Consensus panel recommendations for the optimization of EPIDIOLEX® treatment for seizures associated with Lennox–Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex

Abstract

Following the approval of Epidiolex® (cannabidiol; CBD) for the treatment of seizures associated with Lennox–Gastaut syndrome (LGS), Dravet syndrome (DS), and tuberous sclerosis complex (TSC), healthcare professionals (HCPs) have had substantial experience in treating patients with Epidiolex. However, confusion still remains among HCPs, caregivers, and patients regarding dosing, drug interactions, safety monitoring, and differentiation between Epidiolex and nonapproved CBD products. To establish consensus recommendations for Epidiolex treatment optimization in LGS, DS, and TSC, a panel of seven HCPs with expertise in epilepsy was convened. Panelists participated in a premeeting survey based on a literature review of Epidiolex for the treatment of LGS, DS, and TSC, and survey responses were compiled for discussion. A modified Delphi method was used to assess agreement among panelists regarding recommendation statements following two rounds of discussion. Panelists identified two broad themes – overcoming barriers to initiation and optimization of treatment for seizures associated with LGS, DS, and TSC – for consensus guidelines. Accurate identification of patients with these rare epilepsies is critical for optimization of Epidiolex treatment. Providers should differentiate Epidiolex from nonapproved CBD products and set expectations for the therapeutic effect and safety/tolerability of Epidiolex. Initial target dose and titration rate should be individualized by baseline variables, prior response to antiseizure medications, and therapeutic goals. Awareness of strategies to manage adverse events and concomitant medications, including drug–drug interactions, is critical. Tracking response to the maximum tolerated dose is an important measure of effectiveness. These consensus recommendations provide real‐world experience from neurology HCPs with experience in prescribing Epidiolex and can inform optimal use of Epidiolex for the treatment of seizures associated with LGS, DS, and TSC.

Plain language summary

Epidiolex® (cannabidiol) is approved for treating seizures in Lennox–Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex. Although healthcare professionals have experience in treating patients with Epidiolex, there is a need for better understanding of dosing, drug interactions, and safety of this drug. Therefore, a group of epilepsy experts developed guidelines for best practices in Epidiolex treatment. Two main areas were identified: overcoming barriers to starting Epidiolex and considerations related to Epidiolex dosing. Within these areas, topics, including correct disease identification, managing adverse events, and determining individualized dose, were discussed. These guidelines provide real‐world experience to inform optimal Epidiolex use.

Key points.

• Epidiolex is approved for Lennox–Gastaut syndrome (LGS), Dravet syndrome (DS), and tuberous sclerosis complex (TSC)‐associated seizures.

• Uncertainty remains regarding Epidiolex dosing, drug interactions, safety monitoring, and differentiation versus unapproved products.

• A panel of 7 epilepsy experts developed recommendations based on published data and real‐world experience via a modified Delphi method.

• Panelists identified and addressed 2 areas of need – overcoming barriers to Epidiolex initiation and Epidiolex treatment optimization.

• These recommendations can inform optimal Epidiolex use for seizures associated with LGS, DS, and TSC.

1. INTRODUCTION

The pharmaceutical formulation of plant‐derived, highly purified cannabidiol (CBD; Epidiolex®) is approved in the United States (US) for the treatment of seizures associated with Lennox–Gastaut syndrome (LGS), Dravet syndrome (DS), and tuberous sclerosis complex (TSC) in patients ≥1 year of age. ¹ In the European Union and United Kingdom, Epidyolex® is approved for the treatment of LGS, DS, and TSC (in conjunction with clobazam [CLB] for LGS and DS) in patients ≥2 years of age. ² These approvals were based on results from pivotal, randomized phase 3 trials, in which Epidiolex treatment led to reduced seizure frequency and had an acceptable safety profile. ³ , ⁴ , ⁵ , ⁶

Healthcare professionals (HCPs) have had substantial experience with Epidiolex dosing and adverse event (AE) management since initial approval of the drug in 2018. However, confusion still remains among HCPs, including neurologists, nurse practitioners, physician assistants, pharmacists, family practitioners/generalists, group home providers, and developmental disability care providers, regarding dosing, drug interactions, safety monitoring, and differentiation between Epidiolex and nonapproved CBD products. This reflects an unmet need among HCPs for consensus recommendations on Epidiolex treatment optimization in patients with LGS, DS, and TSC. Consensus recommendations for the treatment of LGS and DS with Epidiolex were previously developed by five neurologists from Spain. ⁷ These recommendations included slow dose escalation, treatment continuation for ≥6 months if tolerated, and reduction in concomitant antiseizure medications (ASMs) if AEs arise. The term “Epidiolex” is used herein to distinguish the approved pharmaceutical product from unregulated, nonapproved CBD‐containing products, which will be referred to as “CBD.”

