Isoxazoline Flea and Tick Products: What to Know About Neurological Reactions in Dogs

In 2018, the FDA strengthened its safety labeling for all isoxazoline-class flea and tick products by adding a black box warning for rare neurological adverse events. The affected products include NexGard (afoxolaner), Bravecto (fluralaner), Simparica and Simparica Trio (sarolaner), and Credelio (lotilaner). This article explains what the warning means, what symptoms to watch for, and when to contact your veterinarian.

These medications require a prescription from a licensed veterinarian. Consult your veterinarian before starting, changing, or stopping any prescription treatment for your pet.

FDA Black Box Warning: The FDA requires a black box warning on all isoxazoline-class products for rare but serious neurological adverse events including seizures, tremors, and loss of coordination. Dogs with a history of seizures or neurological conditions require veterinarian evaluation before use.

The Short Answer

The FDA black box warning reflects real but rare adverse events — muscle tremors, ataxia (loss of coordination), and seizures have been reported in some dogs after receiving isoxazoline-class products. The warning does not mean these products are unsafe for all dogs; it means that a subset of dogs — particularly those with pre-existing neurological conditions or seizure histories — may be at elevated risk. Discussing your dog’s health history with your veterinarian before starting any isoxazoline product is the appropriate first step.

What the Isoxazoline Class Is

Isoxazolines are a class of insecticides that work by inhibiting GABA-gated chloride channels in insects and arachnids, disrupting their nervous system function and killing them. The same mechanism that makes them effective against parasites can, in rare cases, affect the nervous systems of dogs. The FDA label change in 2018 added a class-wide boxed warning that includes all isoxazoline products, regardless of specific differences in chemistry between individual drugs.

Neurological Adverse Events: What Has Been Reported

Post-market surveillance reports to the FDA have included reports of the following neurological symptoms in dogs after isoxazoline product use:

• Muscle tremors: Visible shaking or trembling that is not typical for the dog
• Ataxia: Loss of coordination, stumbling, or difficulty walking
• Seizures: Convulsive episodes, which may range from mild focal seizures to full grand mal seizures

These events are described in the FDA’s safety communication as rare. The large majority of dogs receiving isoxazoline products do not experience neurological side effects. The FDA’s decision to require a boxed warning reflects the seriousness of these events when they do occur, not their frequency.

Dogs at Higher Risk

The FDA safety communication specifically notes that dogs with a history of seizures or neurological conditions may be at elevated risk for neurological adverse events from isoxazoline products. Your veterinarian will consider this history when recommending a flea and tick prevention approach. Dogs without any history of neurological conditions are generally considered lower risk, though the possibility of a first-time reaction cannot be eliminated.

Breeders and owners of breeds known to have elevated neurological condition prevalence — such as Belgian Malinois, Australian Shepherds, and herding breeds with MDR1 gene mutations — may want to specifically discuss genetic and breed-specific risk with their veterinarian before starting any isoxazoline product.

What to Watch For After Giving an Isoxazoline Product

If your dog starts a new isoxazoline product or changes to a new one, watch for the following symptoms in the hours and days following the first dose:

• Unusual trembling or muscle twitching not consistent with the dog’s normal behavior
• Changes in gait or coordination — stumbling, falling, dragging a limb
• Sudden behavioral changes that appear neurological in nature
• Seizure activity of any kind

If you observe any of these symptoms after giving your dog an isoxazoline product, contact your veterinarian immediately. Do not wait to see if the symptoms resolve on their own.

Report any adverse reactions to your veterinarian immediately and to the FDA at 1-888-FDA-VETS (1-888-332-8387).

The Decision Framework: Should You Use an Isoxazoline Product?

The decision to use an isoxazoline product involves weighing the real risk of flea and tick-borne diseases — including Lyme disease, Rocky Mountain spotted fever, and anaplasmosis, all of which can have serious health consequences — against the rare risk of neurological adverse events. This is a clinical judgment your veterinarian is best positioned to make for your specific dog.

For dogs without neurological history and without elevated breed-specific risk, most veterinarians continue to recommend isoxazoline products as effective and appropriate flea and tick prevention. For dogs with seizure history or known neurological conditions, your veterinarian may recommend alternative prevention approaches.

