I’ve spoken to veterinary offices, people in pet stores, and friends in “the business” who all have different opinions about the safety of the treatments prescribed by vets for heartworm, flea and worm “prevention”. A big hot topic is the drug Trifexis.
One of the things I think is important to do in order to educate ourselves is to separate the social media hype from the fear-inducing advertising, from the actual look at the known available information.
You may be familiar with the Facebook pages and websites that are full of stories about dogs that have been killed or become ill after using Trifexis. You may have seen or received information from a vet about the “serious threat to your dog’s health” that can come from parasites in your home or yard. Both points of view are based on experiences. Dog guardians have had their pets die or become ill while both using and not using Trifexis. Veterinarians have given Trifexis doses in the thousands and prevented parasites. What an educated Dog Snob needs to do is get the facts about what really goes on when these drugs are approved for use in our dogs.
When it comes to approving a drug for the market, the Center for Veterinary Medicine (CVM) (a branch of the FDA) relies upon the drug manufacturer’s data to determine the safety of the drugs seeking approval for use. Yes, you read that right. The CVM doesn’t have the ability to do their own testing, so they rely on scientific studies provided by credited laboratories, and supplied by the drug applicants. Since that is the guideline used to make this drug available to the public, I thought it prudent to look at what was actually submitted. I found the January 4, 2011 Freedom of Information Act, Original New Drug Application for Trifexis on the FDA website at http://www.fda.gov/downloads/animalveterinary/products/approvedanimaldrugproducts/foiadrugsummaries/ucm252248.pdf.
When reviewing the numerous “studies” (read experiments) that were done for the drug, one has to understand the actual requirements for these tests include the use of beagles bred for laboratory testing and destruction for necropsy. One has to understand the controlled environment, foods and stressors put on the dogs used for the “studies”. The language is repetitive, excessively scientific, and clinically cold. The most significant aspect of the available information is at the conclusion of each record. No matter what the “study” recorded as far as results, the conclusion was always “The data demonstrate that TRIFEXIS Chewable Tablets, when used according to the label, are safe and effective for the prevention of…” heartworm, flea, or worms, depending upon the “study”.
Also significant are the CVM approval statements:
“VI.AGENCY CONCLUSIONS: The data submitted in support of this NADA (New Animal Drug Application) satisfy the requirements of section 512 of the Federal Food, Drug, and Cosmetic Act and 21 CFR part 514. The data demonstrate that TRIFEXIS Chewable Tablets, when used according to the label, are safe and effective for the prevention of heartworm disease (Dirofilaria immitis). TRIFEXIS Chewable Tablets kill fleas and are indicated for the prevention and treatment of flea infestations (Ctenocephalides felis), and the treatment and control of adult hookworm (Ancylostoma caninum), adult roundworm (Toxocara canis and Toxascaris leonina) and adult whipworm (Trichuris vulpis) infections in dogs and puppies 8 weeks of age or older and 5 pounds of body weight or greater.”
When I read the document, I was not surprised that my standards for what is considered “safe” did not seem to be in line with what the veterinary branch of the FDA thinks is “safe”. This is the reason I find it necessary to look things up for myself rather than assuming a product is safe because it made it onto the market. It’s also interesting that the word “safe” is only used in the first section referring to the prevention of heartworm disease. It’s not used in reference to the other applications.
When I actually read the Trifexis study information from the actual drug application, I had no explanation for why anyone would believe this product was safe to give to a dog at any time.
While not all of the “studies” reported “adverse reactions”, the most consistent statements were:
“Vomiting and diarrhea were likely associated with treatment with TRIFEXIS Chewable Tablets.”
“… loose stool in one dog and regurgitation of food … These adverse reactions were likely treatment related.”
“The vomiting in each case occurred within two hours after dosing with TRIFEXIS Chewable Tablets.”
“… loose stool, were observed in three dogs treated with TRIFEXIS Chewable Tablets”
“The most frequently reported adverse reactions for TRIFEXIS Chewable Tablets were vomiting, pruritus, lethargy, diarrhea, dermatitis, reddening of the skin, decreased appetite, and reddening of the ears.” (This was in a “Field safety study” of “client owned” dogs.)
Some of the studies accounted for 20% to 30% of the animals having adverse reactions to the Trifexis.
That’s a 1 in 5 or better chance of having a reaction. While some “studies” showed no recorded reactions, if it was a food no one would feed it. When a dog has a month to try to recover from the effects of this drug combination, the likelihood that consistent and close consumption would result in increased side-effects to serious illness is obvious. Why people don’t make this connection is not clear to me. Maybe it’s just a memory problem. The symptoms go away till the next time they give it. Until they don’t go away, but get worse. Is it too late then?
