Cenobamate - An Antiepileptic Medication with Great Effectiveness

This article explains the new medication for epilepsy Cenobamate or Xcopri and reviews its uses and interactions.

In November 2019, the FDA approved a variety of antiepileptic medication known as Cenobamate (Xcopri). It was approved for its use as a treatment for focal epilepsy in patients aged 18 years old and above.

Early Days

It is a new compound that works by blocking sodium channels in the nerve cells of the hippocampus of the brain. When these sodium channels are blocked, they reduce the excitability of these neurons, reducing the likelihood of developing seizures. They also activate a receptor in brain neurons responsible for reducing the excitability of neuron cells called GABA-A receptors, which further stabilizes the brain, reducing the development of spontaneous seizures. [1] 

At first, with the huge variety of medication released every day, claiming to be effective a certain type of ailment, it’s difficult to get excited about the potential of Cenobamate. Especially since at the time, the documented literature spoke of adverse reactions of Cenobamate such as a severe form of an allergic reaction known as drug reaction with eosinophilia and systemic symptoms (DRESS), which is associated with the development of an extensive skin rash in association with internal organ involvement, causing damage to the lymph nodes of the body, and causing changes in the number of white blood cells, particularly decreasing eosinophils and causing increased formation of lymphocytes white blood cells. Luckily, this reaction only happened to 3 patients at the begigning of the clinical trails and after adjusting the titration schedule, we did not see it again. 

This however didn’t stop the international discourse that took place around the effectiveness of Cenobamate, as well as the possible efficacy in patients with recurrent unresolved focal epilepsy. As a result, with many good things told about Cenobamate by other doctors I met in global neurological conferences, I decided a make a commitment to research Cenobamate and begin prescribing it to my patients.

The First Clinical Trial

Dr. Gregory Krauss from the Johns Hopkins University, who conducted the first clinical trial for Cenobamate mentions that Cenobamate is particularly effective in treating drug resistant epilepsy.

Drug resistant epilepsy is defined as failure of two or more anti-epileptic medication in inducing seizure control. Studies show that less than 5% become treated with continued medication. However, Cenobamate showed a control rate for drug resistant epilepsy of 25% which is 5 times more than previous medication, according to Dr. Krauss. 

He also noted that Cenobamate was also effective in completely controlling the most dangerous and severe, generalized tonic-clonic seizures or grand mall seizure variety.

Currently, one of the most prescribed medication for focal epilepsy is Levetiracetam (Keppra). They show a highest dose response rate of 39.8% and a seizure freedom rate of 5.5% in studies conducted and continued use of the drug. This basically means that 40% of patients who are taking the highest dose of the drug show an effective response and 5.5% of patients are able to experience no seizures at all. In comparison, Cenobamate, had figures for highest dose response rate and a seizure freedom rate of 64% and 28% respectively. These weren’t just lucky outcomes, but were rates sustained after long term use of Cenobamate of up to 2 to 3 years in phase 3 trials. [2]

Adverse Effects

After covering the mechanism of action, as well as the quite apparent clinical effectiveness of Cenobamate, it does show some peculiar adverse effects. Namely, sleepiness, dizziness, headache, fatigue and double vision. These are dose dependent reactions, which means that they could be reduced by lowering the dose of the medication as well as they usually get better with time as the body gets used to the medication. Furthermore, it is advised to stop driving and operating heavy machinery when starting Cenobamate as a medication, until the symptoms improve. Either way, if a patient suffers from uncontrolled recurrent seizures, they must not drive nor operate heavy machinery. 

There are two more rare side effects known as Short QT syndrome, which is related to electrical conducting system of the heart muscle, where you should not use it if you have a family history of familial short QT syndrome.

The second rare side effect which was discussed as DRESS earlier in this article, was only seen in 3 patients in clinical trials. It was also mentioned in studies that the risk of developing DRESS, can significantly be reduced by slow titration, which means introducing the drug to the patient slowly, allowing the patients biochemistry to adjust to the medication. 

Pregnancy and Breastfeeding

For patients who are pregnant or breast feeding, currently the effects of Cenobamate on the fetus or infant are unknown. Currently, animal studies have shown that Cenobamate can cause possible harm to the fetus during its development. If you get pregnant while taking Cenobamate, please enroll yourself in pregnancy registries within your country to learn more about this medication.

Dr. Krauss has stated a lot of information about the potential drug interactions that Cenobamate can have when used concurrently with other drugs. He states that it is similar to Lamotrigine, which is another antiepileptic medication and its risk in causing allergic drug reaction, but this was when lamotrigine was started at high doses immediately. However, it was found out that when lamotrigine was administered little by little, it will have much lower adverse allergic reaction. This is the same behavior shown by Cenobamate, starting it at low doses and then increasing it over a span of time. There are drugs that due to the action of Cenobamate increase in concentration in the blood. These drugs have a likelihood of becoming toxic if their doses are not altered. So neurologists are responsible for decreasing the dose of such drugs. At the same time, there are drugs that increase the blood concentration of Cenobamate, in which case you may see the adverse effects of Cenobamate come up. So alterations need to be made in the drug regimen to prevent this. The highest dose that’s tested and approved for Cenobamate is 400mg. However the therapeutic dose is between 150 to 300mg.

Drug Interactions

Cenobamate as mentioned above, can block the metabolism of certain drugs, increasing their concentration in the blood. These drugs are Clobazam, Phenytoin and Phenobarbital. So if these drugs are used in parallel to Cenobamate, their dose should be reduced by at least to forgo the development of drug toxicity in these medications. 

If there on high doses of drugs that have similar action to Cenobamate like Lacosamide, these drugs should be administered at a lower dose as well, if used together with Cenobamate. Making these changes is beneficial due to Cenobamate’s good efficacy, and the drop in the other drugs will not reduce the positive outcome associated with Cenobamate.

What I Prefer

In my personal practice, I began using Cenobamate in all my patients who have drug resistant epilepsy and so far, I have had good results in these patients, who have at first had many seizures, but have become seizure free because of Cenobamate. My fellow neurologists, prescribing Cenobamate as well have had a similarly positive experience. I currently have  a dozen patients on Cenobamate and all have shown positive responses. One doctor told me, that his patient regards him as a genius, because ever since this doctor prescribed Cenobamate, it was able to stop this patients’ brain tumor induced seizures, and the patient is now seizure free.

In fact, Dr. Krauss mentions that if you are a candidate for difficult surgical intervention for epilepsy, it is best to try Cenobamate to try to induce seizure control if the surgery has high potential risks.

Parting Words

There are as of yet, over 7000 patients currently on Cenobamate who have not shown any adversely dangerous reactions. Whilst this is a good indicator, patients using this medication should be closely followed up to avoid missing rare and potentially dangerous side effects, when the drug is used more widely. However, it is quite clear that the benefits of Cenobamate in inducing seizure freedom should motivate doctors treating epilepsy to offer it as an option to patients who may benefit.

Cenobamate is currently under study for its use in the pediatric population as well as its effectiveness in generalized epilepsy.

References

• Specchio, N., Pietrafusa, N. and Vigevano, F. (2021) ‘Is Cenobamate the Breakthrough We Have Been Wishing for?’, International Journal of Molecular Sciences, 22(17). doi: 10.3390/IJMS22179339.
• Sperling MR, Klein P, Aboumatar S, et al. Cenobamate (YKP3089) as adjunctive treatment for uncontrolled focal seizures in a large, phase 3, multicenter, open-label safety study. Epilepsia. 2020;61(6):1099-1108. doi:10.1111/epi.16525