Wednesday, June 26, 2019

Supratherapeutic clobazam

Gedela S, Gedela S, Glynn P, Salvator A, Patel AD. Safety and Efficacy of Supratherapeutic Doses of Clobazam. J Child Neurol. 2019 Jun 19:883073819856834. doi: 10.1177/0883073819856834. [Epub ahead of print]

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.

From the article:

Clobazam dose was calculated into milligrams per kilogram body weight for each patient using the weight from the same visit that dose was obtained. Patients were then classified as supratherapeutic dosing (SUPRA, defined as using a dose of >1 mg/kg/d or 40 mg/d) or therapeutic dosing for patients with doses less than the FDA-approved maximum dose of 1 mg/kg/d or 40 mg/d (THERA)…

Overall, patients with supratherapeutic doses of clobazam were younger and more likely to have generalized onset seizures. Patients given therapeutic doses were more likely to have focal onset seizures. In addition, these higher doses were well tolerated, and there was no statistical difference in adverse events for the 2 groups. Importantly, no differences in seizure frequency or health care utilization were noted between the 2 groups…

In summary, supratherapeutic doses of clobazam were well tolerated, without an increased reporting of side effects compared to patients receiving doses that are in the normal therapeutic range as recommended by the FDA. Therefore, patients who do require higher doses can be counseled that the likelihood of side effects may not increase with elevated dosing. Interestingly, patients in our study receiving higher doses of clobazam did not appear to have greater benefit in seizure reduction when compared to normal dose ranges of clobazam. However, it is unclear if this correlation is accurate based on the difficulty of seizure frequency reporting in our chart review. Further work with a uniform and accurate method of detailing seizure frequency would be needed to determine truly if differences in seizure reduction exist between higher doses compared to lower doses of clobazam. In addition, the patients receiving higher doses of clobazam may have had more difficult to treat seizures, thus necessitating increased doses in a treatment-resistant population. Finally, the patients receiving supratherapeutic doses of clobazam were younger and more likely to have generalized onset seizure types, which may have reflected a population with a higher likelihood of treatment failure or not having a reduction in seizure frequency.18 Further randomized controlled prospective studies are needed to fully understand the differences between dosing strategies in epilepsy patients treated with clobazam.

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