cannabidiol and stiripentol

Cannabidiol (CBD) is one of the main components of the cannabis plant that has demonstrated anti-epileptic seizure effect. Following its clinical development, in September 2019 the European Medicines Agency approved its indication for the adjunctive therapy of epileptic seizures associated with Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS), combined with clobazam (CLB), in patients of 2 years of age and older.. To establish recommendations on the use of plant-derived highly purified CBD on which Spanish experts have reached consensus for the treatment of epilepsy in patients with DS and LGS based on their clinical experience and the scientific evidence.. Consensus meeting with the participation of four Spanish neurologists and neuropediatric who are experts in epilepsy secondary to DS and LGS and with clinical experience in the use and management of CBD. They discussed on several topics, including posology (starting dose, dose escalation schema), efficacy (assessment of outcomes and indications for treatment withdrawal), and safety (evaluation, drug-drug interactions, adverse events management).. In order to optimise CBD treatment, a slow dose escalation (= 4 weeks) is recommended until the maximum recommended dose or the desire effect is reached. It is also recommended that the concomitant antiseizure medications (ASMs) be reduced in case of adverse events due to interactions, and that the treatment continues for at least 6 months if it is well tolerated. The efficacy and safety of CBD must be assessed individually, considering the benefits and risks for individual patients.. Cannabidiol para el tratamiento del síndrome de Lennox-Gastaut y del síndrome de Dravet: recomendaciones de expertos sobre su uso en la práctica clínica en España.. Introducción. El cannabidiol (CBD) es uno de los componentes principales de la planta del cannabis que ha demostrado efecto ante las crisis epilépticas. Tras su desarrollo clínico, obtuvo su aprobación por la Agencia Europea del Medicamento en septiembre de 2019 para el tratamiento de las crisis epilépticas asociadas con el síndrome de Lennox-Gastaut (SLG) y el síndrome de Dravet (SD), en combinación con el clobazam (CLB), en pacientes a partir de los dos años. Objetivo. Establecer unas recomendaciones de manejo del CBD derivado de la planta altamente purificado consensuadas por expertos españoles en el tratamiento de la epilepsia para su uso en pacientes con SD y SLG, basándose en su experiencia clínica y en la evidencia científica. Desarrollo. Reunión de consenso de un grupo de cuatro neurólogos y neuropediatras españoles expertos en el manejo de la epilepsia asociada al SD y el SLG y con experiencia clínica en el uso de CBD. Se debatió sobre diferentes áreas, incluyendo la posología (dosis de inicio, pauta de escalada), la eficacia (valoración de resultados e indicaciones para la suspensión del tratamiento) y la seguridad (evaluación, interacciones entre fármacos, manejo de efectos adversos). Conclusiones. Para optimizar el tratamiento con CBD, se recomienda una pauta lenta de escalada de dosis (de cuatro semanas o más) hasta alcanzar la dosis máxima recomendada o el efecto deseado, reducir los fármacos anticrisis epilépticas concomitantes si aparecen efectos adversos por interacciones y mantener el tratamiento al menos seis meses si se tolera. La eficacia y la seguridad del CBD deben evaluarse de forma individual, considerando el beneficio y el riesgo para cada paciente.

Topics: Anticonvulsants; Cannabidiol; Clobazam; Clonazepam; Diazepam; Dioxolanes; Drug Administration Schedule; Drug Synergism; Drug Therapy, Combination; Epilepsies, Myoclonic; Humans; Lennox Gastaut Syndrome; Phenobarbital; Practice Guidelines as Topic; Pyrrolidinones; Spain; Triazoles; Valproic Acid

Topics: Adolescent; Anticonvulsants; Cannabidiol; Child; Child, Preschool; Clinical Trials as Topic; Cytochrome P-450 Enzyme Inducers; Dioxolanes; Drug Therapy, Combination; Epilepsies, Myoclonic; Humans

Multiple medications have recently been approved or are nearing US Food and Drug Administration approval for treatment of pediatric epilepsy, while a number of other compounds are in development. Many of these therapies are seeking indications in rare epilepsy syndromes and present novel mechanisms of action for the treatment of epilepsy.. Data related to drugs in development or under study were accessed following literature search via PubMed or author knowledge of publically available data.. Several new compounds are recently approved or under study for epilepsy in children.. The following is a brief overview of the new and emerging medications for the treatment of pediatric epilepsy.

