Pitolisant 18mg tablets

BackgroundIn people with OSA, excessive daytime sleepiness is a prominent symptom and can persist despite adherence to CPAP, the first-line therapy for OSA. Pitolisant was effective in reducing daytime sleepiness in two 12-week randomized controlled trials (RCTs), one in patients adherent to CPAP (HAROSA 1) and the other in patients refusing or not tolerating CPAP (HAROSA 2).Research QuestionDoes the efficacy and safety of pitolisant persist when these patients take it long-term?Study Design and MethodsAll adults included in the HAROSA 1 and HAROSA 2 RCTs (both pitolisant and placebo arms) were offered pitolisant (up to 20 mg/d) after completion of the short-term double-blind phase (ie, from week 13) in an open-label cohort study. The primary efficacy outcome was the change in Epworth Sleepiness Scale score between baseline and week 52. Safety outcomes were treatment-emergent adverse event(s) (TEAE[s]), serious TEAEs, and special interest TEAEs.ResultsOut of 512 adults included in the two RCTs, 376 completed the 1-year follow-up. The pooled mean difference in Epworth Sleepiness Scale score from baseline to 1 year for the intention-to-treat sample was −8.0 (95% CI, −8.3 to −7.5). The overall proportions of TEAEs, serious TEAEs, and TEAEs of special interest were 35.1%, 2.0%, and 11.1%, respectively, without any significant difference between patients in the initial pitolisant and placebo arms. No cardiovascular safety issues were reported.InterpretationPitolisant is effective in reducing daytime sleepiness over 1 year in adults with OSA, with or without CPAP treatment. Taken for 1 year, it has a good safety profile (including cardiovascular).Trial RegistrationClinicalTrials.gov; Nos.: NCT01071876 and NCT01072968; URL: www.clinicaltrials.gov In people with OSA, excessive daytime sleepiness is a prominent symptom and can persist despite adherence to CPAP, the first-line therapy for OSA. Pitolisant was effective in reducing daytime sleepiness in two 12-week randomized controlled trials (RCTs), one in patients adherent to CPAP (HAROSA 1) and the other in patients refusing or not tolerating CPAP (HAROSA 2). Does the efficacy and safety of pitolisant persist when these patients take it long-term? All adults included in the HAROSA 1 and HAROSA 2 RCTs (both pitolisant and placebo arms) were offered pitolisant (up to 20 mg/d) after completion of the short-term double-blind phase (ie, from week 13) in an open-label cohort study. The primary efficacy outcome was the change in Epworth Sleepiness Scale score between baseline and week 52. Safety outcomes were treatment-emergent adverse event(s) (TEAE[s]), serious TEAEs, and special interest TEAEs. Out of 512 adults included in the two RCTs, 376 completed the 1-year follow-up. The pooled mean difference in Epworth Sleepiness Scale score from baseline to 1 year for the intention-to-treat sample was −8.0 (95% CI, −8.3 to −7.5). The overall proportions of TEAEs, serious TEAEs, and TEAEs of special interest were 35.1%, 2.0%, and 11.1%, respectively, without any significant difference between patients in the initial pitolisant and placebo arms. No cardiovascular safety issues were reported. Pitolisant is effective in reducing daytime sleepiness over 1 year in adults with OSA, with or without CPAP treatment. Taken for 1 year, it has a good safety profile (including cardiovascular). ClinicalTrials.gov; Nos.: NCT01071876 and NCT01072968; URL: www.clinicaltrials.gov Take-Home PointsStudy Question: Pitolisant was effective in reducing daytime sleepiness caused by OSA in two 12-week randomized controlled trials, but does the efficacy and safety of pitolisant persist when these patients take it long term?Results: The efficacy of pitolisant persisted during continuation to 1 year and reduced daytime sleepiness in patients initially on placebo, in both cases with a good safety profile, including no emergent cardiovascular issues.Interpretation: One-year treatment with pitolisant is effective and safe in reducing residual daytime sleepiness in patients with OSA, with or without CPAP. Study Question: Pitolisant was effective in reducing daytime sleepiness caused by OSA in two 12-week randomized controlled trials, but does the efficacy and safety of pitolisant persist