To prove this common-sense string of logic wrong, companies perform “studies” that give the dogs multiple times the recommended dose over the same amount of time. If they come out alive and with minimal side-effects, the company considers it proof of safety. In the case of Trifexis it went something like:
“c. Study Design: 1) Objective: Evaluate the safety of TRIFEXIS Chewable Tablets when first administered to 8-week old dogs at 1X, 3X, and 5X the upper half of the recommended therapeutic dose based for six dosing periods.”
The significant part of this “study” is the conclusion:
“A conclusion about dose proportionality for plasma milbemycin A3 5-oxime could not be made because of a limited number of quantifiable concentration measurements. One dog in the 1X group had a red ovarian cyst found at necropsy. The few additional macroscopic observations were considered incidental and unrelated to treatment. There was a decrease in mean kidney/brain weights for the 3X dogs and an increase in mean kidney/body weight values in the 5X group both when compared to controls. The relevance of the changes in the 3X group is unknown as that group was not histologically examined. One 5X dog had minimal glomerular lipidosis observed microscopically. The clinical relevance of this finding is unknown. Conclusions: The oral administration of TRIFEXIS Chewable Tablets at 1X, 3X, and 5X the upper half of the therapeutic dose band once monthly for six dosing periods in dogs was well tolerated in this study. Plasma concentrations of spinosad and milbemycin oxime indicate that expected systemic exposures were achieved throughout the study. Clinical signs related to treatment were salivation, tremors, decreased activity, cough and vocalization. Vomiting was seen in all groups, including the control group.”
Just so you understand what I hear when I read this, I will give my synopsis.
Scientists gave puppies 1 times, 3 times and 5 times the recommended dose of Trifexis in a controlled study to evaluate the safety of the product. They couldn’t make any conclusions about dosing Trifexis because some unexpected things showed up that they weren’t prepared to factor into the study. To keep things moving along they noted them as ‘things they saw’, and said they don’t know why they happened.
The conclusion was that the puppies tolerated the excessive doses of Trifexis for 6 months very well because they got the drug in them and all groups, even the control groups that didn’t receive the Trifexis, had side-effects like tremors, low energy, coughing, vomiting and crying.
As far as I know, a study is not considered to be done correctly if the control group and the dosed group have even some of the same responses. I think they call that “inconclusive”. Oh yea, they actually did say “A conclusion…could not be made…” That study should have been done over with different results in order to make any properly scientific conclusions. To say they saw things they couldn’t account for and then write that off as not significant seems completely…what’s the word? ABSURD!
As if that wasn’t enough, the “study” done on pregnant females noted “With the exception of weight loss in the first six weeks at the 3X dose, spinosad and milbemycin oxime (Trifexis) administration throughout the female reproductive cycle was clinically well-tolerated in adult Beagle dogs. 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.”
Again- ‘We don’t know why the stuff we saw happened so…’
The “specific malformations” referred to included: “… a pup with cleft palate and a littermate with anophthalmia (absence of one or both eyes), fused single nares (fused nose), misshapen palate, hydrocephalus (fluid on the brain), omphalocele (organs outside the body), and small testes malpositioned cranial to kidneys; a pup with a malformation of the anterior tip of the urinary bladder and umbilical blood vessel; and a 4-day-old pup with patent ductus arteriosus (PDA)(blood vessels around the lungs don’t close and abnormal blood flow results between the aorta and the pulmonary artery, ie heart disease).”
The significance of these birth defects to the puppies of the bitches given 1 to 3 times the recommended dose of Trifexis is interesting in two ways. One: it happened. Um, perhaps we need to look into this more, or maybe recommend it not be given to pregnant females. The package recommend “use with caution in breeding females” and notes it has not been evaluated for breeding males.
Two: the second part of the report states”
Malformations in the 3X group included three 2- to 3- day-old littermates with PDA Malformations in the control group included a pup with a malformed sternum (pectus excavatum), and a 2-day-old pup with PDA and a malpositioned superior vena cava. The incidence of cleft palate is not unexpected based on the historical data collected at the breeding site.
That means the dogs used in the study are noted as having a predisposition for heart disease in the tested groups, as well as an additional heart diseases, cleft palate and sternal malformations. This is why they write the birth defects off as not related to the drug being tested.
Now I’m no scientist, but I do have a brain, and if there’s no sure method of testing a drug to make sure it’s safe, I’m not o.k. with pretending. I think most actual scientists are not big fans of just pretending either.
Now there’s a whole lot more in that original drug application that I can expand on, like the significance of vomiting and diarrhea, the build-up of toxins in the body, and the testing parameters used in 6 month experiments.
However, I think you understand my concerns.
My biggest concern for everyone out there using Trifexis is this:
Almost every significant part of the “studies” done on Trifexis are actually printed on their labels.
Check it out at http://www.elanco.us/labels/Companion-Animals/Trifexis.pdf
If you have a package at home, you should already know about everything I just wrote. Take a closer look.
Get Educated For Dogs’ Sake.