Revolution Plus (Canada)

This treatment applies to the following species:

Cats

Company: Zoetis

selamectin and sarolaner topical solution

DIN 02482266

Veterinary Use Only

Parasiticide for cats

Description

REVOLUTION^® PLUS (selamectin 60 mg/mL and sarolaner 10 mg/mL) is available as a colorless to yellow, ready to use solution in single dose tubes for topical (dermal) treatment. The content of each tube is formulated to provide a minimum of 6 mg/kg (2.7 mg/lb) of body weight of selamectin and 1 mg/kg (0.45 mg/lb) of body weight of sarolaner.

Revolution Plus Indications

REVOLUTION PLUS is recommended for use in cats and kittens 8 weeks of age and older, and weighing 1.3 kg or greater, for the following indications:

- REVOLUTION PLUS kills adult fleas (Ctenocephalides felis) and is indicated for the treatment and prevention of flea infestations for 5 weeks (35 days),

- For the treatment and control of tick infestations with Ixodes scapularis (black-legged tick) and Dermacentor variabilis (American dog tick) for 5 weeks (35 days) and with Amblyomma maculatum (Gulf Coast tick) for 4 weeks (28 days),

- For the prevention of heartworm disease caused by Dirofilaria immitis,

- For the treatment and control of ear mite (Otodectes cynotis) infestations, and

- For the treatment and control of roundworm (Toxocara cati) and intestinal hookworm (Ancylostoma tubaeforme) infections.

Dosage and Administration

The recommended minimum dosage is 6 mg selamectin per kg (2.7 mg/lb) of body weight and 1 mg sarolaner per kg (0.45 mg/lb) of body weight.

REVOLUTION PLUS is applied topically on a monthly basis. REVOLUTION PLUS needs to be administered every 28 days in case of exposure to Amblyomma maculatum. In case of tick infestation, accurate tick identification is recommended prior to administering the product.

Visit https: / / biologicalsurvey.ca / public / Bsc / Controller / Page / AGR - 001 - Ticks - Monograph.pdf for more information on tick morphology and species differentiation.

Administer the entire contents of a single tube (or two tubes in combination for cats weighing over 10 kg (22 pounds)) in accordance with the following table.

Dosage Schedule:

Body Weight		Tube Volume (mL)	Tube Contents
In kg	In lbs	Tube Volume (mL)	Selamectin (mg/tube)	Sarolaner (mg/tube)
1.3 to 2.5 kg	2.8 to 5.5 lbs	0.25	15	2.5
2.6 to 5.0 kg	5.6 to 11.0 lbs	0.50	30	5.0
5.1 to 10.0 kg	11.1 to 22.0 lbs	1.00	60	10.0

*Cats over 10 kg (> 22 lbs) should be treated with the appropriate combination of tubes

Note: The amount of liquid in the tube varies for each weight range (1.3-2.5 kg, 2.6-5.0 kg and 5.1-10.0 kg). Tubes are never completely filled.

A veterinarian or veterinary technician should demonstrate or instruct the pet owner regarding the appropriate technique for topical application of REVOLUTION PLUS to cats and kittens prior to first administration.

Step 1: Firmly press the cap down to puncture the seal on the tube; a clicking sound will confirm that the cap has successfully punctured the seal. Remove the cap and check to ensure that the tip of the tube is open.

Step 2: Part the hair on the back of the animal at the base of the neck in front of the shoulder blades until the skin is visible. Place the tip of the tube on the skin and squeeze the tube 3 or 4 times to empty its entire contents directly on to the skin in one spot.

Step 3: Keeping the tube squeezed, glide it on the skin and away from the liquid, then lift. Check the tube to ensure that it is empty. Empty tubes can be discarded in your ordinary household refuse.

Important:

● Do not massage the product into the skin. Avoid contact between the product and fingers.

● Due to alcohol content, do not apply to broken or abraded skin. Do not apply when the hair coat is wet.