when these patients take it long term? Results: The efficacy of pitolisant persisted during continuation to 1 year and reduced daytime sleepiness in patients initially on placebo, in both cases with a good safety profile, including no emergent cardiovascular issues. Interpretation: One-year treatment with pitolisant is effective and safe in reducing residual daytime sleepiness in patients with OSA, with or without CPAP. Worldwide, > 1 billion people suffer from OSA.1Benjafield A.V. Ayas N.T. Eastwood P.R. et al.Estimation of the global prevalence and burden of obstructive sleep apnoea: a literature-based analysis.Lancet Respir Med. 2019; 7: 687-698Abstract Full Text Full Text PDF PubMed Google Scholar,2Lévy P. Kohler M. McNicholas W.T. et al.Obstructive sleep apnoea syndrome.Nat Rev Dis Primers. 2015; 115015Google Scholar Beyond its cardiometabolic consequences, excessive daytime sleepiness (EDS) is the most prominent symptom, reported by up to 50% of patients with OSA. EDS is associated with impaired everyday functioning, including loss of productivity at work, degraded quality of life, and diminution in fitness to drive, leading to a higher risk of traffic accidents.3Fanfulla F. Pinna G.D. Marrone O. et al.Determinants of sleepiness at wheel and missing accidents in patients with obstructive sleep apnea.Front Neurosci. 2021; 15656203Crossref Scopus (6) Google Scholar,4Lal C. Weaver T.E. Bae C.J. Strohl K.P. Excessive daytime sleepiness in obstructive sleep apnea. mechanisms and clinical management.Ann Am Thorac Soc. 2021; 18: 757-768Crossref PubMed Scopus (52) Google Scholar CPAP is the first-line primary treatment for symptomatic moderate to severe OSA.5Pépin J.-L. Bailly S. Rinder P. et al.CPAP therapy termination rates by OSA phenotype: a French nationwide database analysis.J Clin Med. 2021; 10: 936Crossref PubMed Scopus (36) Google Scholar CPAP has a substantial effect in eradicating apneas and hypopneas during sleep, suppressing the associated hypoxic burden and normalizing sleep quality and architecture. In the vast majority of patients with OSA, CPAP reduces daytime sleepiness and improves their quality of life with a dose-response relationship between the extent of recovery and duration of CPAP nightly usage.6Bratton D.J. Gaisl T. Schlatzer C. Kohler M. Comparison of the effects of continuous positive airway pressure and mandibular advancement devices on sleepiness in patients with obstructive sleep apnoea: a network meta-analysis.Lancet Respir Med. 2015; 3: 869-878Abstract Full Text Full Text PDF PubMed Google Scholar Despite appropriate management of CPAP therapy, residual excessive daytime sleepiness (rEDS) continues to be reported as disabling in a subgroup of 6% to 15% of CPAP-treated patients with OSA.7Gasa M. Tamisier R. Launois S.H. et al.Residual sleepiness in sleep apnea patients treated by continuous positive airway pressure.J Sleep Res. 2013; 22: 389-397Crossref PubMed Scopus (129) Google Scholar, 8Pépin J.-L. Viot-Blanc V. Escourrou P. et al.Prevalence of residual excessive sleepiness in CPAP-treated sleep apnoea patients: the French multicentre study.Eur Respir J. 2009; 33: 1062-1067Crossref PubMed Scopus (150) Google Scholar, 9Rosenberg R. Schweitzer P.K. Steier J. Pepin J.-L. Residual excessive daytime sleepiness in patients treated for obstructive sleep apnea: guidance for assessment, diagnosis, and management.Postgrad Med. 2021; 133: 772-783Crossref Scopus (13) Google Scholar Pitolisant is a selective histamine H3 receptor antagonist and inverse agonist with strong wake promoting effects. The efficacy and safety of pitolisant have been demonstrated in EDS associated with narcolepsy.10Szakacs Z. Dauvilliers Y. Mikhaylov V. et al.Safety and efficacy of pitolisant on cataplexy in patients with narcolepsy: a randomised, double-blind, placebo-controlled trial.Lancet Neurol. 2017; 16: 200-207Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar,11Dauvilliers Y. Bassetti C. Lammers G.J. et al.Pitolisant versus placebo or modafinil in patients with narcolepsy: a double-blind, randomised trial.Lancet Neurol. 