What We Know About Epidiolex and the Treatment of Epilepsy

Prior to the new Farm Bill signed by President Trump at the end of December 2018, Epidiolex enjoyed a special position in the market as it was thought of by many as the only “approved”or “lawful”form of CBD. That has all changed and consumer will have access to a variety of products that are not too different at all – at more competitive rates. Whether Doctors and medicare will acknowledge this and give patients a wider range of choice from hereon, remains to be seen: many would argue for that to be highly appropriate.

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More about Epidiolex:

In June 2018, the American Food and Drug Administration, the FDA, approved Epidiolex, a cannabidiol oral solution for the treatment of epilepsy. Epidiolex is the first and only FDA-approved prescription cannabidiol medicine for treating seizures associated with two rare and severe forms of epilepsy: Lennox-Gastaut syndrome and Dravet syndrome in patients who are at least two years old. More than 90% of the children with these two syndromes have multiple seizures per day, so they are at risk of falls and serious injury. Generally the children have high illness and mortality rates. It is not known if Epidiolex is safe and effective for children below two years old. The active ingredient is almost 100% pure cannabidiol (CBD). That means this medicine is not safe for people who are allergic to cannabidiol and the other ingredients within it. However, CBD is a cannabinoid that does not have psychoactive effects (does not cause a high), so it is safe even for children to take it under normal circumstances.

Epidiolex is manufactured by GW Pharmaceuticals, a British company. It is the first FDA-approved drug that contains pure CBD, a purified drug substance extracted from the cannabis plant. At the time of approval, in June 2018, CBD was classified as a schedule 1 compound. That has now changed since CBD has been legalized in the whole of the USA since December 20th, 2018 and will soon be rescheduled.

Scientists who developed Epidiolex have been running preclinical studies of CBD in epilepsy since 2007. Before approval, Epidiolex’s effectiveness was studied in three randomized, double-blind, placebo-controlled clinical studies involving 516 patients suffering from either Dravet syndrome or Lennox-Gastaut syndrome. The medication was found to be effective in reducing the frequency of seizures compared to placebo. The researchers, who published their report in the May 2017 New England Journal of Medicine, reported that 5% of their patients who had Dravet syndrome became seizure-free and 43% had a 50% reduction of seizures (1). However, it was found to cause liver damage and to have side-effects that are listed below.

Epidiolex for Dravet Syndrome

Dravet syndrome is rare, affecting around 1 person out of 15,700 individuals. It is a severe, lifelong and catastrophic type of epilepsy that begins in the first year of a baby’s life. It is characterized by frequent and/or prolonged seizures. There are usually no abnormal EEGs till the second or third year of life. It causes developmental and behavioral delays in babies such as delayed growth, delayed language and speech, sensory integration disorders, movement and balance issues and problems with bone development. Other problems linked to Dravet syndrome are sleeping difficulties, chronic infections, and disruptions of the autonomic nervous system. The autonomic nervous system regulates temperature. Such problems interfere with a child’s development and lowers the quality of life, Basically Dravet syndrome affects the child and disrupts family life since the child needs intense around-the-clock care.

Patients with Dravet syndrome have a 15-20% mortality rate due to sudden unexpected death, prolonged seizures, seizure-related accidents like drowning, and chronic infections. Yet, medical treatment options are limited which makes life difficult for the suffering child and the family. Mostly the doctor has had to find a combination of drugs that will control the various seizures that the child suffers from, normally with undesired side effects. So far there has been no specific medicine for Dravet syndrome. The absence of an effective medicine has been devastating for many families. That is why the search for medications that work is ongoing.

Fortunately, cannabis is well known as a natural remedy for epilepsy that has been used in various traditional medicines for millenia. Therefore, the discovery of various cannabinoids present in cannabis plants and our ability to isolate them, meant that each cannabinoid could be tested. CBD was tested and found to be effective for the treatment of Dravet syndrome without causing harmful side effects and without causing any psychoactive effects.