● Stiff hair, clumping of hair, hair discoloration, or a slight powdery residue may be observed at the treatment site in some cats. These effects are temporary and do not affect the safety or effectiveness of the product.

The effectiveness of REVOLUTION PLUS after bathing has not been evaluated.

Flea Treatment and Prevention - Tick Treatment and Control

Canada has highly variable distribution and abundance of fleas and ticks due to climate variations across the country. Consequently, a comprehensive plan, based on regional risk assessment, is recommended to determine an appropriate dosing regimen. To minimize the likelihood of flea re-infestation, it is important to treat all cats and dogs within a household with an approved flea product. If a cat is already infested with fleas when the first dose of REVOLUTION PLUS is administered, adult fleas on the animal are killed before they can lay eggs. However, an environmental infestation may persist for a short time after beginning the treatment.

Heartworm Prevention

For the prevention of heartworm disease, REVOLUTION PLUS must be administered on a monthly basis. It should be administered year-round or at least within one month after the animal’s first exposure to mosquitoes and monthly thereafter until the end of the mosquito season. The final dose must be given within one month after the last exposure to mosquitoes. If a dose is missed and a monthly interval between dosing is exceeded, then immediately administer a treatment and resume monthly dosing to minimize the opportunity for the development of adult heartworms. When replacing another monthly heartworm preventive product in a heartworm disease prevention program, the first dose of REVOLUTION PLUS must be given within a month of the last dose of the former medication. This product effectively eliminates the tissue stage of heartworm larvae for a month after infection.

At the discretion of the veterinarian, cats 6 months of age and older may be tested to determine the presence of existing heartworm infections before beginning treatment. Cats already infected with adult heartworms can be given REVOLUTION PLUS monthly to prevent further infections. Cats that test negative prior to the initiation of REVOLUTION PLUS may be harboring pre-patent infections at the time of treatment. Testing such cats 3-4 months after initiation of treatment would be necessary to confirm their negative heartworm status.

Ear Mite Treatment and Control

For the treatment of ear mite (Otodectes cynotis) infestations, REVOLUTION PLUS should be administered once as a single topical dose. Prior to administration of REVOLUTION PLUS, cleansing of the infested ears is recommended to remove debris. Monthly use of REVOLUTION PLUS will control any subsequent ear mite infestations.

Nematode Treatment and Control

For the treatment of roundworm (Toxocara cati) and intestinal hookworm (Ancylostoma tubaeforme) infections, REVOLUTION PLUS should be applied once as a single dose, and monthly thereafter to control infections.

Contraindications

Do not use in sick, debilitated or underweight cats.

Cautions:

Sarolaner, one of the ingredients in REVOLUTION PLUS, is a member of the isoxazoline class. This class has been associated with neurologic adverse reactions including tremors, ataxia, and seizures. Neurologic adverse reactions have been reported in cats receiving isoxazoline class drugs, even in cats without a history of neurologic disorders. Use with caution in cats with a history of neurologic disorders.

The safety of REVOLUTION PLUS in cats less than 8 weeks of age (see Animal Safety) and in breeding or lactating animals has not been determined.

Warnings

● Keep out of reach of children.

● Do not contact or allow children to contact the application site and do not share a bed with the animal until the application site is no longer noticeable on the animal’s skin/fur.

● People with known hypersensitivity to selamectin or sarolaner should avoid handling the product.

● Avoid contact with skin. Wear protective gloves when handling and administering the product. Adverse reactions such as hives, itching and skin redness have been reported in a small number of people after accidental dermal contact with selamectin topical solution. If accidental skin contact occurs, wash off any product in contact with the skin immediately with soap and water. Wash hands after use of the product.

● This product can be harmful if ingested. If accidental ingestion occurs, seek medical advice.

