U.S. FDA Approves FINTEPLA[®] ▼(fenfluramine) Oral Solution for Treatment of Seizures Associated with Lennox-Gastaut Syndrome (LGS)

Brussels (Belgium), and Atlanta, Ga. (USA) 28 March 2022 – 7 a.m. CET – UCB (Euronext: UCB), a global biopharmaceutical company, today announced that FINTEPLA^® (fenfluramine) oral solution CIV has been approved in the United States, by the U.S. Food and Drug Administration (FDA) for the treatment of seizures associated with Lennox-Gastaut syndrome in patients two years of age and older.¹ Additionally, the FDA has granted pediatric exclusivity for the product.⁷ It is already approved for the treatment of seizures associated with Dravet syndrome in patients two years of age and older in the US and EU.^1,8 Fenfluramine for LGS is available in the US through a restricted distribution program, called the Risk Evaluation and Mitigation Strategy (REMS) Program. 

LGS is a severe childhood-onset developmental and epileptic encephalopathy (DEE) characterized by drug-refractory seizures with high morbidity⁴ as well as serious impairment of neurodevelopmental, cognitive, and motor functions.⁵ LGS affects an estimated 30,000 – 50,000 patients in the U.S.⁶ LGS has far-reaching effects beyond seizures, including issues with communication, psychiatric symptoms, sleep, behavioral challenges, and mobility.⁹ Additionally, sudden unexpected death in epilepsy (SUDEP) is a major concern for people living with LGS.¹⁰

Fenfluramine has demonstrated efficacy in the most difficult to treat seizure types,^1,2 including drop seizures, which cause a person to suddenly lose muscle tone, become limp, and fall to the ground with a high likelihood of injury.³ Fenfluramine has a mechanism of action different from and complementary to current seizure medications, and it can be used with no disruptions to current antiseizure regimens.¹¹ In the global placebo-controlled phase 3 clinical trial, there were numerically greater improvements on the Clinical Global Impression scale (CG-I) in patients living with LGS when taking fenfluramine.¹

“The approval of fenfluramine for Lennox-Gastaut syndrome highlights our continued commitment to bringing differentiated medicines to patients who may not be well controlled on current therapies, and their caregivers,” said Mike Davis, Head of Global Epilepsy, UCB. “We are proud to add fenfluramine as a treatment for Dravet syndrome, and now Lennox-Gastaut syndrome, to our portfolio of epilepsy medicines to help reduce the impact and burden of seizures, including severe epilepsy syndromes that have high pediatric morbidity and mortality rates.”

The FDA approval was supported by safety and efficacy data from a global, randomized, placebo-controlled Phase 3 clinical trial in 263 patients with LGS (age 2-35 years), which demonstrated that fenfluramine at a dose of 0.7/mg/kg/day significantly reduced the frequency of drop seizures compared to placebo (p=0.0037). Nearly a fourth of those patients on fenfluramine 0.7 mg/kg/day experienced a ≥50% reduction in drop seizure frequency per 28 days;  18% with >50 to <75% reduction and 6% >75% reduction.¹ The common adverse reactions that occurred in patients treated with fenfluramine (incidence at least 10% and greater than placebo) were diarrhea; decreased appetite; fatigue; somnolence; vomiting.¹ The fenfluramine safety database includes long-term cardiovascular safety data for patients treated for up to three years in DS and LGS.¹ 

“LGS is one of the most challenging epileptic encephalopathies to treat, and the vast majority of patients are not well controlled, despite a regimen of multiple antiepileptic drugs,” said Kelly Knupp, M.D., MSCS, FAES, Associate Professor, Children’s Hospital Colorado, USA. “As a complementary therapy, fenfluramine offers a different mechanism of action and demonstrated ability to significantly reduce the number of seizures associated with a drop, a critical measure for managing this severe form of epilepsy.” 

UCB is committed to supporting patient access to fenfluramine, and as part of that commitment, Zogenix Central, a comprehensive support program, will provide ongoing product assistance to patients, caregivers, and their medical teams. Further information is available at www.FINTEPLA.com.

