Dose Of Clobazam Research Articles

Cost-effectiveness of clobazam as an adjunctive treatment for refractory epilepsy in China.

Clobazam (CLB) is an effective, safe and well-tolerated adjunctive treatment for refractory epilepsy. However, the cost-effectiveness of CLB in China remains unclear. The aim of this study was to evaluate the cost-effectiveness of CLB as an adjunctive therapy for patients with refractory epilepsy in China. A Markov model was established to simulate the lifetime epilepsy process in patients. The epilepsy remission rate, health state utility and mortality data were derived from clinical trials and the literature. The costs were collected from the health care system in the hospital. The primary outcome was the incremental cost-effectiveness ratio (ICER), which was calculated by comparing CLB as an add-on therapy with conventional therapy and was assessed in the context of the Chinese health system. One-way and probabilistic sensitivity analyses were conducted to evaluate parameter uncertainty, and several scenario analyses were also conducted. Compared with maintaining conventional therapy, adding CLB as an adjuvant therapy increased the cost of Chinese Yuan (CNY) 1770.17 over a lifetime, with an incremental quality-adjusted life years (QALYs) value of 1.02, resulting in an ICER of CNY 1737.10 per QALY gained. The daily dose of CLB had the strongest effect on the ICER. The probabilistic sensitivity analyses revealed that the probability of CLB being cost-effective was 77.35% at a willingness to pay (WTP) of CNY 85698/QALY. CLB is a cost-effective add-on therapy for refractory epilepsy in the Chinese population.

Therapeutic strategies during cenobamate treatment initiation: Delphi panel recommendations.

The goal of epilepsy treatment is seizure freedom, typically with antiseizure medication (ASM). If patients fail to attain seizure control despite two trials of appropriately chosen ASMs at adequate doses, they are classified as having drug-resistant epilepsy (DRE). Adverse events (AEs) commonly occur in people with DRE because they are typically on ⩾2 ASMs, increasing the potential for drug-drug interactions. Early emerging AEs may impact adherence, decrease quality of life, and delay achieving optimal treatment dosages. Cenobamate is an oral ASM with a long half-life which has proven to be highly effective in clinical trials. An international Delphi panel of expert epileptologists experienced in the clinical use of cenobamate and other ASMs was convened to develop consensus best practices for managing patients during and after cenobamate titration, with consideration for its known pharmacokinetic and pharmacodynamic interactions, to allow patients to reach the most appropriate cenobamate dose while limiting tolerability issues. The modified Delphi process included one open-ended questionnaire and one virtual face-to-face meeting. Participants agreed that cenobamate can be prescribed for most patients experiencing focal-onset seizures. Patients initiating cenobamate therapy should have access to healthcare professionals as needed and their treatment response should be evaluated at the 100-mg dose. Patients with intellectual disabilities may need additional support to navigate the titration period. Proactive down-titration or withdrawal of sodium channel blockers (SCBs) is recommended when concomitant ASM regimens include ⩾2 SCBs. When applicable, maintaining a concomitant clobazam dose at ~5-10 mg may be beneficial. Patients taking oral contraceptives, newer oral anticoagulants, or HIV antiretroviral medications should be monitored for potential interactions. Because clinical evidence informing treatment decisions is limited, guidance regarding dose adjustments of non-ASM drugs was not developed beyond specific recommendations presented in the Summary of Product Characteristics.

Caution in usage of clobazam in elderly patients

Clobazam, one of the newer benzodiazepines, is now used extensively as first add on therapy in focal epilepsy.A 67-year-old diabetic and hypertensive gentleman with a history of frontal contusion one year ago, presented with clustering of seizures. He was started on clobazam 20 mg, and levetiracetam 1000 mg/day. Recurrence of seizures prompted a dose escalation of clobazam to 40 mg/day. The patient developed hepatic encephalopathy and his decompensation was probably precipitated by the use of high dose of clobazam. Clobazam was thus gradually tapered off along with hepatic precoma regimen, and other supportive measures leading to an uneventful recovery.Caution must be taken while administering clobazam to elderly and debilitated patients or those with organic brain syndrome as they are more prone to the central nervous system (CNS) depressant activity of benzodiazepines. Since clobazam requires dealkylation and hydroxylation prior to conjugation, it should be used with caution in patients with hepatic involvement.

