What does FDA approval of Epidiolex (CBD oral solution) mean

This article originally appeared at https://www.epilepsy.com/treatment/alternative-therapies/medical-marijuana

The use of cannabis to treat epilepsy and other neurological conditions has been studied for a number of years. It has been hotly debated too.

On June 25, 2018, the U.S. Food & Drug Administration (FDA) approved EPIDIOLEX^® (cannabidiol, CBD) oral solution for the treatment of seizures associated with two epilepsy syndromes – Lennox-Gastaut syndrome and Dravet syndrome – in people two years of age or older. Epidiolex represents a new medication option for children with these types of epilepsy. It is also the first ever FDA approved medication to treat seizures in Dravet syndrome.

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What does FDA approval of Epidiolex (CBD oral solution) mean?

The FDA approval and Drug Enforcement Administration (DEA) scheduling of Epidiolex brings to market the first plant-based drug derived from the cannabis plant in the U.S.

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What is medical cannabis?

Cannabis is known by many names – the most common is marijuana. Cannabis is the Latin name used most often by botanists and pharmaceutical companies. The word marijuana usually refers to the leaves and female flowers of the cannabis plant. Medical cannabis is whole plant marijuana or chemicals in the plant used for medical purposes.

Cannabinoids are substances in cannabis that act on cells in the body (called cannabinoid receptors) to cause some effect. Two major ingredients include

Tetrahydrocannabinol, or THC, which causes the psychoactive effects of “getting high”
Cannabidiol, or CBD, which does not cause psychoactive effects but has shown some positive effects on certain body systems. This is the part that has been effective in reducing seizures in some people with epilepsy.

Does cannabis help seizures?

Early evidence from laboratory studies, anecdotal reports, and small clinical studies over a number of years suggest that cannabidiol (CBD) could potentially help control seizures. Research on CBD has been hard to do and taken time due to federal regulations and limited access to cannabidiol. There are also many financial and time constraints. In recent years, a number of studies have shown the benefit of specific plant-based CBD product in treating specific groups of people with epilepsy who have not responded to traditional therapies.

What do I need to know about hemp?

Hemp is a variety of Cannabis Sativa L. plant historically grown for fibrous materials found in its stalks and seeds. It has been used to make items such as clothing fiber, upholstery, and other household items.

Hemp traditionally contains lower concentrations of THC and higher levels of CBD. Cannabinoids extracted from hemp plants, including CBD, have until recently been classified as marijuana and considered Schedule I substances. Per the DEA, Schedule I substances currently have no accepted medical use and have a high potential for abuse. A federal law* enacted in December 2018, however, reclassifies hemp and hemp-derived CBD as an agricultural commodity and exempts it from the list of Schedule I Drugs.

Despite this change in the classification of hemp and hemp-derived CBD, the only CBD product that has been rigorously studied and approved to be used as a medical therapy for epilepsy is the drug Epidiolex. While more CBD products may come to market in the coming months, it is important to understand that not every CBD product is the same quality or uniform from batch to batch. Any drug or supplement that is being considered for use as a medical treatment should first be discussed with your doctor. The potential for benefit as well as the interaction with other seizure medications and possible side effects require careful review with your doctor.

*The Agriculture and Nutrition Act of 2018 (H.R. 2) legalizes hemp and hemp-derived CBD. The bill changes the definition of hemp to encompass any plant or product derived from the plant that contain less than 0.3% THC by dry weight and classifies them as exempt from the controlled substance restrictions applied to marijuana. The law further amends the Controlled Substances Act to exempt hemp from Schedule I drugs.

What do I need to know about hemp?

Epidiolex (Cannabidiol, CBD)

Studies in the U.S. of Epidiolex (a plant-based CBD formulation) have been ongoing for a number of years. Data from these studies has helped provide evidence that led to the FDA approval of this product on June 25, 2018.

Epidiolex is a purified (> 98% oil-based) CBD extract from the cannabis plant. It is produced by Greenwich Biosciences (the U.S. based company of GW Pharmaceuticals) to give known and consistent amounts in each dose.

Researchers studied this medicine in controlled clinical trials. These studies used a control group with some people taking a placebo while others were given CBD at different doses. Researchers did not know who was getting the placebo and who was getting CBD. These tpyes of studies are called “gold standard” studies.

