, during treatment with Bravecto Plus, other products that can inhibit p-glycoprotein (e.g. cyclosporine, ketoconazole, spinosad, verapamil) should only be used concomitantly according to the benefit-risk assessment of the responsible veterinarian.

Amounts to be administered and administration route:

For spot-on use.

Bravecto Plus spot-on solution is available in three pipette sizes. The following table defines the size of pipette to be used according to the body weight of the cat (corresponding to a dose of 40‑94 mg fluralaner/kg body weight and 2‑4.7 mg moxidectin/kg body weight):Weight of cat (kg)Pipette size to be used1.2 – 2.8Bravecto Plus 112.5 mg + 5.6 mg spot-on solution for small cats>2.8 – 6.25Bravecto Plus 250 mg + 12.5 mg spot-on solution for medium-sized cats>6.25 – 12.5Bravecto Plus 500 mg + 25 mg spot-on solution for large cats

Weight of cat (kg)

Pipette size to be used

1.2 – 2.8

Bravecto Plus 112.5 mg + 5.6 mg spot-on solution for small cats

>2.8 – 6.25

Bravecto Plus 250 mg + 12.5 mg spot-on solution for medium-sized cats

>6.25 – 12.5

Bravecto Plus 500 mg + 25 mg spot-on solution for large cats

Within each weight band, the content of one whole pipette should be used.

For cats more than 12.5 kg, 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.

Treatment

For the concurrent treatment of infections with ear mites (Otodectes cynotis), a single dose of the product should be applied. Seek further veterinary examination (i.e. otoscopy) 28 days after treatment to determine whether there is re-infestation requiring additional treatment. The choice of the additional treatment (monosubstance or combination product) should be determined by the prescribing veterinarian.

For the concurrent treatment of infections with the gastrointestinal nematodes T. cati and A. tubaeforme, 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 and take into account the local epidemiological situation.

Where necessary, cats can be re-treated at 12-week intervals.

Cats in areas endemic for heartworm, or cats which have travelled to endemic areas, may be infected with adult heartworms. Therefore prior to application of Bravecto Plus for the concurrent prevention of infection with adult D. immitis, the advice provided in section 4.4 should be considered.

Overdose:

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 fluralaner + 4.65 mg moxidectin, 279 mg fluralaner + 13.95 mg moxidectin and 465 mg fluralaner + 23.25 mg moxidectin/kg body weight) on three occasions at shorter intervals than recommended (8-week intervals).

Withdrawal periods:

Not applicable.

Pharmacological particulars

ATC Vet Code: QP54AB52.

Pharmacotherapeutic group: Antiparasitic products, insecticides and repellents, endectocides, milbemycins.

Pharmacodynamic properties

Fluralaner

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

The onset of effect (killing effect) for ticks (I. ricinus) and fleas (C. felis) is within 48 hours after treatment.

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), cyclodienes (tick, flea), phenylpyrazoles (tick, flea), benzophenyl ureas (tick), and pyrethroids (tick).

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.

Moxidectin

Moxidectin, a semisynthetic derivative of nemadectin, belongs to the milbemycin group of macrocyclic lactones (avermectins being the other) and has parasiticidal activity against a range of internal and external parasites (including ear mites (Otodectes cynotis)). Moxidectin lacks substantial efficacy against fleas and ticks. Moxidectin is only active on larvae (L3 and L4) of Dirofilaria immitis and not on adult worms. The effect on Dirofilaria immitis larvae has been shown to last over a period of 60 days after treatment with the product.

Milbemycins and avermectins have a common mode of action that is based on the binding of ligand-gated chloride channels (glutamate-R and GABA-R). This leads to an increased membrane permeability of nematode and arthropod nerve and/or muscle cells for chloride ions and results in hyperpolarization, paralysis and death of the parasites. Binding of glutamate-gated chloride channels, which are specific to invertebrates and do not exist in mammals, is considered the main mechanism for the anthelmintic and insecticidal activity.