2013; 12: 1068-1075Abstract Full Text Full Text PDF PubMed Scopus (270) Google Scholar Among wake-promoting agents that have been studied for treatment of rEDS in OSA, efficacy and safety of pitolisant were also demonstrated in two pivotal 12-week randomized controlled trials (RCTs), the first in patients with moderate OSA and rEDS adherent to CPAP (HAROSA-1) and the second in those refusing or not tolerating CPAP (HAROSA-2).12Dauvilliers Y. Verbraecken J. Partinen M. et al.Pitolisant for daytime sleepiness in patients with obstructive sleep apnea who refuse continuous positive airway pressure treatment. A randomized trial.Am J Respir Crit Care Med. 2020; 201: 1135-1145Crossref PubMed Scopus (0) Google Scholar,13Pépin J.-L. Georgiev O. Tiholov R. et al.Pitolisant for residual excessive daytime sleepiness in OSA patients adhering to CPAP: a randomized trial.Chest. 2021; 159: 1598-1609Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar rEDS is a chronic condition that often requires the long-term use of stimulants on top of primary OSA therapy9Rosenberg R. Schweitzer P.K. Steier J. Pepin J.-L. Residual excessive daytime sleepiness in patients treated for obstructive sleep apnea: guidance for assessment, diagnosis, and management.Postgrad Med. 2021; 133: 772-783Crossref Scopus (13) Google Scholar; however, demonstration of their sustained efficacy and long-term safety is necessary. In short-term RCTs in OSA,12Dauvilliers Y. Verbraecken J. Partinen M. et al.Pitolisant for daytime sleepiness in patients with obstructive sleep apnea who refuse continuous positive airway pressure treatment. A randomized trial.Am J Respir Crit Care Med. 2020; 201: 1135-1145Crossref PubMed Scopus (0) Google Scholar,13Pépin J.-L. Georgiev O. Tiholov R. et al.Pitolisant for residual excessive daytime sleepiness in OSA patients adhering to CPAP: a randomized trial.Chest. 2021; 159: 1598-1609Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar the safety profile of pitolisant appeared favorable, in particular regarding cardiovascular outcomes. Long-term safety has been confirmed in narcolepsy14Dauvilliers Y. Arnulf I. Szakacs Z. et al.Long-term use of pitolisant to treat patients with narcolepsy: Harmony III study.Sleep. 2019; 42: zsz174Crossref PubMed Scopus (57) Google Scholar but remains to be studied in OSA over longer exposure to the compound, particularly in a multimorbid OSA population. This long-term open-label study of pitolisant for up to 1 year, which included participants from the two previous short-term (12-week) placebo-controlled, double-blind, randomized trials, evaluated the maintenance of efficacy and safety of pitolisant in adults with OSA and rEDS at inclusion. HAROSA 113 and HAROSA 212 were prospective, multicenter, European, randomized, double-blind trials of pitolisant (maximum dosage 20 mg) vs placebo, in patients with moderate to severe OSA and EDS (Epworth Sleepiness Scale [ESS] score ≥ 12), adherent to CPAP (HAROSA 1) or refusing or not tolerating CPAP (HAROSA 2). The intervention was pitolisant taken fasted once daily, with individual titration starting from 5 mg/d for 1 week, then 10 mg/d and 20 mg/d based on efficacy and tolerability. Both studies started with a 12-week double-blind period12Dauvilliers Y. Verbraecken J. Partinen M. et al.Pitolisant for daytime sleepiness in patients with obstructive sleep apnea who refuse continuous positive airway pressure treatment. A randomized trial.Am J Respir Crit Care Med. 2020; 201: 1135-1145Crossref PubMed Scopus (0) Google Scholar,13Pépin J.-L. Georgiev O. Tiholov R. et al.Pitolisant for residual excessive daytime sleepiness in OSA patients adhering to CPAP: a randomized trial.Chest. 2021; 159: 1598-1609Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar: visit 1 screening visit (day 14), visit 2 inclusion baseline visit (D0), visit 3 end of up-titration (week 2), follow-up intermediate visits 4 (week 3) and 5 (week 7), end point visit 6 (week 12), and then one single-blind washout period of 1 week with placebo (week 13). From week 13, patients optionally entered the open-label phase. The patients initially treated with pitolisant (group 1) continued their treatment after the end of the RCT (week 13), whereas patients initially treated with placebo (group were treated with pitolisant starting at week the end of the RCTs, a titration was in both with the visit (week 14), visit (week visit (week visit 10 (week visit (week of a washout period