Topics: Anticonvulsants; Cannabidiol; Child; Dioxolanes; Epilepsy; Fenfluramine; Humans; Piperidines; Pregnanolone; Pyridines

Dravet syndrome (DS), previously known as severe myoclonic epilepsy of infancy, is a severe developmental and epileptic encephalopathy caused by loss-of-function mutations in one copy of

Topics: Anticonvulsants; Cannabidiol; Dioxolanes; Epilepsies, Myoclonic; Fenfluramine; Genetic Therapy; Humans; Oligonucleotides, Antisense

Dravet syndrome is a debilitating epileptic encephalopathy of childhood with few treatment options available in the United States before 2018. In the modern era, new genetic testing options will allow diagnosis closer to disease onset. Three new medicines-stiripentol, cannabidiol, and fenfluramine-have documented efficacy and safety as adjunctive therapies for treating pharmacoresistant Dravet syndrome. Early diagnosis resulting in earlier treatment with these and other medications may improve prognosis of long-term outcomes, including less severity of cognitive, motor, and behavioral impairments. New rescue medication formulations can now manage acute seizures and help prevent status epilepticus via intranasal, buccal, and intramuscular routes as opposed to rectal administration. Preventing status epilepticus and generalized tonic-clonic seizures could potentially lower the risk of sudden unexpected death in epilepsy. With this changing landscape in diagnostic and treatment options comes questions and controversies for the practicing clinician, especially as diagnostic techniques outpace clinical treatment strategies. Critical decision points include when to start treatment, what pharmacotherapy combinations to try first, which rescue medication to recommend, and how to advise parents on controversial topics (e.g., immunizations). Given that most patients require polypharmacy, clinicians must be cognizant of drug-drug interactions between new medicines, existing anti-epileptic drugs, and other medications to manage comorbidities and must have an understanding of available therapeutic drug monitoring strategies and pharmacokinetic parameters. This review places new diagnostic, treatment and acute care options into the modern era and provides an overview of the challenges and opportunities facing the pediatric epileptologist in this rapidly changing landscape.

Topics: Anticonvulsants; Cannabidiol; Child; Dioxolanes; Epilepsies, Myoclonic; Fenfluramine; Genetic Testing; Humans

Highly purified cannabidiol (CBD) has demonstrated efficacy with an acceptable safety profile in patients with Lennox-Gastaut syndrome or Dravet syndrome in randomized, double-blind, add-on, controlled phase 3 trials. It is important to consider the possibility of drug-drug interactions (DDIs). Here, we review six trials of CBD (Epidiolex/Epidyolex; 100 mg/mL oral solution) in healthy volunteers or patients with epilepsy, which investigated potential interactions between CBD and enzymes involved in drug metabolism of common antiseizure drugs (ASDs). CBD did not affect CYP3A4 activity. Induction of CYP3A4 and CYP2C19 led to small reductions in exposure to CBD and its major metabolites. Inhibition of CYP3A4 activity did not affect CBD exposure and caused small increases in exposure to CBD metabolites. Inhibition of CYP2C19 activity led to a small increase in exposure to CBD and small decreases in exposure to CBD metabolites. One potentially clinically important DDI was identified: combination of CBD and clobazam (CLB) did not affect CBD or CLB exposure, but increased exposure to major metabolites of both compounds. Reduction of CLB dose may be considered if adverse reactions known to occur with CLB are experienced when it is coadministered with CBD. There was a small increase of exposure to stiripentol (STP) when coadministered with CBD. STP had no effect on CBD exposure but led to minor decreases in exposure to CBD metabolites. Combination of CBD and valproate (VPA) did not cause clinically important changes in the pharmacokinetics of either drug, or 2-propyl-4-pentenoic acid. Concomitant VPA caused small increases in exposure to CBD metabolites. Dose adjustments are not likely to be necessary when CBD is combined with STP or VPA. The safety results from these trials were consistent with the known safety profile of CBD. These trials indicate an overall low potential for DDIs between CBD and other ASDs, except for CLB.

