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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5203_Библиотеки_им_академика_М_И_Перельмана.pdf
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because FBM is a relatively weak NMDA receptor antagonist. FBM, a clinically
available antiseizure medication with moderate afnity for the glycine site of the
NMDA receptor, exhibited robust antiepileptic protective effects in SSSE animal
models. These ndings suggest that FBM might be benecial when standard ASMs
fail in refractory status epilepticus patients. Drugs that act on the NMDA receptor
show promise for treating refractory status epileptic disorder. In addition to its anticonvulsant effect, FBM displays potent neuroprotective effects against excitotoxic
injury during hypoxia, global cerebral ischemia, and ischemia, making it a potential
candidate for status epilepticus treatment. In conclusion, the high efcacy and low
acute toxicity of FBM in the treatment of SSSE make it a promising candidate for
SSSE treatment and worthy of further evaluation [549].
Application ofFelbamate inSpecial Epileptic Populations
Yerby etal. described a case involving a 32-year-old man who had been receiving
valproate (VPA) monotherapy for epilepsy for 4years, during which his wife had
faced infertility issues. The man’s fertility evaluation revealed a severely low sperm
count, a lack of sperm motility, 100% structural abnormalities, and normal levels of
follicle-stimulating hormone, luteinizing hormone, and testosterone. Due to worsening seizure frequency, he transitioned from VPA monotherapy (at 3500mg/day)
to felbamate monotherapy (at 2400mg/day) over a 2-month period to enhance seizure control. Four months later, the couple successfully conceived their second
child. Upon re-examination, the patient’s sperm count signicantly improved, with
50% motility [550]. Mishal etal. presented a case study to explore how felbamate
monotherapy exerted a potent antiepileptic effect in a unique patient, potentially
offering a new treatment avenue for individuals with tuberous sclerosis (TSC) and
neurobromatosis (NF)-associated epilepsy. The patient, a 15-year-old girl, inherited NF1 from her mother and TSC from her father, making her the sole reported
case in the literature with both conditions inherited simultaneously rather than due
to sporadic mutations. Intractable epilepsy began at the age of 5, with seizures resistant to adequate doses of four ASMs until felbamate therapy was initiated at age 7.
Since then, she has remained seizure-free on felbamate monotherapy. Although felbamate acts through multiple mechanisms, its most potent antiepileptic effect is
believed to occur via N-methyl-D-aspartate receptor (NMDAR) inhibition. Studies
have indicated alterations in NMDARs in various epileptic syndromes, particularly
cortical nodules, in patients with TSC.The authors advocate for further research on
the potential role of felbamate or other NMDAR antagonists in epileptic syndromes
with NMDAR alterations [551]. Rabinowicz S etal. conducted a retrospective analysis of the medical records of patients treated with felbamate at a tertiary pediatric
epilepsy clinic from 2009 to 2021. Among the 53 children treated with felbamate,
16 received treatment for epileptic states during sleep, and six received treatment
during both wakefulness and sleep. Of these, 37 patients (51%) achieved a ≥50%
response to treatment, with nine patients (12%) experiencing a complete response.
Adverse reactions occurred in 19 patients (25%), including three patients with elevated liver enzymes and one patient with neutropenia. However, treatment could be
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continued in all patients. All the children with refractory epilepsy after herpetic
encephalitis responded to felbamate. Thus, felbamate has emerged as a safe and
effective antiseizure medication for children [552].
