ISSN: 2469-6706 Vol. 6 2019 A case report of Clobazam toxicity related to Cannabidiol and Clobazam drug-drug interaction Rowida Kheireldin a , 1 Naeem Mahfooz b a Department of Pediatrics, University of Toledo Health Science Campus, Toledo, OH, USA, and b Department of Pediatrics Neurology, University of Toledo, Toledo, OH, USA. Over the past few years, implementation of cannabis (CBD) as an anti-epileptic medication has been investigated in clinical re- search. CBD and Clobazam show remarkable antiepileptic effi- cacy in refractory epilepsies associated with Dravet and Lennox- Gastaut syndrome. There is a known drug-drug interaction be- tween CBD and Clobazam however, there are no recommenda- tions regarding dosing and monitoring of Clobazam while on CBD treatment. We present a 15-year-old female patient with a history of Dravet syndrome who presented to the emergency department with urinary retention and altered mental state four weeks after initiation of CBD treatment while on Clobazam. | Epidiolex | Clobazam | Dravet syndrome | Lennox-Gastuat syn- drome | The interest in the anti-epileptic efficacy of cannabinoids (CBD)has significantly increased over the last 5 years. Trials have shown a remarkable reduction in seizure frequency in patient pop- ulation of Dravet and Lennox-Gastaut syndromes using CBD. Clobazam is an important anti-epileptic medication with a special role in controlling epileptic drop attacks in these patients. CBD re- acts 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 emergency department with urinary retention and altered mental state secondary to Clobazam toxicity related to CBD and Clobazam drug-drug interaction. Case report Patient information. Age: 15 years old. Gender: female. Eth- nicity: caucasian. Related medical problems: Dravet syndrome, hypotonia, and global developmental delay. Objective. Clobazam toxicity can occur secondary to CBD due to drug-drug interaction since CBD inhibits the activity of cy- tochrome P2C19 enzymes leading to a significant elevation of N- desmethylclobazam levels with clinical signs of urinary retention followed by alteration in mentation. The purpose of this case re- port is to focus on Clobazam toxicity secondary to this interac- tion and to signify the importance of monitoring Clobazam and N- desmethylclobazam levels in patients concomitantly using CBD and Clobazam. We suggest decreasing the dose of Clobazam to half of the maintenance dose upon initiating CBD treatment. We also rec- ommend monitoring Clobazam levels every two weeks for the first few months to avoid side effects and toxicity. Case. A 15-year-old female with a past medical history of Dravet syndrome, hypotonia, and global developmental delay pre- sented to the pediatrics emergency department with altered mental status, urinary retention and bowel incontinence. Symptoms started after the patient started Epidiolex (CBD) 160 mg daily four weeks before presentation with no additional dose changes. She was on multiple antiepileptic drugs including Clobazam 80 mg daily, Etho- suximide 250 mg daily, Topiramate 200 mg daily and potassium bromide 2 mg daily. Her seizure frequency dropped from daily to no further seizures since starting Epidiolex however, her mental sta- tus started deteriorating and the patient became lethargic and con- fused. Her baseline was independence in daily life activities as she lived at a home health institute. Her caregivers reported that she had progressively worsened and became dependent. Her first symptom was urinary retention, which lead to an initial emergency depart- ment presentation two weeks prior to this admission. Urinalysis was done and it came back normal, thus the patient was sent home. Symptoms continued and progressively worsened as she developed an unsteady gait, bowel and bladder incontinence along with confu- sion and increased sleepiness. On admission, the patient was disoriented to time, place and person with Glasgow coma scale of 12. She received normal saline bolus, and Foley catheter was placed. Brain CT scan result was normal. Her EEG showed moderate diffuse encephalopathy with background and intermittent slowing with generalized poly-spikes and waves. Clobazam was immediately discontinued due to the pa- tient’s altered mental status. Her other home medications were con- tinued. Lab results revealed topiramate level of 20.2 mg/mL (usual range 5-20 mg/mL), bromide at 138.6 mg/dL (usual range 75-150 mg/dL) and hyperchloremia on basal metabolic panel. Topiramate toxicity was excluded. Differential diagnosis of Acute Disseminated Encephalomyelitis and Acute Flaccid Myelitis were ruled out by normal MRI brain and spine. Clobazam and N- desmethylclobazam levels were found elevated at 512 ng/mL (usual range 30-300 ng/mL) and 15,020 ng/mL (usual range 300 to 3,000 ng/mL) respectively. There was no baseline Clobazam level ob- tained prior to starting Epidiolex. The patient significantly improved through the remainder of her hospital course with marked improve- ment in her mental state within four days. Her urinary retention resolved in 3 day after discontinuing Clobazam. She was discharged home, off of Clobazam and was given a fol- low up appointment with neurology in 1 week. Upon following up as outpatient; her mental status was back to normal. Her Clobazam was not restarted, instead she was placed on Perampanel 2 mg/day. All authors contributed to this paper. 