Topics: Anticonvulsants; Cannabidiol; Clinical Trials as Topic; Clobazam; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP2C19 Inducers; Cytochrome P-450 CYP2C19 Inhibitors; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inducers; Cytochrome P-450 CYP3A Inhibitors; Dioxolanes; Dose-Response Relationship, Drug; Drug Interactions; Drug Therapy, Combination; Epilepsies, Myoclonic; Fatty Acids, Monounsaturated; Humans; Lennox Gastaut Syndrome; Valproic Acid

This is the third of three papers that summarize the second symposium on Transition in Epilepsies held in Paris in June 2016. This paper focuses on treatment issues that arise during the course of childhood epilepsy and make the process of transition to adult care more complicated. Some AEDs used during childhood, such as stiripentol, vigabatrin, and cannabidiol, are unfamiliar to adult epilepsy specialists. In addition, new drugs are being developed for treatment of specific childhood onset epilepsy syndromes and have no indication yet for adults. The ketogenic diet may be effective during childhood but is difficult to continue in adult care. Regional adult epilepsy diet clinics could be helpful. Polytherapy is common for patients transitioning to adult care. Although these complex AED regimes are difficult, they are often possible to simplify. AEDs used in childhood may need to be reconsidered in adulthood. Rescue medications to stop prolonged seizures and clusters of seizures are in wide home use in children and can be continued in adulthood. Adherence/compliance is notoriously difficult for adolescents, but there are simple clinical approaches that should be helpful. Mental health issues including depression and anxiety are not always diagnosed and treated in children and young adults even though effective treatments are available. Attention deficit hyperactivity disorder and aggressive behavior disorders may interfere with transition and successful adulthood but these can be treated. For the majority, the adult social outcome of children with epilepsy is unsatisfactory with few proven interventions. The interface between pediatric and adult care for children with epilepsy is becoming increasingly complicated with a need for more comprehensive transition programs and adult epileptologists who are knowledgeable about special treatments that benefit this group of patients.

Topics: Adolescent; Adult; Age Factors; Anticonvulsants; Cannabidiol; Child; Congresses as Topic; Diet, Ketogenic; Dioxolanes; Epilepsy; Humans; Transition to Adult Care; Treatment Outcome; Vigabatrin; Young Adult

In recent randomized, placebo-controlled, phase III trials, highly purified cannabidiol demonstrated efficacy with an acceptable safety profile in patients with Lennox-Gastaut syndrome or Dravet syndrome. It is anticipated that antiepileptic drugs such as stiripentol and valproate will be administered concomitantly with cannabidiol.. This trial evaluated the effect of cannabidiol on steady-state pharmacokinetics of stiripentol or valproate in patients with epilepsy, and the safety and tolerability of cannabidiol.. In total, 35 patients were recruited to the stiripentol arm (n = 14) or the valproate arm (n = 21). Both the safety and the pharmacokinetic populations of the stiripentol arm comprised 14 patients (2 placebo; 12 cannabidiol). The safety population of the valproate arm comprised 20 patients (4 placebo; 16 cannabidiol; one withdrew before receiving treatment); the pharmacokinetic population comprised 15 patients (3 placebo; 12 cannabidiol). Concomitant cannabidiol led to a small increase in stiripentol exposure (17% increase in maximum observed plasma concentration [C. The clinical relevance of the increase in stiripentol exposure is unknown; patients receiving cannabidiol and stiripentol concomitantly should be monitored for adverse reactions as individual patient responses may vary. Coadministration of cannabidiol did not affect the pharmacokinetics of valproate or its metabolite, 4-ene-VPA, in adult patients with epilepsy. Safety results were consistent with the known safety profile of cannabidiol at a dose of 20 mg/kg/day. Clinicaltrials.gov: NCT02607891.

Topics: Adolescent; Adult; Anticonvulsants; Area Under Curve; Cannabidiol; Dioxolanes; Dose-Response Relationship, Drug; Double-Blind Method; Drug Interactions; Drug Therapy, Combination; Epilepsy; Female; Humans; Male; Middle Aged; Valproic Acid; Young Adult

GW Pharmaceuticals' formulation of highly purified cannabidiol oral solution is approved in the United States for seizures associated with Lennox-Gastaut and Dravet syndromes in patients aged ≥2 years, for which clobazam, stiripentol, and valproate are commonly used antiepileptic drugs. This open-label, fixed-sequence, drug-drug interaction, healthy volunteer trial investigated the impact of cannabidiol on steady-state pharmacokinetics of clobazam (and N-desmethylclobazam), stiripentol, and valproate; the reciprocal effect of clobazam, stiripentol, and valproate on cannabidiol and its major metabolites (7-hydroxy-cannabidiol [7-OH-CBD] and 7-carboxy-cannabidiol [7-COOH-CBD]); and cannabidiol safety and tolerability when coadministered with each antiepileptic drug. Concomitant cannabidiol had little effect on clobazam exposure (maximum concentration [C

Topics: Adult; Anticonvulsants; Cannabidiol; Clobazam; Cytochrome P-450 CYP2C19; Dioxolanes; Drug Interactions; Female; Genotype; Healthy Volunteers; Humans; Male; Valproic Acid