without and visit at the end of the (week The were at including and OSA to a with a of cardiovascular was to the of an The was on the The end were at Sleep with A and of of the and Scale The Sleep was at week and week 52. were over at and 1 a between Safety was by the of patients one or treatment-emergent adverse of at moderate serious treatment-emergent adverse and of special interest and caused by of and were at clinical HAROSA 1 and HAROSA 2 were respectively, and sleep in 10 between and The RCTs were in the NCT01071876 and The RCTs been by the appropriate or of study of and in The RCTs were in of the of The of continuation or to pitolisant at the end of short-term (12-week) follow-up with 1-year follow-up been included in the study and in the by included All randomized patients of the HAROSA 1 and HAROSA 2 studies were The primary end point was the change in score from baseline of the RCTs to the 1-year follow-up The appropriate for double-blind by an open-label cohort study was a of continuous outcome from individual Med. PubMed Scopus (0) Google Scholar treatment treatment over study and as a and an to be significant when the of the was and when the of the change in the residual of when the with and without was significant at the the of the treatment effect and the of the treatment effect of patients by and the placebo was not studied after week the effect of pitolisant at 1 year with placebo was a a Y. the of and for 2013; Scopus Google Scholar with treatment and the of treatment The for the use of is in the is based on missing a that was to for any that the end of and the of the end of was of of the of the was the that the patients were as therapy This was in (ie, started The at to that after the outcomes to those of end and pitolisant safety with placebo were to the for the primary end were with a of the and pivotal studies and randomized a of 512 patients with OSA were the and baseline clinical were between the two inclusion in the RCTs, of the patients a of cardiovascular for which were This was The study is in with 376 participants the 1-year study. 2 a of and clinical between patients who the end and those who This is for both studies and for the of the two in not any between the two of also studied the change in and of the patients over From a mean of at the by (95% CI, to without significant difference between the two CI, to OSA diagnosis, of cardiovascular mean or in a mean or The of the of mean score over in The mean baseline score of those initially treated with placebo was without a significant difference between the studies and for or the (group treated with placebo week a significant change in score was week to pitolisant a of in week with baseline at week by a change to after treatment from week 52. 1 treated a mean change of was at week a significant difference with 2 of by a at 1 year significant difference with 2 of The pooled mean difference in score from baseline to 1 year for the intention-to-treat sample was −8.0 of in 2 1 From visit from week mean change and from baseline for 2 treated week visit from week mean change from baseline for 1 treated from difference between 1 and and (95% CI, mean is the mean score at baseline for a as patients with placebo week in of the two from of the from treatment effect and Epworth Sleepiness visit from week mean change and from baseline for 2 treated week visit from week mean change from baseline for 1 treated from difference between 1 and and mean is the mean score at baseline for a as patients with placebo week in a in of the two from of the from treatment effect and Epworth Sleepiness end in All the end by a significant from baseline the end of 1-year follow-up. a significant difference was in mean in 1 treated by pitolisant with 2 at week with a significant change from baseline for the sample (both at week to sleep, of of the and Scale were at week in 1 with whereas no were for the other end quality of sleep, and of from sleep, and A and from baseline for the sample (both were for end at week 52. 