Felbamate Is aPreferred Addition fortheTreatment ofEpilepsy Duetoits
Efcacy andSafety
Hussain etal. conducted a comprehensive retrospective evaluation of the efcacy,
safety, and tolerability of felbamate in a large single-center cohort of children with
epileptic spasms. Among 476 infants, 62 children treated with felbamate were identied, all of whom had video-EEG-conrmed epileptic spasms, 58 of had previously failed to respond to hormone therapy. Nonammonia exposure was assessed by
calculating the peak and weighted doses per average body weight. Clinical response
was dened as remission of epileptic spasms for at least 28days, starting no more
than 3months after initiating felbamate. An electroclinical response was dened as
a clinical response accompanied by a nighttime video EEG showing the absence of
epileptic spasms and a high degree of arrhythmia. The median peak dose and
weighted average dose of felbamate were 47 and 40mg/kg/day, respectively. Five
children (8%) were classied as clinical responders, and two (3%) were classied
as electroclinical responders. Four of 17 patients (24%) were observed to be clinical
responders with a latency period of less than 12months from seizure spasmodic
onset to nonammonia initiation. The authors suggest that felbamate may be effective in treating epileptic spasms, but further rigorous studies are warranted. They
posited that a higher dose or faster titration may lead to a greater response rate
[553]. Dozieres-Puyravel etal. conducted a 10-year retrospective study of infants
with epileptic spasms who underwent continuous EEG recordings after rst-line
treatment to evaluate the efcacy of felbamate in refractory infantile spasms/West
syndrome. A total of 29 infants were enrolled, with a mean age of 13.8months.
Starting felbamate therapy after continuous administration or in combination with
oral steroids, 23 infants were transitioned to a ketogenic diet. Eight infants continued to experience spasms after a mean dose of 34.6mg/kg/day of felbamate. Among
the 19 infants who discontinued felbamate, the average duration of use was
19months, and no serious side effects were observed. Reversible neutropenia led to
felbamate discontinuation in six patients. One patient experienced spasm relapse
upon felbamate discontinuation. The authors highlighted the sustained seizure control achieved by patients with refractory infantile spasms syndrome, underscoring
the need to assess the benet–risk ratio for each patient when considering felbamate
use. This study also underscores the potential of targeting NMDA receptors for the
treatment of infantile spasm syndrome, potentially paving the way for the development of novel therapeutic agents [554]. de Jong etal. conducted a literature review
and identied 30 articles that met the inclusion criteria to investigate potential associations between various newer ASMs and specic congenital abnormalities. This
study focused on lamotrigine, topiramate, levetiracetam, gabapentin, oxcarbazepine, CBZ, felbamate, pregabalin, runamide, tiagabine, and zonisamide. Congenital
abnormalities were classied according to the European Surveillance for Congenital
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Abnormalities subgroups. The prevalence of specic congenital abnormalities in
fetuses exposed to individual ASMs was compared with the prevalence in the general population reference database. A signicantly higher incidence, based on three
or more abnormal fetuses, was considered a signal. Compared with other newer
ASMs topiramate was associated with a greater rate of congenital abnormalities,
with a strong association between topiramate and cleft lip with/without cleft palate
and hypospadias. A link between lamotrigine and anencephaly and transposition of
large blood vessels was observed in one study but was not supported by others. No
congenital abnormalities were found in fetuses exposed to felbamate, pregabalin,
tiagabine, or zonisamide. No signal was found for other newer ASMs, or the data
were too limited to draw conclusions. The authors recommend further investigation
of topiramate and its association with cleft lip with/without cleft palate and hypospadias in pregnancies during the rst trimester with the use of newer ASM monotherapy. Due to the low number of observations, no conclusions could be drawn
about the risk of congenital abnormalities with other newer ASMs [555]. One study
reported an average reduction in number of seizures of 35.8% with the addition of
felbamate, while another reported a smaller reduction of 4.2%. Both studies noted
an increase in seizure frequency with the addition of a placebo. Signicantly, there
was a notable difference in seizure reduction between the felbamate and placebo
groups, with the discontinuation rate remaining low (below 10%) in the felbamate
group, indicating good tolerability of felbamate [556].
Evidence-Based Medical Research Regarding Felbamate
Zhang etal. undertook a systematic review and network meta-analysis, pooling data
from eight randomized controlled trials (RCTs) involving 1171 patients with
Lennox–Gastaut syndrome (LGS), to assess the effectiveness and safety of ASMs
(ASMs) for LGS.The analysis included six RCTs investigating lamotrigine, runamide, cannabidiol, topiramate, clobazam, and felbamate. The efcacy and safety
of felbamate have been reported to reduce the monthly frequency of seizures by at
least 50% in terms of reduced seizures, drop-outs, and serious adverse events. The
results were ranked using the surface under the cumulative ranking curve (SUCRA).
