Mimi

Photo by Nina Pullella

After being given NexGard Combo for the first time in April, Mimi became sick and was hospitalized for three days. Genetic testing shows she has a mutation believed to cause hypersensitivity to certain drugs.

Reports of serious, sometimes deadly, neurologic problems in cats given certain parasite-control treatments are drawing scrutiny to NexGard Combo, a topical medication introduced in the United States last year.

NexGard Combo is the third product for cats sold by the drug company Boehringer Ingelheim to contain eprinomectin, a dewormer. Research from Washington State University indicates that cats with a particular genetic mutation may be highly sensitive to eprinomectin.

The hallmark sign of the suspected sensitivity is ataxia, or loss of muscle coordination. Initially, the apparent drug reaction may manifest as lethargy or weakness, then progress to difficulty with walking and worsen to complete recumbency and coma. Some cats have died from severe depression of their central nervous system.

Dr. Katrina Mealey, a veterinary clinical pharmacologist and internal medicine specialist at WSU who discovered the gene mutation and identified the apparent sensitivity of affected felines to eprinomectin, is calling for a warning statement on eprinomectin products marketed for cats.

Dr. Dean Dailey, senior associate director for U.S. pet veterinary technical marketing at Boehringer Ingelheim, said it's important for the veterinary community to be aware of the "emerging research" but that not enough is known to make definitive statements about product risk. And for the vast majority of cats that use NexGard Combo, the product is safe, he maintained, citing more than 110 million doses of eprinomectin products sold for cats worldwide to date, with adverse effects of all types amounting to fewer than one in every 10,000 doses sold.

The most common side effects reported to the U.S. Food and Drug Administration through May 31 were lethargy, vomiting and hypersalivation.

The company says it is supporting research into the question of genetic sensitivity. It also noted the need to protect pets from the known health risks of parasites. "It is important to recognize that all medicines carry benefits and risks," Dailey said.

The FDA is aware of the matter and "actively reviewing all post-market data, including adverse drug event data," according to spokesperson Siobhan DeLancey. She said the agency does not have a timeline for when it will complete its review.

Evaluating drug safety through the number and types of adverse event reports can be tricky because a reported incident might actually have a cause unrelated to the drug. Conversely, true negative side effects from a drug can go unreported.

ABCs of the science

In addition to a drug warning label, Mealey recommends cats be tested for a variant of a gene called ABCB1, better known as the MDR1 gene. The variant was first documented in cats nine years ago. Awareness of it has only recently begun spreading, even among veterinarians.

A canine MDR1 gene, discovered by Mealey in 2001, is far better known. It occurs typically, but not exclusively, in collies and other herding breeds. The canine and feline gene variants are not identical but, according to Mealey, they have the same effect on a protein encoded by the gene, known as P-glycoprotein.

P-gp, as it's called for short, helps the body to excrete certain drugs and prevents them from entering the central nervous system. In those with the gene variant, Mealey said, the protein is absent, enabling drugs to stay in the body longer and potentially cross into the brain, with severe, even lethal, results.

One class of drugs for which P-gp is known to be important in dogs is macrocyclic lactones. The class includes eprinomectin and ivermectin, both long used in cattle. Ivermectin has been used in companion animal medicine for decades, as well.

It was introduced commercially during the 1980s to control parasites in cattle and became a go-to treatment for mange in dogs. Veterinarians subsequently became aware that herding dogs tended to be hypersensitive to ivermectin. The awareness inspired a saying in the profession that alludes to the white-furred paws sported by many herding breeds: White feet, don't treat.

Mealey was a doctoral student probing the role of P-gp in chemotherapy resistance in people when she learned about research mice in which the gene for P-gp had been knocked out, or inactivated. Some of the mice happened to develop mange, a skin disease caused by mites.

"So they sprayed the room with ivermectin, and all of the knockout mice died, but the normal mice didn't," Mealey recounted. "They had 100 times higher concentration of ivermectin in their brain than the normal mice."

That led her to hypothesize about the genetic cause of ivermectin sensitivity in dogs. She later sequenced the gene for P-gp in collies that had exhibited sensitivity and discovered the canine mutation, publishing the finding in 2001 in what became a seminal paper.

Back then, Mealey wasn't thinking about cats. Years later, she learned of a family of felines that had been treated with ivermectin for ear mites. Some developed neurotoxicity and some did not, raising the question: Could an MDR1 mutation explain why?

Mealey examined the MDR1 gene in cats, leading to the discovery of a mutation apparently similar to the one in dogs. Complicating the picture, though, some of the cats in the study that had reactions to macrocyclic lactones did not have the MDR1 mutation but had other gene variants for which the function is unknown. That result led Mealey to conclude, in a paper published in 2015, that "there may be multiple causes in cats" of central nervous system drug toxicities.

