Vigabatrin therapy for infantile spasms: review of major trials in Europe, Canada, and the United States; and recommendations for dosing

Abstract

Carmant L. Vigabatrin therapy for infantile spasms: review of major trials in Europe, Canada, and the United States; and recommendations for dosing. Acta Neurol Scand: 2011: 124 (Suppl. 192): 36–47. © 2011 John Wiley & Sons A/S. Infantile spasms (IS) are a unique and severe form of epilepsy associated with poor neurologic and developmental outcomes. The refractory spasms and abnormal electroencephalogram (EEG) patterns associated with the condition are believed to have a progressively detrimental impact. Therefore, rapid and complete control of spasms is the primary goal of treatment. Well‐controlled clinical trials in Europe, Canada, and the United States have demonstrated that vigabatrin is efficacious and generally well‐tolerated as monotherapy for IS. Several key studies, including pivotal trials that led to United States approval of vigabatrin in 2009, as well as comparative trials of vigabatrin and hormonal treatment, are the focus of this review. All studies assessed spasm cessation — usually as the primary endpoint — and adverse events. Vigabatrin dosages generally ranging from 100 to 150 mg/kg/day demonstrated efficacy to decrease or eradicate spasms and eliminate hypsarrhythmic EEG in patients with newly diagnosed IS. Several studies demonstrated long‐term sustainability of spasm freedom with no negative impact on developmental outcomes. Vigabatrin was generally well‐tolerated with few severe adverse events. Visual field defects cannot be adequately assessed in infants and young children, so this potential adverse effect was not evaluated in children with spasms. Notably, the time to response with vigabatrin was very rapid, generally occurring within 2 weeks of initial treatment. This allows for early treatment modification as needed. For infants who respond well to vigabatrin, treatment duration up to 6 months appears to be appropriate for realizing spasm freedom while limiting potential risks of adverse events and recurrences.

Long‐term outcome in children with infantile spasms treated with vigabatrin: A cohort of 180 patients

“…Vigabatrin is effective and well‐tolerated as first‐line therapy for infantile spasms. The major trials in Europe, Canada, and the United States reported complete resolution of infantile spasms in 35–75% of cases . Our finding of a 56% electroclinical resolution is similar to previous studies, including the UKISS study .…”

Long‐term outcome in children with infantile spasms treated with vigabatrin: A cohort of 180 patients

“…Vigabatrin is effective and well‐tolerated as first‐line therapy for infantile spasms. The major trials in Europe, Canada, and the United States reported complete resolution of infantile spasms in 35–75% of cases . Our finding of a 56% electroclinical resolution is similar to previous studies, including the UKISS study .…”

Reconsideration of Vigabatrin Effect in Infantile Spasms Treatment

“…Many animal studies and retrospective studies have discussed bilateral VFDs due to use of VGB [6,[10][11][12][13][14]. However, no patient in the present study experienced such adverse drug reaction when regular eye examination was performed, consistent with a small prospective study recently conducted in Japan [16].…”

Efficacy and safety of vigabatrin in Japanese patients with infantile spasms: Primary short-term study and extension study

“…Vigabatrin was efficacious and well tolerated in Japanese infants with infantile spasms and a broad range of underlying etiologies at a dose of 75-150 mg/kg/day. The efficacy and safety of vigabatrin in this study were consistent with observations from prospective, randomized controlled studies in the US, Europe, and Canada, where 35-75% of patients were completely spasm-free [10]. Likewise, the effective dose of vigabatrin reported in this study is comparable with that reported in a small German study, where patients with infantile spasms, who have seizures that were treatment-refractory to other therapies but 0 (0.0) 0 0 (0.0) 0 Serious AEs 1 (7.7) 1 0 (0.0) 0 Events resulting in discontinuation 0 (0.0) 0 0 (0.0) 0 Treated events 11 (84.6) 29 5 (38.5) 6 AESI 0 (0.0) 0 0 (0.0) 0 Death 0 (0.0) 0 0 (0.0) 0 ADR, adverse drug reaction; AE, adverse event; AESI, adverse events of special interest.…”

“…In our study on Japanese infants with infantile spasms, the overall safety profile of vigabatrin was similar to that reported in other sample populations. It was also consistent with previous studies that reported a low or nonexistent incidence of SAEs and no vigabatrin-related deaths [10,21]. Sedation, somnolence, and irritation are the most commonly reported AEs, but tend to be dose-dependent and transient [10,21,28].…”

“…No peripheral VFDs or confirmed ophthalmologic abnormalities were observed in patients treated with vigabatrin during the primary short-term study or after follow-up at Week 32 of the extension study, but it is acknowledged that peripheral VFDs have been correlated with the cumulative exposure to vigabatrin over extended periods of time, generally N 12 months, which are greater than the duration of this study so far [10,15,16,19]. On the other hand, in most cases peripheral VFDs are mild in severity and differentiating between disease-and treatment-related VFDs can be difficult given that infantile spasms are commonly associated with vision impairment [5].…”

Long‐term outcome in children with infantile spasms treated with vigabatrin: A cohort of 180 patients

“…Vigabatrin is effective and well‐tolerated as first‐line therapy for infantile spasms. The major trials in Europe, Canada, and the United States reported complete resolution of infantile spasms in 35–75% of cases . Our finding of a 56% electroclinical resolution is similar to previous studies, including the UKISS study .…”