A summary of the Epidiolex clinical trials is found below:

In controlled and uncontrolled trials in people with Lennox-Gastaut syndrome (LGS) and Dravet syndrome, 689 people were treated with Epidiolex (CBD), including 533 people treated for more than 6 months and 391 people treated for more than 1 year.
In an expanded access program and other compassionate use programs, 161 people with Dravet syndrome and LGS were treated with Epidiolex, including 109 people treated for more than 6 months.
All study participants were taking other seizure medications.
In controlled trials, the rate of stopping the medicine due to any side effect was small and happened most in people taking the higher dose of Epidiolex.
The most frequent cause of stopping treatment with Epidiolex was a change in liver function.
Sleepiness, sedation, and lethargy led to stopping Epidiolex in 3% of people taking the higher dose.
The most common side effects were sleepiness, decreased appetite, diarrhea, change in liver function, fatigue, malaise, asthenia (weakness or lack of energy), rash, insomnia, sleep disorder, poor quality sleep, and infections.

Results from Gold Standard Studies of Epidiolex (CBD)

NEJM May 2018

Summarized below are the results from a study published in the New England Journal of Medicine in May 2018.

Randomized double-blind, placebo-controlled trial (gold standard) was done at 30 clinical centers.

People with LGS (age range 2 to 55 years) who had had two or more drop (atonic) seizures each week during a 28-day baseline period were included. They were randomly selected to receive CBD oral solution at a dose of either 20 milligram per kilogram of body weight (20-mg cannabidiol group) or 10 milligram per kilogram of body weight (10-mg cannabidiol group) or matching placebo.
A total of 225 people were enrolled in the 3 groups:
- 76 people were assigned to the 20-mg CBD group
- 73 to the 10-mg CBD group
- 76 to the placebo (no CBD) group
CBD was given to people twice a day for 14 weeks.
The researchers measured the percentage of change in drop seizures from baseline.
During the 28-day baseline period, the average number of drop seizures was 85 in all 3 groups combined.
During the treatment period, drop seizures decreased from baseline by:
- 41.9% in the 20-mg CBD group
- 37.2% in the 10-mg CBD group
- 17.2% in the placebo group
The most common side effects in people taking cannabidiol were sleepiness, decreased appetite, and diarrhea. These happened more often in people taking the higher dose of CBD.
Only 6 people in the 20-mg CBD group and 1 person in the 10-mg CBD group stopped the study because of side effects.
14 people who received CBD had an increase in a test of liver function. Many of these children were on valproic acid too.

This study showed that the addition of CBD to a traditional seizure medication decreased the frequency of drop seizures significantly in children and adults with LGS.

NEJM May 2017

Summarized below are results from the May 2017 New England Journal of Medicine study examining the effectiveness of Epidiolex (CBD) in people with drug resistant seizures with Dravet syndrome.

Randomized double-blind, placebo-controlled trial (gold standard) included 120 children and young adults with Dravet syndrome and drug-resistant seizures. They were randomly assigned to receive either CBD oral solution (20 milligrams per kilogram of body weight per day) or placebo.

CBD was given in addition to standard seizure medications.
The study measured the change in the number of convulsive seizures over the CBD treatment period, as compared to baseline period.
The percentage of people who had at least a 50% reduction in convulsive-seizure frequency was
- 43% with cannabidiol
- 27% with placebo
The frequency of total seizures of all types was significantly reduced with CBD, but there was no significant reduction in non-convulsive seizures.
The percentage of people who became seizure-free was 5% with CBD and 0% with placebo.
Adverse events that occurred more frequently in the CBD group than in the placebo group included diarrhea, vomiting, fatigue, fever, somnolence (sleepiness), and abnormal results on liver-function tests. There were more withdrawals from the trial in the cannabidiol group.

This study was able to show that among people with the Dravet syndrome, CBD resulted in a greater decrease in convulsive-seizures than placebo. It also showed that CBD was associated with higher rates of adverse events.

Results from 214 people who received Epidiolex (99% CBD) in an open-label study (without a placebo control) and who completed 12 weeks or more on the drug were published in 2015 in Lancet Neurology.

People who received Epidiolex ranged from 2 to 26 years old with an average age of 11.
All had epilepsy that did not respond to currently available treatments.
During the study, seizures decreased by an average of 54%.
People taking the anti-seizure medication clobazam (Onfi) seemed to have a better response when compared to those who were not on this medication.

An Israeli study using a product that had 20 parts of CBD to 1 part of THC was performed in an open-label format for children up to age 18 years with hard to control epilepsy. A significant number of people reported seizure reduction with 7% stating seizures worsened.

