The most frequently reported side effects of Xcopri (cenobamate) are dizziness, drowsiness, and fatigue, with roughly one in four people experiencing at least one of these during treatment.1PubMed Central. Cenobamate (YKP3089) as adjunctive treatment for uncontrolled focal seizures in a large, phase 3, multicenter, open-label safety study These side effects are broadly similar to those seen with other seizure medications, but Xcopri carries one distinctive safety concern, a rare but serious allergic reaction called DRESS syndrome, that shapes the way the drug is prescribed and started.
The Most Frequently Reported Side Effects
In a large safety study of over 1,300 patients taking Xcopri as an add-on therapy for focal seizures, the three most common treatment-related side effects were drowsiness (reported by about 28% of patients), dizziness (about 24%), and fatigue (about 17%).2PubMed Central. Cenobamate (YKP3089) as adjunctive treatment for uncontrolled focal seizures in a large, phase 3, multicenter, open-label safety study Long-term extension data from a separate study confirmed the same pattern: dizziness, drowsiness, fatigue, and headache were the side effects that came up most consistently.3PubMed Central. Long-term Efficacy and Safety From an Open-Label Extension of Adjunctive Cenobamate in Patients With Uncontrolled Focal Seizures Gait disturbances, or trouble walking steadily, and double vision (diplopia) also showed up across multiple studies, fitting a pattern common to drugs that act on sodium channels in the brain.4PubMed Central. Critical Appraisal of Cenobamate as Adjunctive Treatment of Focal Seizures in Adults
These side effects are dose-related, meaning they tend to become more noticeable at higher doses. Because Xcopri is typically used alongside other seizure medications, many of which cause their own dizziness and drowsiness, the combined burden can make these effects feel more intense than the numbers from any single drug suggest. For most people, though, these side effects are manageable and tend to ease as the body adjusts over the first several weeks of treatment.
DRESS Syndrome and Why the Dose Start Is So Slow
The side effect that sets Xcopri apart from most other seizure drugs is DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms). DRESS is a rare but potentially life-threatening allergic reaction that can affect the skin, liver, kidneys, and other organs. During the early clinical development program for cenobamate, cases of DRESS were identified, and these events became a central focus of the drug’s safety profile.5PubMed. Cenobamate tablets as a treatment for focal-onset seizures in adults
The cases of DRESS observed in early trials were linked to a faster dose escalation schedule than the one ultimately approved. In response, the prescribing protocol was redesigned with a very slow titration. Patients start at just 12.5 mg per day and increase the dose in small steps over many weeks, eventually reaching a target range that can go up to 400 mg per day. This glacial ramp-up is not typical for seizure medications, and it exists specifically to reduce the risk of triggering DRESS. In the large safety study that used this slower titration, no cases of DRESS were observed.6PubMed Central. Cenobamate (YKP3089) as adjunctive treatment for uncontrolled focal seizures in a large, phase 3, multicenter, open-label safety study A real-world multicenter study also reported no cases of DRESS or other notable skin reactions among its patients.7PubMed Central. Cenobamate: real-world data from a retrospective multicenter study
Still, DRESS remains a labeled warning and something prescribers take seriously. If you develop a fever, rash, swollen lymph nodes, or facial swelling during the early weeks of treatment, those are signs that need immediate medical attention. The slow titration schedule is the main protection, which is why skipping doses and then restarting at a higher dose is something doctors will specifically warn against.
Psychiatric and Cognitive Side Effects
Any drug that alters brain activity raises questions about mood, thinking, and behavior. The data on Xcopri in this area are actually more reassuring than people often expect. Across phase 2 and phase 3 clinical studies, psychiatric side effects occurred at rates only slightly above placebo. Cognitive side effects were reported by fewer than 2% of patients on cenobamate versus 0.5% or less on placebo, and psychiatric side effects were reported by up to about 4% versus roughly 3% on placebo.8PubMed. Cognitive and psychiatric adverse events during adjunctive cenobamate treatment in phase 2 and phase 3 clinical studies Over longer-term follow-up of up to seven years, these rates remained low.9PubMed. Cognitive and psychiatric adverse events during adjunctive cenobamate treatment in phase 2 and phase 3 clinical studies
That said, the real-world picture adds an important footnote. In one multicenter retrospective study, a patient in their twenties developed suicidal thoughts about two months after starting cenobamate. This person had a pre-existing history of depression and anxiety, and the suicidal thoughts resolved after the drug was stopped and psychological follow-up was provided.10PubMed Central. Cenobamate: real-world data from a retrospective multicenter study This is a reminder that all seizure medications carry a class-wide FDA warning about suicidality, and people with a history of mood disorders should be monitored more carefully during the first months of treatment. The low overall rate of psychiatric side effects does not mean the risk is zero for every individual.