The cenobamate-clobazam interaction- evidence of synergy in addition to pharmacokinetic interaction

ObjectivesReport insights into the pharmacokinetic and pharmacodynamic interaction between cenobamate (CNB) and clobazam (CLB), derived from data in patients enrolled at our center in a global multicenter open-label safety study of CNB. Materials & MethodsPatients in this study either took CLB at baseline (n = 6) or had CLB added after CNB titration to maximal dose (n = 5) in addition to other antiseizure medications. Clobazam was always administered as a single bedtime dose. Random serum concentrations of CLB and N-desmethylclobazam (N-CLB) were obtained. ResultsBaseline daily CLB doses were 20–50 mg. Sedation began in the six baseline CLB patients at CNB doses of 25–100 mg. The N-CLB/ CLB ratio increased proportionally to the CNB dose. CLB was stopped in all six patients, five of whom were ≥50% responders. Seizure control deteriorated after stopping CLB, with only one remaining responder. Clobazam was restarted at 5 mg/d in five of the six patients. At the last follow-up, four of these patients were continuing CLB; two were seizure-free and 2 were ≥50% responders. Among the five patients that added 5 mg/d CLB de novo, three were responders. All patients were still on CNB at the end of the study. DiscussionData suggest starting CLB dose reduction at CNB doses of 25–100 mg/d. Due to possible synergy, the addition of low-dose CLB could be considered in patients with incomplete response to CNB.

Tolerability of clobazam as add-on therapy in patients aged 50years and older with drug-resistant epilepsy.

To evaluate the tolerability of clobazam in patients with drug-resistant epilepsy aged 50years and older. We performed a single center, retrospective chart review of patients at least 50years of age with drug resistant epilepsy of any type who started clobazam as an add on therapy. Retention rate, safety, and tolerability at 6 and 12months and last follow-up, and the discontinuation rate due to side effects were analyzed. A total of 26 patients met inclusion criteria. Mean age was 62 ± 7.1years, and 69.2% of patients were female. The mean baseline seizure frequency before initiation of clobazam was 2 (range 1-30) seizures per month. The mean total daily dose of clobazam administered was 13 (range 5 to 30) mg/day. At the 12-month follow-up visit after clobazam initiation, 40% of patients were seizure-free and an additional 45% of patients had > 50% reduction in seizure frequency. The mean seizure frequency at 12-month follow-up was 1.5 (range 0-24) seizures per month. The mean total dose of clobazam at 12-month follow-up was 14.25 (range 5 to 25) mg/day. The mean duration of clobazam at last follow was 55.2 ± 27.02 (mean ± SD months) and 18 (69.2%) patients remained on clobazam. Twenty out of 26 (76.9%) patients reported at least one side effect and 6/26 (23%) discontinued the medication within a month of initiation. At last follow-up, 40% remained seizure free on stable dosing. Clobazam can be a safe and tolerable, add-on treatment older adults with drug-resistant epilepsy. Those who responded tolerated the medication well. Discontinuation due to side effects occurred soon after initiation of therapy.

