Results From an Italian Expanded Access Program on Cannabidiol Treatment in Highly Refractory Dravet Syndrome and Lennox–Gastaut Syndrome

Iannone, Luigi Francesco; Arena, Gabriele; Battaglia, Domenica; Bisulli, Francesca; Bonanni, Paolo; Boni, Antonella; Canevini, Maria Paola; Cantalupo, Gaetano; Cesaroni, Elisabetta; Contin, Manuela; Coppola, Antonietta; Cordelli, Duccio Maria; Cricchiuti, Giovanni; Giorgis, Valentina De; Leva, Maria Fulvia de; Rinaldis, Marta De; D’Orsi, G.; Elia, Maurizio; Galimberti, Carlo; Morano, Alessandra; Granata, Tiziana; Guerrini, Renzo; Lodi, Monica; Neve, Angela La; Marchese, Francesca; Masnada, Silvia; Michelucci, Roberto; Nosadini, Margherita; Pilolli, Nicola; Pruna, Dario; Ragona, Francesca; Rosati, Anna; Santucci, Margherita; Spalice, Alberto; Pietrafusa, Nicola; Striano, Pasquale; Tartara, Elena; Tassi, Laura; Papa, Amanda; Zucca, Claudio; Russo, Emilio; Mecarelli, Oriano

doi:10.3389/fneur.2021.673135

Cited by 26 publications

(30 citation statements)

References 21 publications

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“…Increases in transaminases at similar dose levels were also found in open‐label extensions of these trials as well as other open‐label studies with patients with epilepsy with durations of up to 2 years (Devinsky et al., 2016 , 2019 ; Szaflarski et al., 2018 ; Sands et al., 2019 ; Thiele et al., 2019 ; D’Onofrio et al., 2020 ; Iannone et al., 2021 ).…”

Section: Limitations and Uncertainties In Scientific Literaturesupporting

confidence: 70%

“…Several open‐label trials also reported the occurrence of diarrhoea as the most common and consistently observed gastrointestinal effect associated with oral intake of CBD, albeit none of them included placebo or control groups. Most of these studies were again on patients suffering from epilepsy of various aetiologies (age range 0.4–62 years), whereby purified plant‐derived CBD or, in one case, also synthetic (+)CBD was given as adjunctive therapy to multiple antiepileptic medication (Devinsky et al., 2016 , 2019 ; Klotz et al., 2019 ; Laux et al., 2019 ; Sands et al., 2019 ; D'Onofrio et al., 2020 ; Gaston et al., 2021 ; Iannone et al., 2021 ; Patel et al., 2021 ). These studies included between 26 and 607 patients, who ingested doses of 14 up to 32 mg/kg bw per day over periods varying between 12 weeks up to 2 years.…”

Section: Limitations and Uncertainties In Scientific Literaturementioning

confidence: 99%

See 1 more Smart Citation

Statement on safety of cannabidiol as a novel food: data gaps and uncertainties

Turck¹,

Bohn²,

Castenmiller³

et al. 2022

EFS2

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The European Commission has determined that cannabidiol (CBD) can be considered as a novel food (NF), and currently, 19 applications are under assessment at EFSA. While assessing these, it has become clear that there are knowledge gaps that need to be addressed before a conclusion on the safety of CBD can be reached. Consequently, EFSA has issued this statement, summarising the state of knowledge on the safety of CBD consumption and highlighting areas where more data are needed. Literature searches for both animal and human studies have been conducted to identify safety concerns. Many human studies have been carried out with Epidyolex ® , a CBD drug authorised to treat refractory epilepsies. In the context of medical conditions, adverse effects are tolerated if the benefit outweighs the adverse effect. This is, however, not acceptable when considering CBD as a NF. Furthermore, most of the human data referred to in the CBD applications investigated the efficacy of Epidyolex (or CBD) at therapeutic doses. No NOAEL could be identified from these studies. Given the complexity and importance of CBD receptors and pathways, interactions need to be taken into account when considering CBD as a NF. The effects on drug metabolism need to be clarified. Toxicokinetics in different matrices, the half‐life and accumulation need to be examined. The effect of CBD on liver, gastrointestinal tract, endocrine system, nervous system and on psychological function needs to be clarified. Studies in animals show significant reproductive toxicity, and the extent to which this occurs in humans generally and in women of child‐bearing age specifically needs to be assessed. Considering the significant uncertainties and data gaps, the Panel concludes that the safety of CBD as a NF cannot currently be established.

