Are Generic and Branded Versions of Lamotrigine Bioequivalent?

PHILADELPHIA—Among patients with epilepsy, a branded version of lamotrigine is bioequivalent to two of the most disparate generic lamotrigine products, according to trial results presented at the 69th Annual Meeting of the American Epilepsy Society. In addition, no patients in the prospective, multicenter trial were outliers with differential pharmacokinetic reactions to any of the products studied, researchers said.

Anecdotal reports of patients experiencing seizures after switching versions of antiepileptic drugs (AEDs) caused neurologists to question whether bioequivalence testing performed in healthy subjects for the FDA translated to similar bioequivalence in patients with epilepsy in real-world conditions.

To investigate this question, Michel Berg, MD, Professor of Neurology at the University of Rochester, and colleagues conducted the Equivalence Among Generic Antiepileptic Drugs (EQUIGEN) single-dose study, a masked, replicate, sequence-randomized pharmacokinetic trial in people with epilepsy on concomitant AEDs.

Two other studies—the EQUIGEN chronic-dose study and the Bioequivalence in Epilepsy Patients (BEEP) study—also found that, in patients with epilepsy, generic lamotrigine products demonstrated bioequivalence to the branded product Lamictal. The EQUIGEN chronic-dose study results were presented at last year’s American Epilepsy Society meeting. The BEEP study findings were published in the September issue of Epilepsia.

“Thinking about lamotrigine as a model agent, it looks like the FDA regulations result in drugs that are truly bioequivalent,” Dr. Berg said. “There should be an improved confidence that the FDA’s rules and regulations regarding their approval process for generic medications are sound and that people can be changed and interchanged between generics and brand with reasonable confidence that these are equivalent products.”

Anecdotal Reports

Dr. Berg and colleagues chose to study lamotrigine because of multiple reports of possible problems with substitution, the drug’s pharmacokinetic characteristics, and the large number of patients taking the drug. The investigators studied Lamictal and the two most disparate generic products based on in vitro dissolution and content testing, as well as data that manufacturers submitted to the FDA. Subjects were taking at least one AED. Researchers excluded patients who were taking lamotrigine, valproate, estrogens, or sertraline.

Statistical analyses followed FDA methods for average bioequivalence, scaled average bioequivalence, and individual bioequivalence. The investigators also performed an outlier analysis.

Of the 48 subjects randomized to treatment, 45 completed all six periods. Three subjects who completed only three periods were included in the average bioequivalence analysis, but not the variability analyses. Three serious adverse events were deemed unrelated to the study.

All three products had similar concentration-time curves. Both generic products met bioequivalence criteria for area under curve and maximum level, compared with the branded product. Replicate testing revealed no significant within-subject variability.

Possible Explanations

During an FDA Town Hall Update about generic AED bioequivalence, Michael Privitera, MD, first author of the EQUIGEN chronic-dose study and President of the American Epilepsy Society, discussed possible reasons why physicians and patients reported potential problems with AED substitution. They may attribute spontaneous seizures to a recent substitution even if the substitution was unrelated, said Dr. Privitera, Professor of Neurology and Director of the Epilepsy Center at the University of Cincinnati Neuroscience Institute. Patients who expect generic drugs to be less effective may experience a nocebo effect. In addition, research has shown that when patients encounter a change in pill appearance, it may reduce their medication compliance.

Tricia Ting, MD, Associate Professor of Neurology at the University of Maryland and first author of the BEEP study, said, given the findings of bioequivalence, researchers need to consider factors such as patient expectation. “Any time a patient is dependent on a drug that lets them have a normal life, and you’re changing it, does that level of stress affect the clinical outcome?” she said.

Dr. Ting noted that one patient in their double-blind, replicated study experienced more seizures on generic medication even though his brand and generic pharmacokinetic profiles were essentially identical. The investigators rechallenged patients for reproducibility and are analyzing data from that follow-up study, she said.

—Jake Remaly

PHILADELPHIA—Among patients with epilepsy, a branded version of lamotrigine is bioequivalent to two of the most disparate generic lamotrigine products, according to trial results presented at the 69th Annual Meeting of the American Epilepsy Society. In addition, no patients in the prospective, multicenter trial were outliers with differential pharmacokinetic reactions to any of the products studied, researchers said.

Anecdotal reports of patients experiencing seizures after switching versions of antiepileptic drugs (AEDs) caused neurologists to question whether bioequivalence testing performed in healthy subjects for the FDA translated to similar bioequivalence in patients with epilepsy in real-world conditions.

To investigate this question, Michel Berg, MD, Professor of Neurology at the University of Rochester, and colleagues conducted the Equivalence Among Generic Antiepileptic Drugs (EQUIGEN) single-dose study, a masked, replicate, sequence-randomized pharmacokinetic trial in people with epilepsy on concomitant AEDs.

Two other studies—the EQUIGEN chronic-dose study and the Bioequivalence in Epilepsy Patients (BEEP) study—also found that, in patients with epilepsy, generic lamotrigine products demonstrated bioequivalence to the branded product Lamictal. The EQUIGEN chronic-dose study results were presented at last year’s American Epilepsy Society meeting. The BEEP study findings were published in the September issue of Epilepsia.

“Thinking about lamotrigine as a model agent, it looks like the FDA regulations result in drugs that are truly bioequivalent,” Dr. Berg said. “There should be an improved confidence that the FDA’s rules and regulations regarding their approval process for generic medications are sound and that people can be changed and interchanged between generics and brand with reasonable confidence that these are equivalent products.”

Anecdotal Reports

Dr. Berg and colleagues chose to study lamotrigine because of multiple reports of possible problems with substitution, the drug’s pharmacokinetic characteristics, and the large number of patients taking the drug. The investigators studied Lamictal and the two most disparate generic products based on in vitro dissolution and content testing, as well as data that manufacturers submitted to the FDA. Subjects were taking at least one AED. Researchers excluded patients who were taking lamotrigine, valproate, estrogens, or sertraline.

