Deconstructing tolerance with clobazam

Gidal, Barry E.; Wechsler, Robert; Sankar, Raman; Montouris, Georgia; White, H. Steve; Cloyd, James C.; Kane, Mary Clare; Peng, Guangbin; Tworek, David M.; Shen, Vivienne; Isojärvi, Jouko

doi:10.1212/wnl.0000000000003253

Cited by 14 publications

(4 citation statements)

References 26 publications

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“…21 A later open-label study defined tolerance as a dosage increase of 40% plus loss of response and found a rate of tolerance of 12%. 6 We broadly considered either a relapse in seizure frequency or dose increase to represent tolerance; our study found development of tolerance at 1 year in approximately one-fourth of patients, a lower rate than most prior studies, and a rate of discontinuation that is highest in the first month after initiation of clobazam.…”

Section: Discussionmentioning

confidence: 79%

“…3,4 As the a 1 receptor is largely responsible for sedating effects of benzodiazepines, clobazam is therefore less sedating; this increased specificity has also been proposed to contribute to the lesser degree of tolerance seen with clobazam than with other benzodiazepines. 5,6 Clobazam was approved by the United States Food and Drug Administration (FDA) in 2011 for treatment of Lennox-Gastaut syndrome (LGS). 7 Since that time, there has been increasing off-label use of clobazam in adults with refractory epilepsy and anecdotal evidence that it may be more effective than other AEDs.…”

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confidence: 99%

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Efficacy and Tolerability of Clobazam in Adults With Drug-Refractory Epilepsy

et al. 2021

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ObjectivesTo evaluate the effectiveness and tolerability of clobazam as an adjunctive treatment for adults with drug-resistant epilepsy.MethodsWe performed a single-center, retrospective chart review of patients ≥18 years of age with drug-resistant epilepsy who started clobazam between 2010 and 2018. Included patients had outpatient visits both before and ≥1 month after clobazam initiation. Epilepsy classification, seizure frequency before and after clobazam, duration of clobazam treatment, and adverse effects were analyzed.ResultsA total of 417 patients met inclusion criteria. Mean age was 37.5 years, and 54% of patients were female. Patients were on a mean of 2.4 antiepileptic drugs at time of initiation of clobazam. Epilepsy types were focal (56.8%), Lennox-Gastaut syndrome (LGS) (21.1%), generalized (15.1%), and unclassified (7.0%). At the first follow-up visit ≥1 month after clobazam initiation, 50.3% of patients had >50% reduction in seizure frequency, and 20.5% were seizure-free. Of the initial cohort, 17.1% were followed >1 year and were seizure-free at last follow-up. Response rates did not differ between different epilepsy classifications. Fifty-one percent of patients experienced ≥1 side effect, most commonly lethargy/fatigue (30.7%) or mood changes (10.8%). A total of 178 (42.6%) patients discontinued clobazam, most commonly due to adverse effects (55%).ConclusionsClobazam is effective and safe as a long-term adjunctive therapy for adults with drug-resistant epilepsy; efficacy in off-label use is similar to that in LGS.Classification of evidenceThis study provides Class IV evidence that clobazam is an effective treatment for adults with drug-resistant epilepsy, independent of epilepsy classification.

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Section: Discussionmentioning

confidence: 79%

mentioning

confidence: 99%

Efficacy and Tolerability of Clobazam in Adults With Drug-Refractory Epilepsy

et al. 2021

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“…Although tolerance is typically associated with prolonged treatment and high doses of antiseizure drugs [2], it may be associated with a number of other factors, key of which are pharmacokinetic and pharmacodynamic properties of the drug [1,2], as well as other factors that may occur acutely. Tolerance may also vary with seizure type, even with the same agent, as illustrated by studies of clobazam showing higher levels of tolerance in patients with temporal lobe epilepsy (27% at 1 year [3]) compared with Lennox-Gastaut syndrome (12% at 2 years [4]). Those studies defined tolerance as the development of partial or complete loss of therapeutic effectiveness [3] or a dosage increase !40% plus loss of response [4].…”

Section: Introductionmentioning

confidence: 99%

“…Tolerance may also vary with seizure type, even with the same agent, as illustrated by studies of clobazam showing higher levels of tolerance in patients with temporal lobe epilepsy (27% at 1 year [3]) compared with Lennox-Gastaut syndrome (12% at 2 years [4]). Those studies defined tolerance as the development of partial or complete loss of therapeutic effectiveness [3] or a dosage increase !40% plus loss of response [4].…”

