Comfortis Chewable Tablets (1,620 mg) (Canada)

(spinosad)

Active Ingredient: Spinosad

Description

COMFORTIS chewable tablets (spinosad) are available in five chewable flavoured tablet sizes for oral administration to dogs and puppies 14 weeks of age and older according to their weight. Each chewable tablet is formulated to provide a minimum spinosad dosage of 30 mg/kg. Spinosad is a member of the class of antiparasitics, spinosyns, which are novel non-antibacterial tetracyclic macrolides. Spinosad contains two major factors, spinosyn A and spinosyn D, derived from the naturally occurring bacterium, Saccharopolyspora spinosa.

Comfortis Chewable Tablets (1,620 mg) Indication

COMFORTIS chewable tablets kill fleas and are indicated for the prevention and treatment of flea infestations (Ctenocephalides felis) on dogs for one month.

Comfortis Chewable Tablets (1,620 mg) Dosage And Administration

COMFORTIS chewable tablets are given orally once a month, at the recommended minimum dosage of 30 mg/kg to a maximum of 60 mg/kg.

Recommended Dosage Schedule

*Dogs over 54.5 kg should be administered the appropriate combination of tablets.

Administer COMFORTIS chewable tablets with food for maximum effectiveness.

COMFORTIS is a chewable tablet and is readily consumed by dogs when offered by the owner just prior to feeding. Alternatively, COMFORTIS chewable tablets may be offered in food or administered like other tablet medications. COMFORTIS chewable tablets should be administered at monthly intervals.

If vomiting occurs within an hour of administration, re-dose with another full dose. If a dose is missed, administer COMFORTIS chewable tablets with food and resume a monthly dosing schedule.

Treatment with COMFORTIS chewable tablets may begin at any time of the year. For prevention of flea infestations COMFORTIS should be administered preferably starting one month before fleas become active and administered at regular monthly intervals through the end of flea season. For maximum efficacy, it is important to dose COMFORTIS on a consistent, monthly interval during seasonal periods of flea activity.

To minimize the likelihood of flea reinfestation, it is important to treat all animals within a household with an approved flea product.

Comfortis Chewable Tablets (1,620 mg) Cautions

Use of COMFORTIS concurrently with ivermectin at any dose other than the approved label dose for heartworm prophylaxis should be avoided. Concurrent use of COMFORTIS with high extra-label doses of ivermectin for parasitic mange or demodicosis has been associated with an increased risk of developing neurological signs typically associated with ivermectin toxicity.

Use of COMFORTIS in dogs with a history of epilepsy or seizures should be avoided. COMFORTIS should only be administered to dogs with a history of epilepsy or seizures under the supervision of a veterinarian, and where alternative therapies are not appropriate or likely to be efficacious.

COMFORTIS chewable tablets are for use in dogs and puppies 14 weeks of age and older (see ANIMAL SAFETY).

Use with caution in breeding females (see ANIMAL SAFETY). The safe use of COMFORTIS chewable tablets in breeding males has not been evaluated.

Adverse Reactions

In a well-controlled field study, which included a total of 470 dogs (330 dogs treated with COMFORTIS chewable tablets and 140 dogs treated with an active control), no serious adverse reactions were observed with COMFORTIS. All reactions were regarded as mild and did not result in any dog being removed from the study.

Over the 90-day study period, all observations of potential adverse reactions were recorded. Reactions that occurred at an incidence > 1% within any of the 3 months of observation are presented in the following table. The most frequently reported adverse reaction in dogs in the COMFORTIS chewable tablets and active control groups was vomiting. Reports of vomiting, most commonly within 48 hours after treatment, decreased with repeated doses of COMFORTIS chewable tablets.

Percentage of Dogs (%) with Adverse Reactions

*One dog joined the study late, only dosed once at month 3.

In US and European field studies, no dogs experienced seizures when dosed with COMFORTIS chewable tablets at the therapeutic dose range of 30-60 mg/kg, including 4 dogs with pre-existing epilepsy. Four epileptic dogs that received higher than the maximum recommended dose of 60 mg/kg experienced at least one seizure within the week following the second dose of COMFORTIS chewable tablets, but no seizures following the first and third doses.

Mode Of Action

The primary target of action of COMFORTIS chewable tablets in insects is an activation of nicotinic acetylcholine receptors (nAChRs). Spinosad does not interact with known insecticidal binding sites of other nicotinic or GABAergic insecticides such as neonicotinoids, fiproles, milbemycins, avermectins, and cyclodienes. Insects treated with spinosad show involuntary muscle contractions and tremors resulting from activation of motor neurons. Prolonged spinosad-induced hyperexcitation results in prostration, paralysis, and flea death. The selective toxicity of spinosad between insects and vertebrates may be conferred by the differential sensitivity of the insect versus vertebrate nAChRs.