Are there ongoing CBD clinical trials?

A number of clinical trials are active and recruiting people, including studies using Epidiolex in people with Tuberous Sclerosis Complex and Sturge-Weber Syndrome.

Find a list of clinical trials

Does cannabis have side effects?

Marijuana or cannabis in general has a number of side effects depending on how it is used. For example, if smoked, the negative effect of smoking on a person’s lungs and heart also apply to marijuana.

It is important to know that even though marijuana is a plant, it is broken down in a person’s liver like many medicines. People mistakenly believe that marijuana is completely safe because it is a plant or oil from a plant. However, medication interactions can occur.

The safety data from the trials in people with Lennox-Gastaut syndrome and Dravet syndrome has shown similar side effects. Tiredness, diarrhea, and upset stomach are reported the most. Interestingly, people getting the placebo also reported diarrhea and upset stomach feeling as well. This may be due to both products being oil.

Should I worry about drug interactions?

There are some drug-to-drug interactions that have been revealed during the studies of CBD in epilepsy syndromes. More research continues to be done examining these interactions. We know from studies that have been done:

People who had increases in their liver enzymes to a level three times or more than normal were also on valproic acid (VPA), a commonly used anti-seizure medication. The levels of VPA were not increased when taken with CBD. It is thought that a part or byproduct of VPA may interact with CBD when it is broken down. This may put some people at increased risk for liver issues.
As clobazam (Onfi) is broken down, a major component of the drug appears to interact with CBD in some people. This may be the cause of tiredness that is seen in some people who are on both CBD and Onfi.

What are the laws governing medical marijuana and cannabidiol?

The 2018 Farm Bill, signed into law by President Trump in December 2018, exempts hemp and hemp-derived products, including CBD, from the Controlled Substances Act. Previously, hemp-derivatives were classified as Schedule I cannabis products, meaning they had no acceptable medical use and had a high potential for abuse. The Farm Bill lifts federal restrictions surrounding CBD and legalizes the cultivation, manufacturing, and sale of these products across the United States. However, this does not mean that all hemp-derived products, including CBD, are medically appropriate.

Over half of U.S. states have laws allowing cannabis to be recommended and dispensed to people for medical reasons. The 2018 Farm Bill does not change existing laws surrounding state medical cannabis programs. Individuals who purchase treatments through a medical dispensary and via a recommendation from their physician are still required to follow the regulations set forth including registration, renewal of medical cards, and other requirements decided by each state.

In June 2018, the FDA approved Epidiolex allowing medical providers to prescribe this medication for Lennox-Gastaut and Dravet syndromes, similar to how they are able to prescribe other seizure medications. In late September 2018, the DEA rescheduled Epidiolex to Schedule V and all states and the District of Columbia have created pathways so that it can be brought to market for consumers. Read an FAQ to learn more.

Providers do not need a special license or certificate to prescribe Epidiolex. Epidiolex is the first and only plant-based treatment derived from cannabis for use as a treatment for seizures with FDA approval. Other formulations of medical cannabis have not been approved by the FDA.

In May 2019, the Transportation Security Administration (TSA) updated its guidelines on traveling with CBD products. When you fly, you can now carry on or pack in checked baggage products/medications that contain hemp-derived CBD (with less than 0.3% THC) or are approved by the FDA, such as Epidiolex.

While the carry-on quantity of liquids is less than 3.4 ounces/100mL, TSA allows larger amounts of medically necessary liquids in reasonable quantities for your trip. However, you must declare them to security officers at the checkpoint for inspection. In checked baggage, liquid medications are allowed without packing requirements, quantity limitations, or notification requirements. Learn more on TSA’s website.

Should a person with epilepsy pursue medical cannabis if all other medications do not work?

When conventional treatments do not work to control seizures, as is the case for roughly 30% of people with epilepsy, it is not unreasonable to consider CBD oil. However, this should only be considered after a thorough evaluation at a specialized epilepsy center to look at whether all possible treatments (including FDA-approved new and add-on medicines, dietary therapy, devices, and surgery) have been reasonably tried.

The Epilepsy Foundation urges anyone exploring any treatment for their epilepsy, as permitted under their state law, to work with their treating physician to make the best decisions for their own care.

Where can I learn more?

Learn about the Epilepsy Foundation’s state and federal advocacy efforts on removing barriers to cannabis research and supporting access to medical cannabis (marijuana) in consultation with the treating physician.