What Happens to Thinking and Memory Over Time
One of the more interesting findings about Xcopri is that it may actually improve certain aspects of cognition for some patients, a counterintuitive outcome for a drug that also causes drowsiness. An exploratory study found that after six months of cenobamate treatment, patients showed statistically significant improvements in verbal memory and visuospatial memory. However, attention scores worsened over the same period.11PubMed Central. Effect of Cenobamate on Cognition in Patients with Drug-Resistant Epilepsy with Focal Onset Seizures: An Exploratory Study
Longer follow-up painted an even more favorable picture. At 18 months, improvements in verbal memory, visuospatial memory, and processing speed all reached statistical significance.12PubMed Central. Long-term Impact of Cenobamate on Cognition in Patients with Drug-Resistant Focal Epilepsy: Outcomes from an Exploratory Real-World Study The researchers found that these cognitive gains appeared to be more closely tied to reductions in the overall drug burden, meaning patients were able to drop or lower doses of other seizure medications once cenobamate was working, rather than being a direct cognitive benefit of cenobamate itself.13PubMed Central. Effect of Cenobamate on Cognition in Patients with Drug-Resistant Epilepsy with Focal Onset Seizures: An Exploratory Study In other words, if Xcopri works well enough that your doctor can reduce other medications you’re taking, your thinking and memory may benefit from shedding those other drugs’ cognitive side effects.
This is worth understanding because it shifts the conversation about Xcopri’s cognitive impact. The short-term picture, where drowsiness and impaired attention are common, can look discouraging. But for people who respond well and whose overall medication load decreases, the longer-term trajectory can actually trend in the other direction.
Drug Interactions That Can Make Side Effects Worse
Xcopri both induces and inhibits certain liver enzymes involved in processing other drugs, which creates a pharmacological tangle that matters for side effects. The most clinically studied interaction involves clobazam, a benzodiazepine commonly used alongside other seizure medications. When cenobamate is added, it can cause a substantial increase in the blood levels of clobazam’s active breakdown product, N-desmethylclobazam. In one study, this increase ranged widely between patients, and the resulting buildup caused fatigue that improved once the clobazam dose was reduced.14PubMed. A retrospective non-interventional study evaluating the pharmacokinetic interactions between cenobamate and clobazam
The variability between patients is the tricky part. Some people saw moderate increases, while others experienced enormous jumps in the active metabolite’s levels. Genetic differences in liver enzymes likely play a role in this variability, and individuals with certain genetic variations in the CYP450 system may be especially vulnerable to a buildup of side effects when taking both drugs.15Epilepsy & Behavior Reports. Synergistic seizure reduction in patient with persistently elevated N-desmethylclobazam levels, CYP450 genetic polymorphism, and responsive neurostimulator targeting centromedian nuclei of bilateral thalami The practical takeaway is that if you’re already on clobazam (or potentially other drugs metabolized by the same pathways) and you start Xcopri, your doctor should be monitoring your blood levels and symptoms closely. If fatigue or excessive sedation suddenly worsens after Xcopri is added, the culprit may be rising levels of the other drug rather than a direct effect of cenobamate.
Experts in the field have noted that proactively adjusting other seizure medications when starting cenobamate, rather than waiting for side effects to appear, is a practical strategy that can make the transition smoother and keep tolerability problems from derailing treatment.16Wiley Online Library (Epilepsia). Improving the tolerability of antiseizure medications: When and how to use cenobamate and other new antiseizure medications
Side Effects in Older Adults
Older patients taking Xcopri experienced the same general side-effect profile as younger adults, but several effects showed up more frequently and in ways that carry extra practical weight. Dizziness, falls, balance problems, drowsiness, and fatigue were all reported in at least 20% of older patients during 36 months of adjunctive treatment. Notably, dizziness, falls, and balance disorders occurred at rates at least 10 percentage points higher in the older group compared with the overall study population.17PubMed Central. Safety and Efficacy of Cenobamate for the Treatment of Focal Seizures in Older Patients: Post Hoc Analysis of a Phase III, Multicenter, Open-Label Study
Falls are not just an inconvenience in older adults. A fall in someone over 65 can mean fractures, head injuries, and hospitalizations. The higher rate of balance problems and dizziness with Xcopri means that fall prevention should be an explicit part of the conversation when an older adult starts this medication. This might involve physical therapy for balance training, removing tripping hazards at home, or being especially cautious about nighttime ambulation during dose increases. Experts have also recommended that more aggressive reductions in other seizure medications may be needed in older patients specifically to keep the combined side-effect burden tolerable.18Wiley Online Library (Epilepsia). Improving the tolerability of antiseizure medications: When and how to use cenobamate and other new antiseizure medications
How Often Do People Stop Xcopri Because of Side Effects
The overall tolerability picture in real-world practice looks reasonably good, though not everyone stays on the drug. In a multicenter retrospective study, about 8% of patients discontinued cenobamate because of side effects. The most common reasons for stopping were extreme fatigue and weight loss. Roughly half of those who discontinued did so within the first 18 months, while the other half stopped later, suggesting that some tolerability problems develop or become intolerable only with extended use.19PubMed Central. Cenobamate: real-world data from a retrospective multicenter study
Side effects like dizziness, gait disturbance, tremor, and double vision were reported in this same cohort but were usually not severe enough to be the reason someone stopped treatment.20PubMed Central. Cenobamate: real-world data from a retrospective multicenter study The fact that fatigue was the most common real-world side effect, reported by about 30% of patients in this study, while also being the main reason people quit the medication, makes it the single most important tolerability issue to watch for and manage early.
