CBD found to not affect safety, efficacy of Valtoco rescue therapy

Nasal spray still works long term in Dravet, other epilepsy patients

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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The safety and effectiveness of Valtoco, a diazepam nasal spray approved in the U.S. for use as an intermittent rescue therapy for people with epilepsy, was not compromised among patients also using cannabidiol (CBD) as part of their daily treatment regimen.

These findings come from a new analysis of data from an open-label Phase 3 trial (NCT02721069) that evaluated the long-term efficacy and safety of Valtoco in individuals with epilepsy, including those with Dravet syndrome.

Patients specifically using Epidiolex, a highly purified oral CBD formulation approved in the U.S. for Dravet and certain other conditions, had fewer treatment-related side effects and less often required an extra dose of Valtoco to control their seizures compared with patients not using CBD or those using other cannabidiol products.

While larger studies specifically designed to evaluate potential interactions between Valtoco and cannabidiol are needed to validate these findings, the researchers say the data in general indicate that “intermittent use of diazepam nasal spray remained safe and effective for those patients who also used CBD as part of their daily … regimen.”

The results were reported in a new study, titled “Concomitant cannabidiol does not impact safety and effectiveness of diazepam nasal spray for seizure clusters: Post hoc analysis of a phase 3 safety study,” published in the journal Epilepsy & Behavior. The study was funded by Neurelis, the company that markets Valtoco.

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Patients with Dravet syndrome or other types of epilepsy commonly use several daily anti-seizure medications to keep seizures at bay.

One such therapy that’s gained popularity in recent years is CBD, a non-psychoactive constituent of marijuana with anti-seizure effects. Epidiolex, a highly purified oral formulation of CBD, is approved in the U.S. as an add-on therapy for patients at least 1 year old with Dravet, Lennox-Gastaut syndrome (LGS), and tuberous sclerosis complex (TSC).

When patients experience seizure clusters, or increases in seizure activity that aren’t controlled with daily medications, they may also require rescue therapies. Most commonly, rescue therapies belong to a class of medicines called benzodiazepines, which include diazepam or midazolam. Valtoco, or nasal diazepam, was approved in 2020 to treat seizure clusters in epilepsy patients ages 6 and older.

While CBD has previously been found to interact with other daily anti-seizure medications, namely clobazam (sold as Onfi among other brand names), it is not known whether it could influence the safety and efficacy of benzodiazepine rescue therapies.

The Phase 3 trial that had tested Valtoco had enrolled 175 people with epilepsy, ages 6-65. All had required rescue therapies an average of six times per year despite being on a stable anti-seizure medication regimen, which could include CBD.

Participants used Valtoco as needed to treat seizure clusters over a period of one year while remaining on their other daily therapies.

Of 163 people who received at least one dose of Valtoco during the trial, 23 were using Epidiolex and 21 were using another form of CBD treatment. Most patients with Dravet syndrome or LGS received Epidiolex.

Patients who received any form of CBD reported numerically greater rates of side effects (90.9%) following Valtoco treatment than those who were not on CBD therapy (79%). Likewise, rates of serious side effects were more common in the CBD group (45.5% vs. 26.1%).

Other than seizures, the most common side effects reported in patients given CBD were upper respiratory tract infection (22.7%), cold-like symptoms (22.7%), and fever (15.9%), which were consistent with the most common side effects observed among all trial participants.

Still, patients specifically using Epidiolex had fewer side effects that were deemed related to treatment (13%) than those using other CBD products ( 23.8%) or no CBD (18.5%).

Moreover, patients in the Epidiolex group less often required a second dose of Valtoco to control seizures than those in the other CBD or no CBD groups. Specifically, 8.2% of seizure clusters in the Epidiolex group required an extra dose, compared with 20.3% in the other CBD group and 11.6% in the no CBD group.

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Researchers: Results should be ‘interpreted with caution’

A subgroup analysis of trial participants also using clobazam indicated that treatment-related side effects still remained lowest among Epidiolex users regardless of clobazam use. A similar rate of seizure clusters (8.8%) required a second dose of Valtoco among Epidiolex users on clobazam as in the overall Epidiolex group.

“In all, highly purified CBD did not negatively influence the safety or effectiveness profile of diazepam nasal spray,” the researchers wrote.

The disparities in safety and efficacy findings between Epidiolex and other CBD products may be related to the fact that there is an uncertain amount of CBD  in these other products, which are not federally regulated. Moreover, such products may contain other compounds, such as tetrahydrocannabinol, that could impact seizure activity.

In all, highly purified CBD did not negatively influence the safety or effectiveness profile of diazepam nasal spray.

Researchers noted the findings are limited by a small number of patients using CBD in the trial, which was originally designed to evaluate Valtoco itself, and not CBD specifically.

As such, the team emphasized that the study was not powered to detect statistically significant differences between these groups and thus, “results should be interpreted with caution.”

Larger, well-controlled studies are needed to validate the findings.