1 year, for end the mean change from baseline was not between 1 and for All for the overall from baseline of 2 treated during the double-blind at week from baseline of 2 treated during the double-blind at week difference between both at week difference between both at week change from baseline for the sample (both difference at difference at difference at difference at difference at difference at difference at difference at difference at difference at difference at difference at difference at difference at difference at difference at difference at difference at difference at difference at and Scale in from to with a of Sleep of from Sleep and Sleep to Sleep quality of Sleep of the for the overall from baseline of 2 treated during the double-blind at week from baseline of 2 treated during the double-blind at week difference between both at week difference between both at week change from baseline for the sample (both difference at in a Both and Scale in from to with a of Sleep of from Sleep and Sleep to Sleep quality of Sleep of the The effect of on treatment effect by an treatment effect was to be The of the treatment effect of patients was by and as and for with treatment. No significant effect or effect of these was the long-term effect of pitolisant was placebo by a based on the The of of the was confirmed by a of the effect of pitolisant mg/d) with placebo at 1 year was a in score of (95% CI, to for the and of The of of an significant effect of a reduced effect in no effect of and no effect of the treatment at any of were for and A in of vs 12: in HAROSA 1 at with no reported in the HAROSA 2 study at any of the one of moderate in a treated by CPAP during the 1-year by the in No were between baseline and regarding and in or Safety was evaluated as the of patients at one of the end and during the follow-up and in the placebo treated week pitolisant treated from 20 mg/d placebo treated week pitolisant treated from 20 mg/d placebo treated week pitolisant treated from 20 mg/d of patients treatment-emergent adverse of special serious treatment-emergent adverse placebo treated week pitolisant treated from in a of patients treatment-emergent adverse of special serious treatment-emergent adverse in the open-label a of of patients treatment-emergent serious adverse Among 10 were reported in patients in 1 of and two in two patients with CPAP, one without in 2 of was reported during open-label follow-up without CPAP in 1 pitolisant in double-blind was to be to the study treatment in the the open-label phase after the study were reported in patients in patients in 1 and 10 in 10 patients in 2 The most reported was with patients in 1 and patients in was but for patients in 1 and not for two In of the patients in was The other reported during the open-label phase in In 1 in the double-blind were and both as and as In the severe was which was In the open-label phase after the study were reported in 20 patients in patients in 1 and in patients in 2 The most reported was which was for patients in 1 and patients in reported during the double-blind phase in but one the were of or moderate in 1 a severe during the open-label phase. patients for was the relationship was or This study demonstrated that the efficacy of pitolisant for residual sleepiness in OSA is for up to 1 year of treatment. In the subgroup of 376 patients the the primary baseline overall mean was with a at week of open-label of 1-year mean were for patients who initially been started on placebo or started on pitolisant and of demonstrated that the was after the of effective treatment and to a after 6 or with a maintenance of long-term This study also for the first the long-term safety and profile of pitolisant in multimorbid OSA, in particular for cardiovascular The sustained at 1 year in daytime sleepiness is and by the difference in the at between and S. et difference of the Epworth Sleepiness Scale in obstructive sleep apnoea: from randomised controlled 2019; PubMed Scopus Google S. et Epworth Sleepiness difference in obstructive sleep J Respir Crit Care Med. PubMed Scopus Google Scholar in patients with OSA. The which the of is the most in RCTs to the effect of wake-promoting for residual EDS in OSA. The placebo effect is significant in and has been reported in a and as higher the R. et in and of in randomized clinical trials on obstructive sleep apnea. A and Scopus Google Scholar The placebo effect in study was in the of reported by the R. et in and of in randomized clinical trials on obstructive sleep apnea. A and Scopus Google Scholar and by the significant in of the in the The two randomized, short-term studies with pitolisant were in two OSA Y. Verbraecken J. Partinen M. et al.Pitolisant for daytime sleepiness in patients with obstructive sleep apnea who refuse continuous positive airway pressure treatment. A randomized trial.Am J Respir Crit Care Med. 2020; 201: 1135-1145Crossref PubMed Scopus (0) Google Scholar,13Pépin J.