Reconsideration of Vigabatrin Effect in Infantile Spasms Treatment

“…Many animal studies and retrospective studies have discussed bilateral VFDs due to use of VGB [6,[10][11][12][13][14]. However, no patient in the present study experienced such adverse drug reaction when regular eye examination was performed, consistent with a small prospective study recently conducted in Japan [16].…”

Efficacy and safety of vigabatrin in Japanese patients with infantile spasms: Primary short-term study and extension study

“…Vigabatrin was efficacious and well tolerated in Japanese infants with infantile spasms and a broad range of underlying etiologies at a dose of 75-150 mg/kg/day. The efficacy and safety of vigabatrin in this study were consistent with observations from prospective, randomized controlled studies in the US, Europe, and Canada, where 35-75% of patients were completely spasm-free [10]. Likewise, the effective dose of vigabatrin reported in this study is comparable with that reported in a small German study, where patients with infantile spasms, who have seizures that were treatment-refractory to other therapies but 0 (0.0) 0 0 (0.0) 0 Serious AEs 1 (7.7) 1 0 (0.0) 0 Events resulting in discontinuation 0 (0.0) 0 0 (0.0) 0 Treated events 11 (84.6) 29 5 (38.5) 6 AESI 0 (0.0) 0 0 (0.0) 0 Death 0 (0.0) 0 0 (0.0) 0 ADR, adverse drug reaction; AE, adverse event; AESI, adverse events of special interest.…”

“…In our study on Japanese infants with infantile spasms, the overall safety profile of vigabatrin was similar to that reported in other sample populations. It was also consistent with previous studies that reported a low or nonexistent incidence of SAEs and no vigabatrin-related deaths [10,21]. Sedation, somnolence, and irritation are the most commonly reported AEs, but tend to be dose-dependent and transient [10,21,28].…”

“…No peripheral VFDs or confirmed ophthalmologic abnormalities were observed in patients treated with vigabatrin during the primary short-term study or after follow-up at Week 32 of the extension study, but it is acknowledged that peripheral VFDs have been correlated with the cumulative exposure to vigabatrin over extended periods of time, generally N 12 months, which are greater than the duration of this study so far [10,15,16,19]. On the other hand, in most cases peripheral VFDs are mild in severity and differentiating between disease-and treatment-related VFDs can be difficult given that infantile spasms are commonly associated with vision impairment [5].…”

Long‐term outcome in children with infantile spasms treated with vigabatrin: A cohort of 180 patients

“…Vigabatrin is effective and well‐tolerated as first‐line therapy for infantile spasms. The major trials in Europe, Canada, and the United States reported complete resolution of infantile spasms in 35–75% of cases . Our finding of a 56% electroclinical resolution is similar to previous studies, including the UKISS study .…”

Reconsideration of Vigabatrin Effect in Infantile Spasms Treatment

“…Many animal studies and retrospective studies have discussed bilateral VFDs due to use of VGB [6,[10][11][12][13][14]. However, no patient in the present study experienced such adverse drug reaction when regular eye examination was performed, consistent with a small prospective study recently conducted in Japan [16].…”

Efficacy and safety of vigabatrin in Japanese patients with infantile spasms: Primary short-term study and extension study

“…Vigabatrin was efficacious and well tolerated in Japanese infants with infantile spasms and a broad range of underlying etiologies at a dose of 75-150 mg/kg/day. The efficacy and safety of vigabatrin in this study were consistent with observations from prospective, randomized controlled studies in the US, Europe, and Canada, where 35-75% of patients were completely spasm-free [10]. Likewise, the effective dose of vigabatrin reported in this study is comparable with that reported in a small German study, where patients with infantile spasms, who have seizures that were treatment-refractory to other therapies but 0 (0.0) 0 0 (0.0) 0 Serious AEs 1 (7.7) 1 0 (0.0) 0 Events resulting in discontinuation 0 (0.0) 0 0 (0.0) 0 Treated events 11 (84.6) 29 5 (38.5) 6 AESI 0 (0.0) 0 0 (0.0) 0 Death 0 (0.0) 0 0 (0.0) 0 ADR, adverse drug reaction; AE, adverse event; AESI, adverse events of special interest.…”

“…In our study on Japanese infants with infantile spasms, the overall safety profile of vigabatrin was similar to that reported in other sample populations. It was also consistent with previous studies that reported a low or nonexistent incidence of SAEs and no vigabatrin-related deaths [10,21]. Sedation, somnolence, and irritation are the most commonly reported AEs, but tend to be dose-dependent and transient [10,21,28].…”

“…No peripheral VFDs or confirmed ophthalmologic abnormalities were observed in patients treated with vigabatrin during the primary short-term study or after follow-up at Week 32 of the extension study, but it is acknowledged that peripheral VFDs have been correlated with the cumulative exposure to vigabatrin over extended periods of time, generally N 12 months, which are greater than the duration of this study so far [10,15,16,19]. On the other hand, in most cases peripheral VFDs are mild in severity and differentiating between disease-and treatment-related VFDs can be difficult given that infantile spasms are commonly associated with vision impairment [5].…”