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

Adverse Reactions

Although all adverse reactions are not reported, the following information is based on voluntary post-approval drug experience reporting. It is generally recognized that this results in significant under-reporting. The adverse events listed here reflect reporting and not necessarily causality. Adverse events are listed by body system, in decreasing order of frequency:

● Application site disorders: application site alopecia, application site pruritus

● Systemic disorders: lethargy, anorexia

● Neurological disorders: ataxia, seizure

● Digestive tract disorders: hypersalivation

In a field safety and effectiveness study, REVOLUTION PLUS was administered to cats infested with fleas. The study included a total of 430 cats (282 treated with selamectin + sarolaner topical solution and 148 treated with an active control (imidacloprid + moxidectin) once monthly for three treatments). Over the 90-day study period, all observations of potential adverse reactions were recorded. Reactions reported in the REVOLUTION PLUS group included those presented in the following table.

Adverse Reactions by Treatment Group

Clinical Sign	REVOLUTION PLUS n = 282	Active Control n = 148
Lethargy	4.3%	0.7%
Emesis (e.g. mild vomiting)	3.5%	2.7%
Dermatitis and eczema (e.g. scabs, scratches, miliary dermatitis, mild excoriations)*	3.5%	8.8%
Anorexia (e.g. decreased appetite, inappetance)	3.2%	2.0%
Pruritus (e.g. scratching at ears or around neck)	2.5%	2.0%
Conjunctivitis	2.5%	0.7%
Sneezing	2.1%	0.7%
Administration site hair changes (alopecia)	1.8%	0.0%
Administration site lesions (scabbing)	0.7%	0.0%

*Lesions not associated with application site.

In a separate field safety and effectiveness study, REVOLUTION PLUS was administered to 124 cats with ear mites.

Observed adverse reactions included emesis, dermatitis and eczema, and pruritus.

In a third field safety and effectiveness study, REVOLUTION PLUS was administered to 70 cats with hookworms. Observed adverse reactions included lethargy, emesis, anorexia, and diarrhea.

To report adverse reactions, call Zoetis Canada Inc. at 1-800-461-0917.

Clinical Pharmacology

Selamectin is a member of the macrocyclic lactone class of parasiticides and the chemical name is (5Z,25S) - 25 - cyclohexyl - 4’ - O - de(2,6 - dideoxy - 3 - O - methyl - α - L - arabino - hexopyranosyl) - 5 - demethoxy - 25 - de(1 - methylpropyl) - 22,23 - dihydro - 5 - hydroxyiminoavermectin A1a.

The chemical structure of selamectin is:

Sarolaner is a member of the isoxazoline class of parasiticides and the chemical name is 1 - (5’ - ((5S) - 5 - (3,5 - Dichloro - 4 - fluorophenyl) - 5 - (trifluoromethyl) - 4,5 - dihydroisoxazol - 3 - yl) - 3’ - H - spiro(azetidine - 3,1’ - (2)benzofuran) - 1 - yl) - 2 - (methylsulfonyl)ethanone. REVOLUTION PLUS contains the S-enantiomer of sarolaner.

The chemical structure of the S-enantiomer of sarolaner is:

Mode of Action

REVOLUTION PLUS contains two active pharmaceutical ingredients, selamectin and sarolaner. Selamectin is a semi-synthetic compound of the avermectin class. Selamectin paralyzes and/or kills a wide range of invertebrate parasites through interference with their chloride channel conductance causing disruption of normal neurotransmission. This inhibits the electrical activity of nerve cells in nematodes and muscle cells in arthropods leading to their paralysis and/or death. It has been shown that the addition of sarolaner does not interfere with this activity. Sarolaner is an acaricide and insecticide belonging to the isoxazoline family. The primary target of action of sarolaner in insects and acarines is functional blockade of ligand-gated chloride channels (GABA-receptors and glutamate-receptors). Sarolaner blocks GABA- and glutamate-gated chloride channels in the nervous system of insects and acarines. Disruption of these receptors by sarolaner prevents the uptake of chloride ions by GABA and glutamate ion channels, thus resulting in increased nerve stimulation and death of the target parasite. Sarolaner exhibits higher functional potency to block insect/acarine receptors compared to mammalian receptors. Sarolaner does not interact with known insecticidal binding sites of nicotinic or other GABAergic insecticides such as neonicotinoids, fiproles, milbemycins, avermectins, and cyclodienes.

