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.

Cannabryl® (Ca-ne’-bryl) oral solution CV is the brand name for the cannabidiol oral solution, also referred to as CBD, from Indogenix Biosciences. The dose (measured in milligrams, abbreviation "mg") will be the same. Cannabryl oral solution is available as 100 mg in each milliliter (abbreviated as "mL").

Each bottle contains 15 mL of a clear colorless to yellow solution.

The dose in children is based on weight, written as milligrams per kilograms or "mg per kg". It is important to follow the instructions given by the prescribing health care provider.

The recommended starting dose is 2.5 mg per kg taken twice a day. (Total daily dose would be 5 mg per kg).Your provider may recommend increasing the dose after 1 week to 5 mg per kg twice a day. (Total daily dose would be 10 mg per kg). Epidiolex can be increased higher if needed to 10 mg per kg twice a day. (Total daily dose would be 20 mg per kg).The dose may be different or changed for people with liver problems.

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.

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.

Gold standard” studies

Researchers studied this medicine in controlled clinic al 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 types 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.

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.

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.

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.

Traveling With CBD Products

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.

Medical Cannabis and Cannabidiol (CBD) Frequently Asked Questions

What is medical cannabis?

The term medical cannabis is used to describe cannabis that is recommended by a doctor or other licensed prescribing health care provider (e.g. nurse practitioner or physician assistant) for the treatment of a medical condition.

Medical cannabis is generally used to refer to a large variety of cannabis products including extracts and tinctures of isolated cannabinoids such as cannabidiol (CBD). Because medical cannabis can be used in the treatment of a medical condition, it is critical to treat it as any other medication and consult your health care provider who can best monitor your health and any medication interactions medical cannabis may have.

What is cannabidiol (CBD)?

Cannabidiol (CBD) is a compound derived from the Cannabis Sativa L. plant. CBD is one of over 100 chemicals, also known as cannabinoids, found in the cannabis plant. Unlike tetrahydrocannabinol (THC), another cannabinoid found in the plant, CBD does not cause euphoria (often referred to as the “high”). While derived from the cannabis plant, CBD does not produce the same effect as the whole plant.

What is the Indogenix Bioscience position on medical cannabis and CBD?

The Indogenix LLP is committed to supporting provider-directed care and to exploring and advocating for all potential treatment options, including medical cannabis and CBD. We support lifting barriers to research on cannabis and CBD and support access to these potential therapies, through state-regulated programs, for individuals when other treatment options have failed them. If an individual and their health care team feel that the potential benefits of medical cannabis for uncontrolled epilepsy outweigh the risks, then the individual should have safe, legal access to medical cannabis. Medical cannabis and/or CBD must be used under the close supervision of your treating physician or prescribing provider. The combination and amount of medications an individual takes to control their seizures is specifically formulated for them depending on a number of factors. While there may be some trial-and-error in finding the right combination of medications that work for you, once a treatment regimen is determined it is critical to continue that regimen as instructed. If an individual unilaterally, without the consultation or supervision of their treating physician, introduces medical cannabis and/or CBD to their treatment plan, they could be at a greater risk of breakthrough seizures, side effects, or other complications.

What is the legal status of CBD in USA?

On December 12, 2018, Congress passed, and the President later signed into law, the 2018 Farm Bill which included provisions legalizing the cultivation of hemp and hemp-based products, including CBD derived from hemp. Previously, CBD was considered cannabis under the federal definition of the term. As such, cannabis, and by extension CBD, were considered Schedule I substances, which means there was no acceptable medical use and the substance had a high potential for abuse. Under the 2018 Farm Bill, the federal definition of hemp was changed to encompass any cannabis plant or product derived from a cannabis plant that contains less than 0.3% THC by dry weight. The Farm Bill further amended the Controlled Substances Act to exempt hemp from the definition of cannabis, meaning hemp and its derivatives are no longer Schedule I substances. This change, however, does not mean that all hemp-derived products, including CBD, are medically appropriate for all individuals living with epilepsy.

Are there any side effects or drug interactions associated with medical cannabis or CBD?

Medical cannabis and CBD are not without side effects and may affect the efficacy of other medications you take. In controlled research trails of a plant-based formulation of CBD (Epidiolex® ), the most common side effects were sleepiness, sedation and lethargy, elevated liver enzymes, decreased appetite, diarrhea, rash, fatigue, malaise and weakness, and insomnia. There is also the risk of liver injury, generally mild, but which raises the possibility of rare, but more severe injury. This was seen more often when CBD was combined with valproic acid (Valproate, DepakoteTM). CBD can significantly interact with a number of other medications taken for seizures. CBD can slow the ability of the liver to eliminate a breakdown product of clobazam.

