U.S. Food and Drug Administration
FDA News Release
The U.S. Food and Drug Administration today approved Epidiolex (cannabidiol) [CBD] oral solution for the treatment of seizures associated with two rare and severe forms of epilepsy, Lennox-Gastaut syndrome and Dravet syndrome, in patients two years of age and older. This is the first FDA-approved drug that contains a purified drug substance derived from marijuana. It is also the first FDA approval of a drug for the treatment of patients with Dravet syndrome.
CBD is a chemical component of the Cannabis sativa plant, more commonly known as marijuana. However, CBD does not cause intoxication or euphoria (the “high”) that comes from tetrahydrocannabinol (THC).
It is THC (and not CBD) that is the primary psychoactive component of marijuana.
“This approval serves as a reminder that advancing sound development programs that properly evaluate active ingredients contained in marijuana can lead to important medical therapies. And, the FDA is committed to this kind of careful scientific research and drug development,” said FDA Commissioner Scott Gottlieb, M.D. “Controlled clinical trials testing the safety and efficacy of a drug, along with careful review through the FDA’s drug approval process, is the most appropriate way to bring marijuana-derived treatments to patients. Because of the adequate and well-controlled clinical studies that supported this approval, prescribers can have confidence in the drug’s uniform strength and consistent delivery that support appropriate dosing needed for treating patients with these complex and serious epilepsy syndromes. We’ll continue to support rigorous scientific research on the potential medical uses of marijuana-derived products and work with product developers who are interested in bringing patients safe and effective, high quality products. But, at the same time, we are prepared to take action when we see the illegal marketing of CBD-containing products with serious, unproven medical claims. Marketing unapproved products, with uncertain dosages and formulations can keep patients from accessing appropriate, recognized therapies to treat serious and even fatal diseases.”
Dravet syndrome is a rare genetic condition that appears during the first year of life with frequent fever-related seizures (febrile seizures). Later, other types of seizures typically arise, including myoclonic seizures (involuntary muscle spasms). Additionally, status epilepticus, a potentially life-threatening state of continuous seizure activity requiring emergency medical care, may occur. Children with Dravet syndrome typically experience poor development of language and motor skills, hyperactivity and difficulty relating to others.
Lennox-Gastaut syndrome begins in childhood. It is characterized by multiple types of seizures. People with Lennox-Gastaut syndrome begin having frequent seizures in early childhood, usually between ages 3 and 5. More than three-quarters of affected individuals have tonic seizures, which cause the muscles to contract uncontrollably. Almost all children with Lennox-Gastaut syndrome develop learning problems and intellectual disability. Many also have delayed development of motor skills such as sitting and crawling. Most people with Lennox-Gastaut syndrome require help with usual activities of daily living.
“The difficult-to-control seizures that patients with Dravet syndrome and Lennox-Gastaut syndrome experience have a profound impact on these patients’ quality of life,” said Billy Dunn, M.D., director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research. “In addition to another important treatment option for Lennox-Gastaut patients, this first-ever approval of a drug specifically for Dravet patients will provide a significant and needed improvement in the therapeutic approach to caring for people with this condition.”
Epidiolex’s effectiveness was studied in three randomized, double-blind, placebo-controlled clinical trials involving 516 patients with either Lennox-Gastaut syndrome or Dravet syndrome. Epidiolex, taken along with other medications, was shown to be effective in reducing the frequency of seizures when compared with placebo.
The most common side effects that occurred in Epidiolex-treated patients in the clinical trials were: sleepiness, sedation and lethargy; elevated liver enzymes; decreased appetite; diarrhea; rash; fatigue, malaise and weakness; insomnia, sleep disorder and poor quality sleep; and infections.
Epidiolex must be dispensed with a patient Medication Guide that describes important information about the drug’s uses and risks. As is true for all drugs that treat epilepsy, the most serious risks include thoughts about suicide, attempts to commit suicide, feelings of agitation, new or worsening depression, aggression and panic attacks. Epidiolex also caused liver injury, generally mild, but raising the possibility of rare, but more severe injury. More severe liver injury can cause nausea, vomiting, abdominal pain, fatigue, anorexia, jaundice and/or dark urine.
Under the Controlled Substances Act (CSA), CBD is currently a Schedule I substance because it is a chemical component of the cannabis plant. In support of this application, the company conducted nonclinical and clinical studies to assess the abuse potential of CBD.
The FDA prepares and transmits, through the U.S. Department of Health and Human Services, a medical and scientific analysis of substances subject to scheduling, like CBD, and provides recommendations to the Drug Enforcement Administration (DEA) regarding controls under the CSA. DEA is required to make a scheduling determination.