Pharmacokinetics

Following topical administration of REVOLUTION PLUS, both selamectin and sarolaner are well absorbed with a mean bioavailability of 40.5% and 57.9%, respectively, and distribute systemically. In cats, selamectin and sarolaner are low clearance compounds with long half-life values, 12.5 days and 41.5 days respectively, following topical administration. Sarolaner and selamectin steady-state is reached in 3-4 months, when dosed on a once-month regimen. The primary route of elimination for both drugs is hepatobiliary excretion (approximately50% of dose in feces).

Efficacy:

Flea Treatment And Prevention

In a well-controlled laboratory study, REVOLUTION PLUS started to kill fleas within 12 hours of treatment, killed 98.1% of fleas within 24 hours, and then 100% within 48 hours. During subsequent weekly infestations, REVOLUTION PLUS started to kill fleas within 6 hours and killed ≥93.8% of fleas within 12 hours through Day 28 and 100% of fleas within 24 hours through Day 35. In a separate well-controlled laboratory study, REVOLUTION PLUS killed 100% of fleas within 24 hours of treatment and within 24 hours of subsequent infestation for 5 weeks.

In a separate well-controlled laboratory study looking at flea development, there was a 100% reduction in adult flea count against an existing infestation and weekly re-infestation for at least 36 days. No flea eggs were recovered from cats treated with REVOLUTION PLUS through Day 22, and on Day 36. Four flea eggs were recovered from one cat on Day 29, but none of these four eggs hatched and developed into adult fleas. Fleas on placebo control cats continued to produce eggs throughout the study, with counts ranging from 110 - 1,256 eggs per cat.

In a 90-day multi-center field study in the United States, conducted in households with existing flea infestations, the effectiveness of REVOLUTION PLUS against fleas was 95.9%, 99.4%, and 99.8% when assessed on Days 30, 60, and 90, respectively. Cats with signs of flea allergy dermatitis showed 91.2% improvement in alopecia, 96.4% improvement in dermatitis/pyodermatitis, 100% improvement in pruritus, erythema, and papules, and 86.7% improvement in scaling, as a direct result of eliminating the flea from the animals and the environment.

Tick Treatment And Control

In a well-controlled laboratory study, REVOLUTION PLUS killed over 90% of Ixodes scapularis ticks within 24 hours after initial administration and through Day 21 of subsequent tick infestations. The speed of kill was longer than 24 hours for Days 28 and 35 infestations.

In additional well-controlled laboratory studies, REVOLUTION PLUS demonstrated ≥91.1% effectiveness against Ixodes scapularis 48 hours post-infestation for 35 days. It also demonstrated ≥91.6% effectiveness against Amblyomma maculatum 48 hours post-infestation for 28 days. At 72 hours post-infestation, REVOLUTION PLUS demonstrated ≥93.5% effectiveness against Dermacentor variabilis for 36 days.

Heartworm Prevention

In two well-controlled laboratory studies, a single topical dose of REVOLUTION PLUS was 100% effective in preventing the development of heartworms in cats inoculated with infective larvae of Dirofilaria immitis 30 days prior to treatment.

Ear Mite Treatment And Control

In a well-controlled laboratory study, a single topical dose of REVOLUTION PLUS resulted in > 99% efficacy against an existing Otodectes cynotis infestation at 30 days post treatment.

In a multi-center field study conducted in households with existing Otodectes cynotis infestations in the United States, 94.4% of cats in the group treated with REVOLUTION PLUS were negative for ear mites at Day 30.

Nematode Treatment And Control

Elimination of intestinal hookworm (Ancylostoma tubaeforme) and roundworm (Toxocara cati) infections was demonstrated in well-controlled laboratory studies.

In a 60-day multi-center field study in the United States, the effectiveness of REVOLUTION PLUS in reducing Ancylostoma tubaeforme fecal egg counts was 99.4% and 99.7% on Days 30 and 60, respectively. The corresponding values for Toxocara cati were 100% on both study days.