For our analysis, a multidisciplinary panel of neurology HCPs with experience in prescribing Epidiolex was convened to establish consensus recommendations for dose optimization and response assessment in the treatment of seizures associated with LGS, DS, and TSC in the US.

2. METHODS

2.1. Literature review

A literature review was conducted to summarize published information on Epidiolex for the treatment of seizures associated with LGS, DS, or TSC and to guide the generation of recommendation topics during advisory panel meetings (see Appendix S1 for additional details).

2.2. Advisory panel and consensus generation

The advisory panel included seven individuals with clinical and/or research expertise in epilepsy (D.E. Burdette, B.E. Gidal, A. Hyslop, P.E. McGoldrick, E.A. Thiele, J.P. Valeriano, and R. Wechsler). Informed consent and ethical approval were not applicable. Panelists completed a premeeting survey about recommendation topics based on the literature review. Survey responses were used to generate recommendations about Epidiolex treatment optimization at the first consensus panel meeting, held on November 19, 2022. During the second panel meeting, held on January 11, 2023, advisors discussed and revised recommendations until a consensus was reached on all statements. Recommendations were developed for two key topics: (1) overcoming barriers to initiation of Epidiolex; and (2) Epidiolex dosing for seizures associated with LGS, DS, and TSC (Box 1). All seven advisors participated in the development of this report, which presents the final consensus recommendations.

BOX 1. Recommendations for the optimization of Epidiolex for seizures associated with LGS, DS, and TSC.

Overcoming barriers to Epidiolex initiation

Identifying patients with LGS History of multiple drug‐resistant seizures Some degree of cognitive impairment EEG SSW activity Review patient history and utilize REST‐LGS for identification of potential LGS Identifying patients with DS Reference: 2022 International Consensus on Diagnosis and Management of DS 22 Genetic testing recommended as SOC* Identifying patients with TSC Reference: 2021 Updated International TSC Diagnostic Criteria 13 Conduct detailed skin examination Differentiating Epidiolex from non‐FDA‐approved CBD products Inform patients and their families that Epidiolex is approved and evaluated in RCTs Setting expectations for therapeutic effect and safety/tolerability of Epidiolex Proven efficacy in seizure reduction and anecdotal behavior/mood improvement

Epidiolex dosing for seizures associated with LGS, DS, and TSC

6 Initiation, titration, and maintenance of Epidiolex Inform patients that response to Epidiolex is individualized Determine initial target dose and titration rate based on patient baseline variables, prior response to ASMs, and therapeutic goals 7 Food effects Epidiolex should be taken with or without food consistently, preferably with food, particularly high‐fat food Epidiolex can be taken while on dietary therapies 8 Managing AEs associated with Epidiolex 8a Gastrointestinal AEs No proactive changes to bowel regimen needed Diarrhea mitigation: slower dose titration; diet/concomitant medication adjustments; Epidiolex dose reduction if other efforts fail 8b Liver function AEs Monitor liver function: pre‐Epidiolex initiation, and 1, 3, and 6 mos post‐initiation Periodic LFTs thereafter or as clinically indicated 8c Sedation AEs Initiate sedating medications at lower dose with slow titration when added to Epidiolex Administer either a higher evening dose of Epidiolex or CLB (or both), or a single evening dose of Epidiolex QD if daytime sedation is a concern 9 Managing Epidiolex and concomitant medications 9a Epidiolex and CLB If tolerated, maintain CLB without immediate dose adjustment when adding Epidiolex If patients experience sedation, reduce CLB dose when adding Epidiolex Consider low‐dose CLB in patients who do not obtain optimal benefit from Epidiolex 9b Epidiolex and VPA When adding Epidiolex to VPA or vice versa, monitor LFTs upon drug initiation and at 1, 3, and 6 mos after initiation If LFTs are persistently elevated or patient is symptomatic while on VPA, and if patient failed VPA, gradually decrease or eliminate VPA; reduce Epidiolex dose if elevated LFTs not resolved If VPA is added to Epidiolex, the same safety monitoring is recommended 9c Epidiolex and oral mTOR inhibitors Epidiolex added to oral mTOR inhibitor: monitor mTOR inhibitor levels, reduce dosage Oral mTOR inhibitor added to Epidiolex: initiate mTOR inhibitor at lower dose, titrate slowly, and monitor mTOR inhibitor levels When discontinuing Epidiolex, consider increasing mTOR inhibitor dose 9d Epidiolex and other concomitant medications Consider potential DDIs between Epidiolex and other concomitant medications Consider increasing Epidiolex dosage up to 2‐fold when coadministered with a strong CYP3A4 and/or CYP2C19 inducer Reduce dosage of substrates of UGT1A9, UGT2B7, CYP1A2, CYP2C8, and CYP2C9 if patients experience AEs during coadministration with Epidiolex 10 Determining whether the optimal dose is reached Increase Epidiolex dose as tolerated; consider response to maximum tolerated dose as effectiveness measure Add other ASMs if Epidiolex is not optimally effective at maximum tolerated dose; medications should not be added when titrating Epidiolex 11 Assessing outcomes Assess outcomes during each patient encounter Primary efficacy outcome: reduction in seizure burden Secondary efficacy outcomes: use of rescue medications, emergency room visits, and days missed from school/work Effects on total medication regimen, mood, and behavior should also be assessed 12 Discontinuation of Epidiolex Gradually taper patients off Epidiolex If the situation is emergent or patient is having intolerable AEs, discontinue Epidiolex without tapering Concomitant medications may need adjustment when discontinuing Epidiolex due to PK/PD interactions