Real-world, long-term evaluation of the tolerability and therapy retention of Epidiolex® (cannabidiol) in patients with refractory epilepsy

ObjectiveEpidiolex® (CBD) is FDA-approved for seizures associated with Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), and tuberous sclerosis complex (TSC). Phase III studies suggest that certain adverse effects (AEs), possibly linked to pharmacokinetic/pharmacodynamic (PK/PD) interactions may be therapy-limiting. We sought to identify these factors that contribute to treatment success and retention of therapy. MethodsA single-center, retrospective review of patients with refractory epilepsy taking Epidiolex® was performed. Kaplan-Meier analysis was performed to describe Epidiolex® retention, as a measure of overall effectiveness. ResultsOne hundred and twelve patients were screened; 4 were excluded due to loss to follow-up or never starting Epidiolex®. Of 108 patients, mean age was 20.3 years (13.1, range 2 to 63), and 52.8% were female. Mean initial and maintenance doses were 5.3 mg/kg/day (1.3) and 15.3 mg/kg/day (5.8), respectively. At the final evaluation, 75% of patients remained on Epidiolex®. The 25th percentile for discontinuation was 19 months. 46.3% of patients experienced at least one treatment-emergent adverse effect (TEAE) with 14.5% d/c Epidiolex® due to treatment emerging adverse effects (TEAE). The most common reasons for discontinuation were lack of efficacy (37%), increased seizure activity (22%), worsened behavior (22%), and sedation (22%). One out of 27 discontinuations was due to liver function test (LFT) elevations (3.7%). At initiation, 47.2% were concurrently taking clobazam, and 39.2% of those patients had an initial clobazam dose decrease. 53% of patients were able to either discontinue or lower the dose of at least one other antiseizure medication. SignificanceEpidiolex® is generally well-tolerated and the majority continued long-term treatment. Patterns of adverse effects were similar to clinical trials, however gastrointestinal complaints, and significant LFT elevations were less common. Our data suggest most patients discontinue within the first several months of treatment and suggest that further studies designed to evaluate early identification and potential mitigation of adverse effects and including drug interactions are warranted.

Dose Adjustment of Concomitant Antiseizure Medications During Cenobamate Treatment: Expert Opinion Consensus Recommendations.

Our objective was to provide expert consensus recommendations to improve treatment tolerability through dose adjustments of concomitant antiseizure medications (ASMs) during addition of cenobamate to existing ASM therapy in adult patients with uncontrolled focal seizures. A panel of seven epileptologists experienced in the use of ASMs, including cenobamate, used a modified Delphi process to reach consensus. The panelists discussed tolerability issues with concomitant ASMs during cenobamate titration and practical strategies for dose adjustments that may prevent or mitigate adverse effects. The resulting recommendations consider concomitant ASM dose level and specify proactive (prior to report of an adverse effect) and reactive (in response to report of an adverse effect) dose adjustment suggestions based on concomitant ASM pharmacokinetic and pharmacodynamic interactions with cenobamate. Specific dose adjustment recommendations are provided. We recommend proactively lowering the dose of clobazam, phenytoin, and phenobarbital due to their known drug-drug interactions with cenobamate, and lacosamide due to a pharmacodynamic interaction with cenobamate, to prevent adverse effects during cenobamate titration. Reactive lowering of a concomitant ASM dose is sufficient for other ASMs at standard dosing owing to quick resolution of adverse effects. For carbamazepine and lamotrigine doses exceeding the upper end of standard dosing (e.g., carbamazepine, greater than 1200mg/day; lamotrigine, greater than 500mg/day), we encourage consideration of proactive dose reduction at cenobamate 200mg/day to prevent potential adverse effects. All dose reductions for adverse effects can be repeated every 2weeks as dictated by the adverse effects. At cenobamate 200mg/day, we recommend that patients be evaluated for marked improvement of seizures and further dose reductions be considered to reduce potentially unnecessary polypharmacy. The primary goal of the recommended dose reductions of concomitant ASMs is to prevent or resolve adverse effects, thereby allowing cenobamate to reach the optimal dose to achieve the maximal potential of improving seizure control.

