The challenges of managing adults with LGS
Lennox-Gastaut syndrome (LGS) is a childhood-onset epilepsy syndrome that can be challenging to diagnose in adults. Its presenting features in childhood are multiple seizure types that often include seizure-induced falls, developmental slowing or regression, and an electroencephalogram (EEG) that has a characteristic abnormality termed “slow spike and wave.”1
However, as the patient grows from childhood through adolescence and into adulthood, there are changes to the seizure types and the EEG abnormality that can overlap with the features of other epilepsy syndromes. This produces a distinct challenge while caring for adults living with LGS.1,2 As another challenge, many adults living with LGS have tried multiple antiseizure medications (ASMs) due to years of inadequate seizure control, yet details of this treatment history are often not available or lost in the continuation of care. Additionally, adults living with LGS typically experience cognitive impairment across a broad range of intellectual function, and sometimes have behavioral issues such as hyperactivity and aggression.3
Compounding these challenges, individuals living with LGS often reach adulthood without a specific diagnosis, which may lead to suboptimal treatment.
“An accurate and specific diagnosis is the first step toward better outcomes.”
— Dr John Stern
“I consider the most important, also possibly the first, step in providing care for adults with LGS is recognizing that LGS is the diagnosis,” says Dr John Stern, professor in the Department of Neurology and director of the Epilepsy Clinical Program at the Geffen School of Medicine at the University of California, Los Angeles. “Often patients present to the adult epileptologist or general neurologist with a history of seizures and developmental disability, and the history doesn’t include the term LGS. Recognizing LGS is then a matter of it coming to mind and knowing that a specific diagnosis within epilepsy can be useful.” A diagnosis of LGS may then help patients access appropriate treatment options for their seizures.
EPIDIOLEX® (cannabidiol): A treatment option for adults with LGS
Given the realities of the condition, the main goal of treatment for many adult patients with LGS is to balance optimal seizure reduction with the side effects of treatment.2 Additional goals should include reducing the number of medications where possible and addressing seizure-related comorbidities.
With demonstrated seizure reduction in patients with LGS, EPIDIOLEX may be an appropriate treatment option. In 2 phase 3 clinical trials, EPIDIOLEX significantly reduced the frequency of drop and total seizures in patients ages 2 to 55 with LGS.4
In a prespecified exploratory analysis, adult patients (≥18 years) taking EPIDIOLEX 10 mg/kg/day or 20 mg/kg/day experienced a greater reduction in the monthly frequency of drop seizures than those taking placebo.5
Reduction in monthly frequency of drop seizures5-7
Prespecified exploratory subgroup analysis: drop seizure reduction in adult patients
Note: Adult data represent ~1/3 of the total trial population.6,7 Subgroup analysis is exploratory and descriptive in nature.5
Results from the 14-week treatment period. Drop seizures were defined as atonic, tonic, or tonic-clonic seizures that led to or could have led to a fall or injury.6,7
Additionally, a higher proportion of adults in both dosage groups of EPIDIOLEX experienced a ≥50% reduction in drop seizures as compared with placebo.5 Administration of the 20-mg/kg/day dosage resulted in somewhat greater reductions in seizure rates than the recommended maintenance dosage of 10 mg/kg/day, but with an increase in adverse reactions.
Responder Rates (≥50% Reductions in Drop Seizures from Baseline)5-7
Prespecified exploratory subgroup analysis: ≥50% seizure reduction in adult patients
Note: Adult data represent ~1/3 of the total trial population.6,7 Subgroup analysis is exploratory and descriptive in nature.5
Results from the 14-week treatment period.6,7
To start EPIDIOLEX in adults, it is important to consider the recommended maintenance dosage for tolerability and response optimization. EPIDIOLEX is started at 5 mg/kg/day and is recommended to titrate in weekly increments of 5 mg/kg/day as tolerated.
