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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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2.1.2.6 Clobazam
Drug Characteristics
[Chemical name] 7-Chloro-1-methyl-5-phenyl-1,5-diazepine-2,4 (3H)-dione
[Chemical structure]
[Molecular formula] C16H13ClN2O2
[Molecular weight] 300.74
[Indications] For the treatment of refractory epilepsy in which other ASMs are
ineffective, it can be used alone or as an adjuvant treatment. It is more effective for
generalized seizures secondary to complex partial seizures and Lennox-Gaslaut
syndrome.
[Specication] 10mg, 20mg
[Dosage]
Oral administration is started with a small dose of 20–30mg (0.5–1mg/kg) per day,
and the dose is gradually increased. When combined with other ASMs, the dose of
this product should be reduced, and 5–15mg (0.1–0.3mg/kg) should be administered daily.
If it is used continuously, its anticonvulsant effect gradually weakens, and “holiday therapy” can be used; for example, during the onset of menstruation, female
patients can start the drug 2–3days before the onset of menstruation and stop using
it after 10days.
[Adverse reactions]
The adverse effects are similar to those of other benzodiazepines, but they are all
mild, with occasional mild sedation, agitation, depression, and muscle weakness.
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Clinical Application andBasic Research
Historical Evolution ofClobazam
Clobazam was synthesized in 1966 and began to be used worldwide as an anxiolytic and antiseizure drug in the 1970s. In 2005, clobazam was used in Canada
as an additive for epilepsy-related generalized tonic–clonic seizures, myoclonic
seizures, and focal-onset perceptual impairment seizures [515]. In 2011, the US
Food and Drug Administration (FDA) approved clobazam as an adjunct treatment for seizures in patients ≥2years of age with Lennox–Gastaut syndrome
(LGS) [516]. Indications not approved by the FDA include adjuvant therapy for
Dravet syndrome seizures, adjuvant therapy for refractory status epilepticus,
and adjuvant therapy for refractory focal epilepsy, menstrual epilepsy, and anxiety disorders [517]. In 2021, Nupur etal. reported that clobazam can be used as
an add-on antiseizure medication treatment for tumor-related epilepsy
(TRE) [518].
Clobazam Monotherapy Efcacy
A substantial clinical investigation conducted in Canada demonstrated the efcacy of clobazam monotherapy in children aficted with partial epilepsy or generalized tonic–clonic seizures. Notably, clobazam was found to be as effective
as phenytoin and CBZ but exhibited fewer side effects, such as rash, than the
other two agents. Consequently, the Canadian Child Epilepsy Study Group has
recommended clobazam as the primary treatment option for focal epilepsy and
generalized tonic–clonic seizures in children [519]. Despite the scarcity of
high-quality randomized controlled trials on clobazam monotherapy, a pooled
analysis from a 2018 Cochrane Review of three clinical trials suggested that
clobazam monotherapy may be comparably effective to CBZ and phenytoin for
new-onset focal or generalized epilepsy [520]. The researchers administered
clobazam monotherapy to 25 children with epilepsy for a duration of 26months,
revealing a notable decrease in seizure frequency in 75% of the participants.
Although studies on clobazam monotherapy in adults with epilepsy are limited,
small-scale investigations have indicated its efcacy in this population as well
[521]. Another group conducted a study involving 26 adult patients with epi-
lepsy in which 64% of patients achieved seizure freedom and 84% experienced
a reduction of over 50% in seizure frequency following 24weeks of clobazam
monotherapy [522]. Moreover, clobazam has been reported to be effective and
well tolerated among pediatric patients, resulting in a signicant reduction in
seizure rates (57.3%), with a favorable overall treatment response and a low
incidence of seizure recurrence [523].