CLB add-on treatment in patients with epileptic encephalopathy: a single center experience with long-term follow-up

Clobazam (CLB) is an effective anticonvulsant used as an adjunctive treatment for several seizures and epilepsy syndromes. Data are limited on efficacy and safety of CLB as add-on therapy for epileptic encephalopaties (EEs) other than Lennox-Gastaut syndrome (LGS). This retrospective study aimed to assess efficacy and safety of long-term CLB add-on therapy for various EE syndromes. Data on CLB add-on therapy were assessed in 74 children (60.8% male) after 3months (early) and 12months (late) follow-up as well as in 57 (77%) patients who had been on CLB therapy longer than 12months (mean:39.11 ± 30.29; range:12-129months) (very late) were reported.Data on CLB add-on therapy were assessed in 74 children (60.8% male) after 3months (early) and 12months (late) follow-up as well as in 57 (77%) patients who had been on CLB therapy longer than 12months (mean:39.11 ± 30.29; range:12-129months) (very late) were reported. Good response rate (> 50%) for seizures was achieved in 24% at early follow-up, 30% at late follow-up, and 35% during very late follow-up. Complete seizure remission was achieved for 15% seizures; 72.7% occurred at very late follow-up. Myoclonic seizures were the most responsive (35%); this response increased during late follow-up (46%), whereas 27.3% of myoclonic-atonic/atonic seizures had good response at early and very late follow-up. At late follow-up, comparison of mean effective doses of CLB did not show significant difference among types of seizures with good response. Adverse effects reported in 15% of patients did not require stopping CLB therapy. Generalized epileptogenic potentials significantly decreased while focal epileptogenic potentials significantly increased at first year of treatment in comparison to basal EEG findings (p < 0.001). CLB should be considered as an optional antiepileptic that is well tolerated, particularly in EEs with myoclonic and myoclonic-atonic/atonic seizures.

Starting stiripentol in adults with Dravet syndrome? Watch for ammonia and carnitine.

Dravet syndrome (DS) is a rare cause of severe and pharmacoresistant epileptic encephalopathy. Stiripentol (STP) has a significant therapeutic benefit in the pediatric DS population. However, STP effects on adult patients have not been well studied. In our adult STP-naive DS patient population, STP initiation was associated with encephalopathy, despite decreases in valproate and clobazam dosage. Here we explored the cause and treatment of encephalopathic manifestations associated with STP in adults. Twenty-eight patients with a confirmed clinical and genetic diagnosis of DS who attended the Adult Epilepsy Genetics Clinic were identified retrospectively. Patients who declined or discontinued STP after fewer than 3months of use, patients who were deceased before starting STP or seizure-free when the genetic diagnosis was confirmed, and those who started STP before leaving the pediatric system (<18years) were excluded. Levels of ammonia, carnitine, and other anti-epileptic drugs (AEDs) were observed for patients receiving STP. Patients with high ammonia levels who received carnitine supplementation were reevaluated. They were also offered an increased dosage of stiripentol if treatment with carnitine improved the encephalopathy. We observed hyperammonemic encephalopathy in 77% of patients treated with STP. In seven of nine patients, we observed a rate of improvement in ammonia levels of 35% (95% confidence interval [CI] 21%-49%) at a mean carnitine dose of 991±286mg/d (range 660-1320mg/d). Five patients whose ammonia levels normalized were also offered an increase in STP dose and they were able to tolerate higher doses with improvement in side effects. Despite such adjustments, the mean maximum stiripentol dose reached was 14.89±8.72mg/kg/d, which is lower than what is typically recommended in children (50mg/kg/d). We report hyperammonemia in adult STP-naive patients who were on valproate and clobazam, despite dose reduction of the latter drugs. We also report that treatment with carnitine improved hyperammonemia, allowing the continuation of STP.

