Midazolam Oromucosal Solution for the Management of Prolonged Convulsive Seizures in Adult Outpatients: Addressing Unmet Needs in Europe

Abstract

Rapid treatment of prolonged convulsive seizures (PCS), preferably within the first few minutes after onset in most patients, is important to prevent progression to life-threatening status epilepticus (SE) and its associated complications. In community settings, benzodiazepine rescue medication for PCS is often administered by non-medical caregivers to achieve timely seizure control. Until recently, rectally administered diazepam was the only treatment approved by the European Medicines Agency (EMA) for PCS in adults. However, an oromucosal midazolam formulation, which has been approved by the EMA for PCS treatment in paediatric patients for over a decade, has now also received such approval for use in adults. The aim of this narrative review is to describe the role of midazolam oromucosal solution in the management of PCS in adults in community settings in Europe. The approval of midazolam oromucosal solution was supported by pharmacokinetic modelling studies, which extrapolated the efficacy of oromucosal midazolam to adults through exposure matching, alongside European clinical studies where oromucosal midazolam was used as an off-label treatment, thereby demonstrating its effectiveness for treating PCS and SE in adults and paediatric patients. With this approval, adult patients across Europe now have access to an alternative to rectal diazepam that is easy to administer, socially acceptable, and pharmacokinetically appropriate. The increased willingness of caregivers to administer rescue medication by the oromucosal compared with the rectal route should encourage its appropriate use, thus potentially improving outcomes for adults with PCS in Europe.

Plain Language Summary

Prolonged convulsive seizures (PCS) can occur in people of all ages, can be difficult to manage, and may begin at home, work, or school. If these seizures last for more than 5 min, they can lead to life-threatening status epilepticus (SE), which may have serious complications. PCS are usually managed with medicines called benzodiazepines, such as midazolam, diazepam and lorazepam, that are often given to the patient by caregivers and family members. Until recently, diazepam administered into the rectum was the only treatment approved by the European Medicines Agency (EMA) for PCS in adults. However, rectal treatments can be difficult to administer and are not suitable to use outside a hospital in adults experiencing seizures because it is not socially acceptable. Since 2011, an effective treatment has been available in Europe to manage PCS in children—a solution of midazolam that can be placed on the gums (called oromucosal midazolam). Recently, this medicine was approved by the EMA for use in adults to manage PCS and prevent SE. Thus, adult patients across Europe now have access to a product that is easier to administer and more socially acceptable than rectal diazepam. Caregivers of people who experience PCS are more confident and prefer to administer rescue medication by the oromucosal than by the rectal route. Therefore, oromucosal midazolam may improve outcomes for adult patients with PCS in Europe.

Key Points

Benzodiazepine rescue medication is often administered in community settings to provide rapid treatment of prolonged convulsive seizures (PCS), preferably within the first few minutes after onset in many cases, to prevent status epilepticus.

In Europe, an oromucosal formulation of midazolam, which has been available to treat paediatric patients, was recently approved for use in adults with PCS, thus ensuring broader access to this treatment.

Adult patients across Europe can now receive an easy-to-administer, socially acceptable, and pharmacokinetically appropriate treatment to manage PCS in the community setting.

Introduction

Prolonged convulsive seizures (PCS) require timely intervention to prevent progression to status epilepticus (SE), a medical emergency associated with significant short- and long-term consequences due to neuronal damage [1–3]. Most tonic-clonic seizures stop within 2 min, so PCS is defined as major motor seizures lasting for ≥ 2 min that have not yet progressed to SE (defined as seizures lasting ≥ 5 min) [1, 4, 5]. To prevent progression to SE and reduce the risk of seizure-related morbidity and mortality, PCS treatment with rescue medication is recommended within 5 min of seizure onset in most cases.

Since most PCS occur in a community setting (e.g., at home, school, or work), timely administration of rescue medication often depends on non-medical caregivers or family members [1, 4]. Benzodiazepines, including clonazepam, diazepam, lorazepam, and midazolam, are the first-line rescue medications for PCS [6]. These drugs exert their anticonvulsant effects by potentiating the gamma-aminobutyric acid (GABA) neurotransmitter system. The benzodiazepine-induced activation of the GABA_A receptor leads to reduced neuronal excitation [7]. Although benzodiazepines are available in various formulations—intravenous, intramuscular, oral, sublingual, oromucosal, and intranasal—intravenous administration is typically reserved for hospital settings with established venous access [6, 8]. In community settings, non-intravenous formulations are preferred, with key attributes including rapid onset of effect, ease of administration, and social acceptability. Among these, oromucosal administration has emerged as a favourable option [6, 8–11].

