Cannabinoids in Epilepsy: New Horizons for Improving the Management of Severe Seizure Disorders
For purposes of this monograph, we will use both the brand and generic name for the FDA approved form of cannabidiol (Epidiolex) to differentiate it from forms available in dispensaries.
Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) are rare conditions that begin in infancy or early childhood. They are characterized by severe refractory seizures—seizures that are considered catastrophic. Many patients with these syndromes will experience status epilepticus (a life-threatening form of repetitive seizures) in early childhood or throughout their lifetime. For both DS and LGS, diagnosis early in the disease state is essential to providing optimal treatment, since treatment differs for these types of rare seizure disorders compared to other more common seizure types. Patients with DS and LGS often take several medications to treat their seizures, which makes managing drug-drug interactions and side effects challenging; however, the medications are critically important for successful management of seizures, and appropriate treatment decreases morbidity and mortality and increases quality of life.
There are more than 22 anti-seizure drugs (ASDs) approved by the United States (U.S.) Food and Drug Administration (FDA) for the treatment of focal and generalized seizures. Currently, 2 of these medications are approved for DS and 6 are approved for LGS. Pharmacists can impact the management of patients with DS and LGS by providing pharmacovigilance and medication therapy management to provide optimal outcomes.
DS AND LGS DIAGNOSIS AND TREATMENT
DS and LGS are epileptic encephalopathies. While they share some similarities in presentation and progression, there are differences in their ages of onset, causes, and associated comorbidities. Lack of effective treatment options is an obstacle in both syndromes.
DS is a rare genetic infantile epileptic encephalopathy that occurs due to an SCN1A mutation: the mutation in the voltage-gated sodium channel is present in as many as 85% of children with DS.1-4 In the U.S., the incidence of DS is estimated to be 1 in 40,000.5 DS is characterized by onset before 12 months of age with normal development before seizure onset. At 2 to 3 years of age, patients exhibit frequent and prolonged seizures, including refractory hemiclonic, myoclonic, and generalized tonic-clonic seizures, as well as febrile seizures.5-8 Poor motor skills and language development, as well as hyperactivity and poor interpersonal skills, are also frequent problems.9 Patients with DS often experience other comorbidities, such as autonomic dysfunction and sleep problems.9
Status epilepticus is a recurring issue for patients with DS, particularly in early childhood; mortality in patients with DS reaches approximately 10% in the first 10 years of life and continues to increase as patients get older.9 Adult patients with DS are rarely able to live independently. The goals of treatment for patients with DS are to decrease the number of seizures they are experiencing and to balance the side effects of treatment with quality of life. Unlike with other types of epilepsy, few patients with DS will experience total seizure freedom, so an active treatment plan with a rescue medication such as a benzodiazepine should be enacted in the event of status epilepticus, since it is life threatening.9 Sudden unexplained death in epilepsy (SUDEP) is a concern for caregivers and practitioners of patients with DS because, in adolescence and adulthood, seizures tend to be more generalized tonic-clonic and nocturnal in nature.9-11
TO is a 10-year-old female with a diagnosis of DS. She experiences an average of 4 seizures each day. TO has taken multiple ASDs, including topiramate, phenytoin, and levetiracetam. Recently, she was placed on clobazam and the dose has been escalated to 20 mg orally twice daily. What do you think about TO’s previous ASDs?
The FDA has approved 2 medications for DS: cannabidiol (Epidiolex), which was the first FDA-approved drug for this condition, and stiripentol (Diacomit). It is important to note that stiripentol should not be used as monotherapy, since there is no data to support its use in this way. Additionally, other first-line agents that are used off-label include clobazam and valproic acid.12 Benefit has also been observed with topiramate, levetiracetam, vagal nerve stimulation, and the ketogenic diet, and fenfluramine has shown some promise in clinical trials.9 Sodium channel-blocking medications may make DS worse and should be avoided.