Objectively measured sleep–wake patterns in patients with drug-resistant epilepsy – Interaction with quality of life and antiepileptic treatment

RationalePatients with epilepsy experience frequent episodes of fragmented sleep which may contribute to chronic sleep loss. Enhancing sleep patterns might lead to improved quality of life in these patients. Currently, unlike some other antiepileptic drugs (AEDs), there are no data on the effects of clobazam, a novel AED on sleep. Therefore, we tested the hypothesis that patients with epilepsy will have longer, more consolidated sleep after treatment with clobazam. MethodsIn this prospective study, we included adults with drug-resistant epilepsy who were being considered for treatment with clobazam. Patients with known untreated moderate/severe sleep apnea or with major circadian rhythm disorders were excluded. We tested a set of the following subjective sleep measures: Pittsburgh Sleep Quality Inventory (PSQI), Epworth Sleepiness Scale (ESS), Karolinska Sleepiness Scale (KSS), Insomnia Severity Index (ISI), and Quality of Life in Epilepsy (QOLIE) prior to starting the treatment, as well as after achieving a stable clobazam dose. We also measured sleep pattern using wrist actigraphy – before starting therapy and after achieving stable dose. ResultsA total of 12 participants completed all parts of the study. After treatment, a lower number of awakenings and less wake after sleep onset (WASO) were seen, as well as a lower number of seizures. Average pretreatment bedtime was 23:45, and average wake time was 8:24. A higher seizure frequency significantly correlated with all subjective sleep measures, as well as with a higher amount actigraphy measured WASO and less total sleep time (TST) measured both by sleep log and by actigraphy. Those with higher baseline WASO by actigraphy also had more depressive symptoms, worse quality of life, longer duration of epilepsy, and a higher seizure frequency. ConclusionBoth objective and subjective sleep metrics correlate with depressive symptoms and quality of life. After treatment, there were fewer awakenings as well as fewer seizures.

Clinical implications of trials investigating drug-drug interactions between cannabidiol and enzyme inducers or inhibitors or common antiseizure drugs.

Highly purified cannabidiol (CBD) has demonstrated efficacy with an acceptable safety profile in patients with Lennox‐Gastaut syndrome or Dravet syndrome in randomized, double‐blind, add‐on, controlled phase 3 trials. It is important to consider the possibility of drug‐drug interactions (DDIs). Here, we review six trials of CBD (Epidiolex/Epidyolex; 100 mg/mL oral solution) in healthy volunteers or patients with epilepsy, which investigated potential interactions between CBD and enzymes involved in drug metabolism of common antiseizure drugs (ASDs). CBD did not affect CYP3A4 activity. Induction of CYP3A4 and CYP2C19 led to small reductions in exposure to CBD and its major metabolites. Inhibition of CYP3A4 activity did not affect CBD exposure and caused small increases in exposure to CBD metabolites. Inhibition of CYP2C19 activity led to a small increase in exposure to CBD and small decreases in exposure to CBD metabolites. One potentially clinically important DDI was identified: combination of CBD and clobazam (CLB) did not affect CBD or CLB exposure, but increased exposure to major metabolites of both compounds. Reduction of CLB dose may be considered if adverse reactions known to occur with CLB are experienced when it is coadministered with CBD. There was a small increase of exposure to stiripentol (STP) when coadministered with CBD. STP had no effect on CBD exposure but led to minor decreases in exposure to CBD metabolites. Combination of CBD and valproate (VPA) did not cause clinically important changes in the pharmacokinetics of either drug, or 2‐propyl‐4‐pentenoic acid. Concomitant VPA caused small increases in exposure to CBD metabolites. Dose adjustments are not likely to be necessary when CBD is combined with STP or VPA. The safety results from these trials were consistent with the known safety profile of CBD. These trials indicate an overall low potential for DDIs between CBD and other ASDs, except for CLB.