Recommended dosages
| Recommended starting dosage | Dosage increase* | Recommended maintenance dosage range† | |
|---|---|---|---|
| LGS | Week 1: 5 mg/kg/day (2.5 mg/kg twice daily) | Weekly increments, as tolerated, of 5 mg/kg/day (2.5 mg/kg twice daily) | 10 to 20 mg/kg/day (5 to 10 mg/kg twice daily) |
| LGS | |
|---|---|
| Recommended starting dosage | Week 1: 5 mg/kg/day (2.5 mg/kg twice daily) |
| Dosage increase* | Weekly increments, as tolerated, of 5 mg/kg/day (2.5 mg/kg twice daily) |
| Recommended maintenance dosage range† | 10 to 20 mg/kg/day (5 to 10 mg/kg twice daily) |
*For patients in whom a more rapid titration is warranted, the dosage may be increased no more frequently than every other day.
†In the full and adult patient population, administration of EPIDIOLEX at 20 mg/kg/day resulted in greater reduction in seizures, but with an increase in adverse reactions.
“Typically, I see that the seizure reduction is dose dependent, so getting into the higher range can provide further benefit. Stopping prematurely by not trying EPIDIOLEX at the higher end of the maintenance dosing range means not using what you have already decided to try to its fullest potential.”
— Dr John Stern
EPIDIOLEX offers flexible dosing for adults with LGS
The minimum recommended maintenance dosage of EPIDIOLEX is 10 mg/kg/day with flexibility up to 20 mg/kg/day based on patient response. In considering titration schedules, Dr Stern recommends that clinicians first “titrate to a dose in the low range of the recommended schedule to allow a patient to return for follow-up to discuss tolerability and any signs of benefit prior to potentially increasing the dose. Calculating the dose for an individual patient based on their weight is simple and should not be a deterrence to using EPIDIOLEX at appropriate doses.”
Safety considerations on the use of EPIDIOLEX in adults with LGS
It is also important to consider potential adverse events that may occur.
Most common AEs (≥10% and greater than placebo) in patients with LGS
- Somnolence
- Decreased appetite
- Diarrhea
- Transaminase elevations
- Fatigue
- Malaise
- Asthenia
- Rash
- Insomnia
- Sleep disorder
- Poor-quality sleep
- Infections
- Somnolence
- Fatigue
- Insomnia
- Decreased appetite
- Malaise
- Sleep disorder
- Diarrhea
- Asthenia
- Poor-quality sleep
- Transaminase elevations
- Rash
- Infections
In all 3 indications, EPIDIOLEX was found to have a consistent safety profile in children and adults.
EPIDIOLEX can cause dose-related elevations of liver transaminases. Because of the risk of hepatic injury, it is important to obtain serum transaminases (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) and total bilirubin levels in all patients prior to starting treatment with EPIDIOLEX and periodically thereafter or as clinically indicated.
“When thinking of treatment options, you need to think about the safety and tolerability profiles. Some patients may be more sensitive to sedation or gastrointestinal side effects. Determining tolerability must be considered on an individual basis.”
— Dr John Stern
Managing drug interactions is also a key consideration, as treatment regimens for adults will likely include concomitant ASMs. In the LGS clinical trials, clobazam and valproate were among the most commonly used concomitant ASMs. As EPIDIOLEX produces a 3-fold increase in plasma concentrations of the active metabolite of clobazam (with no effect on clobazam levels), the risk of clobazam-related adverse reactions may increase with concomitant use. These adverse reactions may include somnolence/sedation, pneumonia, and liver enzyme elevations. Dosing adjustments should be made by clinicians based on individual patient response, tolerability, and physician experience.
Coadministration of EPIDIOLEX
Coadministration of EPIDIOLEX with valproate increases the incidence of liver enzyme elevation. In drug interaction studies, there was no clinically relevant effect on valproate exposure. Ongoing liver monitoring is recommended, especially in patients taking both EPIDIOLEX and valproate, clobazam, or other concomitant medications known to affect the liver.
