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Clobazam (CLB) is a benzodiazepine that is used in many types of epilepsy. Although therapeutic drug monitoring (TDM) of CLB is not routine, there is evidence that TDM may be of value in conditions where pharmacokinetic alterations are suspected. Therefore, determination of both CLB and its active metabolite concentrations is essential for TDM. Herein, we present a simple and practical method for determination of CLB and N-desmethylclobazam (NDMCLB) in human plasma by highperformance liquid chromatography (HPLC). The drugs were extracted by hexane:dichloromethane (1:1, v/v) from 0.3 mL plasma. The separation was carried out with a C18 reverse phase column using a mobile phase of water:acetonitrile (57:43, v/v) pumped at 0.8 mL/min. The analytes were detected at 228 nm. The method was linear over the concentration range 20-500 ng/mL for CLB and 200-3000 ng/mL for NDMCLB. The intra-day coefficient of variation (CV) was <10% for CLB and <6% for NDMCLB, while the inter-day CV for CLB was <16%. The metabolite inter-day CV was <6%. The accuracy of intra- and inter-day assessments determined for CLB and NDMCLB was within 10%. This paper describes a rapid, reliable, and simple method for measuring CLB and its metabolite NDMCLB in human plasma. This UV-HPLC procedure offers acceptable precision and accuracy to quantify CLB and its metabolite in human plasma. [ABSTRACT FROM AUTHOR]

IntroductionIn treating refractory epilepsy, many clinicians are interested in methods used to transition patients receiving clonazepam to clobazam to maintain or increase seizure control, improve tolerability of patients' overall drug therapy regimens, and to enhance quality of life for patients and their families. However, no published guidelines assist clinicians in successfully accomplishing this change safely.Case presentationsThe following three case reports provide insight into the transition from clonazepam to clobazam. First, an 8-year-old Caucasian boy with cryptogenic Lennox-Gastaut syndrome beginning at 3.5 years of age, who was experiencing multiple daily generalized tonic-clonic, absence, myoclonic, and tonic seizures at presentation. Second, a 25-year-old, left-handed, White Hispanic man with moderate mental retardation and medically refractory seizures that he began experiencing at 1 year of age, secondary to tuberous sclerosis. When first presented to an epilepsy center, he had been receiving levetiracetam, valproate, and clonazepam, but reported having ongoing and frequent seizures. Third, a 69-year-old Korean woman who had been healthy until she had a stroke in 2009 with subsequent right hemiparesis; as a result, she became less physically and socially active, and had her first convulsive seizure approximately 4 months after the stroke.ConclusionsFrom these cases, we observe that a rough estimate of final clobazam dosage for each mg of clonazepam under substitution is likely to be at least 10-fold, probably closer to 15-fold for many patients, and as high as 20-fold for a few. Consideration and discussion of the pharmacokinetic, pharmacologic, and clinical properties of 1,4- and 1,5-benzodiazepine action provide a rationale on why and how these transitions were successful.

Background: Stevens‐Johnson syndrome (SJS) and toxic epidermal necrolysis Syndrome (TEN) are rare immune‐mediated diseases. Extensive research on adult triggers of SJS and TEN is available; however, research in children is more limited. Objective: We sought to investigate and report the experience with pediatric SJS and TEN in our center, identifying associated medications. Methods: A retrospective review from 1990 to 2015 at the Shriner's Burn Hospital in Galveston, Texas was performed to identify patients diagnosed with SJS, SJS/TEN overlap, and TEN. Data pertaining to demographic characteristics, medical history, physical exam, treatment, and outcomes were collected. Results: We identified SJS/TEN overlap or TEN in 51 patients. Antiepileptic drugs were the most common group of causative agents, closely followed by antibiotics. The most common causative agents were trimethoprim‐sulfamethoxazole, phenytoin, and lamotrigine used concomitantly with valproic acid. Newer generation agents, with the definition of agents approved after 1990, were the cause in 13/51 (25.5%) cases. Newer generation agents included lamotrigine, clobazam, and zonisamide. Seven patients died, resulting in a 13.7% mortality rate. Renal failure, liver failure, sepsis, and gastrointestinal involvement each had a statistically significant association with mortality. SCORTEN was statistically significantly greater in patients who died compared to children who lived (3 vs 2). Limitations: This is a retrospective study. Conclusion: Three drugs introduced into the market since 1990 have emerged as causes of SJS/TEN overlap and TEN: lamotrigine, clobazam, and zonisamide. These medications are being used more widely to treat seizures, as well as mood disorders. It is also important for clinicians to be aware of the extremely commonly used medications such as amoxicillin, tetracyclines, NSAIDs, and acetaminophen that can rarely cause SJS and TEN. [ABSTRACT FROM AUTHOR]

New warnings have been added to the labeling of the antiseizure medications levetiracetam and clobazam regarding a rare but potentially life-threatening adverse effect known as drug reaction with eosinophilia and systemic symptoms, or DRESS. [ABSTRACT FROM AUTHOR]