“LGS is a severe, life-long disease with wide-ranging effects beyond seizures. It impacts every aspect of daily life and puts great strain on the entire family. There is a desperate need for more effective treatment options,” said Dr. Tracy Dixon-Salazar, Executive Director of the Lennox-Gastaut Syndrome Foundation and mother to an adult daughter with LGS. “The potential for fenfluramine to make a difference in the daily, horrific seizures we are dealing with in LGS cannot be understated. We are so grateful for the researchers who have worked so hard to help all of us suffering at the hands of LGS.”

UCB acquired Zogenix and fenfluramine on March 7, 2022. The acquisition is consistent with UCB’s sustainable patient value strategy and continued commitment to providing world leading patient value to all people living with epilepsy, with an increasing focus on creating value and new solutions that address the unmet needs of people with certain specialized or rare types of epilepsy, where few or no options exist.

About FINTEPLA^® (fenfluramine) C-IV

FINTEPLA^® (fenfluramine) oral solution is a prescription medication approved by the FDA and authorized by the EU Commission, and under regulatory review with the PMDA (Japan), for the treatment of seizures associated with Dravet syndrome in patients two years of age and older.^8,12 A Type II Variation Application has also been submitted to the European Medicines Agency (EMA) for the treatment of seizures associated with LGS.¹³

In the United States, FINTEPLA is available only through a restricted distribution program called the FINTEPLA REMS program. FINTEPLA is available in EU under a controlled access program requested by the EMA to prevent off-label use for weight management and to confirm that prescribing physicians have been informed of the need for periodic cardiac monitoring in patients taking FINTEPLA. Further information is available at www.FinteplaREMS.com or by telephone at +1 877 964 3649. 

Please see full Prescribing Information, including Boxed Warning, for additional important information on FINTEPLA.

Please refer to Summary of Product Characteristics (SmPC) before prescribing. 

Important Safety Information about FINTEPLA^® ▼ in the EU and EEA⁸

Contraindications
Hypersensitivity to the active substance or any of the excipients listed in section 6.1. Aortic or mitral valvular heart disease. Pulmonary arterial hypertension. 4 Within 14 days of the administration of monoamine oxidase inhibitors due to an increased risk of serotonin syndrome

Summary of the safety profile 
The most commonly reported adverse reactions are decreased appetite (44.2%), diarrhoea (30.8%), pyrexia (25.6%), fatigue (25.6%), upper respiratory tract infection (20.5%), lethargy (17.5%), somnolence (15.4%), and bronchitis (11.6%)

Special warnings and precautions for use
Aortic or mitral valvular heart disease and pulmonary arterial hypertension
Because of reported cases of valvular heart disease that may have been caused by fenfluramine at higher doses used to treat adult obesity, cardiac monitoring must be performed using echocardiography. In the controlled clinical studies of fenfluramine for the treatment of Dravet syndrome, no valvular heart disease was observed.

Prior to starting treatment, patients must undergo an echocardiogram to establish a baseline prior to initiating treatment (see section 4.3) and exclude any pre-existing valvular heart disease or pulmonary hypertension.

Echocardiogram monitoring should be conducted every 6 months for the first 2 years and annually thereafter. If an echocardiogram indicates pathological valvular changes, a follow-up echocardiogram should be considered at an earlier timeframe to evaluate whether the abnormality is persistent. If pathological abnormalities on the echocardiogram are observed, it is recommended to evaluate the benefit versus risk of continuing fenfluramine treatment with the prescriber, caregiver, and cardiologist.
If treatment is stopped because of aortic or mitral valvular heart disease, appropriate monitoring and follow-up should be provided in accordance with local guidelines for the treatment of aortic or mitral valvular heart disease.