LGS is a severe developmental epileptic encephalopathy that is generally reported in children from 1 to 7 years of age; it is 5 times more common in boys than in girls.13-15 The incidence is approximately 2.8 cases per 100,000 live births,16 and LGS represents 4% to 10% of all childhood epilepsies.15-18 LGS has a poor prognosis: less than 10% of patients will ever be seizure free.19 Symptoms of LGS evolve over time and several seizure types and characteristic electroencephalogram patterns have been noted. Often, patients with LGS have many types of seizures, including generalized tonic-clonic seizures, atonic seizures, and atypical absence seizures, multiple times per day. Most patients (50% to 75%) will develop non-convulsive status epilepticus with intermixed brief recurring tonic seizures.20
The cause of LGS is unknown in 25% to 35% of all cases20,21; West syndrome (infantile spasms) may be associated with as many as 30% of LGS cases,21-23 but LGS may evolve from other disorders, such as brain insult, developmental structural malformation, tumor, infection,24 or genetic mutation.25 SUDEP is a concern for patients with LGS.
In 2017, an expert opinion on disease management, treatment algorithms, and practical considerations in LGS was published to guide practitioners in the medical care of patients with LGS.25 The FDA has approved 6 medications for the treatment of LGS: valproate, which is considered first-line therapy, clobazam, lamotrigine, topiramate, felbamate, rufinamide, and, most recently, cannabidiol (Epidiolex) for a total of 7 treatment options. Despite the handful of drug approvals for DS and LGS, these syndromes with difficult-to-control seizures are often refractory to treatment and associated with severe outcomes, including death; new or novel treatments must be developed to treat these rare, life-threatening seizure disorders.
Both DS and LGS are devastating neurological illnesses. Patients experience generalized seizures of many types, but current ASDs, even in combination, are not sufficient to prevent recurrent severe seizures.25 Associated comorbidities, including SUDEP, developmental disabilities, and broken bones from severe seizures or falling, are challenges for patients diagnosed with DS and LGS. Patients and families continue to search for relief from frequent seizures to improve quality of life with DS and LGS. These searches have led to anecdotal reports of improvement in seizure control with a specific brand of hemp-derived cannabidiol (CBD) called Charlotte’s web.26
Patient case, continued
Upon review of TO’s past ASDs, topiramate and levetiracetam may have been beneficial at reducing her seizures and increasing her quality of life. Unfortunately, data now suggest that sodium channel-blocking ASDs, such as phenytoin, will precipitate seizures and, therefore, negatively impact quality of life, morbidity, and mortality. Practitioners must always recognize the complexity of treating the catastrophic epilepsies of DS and LGS and be ready to treat status epilepticus when it occurs.
REVIEW OF CANNABIS-BASED MEDICATIONS
There are more than 100 different cannabinoids present in the cannabis plant, although the primary active components are CBD and tetrahydrocannabinol (THC).27 CBD is the non-psychoactive component of the cannabis plant and THC is the psychoactive component from which patients experience a “high” or euphoric feeling. “Marijuana” is generally used as the slang or street term for the plant-based material, and “cannabis” is the broad medical term used for medicinal cannabis.
“Hemp” usually refers to the seeds of the cannabis plant, but it can also contain the stems and non-flower parts of the plant.28 By definition, hemp is mostly CBD and can contain no more than 0.3% THC.28 Hemp is used in the making of rope and clothing and, in many states, a patient can order it on the internet. The Controlled Substances Act (CSA) exempts certain parts of the cannabis plant, such as sterilized seeds, fiber, and stalk, from its definition of marijuana as a Schedule I drug. The CSA does not define hemp. Additionally, no standardized definitions exist in the CSA for the terms “medical marijuana,” “high-CBD,” or “low-THC” due to the lack of regulation among associated products. State laws regarding the use of medical marijuana and cannabis products vary from state to state.