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Efcacy andSafety ofClobazam asanAdjuvant Treatment forEpilepsy
Alisha Jami et al. conducted a single-center, retrospective chart review involving
patients over 18years of age with drug-resistant epilepsy who received clobazam
therapy between 2010 and 2018. These patients underwent outpatient visits both
before and 1month after commencing clobazam therapy. The ndings indicated that
clobazam is an effective and safe long-term adjunctive treatment for drug- resistant
epilepsy in adults, with off-label use demonstrating efcacy similar to that in Lennox–
Gastaut syndrome patients. Level IV evidence from various studies suggests that clobazam is efcacious in treating drug-resistant epilepsy in adults, irrespective of
epilepsy classication [524]. Talwar A etal. reported that CBZ is effective as both a
stand-alone therapy and in combination with clobazam for controlling seizures in DS,
LGS, and TSC patients while limiting side effects [525]. Nagarajan, E. etal. evaluated
the tolerability of clobazam in patients aged 50years and older with drug-resistant
epilepsy and concluded that clobazam represents a safe and well-tolerated adjunctive
treatment for older individuals with drug- resistant epilepsy [526].
Efcacy ofClobazam inOther Refractory Epilepsy
Clobazam has been utilized in various countries for treating different types of epilepsy,
particularly refractory epilepsy. In a retrospective study involving 877 adults and children with refractory epilepsy, the addition of clobazam to a treatment regimen led to a
greater than 50% reduction in seizure frequency and demonstrated efcacy across all
seizure types [527]. Another single-center retrospective study in the United States spanning 2010–2018 involving 417 adults with refractory epilepsy revealed that approximately half of the patients experienced a 50% reduction in seizure frequency with
clobazam treatment, and 17% of patients remained seizure- free after more than 1year
of follow-up. Clobazam was also effective in treating focal epilepsy, generalized epilepsy, and Lennox–Gastaut syndrome [524]. In a study conducted in India involving 88
children with refractory epilepsy, clobazam was found to be effective as an adjunctive
therapy for all epilepsy types, with 60.2% of the children achieving complete seizure
control [528]. A Cochrane review that pooled data from four clinical studies, predominantly involving individuals with focal refractory epilepsy, concluded that clobazam as
an adjunctive therapy may be effective for drug-refractory focal epilepsy. Additionally,
numerous small-scale clinical studies have demonstrated the effectiveness of clobazam
as an adjunctive therapy for refractory epilepsy in both adults and children. In recent
years, clobazam has also been employed for refractory status epilepticus, with control
achieved in 76.5% of patients when clobazam is used as an adjunctive therapy.
Observation oftheEfcacy ofClobazam asanAdjuvant Treatment forOther
Refractory Epilepsy
Brain tumor-associated epilepsy (TRE) often shows resistance to currently
available ASMs. While clobazam was initially approved as an adjunct ASMs for
patients with Lennox–Gastaut syndrome, it has also shown promise in
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managing TRE.An observational study investigating the impact of clobazam on
seizure frequency in patients with primary CNS tumors revealed that clobazam
effectively reduced seizure frequency, yielding a response rate of 93.9% [518].
Moreover, the addition of clobazam not only signicantly improved seizure frequency but also aided in reducing the burden of multiple ASMs combinations
typically used to manage seizures in this patient population. This simplication
of treatment options is particularly benecial for patients who already have to
take numerous medications for cancer treatment or comorbidities. Future
research should include prospective studies utilizing clobazam as a rst-line
agent and comparative studies assessing clobazam against other ASMs as
adjunctive therapy in this population. In a separate report, Maille etal. documented successful treatment of drug-resistant seizures through the addition of
clobazam in Heidenhain-variant Creutzfeldt–Jakob disease (CJD), suggesting
potential clinical benets of clobazam in patients with suspected CJD [529].
Serrano-Castro PJ etal. showed that the combination of sambicaut (CNB)+clobazam (CLB) may be an individualized regimen for patients with anti-GAD65associated AAEs [530]. Cannabidiol (CBD) and clobazam (CLB) are important
factors for enhancing antiepileptic effects during simultaneous use in patients
with refractory epilepsy [531].
Application ofClobazam inSpecial Populations withEpilepsy
Kamaşak etal. conducted a retrospective cohort study involving 1710 children
with epilepsy across eight centers and demonstrated the efcacy and tolerability
of clobazam. The study revealed that clobazam signicantly reduced seizure
rates by 57.3% and exhibited a low rate of seizure recurrence, providing substantial reversible benets in pediatric patients [523]. Another group reported
that clobazam serves as a potent adjunctive antiseizure medication for brain
tumor-associated epilepsy (TRE), with 94% of patients experiencing a signicant response within 6months. Sharma etal. identied eosinophilic systemic
symptoms syndrome (DRESS syndrome) as a novel symptom associated with
clobazam [532].
