Wednesday, December 11, 2019

Levetiracetam versus sodium channel blockers as first prescribed treatment

Levetiracetam (Keppra) is favored by clinicians over sodium channel blockers as the first prescribed treatment for their patients, but it is also more frequently discontinued due to mood-altering adverse events, researchers reported here at the annual meeting of the American Epilepsy Society.

Through the Human Epilepsy Project, the researchers were able to pull data on 405 newly-diagnosed patients with epilepsy who had been initiated on monotherapy and had two years or more data since they started their antiepileptic drug. They found that 232 clinicians started

their patients on levetiracetam—more than three times greater frequency than the next drug of choice, lamotrigine, which was prescribed to 72 patients, reported Jacqueline A. French, MD, FAAN, professor of neurology at NYU Langone Health.

But after two years, just 86 patients, or 37.1 percent, who had been prescribed levetiracetam as monotherapy were still on that regimen; 14.2 percent of patients who started on levetiracetam had added another medication to their regimen, and 48.1 percent of the patients had switched from levetiracetam to another agent, Dr. French said at her poster presentation.

"Overwhelmingly they chose levetiracetam as the first drug for treatment, and we think that is because it is an easy drug to prescribe. It doesn't require titration, and theoretically it is well-tolerated," she said. "However, when we followed the treatment of these patients, the drug that was chosen most often was discontinued at twice the rate of the older sodium channel blockers.

"So, we are asking the question: Is it really the drug that should be started first?" Dr. French said. "There are people in the community who are now being told that when you have a patient with epilepsy, the only thing you have to know is to prescribe levetiracetam This study appears to show that such advice may not be true."

Patients said they discontinued levetiracetam mainly because of mood alterations—36.3 percent of patients on the drug said they dropped it due to mood changes such as depression and 36.3 percent cited irritability and aggression as reasons for discontinuing the drug. Dr. French also noted that 31.4 percent of the patients originally assigned to levetiracetam discontinued it due to lack of seizure control.

On the other hand, she said, patients who were on sodium channel blockers tended to stay on those treatments: 70.8 percent of patients taking lamotrigine remained on the drug, for example.

Commenting on the data, one neurologist said that he would still offer levetiracetam to his patients as a first choice.  "This information does not necessarily change my practice, which is to prescribe levetiracetam first to these patients," said Aaron Geller, MD, a neurologist with the Northeast Regional Epilepsy Group of Morristown, NJ, as well as Hackensack University Medical Center and Overlook Medical Center. "I think levetiracetam is a sufficiently benign medication, and it is worth prescribing it to patients and see if they can tolerate it. I would want them to tell me that they felt bad on it before I would want to try another treatment."

He pointed out that all the treatments have side effects. "There are strikes against all of them so I would wait to see if there was a problem with levetiracetam before considering a second drug in this population," Dr. Geller said. "Having to switch a medication is not the end of the world."

But Shaun O. Smart, MD, assistant professor of neurology at Memorial-Hermann Texas Medical Center of UTHealth in Houston, had a different perspective. "We have seen a lot of problems with our patients who have been on levetiracetam due to these mood changes. It can be a serious problem."

Angela Parsons, MD, a senior epilepsy fellow at the Mayo Clinic in Scottsdale, AZ, reported outcomes similar to those in the current study here at the AES annual meeting. "We think that you should discuss with patients if they have mood problems at the time of prescribing levetiracetam, and avoid the drug if there is a problem at baseline. We found that even mild behavioral complications from levetiracetam can impact quality of life."

"In patients at risk of mood problems, the transition from levetiracetam to another antiepileptic drug with a lower incidence of adverse mood effects should be considered," Dr. Parsons said. In her clinic, patients were transitioned to lamotrigine.

In Dr. French's study, none of the patients who were originally treated with lamotrigine expressed any of these mood disturbances as a reason for discontinuation.

The Human Epilepsy Project study is supported by the Epilepsy Study Consortium, a non-profit organization dedicated to accelerating the development of new therapies in epilepsy to improve patient care. The funding provided to the consortium comes from industry, philanthropy, and foundations: UCB Pharma, Eisai, Pfizer, Lundbeck, Sunovion, The Andrews Foundation, The Vogelstein Foundation, Finding A Cure for Epilepsy and Seizures [FACES], and Friends of Faces.