In Europe, oromucosal midazolam has been widely used for the management of PCS in paediatric patients (infants, toddlers, children, and adolescents, aged 3 months to 18 years) since its European Medicines Agency (EMA) approval in 2011 [8, 11]. Until recently, midazolam oromucosal solution was not approved by the EMA to treat PCS in adults but, being a preferred treatment option, it was commonly used off label for this purpose [10–14]. The recent EMA approval of midazolam oromucosal solution for adult PCS has eliminated the ensuing administrative and reimbursement challenges associated with off-label prescription of the product in this patient population, thereby facilitating broader access to this treatment.

The aim of this narrative review is to provide an overview of the role of midazolam oromucosal solution in the management of PCS in adults and to discuss how the characteristics of this formulation help to address previously unmet needs in adults who experience PCS in community settings in the EU and UK.

Methods

Literature discussed in this review was identified via a PubMed database search, with no date or language limits. Search terms included prolonged convulsive seizures, status epilepticus, adults, midazolam, oromucosal, and buccal. The reference lists of identified articles were also searched for relevant articles.

Benzodiazepine Rescue Formulations Used in Community Settings

Routes of Administration

The goal of treatment for PCS is to stop clinical and electrographic seizure activity as quickly as possible; so rescue medications should have rapid and consistent absorption, leading to a rapid onset of effect [9, 15]. Without sacrificing efficacy, rescue treatments for PCS that occur in community settings should also have several practical attributes, as outlined in Table 1 [6, 8, 9, 11, 15–18]. Importantly, administration should be as easy, quick, and stress free as possible for patients’ non-medical caregivers and family members.

Table 1.

Characteristics of benzodiazepine rescue medications for the treatment of prolonged convulsive seizures in community settings according to route of administration [6, 8, 9, 11, 15–18]

Ideal characteristics for use in community settings	Route of administrationa
	Oromucosal	Rectal	Sublingual	Intranasal	Oralb	Intravenous	Intramuscular
Rapid onset of effect	✓	✓	✓	✓	X	✓	✓
Minimal caregiver training/experience required	✓	✓	✓	✓	✓	X	X
Easy for caregivers to administer	✓	X	✓	✓	✓	X	X
No pain or discomfort	✓	X	✓	X	✓	X	X
Patient cooperation not required	✓	✓	X	✓	X	✓	✓
No risk of aspiration	X	✓	X	✓	X	✓	✓
Seizure-related body movements do not affect administrationc	✓	X	✓	✓	✓	X	X
Seizure-related facial movementsd and salivation and/or nasal secretions do not affect administration	X	✓	X	X	X	✓	✓
Patient dignity maintained	✓	X	✓	✓	✓	✓	✓
Socially acceptable	✓	X	✓	✓	✓	✓	✓

^aAvailable routes of administration differ for individual benzodiazepines.

^bTraditional tablet or capsule.

^cAlthough seizure-related body movements make it more difficult to administer any drug, certain routes of administration are easier than others in such situations.

^dSuch as jaw clenching.

Like intravenous administration, which can only be undertaken by medical professionals in the hospital setting, the intramuscular administration route requires advanced training and can be challenging for non-medical caregivers to use when patients are actively convulsing in the community setting [6, 9]. When administered by inexperienced individuals, variation in the thickness of subcutaneous fat can inadvertently result in medication intended for intramuscular administration being delivered subcutaneously, which increases the time to onset of an anticonvulsant effect [16].

In contrast to oral tablet or capsule benzodiazepine formulations, which are slowly absorbed and not suitable for the emergency treatment of PCS, oromucosal or sublingual administration results in direct absorption of the medication across the oral mucosa into the systemic circulation without the first-pass metabolism that occurs in the gastrointestinal tract after traditional oral administration [8, 9]. Unlike the sublingual route, oromucosal administration between the lower gum and inside of the cheek does not require the caregiver to part the patient’s jaws, which may be clenched during PCS, decreasing the risk of caregiver injury (bitten fingers) [6, 16, 18].

The intranasal route also avoids first-pass metabolism, but variations in nasal secretions and the health of the nasal mucosa can affect absorption and bioavailability [9, 11, 15]. Variable absorption may also be an issue for oromucosal or sublingual administration in cases of ictal hypersalivation [6, 11, 16] and will be influenced by mucosal characteristics and integrity [19].