Felbamate, cannabidiol, and topiramate emerged as having the highest likelihood of
efcacy according to the calculated SUCRA values. However, no signicant differences were detected among these treatments. Cannabidiol, topiramate, and felbamate were associated with higher rates of withdrawal. Additionally, patients treated
with cannabidiol had a signicantly greater rate of premature discontinuation than
those receiving placebo or lamotrigine. The response rates were signicantly greater
in all ASM groups than in the placebo group. The SUCRA rankings suggested that
felbamate and cannabidiol were more effective than other treatments in reducing
epilepsy, although there were no signicant differences between them. In the ve
RCTs with no reported seizures, no signicant disparities were found among treatments, nor were they deemed more effective than placebo. SUCRA rankings indicated that topiramate, felbamate, and cannabidiol outperformed the other ASMs.
However, lamotrigine, cannabidiol, and felbamate were associated with a higher
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incidence of serious adverse events [431]. Another group conducted a comprehensive review of the literature, encompassing randomized controlled trials (RCTs) and
open-label extension (OLE) studies, to compare ASMs with either placebo or other
ASMs in patients with Lennox–Gastaut syndrome (LGS), aiming to assess the
short- and long-term comparative efcacy and safety of ASMs in this context. Their
analysis involved 15 studies comprising 1263 LGS patients aged 2–54years who
received treatment with six different ASMs (CBD, clobazam (CLB), felbamate
(FLB), lamotrigine (LTG), runamide (RFM), topiramate (TPM)), or placebo. A
reduction of ≥50% in seizure frequency from baseline and the occurrence of therapeutic emergent adverse events (TEAEs) were the primary efcacy and safety outcomes. High doses of CLB (1.0 mg/kg/day; CLB_H) [or: 4.9; 95% condence
interval: 2.3–10.8] reduced seizure frequency by ≥50% compared with placebo and
obtained a high probability (0.89) based on SUCRA values (despite overlap between
the effect sizes of CLB, RFM, and CBD) compared with high doses of CBD (20mg/
kg/day; CBD_H) [or: 3.8; 95% condence interval: 1.6–9.0], which had a greater
chance of any treatment-related emergent adverse event (TEAEs) and the highest
ranking probability (0.85). Long-term use of CLB was associated with a greater
proportion of patients experiencing reduced seizures (78%; 95% CI: 70–85%),
while long-term use of CBD was linked to a greater frequency of TEAE occurrence
(96%; 95% CI: 95–98%). Short-term results, reported as odds ratios (ORs) using a
network meta-analysis (NMA), were accompanied by 95% condence intervals
(CIs) and levels of competitive intervention (cumulative ranking under the curve
(SUCRA)). Additionally, the ratio of long-term outcomes to 95% CIs was calculated using a random effects model. The authors propose that CLB_H, CBD, and
RFM are the most effective and safest options in both the short and long term, with
CLB_H likely exhibiting superior efcacy. Future comparative trials directly comparing these ASMs are needed to further elucidate their comparative effectiveness
and safety proles [557].
Effects ofFelbamate onEEG andCognitive Function
To evaluate the evidence concerning cognitive changes linked with ASM therapy in
children with epilepsy, Beyag etal. conducted an extensive review of the literature
indexed in PubMed. Cognitive impairment frequently accompanies epilepsy and
might be induced or exacerbated by ASMs, although certain ASMs may have benecial effects on cognition. The ASM under scrutiny aligns with the current edition
of the UK National Prescription (BNF). Although there is a paucity of reliable data
on cognitive decits in pediatric patients for most ASMs, some studies have indicated that phenobarbital treatment may be associated with cognitive impairment.