• Clobazam shortage may result in heightened seizure frequency. • Abrupt switching from clobazam to clonazepam at a 10:1 ratio increases seizure frequency. • Despite the abrupt switch from clobazam to clonazepam, clonazepam-associated side effects can be tolerated. Antiseizure medication (ASM) shortages are a global problem that have a negative impact on outcomes such as seizure control in patients with epilepsy (PWE). In the case of clobazam (CLB) shortage, there is no study regarding the management strategy. This study aims to investigate the alteration in seizure frequency and the occurrence of side effects in PWE undergoing an abrupt switch from clobazam (CLB) to clonazepam (CLZ), during CLB shortage. A retrospective study was conducted from electronic health records at our neurology outpatient clinic from January to July 2022. Change in seizure frequency and percentage of CLZ-associated side effects were determined as primary and secondary outcomes, respectively. Potential drug-drug interactions (Level C and above) were evaluated by using Lexicomp Drug Interaction Checker. The analysis included a total of 29 adult patients (15F, median age: 29). The switching ratio was 10 mg CLB for every 1 mg CLZ (10:1). Seizure frequency was higher during the CLZ period compared to the CLB period (p < 0.05), but no status epilepticus cases were observed. All patients exhibited potential drug-drug interactions, leading to reduced CLZ levels in 12 cases. A total of 36 CLZ-associated side effects were identified, with fatigue (19.4 %), drowsiness (16.6 %), and somnolence (13.8 %) being the most prevalent. A positive and strong correlation was found between CLZ dose and the number of side effects (r: 0.556; p: 0.002). The abrupt switch from CLB to CLZ was observed to increase seizure frequency without leading to status epilepticus in PWE. CLZ-associated side effects were found to be tolerable despite the abrupt switch. Future studies may explore the effect of alternative switching ratios. [ABSTRACT FROM AUTHOR]

Objectives: To assess the efficacy and safety profile of add‐on cannabidiol (CBD) in patients with Lennox–Gastaut syndrome (LGS) and Dravet syndrome (DS) on clobazam and in the overall population of four randomized, controlled phase 3 trials. Methods: Patients received plant‐derived, highly purified CBD medicine (Epidiolex® in the USA; Epidyolex® in Europe; 100 mg/ml oral solution) at a dose of 10 or 20 mg/kg/day, or placebo for 14 weeks. A subgroup analysis of patients on clobazam and meta‐analysis by syndrome were conducted. The primary endpoint was percentage reduction in primary seizure type during the treatment period. Results: 396 patients with LGS (49% on clobazam) and 318 patients with DS (64% on clobazam) were included. CBD treatment resulted in a reduction in primary seizure frequency vs placebo in the overall population (treatment ratio [95% confidence interval]: LGS, 0.70 [0.62‐0.80]; DS, 0.71 [0.60‐0.83]) and in patients receiving clobazam (LGS, 0.56 [0.47‐0.67]; DS, 0.63 [0.52‐0.77]). The antiseizure efficacy of CBD was also demonstrated across other endpoints vs placebo (≥50% responder rate, total seizure frequency, number of seizure‐free days, and Subject/Caregiver Global Impression of Change scores) in the overall populations and in patients receiving clobazam. There were higher incidences of somnolence and sedation in patients on CBD and clobazam. Most incidences of elevated transaminases occurred in patients on concomitant valproate and, to a lesser extent, clobazam. Conclusions: Add‐on CBD was effective in reducing seizures in the overall populations and in conjunction with clobazam. Somnolence and sedation occurred more frequently in patients on CBD and clobazam. [ABSTRACT FROM AUTHOR]

Purpose: Brain tumor-related epilepsy (TRE) is often resistant to currently available antiepileptic medications (AEDs). Clobazam was initially approved as adjunctive AED for patients with Lennox Gastaut syndrome but has been used in TRE, despite limited evidence in this context. This observational study aims to examine the effect of clobazam on seizure frequency on patients who have a primary CNS tumor and continued seizures despite their current AEDs. Methods: A retrospective review of patients with histologically-confirmed primary brain tumors seen in the neuro-oncology interdisciplinary clinic from April 2016–2019 was completed, and patients on clobazam were identified. Response to clobazam was defined as a greater than 50% reduction in seizure frequency. Additional data including patient and tumor characteristics, treatment course, tolerability, AEDs used prior to addition of clobazam, and AEDs concomitantly used with clobazam were collected. Results: A total of 35 patients with TRE on clobazam were identified, with 2 patients unable to tolerate the medication due to side effects. Of the 33 remaining patients, a total of 31 (93.9%) of patients were deemed responders. Ten patients (30.3%) were seizure free within 6 months of clobazam initiation and 21 (63.6%) reported a significant reduction in seizure frequency. This reduction also allowed several patients to modify concurrent AEDs. Conclusions: Clobazam is an effective agent to use as add-on AED in TRE, with 94% of patients showing a significant response within 6 months. Furthermore, the addition of clobazam may yield a reduction in polypharmacy, as concomitant AEDs can be reduced and potentially withdrawn. [ABSTRACT FROM AUTHOR]