The FDA granted Priority Review designation for this application. Fast-Track designation was granted for Dravet syndrome. Orphan Drug designation was granted for both the Dravet syndrome and Lennox-Gastaut syndrome indications.
The FDA granted approval of Epidiolex to GW Research Ltd.
FDA approved Epidiolex (cannabidiol) oral solution, the first drug comprised of an active ingredient derived from marijuana, to treat two rare and severe forms of epilepsy.
Cannabidiol oral solution
Epidiolex ® (EH-peh_DYE-oh-lex) oral solution CV is the brand name for the cannabidiol oral solution, also referred to as CBD, from Greenwich Biosciences. The name or look may be different in other countries, but the dose (measured in milligrams, abbreviation “mg”) usually will be the same. Epidiolex is a quality grade of cannabidiol oil that is different from CBD or cannabidiol that is not U.S. Food and Drug Administration (FDA) approved.
Epidiolex is Approved for Use:
In people age 2 years and older for seizures associated with Lennox-Gastaut Syndrome and Dravet Syndrome.
Cannabidiol oral solution is availabe as 100 mg in each milliliter (abbreviated as “mL”).
- Each bottle contains 100 mL of a clear colorless to yellow solution with a strawberry flavor.
- Two 5 mL syringes will come with each bottle of medicine. These can be reused.
- A 1 mL syringe is available from the pharmacist when smaller doses are needed.
Blood tests for liver function, called serum transaminases (ALT and AST) and total bilirubin levels should be done in each person before starting Epidiolex.
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.
How To Take:
Take Epidiolex exactly as your health care provider prescribes it. Do not change your dose without talking to your provider first. Stopping a seizure medicine suddenly can cause seizures that will not stop (status epilepticus).
- Take the medicine twice a day by mouth.
- Check the amount and concentration of the oral solution from the pharmacy.
- A special measuring device (called a syringe) will come with each prescription bottle. Use this syringe to measure the exact dose of medicine. Do not use a regular teaspoon to measure the medicine.
- Use a dry syringe each time you measure a dose of Epidiolex. Water inside the syringe could make the oil-based medicine look cloudy.
- Take the medicine about the same time each day with or without food. Certain foods can increase the amount of Epidiolex that is absorbed in your body, so take it the same way each day.
- Take only the amount that your provider tells you to take.
- If you take an extra dose, call your provider for advice.
- If you take a larger amount of the liquid, call the poison control center (800-222-1222) or call your hospital emergency department for instructions.
- When Epidiolex is stopped, the dose should be lowered slowly. Your provider will give you specific instructions on how to do this.
How To Store:
- Store Epidiolex in its original bottle in an upright position at 68°F to 77°F.
- Do not refrigerate or freeze the medicine.
- Keep the child proof cap closed tightly.
- Use the medicine within 12 weeks of first opening the bottle. Throw away any unused medicine after 12 weeks.
- Keep Epidiolex out of reach of children.
Taking the right amount of seizure medicine, on time every day, is the most important way to control seizures.
- If you miss a dose, take it as soon as you remember it.
- If it is almost time for the next dose, skip the missed dose and take the next dose at the regular time.
- Avoid taking 2 doses at the same time or taking extra doses.
- If you are not sure about what to do, call your provider’s office for advice and follow their directions.
- To avoid missed doses, set an alarm on your watch, phone or other digital device.
- Use an online seizure diary or text message system (Texting 4 Control) to send you reminders of when to take medicines.
- Write down any missed doses in your seizure diary. Share this with your health care provider at each visit.
There are different ways that medicines can affect the brain to stop seizures. In general, seizure medicines make the brain less likely to have seizures by lowering the excitability of brain cells that cause seizures.
- The exact way that Epidiolex works to control seizures is unknown. Scientists believe Epidiolex works in more than one way.
- Epidiolex may inhibit or slow down the way messages or signals are sent in the brain. It may change calcium levels in brain cells that are important for sending messages or signals between cells. The medicine may also decrease inflammation in the brain.
- Researchers continue to study how cannabidiol works to help stop seizures.
- After a medicine is swallowed, it is absorbed into the bloodstream and travels through the body and to the brain.
- The way the body metabolizes or breaks down a medicine affects how often it must be taken.
- Epidiolex is broken down primarily in the liver and the gut. It is cleared from the body through the feces and in a small amount through urine.
Epidiolex has been tested in people with Lennox-Gastaut (LGS) and Dravet Syndrome (DS).