*SCNA1 variants are not required for diagnosis.

Abbreviations: AE, adverse event; ASM, antiseizure medication; CBD, cannabidiol; CLB, clobazam; DDI, drug–drug interaction; DS, Dravet syndrome; EEG, electroencephalogram; FDA, Food and Drug Administration; LFT, liver function test; LGS, Lennox–Gastaut syndrome; mos, months; mTOR, mammalian target of rapamycin; PD, pharmacodynamic; PK, pharmacokinetic; QD, once daily; RCT, randomized controlled trial; REST‐LGS, Refractory Epilepsy Screening Tool for LGS; SOC, standard of care; SSW, slow‐spike–wave; TSC, tuberous sclerosis complex; VPA, valproate.

A modified Delphi method ⁸ was used to assess agreement among panelists regarding the recommendation statements. Advisors were asked to rate their level of agreement with each statement on a scale from 0 (not at all) to 4.0 (very much). Following the first meeting, agreement scores ranged from 3.0 to 4.0. After the second meeting, the panel achieved a high level of consensus (average agreement rating of 4.0) for each revised recommendation statement.

3. DISCUSSION/OBSERVATIONS

3.1. Overcoming barriers to initiation of Epidiolex

3.1.1. Identifying patients with LGS, DS, and TSC

A major barrier to initiating Epidiolex treatment is the accurate diagnosis of LGS, DS, and TSC in patients with treatment‐resistant epilepsy. Characteristics of LGS and DS often vary over time, making diagnosis particularly challenging in adults, and TSC has a highly heterogeneous presentation that can delay diagnosis. ⁹ , ¹⁰ , ¹¹ , ¹² , ¹³

3.1.2. Identifying patients with LGS

Recommendation #1: Classically, LGS diagnosis is based on a triad of symptoms: multiple seizure types, cognitive impairment, and slow‐spike–wave (SSW) activity on an electroencephalogram (EEG). ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷ Of these, the panelists recommend that the former two are the most important diagnostic criteria, as EEG activity can improve over time and may not be present in adults with the LGS phenotype. ¹⁰ Additionally, generalized paroxysmal fast activity in sleep may be more specific to LGS than SSW activity. Thus, the absence of EEG abnormalities should not exclude LGS diagnosis.

The panel recommends a review of all historical data, including EEGs and seizure semiology, which are more informative than single data points. Unlike many other syndromic epilepsies, LGS is not associated with a specific genetic abnormality, although genetic testing may identify the underlying etiology of LGS. A history of infantile spasms can be a precursor to LGS development, ¹⁸ and seizure semiology can help differentiate LGS from epilepsy with myoclonic‐atonic seizures. ¹⁹

There are different challenges associated with LGS diagnosis in pediatric and adult patients. Delayed LGS diagnosis in pediatric patients is common, and patients may be older at diagnosis. ¹⁵ , ²⁰ LGS is more challenging to diagnose in adults because data on seizure onset in early childhood and prior EEGs are often not available. The Refractory Epilepsy Screening Tool for LGS (REST‐LGS) comprises eight criteria (four major, four minor) that can help identify patients with potential LGS. ²¹ In a preliminary validation study of patients with drug‐resistant epilepsy or confirmed LGS, most patients with LGS met three major and two to three minor criteria. ²¹

3.1.3. Identifying patients with DS

Recommendation #2: The 2022 International Consensus on Diagnosis and Management of DS ²² should be referenced for current DS diagnostic criteria. The patient's clinical features and, when available, corroborative childhood history can aid in DS diagnosis.