Central pontine myelinolysis (CPM) is a rare neurological disorder characterized by demyelination within the central portion of the pons. While hyponatremia is a well-known precipitating factor, other etiologies, including medication use, have been reported. We present a case of a 69-year-old male with a history of obsessive-compulsive disorder, stroke, and type 2 diabetes mellitus who developed confusion, altered sensorium, and weakness in all four limbs. An MRI brain imaging revealed characteristic findings suggestive of CPM. Despite normal serum sodium levels, discontinuation of clobazam and quetiapine, medications taken by the patient, led to clinical improvement. This case underscores the importance of considering medication-induced CPM in the differential diagnosis of patients presenting with neurological symptoms, even in the absence of electrolyte abnormalities., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Bedi et al.)

Objective: The efficacy of cannabidiol (CBD) with and without concomitant clobazam (CLB) was evaluated in stratified analyses of four large randomized controlled trials, two in Lennox‐Gastaut syndrome, and two in Dravet syndrome. Methods: Each trial of CBD (Epidiolex® in the US; Epidyolex® in the EU; 10 and 20 mg/kg/day) was evaluated by CLB use. The treatment ratio was analyzed using negative binomial regression for changes in seizure frequency and logistic regression for the 50% responder rate, where the principle analysis combined both indications and CBD doses in a stratified meta‐analysis. Pharmacokinetic data were examined for an exposure/response relationship based on CLB presence/absence. Safety data were analyzed using descriptive statistics. Results: The meta‐analysis favored CBD vs. placebo regardless of CLB use. The treatment ratio (95% CI) of CBD over placebo for the average reduction in seizure frequency was 0.59 (0.52, 0.68; P <.0001) with CLB and 0.85 (0.73, 0.98; P =.0226) without CLB, and the 50% responder rate odds ratio (95% CI) was 2.51 (1.69, 3.71; P <.0001) with CLB and 2.40 (1.38, 4.16; P =.0020) without CLB. Adverse events (AEs) related to somnolence, rash, pneumonia, or aggression were more common in patients with concomitant CLB. There was a significant exposure/response relationship for CBD and its active metabolite. Conclusions: These results indicate CBD is efficacious with and without CLB, but do not exclude the possibility of a synergistic effect associated with the combination of agents. The safety and tolerability profile of CBD without CLB show a lower rate of certain AEs than with CLB. [ABSTRACT FROM AUTHOR]

Clobazam (CLB) was approved in October 2011 by the United States FDA as an adjunctive therapy for the treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients older than the age of 2. Due to its unique chemical design and selective binding to the alpha-2 GABA-receptor, CLB has a decreased tendency for sedation compared to other benzodiazepines. A recent literature review shows that sedation, hypersalivation (drooling), and behavior changes are the most common side effects of CLB. It has also been shown that a patient's level of consciousness is indirectly related to the risk of aspiration. Hypersalivation is too is a significant predisposing factor for aspiration. In this report, we present three adult patients with epilepsy who had aspiration pneumonia during treatment with CLB. We would like to raise awareness of increased drooling and somnolence in patients with predisposing factors for aspiration such as treatment with CLB and emphasize vigilance in this regard.

The interest in the anti-seizure efficacy of cannabinoids (CBD)has significantly increased over the past decade. Trials have shown a remarkable reduction in the frequency of convulsive seizures in Dravet and Lennox-Gastaut syndromes patient population. Studies have shown that CBD reacts with Clobazam leading to a significant increase in the levels of N-desmethylclobazam, the active metabolite of Clobazam. We present a case of a patient with Dravet syndrome who presented to the emergency department with altered mental status secondary to Clobazam toxicity related to CBD and Clobazam drug-drug interaction. We present a case of a patient with Dravet syndrome who presented to the emergency department with altered mental status. Patient was hospitalized and Clobazam was held off. Clobazam level and N-desmethylclobazam levels were obtained and came back elevated at 512 ng/mL and 15020 ng/mL respectively (reference range 30-300 ng/mL and 300 to 3000 ng/mL respectively). Rowida Kheireldin (a) (1) Naeem Mahfooz (b)

Febrile seizure is the most common seizures seen in infancy and pre-school era. They are mostly benign in nature. There are two categories of febrile seizures, simple and complex. Both the International League against Epilepsy and the American academy of paediatrics have published definitions on the classification of febrile seizures. Simple febrile seizures are mostly benign, but a prolonged (complex) febrile seizure can have long term consequences. Most children who have a febrile seizure have normal health and development after the event, but recent evidence suggests a small subset of children presenting with seizures and fever may have recurrent seizure or develop epilepsy. Diagnosis is solely clinical. But other causes of fever and seizure must be ruled out. Electroencephalogram, lumbar puncture and neuroimaging, all are to be used for specific indications but not routinely. Treatment consists of acute management and prophylaxis for further attack. This review will give an overview of the definition of febrile seizures, epidemiology, evaluation, treatment, outcomes and recent research.