Products debut; suspected problems surface

NexGard Combo packaging

Photo by Krista Ziec

NexGard Combo for cats is approved for use in more than 45 countries. It was introduced to the United States pet parasite-control market in spring 2023.

In 2014, Boehringer Ingelheim introduced Broadline in Europe and New Zealand. It was the first antiparasitic for cats to contain eprinomectin. Designed to counter a broad spectrum of parasites — fleas, ticks and worms including heartworms — Broadline has four active ingredients: fipronil, (s)-methoprene, eprinomectin and praziquantel.

In the U.S., following FDA approval in 2018, eprinomectin paired with praziquantel arrived in the form of Centragard, an antiparasitic for cats. NexGard Combo, containing eprinomectin, esafoxalaner and praziquantel, launched in the European Union after receiving regulatory approval there in January 2021. It debuted in the U.S. in May 2023. Today, it's approved for use in more than 45 countries, including Canada, Colombia, Japan, Mexico and Turkey, according to Boehringer Ingelheim.

The eprinomectin products are "spot on" solutions that are applied monthly to the cat's back, between the shoulder blades.

In 2020, Mealey became aware of suspected problems with eprinomectin after being contacted by veterinarians, veterinary technicians and pet owners in Australia who'd seen or owned cats that had apparent neurologic reactions to Broadline. Examining the genes of five of the cats, Mealey found the MDR1 mutation in four. The variant was homozygous in all four, meaning it was present on both copies of the gene pair.

To determine how unusual that was, Mealey and colleagues examined 1,006 samples from a cat DNA bank. None were homozygous for the mutation, while 47 were heterozygous, meaning that one copy of the gene pair had the mutation. The rest did not have the mutation at all.

That finding suggested that eprinomectin was, in effect, identifying cats with two copies of the mutated gene by prompting neurologic reactions. The research was published in 2021.

Following the launch of NexGard Combo in spring 2023, the Washington State University lab that tests for MDR1 received a number of requests for tests in cats, "with many of the corresponding submission forms noting adverse events after application of that product and that the manufacturer had recommended feline MDR1 genotyping," Mealey and colleagues said in a scientific journal article published in February 2024.

Of 14 cases that the researchers found to be "highly consistent with eprinomectin toxicosis," eight were homozygous for the mutation. Three of them died. The other six did not have the mutation at all. Two in that group died.

While the mutation didn't explain all the adverse reactions, the researchers stated, "Results indicate that topical eprinomectin products should be avoided in cats homozygous for [the mutation]," adding, "This is a serious, preventable adverse event occurring in an identifiable subpopulation treated with FDA-approved products in accordance with label directions."

Mealey noted that P-gp deficiency is not only heritable but may occur in patients that don't have the mutation but who are given multiple drugs that are transported by the protein. The combination can overwhelm P-gp's protective power. (For dogs with the MDR1 mutation, Washington State has developed a list of drugs known to be potentially dangerous.)

With the eprinomectin products for cats, she said, "The label dose of a drug used in healthy animals can cause severe and even fatal neurotoxicity. To me, that's a huge deal. If owners follow the instructions on the label exactly the way they're supposed to, their cat can end up dead."

After Mealey's latest research was published, Washington State issued a press release to disseminate the results more widely. "We wanted to get the information out there. We wanted people to know," she explained.

The March 28 press release states that more than a half-million cats in the United States — in a population of more than 60 million — could be at risk. The figure is derived from an estimate in Mealey's 2015 paper that 1% of cats have two copies of the gene mutation.

More recently, Mealey told the VIN News Service that her lab had just received test results on a cat that experienced tremors, but not ataxia, after its first dose of NexGard Combo and again after its second dose. The cat was heterozygous for the mutation, suggesting "an intermediate type of sensitivity ..." she said. "That means even more cats in the population may have a susceptibility to NexGard Combo."

Product maker responds

Dailey at Boehringer Ingelheim disputes the 1% prevalence estimate. Existing published research, he said, including Mealey's 2021 study that found no cats out of 1,006 to be homozygous for the mutation, suggest the prevalence is well below 1%.

He also highlighted that Mealey's 2015 study identifying the feline mutation found other mutations, the effects of which are unknown. "There is the potential of other things going on that aren't being captured in the [MDR1 genetic] testing," he said.

"I'm not questioning that the mutation is there," he added. "Some of the implications of the mutation, we have more to learn about."

Stating "we take safety very seriously," Dailey said the company is committed to doing research internally and in collaboration with researchers at outside institutions "to really advance the science related to what is known about MDR1. Currently, the information we have is based on case series. The information we have shows a correlation. It doesn't show causation."

Underscoring the company's desire to find answers, he said that when it received "the rare reports" from veterinarians and pet owners of neurologic side effects, Boehringer Ingelheim referred many for genetic testing at the Washington State lab. "The awareness to this issue has been raised because of us raising it ourselves," he said.

