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Trifexis (270 mg/4.5 mg) (Canada)

This page contains information on Trifexis (270 mg/4.5 mg) for veterinary use.
The information provided typically includes the following:
  • Trifexis (270 mg/4.5 mg) Indications
  • Warnings and cautions for Trifexis (270 mg/4.5 mg)
  • Direction and dosage information for Trifexis (270 mg/4.5 mg)

Trifexis (270 mg/4.5 mg)

This treatment applies to the following species:
Company: Elanco

(spinosad and milbemycin oxime)

Chewable Tablets


Active Ingredients

Spinosad and milbemycin oxime


TRIFEXIS contains the active ingredients spinosad and milbemycin oxime. Spinosad is a member of the spinosyns class of insecticides, which are non-antibacterial tetracyclic macrolides. Spinosad contains two major factors, spinosyn A and spinosyn D, derived from the naturally occurring bacterium, Saccharopolyspora spinosa.

Milbemycin oxime is a macrocyclic lactone anthelmintic, containing two major factors, A3 and A4 of milbemycin oxime. The approximate ratio of A3:A4 is 20:80.

Trifexis (270 mg/4.5 mg) Indications

TRIFEXIS is indicated for the prevention of heartworm disease (Dirofilaria immitis) and for the treatment and control of parasitic infections caused by adult hookworm (Ancylostoma caninum), adult roundworms (Toxocara canis and Toxascaris leonina) and adult whipworm (Trichuris vulpis) and adult flea (Ctenocephalides felis) infestations in dogs and puppies 8 weeks of age or older and 2.3 kg of body weight or greater.

Dosage and Administration

TRIFEXIS is given orally, once a month at the recommended minimum dosage of 30 mg/kg spinosad and 0.5 mg/kg milbemycin oxime body weight. For heartworm prevention, administer at monthly intervals beginning within 1 month of the dog’s first seasonal exposure and continuing once monthly for 3 months after the dog’s last seasonal exposure to mosquitoes (see EFFECTIVENESS).

Dosage Schedule

Body Weight (kg)

Spinosad Per Tablet (mg)

Milbemycin oxime Per Tablet (mg)

Tablets Administered

2.3 to 4.5




4.6 to 9.1




9.2 to 18.2




18.3 to 27.2




27.3 to 54.5




Over 54.5

Administer the appropriate combination of tablets

Administer TRIFEXIS with food for maximum effectiveness. If a dose is missed and a monthly interval between doses is exceeded, then immediate administration of TRIFEXIS with food and resumption of monthly dosing will minimize the opportunity for the development of adult heartworm infections and flea reinfestations. If vomiting occurs within an hour of administration, redose with another full dose.

Heartworm Prevention:

TRIFEXIS should be administered at monthly intervals beginning within 1 month of the dog’s first seasonal exposure and continuing until 3 months after the dog’s last seasonal exposure to mosquitoes (see EFFECTIVENESS).

Flea Treatment and Prevention:

Treatment with TRIFEXIS should begin one month before fleas become active and continue monthly through the end of flea season.

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

Intestinal Nematode Treatment and Control:

TRIFEXIS also provides treatment and control of adult roundworms (T. canis, T. leonina), adult hookworms (A. caninum), and adult whipworms (T. vulpis). Dogs may be exposed to and can become infected with roundworms, whipworms and hookworms throughout the year, regardless of season or climate. Clients should be advised of measures to be taken to prevent reinfection with intestinal parasites.


Concurrent use of spinosad, one of the components of TRIFEXIS, with high extra-label use of ivermectin for parasitic mange or demodicosis has been associated with an increased risk of developing neurological signs typically associated with ivermectin toxicity (see ADVERSE REACTIONS).

Use of spinosad, one of the components of TRIFEXIS, in dogs with a history of epilepsy or seizures should be avoided. TRIFEXIS 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 (see ADVERSE REACTIONS).

All dogs 6 months of age or older should be tested for existing heartworm infections before the administration of TRIFEXIS. In North America drug resistance to some strains of Dirofilaria immitis appears to be developing in the macrocyclic lactone class of drugs, so regular heartworm testing is an important part of any heartworm prevention program. The appropriate frequency of testing needs to be determined by the veterinarian based on the risk of infection in their area and on the travel history of the dog. Infected dogs should be treated with an adulticide to remove adult heartworms. TRIFEXIS is not effective against adult D. immitis. While the number of circulating microfilariae may decrease following treatment, TRIFEXIS is not indicated for microfilariae clearance (see ANIMAL SAFETY).

Mild, transient hypersensitivity reactions manifested as laboured respiration, vomiting, salivation, and lethargy, have been noted in some dogs treated with milbemycin oxime carrying a high number of circulating microfilariae. These reactions are presumably caused by release of protein from dead or dying microfilariae.