- In controlled trials in people with LGS (age 2 to 55 years), the number of drop seizures (atonic, tonic, or tonic-clonic seizures) decreased significantly from baseline for people taking 10 mg per kg per day and 20 mg per kg per day. Improvements were also seen in non-drop seizures.
- In trials of 120 people with DS (age 2 to 18 years), the average (median) decrease in number of convulsive seizures was significantly greater for people taking 20 mg per kg per day (39% decrease) than for people taking placebo (13% decrease).
Call your health care provider if side effects occur that bother you. These may go away on their own or the dose of medicine may need to be changed. Sometimes side effects mean that you don’t tolerate the medicine and the medicine may need to be stopped. Don’t stop taking any medicine suddenly on your own.
- Decreased appetite
- Increase in liver enzymes
- Sleep problems
Since Epidiolex may make some people sleepy, do not drive, use heavy equipment or do other dangerous activities until you know how Epidiolex affects you. People who are not seizure free also may not drive due to legal restrictions. Talk to your doctor about your seizure control, medicines, and ability to drive.
Serious side effects of Epidiolex are rare. It is important to be aware of possible reactions and what to do if they happen. Only a very small number of people have died from them.
- Read the package insert for a complete list of all reactions to Epidiolex.
- Call your provider’s office right away if any of these problems occur.
Allergic or hypersensitivity reactions: Tell your provider if you develop any redness, itching, rash, or swelling after starting Epidiolex. These may need treatment or the drug may be stopped.
- Epidiolex should not be given to anyone with a prior reaction or sensitivity to cannabidiol or any of the other ingredients in the product. Sesame seed oil is present in Epidiolex.
Liver problems: Increases in liver function can be seen on blood tests in some people taking Epidiolex, especially people who may also be taking valproate (also called valproic acid or sodium valproate). It has also been seen in people taking clobazam with Epidiolex.
- Increases in the liver function tests were usually seen in the first two months of starting the drug. The changes can be seen months later however, especially if a person also takes valproate.
- In 1 out of 3 people the blood tests returned to normal without any changes in medicine. In other people, the problems went away when Epidiolex was stopped or the dose of valproate or Epidiolex was lowered.
Monitoring for liver function: Blood tests for liver function should be done before starting Epidiolex and after taking it for 1, 3 and 6 months. Talk to your health care provider about when to have these done.
Some symptoms of liver problems may include:
- Black or pale color of bowel movements
- Loss of appetite
- Nausea, upset stomach, vomiting
- Stomach pain
- Yellow eyes or skin
- Dark urine
Tell your health care provider right away if you notice any of these problems. Do not stop taking Epidiolex or any seizure medicine without your doctor’s advice.
Somnolence and Sedation: Some people taking Epidiolex may be unusually tired, sleepy or sedated. In controlled trials, these symptoms were seen in 1 out of 3 people taking the drug compared to 1 out of 10 people taking a placebo (inactive pill).
- Sleepiness and sedation happened more often in people also taking clobazam (Onfi).
- The symptoms were seen early when the medicine was started and tended to improve over time.
- Other medicines that cause sedation or sleepiness or using alcohol could make this worse in people taking Epidiolex.
- Talk to your health care provider if sleepiness happens and if you are taking clobazam (Onfi) or other substances that cause sleepiness.
Suicidal thoughts and behavior: In 2008, the Food and Drug Administration (FDA) reviewed data from drug studies that showed a possible relationship between many seizure medicines and suicidal thoughts and behavior. Together, these thoughts and behavior are called suicidality. According to the FDA’s Alert, among the patients with epilepsy in these drug studies, more had symptoms of suicidality than people taking a placebo or inactive substance – 3.5 of 1,000 people taking a seizure medicine had suicidality compared to 1 of 1,000 people taking a placebo.
- Taking seizure medicines may increase the risk of having suicidal thoughts or actions.
- Do not make any changes to the medicines without first talking to your prescribing health care provider.
- Pay close attention to any day-to-day changes in mood, behavior and actions. These changes can happen very quickly so it is important to be mindful of any sudden differences.
- Be aware of common warning signs that might be a signal for risk of suicide. Some of these are:
- Talking or thinking about wanting to hurt yourself or end your life
- Withdrawing from friends and family
- Becoming depressed or having your depression get worse
- Becoming preoccupied with death and dying
- Giving away prized possessions
- Contact your health care provider before stopping any seizure medicine. This could possibly lead to worsening of seizure and mood.
Withdrawal of seizure medicines: Epidiolex, just like any seizure medicine, should be withdrawn slowly when it is being stopped. Stopping Epidiolex or any seizure medicine suddenly can lead to more seizures and life-threatening status epilepticus.