THE ENDOCANNABINOID SYSTEM: A NEW APPROACH TO SEIZURE TREATMENT
As mentioned, there are hundreds of chemical compounds in cannabis and more research involving these compounds is warranted.29 Much of the research to date has been conducted on cannabinoid receptors, CB1 and CB2, and THC, but the endocannabinoid system (ECS) is much more complex than these simple components.
The ECS is a receptor system located throughout the body that functions to help maintain homeostasis.31 This system comprises 2 main receptors: the CB1 receptors, which are located mainly in the brain and peripheral nervous system, and the CB2 receptors, which are located mainly in the gastrointestinal tract and immune system. Cannabinoids are the chemical compounds that bind to these receptors and they can be found endogenously in the body (endocannabinoids) or exogenously in both marijuana and hemp plants (phytocannabinoids).31
The most well-known phytocannabinoids are THC and CBD. It is important to understand the difference between these in order to properly assess pharmaceutical and nutraceutical products that are currently available. CBD does not have the hallmark euphoric effects that are associated with other cannabinoids, but it can still cause some drowsiness and lethargy. Importantly, it has proposed benefits, such as anti-inflammatory, analgesic, neuroprotective, antiepileptic, and anxiolytic functions.31 CBD also suppresses the psychoactive effects of THC at the CB1 receptor and has been found to suppress the fatty acid amide hydrolase (FAAH) enzyme and inhibit the cyclooxygenase (COX-2) enzyme among several other activities.30 CBD is the major cannabinoid compound found in the orally administered oil extract, cannabidiol (Epidiolex), which has recently gained FDA approval for use in LGS and DS and is considered a Schedule V substance by the Drug Enforcement Administration (DEA).32 Comparatively, THC is a phytocannabinoid that binds to CB1 and CB2 receptors and acts as a partial agonist. It is associated with the reported euphoric effect of “feeling high” and is a component of natural plant-based products that are federally classified as Schedule I substances by the DEA. However, similar benefits, such as pain relief, anti-nausea effects, and appetite stimulation, have been reported with THC.31
The known properties of CBD and THC have led to the hypothesis that these 2 cannabinoids, when used in combination, produce an “entourage effect.” This hypothesis proposes a mechanism of synergy that would lead to a stronger effect than either one component can achieve alone.31 DEA scheduling and the FDA approval process limit scientific research of this hypothesis.
FAAH and monoacylglycerol lipase (MAGL) are the enzymes in the ECS that are believed to be involved in epilepsy, but there are hundreds of different enzymes involved in the ECS because of its role in regulating many different body processes.33 Three primary components are involved in propagation of the ECS in the central nervous system (CNS): the neurotransmitter agonist (endocannabinoids such as 2-arachidonoylglycerol [2-AG] or anandamide [AEA]), the receptor or ligand to which the neurotransmitter binds (CB1 in the CNS), and the enzymes or transporters that recycle or degrade the neurotransmitters at the synapse (FAAH, COX-2, and MAGL).30,33 FAAH is involved in the metabolism of AEA; MAGL is involved in the metabolism of 2-AG. It has been suggested that patients with epilepsy have decreased endogenous levels of AEA and 2-AG. Inhibitors of both FAAH and MAGL have shown benefit in a rodent model of epilepsy, which further supports this theory. CBD has also been found to attenuate the effects of both of these enzymes. To substantiate this claim and delineate the exact mechanism of action of cannabidiol (Epidiolex), more rigorous research needs to be conducted.
PIVOTAL CLINICAL TRIALS EVALUATING CANNABIDIOL
The FDA approval of cannabidiol (Epidiolex) was based on several trials conducted with patients with DS and LGS. The approval represented the first time a purified form of a cannabis-derived compound was approved for use in patients, and it also represented the first approval of any drug for the treatment of DS.