Drs. Geller, Smart, and Parsons disclosed no relevant relationships with industry.

Authors: Lydia Cassard, New York University; Manu Hegde, University of California, San Francisco; Barry E. Gidal, University of Wisconsin, Madison; Tracy Glauser, Cincinnati Children's Hospital; R. Edward Faught, Emory University; David M. Ficker, University of Cincinnati; Scott Mintzer, Thomas Jefferson University; Bassel Abou-Khalil, Vanderbilt University; Brian Alldredge, University of California, San Francisco; Pavel Klein, Mid-Atlantic Epilepsy and Sleep Center; Sarah N. Barnard, Monash University; Jon Shadan, New York University; Jacqueline A. French, New York University



We wished to assess current prescribing practices in newly diagnosed focal epilepsy. The Human Epilepsy Project (HEP) is a prospective, observational study whose goal is to identify markers of treatment response in newly diagnosed focal epilepsy. We assessed the AED exposures over the first 2 years of treatment.


Subjects were recruited from 33 sites in the US, Australia, Austria, and Finland. Inclusion criteria included: focal epilepsy, within 4 months of initial diagnosis, and all data related to AED therapy initiation available. 450 subjects have been enrolled. We selected those initiated on monotherapy and with two years or more data since AED start (N=403).  We also excluded subjects who did not have medical records available (10), did not have a known treatment start date (65), or had missing data (64), leaving 264 for analysis. We assessed only the AEDs used in the first 2 years.


157 (59.5%) initiated levetiracetam (LEV), 49 (18.6%) lamotrigine (LTG), 21 (8%) oxcarbazepine (OXC), 11 (4.2%) phenytoin, 5 (1.9%) topiramate, 12 (4.5%) carbamazepine, (CBZ)  2 (0.8%) lacosamide, 5 (1.9%) valproic acid, 1 (0.4%) pregabalin, and 1 (0.4%) zonisamide.Of the 157 started on LEV, 63 (31.6%) remained on the drug in monotherapy, 76 (48%) switched to another AED, 12 (7.6%) added an AED in conjunction, and 6 (3.8%) ceased AED usage. Of the 49 started on LTG,  34 (69.4%) remained on the drug in monotherapy,  10 (20%) switched to another AED, 4 (8.2%) added an AED in conjunction, and 1 (2%) ceased AED usage. Of the 21 started on OXC, 11 (52.4%) remained on the drug in monotherapy, 9(43%) switched to another AED, 1 (4.8%) added an AED in conjunction. Of the 12 started on CBZ, 6 (50%) remained on the drug for at least 2 years, 3 (25%) switched AEDs, and 3 (25%) ceased usage. Combining the sodium channel blockers LTG, OXC, and CBZ, (PHT excluded since often d/c’d after start in the ER) 51/82 (62%) of patients remained on initial monotherapy. By the end of the study, pts were receiving the following AEDs alone or in combination: LEV 36.0%, LTG 37.5%, CBZ 6.8%, OXC 17.0%, PHT 0.8%, topiramate 2.3%, lacosamide 7.2%, valproic acid 1.9%, zonisamide 4.9%, lorazepam 0.8%, clobazam 0.4%, clonazepam 0.4%. 79.9% of patients were on monotherapy, 16.7% on polytherapy, and 2.7% discontinued AED usage.


LEV is by far the most commonly initiated AED for focal epilepsy (3 X more than any other single AED). The likelihood of remaining on initial monotherapy was twice as high for a sodium channel blocker as for LEV in the first 2 years of treatment. (P=.001)

The HEP study is supported by the Epilepsy Study Consortium (ESCI), a non-profit organization dedicated to accelerating the development of new therapies in epilepsy to improve patient care. The funding provided to ESCI to support HEP comes from industry, philanthropy, and foundations (UCB Pharma, Eisai, Pfizer, Lundbeck, Sunovion, The Andrews Foundation, The Vogelstein Foundation, Finding A Cure for Epilepsy and Seizures [FACES], Friends of Faces and others).

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