Animal Safety:

Margin of Safety Studies: One exploratory and two pivotal margin of safety studies were conducted with REVOLUTION PLUS. In the first pivotal study, REVOLUTION PLUS was applied topically to kittens eight weeks of age at doses of 12/2 (selamectin/sarolaner) mg/kg (1X), 36/6 mg/kg (3X), 45/7.5 mg/kg (3.75X), and 60/10 mg/kg (5X) every 28 days for eight consecutive doses. One female cat in the 3.75X group was found dead on study day 115. The cause was determined to be hemorrhage in multiple tissues secondary to a low platelet count. The cause of the decreased platelet count was not determined. Insufficient information was available to reach a conclusion and rule out a possibility that this was an adverse drug event. No significant changes related to REVOLUTION PLUS were observed among the remaining cats for physical examination, body weight, clinical pathology (hematology, coagulation, and serum chemistry), gross pathology, histopathology or organ weights.

In the second pivotal study, REVOLUTION PLUS was applied topically to cats 9 months of age at doses of 1X, 3X, and 5X every 28 days for six consecutive doses. Cosmetic changes at the application site occurred sporadically in all treatment groups and included wet appearance and dried white material. Hair loss at the dose site was also noted in two cats in the 1X group and one cat in the 5X group within 1-8 days after the fourth dose administered on day 84. No significant changes related to REVOLUTION PLUS were observed for physical examination, body weight, clinical pathology (hematology, coagulation, and serum chemistry).

During an exploratory margin of safety study, one cat in the 60 mg/kg/ 10 mg/kg (selamectin/sarolaner) group (5X dose group) experienced piloerection, tremors, and mydriasis approximately 24 hours after receiving the third monthly dose of the combination. Signs resolved without treatment within 2 hours. This cat completed the study, receiving 3 subsequent 5X doses with no abnormal observations.

Oral safety study: The safety of REVOLUTION PLUS administered orally to 12-week old kittens was tested in case of accidental oral ingestion. Oral administration of the highest recommended topical dose of REVOLUTION PLUS (2 mg sarolaner/12 mg selamectin) to kittens resulted in transient lower food consumption and clinical findings of emesis, soft feces, and salivation. In one male, mild tremors were observed and resolved within 3 hours after dosing; the same cat demonstrated reduced activity approximately 6 hours after dosing. Tremors were considered possibly related to the administration of REVOLUTION PLUS.

Safety in heartworm-positive cats: In a safety study in which selamectin topical solution (REVOLUTION) was applied at 4 times the recommended dose to patent heartworm infected cats, no adverse reactions were observed.

Field safety: In three well-controlled field studies in the United States, REVOLUTION PLUS was used concurrently with other medications, such as vaccines, cestocidal anthelmintics, antibacterials, sedatives, anesthetics, opioid analgesics, corticosteroids, and non-steroidal anti-inflammatories. No adverse reactions were associated with the concurrent use of REVOLUTION PLUS and other medications.

Storage

Store at or below 30°C.

Flammable - Keep away from heat, sparks, open flames or other sources of ignition.

Presentation:

REVOLUTION PLUS is available in three separate dose strengths for cats of different weights (see DOSAGE AND ADMINISTRATION). REVOLUTION PLUS is offered in cartons containing three or six single dose tubes. Not all pack sizes may be marketed.

Zoetis is a trademark and Revolution is a registered trademark of Zoetis or its licensors, used under license by Zoetis Canada Inc.

Zoetis Canada Inc., Kirkland QC H9H 4M7

10020420-11-0

40024887

CPN: 1198560.0

ZOETIS CANADA INC.
16,740 TRANS-CANADA HIGHWAY, KIRKLAND, QC, H9H 4M7

Order Desk:		800-663-8888
Technical Services Canada:		800-461-0917
Technical Services USA:		800-366-5288
Website:		www.zoetis.ca

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