Patient case, continued
TO is starting to have more frequent and longer-lasting seizures and her recovery time is slower. At this point, her epileptologist recommends that she join a clinical trial for DS that is studying cannabidiol (Epidiolex). As a clinical pharmacist and co-investigator of this trial, you agree with enrolling TO but caution her parents and epileptologist about possible drug-drug interactions.
Two randomized, double-blind, placebo-controlled trials have evaluated the use of cannabidiol (Epidiolex) in patients with LGS who are between 2 and 55 years old. The first was Cannabidiol in Patients with Seizures Associated with Lennox-Gastaut Syndrome (GWPCARE4): A Randomised, Double-Blind, Placebo-Controlled Phase 3 Trial.34 Patients were randomized to receive either cannabidiol (Epidiolex) at a dose of 20 mg/kg/day divided twice daily or placebo for 14 weeks, which included a 2-week dose titration schedule. At baseline, patients had previously tried a median of 6 ASDs, which were eventually discontinued, and reported 3 concomitant ASDs; the most common were clobazam (49%), valproate (41%), and lamotrigine (37%). Patients had to have at least 2 drop seizures (also called atonic seizures) per week. The mean age was 15.5 ± 8.7 years in the cannabidiol (Epidiolex) group and 15.3 ± 9.8 years in the placebo group.
The primary outcome was the percentage change in the frequency of monthly drop seizures from baseline. The monthly frequency of drop seizures was reduced by 43.9% in the cannabidiol (Epidiolex) group and by 21.8% in the placebo group. The estimated mean difference between treatment groups was -17.21 (p=0.0135, 95% confidence interval [CI]: -30.32 to -4.09).
Key secondary endpoints included the proportion of patients who achieved a 50% or more reduction in drop seizures from baseline and the change from baseline in the Subject/Caregiver Global Impression of Change (S/CGIC) at 14 weeks. (The S/CGIC assesses overall quality of life using a 7-point Likert-type scale.) In all, 44% of patients in the cannabidiol (Epidiolex) group achieved a reduction in drop seizure frequency of at least 50%; only 24% of patients in the placebo group experienced the same change (p=0.0043). Additionally, 58% of patients in the cannabidiol (Epidiolex) group and 34% of patients in the placebo group reported improvement in overall condition from baseline.
Adverse events were reported in 86% of patients in the cannabidiol (Epidiolex) group and 69% of patients in the placebo group. Common adverse events (>10%) included diarrhea, somnolence, pyrexia, decreased appetite, and vomiting. The most common serious treatment-related adverse events were increased concentrations of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyltransferase (GGT).
The second pivotal study was entitled Effect of Cannabidiol on Drop Seizures in the Lennox-Gastaut Syndrome.35 Patients in this study received either cannabidiol (Epidiolex) at a divided twice-daily dose of 20 mg/kg/day or 10 mg/kg/day or matching placebo. The patients were put on a fixed titration schedule starting at 2.5 mg/kg/day administered twice daily in equally divided doses and increased to 5 mg/kg/day every other day until the target dose was reached. At baseline, patients were receiving a median of 3 concomitant ASDs, with the most common being clobazam (49%), valproate (38%), and levetiracetam (31%). Patients had to have at least 2 drop seizures per week. Mean ages were 16.0 ± 10.8 years, 15.4 ± 9.5 years, and 15.3 ± 9.3 years in the 20-mg cannabidiol (Epidiolex), 10-mg cannabidiol (Epidiolex), and placebo groups, respectively.
The primary efficacy endpoint was the median percent reduction from baseline in the frequency of drop seizures per 28 days during the treatment period. Results showed a 41.9% reduction in the 20 mg/kg/day cannabidiol (Epidiolex) group, a 37.2% reduction in the 10 mg/kg/day cannabidiol (Epidiolex) group, and a 17.2% reduction in the placebo group. The estimated mean difference in reduction between the 20-mg cannabidiol (Epidiolex) group and the placebo group was 21.6 (p=0.005, 95% CI 6.7-34.8). The estimated mean difference in reduction between the 10-mg cannabidiol (Epidiolex) group and the placebo group was 19.2 (p=0.002, 95% CI: 7.7-31.2).