Pharmacokinetic particulars

Fluralaner is readily systemically absorbed from the topical administration site, reaching maximum concentrations in plasma between 3 and 21 days after administration. Fluralaner is slowly eliminated from plasma (t1/2 = 15 days) and excreted in faeces and to a very low extent in urine.

Moxidectin is readily systemically absorbed from the topical administration site, reaching maximum concentrations in plasma between 1 and 5 days after administration. Moxidectin is slowly eliminated from plasma (t1/2 = 26 days) and excreted in faeces and to a very low extent in urine.

The pharmacokinetic profiles of fluralaner and moxidectin are not affected by co-administration.

Pharmaceutical particulars

Excipients:

Butylhydroxytoluene

Dimethylacetamide

Glycofurol

Diethyltoluamide (DEET)

Acetone

Major incompatibilities:

None known.

Shelf-life:

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

Special precautions for storage:

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

Immediate packaging:

Unit dose pipette made of laminated aluminium/polypropylene foil closed with a high-density polyethylene (HDPE) cap and packed in a laminated aluminium foil sachet.

Each cardboard box contains 1 or 2 pipettes. Not all pack sizes may be marketed.

Disposal:

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

Do not allow the product to enter water courses as this may be dangerous for fish and other aquatic organisms.

Marketing Authorisation Holder (if different from distributor)

Intervet International B. V.

Marketing Authorisation Number

EU/2/18/224/001-006

Date of the first authorisation or date of renewal

Date of first authorisation: 08/05/2018

Date of revision of the text

04/07/2019.

Any other information

For animal treatment only. Keep out of the sight and reach of children.

Legal category

Bravecto® Plus spot-on solution for cats

Qualitative and quantitative composition

Active substance:

Each ml of solution contains 280 mg fluralaner and 14 mg moxidectin.

Each pipette delivers:BRAVECTO PLUS spot-on solutionPipette content (ml)Fluralaner (mg)Moxidectin (mg)for small cats 1.2 – 2.8 kg0.4112.55.6for medium-sized cats >2.8 – 6.25 kg0.8925012.5for large cats >6.25 – 12.5 kg1.7950025

BRAVECTO PLUS spot-on solution

for small cats 1.2 – 2.8 kg

for medium-sized cats >2.8 – 6.25 kg

for large cats >6.25 – 12.5 kg

Excipient(s):

Butylhydroxytoluene 1.07 mg/ml

For the full list of excipients, see section “Pharmaceutical particulars”.

Pharmaceutical form

Spot-on solution.

Clear colourless to yellow solution.

Clinical particulars

Target Species:

Cats.

Indications for use:

For cats with, or at risk from, mixed parasitic infestations by ticks or fleas and ear mites, gastrointestinal nematodes or heartworm. The veterinary medicinal product is exclusively indicated when use against ticks or fleas and one or more of the other target parasites is indicated at the same time.

For the treatment of tick and flea infestations in cats providing 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 flea allergy dermatitis (FAD).

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

For the treatment of infections with intestinal roundworm (4th stage larvae, immature adults and adults of Toxocara cati) and hookworm (4th stage larvae, immature adults and adults of Ancylostoma tubaeforme).

For the prevention of heartworm disease caused by Dirofilaria immitis for 8 weeks.

Contra-indications:

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

Special warnings for each target species:

Ticks and fleas 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.

Cats in areas endemic for heartworm (or those which have travelled to endemic areas) may be infected with adult heartworms. No therapeutic effect against adult Dirofilaria immitis has been established. It is therefore recommended, in accordance with good veterinary practice, that animals of 6 months of age or older and living in areas where a vector exists, should be tested for existing adult heartworm infections before application of the veterinary medicinal product for the prevention of heartworm disease.

For the prevention of heartworm disease in cats that are only temporarily in endemic areas, the product should be applied before the first expected exposure to mosquitoes. The period between treatment and return from the endemic areas should not exceed 60 days.

For the treatment of infections with ear mites (Otodectes cynotis) or the gastrointestinal nematodes T. cati and A. tubaeforme, the need for, and the frequency of, re-treatment as well as the choice of the treatment (monosubstance or combination product) should be evaluated by the prescribing veterinarian.