Effectiveness of cannabidiol in a prospective cohort of children with drug-resistant epileptic encephalopathy in Argentina

ObjectiveWe report our preliminary findings regarding effectiveness, safety, and tolerability of cannabidiol (CBD) added to antiepileptic therapy in a cohort of children with drug-resistant epileptic encephalopathies (EEs) with a mean follow-up of 8.5 months (range, 3–12 months). MethodsA prospective cohort study was designed with the aim of assessing the effectiveness, safety, and tolerability of the addition of CBD to standard antiseizure medications (ASMs) in children with drug-resistant EE enrolled at a single center (Neurology Department, Hospital de Pediatría "Juan P. Garrahan", Buenos Aires, Argentina). ResultsFifty patients were enrolled between October 2018 and October 2019, 49 of whom had a follow-up of at least 3 months at the time this interim analysis was performed. Mean age at enrollment was 10.5 years (range 2–16). Median age at first seizure was 7 months. Up to the last visit of each patient (follow-up 3–12 months) 39/49 children (80 %) had responded to treatment with a decrease in seizure frequency. Overall, 77.6 % of the patients had a seizure reduction of at least 25 %, 73.5 % had a ≥ 50 % reduction, and 49 % had a ≥ 75 % reduction. Mean monthly seizure frequency was reduced from 959 to 381 (median decrease from 299 to 102, range, 38–1900; median decrease 66 %, p < 0.001). All adverse effects were mild or moderate. The most common adverse effect was drowsiness (in 32 %), usually reversed by adjusting clobazam dose (in 12 children). ConclusionIn children with drug-resistant EEs, CBD oil as an adjuvant therapy to antiepileptic therapy seems safe, well tolerated, and effective.

Method development and validation of clobazam in bulk and pharmaceutical dosage forms by using high performance thin layer chromatographic method

In the present research a simple, accurate, precise and cost-effective High-performance thin layer chromatographic method for the estimation of clobazam, in bulk and pharmaceutical dosage form was illustrated. The RF value of the drug was found to be 0.74 in the mobile phase, acetone: toluene: formic acid (1: 1: 0.05 v/v/v). A linear response was observed in the range of 100-700 ng with a regression coefficient of 0.999. Validation parameters were carried out as per the guidelines of International Conference for Harmonization (ICH). This method can be used in the industries for determination of clobazam to analyze the quality of formulation without interference of the excipients.Â

Drug–drug interactions and pharmacodynamics of concomitant clobazam and cannabidiol or stiripentol in refractory seizures

ObjectiveThe goal of this study was to characterize the drug–drug interactions between clobazam and 2 antiseizure drugs, cannabidiol and stiripentol, for treatment of refractory seizures through the use of pharmacokinetic modeling. MethodsA population pharmacokinetic/pharmacodynamic model was developed to characterize the combined effect of clobazam and its active metabolite, N-desmethylclobazam (i.e., N-clobazam), on seizure protection in patients with Lennox–Gastaut syndrome using data from the phase 3 CONTAIN trial. Drug–drug interactions between clobazam and cannabidiol were examined by comparing model-generated data to data from a study of 13 patients taking concomitant clobazam and cannabidiol. Modeling data were also descriptively compared with studies of patients administered both clobazam and stiripentol. Sedation-related adverse events from CONTAIN were analyzed to determine the exposure–somnolence relationship of clobazam. ResultsExposure-efficacy analysis from the pharmacokinetic/pharmacodynamic model using CONTAIN data indicated that clobazam (half-maximal effective concentration [EC50], 303 ng/mL) was 3 times more potent than N-clobazam (EC50, 899 ng/mL). After administration of clobazam, when both clobazam and N-clobazam concentrations were each 1 to 2 times the EC50 value (clobazam dose, 20 mg), 70.0%–74.9% seizure protection was predicted; when concentrations were >2 times the EC50 value (clobazam dose, 40 mg), 74.0%–96.9% seizure protection was predicted. Generalized additive model analyses demonstrated decreased seizure probability with higher plasma concentration of clobazam. Coadministration of stiripentol and clobazam resulted in increased respective median plasma concentrations of clobazam and N-clobazam (1.1–1.2 times and 5.2–8.2 times) compared with administration of placebo and clobazam. Probability of somnolence significantly increased with age and higher N-clobazam plasma concentration. SignificanceAwareness of drug–drug interactions between clobazam and cannabidiol is needed when adding cannabidiol or stiripentol to a regimen of clobazam or vice versa. Based upon our population pharmacokinetic/pharmacodynamic model, we predict that an increase in N-clobazam levels, which patient data show may enhance efficacy and/or make adverse events such as somnolence more likely.