Side Effects ofClobazam
Regarding the side effects of clobazam, Jeff F.Zhang etal. described a female pediatric patient who developed signicant tongue swelling, protruding outside the oral
cavity, following treatment for refractory epilepsy with clobazam. Symptoms did not
respond to antihistamines or steroids but gradually resolved within a few days after
discontinuation of clobazam, with no lasting effects. This suggests that macroglossia
may be a potential side effect associated with clobazam in the treatment of drugresistant epilepsy [533]. Kart PÖ etal. reported that long-term administration of
ASMs, including zonisamide, sultiam, lacosamide, clobazam, and runamide, from
prepuberty to adulthood could lead to follicular apoptosis and disruption of follicular
development in nonepileptic rats [534]. Furthermore, a pharmacokinetic trial
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demonstrated that concurrent administration of sembacot and chlorocazam resulted
in a signicant increase in the serum concentration of N-desmethylclobazam. While
this could have a positive therapeutic effect, it may also lead to unnecessary
fatigue [535].
Basic Research onClobazam
Clobazam, by binding to the γ-aminobutyric acid-A (GABAA) receptor, increases
the seizure threshold and enhances GABA action by facilitating chloride-responsive
ligand-binding channel conduction. Unlike those of typical benzodiazepines, the
nitrogen atoms of clobazam occupy the rst and fth positions of the diazepine ring,
resulting in partial agonism of the GABA-A receptor rather than the rst and fourth
positions found in other benzodiazepines, which act as full agonists. This structural
alteration, leading to increased binding afnity for the α2β3γ2 isoform of GABA-A,
not only improves side effects but also enhances its anxiolytic and antiepileptic
properties [536].
Evidence-Based Medical Studies ofClobazam
Evidence-based medical studies spanning the 1980s have demonstrated the efcacy
of clobazam as an ASMs across more than 100 countries. Early clinical trials
revealed that more than half of patients experienced a reduction in seizure frequency
of more than 50%, with 42% achieving sustained benets for more than a year.
Remarkably, up to 10% of patients with refractory epilepsy achieved remission over
a retrospective study period of up to 7years. Two multicenter controlled studies
conrmed the efcacy of clobazam as an adjunctive treatment for seizures in
patients with Lennox–Gastaut syndrome (LGS). The participants in these studies
exhibited characteristics similar to those of patients treated with other ASMs,
including sodium valproate, lamotrigine, levetiracetam, and topiramate. The primary efcacy endpoint was the percentage reduction in weekly fall frequency,
encompassing atonic, myotonic, and myoclonic seizures, compared to baseline.
Notably, the high-dose clobazam group demonstrated a signicant decrease in fall
episodes compared to the low-dose group (93% vs. 29%, respectively, p<0.05),
with most adverse reactions being mild to moderate and showing no statistically
signicant differences between the two groups [537]. A meta-analysis examining
patients taking clobazam in conjunction with other medications, including CBD,
revealed a greater incidence of drowsiness and sedation. Notably, the combination
of valproate and clobazam may lead to elevated aminotransferase levels, albeit to a
lesser extent. Overall, the addition of CBD and clobazam effectively reduces seizures, albeit with an increased likelihood of drowsiness and sedation in patients
taking both medications [538].
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2.1.2.7 Felbamate
Drug Characteristics
[Chemical name] 2-Phenyl-1,3-propanediol dicarbamate
[Chemical structural formula]
[Molecular formula] C11H14N2O4
[Molecular weight] 238.24
[Adaptation disease] (1) Adjuvant therapy and monotherapy for partial seizures
and secondary general seizures in adults and children; (2) Adjuvant treatment of
Lennox–Gastaut syndrome and its associated partial and general episodes; (3)
Treatment of primary generalized tonic–clonic convulsions or seizures of absence;
(4) Adjuvant treatment of refractory incomplete seizures.
[Specication] Tablet: 400mg, 600mg
Oral liquid: 600mg/5mL
[Usage and dosage]
Felbamate 1200–3600mg/day.