“I have many patients using clobazam and EPIDIOLEX. When those two are used in combination, there is a greater sensitivity to the side effect of drowsiness. A reduction of the clobazam dose is typically helpful for reaching an EPIDIOLEX dose that may have a greater advantage.”
— Dr John Stern
A dose reduction of clobazam is recommended if known clobazam adverse reactions occur.
Liver enzyme elevations in overall population of patients with LGS, Dravet syndrome, and tuberous sclerosis complex (TSC)
Incidence of ALT elevations >3x the upper limit of normal (ULN) in patients with LGS and Dravet syndrome treated with EPIDIOLEX
EPIDIOLEX + clobazam and valproate |
30% |
| EPIDIOLEX + valproate (without clobazam) | 21% |
| EPIDIOLEX + clobazam (without valproate) | 4% |
| EPIDIOLEX (without clobazam and valproate) | 3% |
Elevations resolved in 2/3 of patients following:
- Discontinuation of EPIDIOLEX, or
- Reduction of EPIDIOLEX and/or concomitant valproate
And in 1/3 of patients:
- With no change in EPIDIOLEX treatment
Elevations typically occurred within the first 2 months of treatment; however, there were some cases observed up to 18 months after initiation.
- There were cases of transaminase elevations associated with hospitalization
Risk factors for elevated transaminases include:
- Increased EPIDIOLEX dose
- Concomitant use of valproate and, to a lesser extent, clobazam
- Baseline transaminase elevations
Less than 1% of EPIDIOLEX patients had ALT or AST >20x the ULN.
Obtain serum transaminases (ALT and AST) and total bilirubin levels
Consider more frequent monitoring of serum transaminases and bilirubin in patients who are taking valproate or who have elevated liver enzymes at baseline.
- Monitor within 1 month following changes in EPIDIOLEX dosage and addition of or changes in medications that are known to impact the liver
Consider discontinuation or dose reduction of EPIDIOLEX or concomitant medications known to affect the liver (eg, valproate or clobazam) if liver enzyme elevations occur (transaminase levels >3x the ULN and bilirubin levels >2x the ULN, or sustained transaminase elevations >5x the ULN).
Treating adults with LGS
Adults living with LGS have unique needs and challenges that should be at the forefront of clinical decision-making. Treatment approaches for this patient population should consider the need for seizure reduction balanced with the overall tolerability of the regimen.2 With the ability to dose for optimized treatment response and tolerability, EPIDIOLEX should be considered an appropriate ASM choice for adults with LGS.2,5
“Maximizing seizure reduction with the fewest side effects at a specific dose is going to vary across individuals, but we should be taking advantage of the clinical data that exist in choosing treatments for patients diagnosed with LGS. With EPIDIOLEX, I find the flexible dosing schedule to be worthwhile, and we’re fortunate that the safety profile has not greatly changed over the years with many, many more people having used it.”
— Dr John Stern
References
- Patel AD, Mazurkiewicz-Bełdzińska M, Chin RF, et al. Epilepsia. 2021;62(9):2228-2239.
- van Rijckevorsel K. Neuropsychiatr Dis Treat. 2008;4(6):1001-1019.
- Ferlazzo E, Nikaronova M, Italiano D, et al. Epilepsy Res. 2010;89(2-3):271-277.
- Privitera M, Bhathal H, Wong M, et al. Epilepsia. 2021;62(5):1130-1140.
- Data on file. Jazz Pharmaceuticals, Inc.
- Thiele EA, Marsh ED, French JA, et al. Lancet. 2018;391(10125):1085-1096.
- Devinsky O, Patel AD, Cross JH, et al. N Engl J Med. 2018;378(20):1888-1897.
This monograph is sponsored by Jazz Pharmaceuticals and was developed with input from Dr. John Stern, who has been compensated for his time.
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