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Section: Limitations and Uncertainties In Scientific Literaturesupporting

confidence: 70%

Section: Limitations and Uncertainties In Scientific Literaturementioning

confidence: 99%

Statement on safety of cannabidiol as a novel food: data gaps and uncertainties

Turck¹,

Bohn²,

Castenmiller³

et al. 2022

EFS2

View full text Add to dashboard Cite

show abstract

“…Cannabidiol was also associated with improvements in overall condition assessed using the Caregiver Global Impression of Change, as well as increases in seizure-free days. Longer term efficacy and safety (up to 3 years) has been determined in an open-label extension of the pivotal phase III trials [ 67 , 68 ], and importantly from an expanded access programme confirming its efficacy in real-world clinical practice [ 69 – 72 ].…”

Section: Highly Purified Cannabidiol (Cbd)mentioning

confidence: 99%

A Practical Guide to the Treatment of Dravet Syndrome with Anti-Seizure Medication

Strzelczyk

Schubert‐Bast

2022

CNS Drugs

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Dravet syndrome is a severe developmental and epileptic encephalopathy characterised by refractory seizures and cognitive dysfunction. The treatment is challenging, not least because the seizures are highly drug resistant, requiring multiple anti-seizure medications (ASMs), while some ASMs can exacerbate seizures. Initial treatments include the broad-spectrum ASMs valproate (VPA), and clobazam (CLB) in some regions; however, they are generally insufficient to control seizures. With this in mind, three adjunct ASMs have been approved specifically for the treatment of seizures in patients with Dravet syndrome: stiripentol (STP) in 2007 in the European Union and 2018 in the USA, cannabidiol (CBD) in 2018/2019 (in combination with CLB in the European Union) and fenfluramine (FFA) in 2020. These "add-on" therapies (mostly to VPA/ CLB) are used as escalation therapies, with the choice dependent on availability in different countries, patient characteristics and caregiver preferences. Topiramate is also frequently used, with evidence of efficacy in Dravet syndrome, and there is anecdotal evidence of efficacy with bromide, which is frequently used in Germany and Japan. With a growing treatment landscape for Dravet syndrome, there can be practical challenges for clinicians, particularly with issues associated with polypharmacy. This practical guide provides an overview of these main ASMs including their indications/contraindications, mechanism of action, efficacy, safety and tolerability profile, dosage requirements, and laboratory and clinical parameters to be evaluated. Standard laboratory and clinical parameters include blood counts, liver function tests, serum concentrations of ASMs, monitoring the growth of children, as well as weight loss and acceleration of behavioural problems. Regular cardiac monitoring is also important with FFA as it has previously been associated with cases of cardiac valve disease when used in adults at high doses (up to 120 mg/day) in combination with phentermine as a therapy for obesity. Importantly, no signs of heart valve disease have been documented to date at the low doses used in patients with developmental and epileptic encephalopathies. In addition, potential drug-drug interactions and their consequences are a key consideration in everyday practice. Interactions that potentially require dosage adjustments to alleviate adverse events include the following: STP + CLB resulting in increased plasma concentrations of CLB and its active metabolite norclobazam may increase somnolence, and an interaction with STP and VPA may increase gastrointestinal adverse events. Cannabidiol has a bi-directional interaction with CLB producing an increase in plasma concentrations of 7-OH-CBD and norclobazam resulting in the potential for increased somnolence and sedation. In addition, CBD is associated with elevations of liver transaminases particularly in patients taking concomitant VPA. The interaction between FFA and STP requires a dose reduction of FFA. Furthermore,

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“…Nowadays, CBD's efficacy was demonstrated in five placebo-controlled pivotal trials, two conducted in LGS (190,191), two in DS (53,192), and one in epilepsy associated with TSC (13). Furthermore, numerous expanded access use studies as well as open label extension of RTCs have been published so far (193)(194)(195)(196)(197)(198) and numerous comprehensive reviews and metanalysis investigating the clinical…”

Section: Epilepsymentioning

confidence: 99%

Cannabidiol and the central nervous system: translating into clinics

Saviano¹,

Raucci²,

Tallarico³

et al. 2021

Pharm Adv

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Cannabis plants contain more than a hundred cannabinoids of which we have only limited knowledge about their effects and exact mechanisms of action. Cannabidiol (CBD) represents one of the most studied; it was discovered at the beginning of the last century while only recently has attracted greater attention. CBD mechanism of action is still unclear and debated; in the plant only the (-) enantiomer can be found and it seems that only the (+) enantiomer is able to bind to the cannabinoid receptors although evidence of a modulation of the endocannabinoid system exists. Furthermore, several other mechanisms have been proposed which may be differently relevant for different disease spanning from ion channels to immune responses and modulation of inflammation. It is a highly lipophilic drug with a peculiar pharmacokinetic which has led to the use and proposal of different formulations and routes of administration; of note, CBD has a complex interaction with cytochromes and is at high risk of drug-drug interaction with many drugs. Nowadays, CBD has been studied for potential efficacy in several pathologies and central nervous system (CNS) diseases are the most promising with clinical studies already in the started and some formulations with CBD already authorized for the treatment of spasticity in multiple sclerosis and seizures in some specific epileptic syndromes such as Lennox-Gastaut or Dravet. This review article is summarizing the relevant studies and perspectives of CBD use in the most relevant areas of CNS disorders also including a detailed description of its proposed mechanism(s) of action, pharmacokinetic characteristics and safety profile.

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Results From an Italian Expanded Access Program on Cannabidiol Treatment in Highly Refractory Dravet Syndrome and Lennox–Gastaut Syndrome

Cited by 26 publications

References 21 publications

Statement on safety of cannabidiol as a novel food: data gaps and uncertainties

Statement on safety of cannabidiol as a novel food: data gaps and uncertainties

A Practical Guide to the Treatment of Dravet Syndrome with Anti-Seizure Medication

Cannabidiol and the central nervous system: translating into clinics

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