A miniature schnauzer named Gigi developed tremors more than a year ago, but only in the past two weeks has her owner, a veterinarian in Minnesota, suspected the cause to be medication she's given the dog to kill fleas and ticks.

The possibility came to the doctor's attention in a public notice issued Sept. 20 by the U.S. Food and Drug Administration. "[B]e aware of the potential for neurologic adverse events in dogs and cats when treated with drugs that are in the isoxazoline class," the alert reads.

Possible side effects of isoxazolines include muscle tremors, ataxia (loss of body control) and seizures. Drugs sold containing isoxazolines are Bravecto, Credelio, NexGard and Simparica.

Gigi started taking NexGard shortly after it was introduced in 2013, and she's taken Bravecto at times, too, according to her owner, Dr. Ginger Garlie. The 18-pound dog, now age 13, tends to be sensitive — she's had reactions in the past to vaccines, such as pain at the injection site, lethargy and loss of appetite. When Gigi began to shake involuntarily while standing, Garlie thought the tremors were perhaps a sign of advancing age.

Then the FDA notice came out. Information in the notice and an associated fact sheet is alternately reassuring and disquieting. "The FDA considers products in the isoxazoline class to be safe and effective for dogs and cats ..." so the products aren't being pulled from the market. The fact sheet goes on to note, "Although most dogs and cats haven’t had neurologic adverse reactions, seizures may occur in animals without a prior history."

Veterinarians are finding the nuanced message hard to parse. "I'm torn between overreacting and being really concerned about this," said Garlie, a practitioner for 33 years, a clinic owner and a past president of the Minnesota Veterinary Medical Association.

Her mixed feelings reflect the profession's struggle to respond appropriately to the uncertain risk. In a message-board discussion of the Veterinary Information Network, an online community for the profession, many veterinarians, especially those who have prescribed the drugs to numerous patients and seen no side effects, aren't worried. Some, who like Garlie have personal experience with a suspected adverse effect, are uneasy. And many simply are unsure what to think, given a lack of details in the FDA alert.

"I find the warning kinda vague. What is the rate of reaction? Are there other meds associated/given at the same time? What do I do with this ... clients are calling," commented Dr. Caitlin Savagian, a veterinarian in Wisconsin.

In emailed responses to questions from the VIN News Service, the FDA said it has logged about 53,100 adverse drug event (ADE) reports for isoxazoline products through July 31. (The first isoxazoline product, NexGard, was introduced five years ago.) About 5,400 of the reports cite one or more neurologic signs, such as ataxia, muscle tremors and/or convulsions. Other, more common, side effects cited on product labels include vomiting, diarrhea, loss of appetite, lethargy and skin reactions.

In about 9 percent of the reports involving neurologic signs, the pet died naturally or by euthanasia. "It is important to remember that for any given ADE report ... there is no certainty that the reported drug caused the adverse event/outcome," the FDA said. "Confounding factors may include underlying disease, using other drugs at the same time, or other non-drug related causes."

In other words, not every perceived bad reaction to a drug actually is that. There could be another reason or reasons for the health problem.

Asked whether the reports reveal any patterns, such as size, breed or medical history, to suggest which animals might be apt to experience neurological side effects, the FDA replied:

"The reports we receive vary in their level of detail and are often incomplete, but to date, no patterns have been observed to suggest which animals may be susceptible to having an adverse event. Please note that underreporting occurs with most adverse event reporting systems and the frequency of reporting for a given drug product varies over time and may be greater when the drug is newly marketed, or when media publicity occurs."

The agency added, "Side effects do not mean that a drug is unsafe. The vast majority of the treated population might not experience any side effects; however, it is important for the health provider and client to understand any risks associated with the use of a given product."

For perspective, an agency spokesperson said that "millions of animals have received one or more doses" of isoxazoline products.

Dr. Sharon Gwaltney-Brant, a veterinary toxicologist, said the small number of reported incidents so far, relative to the number of animals taking the drugs, suggests the chances of a neurological reaction in a given pet are miniscule.

"Am I taking my dog off NexGard? No," she said.

But stopping the drug makes sense for some, she said. "If you have a dog that has neurological problems, you probably want to switch to something else until we figure out what's going on," Gwaltney-Brant said.

On Friday, the FDA released summaries of the adverse-event reports for each of the isoxazoline drugs: afoxolaner, fluralaner, lotilaner and sarolaner. The summaries are posted in the agency's Center for Veterinary Medicine FOIA Electronic Reading Room under "Safety & Health."

Early studies hinted at rare neurologic effects

Even before the drugs were approved for market, safety studies and clinical trials revealed the possibility that they could elicit neurologic reactions in a small subset of animals. The signs sometimes developed immediately, and sometimes not until days or weeks after the drug was given for the first time, or not until several doses of the drug were given. In some cases, the affected animal took other drugs for other purposes, such as to prevent heartworm.

NexGard, which contains afoxolaner in a soft chew for dogs, was the first isoxazoline product to be sold in the U.S., approved by the FDA in September 2013. The NexGard product label states: "In the U.S. field study, one dog with a history of seizures experienced a seizure on the same day after receiving the first dose and on the same day after receiving the second dose .... This dog experienced a third seizure one week after receiving the third dose. The dog remained enrolled and completed the study. Another dog with a history of seizures had a seizure 19 days after the third dose of NexGard. The dog remained enrolled and completed the study. A third dog with a history of seizures received NexGard and experienced no seizures throughout the study."

The study lasted for 90 days and involved 415 dogs given NexGard. Another 200 dogs serving as controls were given a different flea and tick product.