-L. Georgiev O. Tiholov R. et al.Pitolisant for residual excessive daytime sleepiness in OSA patients adhering to CPAP: a randomized trial.Chest. 2021; 159: 1598-1609Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar: patients adherent to J.-L. Georgiev O. Tiholov R. et al.Pitolisant for residual excessive daytime sleepiness in OSA patients adhering to CPAP: a randomized trial.Chest. 2021; 159: 1598-1609Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar and patients and refusing Y. Verbraecken J. Partinen M. et al.Pitolisant for daytime sleepiness in patients with obstructive sleep apnea who refuse continuous positive airway pressure treatment. A randomized trial.Am J Respir Crit Care Med. 2020; 201: 1135-1145Crossref PubMed Scopus (0) Google Scholar no in the long-term efficacy of pitolisant in these two with for at 1 Residual sleepiness is associated with a of quality of life and the overall of good M. Tamisier R. Launois S.H. et al.Residual sleepiness in sleep apnea patients treated by continuous positive airway pressure.J Sleep Res. 2013; 22: 389-397Crossref PubMed Scopus (129) Google R. R. P. management of residual excessive daytime sleepiness to obstructive sleep apnea: for 2021; 10: Scopus Google Scholar In the significant and sustained were also demonstrated for a and for quality of life, and the global In demonstrated a effect of the treatment of the baseline and the of in a and the between participants who were adherent and to primary OSA This remains follow-up management of patients treated with CPAP between but also residual sleepiness and the of sleepiness by and or In from the Sleep Pepin F. et daytime sleepiness in obstructive sleep apnea patients treated with continuous positive airway from the Sleep Neurol. 2021; Scopus Google Scholar EDS appeared both at baseline and CPAP that it is by and in study were from and it is for the of the that no significant difference was in the is the first study regarding the long-term safety profile of pitolisant in a with OSA. the safety profile was good during the 1-year with to moderate the long-term safety profile of pitolisant in patients with Y. Arnulf I. Szakacs Z. et al.Long-term use of pitolisant to treat patients with narcolepsy: Harmony III study.Sleep. 2019; 42: zsz174Crossref PubMed Scopus (57) Google Scholar OSA is a multimorbid and particular be to cardiovascular risk in with and This cardiovascular risk with an to the of of modafinil in for the use of Scholar a is an wake reducing sleepiness by to that of the efficacy of has also been reported as of adherence or not to primary OSA P.K. R. et controlled of for excessive daytime sleepiness in an of adherent or to OSA 2021; Full Text Full Text PDF PubMed Scopus (0) Google P.K. Strohl K.P. et of in a long-term of participants with obstructive sleep apnea who adherent or to airway Clin Sleep Med. 2021; Google Scholar the of and both and have the to R. R. P. management of residual excessive daytime sleepiness to obstructive sleep apnea: for 2021; 10: Scopus Google Scholar In long-term open-label at 1 year, no significant in or were reported with a of 6 was in at the use of pitolisant with that the be 376 patients completed the study with 1 year of the study was not to on long-term cardiovascular outcomes. an effect is of the of on long-term outcomes and studies between sleep and Study the difference in in the pivotal however, the two trials the and end the patients a of 20 of of and of the no effect on the the pooled of the mean of after 1 year of treatment. of the study was to the participants who during the 1-year treatment with a in of good with good of missing for the for including patients for of or for a adverse Despite the of at 1 year, can be as on a and included the 512 patients starting at not a double-blind randomized phase during the open-label which from long-term maintenance of the efficacy of and were not the long-term maintenance of efficacy of pitolisant in the treatment of rEDS in with OSA. 