Key secondary endpoints included the percentage of patients who achieved at least a 50% reduction from baseline in the frequency of all seizure types and change from baseline in S/CGIC. Overall, 39% of patients in the 20 mg/kg/day cannabidiol (Epidiolex) group, 36% in the 10 mg/kg/day cannabidiol (Epidiolex) group, and 14% in the placebo group achieved at least a 50% reduction in seizures from baseline. An improvement from baseline in overall condition according to the S/CGIC at the last visit was reported in 57%, 66%, and 44% of the 20 mg/kg/day cannabidiol (Epidiolex), 10 mg/kg/day cannabidiol (Epidiolex), and placebo groups, respectively.
The most common adverse events included somnolence, decreased appetite, diarrhea, upper respiratory tract infections, pyrexia, and vomiting. Serious adverse events were reported in 33 patients (13 in each cannabidiol [Epidiolex] group and 7 patients in the placebo group). Of these, 7 patients had serious adverse events that were attributed to cannabidiol (Epidiolex) treatment, including elevated concentrations of AST, ALT, and GGT; somnolence; increased seizures during weaning; non-convulsive status epilepticus; lethargy; constipation; and worsening chronic cholecystitis.
Cannabidiol (Epidiolex) for the treatment of seizures in DS has been evaluated in 1 randomized, double-blind, placebo-controlled trial in patients aged 2 to 18 years old: the Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome.36 Similar to studies in LGS, patients were randomized to either cannabidiol (Epidiolex) 20 mg/kg/day or placebo with a 2-week dose titration schedule. At baseline, patients had a median of 13 convulsive seizures per month and were taking a median of 3 ASDs: the most common were clobazam (65%), valproate (59%), and stiripentol (42%).
The primary endpoint was the percentage change per 28 days from baseline in convulsive-seizure frequency during the treatment period. Patients receiving cannabidiol (Epidiolex) achieved a 38.9% reduction in monthly seizures and patients in the placebo groups achieved a 13.3% reduction. Between the cannabidiol and placebo groups, the adjusted mean difference in seizure reduction was -22.8% (p=0.01, 95% confidence interval [CI]: -41.1 to -5.4).
The secondary endpoints included the CGIC and the number of patients with a reduction in convulsive seizure frequency of at least 50%. In all, 62% of caregivers in the cannabidiol (Epidiolex) group and 34% of caregivers in the placebo group concluded that their child’s overall condition improved. Additionally, 43% of patients in the cannabidiol (Epidiolex) group and 27% of patients in the placebo group achieved at least a 50% reduction in the frequency of convulsive seizures (p=0.08).
Adverse events were reported in 93% of patients receiving cannabidiol (Epidiolex) and 75% of patients receiving placebo. Common adverse events (>10%) included vomiting, fatigue, pyrexia, upper respiratory tract infections, decreased appetite, and diarrhea.
MECHANISM OF ACTION OF CANNABIDIOL (EPIDIOLEX)
The exact mechanism by which cannabidiol (Epidiolex) exerts its anti-seizure effects in the body is unknown, but it is not thought to work via the cannabinoid receptors or voltage-gated sodium channels.28
Pharmacokinetics, pharmacodynamics, and drug-drug interactions
The time to maximum plasma concentration for cannabidiol (Epidiolex) is approximately 2.5 to 5 hours. When administered with a high-fat or high-calorie meal, the maximum serum concentration is increased by 5-fold and the area under the curve is increased by 4-fold compared to administration in the fasted state. The volume of distribution is highly variable, ranging from 20,963 L to 42,849 L with greater than 94% protein binding in vitro. The half-life of cannabidiol (Epidiolex) when dosed twice daily is 56 to 61 hours. Cannabidiol (Epidiolex) is metabolized primarily in the liver and in the gut by cytochrome P450 (CYP) isozymes 2C19 and 3A4 and UDP-glucuronosyltransferase (UGT) isoforms, including UGT1A7, UGT1A9, and UGT2B7. Cannabidiol (Epidiolex) is primarily excreted in the feces.