Similarly, negative impacts on cognition, particularly word recognition differences
and other language decits, have been linked to topiramate and phenytoin, although
specic data regarding children are scarce. On the other hand, lamotrigine and levetiracetam have been shown to be associated with improvements in certain cognitive
domains, albeit whether these decits stem directly from drug treatment or improved
seizure management remains ambiguous. Available evidence suggests that
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phenobarbital, phenytoin, and topiramate impair neurocognitive functioning, while
levetiracetam, felbamate, and particularly lamotrigine may be linked to cognitive
improvements. CBZ, ethosuximide, lacosamide, oxcarbazepine, perampanel, and
valproate do not seem to pose signicant risks of cognitive deterioration. Data on
cannabidiol, clobazam, eslicarbazepine, eslicarbazepine acetate, runamide, vigabatrin, and zonisamide are limited, but existing studies suggest that these drugs are
not associated with severe cognitive impairments. Insufcient data exist to draw
rm conclusions regarding brivaracetam, felbamate, gabapentin, pregabalin, retigabine, stiripentol, and tiagabine. Felbamate, a second-generation ASM, received initial regulatory approval in 1993 as an adjunct treatment for focal and generalized
seizures associated with Lennox–Gastaut syndrome (LGS). However, subsequent
limitations on felbamate use stemmed from concerns regarding liver toxicity and
the risk of aplastic anemia, limiting its usage to patients with severe refractory epilepsy. Felbamate has various modes of action, primarily by modulating N-methylD-aspartate (NMDA) receptors to inhibit glutaminergic transmission for its
antiepileptic effect. Limited information is available on the cognitive decits associated with felbamate, and no studies have specically evaluated cognitive ability in
pediatric patients receiving felbamate treatment. An open-label study involving
children with LGS treated with felbamate indicated enhancements in cognitive and
behavioral function based on responses to a parent/caregiver questionnaire. Notably,
improvements in social, intellectual, and motor functions; attention; alertness; initiative; performance; and memory variability were observed. However, upon discontinuation of felbamate, these symptoms tended to diminish, possibly correlating
with reduced seizure frequency. The authors emphasize the inadequacy of data on
felbamate to draw denitive conclusions and advocate for future studies on ASMs
in young individuals to incorporate standardized assessments of cognition and
behavior. They recommend routine monitoring of patients undergoing ASM treatment, including evaluation of underlying cognitive decits, with dosage adjustments or medication changes as needed to mitigate adverse cognitive outcomes [78].
Effect oftheAddition ofFelbamate onPatient Quality ofLife
Buraniqi etal. conducted a systematic study reviewing the impact of antiseizure
medication (ASM) use on appetite and weight in children. Randomized controlled
trials and open-label studies (open-label extension and intervention studies) involving children aged 0–18years were included. Each study was classied according to
the American Academy of Neurology (AAN) Classication of Evidence for
Therapeutic Research and was graded based on its effect on children’s appetite and
weight. ASMs linked to reduced appetite and/or weight loss include fenuramine,
topiramate, zonisamide, felbamate, runamide, stiripentol, cannabidiol, brivaracetam, and ethosuximide. Those with minimal impact on children’s weight and appetite include oxcarbazepine, eslicarbazepine, lamotrigine, levetiracetam, lacosamide,
CBZ, vigabatrin, and clobazam. Valproic acid is the ASM most closely associated
with increased appetite and/or weight gain, with pregabalin and perampanel potentially causing moderate weight gain or increased appetite in children. Felbamate,
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which inhibits N-methyl-D-aspartic acid receptor currents and enhances GABAA
activity, was approved by the FDA in 1993 for the treatment of focal epilepsy and
Lennox–Gastaut syndrome in both adults and children. It was proposed as an
adjunctive treatment for refractory infantile spasms. Rare but potentially lifethreatening reactions such as aplastic anemia and liver failure with felbamate use
typically manifest 6–12months after treatment initiation, with one study indicating
that patients with aplastic anemia are often older (17+ years) and have a history of
ASM allergy, cytopenia, and/or autoimmune disease. Major pediatric studies have
reported that 23–44% of patients experience decreased appetite and weight loss. In
a randomized, placebo-controlled trial involving patients with Lennox–Gastaut syndrome, anorexia was signicantly greater in nonamino acid-treated patients than in
placebo-treated patients, although no signicant weight loss was observed. Similar
ndings have been noted in other open-label studies including both adults and children. The authors assert that epilepsy ranks among the most common neurological
disorders in children, with numerous potential factors inuencing the growth of
children with epilepsy, necessitating evaluation in cases of appetite and weight
issues. ASMs carry potential adverse effects, many of which can impact appetite,
thereby affecting normal growth and weight gain, potentially increasing the risk of
underlying diseases and compromising treatment adherence. In addition to ASMrelated effects, other factors to consider include potential causes, associated neurological disorders, comorbidities and their treatment impact, as well as physical
activity levels and dietary habits [80].