Section: Introductionmentioning

confidence: 99%

Lack of observed tolerance to diazepam nasal spray (Valtoco®) after long-term rescue therapy in patients with epilepsy: Interim results from a phase 3, open-label, repeat-dose safety study

Cascino

Tarquinio²,

Wheless

et al. 2021

Epilepsy & Behavior

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Objective: Tolerance is a known consideration for maintenance use of benzodiazepines and other antiseizure drugs; however, clinical experience suggests that tolerance may not be anticipated with longterm intermittent use of benzodiazepines as rescue therapy. Diazepam nasal spray (Valtoco Ò ) is a proprietary intranasal formulation approved for the acute treatment of intermittent, stereotypic episodes of frequent seizure activity (ie, seizure clusters, acute repetitive seizures) in patients with epilepsy aged !6 years. Reported here are exploratory analyses investigating whether there was evidence of development of tolerance in an interim analysis of a long-term, phase 3, open-label safety study of diazepam nasal spray. Methods: Patients and care partners were trained to administer 5, 10, 15, or 20 mg of diazepam nasal spray (age-and weight-based dosing), with a second dose administered 4-12 hours later if needed. A series of analyses were performed to assess evidence of tolerance using 2 equal, adjacent time periods and data for each patient to compare the proportion of events for which second doses of diazepam nasal spray (as a proxy for effectiveness) were administered in period 1 compared with period 2. Results: A total of 175 patients were enrolled at interim cutoff, and 158 were treated with diazepam nasal spray for 3370 seizure-cluster events. For 73.4% of patients, duration of exposure to diazepam nasal spray was !12 months. A total of 191 analyses were conducted; the proportion of analyses in which second doses in period 2 were lower than in period 1 was 72.8%. Only 5 analyses showed nominally statistically significant changes (P < 0.05); this is fewer than expected by chance, and these differences were not directionally consistent. There was no safety signal with continued use. Conclusions: These analyses found no statistical evidence of tolerance with the use of diazepam nasal spray over time based on use of a second dose in an initial period of the study compared with a subsequent period for each patient. These results are in agreement with prior studies of benzodiazepine rescue therapy.

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Systematic review of clobazam use in patients with status epilepticus

Mahmoud

Rans

2018

Epilepsia Open

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SummaryClobazam (CLB) is a commonly used oral antiepileptic drug (AED) that has been shown to be effective in various forms of epilepsy. Given its distinct 1,5‐benzodiazepine structure, rapid absorption, minimal drug interactions, and favorable safety profile, CLB displays unique properties when compared to other commonly used benzodiazepines. Recent evidence has shown that CLB may demonstrate therapeutic efficacy in status epilepticus (SE). The objective of this systematic review was to summarize the available evidence pertaining to the efficacy of CLB use in SE. An electronic literature search of Medline (1946 to November 6, 2017), Embase (1974 to November 6, 2017), and the Cochrane Library (1999 to November 6, 2017) databases was performed to identify reports of CLB use in SE. After screening and full text review, a total of 15 articles were included: 8 retrospective studies, 2 case series, and 5 case reports. Efficacy rates for CLB have varied among reports. Overall, based on the retrospective studies, a total of 76 patients with SE have been reported. CLB was introduced within 2–4 days from SE onset and has been reported to contribute to remission in 36 patients (47%). CLB maintenance dose ranged from 10 to 60 mg/day. However, the results need to be interpreted carefully because SE patients are a heterogeneous group with different etiologies and disease severities, and the response to CLB might vary in different patient population or seizure types. In conclusion, there is not sufficient evidence to determine the safety and efficacy of clobazam in the setting of SE. However, the current limited evidence combined with the unique characteristics of CLB suggest that the drug might be considered as an add‐on option in SE patients, with a suggested dosage range of 10–60 mg/day. Prospective studies are needed to fully establish the role of CLB in the management of SE.

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Deconstructing tolerance with clobazam

Cited by 14 publications

References 26 publications

Efficacy and Tolerability of Clobazam in Adults With Drug-Refractory Epilepsy

Efficacy and Tolerability of Clobazam in Adults With Drug-Refractory Epilepsy

Lack of observed tolerance to diazepam nasal spray (Valtoco®) after long-term rescue therapy in patients with epilepsy: Interim results from a phase 3, open-label, repeat-dose safety study

Systematic review of clobazam use in patients with status epilepticus

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