It is important to screen patients’ medications for drug-drug interactions when they are taking cannabidiol (Epidiolex). Specifically, pharmacists should screen for moderate or strong inhibitors of CYP3A4 or CYP2C19 that will increase the cannabidiol (Epidiolex) plasma concentration. The dose of cannabidiol (Epidiolex) should be reduced if it is coadministered with a moderate or strong inhibitor of CYP3A4 or CYP2C19.28 If a patient is on a strong CYP3A4 or CYP2C19 inducer, then the plasma concentration of cannabidiol (Epidiolex) may be lower, which could lead to a loss of efficacy. In such cases, practitioners should consider an increase in the cannabidiol (Epidiolex) dose based on clinical response and tolerability.32
Additionally, pharmacists should screen for the effect of cannabidiol (Epidiolex) on other drugs that are metabolized by or substrates of the following UGT isoforms and CYP isozymes: UGT1A9, UGT2B7, CYP1A2, CYP2B6, CYP2C9, and CYP2C19. Potential interactions should be appropriately managed when these agents are coadministered with cannabidiol (Epidiolex).
Special considerations and populations
Coadministration of cannabidiol (Epidiolex) with clobazam will produce a 3-fold increase in the plasma concentration of N-desmethylclobazam, the active metabolite of clobazam, which is a substrate of CYP2C19. This may produce significant clobazam-related adverse events and cause toxicity, depending on the dose. In this case, practitioners should strongly consider a reduction in the clobazam dose.28 Investigators in 1 study observed a 60% increase in the active metabolite of clobazam (N-desmethylclobazam) when clobazam and cannabidiol (Epidiolex) were coadministered.37
Patient case, continued
TO and her parents should be counseled on the drug-drug interaction between cannabidiol (Epidiolex) and clobazam. The dose of clobazam should be reduced significantly and the patient should be monitored for adverse events. The patient’s parents would like to know what side effects they may see with the addition of clobazam and they question if valproate may be added to their daughter’s medication profile since she has not used this ASD yet.
Coadministration of cannabidiol (Epidiolex) with valproate increases the incidence of liver enzyme elevations. Practitioners must carefully consider administering these medications concomitantly and ensure the patient’s liver enzymes will be monitored more frequently. Ultimately, this may lead to discontinuation or dose reduction of cannabidiol (Epidiolex) and/or valproate.32
Patient case, continued
TO and her parents were counseled about the possibility of ataxia and sedation with clobazam, the interaction between clobazam and cannabidiol (Epidiolex), and the likelihood of increasing concentrations of liver enzymes if valproate were added to the medication profile.
Coadministration of cannabidiol (Epidiolex) with other CNS drugs that cause sedation will increase the risk of sedation. Practitioners should use caution and patients should be counseled about this pharmacodynamic interaction.32
Currently, the background risks of major birth defects and miscarriage are unknown for cannabidiol (Epidiolex).28 Women who are taking cannabidiol (Epidiolex) and are pregnant should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry.32
INDICATIONS, DOSE, AND ADMINISTRATION OF CANNABIDIOL
Cannabidiol (Epidiolex) is indicated for the treatment of seizures related to LGS or DS in patients who are 2 years of age or older. Cannabidiol (Epidiolex) is contraindicated in any patient with a known hypersensitivity to CBD or any of the ingredients (e.g., sesame oil) in cannabidiol (Epidiolex).32
AST, ALT, and total bilirubin levels should be obtained prior to starting treatment with cannabidiol (Epidiolex). Initial dosing for cannabidiol (Epidiolex) is 2.5 mg/kg per dose taken twice daily. After 1 week, the dose may be increased to 5 mg/kg twice daily. The dose may be increased up to 10 mg/kg per dose twice daily on the basis of clinical response. Dose reductions are recommended for patients with moderate to severe hepatic impairment.32
Cannabidiol (Epidiolex) should be dispensed with a calibrated dosing syringe. The medication should be administered at the same time each day, and, since food may affect levels of cannabidiol (Epidiolex), it should be taken consistently with or without food. Cannabidiol (Epidiolex) should be stored upright in its original container at 20°C to 25°C (68-77°F). Excursions between 15°C and 30°C are permitted. Cannabidiol (Epidiolex) should not be refrigerated or frozen. Any remaining cannabidiol (Epidiolex) should be discarded 12 weeks after first opening the original bottle.32 The product contains dehydrated alcohol, although the package insert does not specify the exact amount.