- If Epidiolex needs to be stopped quicker due to another problem, follow your doctor’s advice on how to make changes.
Some people taking Epidiolex and valproic acid or valproate (Depakene or Depakote) or clobazam (Onfi) have had an increase in liver enzymes.
- Liver tests need to be checked and the dose of one of these medicines may need to be changed. Some people may not be able to take Epidiolex if this happens.
Epidiolex appears to affect a byproduct or metabolite of clobazam (Onfi). This may increase side effects of clobazam, such as excessive sleepiness or sedation.
- Talk to your provider if taking clobazam and Epidiolex together and watch for changes in side effects. The dose of one or both of the medicines may need to be changed.
Using alcohol and other products that depress the central nervous system or brain activity (CNS depressants) while taking Epidiolex can increase sleepiness or sedation.
Epidiolex could affect some other medicines that are broken down or metabolized by the liver.
- Tell your health care provider and pharmacist all the prescription and over the counter medicines that you take.
- Report any changes in symptoms or side effects to your health care team.
Do not take Epidiolex if you are allergic or have a history of reactions to cannabidiol or any of the ingredients in this medicine (such as dehydrated alcohol, sesame seed oil, strawberry flavor, sucralose).
Do not use Epidiolex for other reasons or if not prescribed by a licensed health care provider.
Do not give Epidiolex to other people, even if they have similar symptoms.
- Epidiolex has been studied in children 2 years of age and older for safety and how well it works to control seizures. The safety and effectiveness in children under 2 years old is not known.
- The dose of Epidiolex that is prescribed is based on a person’s weight. Tell your health care providers if weight changes as the dose of medicine may need to be adjusted.
Taking medication during pregnancy is a common concern for women. Most medicines carry some risk, but the extent of risk is often unknown.
Effects of Epidiolex during pregnancy: There are no adequate data on the developmental risks of Epidiolex on a baby when taken by a woman during pregnancy. Based on research in animals, Epidiolex may cause harm to a baby when the mother uses this medicine during pregnancy.
- All women who take seizure medicines and are able to become pregnant should take at least 0.4 mg (400 mcg) of folic acid or folate daily to help prevent birth defects (such as neural tube defects) in a child.
- Women at high risk of having a child with a birth defect (such as those with a history of a birth defect in a prior pregnancy or taking certain seizure medicines) may be asked to take a higher dose, for example 4 mg (4,000 mcg) of folic acid daily before and during pregnancy.
- Talk to your doctor about other possible risks to your unborn child. Ask about the risks of using the medicine during pregnancy and the risks of seizures.
Seizures during pregnancy: Some women may have more seizures during pregnancy, because of hormone changes and how seizure medicine is handled by your body. Blood levels of seizure medicine may need to be checked more regularly during pregnancy so the dose can be adjusted if needed.
Women who are pregnant or are thinking of becoming pregnant, should consider contacting the North American Antiepileptic Drug (NAAED) Pregnancy Registry at 1-888-233-2334 or visiting www.aedpregnancyregistry.org. This and other registries monitor pregnancy outcomes in women taking seizure medicines during pregnancy.
Breastfeeding: There is no information about Epidiolex or its breakdown products being present in breastmilk or the effects on milk production. With most seizure medicines, the amount of medicine the baby is exposed to while breastfeeding is less than during pregnancy. If you want to breastfeed your baby, check with your health care team about the best approach.
Contraception: There is no information about the use of Epidiolex when a woman is taking a hormonal form of birth control. Some other seizure medicines can make certain forms of birth control less effective.
- Tell your health care team and pharmacist if you are taking hormonal birth control such as the pill, injection, or patch.
- Ask what form of birth control would be best if you are also taking Epidiolex.
Epidiolex has not been tested in older adults, thus the use of this medicine in seniors is unknown.
- Older adults may be more sensitive than younger adults to medicines and their side effects.
- Other medical problems (such as changes in liver or kidney function) may affect the dose of medicine prescribed.
- Older adults may also be on other medicines that can interact with each other and cause more side effects.
- In general, lower doses of seizure medicines are given to older adults and the dose is increased more slowly.
Epidiolex and Drug Testing
People who take Epidiolex may test positive for cannabis drug screens. Tell the person giving the drug test that you are taking Epidiolex for a medical reason.
In the United States, companies that manufacture medicines are required to publish a “package insert.” This document gives detailed information about the medicine and what you should know if you are taking it.
Cannabidiol oral solution Epidiolex ® (EH-peh_DYE-oh-lex) oral solution CV is the brand name for the cannabidiol oral solution, also referred to as CBD, from Greenwich Biosciences. The name or