So far, CBD oil has been used for many years to effectively treat children and adults suffering from epilepsy. While it has been very effective, the problem is dosage. Parents had to use trial and error to find a dosage that works since the purity of CBD in the oil differed from manufacturer to manufacturer. Now there is Epidiolex that comes with specific dosages and guidelines to take the guesswork out of treating patients.

Epidiolex is a welcome medication since its active ingredient is cannabidiol and it was developed with the problem of dosage and the problem of uncontrollable seizures in mind. As the first-ever FDA-approved drug made specifically for Dravet syndrome sufferers, Epidiolex will provide a huge and much needed improvement in the treatment and care of the patients. Good news is that as from September 2018, Epidiolex oral solution was rescheduled by the DEA as a schedule 5 agent, the lowest restriction classification. This means it has proven medical use and low abuse potential.

Epidiolex for Lennox-Gastaut Syndrome

Lennox-Gastaut syndrome (LGS) is a severe type of epilepsy that characteristically begins during infancy or early childhood. Affected children experience several different types of seizures, the most common of which are atonic (begins with a sudden loss of muscle strength), tonic (muscles of the arms, the legs and the trunk tense up briefly), and atypical absence seizures (the child will stare but remain slightly responsive). It can be caused by different underlying problems, but in some cases no clear cause can be identified. Children with Lennox-Gastaut syndrome tend to develop learning and memory problems, they struggle to solve problems, and they experience delays in reaching developmental milestones. They also develop behavioral problems. The disease definitely interferes with the affected child’s development and the child cannot live and enjoy a normal life. Nor can the family have a normal life.

Lennox-Gastaut syndrome is usually difficult to treat because it is resistant to many kinds of antiseizure medications. That makes life very difficult for the children who suffer from this condition as they cannot properly participate in life. It makes life difficult for the children’s parents who have to look after them all the time in order to keep them safe. This is why research has been going on, and is still ongoing, to identify and assess new therapies for Lennox-Gastaut syndrome. Because cannabis has been known for millennia as a remedy for epilepsy, it was tested many times and found to be effective for Lennox-Gastaut syndrome. The ability to isolate various cannabinoids made research easier. Between THC and CBD, the major cannabinoids found in cannabis plants, CBD is the cannabinoid of choice since it has no psychoactive effects and can be used by people of all ages.

At the 2017 Annual Meeting of the American Academy of Neurology, two studies were presented in which researchers added cannabidiol to anti-epilepsy drugs. The researchers managed to reduce the frequency of drop seisures in the patients suffering from drug-resistant Lennox-Gestaut syndrome. Another study published in the New England Journal of Medicine in May 2018 found that adults and children with Lennox-Gestaut syndrome, who took cannabidiol together with regular anti-epilepsy drugs, had a higher reduction in the frequency of drop seizures than placebo (2). It is obvious that, since Lennox-Gestaut is normally resistant to drugs, CBD was responsible for the results.

CBD has been used now for many years to treat patients with Lennox-Gastaut syndrome. The only problem has been that of dosage as each CBD oil manufacturer tends to come up with a different purity level for CBD. Epidiolex, whose active ingredient is CBD, is a welcome medication for the control of Lennox-Gastaut syndrome. It comes with proper guideline for its use, taking guesswork out of treating patients. Now parents can breathe a sigh of relief as they will now see their children living with less frequent seizures that are less severe.

Epidiolex Dosages

Epidiolex dosage is based on body weight. The manufacturer recommends a starting dose of 2.5mg per kg of body weight twice daily. After one week of use, the dose may be increased to a maintenance dose of 5mg per kg of body weight twice daily.

If more seizure reduction is required, the patient can take the maximum dose of Epidiolex at 10mg per kg of body weight twice daily or 20mg per kg of body weight once per day. Users should be aware that the higher dosage may result in increased adverse reactions that are mentioned below. However, studies have established that Epidiolex is effective and has a favorable safety profile at both doses.