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

Puppies less than 14 weeks of age may experience a higher rate of vomiting.


Keep out of reach of children.

Adverse Reactions

Although all adverse events are not reported, the following information is based on voluntary post-approval drug experience reporting. It is not always possible to reliably estimate the adverse event frequency or establish a causal relationship to product exposure using this data.

The post-marketing adverse events reports for TRIFEXIS have shown emesis/vomiting to be uncommonly observed shortly after dosing (reported in at least 1 but not more than 10 animals in 1,000 animals). In the majority of cases, vomiting was transient and mild and did not require symptomatic treatment. Lethargy, anorexia/decreased appetite, diarrhea, and pruritus were rarely seen (reported in at least 1 but not more than 10 animals in 10,000 animals). Muscle tremors, ataxia, and convulsions were also rare.

Some Collies and other P-glycoprotein-deficient dogs (e.g. with MDR or ABCB1-1-delta gene mutation) are known to be more sensitive to the macrocyclic lactone class of medications. Such dogs may be susceptible to macrocyclic lactone toxicity with over-dosing or when used in combination with other P-glycoprotein-inhibiting drugs (see ANIMAL SAFETY).

Following concurrent use of spinosad, one of the components of TRIFEXIS, with high extra-label doses of ivermectin, some dogs have experienced the following clinical signs associated with ivermectin toxicity: trembling/twitching, salivation/drooling, seizures, ataxia, mydriasis, blindness and disorientation. Spinosad alone has been shown to be safe when administered concurrently with heartworm preventives at label directions.

In a well-controlled US field study, which included a total of 352 dogs (176 treated with TRIFEXIS and 176 treated with an active control), no serious adverse reactions were attributed to administration of TRIFEXIS. All reactions were regarded as mild.

Over the 180-day study period, all observations of potential adverse reactions were recorded. Reactions that occurred at an incidence >1% (average monthly rate) within any of the 6 months of observation are presented in the following table. The most frequently reported adverse reaction in dogs in the TRIFEXIS group was vomiting.

Average Monthly Rate (%) of Dogs With Adverse Reactions

Adverse Reaction

TRIFEXIS Chewable Tabletsa

Active Control Tabletsa
















Skin Reddening



Decreased appetite



Pinnal Reddening



an=176 dogs

In the US field study, one dog administered TRIFEXIS experienced a single mild seizure 2 1/2 hours after receiving the second monthly dose. The dog remained enrolled and received four additional monthly doses after the event and completed the study without further incident.

In US and European field studies, no dogs experienced seizures when dosed with spinosad alone 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 spinosad, but no seizures following the first and third doses.


Mode of Action:

The primary target of action of TRIFEXIS 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.

Milbemycin oxime acts by binding to glutamate-gated chloride ion channels in invertebrate nerve and muscle cells. Increased permeability by the cell membrane to chloride ions causes hyperpolarization of affected cells and subsequent paralysis and death of the intended parasites. Milbemycin oxime may also act by disrupting the transmission of invertebrate neurotransmitters, notably gamma amino butyric acid (GABA).


Heartworm Prevention:

In a well-controlled laboratory study, TRIFEXIS was 100% effective against induced heartworm infections when administered for 3 consecutive monthly doses. Two consecutive monthly doses did not provide 100% effectiveness against heartworm infection. This trial was conducted using a heartworm isolate obtained from Georgia (MP3 strain). In another well-controlled laboratory study, a single dose of TRIFEXIS was 100% effective against induced heartworm infections using a heartworm isolate obtained from Michigan (Michigan strain).

In a well-controlled six-month US field study conducted with TRIFEXIS, no dogs were positive for heartworm infection as determined by heartworm antigen testing performed at the end of the study and again three months later.

Flea Treatment and Prevention:

In a well-controlled laboratory study, TRIFEXIS demonstrated 100% effectiveness on the first day following treatment and 100% effectiveness on day 30.

Treatment and Control of Intestinal Nematode Infections:

In well-controlled laboratory studies, TRIFEXIS was ≥ 90% effective in removing naturally and experimentally induced adult roundworm, whipworm and hookworm infections.


TRIFEXIS is a flavoured chewable tablet. In a field study of client-owned dogs where 175 dogs were each offered TRIFEXIS once a month for 6 months, dogs consumed 54% of the doses when offered plain as if a treat and 33% when offered in or on food. The remaining 13% of doses were administered by pilling TRIFEXIS like other tablet medications.