The initial dose for the treatment of seizures in adults and children over 14years
of age is 1200mg/day, divided into three to four oral doses, gradually increasing the
dose to 600mg every 2weeks and up to 3600mg/day depending on the individual’s
clinical response and tolerance. The initial dose of adjuvant therapy for the onset of
Lennox–Gastaut syndrome in children aged 2–14years is 15mg/kg/day in three to
four oral doses. It can be increased by 15mg/kg/day per week, up to 45mg/kg/day
or 3600mg/day depending on the individual’s clinical response and tolerance. In
elderly patients or those with renal insufciency, the amount of felbamate should be
reduced as appropriate. When combined with phenytoin, CBZ and valproic acid, the
dosage of the latter should be reduced based on clinical observation and steady-state
blood concentrations.
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[Adverse reactions]
The predominant adverse reactions include mild gastrointestinal and central nervous system symptoms, ranging from loss of appetite, taste alterations, and nausea
to vomiting, fatigue, dizziness, and headache. Additionally, insomnia, double vision,
ataxia, cognitive impairment, and gait disturbances may occur, as may inuenzalike symptoms, palpitations, rashes, and weight loss. These adverse effects typically
reverse upon discontinuation or dose adjustment. In postmarketing trials, two rare
yet severe adverse events noted were aplastic anemia and hepatotoxicity. Notably,
when used in combination therapy, this product tends to elicit more side effects than
when it is used as a monotherapy.
Clinical Application andBasic Research
Historical Evolution ofFelbamate
The precise mechanism of action of felbamate remains incompletely understood.
Felbamate, which was originally developed by the Carter-Wallace Company in the
United States, is recognized for its high efcacy and low toxicity as an antiseizure
medication. Acting as a 5α-reductase inhibitor, it modulates NMDA and GABA
reactions, exhibiting no direct afnity for NMDA receptors but binding to the glycine recognition site of NMDA.In animal models of epilepsy, felbamate has been
shown to exhibit broad-spectrum antiepileptic activity. In 1985, A.J. Wilensky etal.
evaluated the pharmacokinetics and toxicity of felbamate in 8 adult male patients
with epilepsy, laying the groundwork for subsequent research [539]. A pivotal
double- blind, randomized, placebo-controlled clinical trial conducted by I.E. Leppik
etal. in 1991 demonstrated the safety and efcacy of felbamate as an adjunct treatment for severe refractory epilepsy, with mild adverse reactions primarily comprising nausea and central nervous system effects [540]. This study provides compelling
evidence supporting the integration of felbamate into epilepsy treatment protocols.
In August 1993, Felbamate received approval from the United States FDA, marking
it as the rst new antiseizure medication since the approval of valproic acid in 1978
and the rst anticonvulsant to exert dual effects on brain excitatory and inhibitory
mechanisms. Subsequent research, including a study by M.Gasior etal. in 1998,
highlighted Felbamate’s distinct prole, including its reduced interaction potential
with Ca2+ channel modulators and methylxanthine, thereby broadening the scope
of nonammonia ester applications [541]. This, as one of its advantages, broadens the
application range of nonammonia esters. In 2004, K K Borowicz etal. conducted a
study and reported that the combination of felbamate and CBZ may be useful for
patients with drug-resistant partial epilepsy [542]. Further investigations, such as
the 2004 study by K.K. Borowicz etal., suggested the potential utility of combining
felbamate with CBZ for patients with drug-resistant partial epilepsy [543]. In 2014,
Eli Heyman etal. advocated for the early use of felbamate in children with refractory epilepsy based on accumulating efcacy and safety data. More recently, a 2024
study by Laurel Reed et al. highlighted Felbamate’s effectiveness in treating
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epilepsy with myoclonic atonic seizures (EMAtSs), emphasizing its importance in
treatment strategies [544]. The continual emergence of research underscores the
ongoing exploration of the diverse clinical applications of felbamate in epilepsy
management.
