It appears to be well known that spinosad can interact badly with ivermectin (Heartgard®). A study found ivermectin toxicity in dogs when given in conjunction with spinosad (Comfortis®). The findings suggest that spinosad increases the risk of ivermectin neurotoxicity by inhibiting the secretion of ivermectin to increase systemic drug levels and by inhibiting P-gp at the blood-brain barrier
There are lots of anecdotal reports of dogs suffering severe vomiting, stomach issues, lethargy, lack of appetite, kidney failure, seizure-like symptoms, vestibular symptoms and death after being dosed with Comfortis®. Many of these stories can be found in the comments under this veterinary article
advocating Comfortis as a wonder drug.
The second active ingredient in Trifexis®, milbemycin oxime
(trade name Interceptor), is also used in Milbemax (with praziquantel), and Sentinel Flavor Tabs (with lufenuron). It acts by binding to glutamate gated chloride ion channels in invertebrate nerve and muscle cells, causing paralysis and death of the parasites. It may also act by disrupting the transmission of invertebrate neurotransmitters.
Adverse effects reported for milbemycin show (in order of frequency) 9,359 instances of it being ineffective against heartworm
, vomiting (2453), diarrhea, ineffective against ascarids, depression/lethargy, ineffective against hookworms, whipworms, anorexia and many more.
is also marketed under the private label Vethical ComboGuard for VCA vet clinics. Vethical also has a Comfortis® equivalent called Acuguard.