The side effects of clobazam as add-on therapy in pediatric epilepsy patients

Abstract

Objectives: Epilepsy is a long-term cerebral disorder that accompanies a lifelong predisposition to epileptic seizures, resulting in neurobiological, cognitive, psychological, and social problems. Clobazam is considered a relatively safe and effective anticonvulsant, frequently prescribed for the management of pediatric epilepsy. This study was designed to rigorously evaluate the safety profile of clobazam in pediatric epilepsy, with a particular focus on the incidence and nature of treatment-emergent side effects.

Methods: Patients aged 2 to 17 years, who received clobazam as an adjunct to valproic acid, levetiracetam, or carbamazepine therapy, who were referred to Diyarbakır Children's Hospital between December 2021 and March 2023 were included. We evaluated the safety profile of clobazam in pediatric epilepsy, with a particular focus on the incidence and nature of treatment-emergent side effects.

Results: The study included 100 patients using clobazam as an add-on anti-seizure medication. The mean age was 11.0±4.0 years, with males comprising 48% of the cohort. The average duration of clobazam use was 16.3±7.2 months. Side effects were reported in 30 patients (30%), with the most common being insomnia (10%), agitation (9%), and somnolence (6%). Allergic reactions were the least frequent. No patients experienced enuresis, ataxia, hypertension, hypotension, or constipation in our study. Clobazam was discontinued by 12% of the patients due to side effects.

Conclusions: Clobazam is regarded as safe in pediatric epilepsy patients, with minimal concerns regarding drug interactions and adverse reactions. Although it may cause some side effects, initiating low-dose treatment and gradually increasing the dosage can enhance treatment success.

Keywords

• Clobazam
• epilepsy
• pediatric patients
• side effects

References

1. 1. Faulkner MA. Comprehensive overview: efficacy, tolerability, and cost-effectiveness of clobazam in Lennox-Gastaut syndrome. Ther Clin Risk Manag. 2015;11:905-914. doi: 10.2147/TCRM.S55930.
2. 2. Gauthier AC, Mattson RH. Clobazam: A Safe, Efficacious, and Newly Rediscovered Therapeutic for Epilepsy. CNS Neurosci Ther. 2015;21(7):543-548. doi: 10.1111/cns.12399.
3. 3. Ng YT, Collins SD. Clobazam. Neurotherapeutics. 2007;4(1):138-144. doi: 10.1016/j.nurt.2006.11.002.
4. 4. Nagarajan E, Lynch TM, Frawley B, Bunch ME. Tolerability of clobazam as add-on therapy in patients aged 50years and older with drug-resistant epilepsy. Neurol Sci. 2023;44(8):2883-2888. doi: 10.1007/s10072-023-06765-1.
5. 5. Dean L. Clobazam Therapy and CYP2C19 Genotype. 2019 Sep 23. In: Pratt VM, Scott SA, Pirmohamed M, Esquivel B, Kattman BL, Malheiro AJ, editors. Medical Genetics Summaries [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2012–.
6. 6. An P, Liu X, Zhang B. Safety profile of clobazam in the real world: an analysis of FAERS database and systematic review of case reports. Expert Opin Drug Saf. 2024;23(1):119-128. doi: 10.1080/14740338.2023.2204227.
7. 7. Giarratano M, Standley K, Benbadis SR. Clobazam for the treatment of epilepsy. Expert Opin Pharmacother. 2012;13(2):227-233. doi: 10.1517/14656566.2012.647686.
8. 8. Arya R, Giridharan N, Anand V, Garg SK. Clobazam monotherapy for focal or generalized seizures. Cochrane Database Syst Rev. 2018;7(7):CD009258. doi: 10.1002/14651858.CD009258.pub3.

9. 9. Thurman DJ, Beghi E, Begley CE, et al; ILAE Commission on Epidemiology. Standards for epidemiologic studies and surveillance of epilepsy. Epilepsia. 2011;52 Suppl 7:2-26. doi: 10.1111/j.1528-1167.2011.03121.x.
10. 10-Sankar R. GABA(A) receptor physiology and its relationship to the mechanism of action of the 1,5-benzodiazepine clobazam. CNS Drugs. 2012;26(3):229-244. doi: 10.2165/11599020-000000000-00000.
11. 11. Kaplan YC, Demir O. Use of Phenytoin, Phenobarbital Carbamazepine, Levetiracetam Lamotrigine and Valproate in Pregnancy and Breastfeeding: Risk of Major Malformations, Dose-dependency, Monotherapy vs Polytherapy, Pharmacokinetics and Clinical Implications. Curr Neuropharmacol. 2021;19(11):1805-1824. doi: 10.2174/1570159X19666210211150856.
12. 12. Uzunhan TA, Gor Z. Efficacy and Side Effect Profile of Clobazam in Children with Different Etiologies of Epilepsy from a Single Center. Sisli Etfal Hastan Tip Bul. 2020;54(2):236-244. doi: 10.14744/SEMB.2020.60252.
13. 13. Ng YT, Conry JA, Drummond R, Stolle J, Weinberg MA; OV-1012 Study Investigators. Randomized, phase III study results of clobazam in Lennox-Gastaut syndrome. Neurology. 2011;77(15):1473-1481. doi: 10.1212/WNL.0b013e318232de76.
14. 14. Aylett SE, Cross H, Berry D. Eye rolling as a manifestation of clobazam toxicity in a child with epilepsy. Dev Med Child Neurol. 2006;48(7):612-615. doi: 10.1017/S0012162206001289.
15. 15. Humayun MJ, Samanta D, Carson RP. Clobazam. 2023 Dec 3. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan–.
16. 16. Joshi P, verma S, Sui A, Kuo Y-H, Johnson V, Sultan R. Hematologic Profile Associated With Newer-Generation Anti-Epileptic Medications in the Pediatric Population (P3.283). Neurology. 2014;82(10_Suppl):P3.283. doi: 10.1212/WNL.82.10_supplement.P3.283
17. 17. Kichili NR, Hansen A, Kagithala D, Gonzalez AM, Wilkerson M. Incidence of drug-induced hypersensitivity syndrome associated with levetiracetam and clobazam is likely underreported. Ann Allergy Asthma Immunol. 2024;132(5):652-653. doi: 10.1016/j.anai.2024.02.003.
18. 18. Mathew T, D'Souza D, Nadimpally US, Nadig R. Clobazam-induced pedal edema: "An unrecognized side effect of a common antiepileptic drug". Epilepsia. 2016;57(3):524-525. doi: 10.1111/epi.13316.
19. 19. Incecik F, Ozcanyüz DG. Unusual side effects due to clobazam: a case report with edema of the extremities. Acta Neurol Belg. 2018;118(3):521-522. doi: 10.1007/s13760-018-0901-4.
20. 20. Gimigliano F. Is clobazam monotherapy effective and safe in people with focal or generalized seizures? A Cochrane Review summary with commentary. Dev Med Child Neurol. 2020;62(6):670-672. doi: 10.1111/dmcn.14539.
21. 21. Tolbert D, Larsen F. A Comprehensive Overview of the Clinical Pharmacokinetics of Clobazam. J Clin Pharmacol. 2019;59(1):7-19. doi: 10.1002/jcph.1313.
22. 22. Strzelczyk A, Schubert-Bast S. Psychobehavioural and Cognitive Adverse Events of Anti-Seizure Medications for the Treatment of Developmental and Epileptic Encephalopathies. CNS Drugs. 2022;36(10):1079-1111. doi: 10.1007/s40263-022-00955-9.