Bottom Line

The FDA black box warning on isoxazoline flea and tick products is a meaningful safety label that reflects real reported adverse events. It does not mean these products are unsafe for all dogs — it means that a subset of dogs may be at elevated risk, and that the risk is serious enough to warrant the highest-level warning label. Discuss your dog’s health history with your veterinarian before starting any isoxazoline product, and contact your veterinarian immediately if you observe neurological symptoms after dosing.

Find expert-reviewed pet care guidance at GetPetPros — with product comparisons, safety information, and veterinary resources.

Frequently Asked Questions

Has the FDA recalled any isoxazoline products as a result of neurological reports?

As of the time this article was written, the FDA has not recalled any isoxazoline-class flea and tick products. The 2018 safety labeling update — adding the boxed warning — was the FDA’s regulatory response to the adverse event reports. The agency determined that the products could remain on the market with enhanced safety labeling and appropriate veterinary oversight. Monitor the FDA’s adverse event reporting system and veterinary product recall database for current status, as this may change.

If my dog had a neurological reaction to one isoxazoline product, should they avoid all isoxazoline products?

This is a question for your veterinarian, who will evaluate the severity and nature of the reaction before making a recommendation. The isoxazoline class includes several different compounds with different pharmacokinetic profiles, and individual dogs may respond differently to different compounds within the class. However, a confirmed reaction to one isoxazoline product is important information for your veterinarian when considering any future flea and tick prevention approach. Report the reaction to both your veterinarian and the FDA (1-888-FDA-VETS) so it is part of the adverse event database.

Are neurological reactions to isoxazoline products permanent?

The available evidence from post-market reports and veterinary case literature indicates that neurological signs associated with isoxazoline use — seizures, tremors, ataxia — have been transient and resolved after discontinuation of the product in most reported cases. Permanent neurological outcomes have been reported in a small number of cases, but the causal relationship between the product and a permanent outcome is difficult to establish in post-market reports because many affected dogs have underlying conditions. If your dog shows neurological signs after starting an isoxazoline product, contact your veterinarian immediately. Do not wait for the next scheduled appointment. Early intervention may limit the severity and duration of signs.

Should dogs with no history of seizures be concerned about the black box warning?

The black box warning applies to all dogs starting an isoxazoline product — not only dogs with a prior history of seizures. The FDA added the warning because neurological adverse events occurred in dogs without a documented seizure history. The warning does not mean these products are contraindicated for otherwise healthy dogs; millions of dogs receive isoxazoline products without incident. What it means practically is that owners should be informed of the warning before the first dose, should watch for neurological signs in the days and weeks after starting, and should report any signs promptly to their veterinarian. Dogs with a prior seizure history require a more specific veterinarian evaluation before starting, not a blanket disqualification.

How should an owner report a suspected adverse reaction?

If your dog experiences a suspected adverse reaction to an isoxazoline product, report it through two channels: first, contact your veterinarian for clinical guidance on your dog’s immediate care; second, report directly to the FDA at 1-888-FDA-VETS (1-888-332-8387) or through the FDA Safety Reporting Portal online. You may also report to the manufacturer through the phone number on the product packaging. Adverse event reports to the FDA contribute to post-market safety surveillance and help the agency monitor whether the frequency or severity of reported events changes over time. The FDA’s review of isoxazoline safety in 2018 and 2019, which led to the black box warning requirement, was triggered by the accumulation of post-market adverse event reports from veterinarians and pet owners.

Do cats face the same neurological risk from isoxazoline products?

The FDA black box warning on neurological adverse events applies to isoxazoline products labeled for dogs. Cat-labeled isoxazoline products exist (for example, Bravecto Plus for cats), and as with any prescription product, the labeling and any associated warnings should be reviewed with your veterinarian before use. It is critical to note that some dog-labeled isoxazoline products are toxic to cats and should never be applied to or ingested by cats. If a cat is in a household where a dog is receiving an isoxazoline chew, there is no meaningful risk of secondary exposure from contact with the dog, but cats should not be given products labeled for dogs under any circumstances.