For additional assistance, call the toll-free helpline at 1-833-426-4243 (1-833-GBNGAGE).
Safety and effectiveness of EPIDIOLEX for the treatment of seizures associated with LGS, DS, or TSC have been established in patients 1 year of age and older. The use of EPIDIOLEX in these indications is supported by adequate and well-controlled studies in patients 2 years of age and older with LGS and DS and in patients 1 year of age and older with TSC [see Clinical Studies].
These are not all of the possible side effects of EPIDIOLEX. For more information ask your healthcare provider or pharmacist.
Keep EPIDIOLEX and all medicines out of the reach of children.
(cannabidiol) oral solution 100 mg/mL
Patients with baseline transaminase levels above the ULN had higher rates of transaminase elevations when taking EPIDIOLEX. In the DS and LGS controlled trials (Studies 1, 2, and 3) in patients taking EPIDIOLEX 20 mg/kg/day, the frequency of treatment-emergent ALT elevations greater than 3 times the ULN was 30% when ALT was above the ULN at baseline, compared to 12% when ALT was within the normal range at baseline. No patients taking EPIDIOLEX 10 mg/kg/day experienced ALT elevations greater than 3 times the ULN when ALT was above the ULN at baseline, compared with 2% of patients in whom ALT was within the normal range at baseline. In the TSC controlled trial (Study 4) in patients taking EPIDIOLEX 25 mg/kg/day, the frequency of treatment-emergent ALT elevations greater than 3 and 5 times the ULN were both 11% when ALT was above the ULN at baseline, compared to 12% and 6%, respectively, when ALT was within the normal range at baseline.
Administration of cannabidiol (subcutaneous doses of 0 or 15 mg/kg on Postnatal Days (PNDs) 4-6 followed by oral administration of 0, 100, 150, or 250 mg/kg on PNDs 7-77) to juvenile rats for 10 weeks resulted in increased body weight, delayed male sexual maturation, neurobehavioral effects (decreased locomotor activity and auditory startle habituation), increased bone mineral density, and liver hepatocyte vacuolation. A no-effect dose was not established. The lowest dose causing developmental toxicity in juvenile rats (15 sc/100 po mg/kg) was associated with cannabidiol exposures (AUC) approximately 15 and 8 times that in humans at the RHDs of 20 and 25 mg/kg/day, respectively.
Coadministration of EPIDIOLEX with midazolam (a sensitive CYP3A4 substrate) did not result in changes in plasma concentrations of midazolam compared to midazolam administered alone.
Coadministration of EPIDIOLEX (750 or 1500 mg) with a high-fat/high-calorie meal increased Cmax by 5-fold, AUC by 4-fold, and reduced the total variability, compared with the fasted state in healthy volunteers [see DOSAGE AND ADMINISTRATION]. Coadministration of EPIDIOLEX with a low-fat/lowcalorie meal increased Cmax and AUC by 4-fold and 3-fold, respectively. Furthermore, coadministration of EPIDIOLEX with bovine milk increased exposure by approximately 3-fold for Cmax and 2.5-fold for AUC. Coadministration of EPIDIOLEX with alcohol also caused increased exposure to cannabidiol, with 93% increased Cmax and 63% greater AUC.