Observational Study ofFelbamate Treatment forEpilepsy
Between January 1, 2015, and June 30, 2018, samples were collected from three
U.S. databases by Wilcox etal. Nine compounds were tested, and ve types of liver
tests (LTs) were conducted. The aim of this concise investigation was to outline the
LT compliance of patients using compounds recommended for monitoring at intervals of 2weeks or more across three U.S. administrative claims databases. The
ndings revealed that adherence was less than 33% for patients using each of four
drugs (ketoconazole, succinic acid, pentamidine, and felbamate) and exceeded 60%
for patients using each of ve drugs (oxaliplatin, rifampicin, albendazole, and azathioprine). Among the investigated drugs (excluding succinic acid), patients using
oxaliplatin exhibited the highest LT adherence (75.3%), whereas those using pentamidine showed the lowest (20.6%). The researchers concluded that patients using
the examined drugs displayed varying levels of adherence to frequent liver tests,
with none reaching 80% adherence [545].
Treatment ofRefractory Epilepsy withtheAddition ofFelbamate
The Felbamate Study Group undertook a double-blinded, placebo-controlled, add on trial to assess the efcacy and safety of felbamate in patients with Lennox–
Gastaut syndrome, enrolling 73 patients with the syndrome aged 4–36 years.
Patients received conventional antiepileptic therapy over a baseline period of
28days. Following this phase, patients received an additional 70days of either felbamate or placebo therapy alongside their existing ASMs. During the initial 14days
of treatment, the nonammonia dose was titrated to 45mg/kg/day or 3600mg/day,
whichever was lower. Primary efcacy measures included the total number of seizures during a 4-h videotaped period, overall quality of life assessment by the parent
or guardian, and total number of atonic seizures reported. The results indicated a
34% reduction in atonic seizure frequency among patients treated with felbamate
compared with a 9% reduction in the placebo group (P=0.01). Additionally, the
total seizure frequency decreased by 19% in the felbamate group versus a 4%
increase in the placebo group (P=0.002). From Day 49 onward, overall assessment
scores were signicantly greater in the felbamate group than in the placebo group.
There was no signicant difference in seizure frequency between the control and
video monitoring groups (P>0.05), but during the maintenance period, seizures
were notably reduced in the nonammonia ester group (P=0.017). The incidence
and frequency of adverse reactions were comparable between the two groups. The
authors suggest that felbamate is superior to placebo in reducing the frequency of
refractory partial seizures and is benecial for patients with Lennox–Gastaut syndrome. Improved seizure control and quality of life in treatment-resistant patients,
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along with a favorable safety prole, indicate that felbamate represents a signicant
advancement in epilepsy treatment [546]. Heyman etal. documented their experience with felbamate in treating drug-resistant epilepsy in children through a retrospective analysis of medical records and EEG recordings of all patients treated with
felbamate before May 2012. Despite the introduction of numerous new ASMs over
the past two decades, many individuals with epilepsy still experience uncontrolled
seizures or signicant side effects. Efcacy was assessed by comparing seizure frequency 1week before starting treatment to that 1week after reaching the maximum
felbamate dose. The study included 50 patients (34 boys) aged between 4months
and 17years (mean age 5.5years), nearly one-third of whom were diagnosed with
Lennox–Gastaut syndrome. The average duration of epilepsy was 3.4years (ranging from 1month to 13years), with patients having previously tried an average of
7.5 ASMs. The mean follow-up duration was 1.1years. Of the patients, 29 (58%)
experienced at least a 50% reduction in seizure frequency. Side effects were reported
in 22 patients (44%), none of whom had aplastic anemia or liver failure. In the
group of responders, the maximum felbamate dose was lower, and the patients were
older. The authors suggest initiating felbamate after multiple antiseizure medication
trials. Early use of felbamate in children with refractory epilepsy is recommended
based on its efcacy and safety prole [543]. Shi etal. published a review updating
a previous review on “Felbamate as add-on therapy for refractory epilepsy” in the
Cochrane Database of Reviews (Issue 7, 2014). This review evaluated the efcacy
of felbamate as an adjunct treatment to standard drugs. The efcacy and tolerability
of felbamate versus placebo as adjunctive therapy for patients with refractory focal
seizures were examined. To gather recent information, the authors searched various
databases and contacted manufacturers and experts for data from unpublished or
ongoing studies. They included four randomized controlled trials involving 236 participants. The studies varied in design and risk of bias. Due to signicant methodological and clinical heterogeneity, as well as differences in outcome measures, a
meta-analysis could not be conducted. Only one study reported a 50% or greater
reduction in seizure frequency, while others reported reductions in seizure frequency compared to placebo. Adverse reactions were more prevalent in the felbamate phase, especially headache, nausea, and dizziness. Given the methodological
limitations and insufcient evidence, the authors call for large-scale randomized
controlled trials over longer durations to guide clinical practice [547].
