When a drug loses its patent protection, generic alternatives typically enter the market. To be admitted to the European market generic anti-seizure medications must be equal to brand-name products (EMA, 2018). For this purpose, among other requirements, e.g. that the quality requirements of generic medicines should be equal to brand-name drugs, bioequivalence should be demonstrated. It is considered that when the exposure-in-time profile of the generic is the same as that of the brand-name drug, therapeutic equivalence can be considered in case the drug is taken in line with the posology. However, it is known that mistakes in this switching process, e.g., missed doses, double doses, may happen. Dependent on the therapeutic  window of the drug involved, the consequences of such mistakes can be mild or severe. For anti-epileptic drugs, it cannot be excluded that such mistakes may lead to seizure recurrence or adverse effects. Randomized clinical trials (RTCs) on this topic are rare.

Another important driver for switching originates from drug shortages, which have become increasingly more common in recent years. When the brand-name product is temporarily unavailable, switching to a generic formulation is often not a matter of preference but of necessity to maintain continuity of care. In such situations, clinicians must balance the urgency of preventing treatment interruption against the potential risk of altered serum concentrations or breakthrough seizures.

This module focuses on the comparison between generic drugs and their brand-name counterparts, exploring both clinical outcomes and, if possible, economic implications.

Summary of Findings

Observational studies included in 2025

Generic anti-seizure medication versus brand-name (specialty) anti-seizure medication with outcomes seizure incidence (seizure freedom, 50% seizure reduction), time to seizure recurrence, adverse events, retention/discontinuation rate

Population: Adults and children with epilepsy
Intervention: Generic anti-seizure medication 
Comparator: Brand-name (specialty) anti-seizure medication  

_{^1. Risk of bias: serious (-1 level). It is not clear for which specific confounding variables the multivariate analysis adjusted. Imprecision: very serious (-2 levels). The confidence interval crosses both borders of clinical relevance.}

_{^2. Risk of bias: serious (-1 level). The study did not adjust for confounding variables and there was a lack of objective measurements to assess seizure frequency and adverse events. Imprecision: very serious (-2 levels). The confidence interval was very wide.}

_{^3. The evidence could not be graded as no between-group comparison was available.}

Studies included in previous summary of literature
When assessing the studies using the GRADE approach, the strength of evidence is considered moderate for the comparison between Tegretol and generic carbamazepine. Points were deducted due to imprecision (low number of events). For the comparisons between Dilantin and generic phenytoin (Epsolin, Eptoin, Epileptin), and between Depakine and generic valproate, additional points were deducted due to indirectness. In these cases, the strength of evidence is low because only one study provides a direct comparison between these drugs. Due to the small sample sizes of the RCTs, a minor difference in effectiveness between brand-name and generic drugs cannot be ruled out. Furthermore, the short duration of the RCTs prevents any conclusions about potential long-term differences in effectiveness. Lastly, studies on recently marketed anti-seizure medications are lacking.

Conclusions

Description of studies

In the analysis of the literature conducted previously, which was updated until 2020, a total of three studies were included. These were two systematic reviews (Kesselheim, 2010; Yamada, 2011) and one crossover study (Kesselheim, 2016). In 2025, a total of two studies were added to the summary of the literature.

Important study characteristics and results are summarized in the evidence tables (see Tables 2, 3 and the Appendix). The assessment of the risk of bias is summarized in the risk of bias tables (under the tab ‘Evidence tabellen’).

Lang (2021) conducted a retrospective cohort study comparing branded anti-seizure medication (ASM) and generic drugs in children and adolescents with epilepsy. The study data were derived from a database consisting of children who visited one of the 236 pediatricians in Germany between January 2011 and December 2018. Included patients had one of the following diagnoses: localization-related epilepsy, generalized epilepsy, as well as special epileptic syndromes, unspecified ‘‘grand mal”, ‘‘petit mal” seizures, and other unspecified epilepsies. Patients had to have at least one documented seizure during the complete study period, but no seizure within 180 days prior to the index date (the day of the first seizure after a preceding period of 180 seizure-free days). Additionally, at least two prescriptions from the same pediatrician within 360 days and at least one prescription within 180 days prior to the index date were required. Furthermore, individuals needed to be able to be matched 1:1 on an individual level according to age, gender, insurance status, and treating pediatrician to seizure-free patients serving as a control group. The same inclusion criteria applied for the controls, except that their index dates consisted of a randomly selected visit at their treating pediatrician’s office within the study period, since they did not suffer seizures.