Unlike the other routes of administration that avoid first-pass metabolism, rectal administration has poor social acceptability, particularly when used in public areas. Removal of clothing and positioning of seizing adults for rectal administration can be difficult and delay administration [6, 8, 9].

EMA-Approved Formulations

Historically in Europe, PCS in adults were often managed using rectal diazepam, which is approved by the EMA for patients weighing ≥ 10 kg (i.e. approximately ≥ 1 year of age) [6, 20]. Midazolam oromucosal solution has been approved by the EMA for the treatment of PCS in paediatric patients for over a decade; however, until recently, there were no EMA-approved alternatives to rectal diazepam for adults.

Rectal diazepam is an effective treatment [6], but its poor social acceptability in older patients means it is more suitable for the management of seizure emergencies in infants [9]. European and UK guidelines have recommended off-label oromucosal midazolam for PCS in adults [21–24]. However, in the absence of a licensed alternative to rectal diazepam, oromucosal midazolam has been used off label to treat seizure emergencies in adults, and, in some cases, orally administered benzodiazepines (unsuitable for PCS due to their slow absorption) have also been prescribed [10, 12].

Midazolam oromucosal solution (supplied in prefilled syringes) and midazolam intranasal spray are now both approved by the EMA for the treatment of PCS in adults (the latter in specific countries) [25, 26], providing easily administered, socially acceptable, and pharmacokinetically appropriate alternative options to rectal diazepam for adult patients. However, to avoid nasal irritation [27] and obtain more reliable absorption [28], oromucosal administration of midazolam may be preferred to intranasal administration [29]. Additionally, the requirement for specific head orientation, administration angle, and insertion depth, and the impact of breathing rate and nasal physiology on drug delivery may make intranasal administration more difficult and slower than oromucosal administration [30].

Midazolam Oromucosal Solution as Rescue Medication for Prolonged Convulsive Seizures in Adults

Efficacy

The efficacy of midazolam oromucosal solution for the treatment of PCS in children is well established, with numerous studies having shown oromucosal midazolam to be at least as effective as rectal diazepam for the termination of PCS in paediatric patients [31–38]. Compared with rectal diazepam, shorter response times and improved caregiver satisfaction have been reported for children treated with oromucosal midazolam [31, 35, 39]. Oromucosal midazolam has also been reported to be as effective as intramuscular midazolam and intravenous diazepam for the treatment of PCS in children [40–42].

In addition to extensive clinical trial data supporting the use of oromucosal midazolam for the management of PCS in paediatric patients, several notable European studies have evaluated the effectiveness of oromucosal midazolam for the emergency treatment of seizures in adults, including PCS and convulsive SE (Table 2) [13, 18, 43]. The results of these studies suggest the oromucosal midazolam solution to be similarly effective in both paediatric and adult patients [13, 18, 43].

Table 2.

European studies of oromucosal midazolam administered off label for the emergency treatment of seizures in adults