Effectiveness

In a well-controlled laboratory study, COMFORTIS chewable tablets began to kill fleas 30 minutes after administration and demonstrated 100% effectiveness within 4 hours. COMFORTIS chewable tablets kill fleas before they can lay eggs which are precursors to pupae. If a severe environmental infestation exists, fleas may persist for a period of time after dose administration due to the emergence of adult fleas from pupae already in the environment. In field studies conducted in households with existing flea infestations of varying severity, flea reductions of 98.0% to 99.8% were observed over the course of 3 monthly treatments with COMFORTIS chewable tablets.

Dogs with signs of Flea Allergy Dermatitis (FAD), including erythema, papules, scaling, alopecia, dermatitis/pyodermatitis and pruritus showed improvement as a direct result of eliminating fleas.

Animal Safety

COMFORTIS chewable tablets were tested in 91 different pure and mixed breeds of healthy dogs in well-controlled clinical and laboratory studies. No dogs were withdrawn from the field studies due to treatment-related adverse reactions.

In a dose tolerance safety study, COMFORTIS chewable tablets were administered orally to adult Beagle dogs at a dose range of 81-98.8 mg/kg once daily for 10 consecutive days (16.7 times the maximum recommended monthly dose). Vomiting was seen in 5 of 6 treated dogs during the first 6 days of treatment, usually within 2.5 hours of dosing. Treated females lost weight early in the treatment period, but their weights were similar to control dogs by the end of the 24-day study. COMFORTIS chewable tablets were not associated with any clinically significant changes in hematology, blood coagulation or urinalysis parameters; however, mild elevations in ALT occurred in all dogs treated with COMFORTIS chewable tablets. By day 24, ALT values had returned to near baseline levels. Phospholipidosis (vacuolation) of the lymphoid tissue was seen in all dogs treated with COMFORTIS chewable tablets, the long term effects of which are unknown.

In a margin of safety study, COMFORTIS chewable tablets were administered orally to 6-week-old Beagle puppies at average doses of 1.5, 4.4, and 7.4 times the maximum recommended dose at 28-day intervals over a 6-month period. Vomiting was observed across all groups, including the placebo. Increased vomiting was observed at elevated doses, usually within 1 hour following administration. Vomiting at all doses decreased over time and stabilized when puppies were 14 weeks of age. The average daily and total weight gains of treated dogs were smaller than control dogs and were dose dependent. COMFORTIS chewable tablets were not associated with clinically significant changes in hematology, clinical chemistry, coagulation or urinalysis parameters. Phospholipidosis (vacuolation) of the lymphoid tissue was seen in some dogs in the 4.4 X group and all dogs in the 7.4 X group. The long term effects of phospholipidosis are unknown. Treatment with COMFORTIS chewable tablets was not associated with any other clinically significant adverse clinical observations, gross necropsy or histopathological changes.

In a reproductive safety study, COMFORTIS chewable tablets were administered orally to female Beagles at 1.3 and 4.4 times the maximum recommended therapeutic dose every 28 days prior to mating, during gestation, and during a six-week lactation period. No treatment-related adverse effects were noted for conception rates in the dams, or for mortality, body temperature, necropsy or histopathology findings for the dams or puppies. One dam from each treatment group experienced early pregnancy loss and one additional high dose dam aborted late term. The treated dams experienced more vomiting, especially at one hour post-dose, than the control dams. Puppies from dams treated at 1.3 times the maximum recommended therapeutic dose had lower body weights than puppies from control dams. Although puppy mortality between treated and control dams was not different, the puppies from the treated dams experienced more lethargy, dehydration, weakness and felt cold to the touch (4.4 X group only) when compared to puppies from control dams.

A pilot study without a control group was conducted to analyze milk from three lactating dogs treated with an experimental formulation of spinosad at 1.5 times the maximum recommended dose administered at day 28 of gestation and 24 hours prior to parturition. The data demonstrated that spinosyns were excreted in the milk of these dogs. Mortality and morbidity were highest in puppies from the one dam where spinosyns in milk were highest. The spinosad milk:blood exposure ratio calculated from this study ranged from 2.2 to 3.5.

In well-controlled field studies, COMFORTIS chewable tablets were administered in conjunction with other frequently used veterinary products, such as vaccines, anthelmintics, antiparasitics, antibiotics, steroids, tick control products, anesthetics, NSAIDs, antihistamines, alternative/herbal remedies, shampoos, prescription diets, and most generally prescribed medications. Changes in hematology, clinical chemistry and urinalysis values were compared pre- and post-study and were unremarkable.

Warnings

Keep this and all drugs out of the reach of children.

Storage

Store at 20-25°C; excursions permitted between 15-30°C.

How Supplied

COMFORTIS chewable tablets are available in five flavoured tablet sizes: 140, 270, 560, 810 and 1620 mg. Each tablet size is available in colour-coded packages of 6 tablets.

DIN 02332493 (140 mg), 02332507 (270 mg), 02332515 (560 mg), 02332523 (810 mg), 02332531 (1,620 mg)

Elanco™ and Comfortis™ are trademarks of Eli Lilly and Company.

Elanco^® Division Eli Lilly Canada Inc., 150 Research Lane, Suite 120, Guelph, ON N1G 4T2

Canada

June 30, 2009

Nac No.