Nina Pullella, a cat owner in Hawaii, credits Boehringer Ingelheim with providing robust support when her 9-month-old kitten, Mimi, reacted badly to her first (and only) dose of NexGard Combo in April. The first day after treatment, Mimi, normally highly active, was lethargic and ate less than usual, Pullella remembered. The next day, she was uncharacteristically clingy and had a subtle wobble in her gait. On the third day, Mimi developed tremors. Her eyes appeared unseeing and unable to close.

Pullella's partner called the 800 number on the NexGard Combo package and was urged by an agent to take Mimi to the veterinarian, which he did the next day. Pullella said hospital staff initially did not recognize Mimi's condition as a drug reaction. When the Boehringer Ingelheim agent, in a follow-up call to the owners, learned this, she contacted the hospital directly.

"She called and said, 'This cat is having an adverse reaction, and you need to treat this as an adverse reaction,' " Pullella recounted, impressed.

Mimi recovered after a three-day hospital stay that cost some $4,000 — a bill that, according to Pullella, the company has offered to reimburse.

Pullella said she learned about the MDR1 test through her own research. While Mimi was hospitalized, she had the kitten tested, an expense she said Boehringer Ingelheim declined to cover. The test showed Mimi has two copies of the gene mutation.

Confounding factor

Another active ingredient in NexGard Combo — esafoxalaner — is an isoxazoline, a type of chemical used in flea and tick killers that was introduced to the pet market in 2014 and has since been linked to reactions such as tremors and seizures in a subset of dogs and cats.

The FDA alerted the public to the issue in 2018 and asked companies with products containing isoxazolines — of which there are currently 11 — to place cautionary language on the package.

Which dogs or cats are susceptible to neurologic effects and why is unknown. Still, with isoxazolines, Dailey said, "there was a better understanding [of the problem] given the level of evidence that was out there; given the experience we are seeing through the reports" of adverse events.

With feline sensitivity to macrocyclic lactones, he said, "We're at a different, earlier time point in terms of understanding what's going on."

One mystery is why some cats with the mutation seemingly tolerate some chemicals in that class and not others. Macrocyclic lactones such as milbemycin, moxidectin and selamectin have been in feline antiparasitics for longer than eprinomectin and have not raised the same alarm.

Teegan's story

Teegan

Photo by Krista Ziec

Teegan, an affectionate cat that her owner said would come when called "like a dog," was apparently healthy at the time she was given NexGard Combo. The next day, she died. What role the product played in her death, if any, is uncertain.

The experience of Krista Ziec with her cat, Teegan, exemplifies the complicated, uncertain picture around NexGard Combo.

Just before her ninth birthday, Teegan had a veterinary checkup, including blood work, that she "passed with flying colors," having nothing more than a slightly elevated potassium level, Ziec told VIN News by email.

Although Teegan and her 5-year-old feline housemate, Twitch, were kept indoors at their Illinois home, Ziec regularly used an antiparasitic because the family dog would sometimes bring in "tick stowaways," or a mosquito might slip through an open door.

The cats had been on Revolution Plus, which contains the macrocyclic lactone selamectin, with no problems. Ziec decided to try NexGard Combo when the veterinarian explained that the newer product provides greater coverage. It targets tapeworms in addition to fleas, ticks, roundworms, hookworms and heartworms.

Ziec treated both cats at 8 p.m. on May 27. Twitch was fine, but within minutes, Teegan "came up to me dripping massive amounts of foam from her mouth," Ziec said. Calling a pet poison hotline, she learned that cats licking the product from their fur might hypersalivate and was advised to give wet food or tuna to counteract the reaction. That seemed to help, and Teegan slept that night on her owners' bed, as always.

At 1 p.m. the next day, Ziec heard a screech from the basement. She found Teegan lying on her side at the bottom of the stairs, pupils dilated, mucus membranes blue, gasping.

"She started ... flexing and extending her extremities, throwing her head back in the most gut-wrenching screams and paddling all four legs," Ziec said.

She rushed the cat to the veterinarian, but before they reached the clinic, a seven-minute drive away, Teegan died.

The clinic reported the case to Boehringer Ingelheim, which paid for the emergency visit and necropsy. Ziec independently learned about the MDR1 work at Washington State and arranged to have a DNA sample sent.

Teegan didn't have the mutation. The necropsy showed her heart to be mildly enlarged. Whether that played a role in her death and what exactly killed Teegan, Ziec may never know.

Whatever it was, she believes applying NexGard Combo was a triggering event, and it breaks her heart.

"A preventative, elective medication should not have a side effect of death," Ziec said. "I don't care what percentage of cats/dogs fit into that, one loss is too many. I was just trying to do the right thing, and I'm just gutted that it could have been from my own hand trying to keep her safe."