Study	Design	Patients	Treatment	Efficacy	Safety
Meléndez et al. (2006) [43]	Prospective 1-year study conducted in a residential centre	Patients with severe encephalopathy who had seizures lasting ≥ 1 min during the study period (n = 10; aged 27–61 years)	OMM 5–15 mg  One 5 mg dose for seizures lasting ≥ 1 min  2nd dose for seizures lasting > 2 min  3rd dose ± RD 5 mg for seizures lasting > 3 min	52 seizures (32 generalised tonic-clonic, 18 myoclonic, 2 atonic) treated  42 (80.8%) seizures ceased in ≤ 2 min with a single dose  8 (15.4%) seizures required a 2nd dose  2 (3.8%) seizures required a 3rd dose + RD No progression to SE or need for hospitalisation after OMM	Well tolerated, with no cardiorespiratory complications
Nakken et al. (2011) [18]	Prospective 8-month study conducted in a residential centre	Patients with severe, difficult-to-treat epilepsy who had convulsive or non-convulsive seizures lasting > 5 min during the study period (n = 22; aged 25–68 [mean 42.4] years)	OMM 10–30 (mean 26.0) mg or RD 10–20 (mean 15.5) mg, given alternately and dosed according to written protocols based on earlier experiences	80 seizures treated (23 serial convulsive, 23 serial non-convulsive serial, 20 non-convulsive SE, 14 convulsive SE) with OMM (43 episodes) or RD (37 episodes) Convulsive SE  Mean time to treatment of 6.1 min for OMM and 6.3 min for RD  Mean time to seizure termination of 2.8 min after OMM vs 5.0 min after RD (p = 0.012) Serial convulsive or non-convulsive seizures:  Mean time to treatment of 25.4 min for OMM and 24.7 min for RD  Mean to seizure termination of 7.6 min after OMM and 7.4 min after RD Overall treatment success rate (cessation of seizure activity < 10 min after drug administration without relapse in ≤ 2 h): 74.4% with OMM and 83.3% with RD	OMM AEs (% seizure episodes)  None (64.2%)  Tiredness for > 2 h (20.9%)  Ataxia (4.7%)  Prolonged bitter taste in mouth (14.0%)  Mouth numbness (7.0%) RD AEs (% seizure episodes)  None (40.5%)  Tiredness for > 2 h (48.6%)  Ataxia (4.7%)
Shankar et al. (2021) [13]	Retrospective, observational, cross-sectional study conducted in secondary care centres for PWE in the community (2016–17)	Patients aged ≥ 18 (mean 41.0) years with written care plans for OMM rescue medication (n = 146)	Initial OMM dose (% seizure episodes)  5.0 mg (9.6%)  7.5 mg (0.7%)  10.0 mg (84.9%)  15.0 mg (4.1%)  20.0 mg (0.7%)  35.0 mg (0.7%) Mean cumulative OMM dose 10.3 mg	146 seizures treated (106 generalised tonic-clonic, 19 focal, 4 myoclonic, 17 other or not recorded) Seizure cessation achieved after one OMM dose in 124 (82.9%) patients Mean time until seizure cessation  17.9 min after OMM 5 mg (n = 4)  5.5 min after OMM 10 mg (n = 38) Ambulance callouts (% patients):  Yes (9)  No (82)  Not known (9) Hospital admission (% patients)  Yes (7)  No (88)  Not known (5)	Well tolerated

AEs adverse events, OMM oromucosal midazolam, PWE people with epilepsy, RD rectal diazepam, SE status epilepticus

In a small study of adult residents (n = 10) in a Spanish centre for individuals with severe encephalopathy, prolonged seizures lasting > 1 min were treated with midazolam 5 mg administered oromucosally, followed by a second 5 mg dose if seizures continued for > 2 min, and a third dose if seizures continued for > 3 min [43]. Of 52 seizures lasting ≥ 1 min, 62% of which were generalised tonic-clonic seizures, 80.8% were effectively terminated in ≤ 2 min with a single dose of oromucosal midazolam 5 mg. None of the patients treated with oromucosal midazolam developed SE or had to be transferred to hospital.

Oromucosal administration of midazolam was at least as effective as rectal diazepam when used as emergency treatment for the alleviation of convulsive SE in a prospective study of adults living in a Norwegian residential centre for people with difficult-to-treat epilepsy [18]. In total, 80 emergency seizure episodes in 22 patients were treated with oromucosal midazolam (43 episodes) or rectal diazepam (37 episodes), including 14 episodes of convulsive SE (lasting ≥ 5 min). In cases of convulsive SE, oromucosal midazolam or rectal diazepam were given promptly, ideally no later than 5 mi after seizure onset. Treatment success was defined as cessation of seizure activity within 10 min and no seizure relapse within 2 h of drug administration. The doses given in this study were preplanned and based on earlier experiences with the individual patients (overall mean doses of 15.5 mg and 26.0 mg for midazolam and diazepam, respectively). For convulsive SE, mean time to drug administration was similar for oromucosal midazolam and rectal diazepam (6.1 and 6.3 min, respectively), but cessation of convulsive SE occurred significantly more quickly with oromucosal midazolam than with rectal diazepam (2.8 vs 5.0 min, respectively; p = 0.012). There was no significant difference in time to cessation of other seizure types (convulsive and non-convulsive serial seizures and non-convulsive SE) treated with oromucosal midazolam or rectal diazepam (7.6 vs 7.4 min, respectively). There was also no significant difference in the overall success rate between oromucosal midazolam and rectal diazepam (74.4 vs 83.3%, respectively). A trend towards more relapses within the first 2 h after administration of midazolam was suggested as possibly being a result of the drug’s relatively short elimination half-life (1.5–3.5 h) [6, 44]. The oromucosal route of administration was favoured by all 34 nursing staff involved in the study and by six of the seven patients who received oromucosal midazolam and rectal diazepam for separate seizure episodes during the study period [18].

