Switching Antiepileptic Drug Manufacturer Increased Seizure Risk

Hajo Hamer, MD, MHBA

Switching between an antiepileptic drug (AED) made by different manufacturers was associated with increased risk of seizures in a large case-control study in Germany, contrary to findings of a similarly large US population study.

Hajo Hamer, MD, MHBA, Department of Neurology, Epilepsy Center, Friedrich-Alexander Universität Erlangen-Nürenberg, Erlangen, Germany and colleagues considered several factors more likely than bioavailability differences for the apparent increased seizure risk, and suggested some factors that may explain why this association was not evident in the US study. They suspect, for example, that a different dosage appearance could have greater influence on the German population adherence to their medication regimen than in the US.

"This is particularly true in Germany where the different appearance refers to the package itself in addition to color and shape of the tablet," Hamer and colleagues observe. "Changing this appearance by administering the product of another manufacturer has led to reduced adherence."

Hamer and colleagues accessed data from the IMS Disease Analyzer (Quintiles IMS, Frankfurt, Germany) for over 5 million patients who were seen by 163 neurologists in Germany between November 1, 2011 and October 31, 2016 and identified 30,722 diagnosed with epilepsy. Inclusion criteria required at least 2 antiepileptic drug prescriptions from the same physician within 360 days prior to the index date (date of first seizure to reoccur after 180 seizure-free days).

The study cohort comprised 1765 patients with seizures in the study period and a matched (for age, gender, insurance status, and treating physician) control group of 1765 patients with epilepsy but without seizure in this period. Control subjects had at least 2 prescriptions within 360 days prior to the index date (randomly selected visit among controls) as well as at least 1 prescription within 180 days prior to the index date.

The database provided patient demographics, physician specialty, patient visit dates, and prescribing information down to the package level. In addition, records were retrieved from each of the neurologists, including their notes on each visit, which were used to document the occurrence of a seizure.

Hamer and colleagues contrasted this method of documenting seizure from that used in the US study, which had included only patients admitted to a hospital or emergency room department.

"In Germany patients with epilepsy are usually not admitted to hospitals or do not even seek immediate treatment at an emergency room when their typical seizures recur," they related. "They rather schedule an urgent appointment with their treating physician in private practice."

The investigators found a change of manufacturer in the last prescription before the index date occurred more often in the seizure group than in controls. They estimated the risk to be increased by more than 30% for documented seizure-recurrence after switching manufacturer, from either branded to generic or between generic drugs. They noted that there was no difference between the groups in the latency between the last prescription and the index date.

Applying adjusted logistic regression confirmed that switching the manufacturer was an independent risk factor for seizure recurrence. Changing the substance or the strength of the AED did not remain a significant risk factor for seizure recurrence after multivariate regression analysis.

In the US study, Switching Generic Antiepileptic Drug Manufacturer Not Linked to Seizures , a different conclusion was reached by Aaron Kesselheim, MD, JD, MPH, Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, and colleagues.

"We found that among patients with seizures on AEDs who successfully refilled their medications, the outcome was not affected by whether that refill was characterized by a different Food and Drug Administration (FDA)-approved manufacturer or a pill of a different appearance," Kesselhiem and colleagues wrote. "These results add to the growing literature supporting the routine use of interchangeable generic AEDs among patients with seizure disorders."

Hamer and colleagues point to the differences in age group between the studies as another possible factor for the disparate findings, noting that 20% of the US study cohort were children and adolescents and only 1.6% were older than 65 years of age; while approximately 40% of the German study cohort were older than 60 years. In addition, they note that the US study included only generic AED users, while the German study included both branded and generic.

A change from brand to generic in their study could have prompted a nocebo effect, Hamer and colleagues suggest. "In particular, this might affect patients who receive drugs of a different manufacturer under the impression that the replacement has been motivated by cost reduction."

The nationwide study of prescription data in Germany, “Switching the Manufacturer of Anti-epileptic Drugs is Associated with Higher Risk of Seizures,” was published in Annals of Neurology.