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AIM: Whether histamine H3 receptor antagonists (H3R-ANTs)/inverse agonists (H3R-IAs) provides benefit for the treatment of schizophrenia remains unclear. This meta-analysis was conducted to address the above clinical question. METHODS: Cognitive Function Scale's composite score (primary), seven domains of cognitive function (speed of processing, attention/vigilance, working memory, verbal learning, visual learning, reasoning/problem solving, and social cognition) score, University of California San Diego Performance-Based Skills Assessment score, psychopathology scales score, discontinuation rate, and incidence of individual adverse events were among the study outcomes. The standardized mean differences (SMD) or risk ratios (RR) with 95% confidence intervals (CIs) were calculated. RESULTS: Our meta-analysis included 11 double-blind, randomized, placebo-controlled trials (n = 754). Our study evaluated ABT-288, betahistine, betahistine+reboxetine, GSK239512, MK-0249, and pitolisant. Betahistine has an H1-receptor agonistic reaction and H3-receptor antagonistic reaction, while other drugs only have an H3-receptor antagonistic/inverse agonistic reaction. Hence, we conducted a meta-analysis for all outcomes divided by betahistine or other pooled H3R-ANTs/H3R-IAs. The study results show that betahistine outperformed placebo in the improvement of overall cognitive symptoms (SMD [95% CI] = -0.61 [-1.03, -0.18]), speed of processing (-0.44 [-0.87, -0.02]), attention/vigilance (-0.43 [-0.85, -0.01]), working memory (-0.48 [-0.90, -0.06]), verbal learning (-0.62 [-1.04, -0.19]), visual learning (-0.57 [-1.00, -0.15]), and betahistine+reboxetine was superior in the improvement of depressive symptoms (-4.04 [-5.10, -2.97]). Pitolisant outperformed placebo in depressive symptom improvement (-3.24 [-4.22, -2.26]). However, the results were derived from one betahistine, betahistine+reboxetine, or pitolisant study. Other pooled H3R-ANTs/H3R-IAs revealed risk of insomnia (RR [95% CI] = 2.18 [1.05, 4.55]). However, no differences were observed in other any outcomes between betahistine or other pooled H3R-ANTs/H3R-IAs and placebo. CONCLUSIONS: Some H3R-ANTs/H3R-IAs might provide benefit for the treatment of cognitive symptoms and depressive symptoms in individuals afflicted with schizophrenia.

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PURPOSE: Obstructive sleep apnea (OSA) is typically treated with continuous positive airway pressure (CPAP) therapy. Some patients experience residual excessive daytime sleepiness (EDS) under CPAP. Pitolisant demonstrated effectiveness in reducing EDS. An individual patient meta-analysis was conducted assessing the efficacy and safety of pitolisant 20 mg and 40 mg versus placebo to treat EDS in patients with OSA using CPAP. METHODS: A study-patient, hierarchical, random-effects model was used. Epworth Sleepiness Scale (ESS) and Oxford Sleep Resistance test (OSLER) were co-primary endpoints. Secondary endpoints included EDS-Z scores, fatigue, clinical global impression, and quality of life (QoL). RESULTS: The searches identified three randomized controlled trials. Individual patient data were derived from 423 patients (placebo: n = 120, pitolisant 20 mg: n = 183, pitolisant 40 mg: n = 120). Treatment effects on ESS were -3.20 (95 % confidence interval [CI]: 4.37, -2.00; P < 0.001) and -3.57 (95 % CI: 4.87, -2.80); P < 0.001) for the 20 mg and 40 mg doses, with corresponding standardized mean differences (SMD) of -0.71 (95 % CI: 0.45, -0.97) and -0.79 (95 % CI: 0.51, -1.08). Treatment effects in minutes for OSLER were 1.24 (95 % CI: 0.60, 1.10, SMD = 0.61; P = 0.001) and 1.21 (95 % CI: 0.06, 1.38, SMD = 0.51; P = 0.006). Pitolisant 40 mg was superior to the 20-mg dose for older age (≥50 years) and higher baseline apnea-hypopnea index values (≥15). No significant differences were observed for safety outcomes. CONCLUSION: Pitolisant 20 mg and 40 mg were significantly therapeutically superior to placebo in treating residual EDS in patients with OSA who received CPAP on the outcomes for ESS, OSLER, and QoL.