Side Effects ofFelbamate
Vidaurre etal. investigated the acute and chronic management of seizures in patients
with advanced liver disease and examined the hepatotoxic potential of specic
ASMs. Hepatotoxicity, a rare and unexpected side effect of ASMs treatment, poses
challenges in selecting appropriate medications for patients with acute, symptomatic seizures or epilepsy complicating liver disease, given that most drugs are
metabolized by the liver. The study recommended the use of novel ASMs with minimal or no liver metabolism, such as levetiracetam, lacosamide, topiramate, gabapentin, and pregabalin, as rst-line treatments. Conversely, drugs extensively
metabolized by the liver, such as valproic acid, phenytoin, and felbamate, should be
reserved as last-option agents. In specic scenarios, such as acute intermittent porphyria, where exposure to most ASMs may trigger seizures; bromides, levetiracetam, gabapentin, and vigabatrin were deemed safer choices. For status epilepticus,
levetiracetam and lacosamide are recommended as second-line treatments if benzodiazepines fail to control seizures. Notably, certain drugs, including valproic acid,
phenytoin, and felbamate, are associated with well-established hepatotoxicity.
Felbamate, primarily prescribed for Lennox–Gastaut syndrome or refractory epilepsy, inhibits enzymes of the P450 system, posing risks of liver toxicity and signicant drug interactions. Studies have indicated a risk of liver failure with felbamate
use ranging between 1:26,000 and 1:34,000, potentially lower than that of valproic
acid-related hepatotoxicity. However, the factors contributing to this risk remain
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unidentied, although female sex and use of multiple concomitant therapies may
elevate it. Liver failure can occur abruptly without warning signs. The authors
emphasized the importance of physicians exercising vigilance regarding the pharmacokinetic characteristics and hepatotoxic potential of different ASMs in liver disease patients, recommending heightened awareness of clinical symptoms [558]. In
a separate review, Jacob etal. explored the potential of therapeutic drug monitoring
(TDM) for new ASMs, including eslicarbazepine acetate, felbamate, gabapentin,
lacosamide, lamotrigine, levetiracetam, perampanel, pregabalin, runamide, retigabine, stiripentol, tiagabine, topiramate, vigabatrin, and zonisamide. This review
detailed the relationships between serum drug concentrations, clinical effects, and
adverse drug reactions for each ASMs, as well as various analytical methods for
serum drug quantication. Retrospective and prospective data on serum drug concentration efcacy were also discussed. Additionally, the pharmacokinetic parameters, oral bioavailability, reference concentration ranges, and active metabolites of
the new ASMs were proposed. TDM is considered crucial in epilepsy management
because it aids in the treatment of uncontrolled seizures and clinical toxicity, enables
personalized therapy, and accommodates variable or nonlinear pharmacokinetics.
Serum concentrations of nonammonia drugs exhibited wide variability, with higher
levels in patients with renal impairment and a dependence on age and renal function
for an extended half-life. Clearance values were notably greater in children than in
adults (20–65%). Propionaldehyde, an intermediate metabolite, poses risks of serious reproductive toxicity, rendering this drug contraindicated for patients with liver
damage. Limited pharmacokinetic data during pregnancy and the presence of lifethreatening adverse effects, such as hepatotoxicity and aplastic anemia, severely
restrict felbamate use. Enzyme-induced ASMs may decrease the serum felbamate
concentration, while enzyme inhibitors such as VPA can increase the serum felbamate concentration [559].
Basic Research onFelbamate
Celli etal. utilized PubMed to conduct a cross-search on “glutamate receptor and
epilepsy,” resulting in an outcome of 3170 reports. They further searched for “ionic
glutamate receptor,” “AMPA receptor,” “NMDA receptor,” “kainate receptor,” “convulsive seizure,” and “nonconvulsive seizure,” selecting relevant papers for this
review. This comprehensive review explored the involvement of ionotropic glutamate (iGlu) receptors in convulsive and nonconvulsive seizures and their duration
and severity, with the aim of informing new strategies for treating drug-resistant
epilepsy. Research has identied glutamate neurotransmission dysfunction as pivotal in seizure genesis. Glutamate serves as the primary excitatory neurotransmitter
in the cerebral cortex, where seizures manifest. Its action is mediated through iGlu
receptors, which are ligand-gated ion channels that facilitate rapid excitatory synaptic transmission. Experimental studies have demonstrated that iGlu receptor antagonists mitigate seizures, while agonists exacerbate seizures in various animal models.