Tharavichitkun (2022) conducted a retrospective pre-post observational study, comparing the change from the original levetiracetam (Keppra®, UCB Pharma S.A., Braine-l’Alleud, Belgium) to the equivalent generic drug (Lecetam®, Unison Laboratories Co., Ltd., Chachoengsao, Thailand). The study was conducted at the outpatient department of the Neurological Institute of Thailand in Bangkok. Inclusion criteria included being diagnosed with epilepsy at least six months before the transition, stable seizure frequency (within ±25% of their mean seizure frequency), and have been taking a stable dose of the original levetiracetam to maintain a steady-state concentration during the 72 h before the transition. In addition, the patients have abruptly received a generic levetiracetam dose equivalent to that of the brand-name levetiracetam at the transition visit. The dosing regimen of concomitant AEDs was also not modified within 72 h before and after the substitution. Exclusion criteria were an absence seizure, therapy with levetiracetam formulations other than tablets before the substitution, a record of poor compliance or >80% missed doses in the medical chart, death, or loss to follow-up.

Table 2. Characteristics of included studies

_{*For further details, see risk of bias table in the appendix
¹Study characteristics not described separately for intervention and control group (only for mentioned subgroups).
²Study characteristics not described separately for intervention and control group. Due to the pre-post design of the study, both groups consist of the same patients.}

Results

1. Seizure incidence

Observational studies included in 2025
Two studies (Lang, 2021; Tharavichitkun, 2022) reported seizure incidence as an outcome measure.

Comparison of several generic anti-seizure drugs with brand-name original

Lang (2021) reported that a switch from specialty to generic anti-seizure medication was associated with lower odds of recurrent seizures compared to continued use of specialty anti-seizure medication, with OR = 0.56 (95% CI 0.23 to 1.37). This was considered a clinically relevant difference between the groups.

Comparison of generic version of levetiracetam with brand-name levetiracetam
Tharavichitkun (2022) did not show a significant increase in seizure frequency after switching from brand-name to generic anti-seizure medication. Mean seizure frequency was 2.77 (± SD 11.41) per month at baseline, 3.24 (± SD 14.49) per month three months after the switch, and 3.15 (± SD 14.47) per month six months after the switch. After three months, the mean difference compared to baseline was 0.47 (95% CI -3.70 to 4.64) seizures per month, and after six months, this was 0.38 (95% CI -3.27 to 4.03) seizures per month.

The authors also report a subgroup analysis for patients with controlled seizures and patients with uncontrolled seizures. They show that, from baseline to six months, the number of seizures per month in patients with controlled seizures increases from 0.03 (± SD 0.16) to 0.56 (± SD 1.83), which corresponds to a mean difference of 0.53 (95% CI 0.02 to 1.04) seizures per month. As the baseline frequency was close to zero, this likely reflects a clinically relevant change. The change in the subgroup of patients with uncontrolled seizures was not clinically relevant and/or statistically significant.

Studies included in previous summary of literature

The two systematic reviews (Kesselheim, 2010; Yamada & Welty, 2011) analyze both randomized controlled trials (RCTs) and observational studies. Only the RCTs use a direct outcome measure: reduction in seizure frequency. Yamada and Welty (2011) include four RCTs that use seizure frequency as the outcome measure. In Kesselheim (2010), these four RCTs are supplemented by three additional RCTs, and a meta-analysis is conducted (Figure 1). All studies involve patients aged 10 and older, predominantly with treatment-responsive stable epilepsy. Six of the seven RCTs are crossover studies in which patients undergo both the intervention and control treatment in successive periods. Brand-name drugs are compared with their corresponding generic equivalents: Tegretol versus carbamazepine (four studies), Dilantin versus phenytoin (Epsolin, Eptoin, and Epileptin; one study), Depakine versus valproate (one study), and a brand-name versus a generic formulation of sustained-release carbamazepine (one study). These are small studies (10–64 participants), published between 1986 and 1997, with relatively short study durations ranging from 3 days per study arm (one study), to 3–6 weeks (four studies), and 3 months (two studies).