The accuracy of pediatric DS diagnosis has improved with increased awareness resulting from DS clinical trials and increasingly accessible genetic testing. Abnormal gait and movement may occur in some patients with DS, ²³ , ²⁴ but is not a required feature of the disease phenotype.

DS features typical in childhood may be less apparent in adulthood. ¹¹ Diagnosing adults who do not display typical myoclonic seizures can be challenging, particularly if their pediatric seizure history is incomplete or missing. ²⁵ Given the broad phenotypic spectrum of DS, genetic testing, though challenging, should be a standard of care in all patients with developmental epileptic encephalopathies. Pathogenic SCN1A variants are common but not required for a DS diagnosis, and non‐SCN1A gene mutations may present with a DS phenotype. ²⁶ , ²⁷ , ²⁸ There is no evidence that gene variants impact clinical response to Epidiolex.

3.1.4. Identifying patients with TSC

Recommendation #3: The 2021 Updated International TSC Diagnostic Criteria ¹³ should be referenced for current TSC diagnostic criteria. Unless access is limited, patients with TSC should be treated in a TSC clinic. Providers should conduct a detailed skin examination because skin lesions are often missed, are a major defining feature of TSC, and are apparent before other test results are available.

3.1.5. Differentiating Epidiolex from non‐Food and Drug Administration (FDA)–approved CBD products

Insufficient knowledge among patients and caregivers about differences between prescription and nonapproved CBD products may hinder Epidiolex treatment initiation.

Recommendation #4: Patients and caregivers should be informed that FDA‐approved Epidiolex is the only CBD product that has been rigorously evaluated in controlled trials. In contrast, substantial variability in cannabinoid content has been noted in over‐the‐counter, nonapproved CBD products. ²⁹ , ³⁰ , ³¹ , ³² , ³³ , ³⁴ Providers should inform patients that non‐FDA‐approved CBD products are noninterchangeable with Epidiolex and that a previous lack of efficacy with non‐FDA‐approved CBD does not predict treatment response to Epidiolex.

Providers should explain that nonapproved CBD products are often available at much lower concentrations than Epidiolex. Some patients may believe that nonapproved CBD products are effective even at inadequate dosing levels and may select them based on volume instead of milligrams. An additive psychoactive and cognitive impairment effect has been reported when combining CBD and Δ‐9‐tetrahydrocannabinol (THC) in healthy adults. ³⁵ The combination of CBD and Δ‐9‐THC has also been shown to inhibit the activity of several cytochrome P450 enzymes in vivo. ³⁶

Geographic differences exist in expectations of nonapproved CBD products and FDA‐approved CBD. For instance, experience with dispensary cannabis, which varies by geographical location, influences individuals' sentiments about the effects of CBD. ³⁷ Since the side effect profile of Epidiolex has been well established through adequately controlled trials, ³ , ⁴ , ⁵ , ⁶ there can be a misconception that Epidiolex has more side effects than nonapproved products that have not been rigorously evaluated and that are commonly used at subtherapeutic doses.

3.1.6. Setting expectations for effectiveness and safety/tolerability of Epidiolex

Recently, unsubstantiated benefits of nonapproved CBD products for various health conditions have been popularized via consumer‐focused marketing, ³⁸ , ³⁹ , ⁴⁰ which can lead to unrealistic expectations for outcomes with Epidiolex treatment. Thus, HCPs should set accurate and realistic expectations with patients before initiating Epidiolex therapy.