Animal Safety:

TRIFEXIS was tested in 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 margin of safety study with milbemycin oxime and spinosad, TRIFEXIS was administered orally to 8-week-old Beagle puppies at doses of 1, 3, and 5 times the upper half of the recommended therapeutic dose band, every 28 days for 6 dosing periods. Vomiting was seen in all groups including control animals with similar frequency. Adverse reactions seen during the course of the study were salivation, tremors, decreased activity, coughing and vocalization.

Body weights were similar between control and treated groups throughout the study. Treatment with TRIFEXIS was not associated with any clinically significant hematology, clinical chemistry, or gross necropsy changes. One 5X dog had minimal glomerular lipidosis observed microscopically. The clinical relevance of this finding is unknown.

Plasma spinosyn A, spinosyn D, milbemycin A3 5-oxime, and milbemycin A4 5-oxime concentrations increased throughout the study. At each dosing period, plasma spinosyn A and spinosyn D concentrations were greater than proportional across the dose range 1 to 5X. Plasma milbemycin A4 5-oxime concentrations appeared to be dose proportional across range 1 to 5X by the end of the study. Plasma concentrations of spinosad and milbemycin oxime indicate that expected systemic exposures were achieved throughout the study.

In an avermectin-sensitive Collie dog study, TRIFEXIS was administered orally at 1, 3 and 5 times the upper half of the recommended therapeutic dose band every 28 days. No signs of avermectin sensitivity were observed after administration of TRIFEXIS during the study period to avermectin-sensitive Collie dogs. The adverse reactions observed in the treatment groups were vomiting and diarrhea. Body weights in all treatment groups were comparable to the control group. Hematology and clinical chemistry parameters showed no clinically significant changes from study start to end, and all dogs were considered healthy throughout the study.

In a heartworm positive safety study TRIFEXIS was administered orally at 1, 3, and 5 times the upper half of the therapeutic dose band to Beagle dogs with adult heartworm infections and circulating microfilariae, every 28 days for 3 treatments. Vomiting was observed in one dog in the 1X group, in three dogs in the 3X group, and in one dog in the 5X group. All but one incident of vomiting was observed on the treatment day during the first treatment cycle. The vomiting was mild and self-limiting. Hypersensitivity reactions were not observed in any of the treatment groups. Microfilariae counts decreased with treatment.

In a reproductive safety study with milbemycin oxime and spinosad, TRIFEXIS was administered orally to female dogs at 1 and 3 times the upper half of the recommended therapeutic dose band every 28 days prior to mating, during gestation, and during a six-week lactation period. Dogs with confirmed fetal heartbeats on ultrasound examination were evaluated for reproductive safety. One 3X and one 1X group female did not become pregnant. No treatment-related adverse reactions or signs of avermectin toxicosis were noted for adult females. Adult females in the 3X group lost weight during the 6-week pre-mating period, while control group females gained weight during that time. The body weights of the treated groups were comparable to the control group during gestation and post-parturition phases of the study. Gestation length, litter average body weight, litter size, stillborn pups, pup survival, and the proportion of pups with malformations were comparable between treated and control dam groups. Malformations in the 1X group included a pup with cleft palate and a littermate with anophthalmia, fused single naris, misshapen palate, hydrocephalus, omphalocele, and malpositioned testes; a pup with a malformation of the anterior tip of the urinary bladder and umbilical blood vessel; and a pup with patent ductus arteriosus (PDA). Malformations in the 3X group included three littermates with PDA. Malformations in the control group included a pup with a malformed sternum and a pup with PDA and a malpositioned superior vena cava. Clinical findings in pups of the treated groups were comparable to the control group except for one 1X group pup that was smaller and less coordinated than its littermates, and had tremors when excited. The relationship between spinosad and milbemycin oxime treatment and the 1X and 3X dogs that did not become pregnant, the specific pup malformations, and the unthrifty 1X group pup are unknown. The incidence of cleft palate is not unexpected based on the historical data collected at the breeding site.


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

How Supplied

TRIFEXIS is available in five flavoured tablet sizes in colour-coded packages of 6 tablets.

140 mg spinosad and 2.3 mg milbemycin oxime

270 mg spinosad and 4.5 mg milbemycin oxime

560 mg spinosad and 9.3 mg milbemycin oxime

810 mg spinosad and 13.5 mg milbemycin oxime

1620 mg spinosad and 27 mg milbemycin oxime

Trifexis, Elanco and the diagonal bar logo are trademarks of Elanco or its affiliates.

Elanco Canada Limited, 150 Research Lane, Suite 120, Guelph, Ontario, N1G 4T2 Canada

(800) 265-5475

CA4332 DIN 02375451

CA4333 DIN 02375478

CA4334 DIN 02375486

CA4335 DIN 02375494

CA4336 DIN 02375524


CPN: 1231159.0

Customer Service:   800-265-5475
Fax:   519-821-7831
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