Table 1.

Studies on anti-seizure medication switching in the past 10 years

Author (first) of study	Study design	Type of switch	Drug switched	Number of patients	Population type	Main findingsa	Adverse events
Ting et al. [47]	Randomized, double-blind, multiple-dose, steady-state, fully replicated bioequivalence study	Repeated switching every 2 weeks	Generic lamotrigine and brand-name lamotrigine	34	“Generic-brittle” patients already taking lamotrigine	Bioequivalence of generic lamotrigine to brand-name lamotrigine	Adverse events on generic unrelated to the small, allowable pharmacokinetic differences between generic and brand-name
Privitera et al. [48]	Randomized, double-blind, crossover study	Repeated switching every 14 days, for 2 months	Generic to generic lamotrigine	33	Adults (aged ≥ 18 years) with epilepsy from six epilepsy centers receiving immediate-release lamotrigine	Bioequivalence of generic lamotrigine products (high and low) in patients with epilepsy	No significant change in adverse events No study-related serious adverse events
Berg et al. [49]	Crossover, prospective, sequence-randomized, replicate pharmacokinetic study	Subtherapeutic single-dose switching after washout period	Two generic lamotrigine formulations and brand-name lamotrigine	50	Adults (≥ 18 years) with epilepsy on concomitant ASM and not currently receiving lamotrigine	Bioequivalence of generic lamotrigine-high and generic lamotrigine-low to brand-name lamotrigine	Most adverse events were mild and unrelated to treatment Adverse events not related to a particular product
Vari et al. [40]	Prospective study	Switch from brand-name to generic ASM	Brand-name levetiracetam to generic levetiracetam	59	Patients with primary, cryptogenic or symptomatic epilepsy	No increase of seizures and adverse effects after switching from brand-name to generic levetiracetam	3.4% switchback rate Increased adverse effects on generic levetiracetam in 2 (3.4%) Increased seizure on generic levetiracetam in 2 (3.4%)
Markoula et al. [42]	Prospective, open-label, non-randomized, steady-state, multiple-dose, bioequivalence study	One switch after 4 weeks	Brand-name levetiracetam to generic levetiracetam	12	Patients with epilepsy receiving brand-name levetiracetam	bioequivalence of generic levetiracetam to brand-name levetiracetam	No significant change in adverse events
Bosak et al. [38]	Retrospective study	(mostly forced) switch to generic ASM	Brand-name levetiracetam to generic levetiracetam	151	Patients with epilepsy receiving levetiracetam	Switching from brand-name to generic levetiracetam is generally safe	Nine patients (6%) had increased frequency of seizures Six patients (4%) had adverse events
Reimers et al. [43]	Naturalistic, open, prospective, two-center study	Overnight switch to generic ASM	Brand-name levetiracetam to generic levetiracetam	33	Patients with epilepsy receiving levetiracetam	Equal fluctuation of levetiracetam serum concentrations with brand-name and generic levetiracetam	N/A
Fanella et al. [44]	Observational study	Switch to generic ASM	Brand-name levetiracetam to generic levetiracetam	36	Seizure-free patients with epilepsy receiving levetiracetam	Slight, non-statistically significant variability in levetiracetam serum concentration was documented after the switch	8% switchback rate 3 patients dropped out due to adverse events
Gha-hyun and Dae [37]	Prospective study	Switch from brand-name to generic ASM	Brand-name levetiracetam to generic levetiracetam	148	Patients with epilepsy who were treated with brand-name levetiracetam for at least 6 months of sustained use	Minimal risk of increased seizure frequency after generic substitution Increased seizure frequency was noted in seven patients (4.7%), and a decreased seizure frequency was noted in 10 (6.8%)	No significant change in adverse events
Trimboli et al. [41]	Prospective observational real-life study	Switch from brand-name to generic ASM	Brand-name levetiracetam to generic levetiracetam	125	Patients with epilepsy who were treated with brand-name levetiracetam mono- or polytherapy for at least 6 months of sustained use	brand-name-to-generic levetiracetam switching was effective and safe in both monotherapy and polytherapy regardless of the epilepsy syndrome	24% of patients treated with generic monotherapy reported adverse effects, some leading to treatment discontinuation
Tharavichitkun et al. [50]	Retrospective study	Switch from brand-name to generic ASM for 6 months, then switch back	Brand-name levetiracetam to generic levetiracetam	75	Patients with stable seizure frequency	Generic levetiracetam might not show therapeutic equivalence to the original molecule, especially in patients adequately controlled by the brand-name drug	8% experienced adverse events after brand-name to generic substitution
Liang et al. [39]	Retrospective study	Switch from brand-name to domestic generic ASM	Brand-name levetiracetam to generic levetiracetam	154	Children with epilepsy	Switching from brand-name to generic levetiracetam is safe and effective	3 children (1.9%) experienced mild adverse drug reactions
Lang et al. [51]	Retrospective study, database analysis	Switch by the manufacturer of the same ASM at the last prescription before the index date	Any	678	Children and adolescents (< 18 years) with epilepsy and at least 2 prescriptions within 360 days and 1 within 180 days prior to the index date	Manufacturer switch of generic or brand-name ASM does not increase the risk for seizure recurrence in previously seizure-free children and adolescents with epilepsy	N/A
Lang et al. [52]	Retrospective study, database analysis	Switch by the manufacturer of the same ASM at the last prescription before the index date	Any	3530	Patients with epilepsy and at least 2 prescriptions within 360 days and 1 within 180 days prior to the index date	Manufacturer switch of ASM increases the risk for seizure recurrence in previously seizure-free patients	N/A
Kesselheim et al. 2016 [59]	Population-based case-crossover study	Refill of the same ASM from the same manufacturer or a different manufacturer	Any	83,001	Generic ASM users who experienced a seizure-related hospital admission or emergency room	Switch to a different generic manufacturer not associated with increased risk	Use of generic ASM associated with 8% increase in odds of seizure-related events
Hansen et al. 2013 [53]	Retrospective case–control study	Switch between bioequivalent ASM (brand-name to generic, generic to brand-name, generic to generic)	Any	1053	Patients with epilepsy with a claim for an ambulance encounter, emergency department (ED) visit, or inpatient hospitalization	Modest association between ASM switching and seizure-related events	N/A
Polard et al. 2015 [60]	Case crossover study	Brand-name to generic substitution	Any	8379	Adult patients with epilepsy	No association between brand-name-to-generic ASM substitution and risk of seizure-related hospitalization	N/A

Studies in table are organized chronologically by the type of drug switched

ASM Antiseizure medication, N/A not available

^aItalics indicates positive outcome (bioequivalence of ASM switch); bold-italics indicates negative outcome (no bioequivalence)