Parasite resistance to any particular class of anthelmintic may develop following frequent, repeated use of an anthelmintic of that class under specific circumstances. The use of this veterinary medicinal product should be based on the assessment of each individual case and on local epidemiological information about the current susceptibility of the target species in order to limit the possibility of a future selection for resistance. Parasite control is recommended throughout the period of potential infestation risk.

Avoid frequent swimming or shampooing the animal because the maintenance of effectiveness of the product in these cases has not been tested.

Special precautions for use:

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, treatment of kittens less than 9 weeks of age and cats less than 1.2 kg bodyweight is not recommended.

Treatment of male breeding animals is not recommended.

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

Oral uptake of the product at the maximum recommended dose of 93 mg fluralaner + 4.65 mg moxidectin/kg body weight induced some self-limiting salivation or single incidences of vomiting immediately after administration.

It is important to apply the dose as indicated to prevent the animal from licking and ingesting the product.

Do not allow recently treated animals to groom each other.

Do not allow treated animals to come into contact with untreated animals until the application site is dry.

Operator warnings:

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 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. Contact may occur either directly, when handling the product, or when handling the treated animal. In order to avoid contact, disposable protective gloves obtained with this product at the point of sale must be worn when handling and administering the product.

If skin contact does occur, wash the affected area immediately with soap and water. In some cases, soap and water is not sufficient to remove the product spilled on the fingers, therefore gloves must be used.

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.

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

Hypersensitivity reactions to another veterinary medicinal product containing fluralaner and the same excipients as Bravecto Plus have been reported in a small number of people. The product should not be used by persons with a hypersensitivity to the active substance or to any of the excipients (see contraindications, section 4.3). 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.

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.

Adverse Reactions:

Mild and transient skin reactions at the application site (alopecia, flaking skin and pruritus) were commonly observed in clinical trials.

The following other adverse reactions were uncommonly observed in clinical trials shortly after administration: dyspnoea after licking the application site, hypersalivation, emesis, haematemesis, diarrhoea, lethargy, pyrexia, tachypnoea, mydriasis.

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)

Use during pregnancy or lactation:

The safety of the veterinary medicinal product has not been established in pregnant or lactating animals and therefore use in such animals is not recommended.

Interactions:

Macrocyclic lactones including moxidectin have been shown to be substrates for p-glycoprotein. Therefore, during treatment with Bravecto Plus, other products that can inhibit p-glycoprotein (e.g. cyclosporine, ketoconazole, spinosad, verapamil) should only be used concomitantly according to the benefit-risk assessment of the responsible veterinarian.

Amounts to be administered and administration route:

For spot-on use.

Bravecto Plus spot-on solution is available in three pipette sizes. The following table defines the size of pipette to be used according to the body weight of the cat (corresponding to a dose of 40‑94 mg fluralaner/kg body weight and 2‑4.7 mg moxidectin/kg body weight):Weight of cat (kg)Pipette size to be used1.2 – 2.8Bravecto Plus 112.5 mg + 5.6 mg spot-on solution for small cats>2.8 – 6.25Bravecto Plus 250 mg + 12.5 mg spot-on solution for medium-sized cats>6.25 – 12.5Bravecto Plus 500 mg + 25 mg spot-on solution for large cats

Weight of cat (kg)

Pipette size to be used

1.2 – 2.8

Bravecto Plus 112.5 mg + 5.6 mg spot-on solution for small cats

>2.8 – 6.25

Bravecto Plus 250 mg + 12.5 mg spot-on solution for medium-sized cats

>6.25 – 12.5

Bravecto Plus 500 mg + 25 mg spot-on solution for large cats

Within each weight band, the content of one whole pipette should be used.

For cats more than 12.5 kg, 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.