With past use in higher doses to treat adult obesity, fenfluramine was reported to be associated with pulmonary arterial hypertension. Pulmonary arterial hypertension was not observed in the clinical programme, but because of the low incidence of this disease, the clinical trial experience with fenfluramine is inadequate to determine if fenfluramine increases the risk for pulmonary arterial hypertension in patients with Dravet syndrome. If echocardiogram findings are suggestive of pulmonary arterial hypertension, a repeat echocardiogram should be performed as soon as possible and within 3 months to confirm these findings. If the echocardiogram finding is confirmed suggestive of an increased probability of pulmonary arterial hypertension defined as “intermediate probability” by the 2015 European Society of Cardiology (ESC) and the European Respiratory Society (ERS) Guidelines, it should lead to a benefit-risk evaluation of continuation of Fintepla by the prescriber, carer, and cardiologist. If the echocardiogram finding, after confirmation, suggests of a high probability of pulmonary arterial hypertension, as defined by the 2015 ESC and ERS Guidelines, it is recommended fenfluramine treatment should be stopped.

Decreased appetite and weight loss
Fenfluramine can cause decreased appetite and weight loss (see section 4.8). An additive effect on decreased appetite can occur when fenfluramine is combined with other anti-epileptic medicines, for example stiripentol. The decrease in weight appears to be dose related. Most subjects resumed weight gain over time while continuing treatment. The patient's weight should be monitored. A benefit risk evaluation should be undertaken prior to commencing treatment with fenfluramine in patients with a history of anorexia nervosa or bulimia nervosa.

Fintepla controlled access programme
A controlled access programme has been created to 1) prevent off-label use in weight management in obese patients and 2) confirm that prescribing physicians have been informed of the need for periodic cardiac monitoring in patients taking Fintepla.

Somnolence
Fenfluramine can cause somnolence.

Other central nervous system depressants, including alcohol, could potentiate the somnolence effect of fenfluramine (see sections 4.5 and 4.7).

Suicidal behaviour and ideation
Suicidal behaviour and ideation have been reported in patients treated with anti-epileptic medicines in several indications. A meta-analysis of randomised placebo-controlled trials with anti-epileptic medicines that did not include fenfluramine has shown a small increased risk of suicidal behaviour and ideation. The mechanism of this risk is not known, and the available data do not exclude the possibility of an increased risk for fenfluramine. Patients and caregivers of patients should be advised to seek medical advice should any signs of suicidal behaviour and ideation emerge.

Serotonin syndrome
As with other serotonergic agents, serotonin syndrome, a potentially life-threatening condition, may occur with fenfluramine treatment, particularly with concomitant use of other serotonergic agents (including SSRIs, SNRIs, tricyclic antidepressants, or triptans); with agents that impair metabolism of serotonin such as MAOIs; or with antipsychotics that may affect the serotonergic neurotransmitter systems (see sections 4.3 and 4.5).

Serotonin syndrome symptoms may include mental status changes (eg, agitation, hallucinations, coma), autonomic instability (eg, tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (eg, hyperreflexia, incoordination), and/or gastrointestinal symptoms (eg, nausea, vomiting, diarrhoea).

If concomitant treatment with fenfluramine and other serotonergic agents that may affect the serotonergic systems is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.

Increased seizure frequency
As with other anti-epileptic medicines, a clinically relevant increase in seizure frequency may occur during treatment with fenfluramine, which may require adjustment in the dose of fenfluramine and/or concomitant anti-epileptic medicines, or discontinuation of fenfluramine, should the benefit-risk be negative.

Cyproheptadine
Cyproheptadine is a potent serotonin receptor antagonist and may therefore decrease the efficacy of fenfluramine. If cyproheptadine is added to treatment with fenfluramine, patients should be monitored for worsening of seizures. If fenfluramine treatment is initiated in a patient taking cyproheptadine, fenfluramine's efficacy may be reduced.

Glaucoma
Fenfluramine can cause mydriasis and can precipitate angle closure glaucoma. Discontinue therapy in patients with acute decreases in visual acuity. Consider discontinuation if there is ocular pain and another cause cannot be determined.

Strong CYP1A2 or CYP2B6 inducers
Co-administration with strong CYP1A2 inducers or CYP2B6 inducers may decrease fenfluramine plasma concentrations (see section 4.5).
An increase in fenfluramine dosage should be considered when co-administered with a strong CYP1A2 or CYP2B6 inducer; the maximum daily dose should not be exceeded.

Excipients
This medicinal product contains sodium ethyl para-hydroxybenzoate (E 215) and sodium methyl para-hydroxybenzoate (E 219) which may cause allergic reactions (possibly delayed).