Statistical analyses followed FDA methods for average bioequivalence, scaled average bioequivalence, and individual bioequivalence. The investigators also performed an outlier analysis.

Of the 48 subjects randomized to treatment, 45 completed all six periods. Three subjects who completed only three periods were included in the average bioequivalence analysis, but not the variability analyses. Three serious adverse events were deemed unrelated to the study.

All three products had similar concentration-time curves. Both generic products met bioequivalence criteria for area under curve and maximum level, compared with the branded product. Replicate testing revealed no significant within-subject variability.

Possible Explanations

During an FDA Town Hall Update about generic AED bioequivalence, Michael Privitera, MD, first author of the EQUIGEN chronic-dose study and President of the American Epilepsy Society, discussed possible reasons why physicians and patients reported potential problems with AED substitution. They may attribute spontaneous seizures to a recent substitution even if the substitution was unrelated, said Dr. Privitera, Professor of Neurology and Director of the Epilepsy Center at the University of Cincinnati Neuroscience Institute. Patients who expect generic drugs to be less effective may experience a nocebo effect. In addition, research has shown that when patients encounter a change in pill appearance, it may reduce their medication compliance.

Tricia Ting, MD, Associate Professor of Neurology at the University of Maryland and first author of the BEEP study, said, given the findings of bioequivalence, researchers need to consider factors such as patient expectation. “Any time a patient is dependent on a drug that lets them have a normal life, and you’re changing it, does that level of stress affect the clinical outcome?” she said.

Dr. Ting noted that one patient in their double-blind, replicated study experienced more seizures on generic medication even though his brand and generic pharmacokinetic profiles were essentially identical. The investigators rechallenged patients for reproducibility and are analyzing data from that follow-up study, she said.

—Jake Remaly

PHILADELPHIA—Among patients with epilepsy, a branded version of lamotrigine is bioequivalent to two of the most disparate generic lamotrigine products, according to trial results presented at the 69th Annual Meeting of the American Epilepsy Society. In addition, no patients in the prospective, multicenter trial were outliers with differential pharmacokinetic reactions to any of the products studied, researchers said.

Anecdotal reports of patients experiencing seizures after switching versions of antiepileptic drugs (AEDs) caused neurologists to question whether bioequivalence testing performed in healthy subjects for the FDA translated to similar bioequivalence in patients with epilepsy in real-world conditions.

To investigate this question, Michel Berg, MD, Professor of Neurology at the University of Rochester, and colleagues conducted the Equivalence Among Generic Antiepileptic Drugs (EQUIGEN) single-dose study, a masked, replicate, sequence-randomized pharmacokinetic trial in people with epilepsy on concomitant AEDs.

Two other studies—the EQUIGEN chronic-dose study and the Bioequivalence in Epilepsy Patients (BEEP) study—also found that, in patients with epilepsy, generic lamotrigine products demonstrated bioequivalence to the branded product Lamictal. The EQUIGEN chronic-dose study results were presented at last year’s American Epilepsy Society meeting. The BEEP study findings were published in the September issue of Epilepsia.

“Thinking about lamotrigine as a model agent, it looks like the FDA regulations result in drugs that are truly bioequivalent,” Dr. Berg said. “There should be an improved confidence that the FDA’s rules and regulations regarding their approval process for generic medications are sound and that people can be changed and interchanged between generics and brand with reasonable confidence that these are equivalent products.”

Anecdotal Reports

Dr. Berg and colleagues chose to study lamotrigine because of multiple reports of possible problems with substitution, the drug’s pharmacokinetic characteristics, and the large number of patients taking the drug. The investigators studied Lamictal and the two most disparate generic products based on in vitro dissolution and content testing, as well as data that manufacturers submitted to the FDA. Subjects were taking at least one AED. Researchers excluded patients who were taking lamotrigine, valproate, estrogens, or sertraline.

Statistical analyses followed FDA methods for average bioequivalence, scaled average bioequivalence, and individual bioequivalence. The investigators also performed an outlier analysis.

Of the 48 subjects randomized to treatment, 45 completed all six periods. Three subjects who completed only three periods were included in the average bioequivalence analysis, but not the variability analyses. Three serious adverse events were deemed unrelated to the study.

All three products had similar concentration-time curves. Both generic products met bioequivalence criteria for area under curve and maximum level, compared with the branded product. Replicate testing revealed no significant within-subject variability.

Possible Explanations

During an FDA Town Hall Update about generic AED bioequivalence, Michael Privitera, MD, first author of the EQUIGEN chronic-dose study and President of the American Epilepsy Society, discussed possible reasons why physicians and patients reported potential problems with AED substitution. They may attribute spontaneous seizures to a recent substitution even if the substitution was unrelated, said Dr. Privitera, Professor of Neurology and Director of the Epilepsy Center at the University of Cincinnati Neuroscience Institute. Patients who expect generic drugs to be less effective may experience a nocebo effect. In addition, research has shown that when patients encounter a change in pill appearance, it may reduce their medication compliance.

Tricia Ting, MD, Associate Professor of Neurology at the University of Maryland and first author of the BEEP study, said, given the findings of bioequivalence, researchers need to consider factors such as patient expectation. “Any time a patient is dependent on a drug that lets them have a normal life, and you’re changing it, does that level of stress affect the clinical outcome?” she said.

Dr. Ting noted that one patient in their double-blind, replicated study experienced more seizures on generic medication even though his brand and generic pharmacokinetic profiles were essentially identical. The investigators rechallenged patients for reproducibility and are analyzing data from that follow-up study, she said.

—Jake Remaly