Clinical progress in development of iGlu receptor antagonists has been impeded by
adverse effects stemming from the inhibition of rapid excitatory synaptic
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transmission. Currently, perampanel is the sole drug that selectively targets iGlu
receptors and is utilized in focal epilepsy treatment. Other drugs, such as topiramate
and felbamate, also inhibit iGlu receptors via other mechanisms. The authors propose that this review aids in analyzing steps triggered by iGlu receptor activation,
offering insights into potential alterations in antiepileptic efcacy without compromising essential brain physiological functions, thus enhancing the safety and tolerability of iGlu receptor-targeted ASMs. The glycine B site is crucial for ion-mediated
glutamate- induced epileptic activity, potentially contributing to the transition of seizures to a state of sustained epilepsy. For instance, in DBA/2 mice, administration
of the glycine B site antagonist MNQX exhibited protective effects against kindlinginduced status epilepticus. It is widely accepted that felbamate, ramacemide, and
riluzole exert at least some of their anticonvulsant effects through glycine B site
antagonism. However, glycine B site antagonists with weak intrinsic activity may
paradoxically promote convulsive activity [560].
Other Studies Involving Felbamate
Li et al. explored the antidepressant-like effects of felbamate, an anticonvulsant
primarily prescribed for epilepsy, in mice. Initially, they employed the forced swimming test (FST) and tail suspension test (TST) to evaluate the impact of felbamate
and later extended their investigations to chronic unpredictable mild stress (CUMS)
and chronic social defeat stress (CSDS) models. This study assessed alterations in
the hippocampal brain-derived neurotrophic factor (BDNF) signaling cascade following chronic stress and felbamate treatment. The results indicated that felbamate
exhibited antidepressant-like activity in the FST and TST without affecting motor
activity in mice. Moreover, felbamate demonstrated effectiveness in both the CUMS
and CSDS models of depression. Furthermore, felbamate fully reversed the decrease
in BDNF signaling pathway activity in the hippocampi of mice subjected to CUMS
and CSDS.The authors posit that felbamate exerts antidepressant effects in mice
through modulation of the hippocampal BDNF system. This study underscores the
benecial effects of felbamate on depression and presents a potential novel antidepressant medication. This study deepens the understanding of the pharmacological
effects of felbamate and lays the groundwork for the development of new antidepressants [561]. Bayhan etal. conducted a study utilizing 32 male Sprague–Dawley
rats to establish a closed head trauma model and compared the immunological,
histological, and oxidative effects of felbamate and levetiracetam on head trauma in
rats. The rats were divided into four groups, each including eight rats. Following
head trauma, Group 1 received normal saline (control), Group 2 received 50mg/kg
levetiracetam, Group 3 received 100mg/kg felbamate, and Group 4 received a combination of 50mg/kg levetiracetam and 100mg/kg felbamate intraperitoneally once
daily for 20days. On Day 20, the rats were euthanized, and blood and tissue samples were collected for biochemical, immunohistochemical, and histological analyses. The ndings revealed that serum cytokine levels were lower in Groups 2, 3, and
4 than in the control group, with the lowest levels observed in Group 4 receiving
combination therapy. Pial vascular congestion, monocyte inltration, bleeding, and
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neurodegeneration were signicantly reduced in Groups 2 and 3 compared to controls. In Group 2, vascular congestion and Purkinje cell degeneration in the cerebellum were diminished compared to controls. Group 4 exhibited the most favorable
outcomes, with signicantly reduced levels of immune markers (IL-1β, IL-4, IL-6,
and TNF-α), lower accumulation of TBARS, and a signicant increase in SOD and
GSH levels, than controls. The authors suggested that both levetiracetam and felbamate individually exhibit benets in terms of immune, oxidative, and histological
changes, with enhanced efcacy observed when used in combination [562].