1 To whom correspondence should be sent: Rowida.Kheireldin@UToledo.Edu Authors declare no conflict of interest. Submitted: 10/16/2019, published: 11/15/2019. Freely available online through the UTJMS open access option utdc.utoledo.edu/Translation UTJMS 2019 Vol. 6 35–36 There was no repeat Clobazam or N-desmethylclobazam levels for follow up since Clobazam was discontinued and she continued to show improvement in her mental status. No genetic testing for our patient was obtained including genetic polymorphism for CYP2C19 expression. Discussion Multiple trials have shown that CBD can reduce the frequency of convulsive seizures in patients with Dravet syndrome, and may limit epileptic drop attacks in patients with Lennox-Gastaut syn- drome (2). Clobazam is frequently co-administered with CBD, especially in patients with Dravet and Lennox-Gastaut syndromes since this combination has shown to cause a significant decrease in motor seizures (2, 3). Geffrey et al. reported in a case report that the combination of CBD and Clobazam can lead to more than 50% decrease in seizures in patient population (1). In our case report, the patient had no seizures reported after she was started on CBD. A common adverse event reported with CBD is sedation, being more frequent in patients taking Clobazam concomitantly. The onset of sedation as a result of the interaction with Clobazam mostly occurs within the first two weeks of initiation of therapy and usually re- solves after lowering the Clobazam dose (2, 5). In our case, the patient had urinary retention as her first symp- tom which appeared within two weeks of initiating CBD and her mentation progressively worsened over four weeks after starting her CBD treatment. Patients with refractory epilepsy on CBD and Clobazam were reported to have elevated levels of Clobazam and N-desmethylclobazam, its active metabolite (1). This interaction is secondary to the fact that both medications are metabolized by cy- tochrome P450 enzymes and glucuronyl transferases. CBD inhibits the activity of cytochrome P2C19 enzymes leading to a significant elevation of N-desmethylclobazam levels (6). In the study by Gef- frey et al. the combination of CBD and Clobazam resulted in ele- vation of the levels of Clobazam by 60-80%, as well as an increase in the N-desmethylclobazam by 300-500% (1). There are no sig- nificant data regarding the relation between CBD dosing and the drug-drug interaction between CBD and Clobazam. Devinsky et al. reported that in patients with Dravet syndrome, the concentrations of N-desmethylclobazam increased regardless of the CBD dose given (7). However, Chang et al study demonstrated elevation of N-desmethylclobazam levels with increasing the dose of CBD (8). The aim of this case report is to focus on the recom- mendations to modify the Clobazam dose in patients on CBD. The rationale behind these adjustments is to avoid side effects of seda- tion, urinary retention and altered mental status, such as reported in our patient. There was a plan to reduce her Clobazam dose at the time of starting her on CBD, however she was admitted to hospital prior to the next follow up. We suggest decreasing the dose of Clobazam to half of the maintenance dose upon initiating CBD treatment. This prompts emphasis on the relevance of monitoring Clobazam and N- desmethylclobazam levels in patients using the combination of CBD and Clobazam (1, 9). There were no follow up levels obtained for Clobazam and N-desmeythlclobazam in our patient. We recom- mend obtaining baseline Clobazam level before starting CBD and monitoring Clobazam levels every two weeks for a few months to avoid side effects and toxicity. Going forward, randomized con- trolled trials are necessary to look into the required adjustments of Clobazam dose when used concomitantly with CBD. Also, fur- ther studies are needed to determine the relevance of monitoring Clobazam and N-desmethylclobazam levels in patients using the combination of CBD and Clobazam. Conclusion CBD can cause a remarkable increase in the N-desmethylclo- bazam levels, the active metabolite of Clobazam, which can lead to toxicity with clinical sings of urinary retention followed by al- teration in mentation. It is significantly important to monitor blood levels for Clobazam and N-desmethylclobazam before the start of CBD in patients on Clobazam. We suggest decreasing the dose of Clobazam to half of the maintenance dose upon initiating CBD treatment. We also recommend monitoring Clobazam levels every two weeks in the first few months to avoid side effects and toxic- ity. Additional well controlled studies are needed to establish the recommended doses and the management of the doses of other con- comitant anti-epileptic medications with CBD use. Conflict of interest Authors declare no conflict of interest. Authors contributions RK wrote the manuscript, NM revised the manuscript. All au- thors have read and approved the final document. 1. Geffrey AL, Pollack SF, Bruno PL, Thiele EA. (2015) Drug-drug interaction between Clobazam and Cannabidiol in Children with Refractory Epilepsy 56(8):1246-51. 2. Perucca E. (2017) Cannabinoids in the Treatment of Epilepsy: Hard Evidence at Last? J Epilepsy Res. 7(2): 61{76. 3. Bruno P, Savage T, Skirvin L, Wolper E, Thiele E. (2017) Efficacy of Cannabidiol in Patients with Refractory Epilepsy Relative to Concomitant Use of Clobazam. American epilepsy society. Annual meeting abstracts (Abst. 3.181). 4. Klotz KA, Schulze-Bonhage A, Antonio-Arce VS, Jacobs J. (2018) Cannabidiol for Treatment of Childhood Epilepsy-A Cross-Sectional Survey. Front Neurol 7;9:731. 5. Iffland K, Grotenhermen F.(2017) An Update on Safety and Side Effects of Cannabidiol: A Review of Clinical Data and Relevant Animal Studies. Cannabis Cannabinoid Res. 1;2(1):139- 154. 6. Gaston TE, Szaflarski JP. (2018) Cannabis for the Treatment of Epilepsy: an Update. Curr Neurol Neurosci Rep. 8;18(11):73. 7. Devinsky O, Patel AD, Thiele EA, Wong MH, Appleton R, et al. (2018) GWPCARE1 Part A Study Group. Randomized, dose-ranging safety trial of Cannabidiol in Dravet syndrome. Neurology. 3;90(14):e1204-e1211. 8. Chang B. (2018) Cannabidiol and Serum Antiepileptic Drug Levels: The ABCs of CBD With AEDs. Epilepsy Curr. 18(1): 33{34. 9. Gaston, Bebin E, Szaflarski J. (2016) Importance of Monitoring Clobazam and NDesmethylclobazam Levels in Treatment with Cannabidiol (CBD) for Epilepsy. Neurology, Apr 2016, 86 (16 Supplement) S14.001. 36 utdc.utoledo.edu/Translation Kheireldin et al. Editorial cover 2019 336 v7