Treatment

For the concurrent treatment of infections with ear mites (Otodectes cynotis), a single dose of the product should be applied. Seek further veterinary examination (i.e. otoscopy) 28 days after treatment to determine whether there is re-infestation requiring additional treatment. The choice of the additional treatment (monosubstance or combination product) should be determined by the prescribing veterinarian.

For the concurrent treatment of infections with the gastrointestinal nematodes T. cati and A. tubaeforme, 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 and take into account the local epidemiological situation.

Where necessary, cats can be re-treated at 12-week intervals.

Cats in areas endemic for heartworm, or cats which have travelled to endemic areas, may be infected with adult heartworms. Therefore prior to application of Bravecto Plus for the concurrent prevention of infection with adult D. immitis, the advice provided in section 4.4 should be considered.

Overdose:

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 fluralaner + 4.65 mg moxidectin, 279 mg fluralaner + 13.95 mg moxidectin and 465 mg fluralaner + 23.25 mg moxidectin/kg body weight) on three occasions at shorter intervals than recommended (8-week intervals).

Withdrawal periods:

Not applicable.

Pharmacological particulars

ATC Vet Code: QP54AB52.

Pharmacotherapeutic group: Antiparasitic products, insecticides and repellents, endectocides, milbemycins.

Pharmacodynamic properties

Fluralaner

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

The onset of effect (killing effect) for ticks (I. ricinus) and fleas (C. felis) is within 48 hours after treatment.

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), cyclodienes (tick, flea), phenylpyrazoles (tick, flea), benzophenyl ureas (tick), and pyrethroids (tick).

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.

Moxidectin

Moxidectin, a semisynthetic derivative of nemadectin, belongs to the milbemycin group of macrocyclic lactones (avermectins being the other) and has parasiticidal activity against a range of internal and external parasites (including ear mites (Otodectes cynotis)). Moxidectin lacks substantial efficacy against fleas and ticks. Moxidectin is only active on larvae (L3 and L4) of Dirofilaria immitis and not on adult worms. The effect on Dirofilaria immitis larvae has been shown to last over a period of 60 days after treatment with the product.

Milbemycins and avermectins have a common mode of action that is based on the binding of ligand-gated chloride channels (glutamate-R and GABA-R). This leads to an increased membrane permeability of nematode and arthropod nerve and/or muscle cells for chloride ions and results in hyperpolarization, paralysis and death of the parasites. Binding of glutamate-gated chloride channels, which are specific to invertebrates and do not exist in mammals, is considered the main mechanism for the anthelmintic and insecticidal activity.

Pharmacokinetic particulars

Fluralaner is readily systemically absorbed from the topical administration site, reaching maximum concentrations in plasma between 3 and 21 days after administration. Fluralaner is slowly eliminated from plasma (t1/2 = 15 days) and excreted in faeces and to a very low extent in urine.

Moxidectin is readily systemically absorbed from the topical administration site, reaching maximum concentrations in plasma between 1 and 5 days after administration. Moxidectin is slowly eliminated from plasma (t1/2 = 26 days) and excreted in faeces and to a very low extent in urine.

The pharmacokinetic profiles of fluralaner and moxidectin are not affected by co-administration.

Pharmaceutical particulars

Excipients:

Butylhydroxytoluene

Dimethylacetamide

Glycofurol

Diethyltoluamide (DEET)

Acetone

Major incompatibilities:

None known.

Shelf-life:

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

Special precautions for storage:

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

Immediate packaging:

Unit dose pipette made of laminated aluminium/polypropylene foil closed with a high-density polyethylene (HDPE) cap and packed in a laminated aluminium foil sachet.

Each cardboard box contains 1 or 2 pipettes. Not all pack sizes may be marketed.

Disposal:

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

Do not allow the product to enter water courses as this may be dangerous for fish and other aquatic organisms.

Marketing Authorisation Holder (if different from distributor)

Intervet International B. V.

Marketing Authorisation Number

EU/2/18/224/001-006

Date of the first authorisation or date of renewal

Date of first authorisation: 08/05/2018

Date of revision of the text

04/07/2019.

Any other information

For animal treatment only. Keep out of the sight and reach of children.

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