The second isoxazoline product to reach the market was Bravecto, approved by the FDA in May 2014. Bravecto contains fluralaner in a chew for dogs. The product label for Bravecto chews describes no neurological side effects.

Simparica, which contains sarolaner in a chewable tablet for dogs, was approved in February 2016.

The Simparica label states that during its 90-day field trial, one of 315 dogs that received the drug "exhibited lethargy, ataxia while posturing to eliminate, elevated third eyelids and inappetence one day after receiving Simparica concurrently with a heartworm preventative (ivermectin/pyrantel pamoate). The signs resolved one day later." The dog's owner withdrew the pet from the study after two weeks.

In a study to measure margin of safety, some 8-week-old beagle puppies that were given three times and five times the recommended dose of Simparica had a variety of neurologic signs. Six of the 16 puppies given those dosages were affected. All recovered without treatment and showed no lingering neurological signs at the age of 6 months.

In July 2016, topical forms of Bravecto were approved for use in dogs and in cats. Studies done beforehand showed neurological issues in both species.

The label for Bravecto topical solution for dogs says: "In the field study, two dogs treated with Bravecto with no prior history of seizures each experienced a seizure. One dog had two seizures a day apart about 18 days after its first dose. The dog was started on antiepileptic medication and had no additional seizures during the study. A second dog had a seizure 76 days after its first dose and three days after starting fluoxetine for separation anxiety. The fluoxetine was discontinued and the dog experienced no additional seizures during the study. One dog treated with Bravecto was observed by the owner to be off balance for about 30 minutes five days after its first dose and had no similar observations after the second dose."

The label for Bravecto topical solution for cats says that in a U.S. field study in which 224 cats were given the product, two became ataxic. In one, the ataxia — a right head tilt — developed 34 days after the first dose. The cat improved after being given antibiotics, but the ataxia recurred 82 days later. Again, the cat recovered with antibiotics. It received a second dose of Bravecto 92 days after the first dose and showed "no further abnormalities during the study," which lasted 105 days.

In the second cat, ataxia developed 15 days after its first dose. The cat recovered the next day, was re-dosed 82 days later, and had "no further abnormalities during the study."

The label also says that in a field study in Europe, two cats from the same household had tremors, lethargy and anorexia (loss of appetite) within a day of receiving a dose. The signs resolved within three days.

The newest isoxazoline drug for dogs is Credelio, a chewable tablet containing lotilaner. It was approved in January. The Credelio label says one dog out of 198 given the drug in a U.S. field study experienced intermittent head tremors within 1½ hours of administration of vaccines, an ear-cleaning performed by the owner, and its first dose of Credelio. The tremors resolved within a day without treatment. The owner opted to withdraw the dog from the study.

In the same study, two dogs with a history of seizures received Credelio and had no seizures for the duration of the 90-day study.

In a field study in Australia, one dog with a history of seizures experienced tremors and glazed eyes six days after receiving Credelio. It recovered without treatment.

The FDA said it asked all the makers of isoxazoline products to update their labels to reflect the potential for neurologic side effects, and all have agreed to do so.

The websites for NexGard and Simparica also have prominent notices about the possibility of neurologic effects.

Weighing risks, benefits, options

In the years since the drugs have been on the market, pet owners have posted tales of good and bad experiences on a blog maintained by Dr. Elizabeth Carney. A veterinarian in Pennsylvania with a mobile practice focusing on end-of-life care, Carney said it was purely by accident that her blog became a magnet for discussions about isoxazoline.

In November 2014, Carney happened to write a post about Bravecto and NexGard, which at the time were very new. "It was just, 'Hey, here are these newer products for flea and tick control,' " Carney said. She shared some information from the product inserts such as dosing, routes of administration and adverse effects seen in clinical trials.

The post drew "literally hundreds of comments from people all over the world sharing their experiences with the drugs," Carney said. Readers' interest led her to file Freedom of Information Act requests with the FDA for the products' adverse event reports. Years' worth of report summaries provided by the agency to Carney are posted on her blog.

Carney said she's not surprised to see a variety of side effects reported. "When something new comes on the market and it's only been tested in several hundreds of dogs, it just stands to reason that when it gets into several thousand, we're going to see a different profile," she said.

Her hope is that researchers are able to identify what's causing the more serious adverse reactions. "I do think that there are animals that have been harmed, and we don't fully understand why, and that bothers me," she said.

Anyone who's nervous about using isoxazolines has other options, Gwaltney-Brant, the toxicologist, pointed out. "If you're scared about it, no one's putting a gun to your head and saying you have to use [it]. ... It's not like it's the only thing out there," she said.

"Nothing you use is going to be 100 percent safe for 100 percent of the animals," she added.

Garlie, the veterinarian in Minnesota, said she was enthusiastic about the oral drugs as an alternative to topical flea and tick controls because they're easier to administer and not messy.

But when the FDA alert came out, her first impulse was to stop using, selling and recommending the drugs. "I don’t think we know the true risks, as often the clinical signs were not attributed to flea/tick products until now and are likely greatly underreported," Garlie wrote in a post on VIN.

Garlie and the other doctors in her clinic together decided that NexGard, once their top recommendation for flea and tick control, no longer would be their first choice.

Fleas and ticks can transmit disease and cause other health problems, so Garlie stresses that controlling them is important. She's now reviewing with her clients the pros and cons of the various options, which include solutions applied to the skin, flea collars and oral drugs.

"I've had clients who I had the conversation [with] regarding risks and benefits, and they still wanted to use [NexGard]," she said. "For instance, you have little kids and you don't want to put a topical on your dog or a collar, so they're not exposed."

Whatever people decide, what's important is that they are "working with their veterinarians to make an informed decision," Garlie said.