Using a retrospective observational study design, off-label use of oromucosal midazolam was investigated in 146 adults with epilepsy living in community settings in the UK [13]. To be included in the study sample, a written patient care plan for the administration of oromucosal midazolam as a rescue medication for seizures was required, as well as a recent seizure episode requiring emergency treatment with oromucosal midazolam. The most common seizure type treated with oromucosal midazolam was generalized tonic-clonic (72.6%), and the most common initial dose was 10 mg (84.9%). One dose of oromucosal midazolam was sufficient to achieve cessation of 82.9% of seizures, and < 10% of seizures led to post-treatment ambulance callouts and hospital admissions. Following administration of oromucosal midazolam 10 mg, time to seizure cessation was recorded for 38 patients, with a mean time to cessation of 5.5 min.

Safety

Based on studies of midazolam oromucosal solution for the treatment of PCS in children, as well as its extensive use in children in Europe over the last decade, oromucosal midazolam is considered a well-tolerated paediatric treatment option with a well-established safety profile [31–38]. Safety data from European studies evaluating use of oromucosal midazolam as emergency treatment in adults with epilepsy indicate that it is also well tolerated in adult populations, with few adverse events other than potential sedation (reported by 21% of patients) and a bitter aftertaste (reported by 14% of patients) (Table 2) [13, 18, 43].

By virtue of their mechanism of action as GABA_A receptor modulators, benzodiazepines can cause adverse central nervous system reactions, including sedation and respiratory depression [6]. None of the aforementioned European studies in adults reported any adverse respiratory events associated with oromucosal midazolam or secondary to aspiration, the risk of which is minimal, given the small volume of fluid required for administration [18, 43]. Being a short-acting benzodiazepine, midazolam is potentially associated with less prolonged sedation than other EMA-approved emergency treatment options for PCS, as seemed to occur in the Norwegian study, during which tiredness lasting > 2 h occurred less frequently after administration of oromucosal midazolam than after rectal diazepam (21% vs 49%, respectively) [18]. In a questionnaire-based study of adults treated in German epilepsy outpatient clinics, moderate or major sedation was reported by eight of 20 patients with epilepsy who used oromucosal midazolam (median dose 10 mg) as emergency medication [12]. However, the duration of sedation was not reported, and it may be difficult for patients to differentiate between drug-induced sedation and postictal tiredness [12, 18].

Cost Effectiveness

Limited data are available regarding the cost effectiveness of midazolam oromucosal solution, and those that are available are from studies in children/adolescents. From the perspective of various European countries, modelling studies identified cost savings and increased quality-adjusted life-years with the use of oromucosal midazolam for the treatment of PCS in children when compared with rectal diazepam [45–48]. Despite a higher acquisition cost for oromucosal midazolam than for rectal diazepam, the model results indicated that oromucosal midazolam is less costly and more beneficial for patients. This resulted from the increased social acceptability and, thus, willingness of caregivers to administer an oromucosal treatment in community settings, a lower likelihood of treatment failure due to a simpler treatment process, and an increased anticonvulsant effect resulting in fewer ambulance callouts and hospital admissions for oromucosal treatment [46]. Further, oromucosal midazolam was associated with improved health-related quality of life than was rectal diazepam [46, 47]. Similar to its use in children, oromucosal midazolam is also likely to be just as, if not more, cost effective in adults (given the inconvenience of rectal administration in adults experiencing seizures), but studies are needed to confirm this.

It has been pointed out that patients stand to benefit from drug price cost savings with licensed versus unlicensed oromucosal midazolam use [46]. A UK cost-analysis study determined that, when available, prescription of a multi-pack of oromucosal midazolam prefilled syringes would be a cost-saving option for patients with two or more PCS every 6 months as opposed to single-pack units, which are most suitable for patients with one or fewer such seizures every 6 months [49].

Defining the Appropriate Dose of Oromucosal Midazolam Solution in Adults

Given that PCS (and SE) disease pathophysiology and the effects of benzodiazepines on GABA_A receptors are the same in paediatric and adult patients, pharmacokinetic (PK) extrapolation of efficacy data from clinical trials in older children/adolescents to adults (or vice versa) is a valid alternative to performing additional clinical trials to assess efficacy in adults [50–52]. Observational studies further support the reliability of such extrapolations of efficacy data [53].