It also contains sulfur dioxide (E 220) which may rarely cause severe hypersensitivity reactions and bronchospasm.

Patients with rare glucose-galactose malabsorption should not take this medicinal product.

This medicinal product contains less than 1 mmol sodium (23 mg) per the maximum daily dose of 12 mL, that is to say essentially 'sodium-free'.

This medicinal product contains glucose which may be harmful to the teeth.

Refer to the European Summary of Product Characteristics for other adverse reactions and full prescribing information. Date of revision: 04 Nov 2021. 
https://www.ema.europa.eu/en/documents/product-information/fintepla-epar-product-information_en.pdf 

 ▼This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 

Important Safety Information about FINTEPLA^® in the US⁹

INDICATIONS AND USAGE

FINTEPLA is indicated for the treatment of seizures associated with Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) in patients 2 years of age and older.

IMPORTANT SAFETY INFORMATION

BOXED WARNING: VALVULAR HEART DISEASE and PULMONARY ARTERIAL HYPERTENSION

• There is an association between serotonergic drugs with 5-HT2B receptor agonist activity, including fenfluramine (the active ingredient in FINTEPLA), and valvular heart disease and pulmonary arterial hypertension. 
• Echocardiogram assessments are required before, during, and after treatment with FINTEPLA. 
• FINTEPLA is available only through a restricted program called the FINTEPLA REMS.

CONTRAINDICATIONS

FINTEPLA is contraindicated in patients with hypersensitivity to fenfluramine or any of the excipients in FINTEPLA and with concomitant use, or within 14 days of the administration of monoamine oxidase inhibitors because of an increased risk of serotonin syndrome.

WARNINGS AND PRECAUTIONS
Valvular Heart Disease and Pulmonary Arterial Hypertension (see Boxed Warning): Because of the association between serotonergic drugs with 5 HT2B receptor agonist activity, including fenfluramine (the active ingredient in FINTEPLA), and valvular heart disease (VHD) and pulmonary arterial hypertension (PAH), cardiac monitoring via echocardiogram is required prior to starting treatment, during treatment, and after treatment with FINTEPLA concludes. Cardiac monitoring via echocardiogram can aid in early detection of these conditions. In clinical trials for DS and LGS of up to 3 years in duration, no patient receiving FINTEPLA developed VHD or PAH.

Monitoring: Prior to starting treatment, patients must undergo an echocardiogram to evaluate for VHD and PAH. Echocardiograms should be repeated every 6 months, and once at 3-6 months post treatment with FINTEPLA.

The prescriber must consider the benefits versus the risks of initiating or continuing treatment with FINTEPLA if any of the following signs are observed via echocardiogram: valvular abnormality or new abnormality; VHD indicated by mild or greater aortic regurgitation or moderate or greater mitral regurgitation, with additional characteristics of VHD (eg, valve thickening or restrictive valve motion); PAH indicated by elevated right heart/pulmonary artery pressure (PASP >35mmHg).

FINTEPLA REMS Program (see Boxed Warning): FINTEPLA is available only through a restricted distribution program called the FINTEPLA Risk Evaluation and Mitigation Strategy (REMS) Program. Prescribers must be certified by enrolling in the FINTEPLA REMS. Prescribers must counsel patients receiving FINTEPLA about the risk of valvular heart disease and pulmonary arterial hypertension, how to recognize signs and symptoms of valvular heart disease and pulmonary arterial hypertension, the need for baseline (pretreatment) and periodic cardiac monitoring via echocardiogram during FINTEPLA treatment, and cardiac monitoring after FINTEPLA treatment. Patients must enroll in the FINTEPLA REMS and comply with ongoing monitoring requirements. The pharmacy must be certified by enrolling in the FINTEPLA REMS and must only dispense to patients who are authorized to receive FINTEPLA. Wholesalers and distributors must only distribute to certified pharmacies. Further information is available at www.FinteplaREMS.com or by telephone at 1-877-964-3649.

Decreased Appetite and Decreased Weight: FINTEPLA can cause decreases in appetite and weight. Decreases in weight appear to be dose related. Approximately half of the patients with LGS and most patients with DS resumed the expected measured increases in weight during the open-label extension studies. Weight should be monitored regularly during treatment with FINTEPLA, and dose modifications should be considered if a decrease in weight is observed. 