Recommendation #5: Providers should emphasize that the effect of Epidiolex on seizures has been demonstrated in clinical trials; however, nonseizure benefits have also been reported anecdotally. In a recent survey, a substantial proportion of caregivers of patients with LGS or DS reported improvements in emotional functioning, cognition and executive function, and language and communication following Epidiolex treatment. ⁴¹

3.2. Epidiolex dosing for seizures associated with LGS, DS, and TSC

Epidiolex has a broad dose range; therefore, the optimum dose should be based on the relative risks and benefits for each patient. The efficacy of a 10–25 mg/kg/day dose range has been demonstrated, and safety data are available for doses up to 50 mg/kg/day. ⁵ , ⁶ To improve tolerability, it is advisable to start with a low dose (2.5 mg/kg twice daily) and titrate up slowly to a maximum recommended maintenance dosage of 20 mg/kg/day for LGS and DS, and 25 mg/kg/day for TSC. ¹ If tolerated, an adequate trial of Epidiolex should involve dosing to the minimum recommended dose of 10 mg/kg/day, as efficacy of lower doses has not been established in clinical trials.

3.2.1. Initiation, titration, and maintenance of Epidiolex

Recommendation #6: Patients should be informed that response to Epidiolex is individualized ⁴² , ⁴³ , ⁴⁴ ; while the onset of therapeutic effect may be experienced as early as 2 weeks, optimization of the dose may take 3–4 months. Time to therapeutic effect can vary by patient characteristics, such as seizure frequency and use of concomitant ASMs. Providers should determine the initial target dose and titration rate based on patient baseline variables, prior response to ASMs, and mutually agreed‐upon therapeutic goals. Response to Epidiolex should also guide titration rate.

Safety/tolerability data from the Epidiolex clinical trials should be reviewed, emphasizing that the drug is generally well tolerated and focusing on the most common side effects related to Epidiolex ¹ (see Recommendations #8a–#8c). Anecdotally, while some patients hesitate to report side effects to avoid discontinuing Epidiolex, others misattribute side effects to Epidiolex that may not be treatment related.

Panelists expressed concerns about providers stopping Epidiolex titration before reaching the minimum recommended dose. Although some patients may respond to doses lower than those in the trials, patients should be encouraged not to discontinue Epidiolex due to lack of efficacy if the drug has not yet been given a sufficient trial at the maximum tolerated dose. Epidiolex prescribing information can be used as guidance to adjust dosing for patients with hepatic impairment. ¹ No dose adjustment is required on the basis of renal function.

3.2.2. Food effects

The food effect on Epidiolex exposure is well established. Epidiolex systemic bioavailability has been shown to increase by ≈4‐fold when taken with high‐fat meals and by ≈3‐fold with low‐fat meals or whole milk. ⁴⁵ , ⁴⁶

Recommendation #7: Epidiolex should be taken with or without food as consistently as possible, and can be taken while on dietary therapies, including the ketogenic diet. Patients should be encouraged to consistently take Epidiolex with food, particularly food that is higher in fat content, to optimize absorption and bioavailability. ⁴⁵ When assessing patient response, clinicians should consider the marked differences in Epidiolex absorption when given with food. Dose adjustment is not needed when Epidiolex is administered through a feeding tube.

3.2.3. Managing AEs associated with Epidiolex

The most common AEs in patients treated with Epidiolex in clinical trials included somnolence and diarrhea. ³ , ⁴ , ⁵ Elevations in liver aminotransferase concentrations >3× the upper limit of normal (ULN) occurred more frequently among patients on Epidiolex than placebo; the majority of these patients were receiving concomitant valproate (VPA). ³ , ⁴ , ⁵

Recommendation #8a (gastrointestinal AEs): The bowel regimen should not be proactively changed in patients initiating Epidiolex, because diarrhea is experienced by a minority of patients. ¹ Diarrhea can be mitigated by reduction of laxative medications, slower dose titration, initiation of a diet known to improve diarrhea symptoms, and dosing Epidiolex multiple times per day instead of twice daily. If all efforts to improve diarrhea fail, the Epidiolex dose can be reduced.

Recommendation #8b (liver function AEs): When initiating Epidiolex, liver function (aspartate aminotransferase, alanine aminotransferase [ALT], bilirubin levels) should be monitored prior to the first dose and at 1, 3, and 6 months after initiation. ¹ Subsequent liver function tests (LFTs) should be performed periodically thereafter or as clinically indicated and may be particularly important when Epidiolex is used in combination with VPA. ¹ In clinical trials, the incidence of ALT elevations >3× ULN was as high as 30% in patients taking concomitant VPA and CLB, in comparison with up to 6% (up to 3% in LGS or DS clinical trials) in patients not taking these medications. ¹ For patients with elevated LFTs taking Epidiolex and VPA, refer to Recommendation #9b. No severe cases of drug‐induced liver injury/hepatotoxicity related to Epidiolex have been reported, whereas the potential for hepatotoxicity associated with nonapproved CBD is unknown.