Serious side effects in the clinical trial setting were reported by about 8% of patients. The most common serious events were seizure-related (which could reflect the underlying disease rather than the drug), along with occasional cases of pneumonia, falls, and dizziness.21PubMed Central. Cenobamate (YKP3089) as adjunctive treatment for uncontrolled focal seizures in a large, phase 3, multicenter, open-label safety study Nothing in the serious-event data suggested an unexpected pattern beyond what had been seen in the clinical trials.
How Xcopri Compares to Other Seizure Medications on Tolerability
One of the first questions people ask when facing a new medication is “is this going to be worse than what I’m already on?” In broad terms, the side-effect profile of cenobamate is similar to other seizure medications, with most problems falling squarely in the neurological category: dizziness, drowsiness, balance issues, visual disturbances.22PubMed. Cenobamate: A New Adjunctive Agent for Drug-Resistant Focal Onset Epilepsy There is no dramatically new category of side effect here. If you’ve taken other seizure medications and experienced these types of problems, you may recognize them with Xcopri too, though the severity might differ.
What does differ is context. Xcopri is typically prescribed for people whose seizures have not been controlled by other drugs, meaning most patients starting it are already on one or more seizure medications. Adding Xcopri to an existing regimen creates a stacking effect where side effects from all medications combine. Clinical trial data showed that patients on cenobamate experienced both greater seizure reduction and higher rates of adverse effects and drug discontinuation compared with placebo.23PubMed Central. Cenobamate for treatment-resistant focal seizures: current evidence and place in therapy This trade-off is familiar in epilepsy treatment: the drugs that work better for difficult-to-control seizures tend to also come with more tolerability challenges.
The DRESS risk is the one distinctive safety concern that does not have a close parallel with most other common seizure medications. While some other drugs (such as lamotrigine and carbamazepine) can also cause serious skin reactions, the specific early-trial DRESS signal with cenobamate is what drove the unusually slow titration schedule. As long as that schedule is followed, the real-world data so far has been reassuring.
Weight Changes and Other Less Discussed Effects
Weight loss came up in the real-world data as one of the reasons patients discontinued cenobamate, paired with extreme fatigue as the top tolerability complaint.24PubMed Central. Cenobamate: real-world data from a retrospective multicenter study Weight change is not always front and center in clinical trial reports for seizure medications, and cenobamate’s weight effects are less thoroughly characterized than its neurological side effects. For some people, modest weight loss on a seizure drug is neutral or even welcome; for others, especially those who are already underweight or have difficulty maintaining nutrition, it becomes a real problem. It is worth flagging this possibility with your doctor, especially if you notice unintentional weight loss that continues beyond the initial dose-adjustment period.
Upper respiratory tract infections also appeared in the side-effect data, particularly in older patients, though this is a common finding across many drug studies simply because upper respiratory infections are common in general. It has not been identified as a unique risk driven by cenobamate’s mechanism, and it appeared alongside other infections that tend to be incidental rather than drug-related.
The Role of Xcopri’s Mechanism in Its Side-Effect Profile
Understanding how Xcopri works helps explain why its side effects look the way they do. Cenobamate has a dual mechanism: it preferentially blocks persistent sodium currents in the brain (which are involved in generating seizures) while also enhancing a type of inhibitory signaling mediated by GABA-A receptors.25Seizure. Cenobamate: Mechanisms of action and clinical efficacy The sodium-channel activity is what produces the dizziness, double vision, and balance issues, side effects shared with other sodium-channel-blocking seizure drugs. The GABA-related activity is what produces the drowsiness and sedation, similar to benzodiazepines and other GABA-active drugs.
Because cenobamate hits both targets, it can produce a combination of side effects from each pathway. This partly explains why drug interactions with clobazam (which also works through GABA pathways) can be especially pronounced: the two drugs are reinforcing each other’s sedative effects on top of cenobamate boosting clobazam’s blood levels through liver enzyme changes. And it explains why patients already on another sodium-channel blocker may notice more dizziness or coordination problems when Xcopri is added. The good news is that the dual mechanism is also what makes cenobamate effective for seizures that have resisted other treatments. The side effects and the benefits flow from the same pharmacology, and managing the former is often about finding the right balance of doses across all medications in a person’s regimen rather than simply tolerating more symptoms.