What is the evidence for using greater than the FDA recommended dose of clobazam?

Background
Lennox-Gastaut syndrome is a severe childhood epileptic encephalopathy that is associated with multiple etiologies.^1,2 Classical features of this condition include various types of drug-resistant seizures (e.g., atonic, tonic, atypical absences), developmental delay, and interictal electroencephalogram formations.¹ Treatment for Lennox-Gastaut syndrome can be complicated due to incidence of multiple seizure types, refractory seizures, and other psychosocial and intellectual comorbidities.²  There are several anti-seizure medications that are indicated for patients with Lennox-Gastaut syndrome including clobazam.^1,2

Clobazam is an oral benzodiazepine that was initially approved in the United States in October 2011 as an adjunct treatment for seizures associated with Lennox-Gastaut syndrome in patients 2 years of age or older.^3,4 The 2 brand name products of clobazam include Onfi and Sympazan.^3-5 As of 2018 and beyond, generic clobazam (tablets, suspensions, films) have been granted Food and Drug Administration (FDA) approval.⁶ Off-label uses of clobazam include adjunctive therapy for seizures associated with Dravet syndrome, adjunct treatment for refractory status epilepticus, refractory focal epilepsy, catamenial epilepsy, and anxiety.⁷ Dosing for these off-label uses vary.

Dosing for the FDA-approved indication of Lennox-Gastaut syndrome for clobazam is individualized based on body weight, as shown in Table 1.^3,4 Doses of clobazam greater than 5 mg should be given in divided doses, twice daily. Dose escalation should not be done more rapidly than weekly due to the duration it takes clobazam and its active metabolite to reach steady state (5 days and 9 days, respectively). The maximum recommended daily dosage of clobazam according to U.S package inserts is 40 mg per day.

Evidence Literature for Increased Dosage
In some scenarios, there may be a need for higher dosages of clobazam (e.g., refractory seizure or status epilepticus cases). The clobazam package inserts cite a pharmacodynamic study using 20 mg and 80 mg doses of clobazam in 280 healthy subjects.^3,4 This study evaluated the effects of clobazam on the QTc interval compared to an active control (e.g., moxifloxacin 400 mg); the study found that clobazam did not prolong the QTc interval to a clinically significant degree when dosed at 2 times the maximum recommended dose. According to the product monograph for the Canadian clobazam product Apo-Clobazam, a maximum dose of 80 mg per day has been recommended (however, this would be considered off-label use for the U.S FDA-approved product).⁵

A systematic review by Mahmoud et al on clobazam use in patients with status epilepticus identified 2 retrospective cohort studies (Sivakumar et al 2015; Swisher et al 2017) and 1 case series (Corman et al 1998) that evaluated doses of clobazam greater than 40 mg.⁸ In the retrospective electronic medical review study by Sivakumar et al (N=17), authors reported that the median starting  dose  of  clobazam  was  10 mg per day  (range, 10 to 40) and the median maintenance dose was 20 mg per day (range, 10 to 60); however only 1 patient received a dose greater than 40 mg.⁹ The study by Swisher et al (N=17) is a conference abstract that reported on the use of clobazam as add-on therapy in patients with refractory nonconvulsive seizures or nonconvulsive status epilepticus; the median maintenance dose was reported as 20 mg per day (range, 10 to 60).⁸ The case series by Corman et al (N=4) evaluated clobazam use in patients with partial status epilepticus.¹⁰ Each patient received a single oral dose of clobazam that ranged from 60 to 70 mg  along with maintenance dosing (in some cases) and seizure activity was controlled within 2 hours of administration in 3 out of 4 patients.