Recommendation #8c (sedation AEs): Sedation may occur with Epidiolex regardless of concomitant medication but is more common when used with CLB. ¹ Sedation may resolve within a few weeks without dose adjustment. Any sedating medications added to Epidiolex should be started at a lower dose and titrated slowly; dose reduction of other medications that may contribute to sedation can be considered. If daytime sedation is a concern in patients receiving Epidiolex and CLB, providers can consider administering either a higher dose of Epidiolex and/or CLB in the evening, or a single dose of Epidiolex and/or CLB once daily (QD) in the evening. Among healthy volunteers, the half‐life of Epidiolex in plasma is 56–61 h after twice‐daily dosing for 7 days. ¹

Anecdotally, Epidiolex 10–20 mg/kg/day given as a single dose in the evening may mitigate daytime somnolence and sedation. Once‐daily dosing in the evening with high‐fat content food may also improve sleep onset among pediatric patients at night and alleviate daytime sedation. However, there have been no published clinical studies characterizing the efficacy and safety of QD dosing with Epidiolex.

3.2.4. Managing Epidiolex and concomitant medications

Epidiolex can inhibit numerous drug‐metabolizing enzymes, ⁴⁷ including CYP2C9 and CYP2C19, potentially affecting the efficacy and tolerability of other ASMs and other non‐ASM medications. Drug–drug interactions (DDIs) have been reported between Epidiolex and several other ASMs, including CLB, VPA, and mammalian target of rapamycin (mTOR) inhibitors. ¹ , ⁴⁸

Recommendation #9a (Epidiolex and CLB): There is evidence of bidirectional DDIs between CBD and CLB, ⁴⁷ whereby exposure of the active metabolite of each drug (7‐OH‐CBD and N‐desmethylclobazam, respectively) is increased, ⁴⁷ , ⁴⁹ resulting in an additive effect on seizure reductions. ⁵ The increase in N‐desmethylclobazam may increase the risk of CLB‐related adverse reactions, in which case a reduction in CLB dosage can be considered. Of note, CBD–CLB interaction may be less marked or absent in the presence of stiripentol, and levels of N‐desmethylclobazam have been shown not to increase in some patients taking stiripentol. ⁵⁰ CBD treatment can also improve seizure outcomes independently of CLB. When added to an existing antiepileptic regimen, CBD has been associated with a higher rate of seizure response versus placebo in patients with DS and LGS regardless of concomitant CLB use. ⁵¹ These antiseizure effects occurred with CBD doses of both 10 and 20 mg/kg/day. Providers can consider reducing CLB upon initiation of Epidiolex, particularly if the patient is already experiencing sedation or receiving the maximum tolerated dose of CLB. For additional information on sedation with Epidiolex and concomitant medications, refer to Recommendation #8c. Additional considerations for patients receiving concomitant Epidiolex and CLB are detailed in Box 1.

Recommendation #9b (Epidiolex and VPA): When adding Epidiolex to VPA or VPA to Epidiolex, LFTs should be monitored upon drug initiation and at 1, 3, and 6 months after initiation. LFTs may normalize in some patients, typically within the first or second month of therapy, without VPA dose adjustment. If LFTs are persistently elevated or the patient is symptomatic while on VPA, and if the patient already failed VPA, VPA should be gradually decreased or eliminated if possible. If abnormal LFTs are not resolved, the Epidiolex dose can be reduced. If VPA is added to a patient already taking Epidiolex, the same safety monitoring is recommended. For patients taking Epidiolex and VPA concomitantly, no drug level monitoring is required, and discontinuing either drug does not require dose adjustment of the other drug. Although the mechanism of abnormal LFT with concomitant Epidiolex and VPA is not known, it does not appear to be related to changes in VPA. ⁵²

Recommendation #9c (Epidiolex and oral mTOR inhibitors): In patients taking both Epidiolex and an oral mTOR inhibitor, mTOR inhibitor levels should be monitored, because Epidiolex has been shown to increase serum levels of oral mTOR inhibitors (e.g., everolimus and sirolimus). ⁴⁸ , ⁵³ Additional considerations for patients receiving concomitant Epidiolex and an oral mTOR inhibitor are detailed in Box 1.

Recommendation #9d (Epidiolex and other concomitant medications): While the clinical implications of DDIs are known for the aforementioned ASMs, they have been less well studied for other drugs commonly used to treat epilepsy or associated comorbidities.