Warnings and precautions
When taking cannabidiol (Epidiolex), patients may have a positive result on a cannabis drug screen. This may be important for patients to consider if they undergo random drug testing related to employment, schooling, or other programs.32
Cannabidiol (Epidiolex) causes dose-related elevations of liver transaminases. This risk is increased in patients concomitantly taking valproate or clobazam. AST, ALT, and total bilirubin levels should be obtained prior to starting cannabidiol (Epidiolex) and 1, 3, and 6 months after treatment initiation.32
All ASDs, including cannabidiol (Epidiolex), are associated with an increased risk of suicidal thoughts or behaviors. Patients should be monitored for worsening depression, suicidal thoughts or actions, or any changes in mood or behavior.32
Cannabidiol (Epidiolex) may cause hypersensitivity reactions. If a patient develops hypersensitivity to cannabidiol (Epidiolex), the medication should be discontinued.32 As with other ASDs, it is important not to abruptly stop this medication unless medically necessary, as it may precipitate seizures.
Distribution information and other management tips
Cannabidiol (Epidiolex) is not currently available for widespread distribution. The product is expected to be available in the fall of 2018.38 Cannabidiol (Epidiolex) will only be distributed through specialty pharmacies and will be classified as a Schedule V controlled substance by the DEA.38 Cannabidiol (Epidiolex) can currently be obtained for FDA-authorized “expanded access” studies, sometimes called compassionate use, or through FDA-authorized clinical trials until widespread distribution begins.39
WHAT SPECIALTY PHARMACISTS NEED TO KNOW ABOUT CANNABIDIOL (EPIDIOLEX)
Marijuana (cannabis) is a Schedule I drug due to its high abuse potential and, because CBD is derived from the marijuana plant, it is also considered a Schedule I drug.36 When cannabidiol (Epidiolex) was approved by the FDA in June of 2018, the DEA decided to reschedule the product41: cannabidiol (Epidiolex) is now in Schedule V, the least restrictive class, which includes other medications such as pregabalin, lacosamide, and codeine preparations.42 The DEA’s decision to reschedule cannabidiol (Epidiolex) applies only to FDA-approved products that contain no more than 0.15% THC due to the low abuse potential of this type of formulation.38 This is an important education point for prescribers and patients who may not understand the difference between prescription cannabidiol (Epidiolex), CBD obtained from dispensaries, and medical marijuana. Even though it is in the least restrictive class, cannabidiol (Epidiolex) will only be available at specialty pharmacies.
Educating patients, caregivers, and other family members is important when dispensing cannabidiol (Epidiolex). In addition to the provision of an in-depth medication guide, patient counseling should be performed by the prescribing practitioner and the specialty pharmacist. Important counseling points include: the correct administration technique for the product, which includes using a dry syringe to draw up the appropriate dose; the need to take the medication at the same time each day; and the recommendation to take it consistently with or without food.