This can cause additional sleepiness and may mean a reduction in clobazam doses is needed. There may also be interactions with topiramate (TopamaxTM, QudexyTM, TrokendiTM), rufinamide (BanzelTM), eslicarbazepine (AptiomTM) and zonisamide (ZonegranTM).1 In addition, the studies using Epidiolex® show that CBD can interact with medications other than those taken for epilepsy, so it is important to discuss CBD use with any other physician or provider who prescribes medication. Will medical cannabis or CBD replace my other medications? While there have been some instances in which individuals were able to wean off certain medications under medical supervision while taking CBD, it is not true for every individual and you should not make those decisions without the guidance and supervision of your treating physician or prescribing provider. Anticonvulsant medications, including Epidiolex® and CBD, are not one-size-fits-all. What may work for one person may not work for another. Only your treating physician or prescribing provider is in the position to judge whether a particular medication or treatment may work for you and whether it is safe or advisable to begin weaning off medications under close medical supervision. What do I do if my physician or prescribing provider will not recommend medical cannabis or CBD? As with other treatment options, controlling your seizures may involve trial and error. A particular treatment that works for one person may not be beneficial for everyone. When making decisions about changing your treatment regimen, your physician or prescribing provider considers a number of factors including overall health status, current medications, seizure control, and medical history. He or she is in the best position to determine whether the potential benefits of medical cannabis or CBD outweigh possible risks based on your individual situation. If your physician does not believe you will benefit from medical cannabis or CBD, you should not unilaterally change your treatment plan – especially without first telling your physician or prescribing provider. As with all your medical care, you need to develop a relationship of trust with your physician or prescribing provider. If

1 How Does Cannabidiol Interact With Antiepileptic Drugs?,

Medical Cannabis and Cannabidiol (CBD) Frequently Asked Questions

you feel this relationship does not or cannot exist, there is always the option of seeking alternate care. In either case, use of this treatment, as with all seizure medications, should be under a doctor’s supervision. Is there any difference in the commercial-grade CBD I purchase online or from a health food store and the dispensary-grade CBD sold in medical dispensaries? Not all CBD products are the same.

Many products claiming to have CBD also have other chemicals, bacteria, or mold. Further, there is no consistency within these products, which may cause seizures and/or side effects to change from month to month. This is another reason why individuals should not use CBD without consulting and informing their treating physician.

Dispensary-grade CBD products and medical cannabis sold in state-run medical cannabis facilities must comply with state safety and testing guidelines laid out in state law and regulations. However, 1 in 5 failed in California when tested. Many state cannabis laws provide safety mechanisms from growth of the plant to the final product in an attempt to ensure that the final, ingestible product does not contain any foreign compounds or prohibited chemicals. Further, state laws and regulations have labeling requirements for medical cannabis and products which are required to be truthful, supported by testing, and contain information consumers should know including CBD levels and presence and amount of other ingredients. Over-the-counter commercial-grade CBD products that are not sold in state-run medical cannabis facilities are not required to comply with the same laws and regulations that are in place for products sold at a medical cannabis dispensary.

Currently, there are no federal standards, and few state standards, for the cultivation or manufacturing of commercial-grade CBD products. Consumers should be aware that the FDA does monitor some commercial-grade CBD products to ensure they are not making unsubstantiated medical claims, and to make sure product labels are truthful and contain the cannabinoids and other compounds or chemicals they claim. Because of the lack of robust oversight in the commercial-grade CBD space, the FDA has found that some products were making unsubstantiated medical claims or did not contain the amount of CBD they claimed to contain, including, at times, containing no CBD at all.2 Are there currently any FDA-approved therapies derived from CBD? On June 25, 2018, the FDA approved a CBD product, Epidiolex® , a purified (>98% CBD) plant-based formulation that is oil-based, for the treatment of seizures associated with two rare and severe forms of epilepsy, Lennox-Gastaut syndrome and Dravet syndrome, in individuals two years of age or older. This is the first FDA-approved plant-based cannabis derived medication, and it is the first FDA-approved treatment option for individuals with Dravet syndrome. Three controlled clinical trials of Epidiolex® were conducted in 516 patients with Dravet Syndrome or Lennox Gastaut Syndrome. The results3 showed that Epidiolex® was effective in reducing the frequency of seizures when compared with placebo. In each of the three trials, either Epidiolex® or placebo was added to the patients’ existing medication regimen.