Pharmacometrics of clobazam in pediatrics: Prediction of effective clobazam doses for Dravet syndrome

Objective: To describe the use of a population pharmacokinetic (PopPK) model incorporating weight and ontogeny to identify effective clobazam (CLB) dosing for use in a clinical trial in pediatric patients with Dravet syndrome. Methods: Pharmacokinetic data were combined from 3 CLB trials (OV-1012, OV-1017, and study 301) and a simulated study (study 401) for a total of 1306 CLB and 1305 N-desmethyl clobazam (N-CLB) samples from 193 Lennox-Gastaut syndrome patients and healthy subjects aged 6 months to 45 years. A structured approach based on US Food and Drug Administration guidance and pharmacometric knowledge discovery was developed using a nonlinear mixed-effects approach. Graphing and fitting using logistical weight regression were used to identify covariates for inclusion in the final model, which was evaluated using goodness-of-fit criteria and validated using prediction-corrected visual predictive check (pcVPC). Using the final PopPK model, a simulation study determined CLB and N-CLB distributions after 4 weeks of 1.5 and 2.0 mg/kg CLB. Results: The parameters of the final PopPK model were similar to previous reports. Fixed-effect parameters were precisely estimated, with no significant increase in NONMEM objective function value. Intersubject variability estimates were similar to previous reports, with <35% shrinkage associated with parameter variability, except for intercompartmental clearance and apparent volumes of distribution of peripheral compartments. Goodness-of-fit plots and pcVPC show that the model adequately described CLB and N-CLB data. The CLB/N-CLB ratio in virtual study subjects aged <3 years was 0.23 for 1.5 and 2.0 mg/kg and was 0.14 for subjects aged ≥3 years, which is 2 to 3 times those reported in a previous stiripentol/CLB/valproate study in which seizure improvement was reported. Significance: The PopPK model dosing parameters of 1.5 and 2.0 mg/kg are likely to result in efficacious concentrations of CLB and N-CLB in pediatric patients as young as 16 months. Dosages exceeding 1.5 mg/kg should be monitored for tolerability, particularly in patients aged <2 years, as there may be a higher incidence of sedation.

A Case Report and Literature Review of Clobazam Toxicity Related to CBD and Clobazam Drug-Drug Interaction

Background: The interest in the anti-seizure efficacy of cannabinoids 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 ED with altered mental status secondary to clobazam toxicity related to CBD and clobazam drug-drug interaction. Methods and Findings: We present a case of a patient with Dravet Syndrome who presented to the ED with altered mental status. Patient was hospitalized and CBD was held off. Clobazam level and N-desmethylclobazam levels were obtained and came back elevated at 512 and 15020 respectively. Studies have reported clobazam toxicity secondary to CBD and clobazam drug- drug interaction since both drugs are metabolized by cytochrome P450 enzymes and glucuronyl transferases. Conclusion: Studies have shown the drug interactions of CBD with co-anti-epileptics, including a remarkable increase in the N-desmethylclobazam levels, the active metabolite of clobazam,which confirms the significant importance of monitoring blood levels for clobazam and norclobazam in patients using both CBD and clobazam, in addition for the need to reduce the Clobazam doses for this group of patients. Additional well-controlled studies are essential to establish the recommended doses and the management of the doses of other concomitant anti- epileptics medications with CBD use.

Safety and Efficacy of Supratherapeutic Doses of Clobazam.

Clobazam is a commonly used long-acting benzodiazepine approved by the US Food and Drug Administration (FDA) to treat seizures associated with Lennox Gastaut syndrome. The FDA approved maximum dosage of clobazam is 1 mg/kg/d or a total of 40 mg a day. Many providers exceed this dosage but there is limited data on the safety, tolerability, and efficacy of supratherapeutic doses. We reviewed retrospective data at our institution and compared patients on supratherapeutic doses to patients on therapeutic doses. A total of 133 patients met inclusion criteria (65 supratherapeutic, 67 therapeutic). There was no statistically significant difference in terms of seizure control, health care utilization, or side effects between patients on supratherapeutic doses and those on therapeutic doses. This study lends further support to the safety and tolerability of supratherapuetic doses of clobazam.