Providers may consider increasing Epidiolex dosage up to 2‐fold when coadministering with a strong CYP3A4 and/or CYP2C19 inducer (e.g., carbamazepine, phenytoin, phenobarbital, rifampin). Because of potential inhibition of enzyme activity by Epidiolex, providers should consider a reduction in dosage of substrates of UGT1A9, UGT2B7, CYP1A2, CYP2C8, and CYP2C9 if AEs are experienced during coadministration with CBD. ¹ Although we are not aware of studies reporting an interaction between Epidiolex and cenobamate, another CYP2C19 inhibitor, providers could consider potential additive pharmacokinetic effect when coadministering these medications. Patients and their caregivers should be advised that use of Epidiolex with other central nervous system depressants, including alcohol, may increase the risk of sedation and somnolence. ¹

3.2.5. Determining whether the optimal dose is reached

Recommendation #10: The optimal dose is that which yields the best possible seizure control while minimizing side effects. Providers should increase the dose as tolerated and not be discouraged by a lack of efficacy at the lower dose range, but rather consider the response to the maximum tolerated dose as a measure of effectiveness.

Healthcare professionals do not have to rely completely on the safety profile observed in the clinical trials to determine the appropriate dosing for their patients, as many concerning AEs that were observed during the trials can now be managed adequately. Providers should add other ASMs if Epidiolex is not optimally effective at the maximum tolerated dose; medications should not be added when titrating Epidiolex.

3.2.6. Assessing outcomes

Recommendation #11: HCPs should assess outcomes during each patient encounter until optimal efficacy is reached at the maximum tolerated dose. The primary efficacy outcome should be reduction in seizure burden, which includes reductions in seizure frequency, seizure severity, and postictal recovery time, as well as changes in baseline functioning. In patients who have satisfactory improvement in seizure outcomes, changes in the use of rescue medications, emergency room visits, and days missed from school/work should be evaluated. Effects on total medication regimen, mood, and behavior should also be assessed. Patients should be monitored for adherence and response to therapy, timing and adjustment of doses, AEs, concomitant medications, adherence to behavioral therapies, and changes in medical and psychiatric status. The frequency of assessing outcomes depends on each patient's initial seizure frequency and severity; most panelists reported conducting follow‐up visits every 3–4 months. Importantly, potential DDI‐related AEs should be discussed at Epidiolex initiation.

3.2.7. Discontinuation of Epidiolex

Recommendation #12: It is recommended to gradually taper patients off Epidiolex unless the situation is emergent or the patient is having intolerable AEs, in which case Epidiolex should be discontinued without tapering. Concomitant medications may need to be adjusted when discontinuing Epidiolex due to pharmacokinetic/pharmacodynamic interactions.

4. DISCUSSION

These recommendations are intended to address the major concerns that neurology HCPs with limited experience in prescribing Epidiolex may have. Despite increasingly widespread use of Epidiolex for the treatment of seizures associated with LGS, DS, and TSC, knowledge gaps in the optimization of Epidiolex treatment remain.

Unlike TSC and DS, for which published diagnostic criteria exist, ¹³ , ²² there are currently no consensus guidelines for the diagnosis of LGS. LGS is classically characterized by the presence of multiple seizure types, cognitive impairments, and SSW activity on EEG. ¹⁴ Recently, there has been a shift in favor of less rigid, broader LGS diagnostic criteria. ⁵⁴ The REST‐LGS is a valuable tool that can aid in differentiating between LGS and other refractory epilepsies and can be used effectively by both experts and nonexperts in the clinical setting. ²¹

There is a need for more extensive studies investigating potential DDIs between Epidiolex and concomitant nonseizure medications, such as antidepressants, antipsychotics, and anticoagulants (including direct oral anticoagulants). Levels of midazolam, an anxiolytic benzodiazepine, are not increased when administered concomitantly with Epidiolex, suggesting a lack of pharmacokinetic interaction. ⁴⁷ Additionally, Epidiolex does not appear to alter the safety and effectiveness of diazepam nasal spray when used as a rescue medication. ⁵⁵

Panelists also reported a substantial knowledge gap regarding optimal dosing of Epidiolex. Because of relatively limited data on appropriate dosing regimens, some patients may not receive an optimized dose needed for seizure control. Clinical studies are needed to confirm efficacy and safety of once‐daily Epidiolex 10–20 mg/kg/day in the evening to reduce daytime somnolence. Improved education on personalized, optimal dosing of Epidiolex to yield maximum seizure control while minimizing AEs is critical.