Felbamate Treatment forEpileptic Syndrome
Strzelczyk etal. performed a comprehensive examination of current and forthcoming treatment options for seizures linked with Lennox–Gastaut syndrome (LGS).
LGS, a severe developmental and epileptic encephalopathy (DEE) that typically
emerges in childhood, encompasses a diverse range of etiologies lacking a singular
genetic cause. It manifests with various epilepsy types, abnormal EEG patterns, diffuse slow spike-wave discharges, and cognitive impairment and signicantly
impacts patient and family quality of life, often manifesting as drug-resistant epilepsy. In the United States, six adjunctive therapies are utilized for LGS-associated
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epilepsy: lamotrigine, clobazam, runamide, topiramate, felbamate, and most
recently, cannabidiol. Research ndings indicate seizure reduction in 15–68% of
trial patients, with response rates (≥50% reduction in seizures) ranging from 37%
to 78%. Valproate remains the preferred rst-line treatment and is frequently combined with lamotrigine or clobazam. Ongoing clinical development includes the use
of felbamate. Nonpharmacological interventions such as a ketogenic diet, vagus
nerve stimulation, and surgical procedures also play roles. However, despite these
advancements, patients still face signicant challenges. Recognizing LGS heterogeneity, treatments must be individualized rather than adopting a one-size-ts-all
approach. In conjunction with the approved medication lamotrigine or clobazam,
valproate is used as a primary therapy, in combination with other adjunctive options,
including runamide, topiramate, felbamate, and the recent addition of cannabidiol.
Although felbamate is FDA-approved for use in the United States, it lacks approval
from the European Medicines Agency (EMA) due to the risks of aplastic anemia
and liver failure. However, its anticonvulsant mechanism remains unclear. Early
epilepsy models suggest that it increases the seizure threshold and impedes seizure
propagation, potentially effectively preventing generalized tonic–clonic or partial
seizures. Felbamate primarily reduces glutamate-energy transfer and may inhibit
GABA receptor binding to voltage-gated sodium and calcium channels. The authors
advocate for further research on the etiology and pathophysiology of LGS and
advancements in seizure treatment, encompassing the spectrum of symptoms associated with this intricate syndrome [548].
Felbamate Treats Refractory andSuper Refractory Status Epilepsy
Mazarati etal. induced self-sustaining status epilepticus (SSSE) by stimulating the
perforant pathway (PPS) through permanent electrode implantation in male adult
Wistar rats for 30min. This was followed by intravenous administration of felbamate (FBM; at doses of 50, 100, and 200mg/kg), diazepam (DZP; 10mg/kg), or
phenytoin (PHT; 50mg/kg). They examined the effects of FBM in SSSE animal
models and compared them with those of standard ASMs, DZP, and PHT.They
analyzed the electrographic manifestations of SSSE and the severity of SSSEinduced neuronal damage. Although both DZP and PHT were highly effective in the
initial status epilepticus (SE) model, they failed to halt the SSSE after 10 and 40min
(i.e., seizure duration >30 min). Although FBM did not terminate SSSE under
advanced treatment conditions, it was still more effective than PHT.The effects of
FBM were enduring, with no subsequent seizure activity observed. The efcacy of
FBM was found to be dose dependent, and required high doses of ASMs. The effective dose of FBM in this study surpassed the highest dose used in treatment trials.
Administering FBM early in SSSE (10min after PPS termination) shortened the
seizure duration in a dose-dependent manner. The anticonvulsant effect of FBM was
validated by the nding of less severe neuronal damage in the FBM group than in
the control group. The quantity of FBM needed to halt SSSE exceeded the anticonvulsant dose and resembled the neuroprotective dose. The authors speculate that
this is because SE requires more vigorous treatment than standard seizures and