2.1.2.8 Vigabatrin
Drug Characteristics
[Chemical name] (±) 4-Amino-5-hexenoic acid
[Structural formula]
[Molecular formula] C6H11NO2
[Molecular weight] 129.16
[Indications] This product is suitable for many types of seizures. As an adjunct
therapy, it is used to treat patients who do not respond to other ASMs, especially
those with partial seizures (mainly used to control complex partial seizures). It can
also be used in infants with West syndrome (infantile spasm), which usually does
not respond to conventional ASMs. As an adjunct therapeutic drug, this product can
achieve better curative effects.
[Specications] Granules/tablets/oral solution powder/oral solution 500mg
[Usage and dosage] For infants aged 1month to 2years with infantile spasms,
monotherapy typically involves oral solution powder or oral solution forms. The
recommended starting dose is 50mg/kg/day, which is administered in two divided
doses, with subsequent titration upward every 3days by 25–50 mg/kg/day. The
maximum daily dose should not exceed 150mg/kg/day and should be divided into
two doses. Individual dosing should be based on the infant’s body weight.
Withdrawal from vigabatrin therapy should be gradual, reducing the daily dose by
25–50mg/kg/day every 3–4days until it is discontinued. As adjunctive therapy for
adult patients with refractory complex partial seizures, common dosage forms
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include regular tablets, oral solution powder, and oral solutions. Treatment initiation
typically involves a daily dose of 1000 mg (500 mg twice daily), with weekly
increases of 500mg based on clinical response. The recommended maintenance
dose for adults is 3000mg/day (1500mg twice daily). Higher doses of 6000mg/day
have not shown additional benets compared to 3000mg/day and are associated
with increased incidence of adverse events. When vigabatrin use is discontinued,
gradual dose reduction is advised. Vigabatrin can also be used as an adjunctive
therapy for children with refractory complex partial epilepsy. The available dosage
forms are regular tablets, oral solution powder, and oral solutions. The dosing regimen for pediatric patients aged 2–16years varies based on body weight. For patients
weighing 10–60kg, the recommended dosage is divided into two doses, with adjustments based on body weight. Pediatric patients aged 17years and older or weighing
more than 60kg should follow the same dosage regimen as adults.
[Adverse reactions] The most common adverse events associated with vigabatrin
in combination with other ASMs were headache, drowsiness, fatigue, dizziness,
convulsion, nasopharyngitis, weight gain, upper respiratory tract infection, visual
eld loss, depression, tremor, nystagmus, nausea, diarrhea, memory impairment,
insomnia, irritability, abnormal coordination, blurred vision, double vision, vomiting, inuenza, fever, and rash. The most common adverse effects of misusing vigabatrin were convulsions and depression. Among patients with infantile spasm, the
most common adverse effects of discontinuing vigabatrin use were infection, epileptic status, developmental coordination disorder, dystonia, hypotonia, hypertonia,
weight gain, and insomnia. Clinical attention should be given to permanent visual
impairment, magnetic resonance imaging (MRI) abnormalities in infants, neurotoxicity, suicidal behavior and ideation, withdrawal syndrome associated with ASMs,
anemia, salivation and fatigue, peripheral nerve disease, weight gain, and edema.
Clinical andBasic Research
Historical Evolution
In 1977, Schechter PJ etal. described for the rst time the role of vigabatrin in animals [563]; in 1980, Gale K etal. reported that vigabatrin had an effect on epileptic
seizures in animals [564]; in 1981, Gale K etal. identied the antiepileptic action
site of vigabatrin. It was found to be related to the action of gamma-aminobutyric
acid (GABA) [565]. Subsequently, Kalichman MW etal. reported that vigabatrin
had an effect on the occurrence and development of epilepsy in animals with amygdala ignition [566]. In 1983, Gram L etal. reported the results of administration of
vigabatrin to patients with epilepsy. They administered it to 15 patients with refractory epilepsy and found that it could signicantly reduce the seizure frequency of
epilepsy patients, which initially conrmed its antiseizure effect [567]. Since 1989,
vigabatrin has been widely utilized in Europe for the management of infantile
spasms. Its approval for the treatment of infantile spasms and refractory epilepsy in