CBD is metabolized primarily by cytochrome P450 (CYP) 2C19 and CYP3A4 and can inhibit the CYP2C and CYP3A4 families of isoenzymes 1 . The highest plasma concentration of CBD occurs within 2 to 3 hours of exposure to Epidiolex, and the major circulating metabolite of this compound is 7-COOH-CBD, and 6-OH-CBD is a relatively minor metabolite 1 . Exposure to CBD (that is, in the form of Epidiolex) and its metabolites is linearly related to dose over a range of 5 to 20 mg/kg per day with high inter-subject variability in pharmacokinetics, likely related to concomitant medication interactions with the cytochrome P450 system, genetic variation in CYP isoenzymes, food effects, or tissue distribution 1 . At doses ranging between 5 and 20 mg/kg per day, Epidiolex led to significant pharmacokinetic interactions with clobazam (CLB), resulting in elevations of N-desmethylclobazam, a long-acting active metabolite of this drug, by up to 60% via inhibition of cytochrome P450 2C19 1, 22, 24 . This interaction may contribute to its efficacy as adjunctive therapy and also to its associated side effect of sedation, which resolved with reduction of CLB dose in RCTs 22 . The interaction between CLB and CBD (within Epidiolex) is thought to be bidirectional, and clobazam also increases levels of 7-OH-CBD, an active metabolite 27, 28 . No obvious pharmacokinetic effect was seen for several other anti-seizure drugs used in combination with Epidiolex, including valproate, stiripentol, clonazepam, and levetiracetam 1, 29 . Given that elevated aminotransferase concentrations were commonly seen with co-administration of Epidiolex and valproate without a significant increase in serum valproate drug levels, a pharmacodynamic rather than pharmacokinetic interaction has been proposed to exist between these two compounds, presumably resulting in transient metabolic stress on the liver and resulting transaminase (alanine transaminase/aspartate transaminase) elevations 1, 23, 24 . However, the exact mechanism by which Epidiolex causes elevation in liver enzymes remains under further study. Additional studies have also shown increases in serum levels of eslicarbazepine, rufinamide, and zonisamide with adjunctive Epidiolex therapy 29 . With regard to topiramate, studies show opposing results of no interaction versus increased serum topiramate concentrations with the addition of Epidiolex 1, 29 . Concomitant administration of Epidiolex with warfarin showed a non-linear increase in international normalized ratio, requiring warfarin dose to be reduced by 30%, likely because of pharmacokinetic interactions involving CYP2C9 and CYP3A4, although this was reported in only one case report to date 30 . The major RCTs using Epidiolex excluded patients who had recently started treatment with felbamate or vigabatrin (within 12 months) and thus the effect of Epidiolex in this setting requires additional data 23– 25 .
More specifically, with regard to serious adverse effects, status epilepticus was reported in similar numbers for patients receiving placebo and Epidiolex 23, 25 . Increases in liver aminotransferase concentrations, however, were seen in patients taking Epidiolex (5–20 in the Lennox–Gastaut trials and 12 in the Dravet trial) 23– 25 versus one patient taking placebo in both the Dravet 23 and one Lennox–Gastaut 25 study. Again, a dose-dependent effect was seen with 11 patients in the 20 mg/kg per day Epidiolex group versus two patients in the 10 mg/kg per day group 7 . In 79 to 80% of cases where elevated aminotransferase concentrations were greater than three times the upper limit of normal, patients were also taking concomitant valproate 24, 25 . In all such cases, liver enzyme levels either resolved spontaneously after Epidiolex dose was decreased/stopped or the dose of another anti-seizure medication was decreased 23– 25 . Additionally, because no significant elevation of bilirubin (greater than two times the upper limit of normal) was associated with this finding, drug-induced liver injury was not seen 1, 24, 25 . Thrombocytopenia was also observed in patients taking both Epidiolex and valproate (3% mild to moderate) and was severe in 1% of cases with resolution after valproate was discontinued 22 .
Similarly, for patients with Lennox–Gastaut syndrome, the addition of Epidiolex to a stable regimen at doses of both 10 mg/kg per day and 20 mg/kg per day resulted in significant median percentage decreases in drop seizures (atonic, tonic, or tonic-clonic) of 41.9% for 20 mg/kg per day and 37.2% for 10 mg/kg per day versus 17% for the placebo group ( P = 0.005 and P = 0.002, respectively) 24 . Drop-seizure reduction of at least 50% was again significantly higher in each treatment group (39% for 20 mg/kg per day and 36% for 10 mg/kg per day) compared with the placebo group (14%) ( P <0.001 for 20 mg/kg per day and P = 0.003 for 10 mg/kg per day). A dose response was seen with 25% of patients achieving a 75% reduction in drop-seizure frequency when treated with 20 mg/kg per day Epidiolex versus 11% when treated with 10 mg/kg per day of Epidiolex versus 3% receiving placebo. Median reduction of combined seizures types (convulsive and non-convulsive) was again higher in the treatment groups (38.4%, P = 0.009 for 20 mg/kg per day and 36.4%, P = 0.002 for 10 mg/kg per day) versus placebo (18.5%). Similarly, improvement in overall condition (using the CGIC scale) was significantly higher in the treatment versus placebo group ( P = 0.04 for 20 mg/kg per day and P = 0.002 for 10 mg/kg per day); interestingly, a higher percentage of patients reported improvement from baseline in the 10 mg/kg per day group (66%) versus the 20 mg/kg per day group (57%) 24 .