Contraindications

There are no given contraindications for Epidiolex. However, people taking it should be monitored for any signs of hypersensitivity to cannabidiol or any of the ingredients in Epidiolex.

Side Effects of Epidiolex

Epidiolex is known to cause liver problems since it caused liver damaged during trials. Therefore doctors are likely to order blood tests to check the state of the liver before prescribing Epidiolex and also during trreatment. A patient or a parent should ask for these liver tests if the doctor does not take initiative. Any person taking Epidiolex who has signs and symptoms of liver trouble, should call the doctor straight away. The signs are nausea, vomiting, jaundice (yellowing of the skin or the whites of the eyes), unusual darkening of the urine, loss of appetite, unusual tiredness, and pain or discomfort in the upper right part of the abdomen. When there are signs of liver damage the doctor may recommend that a patient stops treatment with Epidiolex.

Other side effects are diarrhea, fever, feeling unwell, rash, itching, feeling weak and infections. Epidiolex may also cause the patient to feel sleepy but this side effect may get better eventually. This problem of sleepiness may be worsened by alcohol and other medicines such as Clobazam so it is wise to avoid these during treatment with Epidiolex. It is also advisable not to drive or operate heavy machinery or to perform activities that may cause danger to self or others while taking Epidiolex.

There are psychological side effects as well. Epidiolex comes with a leaflet that contains information about its uses and risks. According to the leaflet it is likely to cause suicidal thoughts or actions just like other anti-epileptic drugs. So far it is known to affect 1 in 500 people in this manner. It is therefore advisable for anybody taking Epidiolex, or the parent of a such a child, to call a healthcare service provider straight away when they have any signs of anxiety, depression, thoughts about suicide or self-harm, agression, irritability, feelings of agitation, feelings of restlessness, and any other unusual changes in behavior or mood that were not there before.

Because it tends to have side effects, Epidiolex must be taken as prescribed. The side effects may be severe enough to need stopping the drug. However, it should be stopped only with the advice of a medical officer as stopping anti-epilepsy medicine may cause serious problems with seizures.

Because it is a new medication, Epidiolex has to be monitored. Therefore, users are required to report side effects to the FDA at 800-FDA-1088.

Interactions with Other Drugs

Cannabidiol is a very powerful ingredient therefore Epidiolex can easily interact with other medicines. It may either affect how other medicines work or its effectiveness may be affected by other medicines. When the medical practitioner prescribes Epidiolex, the patient (or the parent of young children) should tell him/her about all the prescription and over-the-counter medicines that they are currently taking, including herbal supplements, vitamins, and other cannabis-based products. If a person has to take other medications for other reasons while they are taking Epidiolex, they should not just stop taking Epidiolex as this may lead to seizures. It is better to discuss the situation with the medical officer who will then recommend the best way forward.

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Special Information for Women

There is no data regarding the use of Epidiolex in pregnant women. However, Epidiolex has potential to harm babies considering its long list of side effects. Therefore, pregnant women should stay away from it unless their healthcare provider advises that it is safe to use it. Those women who plan to become pregnant should also discuss their plans with their doctors before they start taking this medicine. Those who become pregnant while using Epidiolex, and they continue to take it, are required to register with the North American Antiepileptic Drug Pregnancy Registry whose function is to collect information about the safety of antiepileptic medicines during pregnancy.

Finally, medicines tend to be passed on to babies through breast milk. Again, it is wise to seek medical advice if a woman has to breastfeed while taking Epidiolex or if she is already breastfeeding and she has to take Epidiolex.

References

1. Devinsky O. & Others. (2017, May). New England Journal of Medicine. Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome. 2. Devinsky O & Others. (2018, May). New England Journal of Medicine. Effect of Cannabidiol on Drop Seizures in the Lennox–Gastaut Syndrome

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