While cannabidiol (Epidiolex) is the first and only FDA-approved prescription CBD product and it will be available in the coming months, the potential communication barrier between practitioners and patients remains a substantial obstacle to its use. Cannabidiol (Epidiolex) is the only FDA-approved cannabis product currently on the market, but patients and providers must consider other cannabis products that are being used for medical purposes. Whether a patient is reaching out to a practitioner to obtain the product as a potential treatment option or a practitioner is making a recommendation to a patient, there are several important considerations from both patient and practitioner viewpoints. From a practitioner’s perspective, if a patient has admitted previous use of marijuana, the practitioner should consider when the patient started using cannabis, how the patient uses it and how often, what other prescription and over-the-counter medications the patient is taking, and the overall expectations the patient has for the product. The patient, on the other hand, may consider asking the practitioner to describe studies that have been done that used cannabis to alleviate symptoms associated with his or her specific condition; to explain the differences between Charlotte’s web and cannabidiol (Epidiolex); to list the potential adverse events or complications and possible interactions that may occur; and to note the costs associated with using the products.
In addition, it is important to educate patients that CBD preparations from dispensaries are not regulated by the same quality standards that FDA-approved medications are required to meet. Therefore, the quality and purity of CBD preparations cannot always be verified, since quality and purity often vary from dispensary to dispensary and even from batch to batch of the same product at a single dispensary.
One of the biggest problems with cannabis use remains the lack of scientific data needed to help practitioners determine whether cannabis should be considered as a treatment option for their patients. Pharmacists should expect that off-label prescribing of cannabidiol (Epidiolex) will soon occur: this may be associated with barriers such as insurance authorization and state or federal laws.
There is a stigma associated with cannabis use that prevents both patients and practitioners from considering cannabis as a potential treatment option. Solutions to this problem include increasing the awareness about how cannabis products can help patients, which would require more clinical trials of specific products in specific disease states, referencing primary literature in educational resources for patients and prescribers, and presentations at educational conferences by clinicians with expertise in using cannabis-based treatments.
Seizure control in patients with DS and LGS remains challenging due to limited efficacy of FDA-approved medications for these conditions and the adverse events and drug-drug interactions associated with several ASDs. Cannabidiol (Epidiolex) has recently been approved by the FDA for DS and LGS; it is a Schedule V medication that will be available at specialty pharmacies. Pharmacists can impact treatment of these rare conditions by educating patients about the benefit of the newly approved product to reduce seizure frequency in DS and LGS and by evaluating for potential drug interactions. It is important to remember that CBD that is obtained from dispensaries is not subject to the same regulatory standards as the FDA-approved cannabidiol product, Epidiolex. The FDA approval of cannabidiol (Epidiolex) was a breakthrough in the medical cannabis world, and further research evaluating cannabinoids in different types of epilepsy is ongoing.
Dr. Bainbridge would like to thank Taylor Y. Ota, Dustin Watt, and Victoria DeJaco, PharmD candidates, and Sarah N. Fischer, PharmD, Clinical Neurology Fellow, for their support while writing this manuscript.
- Escayg A, Goldin AL. Sodium channel SCN1A and epilepsy: mutations and mechanisms. Epilepsia. 2010;51 (9):1650-8.
- Fukuma G, Oguni H, Shirasaka Y, et al. Mutations of neuronal voltage-gated Na+ channel alpha 1 subunit gene SCN1A in core severe myoclonic epilepsy in infancy (SMEI) and in borderline SMEI (SMEB). Epilepsia. 2004;45(2):140-8.
- Wang JW, Kurahashi H, Ishii A, et al. Microchromosomal deletions involving SCN1A and adjacent genes in severe myoclonic epilepsy in infancy. Epilepsia. 2008;49(9):1528-34.
- Zuberi SM, Brunklaus A, Birch R, et al. Genotype-phenotype associations in SCN1A-related epilepsies. Neurology. 2011;76(7):594-600.
- Wu YW, Sullivan J, McDaniel SS, et al. Incidence of Dravet syndrome in a US population. Pediatrics. 2015;136(5):e1310-5.
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