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Introduction Narcolepsy is a rare but disabling neurological disorder involving disruption of the sleep-wake cycle that is often under- or misdiagnosed (Barateau L, et al . J Sleep Res. 2022;31(4):e13631). It is characterized by a classical tetrad of excessive daytime sleepiness (EDS), cataplexy, hypnagogic hallucinations, and sleep paralysis. Narcolepsy is divided into 3 types: Narcolepsy Type 1 (NT1); Narcolepsy Type 2 (NT2); and Secondary Narcolepsy. The pathophysiology remains unclear but is primarily associated with loss of hypocretin (orexin) neurons involving autoimmune and genetic risk factors, particularly for NT1. Objectives To review the currently available therapies for the treatment of narcolepsy. Methods The extant literature was reviewed and discussed in the context of clinical relevance. Results Treatment historically has included medications developed for the treatment of other conditions such as psychostimulants (methylphenidate, modafinil/armodafinil, pemoline) and antidepressants (SSRIs,TCAs). These agents are also associated with limiting side effects in practice. In more recent years a variety of specific treatments have been approved that act on diverse pathways. Pitolisant, a histamine H3 receptor inverse agonist, is approved for the treatment of EDS or cataplexy in adult patients with narcolepsy (and children&gt; 6 years in European Union) (Keam SJ.Paediatr Drugs. 2023;25(4):483-488). Solriamfetol, a dopamine and norepinephrine reuptake inhibitor (DNRI) is indicated to improve wakefulness in adult patients with EDS associated with narcolepsy or obstructive sleep apnea (OSA) (Winter Y, et al. Sleep Med. 2023;103:138-143). Sodium oxybate (SXB), a GABA B receptor agonist, is approved for the treatment of cataplexy associated with narcolepsy and (EDS) in patients 7 years or older (Bogan RK, et al. CNS Drugs. 2023;37(4):323-335). Current research focuses on on-peptide hypocretin receptor-2 agonists (Saitoh T, Sakurai T. Peptides. 2023;167:171051). Conclusions Despite limited understanding of the pathophysiology of narcolepsy there have been substantial advances in the pharmacotherapy, including medications now approved for children. Early diagnosis and treatment are associated with better outcomes. In view of the chronic and disabling morbidity associated with narcolepsy further research and better access to appopriate medications is necessary. Disclosure of Interest None Declared

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Pitolisant, a novel histamine H3-receptor antagonist, holds significant promise for treating narcolepsy. However, a petition, which highlighted that pitolisant was associated with deaths during clinical trials, has propelled it into the spotlight of widespread societal attention on April 3, 2023. Till now, the clinical safety of pitolisant remains a heatedly debated topic. This study aimed to offer a comprehensive assessment of the safety profile of pitolisant in real-world clinical settings. Adverse event reports where pitolisant was the primary suspect drug were extracted from the FDA Adverse Event Reporting System database. The clinical characteristics and concomitant drugs of the pitolisant-associated adverse events were analyzed. The potential adverse event signals of pitolisant were explored using four disproportionality analysis methods. Furthermore, the difference in pitolisant-associated adverse event signals was investigated concerning sex, age, weight, and dose. A total of 526 reports and 1695 adverse events with pitolisant as the primary suspected drug were identified. The most significant adverse event signals were generally mild and of short duration. The concomitant drugs of pitolisant were highly intricate, mainly included drugs for treating narcolepsy as well as antidepressants. Seven new significant adverse event signals emerged. The safety profile of pitolisant exhibited no significant differences across age and dose groups, although slight variations were observed in relation to sex and weight. The findings from reports of death and life-threatening outcomes underscore the importance of enhanced monitoring for cardiac and respiratory adverse reactions when utilizing pitolisant. This study provided a broader understanding of the safety profile of pitolisant.

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The study focuses on developing a new way to deliver the narcolepsy medication pitolisant. Electrospinning was used to make polyvinyl alcohol (PVA) and hyperbranched polyglycerol (HPG) polymers into pitolisant nanofibers (PT-NF). A design expert created the best formulation to optimise the process variables like applied voltage, distance, and feed rate. The nanofibers were characterised using scanning electron microscopy, X-ray diffraction, FT-IR, entrapment efficiency, and in-vitro drug release studies. Results showed that the optimal PT-NF formulation had an average diameter of 172 ​nm with an entrapment efficacy of 95 ​% and 92 ​% drug release within 45 ​min. HPG polymer was included in the optimised formulation, whose average fibre diameter was 118 ​nm with 98 ​% entrapment efficacy and 98 ​± ​2 ​% drug release within 30 ​min. These findings strongly suggest that PT nanofibers hold substantial promise as a viable alternative to conventional solid dosage forms for brain-targeted administration, especially when administered via a transdermal patch to a patient during sleep.

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