Somnolence, Sedation, and Lethargy: FINTEPLA can cause somnolence, sedation, and lethargy. Other central nervous system (CNS) depressants, including alcohol, could potentiate these effects of FINTEPLA. Prescribers should monitor patients for somnolence and sedation and should advise patients not to drive or operate machinery until they have gained sufficient experience on FINTEPLA to gauge whether it adversely affects their ability to drive or operate machinery.

Suicidal Behavior and Ideation: Antiepileptic drugs (AEDs), including FINTEPLA, increase the risk of suicidal thoughts or behaviors in patients taking these drugs for any indication. Patients treated with an AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behaviors, or any unusual changes in mood or behavior.

Anyone considering prescribing FINTEPLA or any other AED must balance the risk of suicidal thoughts or behaviors with the risks of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behaviors. Should suicidal thoughts and behaviors emerge during treatment, consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

Withdrawal of Antiepileptic Drugs: As with most AEDs, FINTEPLA should generally be withdrawn gradually because of the risk of increased seizure frequency and status epilepticus. If withdrawal is needed because of a serious adverse reaction, rapid discontinuation can be considered.

Serotonin Syndrome: Serotonin syndrome, a potentially life-threatening condition, may occur with FINTEPLA, particularly during concomitant administration of FINTEPLA with other serotonergic drugs, including, but not limited to, selective serotonin-norepinephrine reuptake inhibitors (SNRIs), selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), bupropion, triptans, dietary supplements (eg, St. John’s Wort, tryptophan), drugs that impair metabolism of serotonin (including monoamine oxidase inhibitors [MAOIs], which are contraindicated with FINTEPLA), dextromethorphan, lithium, tramadol, and antipsychotics with serotonergic agonist activity. Patients should be monitored for the emergence of signs and symptoms of serotonin syndrome, which include mental status changes (eg, agitation, hallucinations, coma), autonomic instability (eg, tachycardia, labile blood pressure, hyperthermia), neuromuscular signs (eg, hyperreflexia, incoordination), and/or gastrointestinal symptoms (eg, nausea, vomiting, diarrhea). If serotonin syndrome is suspected, treatment with FINTEPLA should be stopped immediately and symptomatic treatment should be started. 

Increase in Blood Pressure: FINTEPLA can cause an increase in blood pressure. Rare cases of significant elevation in blood pressure, including hypertensive crisis, has been reported in adult patients treated with fenfluramine, including patients without a history of hypertension. In clinical trials for DS and LGS of up to 3 years in duration, no pediatric or adult patient receiving FINTEPLA developed hypertensive crisis. Monitor blood pressure in patients treated with FINTEPLA.

Glaucoma: Fenfluramine can cause mydriasis and can precipitate angle closure glaucoma. Consider discontinuing treatment with FINTEPLA in patients with acute decreases in visual acuity or ocular pain.

ADVERSE REACTIONS
The most common adverse reactions observed in DS studies (incidence at least 10% and greater than placebo) were decreased appetite; somnolence, sedation, lethargy; diarrhea; constipation; abnormal echocardiogram; fatigue, malaise, asthenia; ataxia, balance disorder, gait disturbance; blood pressure increased; drooling, salivary hypersecretion; pyrexia; upper respiratory tract infection; vomiting; decreased weight; fall; status epilepticus.

The most common adverse reactions observed in the LGS study (incidence at least 10% and greater than placebo) were diarrhea; decreased appetite; fatigue; somnolence; vomiting.

DRUG INTERACTIONS
Strong CYP1A2, CYP2B6, or CYP3A Inducers: Coadministration with strong CYP1A2, CYP2B6, or CYP3A inducers will decrease fenfluramine plasma concentrations. If coadministration of a strong CYP1A2, CYP2B6, or CYP3A inducer with FINTEPLA is necessary, monitor the patient for reduced efficacy and consider increasing the dosage of FINTEPLA as needed. If a strong CYP1A2, CYP2B6, or CYP3A inducer is discontinued during maintenance treatment with FINTEPLA, consider gradual reduction in the FINTEPLA dosage to the dose administered prior to initiating the inducer.