The effect of Epidiolex on focal seizures associated with LGS, DS, and TSC is currently not well defined in specifically designed clinical trials. Although Epidiolex reduced the frequency of seizures associated with TSC, which included focal seizures, ⁵⁶ further studies are needed to specifically evaluate the effect on focal seizures.

This analysis had several limitations. Although recommendations are based on the available scientific evidence, prescribing panelists also used their clinical judgment, which could result in a potential for bias. Furthermore, there are no standards for the number of individuals or number of rounds of agreement on a Delphi panel.

5. CONCLUSIONS

These recommendations provide consensus‐based guidance on the optimization of Epidiolex treatment for seizures associated with LGS, DS, and TSC. By providing real‐world experience from neurology HCPs with experience in prescribing Epidiolex, these recommendations can inform clinical decision‐making and support optimal usage of Epidiolex.

AUTHOR CONTRIBUTIONS

All authors provided substantial contributions to the conception or design of the work or the acquisition, analysis, or interpretation of data for the work; drafted the work or revised it critically for important intellectual content; and provided final approval of the version to be published.

FUNDING INFORMATION

The consensus panel was sponsored by Jazz Pharmaceuticals, Inc.

CONFLICT OF INTEREST STATEMENT

RW has been a clinical trial investigator for Aquestive, Biohaven, Cerevel, Eisai, Eliem, Engage, Epalex, Equilibre, Greenwich Biosciences, Jazz Pharmaceuticals, Inc., Longboard, Marinus, Neurelis, Otsuka, Rapport, Receptor Neuroscience, SK Life Science, ThirdRock, UCB Pharma, Xenon, and Zogenix; has served on advisory boards and/or carried out consulting work for Aquestive, Biohaven, Brain Sentinel, Catalyst, Cerevel, Eisai, Engage Pharma, Engrail, Greenwich Biosciences, Jazz Pharmaceuticals, Inc., Longboard, Marinus, Neureka, Neurelis, Novella, Otsuka, Rapport, SK Life Science, UCB Pharma, and Xenon; has received speaker bureau honoraria for Aquestive, Catalyst, Eisai, Greenwich Biosciences, Jazz Pharmaceuticals, Inc., Neurelis, SK Life Science, Sunovion, and UCB Pharma; has served as Medical Director of the Epilepsy Center at St. Luke's Health System in Boise, ID; has pay‐for‐call arrangements with St. Luke's Health System in Boise, ID; is a member of the Epilepsy Study Consortium; is a member of the Executive Committee of the Consortium of Private Epilepsy Centers; and is past Board President of the Epilepsy Foundation of Idaho. DEB has received support from NeuroPace and has served as a paid consultant for NeuroPace, Inc. BEG received speaking honoraria from Eisai, Greenwich, and SK Life Science, and served as a consultant for UCB, Eisai, Greenwich, and Aquestive. AH has participated in advisory boards with Aquestive, Eisai, Greenwich, Jazz Pharmaceuticals, Inc., Marinus, and Supernus Pharmaceuticals; participated in a speaker bureau for Aquestive and Jazz Pharmaceuticals, Inc.; received honoraria from the American Epilepsy Society; served as an investigator in sponsored pharmaceutical studies with Eisai, Greenwich, Marinus, Neurocrine, Sage, UCB, and Zogenix. PEM has served as a speaker for Eisai, Greenwich, and Sunovion and on advisory boards to UCB, Neuropace, and Supernus. EAT served as a principal investigator on clinical trials for GW Research Ltd/Jazz Pharmaceuticals Inc., Zogenix/UCB and Stoke Therapeutics and as a consultant for Aquestive Therapeutics, Biocodex, Greenwich Biosciences/Jazz Pharmaceuticals Inc., and Zogenix/UCB, Takeda, LivaNova, Nobelpharma, Marinus, Stoke Therapeutics, SK Life Sciences. JV has received honoraria for speaking on behalf of LivaNova, Eisai, Sunovian, UCB, and Greenwich Pharmaceuticals, and has also provided advisory services to SK Life Sciences.

ETHICS STATEMENT

We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

Supporting information

Appendix S1.

Wechsler RT, Burdette DE, Gidal BE, Hyslop A, McGoldrick PE, Thiele EA, et al. Consensus panel recommendations for the optimization of EPIDIOLEX® treatment for seizures associated with Lennox–Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex. Epilepsia Open. 2024;9:1632–1642. 10.1002/epi4.12956