Pharmacokinetics of clobazam oral soluble film.

Clobazam oral soluble film (COSF) is a novel dosage form under development for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome. The present study was undertaken to assess the pharmacokinetics of clobazam administered as single doses of COSF 20 and 10 mg compared with clobazam tablets (CTAB) 20 and 10 mg in healthy adults. A secondary objective was to assess the safety and tolerability of single doses of COSF 20 and 10 mg. A total of 51 adult volunteers were enrolled in a single-dose, open-label, randomized four-sequence, four-period, crossover study with treatments (A) COSF 20 mg, (B) CTAB 20 mg, (C) COSF 10 mg, and (D) CTAB 10 mg. Pharmacokinetic sampling for clobazam and N-desmethylclobazam was carried out until 21 days postdose with a 28-day washout. Subjects were monitored for adverse events (AEs) throughout the study. Visual inspections of the administration site were performed before and after COSF administration to monitor for mucosal irritation. COSF at single doses of 10 and 20 mg was bioequivalent to CTAB at equivalent doses for both clobazam and its active metabolite N-desmethylclobazam. The pharmacokinetics of both formulations was dose-proportional at doses of 10 and 20 mg. The number of AEs and the number of subjects experiencing AEs were dose-related across the treatment groups, with somnolence the most common event. None of these events was severe or serious, and most were mild. There was no evidence for local irritation at the administration site following COSF. COSF is a novel clobazam dosage form that is bioequivalent to CTAB. Because of its ease of administration, COSF may be expected to improve adherence, reduce likelihood of dosing error, and provide more accurate dosing than formulations of clobazam that are currently available.

A Comprehensive Overview of the Clinical Pharmacokinetics of Clobazam.

Clobazam (CLB) is a 1,5‐benzodiazepine that has been widely used as an anxiolytic and antiseizure drug (ASD) since it was first synthesized over 50 years ago. CLB was approved in the United States in 2011 as adjunctive therapy for seizures in patients ≥2 years old with Lennox‐Gastaut syndrome. CLB pharmacokinetics (PK) have been studied in single‐ and multiple‐dose administrations in healthy subjects. Salient features include high bioavailability, linear PK, and negligible effects from coadministration of other ASDs. CLB is highly and extensively absorbed, with little effect from food; time to maximum plasma concentration is 0.5 to 4 hours following the dose. After CLB doses of 20 to 40 mg/day, the volume of distribution is 99 to 120 L, with oral clearance ranging from 1.9 to 2.3 L/h. CLB is lipophilic and distributes throughout the body after oral administration. It is metabolized in the liver by cytochrome P450 (CYP) isoenzymes CYP3A, CYP2C19, and CYP2B6, and its main active metabolite is N‐desmethylclobazam. The half‐life of CLB after a single oral dose ranges from 36 to 42 hours; the half‐life of N‐desmethylclobazam ranges from 59 to 74 hours. The metabolites of CLB are primarily excreted renally. Population PK modeling using data from healthy subjects and patients with Lennox‐Gastaut syndrome indicates that race, sex, age, weight, and renal function do not influence CLB PK. As CLB has been extensively studied since the 1970s, this review is meant to provide a consolidated and comprehensive resource on CLB PK for both prescribers and scientists alike.

Pharmacometrics of Clobazam in Pediatrics: Population PK Modeling to Predict Effective Clobazam Doses for Dravet Syndrome (P4.265)

Pharmacometrics of Clobazam in Pediatrics: Population PK Modeling to Predict Effective Clobazam Doses for Dravet Syndrome (P4.265)