None of the RCTs showed a statistically significant difference in effectiveness between the brand-name drug and its corresponding generic counterpart. A meta-analysis of the seven RCTs (see Table 1) also revealed no difference in effectiveness (OR: 1.0; 95% CI: 0.7–1.4) among patients who had at least one seizure. This finding remained unchanged after excluding RCTs with low study quality (OR: 1.2; 95% CI: 0.6–2.2), or after excluding studies with a follow-up duration of less than four weeks (OR: 0.8; 95% CI: 0.5–1.2). None of the studies reported safety concerns or serious adverse effects associated with the use of generic drugs.

_{Figure 1. Effectiveness of generic versus brand-name anti-seizure medication}

A case-crossover study investigated the risk of seizure-related events associated with continuing the same generic anti-seizure medication versus switching manufacturers of that same generic drug (Kesselheim, 2016). Data from two large U.S. databases were used, involving 83,001 epilepsy patients who were using a generic anti-seizure medication and visited the emergency department or were hospitalized due to a seizure. In this study design, patients served as their own control group.

Continuing the same generic anti-seizure medication was associated with an 8% increase in the odds of a seizure-related event (odds ratio [OR]: 1.08; 95% confidence interval [CI]: 1.06–1.11). Switching to a different manufacturer of the same generic drug was associated with a 9% increase in the odds of such an event (OR: 1.09; 95% CI: 1.03–1.15). It remains questionable whether emergency department visits or hospitalizations alone are sufficient to conclude whether seizure frequency has increased or decreased (Kesselheim, 2016).

2. Time to seizure recurrence

None of the studies reported time to seizure recurrence as an outcome measure.

3. Retention/discontinuation rate

One study (Tharavichitkun, 2022) reported the retention/discontinuation rate. Five patients (6.7%) switched back from generic levetiracetam to brand-name levetiracetam.

In 22 patients (29.3%) therapy adjustments were needed (increasing the dose of generic levetiracetam, increasing the dose of concomitant anti-seizure medication, adding another anti-seizure medication). In this study, the retention/discontinuation rate was not reported/applicable for (specialty) brand-name levetiracetam.

4. Adverse events

One study (Tharavichitkun, 2022) reported adverse events. Six patients (8.0%) experienced adverse events during the six months of follow-up. These included aggression (n = 2), somnolence (n = 1), dizziness (n = 2), and loss of appetite (n = 1). No information was available regarding adverse events before the medication switch.

A systematic review of the literature was performed to answer the following question(s):

To what extent do generic drugs differ from brand-name drugs in terms of effectiveness and side effects?

Table 1. PICO

Relevant outcome measures

The guideline panel considered seizure incidence and time to seizure recurrence as critical outcome measures for decision making; and retention/discontinuation rate and adverse events as important outcome measures for decision making.

The working group did not define the outcome measures listed above but used the definitions used in the studies. For instance, for seizure freedom this could mean number of patients being seizure free at a certain time point during follow-up or for a certain duration during follow-up.

The working group defined HR/RR ≤0.8 or ≥1.25 (dichotomous variables) and 0.5 SD (continuous variables) as minimal clinically (patient) important difference, and HR/RR between 0.8 and 0.9 or 1.10 and 1.25 as small effects for all outcomes.

Search and select (Methods)

The first version of this module was based on a literature search, which was conducted to compare the effectiveness of generic drugs and brand-name drugs in both adults and children. Seizure frequency and side effects were used as outcome measures. The search covered studies published from January 1, 1999, in the databases Medline, Embase, and the Cochrane Library.

For the current revision, we searched the databases Medline/Pubmed and Embase with relevant search terms from 01-01-2019 (last search) until 5-2-2025. The detailed search strategy is depicted under the tab Methods. The search was limited to systematic reviews and randomized controlled trials. The systematic literature search resulted in 374 articles.

Studies were included based on the following criteria:

• Systematic review or RCT.
• Full-text English language publication.
• Studies according to PICO.

In the revision, 9 studies were selected based on title and abstract screening. After reading the full text, 7 studies were excluded (see the exclusion table under the tab ‘Evidence tabellen’), and two studies were included.

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