A review article by Pernea et al on clobazam and its use in epilepsy identified 2 retrospective cohort studies (da Silveira et al 2006; Silva et al 2006) and 1 prospective cohort study (Vadja et al 1985) that evaluated doses of clobazam greater than 40 mg.¹¹ The study by Da Silveira et al (N=100) included patients with refractory focal epilepsy.¹² The initial dose of clobazam was 5 mg per day and maintenance doses ranged from 5 to 60 mg per day (mean, 23.6 mg). There were 10 patients in the study that received doses greater than 40 mg per day. Silva et al conducted a retrospective study (N=97) in pediatric patients with epileptic encephalopathy.¹³ The clobazam doses given ranged from 5 to 60 mg per day (mean, 37.5 mg), but the number of patients who received greater than 40 mg were not reported. Vadja et a al evaluated clobazam in refractory epilepsy patients (N=14); doses given ranged from 15 to 60 mg per day.¹⁴

Conclusion
According to the U.S package inserts for clobazam, the maximum recommended daily dosage is 40 mg per day in both adults and pediatric patients. Recommended uses of clobazam above this recommended dose is limited for both the approved and off-label uses. The body of evidence regarding use of increased daily dosages of clobazam is small and includes only a few cohort studies and case series with a limited number of patients evaluated. Scenarios where use of higher doses of clobazam has been reported include patients with status epilepticus and refractory seizures. Safety data regarding higher dosages of clobazam is also limited, though it is important to note that in pharmacodynamic study cited in clobazam package inserts, clobazam did not prolong the QTc interval to a clinically significant degree when dosed at 2 times the maximum recommended dose.

References

1. Strzelczyk A, Zuberi SM, Striano P, Rosenow F, Schubert-Bast S. The burden of illness in Lennox-Gastaut syndrome: a systematic literature review. Orphanet J Rare Dis. 2023;18(1):42. Published 2023 Mar 1. doi:10.1186/s13023-023-02626-4
2. Besag FMC, Vasey MJ, Chin RFM. Current and emerging pharmacotherapy for the treatment of Lennox-Gastaut syndrome. Expert Opin Pharmacother. 2023;1-20. doi:10.1080/14656566.2023.2215924
3. Onfi. Package insert. Lundbeck Pharmaceuticals LLC; 2023.
4. Sympazan. Package insert. Aquestive Therapeutics; 2023.
5. Clobazam (Systemic). In: Lexi-Drugs. Lexi-Comp, Inc. Updated June 1, 2023. Accessed June 12, 2023. http://online.lexi.com/
6. Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations [database on the internet]. Silver Spring, MD: Food and Drug Administration (US), Center for Drug Evaluation and Research; 2023. https://www.accessdata.fda.gov/scripts/cder/ob/index.cfm. Accessed June 12, 2023.
7. Humayun MJ, Samanta D, Carson RP. Clobazam. Updated 2022 Jul 4. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan. Available from: https://www.ncbi.nlm.nih.gov/books/NBK541043/
8. Mahmoud SH, Rans C. Systematic review of clobazam use in patients with status epilepticus. Epilepsia Open. 2018;3(3):323-330. Published 2018 Jun 13. doi:10.1002/epi4.12230
9. Sivakumar S, Ibrahim M, Parker D Jr, Norris G, Shah A, Mohamed W. Clobazam: An effective add-on therapy in refractory status epilepticus. Epilepsia. 2015;56(6):e83-e89. doi:10.1111/epi.13013
10. Corman C, Guberman A, Benavente O. Clobazam in partial status epilepticus. Seizure 1998;7:243–247.
11. Pernea M, Sutcliffe AG. Clobazam and its use in epilepsy. Pediatr Rep. 2016;8(2):6516. Published 2016 Jun 15. doi:10.4081/pr.2016.6516
12. da Silveira MR, Montenegro MA, Franzon RC, Guerreiro CA, Guerreiro MM. Effectiveness of clobazam as add-on therapy in children with refractory focal epilepsy. Arq Neuropsiquiatr. 2006;64(3B):705-710. doi:10.1590/s0004-282×2006000500001
13. Silva RC, Montenegro MA, Guerreiro CA, Guerreiro MM. Clobazam as add-on therapy in children with epileptic encephalopathy. Can J Neurol Sci. 2006;33(2):209-213.
14. Vajda FJ, Bladin PF, Parsons BJ. Clinical experience with clobazam: a new 1,5 benzodiazepine in the treatment of refractory epilepsy. Clin Exp Neurol. 1985;21:177-182.

Prepared by:
Faria Munir, PharmD, MS, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

July 2023

The information presented is current as June 19, 2023. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.