On 25th June 2018, the US Food and Drug Administration (FDA) approved Epidiolex, a cannabidiol (CBD)-based prescription medication, making it the first cannabis-based product approved for use in the US. Months later, guidance issued by the National Institute for Health and Care Excellence (NICE) in the UK followed suit, recommending Epidyolex (the UK brand name of the drug) for the treatment of two rare epilepsy syndromes.
Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) are two severe forms of epilepsy syndromes. They are classified as progressive and epileptic encephalopathies, which also cause difficulties with development, in addition to seizures. Patients with DS or LGS can experience multiple types of seizures and often do not respond to many standard epilepsy treatments. As a result, these two epileptic syndromes are associated with a higher mortality rate than other forms of epilepsy or seizure disorders.
According to NICE, Epidyolex is the only cannabis-based medicine available for the treatment of epilepsy caused by DS and LGS on the NHS in the UK and is licensed specifically for these conditions. Current evidence indicates that Epidyolex may be associated with reduced seizure frequency and severity in patients with DS and LGS. Furthermore, most adverse reactions are reported to be mild to moderate, and their clinical significance is relatively low. Such events include drowsiness, reduced appetite, diarrhoea, increased transaminases, fatigue, rash, sleep disorders, and infections.
Nonetheless, there is still a knowledge gap in the real-world clinical use of the adverse events associated with Epidyolex. To more comprehensively understand the safety of this medicine, based on the FDA’s Adverse Event Reporting System (FAERS) database, researchers analysed adverse drug events related to Epidyolex. The authors of the study aimed to improve understanding of the safety and adverse drug effects in real-world clinical practice to provide a basis for improving patient medication safety and guiding rational clinical practice.
Design and Methods of the Study
The study included Epidiolex (Epidyolex) ADE reporting data from the third quarter of 2018 to the first quarter of 2023 from the FAERS database. The search was limited to include “cannabidiol” and “Epidiolex” as the primary suspect drugs. When processing adverse drug effect terminology, the researchers standardised and translated the Preferred Term (PT) to ensure consistency and comparability. Finally, to better present the data, the researchers merged adverse drug effects belonging to the same PT and classified them using the System Organ Class (SOC) for a more organised summarisation and analysis of ADE characteristics.
Results of the Study
The researchers obtained a total of 12,966,710 case reports from the FAERS database from July 2018 to March 2023. After data clearing and drug filtering, the study finally included 13,275 cases related to Epidiolex for in-depth analysis. The main reporting groups included consumers (6,292 cases, 47.40%), followed by physicians (3,306 cases, 24.92%), and pharmacists (2,823 cases, 21.27%).
A correlation was found between the occurrence of ADEs and the date of medications: during the observation period, 630 cases (4.75 %) of adverse drug effects occurred within 0–7 days after medication, 275 cases (2.07 %) within 7–28 days, 263 cases (1.98 %) within 28–60 days, and 1285 cases (9.68 %) occurred after more than 60 days of medication. It should also be noted that 10,822 cases (81.52%) had missing or aberrant records.
Through visual observation, adverse drug effects related to Epidiolex involved 27 organ systems. Those most closely associated with Epidiolex use were primarily concentrated in the following SOC categories: nervous system disorders (n = 6,869), surgical and medical procedures (n = 922), congenital, familial and genetic disorders (n = 17). the researchers also discovered adverse drug effects at the SOC level that were not explicitly labelled in the Epidiolex drug instructions, such as metabolism and nutrition disorders (n = 716), immune system disorders (n = 130), renal and urinary disorders (n = 174).
From the PT-level adverse drug effects the researchers selected 147 PTs that satisfied all four screening methods. The top five PTs were: seizure cluster (n = 81), change in seizure presentation (n = 56), electroencephalogram (n = 4), atonic seizures (n = 54), and blood ketone body reduction (n = 3).
According to the number of cases, the top five PTs related to Epidiolex were: seizure (n = 3,888), product use in unapproved indication (n = 1,563), diarrhoea (n = 1,167), product dose omission issue (n = 994), and somnolence (n = 727).
In addition, there were new adverse drug events discovered after excluding signals unrelated to CBD, including seizure cluster (n = 81), blood ketone body reduction (n = 3), cortical visual impairment (n = 3), hyperactive pharyngeal reflex (n = 3), and poverty of speech (n = 9).
Discussion and Conclusions
Despite being a licensed treatment for seizures, seizure clusters and change in seizure presentation rank highest among adverse drug effects associated with Epidyolex. The researchers note that such reactions may be related to Epidiolex interactions with receptors in neurotransmitter systems, including the endocannabinoid system, and with serotonin receptors and GABA receptors. Furthermore, CBD is known to interact with other drugs, potentially causing changes in the concentration of antiepileptic drugs, thereby affecting epilepsy control. This interaction may have triggered seizure clusters in some patients. Different reactions to Epidiolex may also be related to genetic factors, physiological conditions, and dosing.
Epidiolex may also affect human metabolism, resulting in adverse drug effects such as blood ketone body decreases. The drug may also produce various effects through central nervous system actions, including controlling neural signalling in the cortical area of the brain, pharyngeal reflex, and language centre activity, thereby leading to adverse drug effects such as cortical visual impairment, hyperactive pharyngeal reflex, and poverty of speech.
The current study highlights emerging adverse drug events which may present new risks that physicians should pay particular attention to when prescribing. This highlights the importance of long-term pharmacovigilance strategies when introducing medical cannabis products, such as the UK Medical Cannabis Registry.