Medically refractory epilepsy remains an area of intense clinical and scientific interest since a significant porportion of patients continue to suffer from debilitating seizures despite available therapies. In this setting, recent studies have focused on assessing the benefits of cannabidiol (CBD)-enriched cannabis, a plant based product without psychoactive properties which has been shown to decrease seizure frequency in animal models. More recently, several randomized controlled and open label trials have studied the effects of Epidiolex, a 99% pure oral CBD extract, on patients with refractory epilepsy. This in turn has led to the FDA approval of and more recently, to the Drug Enforcement Administration’s placement of Epidiolex into schedule V of the Controlled Substances Act (CSA). In this review, we summarize the major findings of several recent large-scale studies using this product with a focus on its adverse effects.
The above results are encouraging and support prior preliminary findings suggesting that CBD products may indeed be a highly effective therapy for treatment-refractory epilepsy. However, the above studies and others have also demonstrated several important adverse effects associated with Epidiolex, which must also be considered as it becomes more widely used.
Three recent randomized, multi-center, double-blinded, placebo-controlled trials 23– 25 using Epidiolex have been conducted and published in two epileptic syndromes primarily of childhood: the Dravet (one study) and Lennox–Gastaut (two studies) syndromes. Patients between the ages of 2 to 18 years for Dravet 23 and 2 to 55 years for Lennox–Gastaut 24, 25 with treatment-resistant epilepsy were recruited. A randomized, double-blind, placebo-controlled pilot trial was also initially completed in patients with Dravet syndrome to arrive at a target dose of 20 mg/kg per day for the phase 3 trials described above 1 . For all three multi-center studies, a 2-week titration period was followed by 12 weeks of treatment at the target dose for a total of 14 weeks. Enrolled patients maintained a stable medication regimen (median of three anti-seizure drugs). Ketogenic diet and vagal nerve stimulator (when used) were kept stable for at least 4 weeks prior to study onset. Epidiolex target doses were 10 mg/kg given twice a day (20 mg/kg per day) for the Dravet study 23 and one Lennox–Gastaut study 25 . The target doses for the additional study of Lennox–Gastaut were 5 and 10 mg/kg twice daily (10 and 20 mg/kg per day) in two treatment groups 24 .
Cannabis, derived from the plant Cannabis sativa, Cannabis indica, or Cannabis ruderalis, contains at least 70 known cannabinoids, including seven cannabidiolic acids and 11 tetrahydrocannabinolic acids 4 . Tetrahydrocannabinol (THC) is a high-affinity, partial agonist of cannabinoid type 1 receptor (CB1R) and is primarily responsible for the psychotropic effects of cannabis 5 . Though found mainly in neuron terminals of the basal ganglia, cerebellum, hippocampus, hypothalamus, and limbic system 6 , CB1R is also present in the peripheral nervous system, thyroid, liver, uterus, and testes 7 . Studies have shown that endogenous cannabinoids (anandamide and 2-arachidonoylglycerol) act on presynaptic CB1 receptors to downregulate both excitatory and inhibitory neurotransmitter release and thereby prevent excess neuronal activity 7 . In contrast, exogenous THC, a partial CB1R agonist, is less selective and may inadvertently increase the release of neurotransmitters in certain brain regions 7 , possibly giving rise to its reported pro-convulsant properties 8 . The endocannabinoid system also contains cannabinoid type 2 receptor (CB2R), found mainly within immune cells but also seen in the spleen and the gastrointestinal tract 7 and on microglial cells within the central nervous system for which THC has lower affinity. Whereas studies have shown endogenous cannabinoids to enhance immune response via activation of CB2R, exogenous cannabinoids seem to have the reverse effect 6 .
Since up to 35% of patients with refractory epilepsy have inadequate seizure control despite currently available treatments, there has been growing interest in the use of cannabis-derived products for the treatment of medically refractory epilepsy over the past 10 years 1, 2 . This need, combined with recent media attention focused on the benefits of non-purified cannabidiol (CBD)-enriched cannabis in the treatment of refractory epilepsy 3 , has spurred a series of clinical trials in an attempt to more clearly understand the risks and benefits associated with this treatment.
The third completed phase 3 trial was a comparison of 20 mg/kg per day with placebo in patients with Lennox–Gastaut syndrome 25 . The primary efficacy outcome of median reduction in drop seizures was significantly in favor of Epidiolex with 43.9% versus 21.8% for placebo ( P = 0.0135). The percentages achieving 50% drop-seizure reduction (44% for treatment versus 24% for placebo, P = 0.0043), median total seizure reduction (41.2% for treatment versus 13.7% for placebo, P = 0.0005), and improvement in the CGIC scale (58% for treatment versus 34% for placebo, P = 0.0012) were also significantly improved with 20 mg/kg per day of Epidiolex compared with placebo 25 .