Using a population PK model, the efficacy of oromucosal midazolam for PCS treatment in paediatric patients was extrapolated to adults through PK exposure matching. This model confirmed that a 10 mg dose of midazolam oromucosal solution was the most appropriate dose in adults aged ≤ 70 years with a body mass index (BMI) < 34 kg/m² [54]. The extrapolation of exposure was based on the assessment of both midazolam and its active metabolite, after concluding that both compounds exhibit equipotent pharmacodynamic effects [55–57]. The model was developed with data from a phase I bioavailability study evaluating a single 15 mg-dose of midazolam oromucosal solution in adults aged < 70 years with BMI < 34 kg/m² (study protocol identifier: LESVIBUCCO/23/BQ-3). Simulations were conducted to compare midazolam exposure after 10 mg and 15 mg doses in adults with the exposure achieved with midazolam oromucosal solution doses known to be effective for PCS treatment in children and adolescents (2.5 mg, 5 mg, 7.5 mg and 10 mg). Administration of midazolam oromucosal solution 10 mg to adults was predicted to result in a similar exposure (area under the plasma–concentration time curve from time zero to infinity for midazolam and its active metabolite) to that observed after administration of effective doses in children and adolescents (Fig. 1). Extrapolation of the efficacy of midazolam oromucosal solution 10 mg in children and adolescents to adults was further supported by the findings of the aforementioned European studies investigating off-label use of oromucosal midazolam 10 mg in adults [13, 18, 43].

Fig. 1.

Simulated area under the plasma concentration–time curve from time zero to infinity (AUC_0–inf) for midazolam plus its active metabolite after administration of midazolam oromucosal solution 10 mg in adult patients and after administration of effective doses of oromucosal midazolam in paediatric patients [54]. The dashed lines correspond to the 5th and 95th percentiles of the paediatric reference range for age < 10 years

Conclusions

Early termination of PCS is essential to avoid progression to life-threatening convulsive SE, which is associated with both short- and long-term systemic and potential neurological consequences. Therefore, it is important that caregivers can swiftly manage PCS occurring at home and in community settings. Benzodiazepines are the drugs of choice for the treatment of PCS, with midazolam oromucosal solution providing a rapidly effective treatment option that is easily administered and socially acceptable to administer, irrespective of where in the community PCS occur. These characteristics of midazolam oromucosal solution are particularly important for the treatment of PCS in adults, given that adults are more likely than infants/children to experience PCS in very public environments (such as places of work or higher education) and to require treatment to be administered by caregivers who are not close family members.

The recent EMA approval of midazolam oromucosal solution for the treatment of PCS in adults provides clinicians, patients, and caregivers with an additional treatment option (in terms of drug and formulation) and allows customisation of treatment on the basis of patient characteristics, needs, and preferences. The approval will also ensure that patients across Europe have access to a treatment that is acceptable to both them and their caregivers and that caregivers are prepared to administer it in community settings. It has been reported that training of caregivers with the use of midazolam oromucosal solution increased their confidence in administering it for emergency management of seizures in children [58]; similar effects of training can be anticipated in caregivers of adults, highlighting the importance of PCS awareness and management options. The availability of midazolam oromucosal solution for the treatment of PCS in adults will also allow adolescent patients who currently rely on oromucosal midazolam for the treatment of PCS to seamlessly transition from paediatric to adult treatment.

Compared with rectal diazepam, historically the only EMA-approved option for PCS in adult patients, the increased willingness of caregivers to administer oromucosal midazolam will likely improve outcomes and help avoid emergency ambulance callouts and hospitalisations for PCS whether untreated or treated unsuccessfully in the community setting. The recent EMA approval of oromucosal midazolam 10 mg prefilled syringes for adults will also help to deter its inappropriate off-label use and the prescription of unsuitable orally administered benzodiazepines for the treatment of PCS in adult patients.

Funding

The development of the manuscript and open access publishing fee were supported by Neuraxpharm.

Declarations

Conflict of Interest

MC has received research grants from Eisai and Angelini Pharma; fees for speaking and advisory boards from Biocodex, Arvelle, Neuraxpharm, UCB, Eisai, Jazz Pharmaceuticals, and Livanova; and fees for teaching activities from Angelini Pharma and UCB Pharma. IKN and MFF are full-time employees of Neuraxpharm. PM and CV are full-time employees of CTI Laboratory Services.

Availability of Data and Material

Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.

Ethics Approval

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Consent to Participate

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Consent for publication

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Code Availability

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Author Contributions

MC: conceptualization, methodology, writing and original draft preparation, writing – review and editing. IKN and MFF: conceptualization, methodology, funding acquisition, writing – review & editing. PM and CV: methodology, writing – review & editing. All authors approved the final version for publication and agree to be accountable for the work presented.