Add-on treatment with Epidiolex — an oral form of cannabidiol (CBD) — effectively drops the frequency of seizures in people with Dravet syndrome and Lennox‑Gastaut syndrome (LGS), regardless of co-administration with the anti-seizure medication clobazam, according to a review study.
The findings, which suggest that CDB may have its own anti-epileptic properties, contradict current theories stating that CBD’s benefits are due only to its ability to increase clobazam’s availability in the body, which have restricted its prescription in Europe.
Nevertheless, further studies are needed to clarify whether and to what extent clobazam boosts CBD’s anti-epileptic effects, the researchers noted.
The review study, “Cannabidiol efficacy and clobazam status: A systematic review and meta‐analysis,” was published in the journal Epilepsia.
CBD, the major non-psychoactive cannabinoid (active component) in the cannabis plant, is suggested to have anti-seizure, anti-inflammatory, antioxidant, neuroprotective, and immunomodulatory properties.
GW Pharmaceuticals’ Epidiolex, a purified oral form of CBD, was the first cannabis-based medicine to be approved in the U.S., and more recently, in Europe, to treat seizures associated with Dravet syndrome and LGS — another type of severe childhood epilepsy — in patients 2 and older.
Distinct from its independent indication in the U.S., Epidiolex’s European approval was limited to a combination with clobazam, which is marketed as Onfi and Sympazan in the U.S., and as Frisium and Tapclob, among others, in Europe.
This limitation was driven by a debate over Epidiolex’s individual anti-seizure effects, since 50%–60% of participants in Epidiolex’s trials also were on clobazam, and Epidiolex was found to increase the blood levels of clobazam’s active component.
However, uncontrolled open-label studies suggested that Epidiolex lowers seizure frequency irrespective of clobazam use. Other studies also have highlighted that a bidirectional interaction and effect exist between CBD and clobazam and that their combination only leads to greater anti-seizure effects when CBD is given at its therapeutic dose.
So, the clinical meaning of these interactions remains largely unknown. To assess it it’s of even greater relevance, considering that combining CBD with clobazam was shown to affect CBD’s safety profile, increasing the frequency of adverse events, mainly somnolence, sedation, and pneumonia.
Now, researchers in Italy, Austria, and Switzerland set out to evaluate the impact of clobazam co-administration on CBD’s effectiveness in patients with Dravet and LGS by systematically reviewing published data from randomized, placebo-controlled trials.
Four multi-center, Phase 3 trials, covering 714 participants (429 receiving CBD and 285 a placebo), were included in the meta-analysis. Patients’ mean age ranged from about 9 to 15 and Epidiolex was given twice a day at a total daily dose of 10 or 20 mg/kg.
Participants had been treated previously with a median of four to six anti-epileptic medications (range, 0 to 28) and were receiving a median of four (range, 0 to 5) at enrollment, with clobazam and valproate sodium as the most common.
More than half of patients in the Epidiolex (55.9%) and placebo (55.4%) groups also were being treated with clobazam.
Results showed that a significantly greater proportion of patients treated with Epidiolex achieved at least a 50% drop in seizure frequency, compared with those on a placebo. This was true both for patients not on clobazam (29.1% vs. 15.7% in the placebo group) and for those being co-treated with clobazam (52.9% vs. 27.8%).
Notably, patients not being co-treated with clobazam showed lower response rates (both on Epidiolex and on placebo). The team noted that these patients may be particularly difficult to treat, as they had failed more anti-seizure medications, including clobazam, and had higher seizure frequency at enrollment.
“This analysis suggests CBD to have independent anti-seizure activity and efficacy irrespective of [clobazam] administration and cannot support the current prescription restriction,” the researchers wrote.
They emphasized, however, that these trials had some limitations and larger and adequate studies are needed to clarify the effects of this interaction, which may help to guide treatment decisions.
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