Strong CYP1A2 or CYP2D6 Inhibitors: Coadministration with strong CYP1A2 or CYP2D6 inhibitors will increase fenfluramine plasma concentrations. If FINTEPLA is coadministered with strong CYP1A2 or CYP2D6 inhibitors, the maximum daily dosage of FINTEPLA is 20 mg. If a strong CYP1A2 or CYP2D6 inhibitor is discontinued during maintenance treatment with FINTEPLA, consider gradual increase in the FINTEPLA dosage to the dose recommended without CYP1A2 or CYP2D6 inhibitors. If FINTEPLA is coadministered with stiripentol and a strong CYP1A2 or CYP2D6 inhibitor, the maximum daily dosage of FINTEPLA is 17 mg.

USE IN SPECIFIC POPULATIONS

Administration to patients with hepatic impairment is not recommended. 

To report SUSPECTED ADVERSE REACTIONS, contact Zogenix Inc. at 1-866-964-3649 (1-866-Zogenix) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Please see full Prescribing Information, including Boxed Warning, for additional important information on FINTEPLA.

----------------------------------------------------------------------

For further information, contact UCB: 

Investor Relations
Antje Witte
T +32.2.559.9414
antje.witte@ucb.com

Corporate Communications
Laurent Schots, Media Relations
T+32.2.559.9264
Laurent.schots@ucb.com    

Nick Francis 
T +44 7769 307745
Nick.francis@ucb.com
    
Erica Puntel, U.S. Media Relations
T +404 938 5359
Erica.puntel@ucb.com

About UCB
UCB, Brussels, Belgium (www.ucb.com) is a global biopharmaceutical company focused on the discovery and development of innovative medicines and solutions to transform the lives of people living with severe diseases of the immune system or of the central nervous system. With approximately 8 600 people in approximately 40 countries, the company generated revenue of € 5.8 billion in 2021. UCB is listed on Euronext Brussels (symbol: UCB). Follow us on Twitter: @UCB_news. 

Forward looking statements 
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References

1. FINTEPLA^® (fenfluramine) oral solution CIV. U.S. Prescribing Information. March 2022.
2. Wirrell E, Nickels KC. Pediatric epilepsy syndromes. Continuum (Minneap Minn). 2010;16(3 Epilepsy):57-85.
3. Mastrangelo M. Lennox-Gastaut Syndrome: A State of the Art Review. Neuropediatrics. 2017;48(3):143-151. 
4. Strzelczyk A, Schubert-Bast S. Expanding the Treatment Landscape for Lennox-Gastaut Syndrome: Current and Future Strategies. CNS Drugs. 2021;35(1):61-83. 
5. Arzimanoglou A, French J, Blume WT, et al. Lennox-Gastaut syndrome: a consensus approach on diagnosis, assessment, management, and trial methodology. Lancet Neurol. 2009;8(1):82-93.
6. Data on file, Zogenix, Inc. 2021.
7. Data on file, Zogenix, Inc. 2021.
8. FINTEPLA Summary of Product Characteristics. January 2022.
9. LGS Foundation. LGS Characteristics and Major Concerns Survey. https://www.lgsfoundation.org/wp-content/uploads/2021/08/2019-PFDD-Caregiver-Survey-1.pdf. Accessed March 2022.
10. Harden C, Tomson T, et al. Practice guideline summary: Sudden unexpected death in epilepsy incidence rates and risk factors: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 2017 Apr 25;88(17):1674-1680. 
11. Data on file, Zogenix, Inc.
12. Zogenix Press Release. Zogenix Submits New Drug Application for FINTEPLA^® (Fenfluramine) in Japan for the Treatment of Epileptic Seizures Associated with Dravet Syndrome. 21 December 2021.
13. Zogenix Press Release. Zogenix Submits Type II Variation Application to the European Medicines Agency (EMA) to Expand the Use of FINTEPLA^® (fenfluramine) for the Treatment of Seizures Associated with Lennox-Gastaut Syndrome. Accessed 20 December 2021.