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Pitolisant

Pitolisant is a selective histamine H3 receptor antagonist and inverse agonist approved for the treatment of excessive daytime sleepiness (EDS) or cataplexy in adult patients with narcolepsy, as well as EDS in pediatric patients aged 6 years and older with narcolepsy.^[1] Marketed under the brand name Wakix, it is available as oral tablets in strengths of 4.45 mg, 8.9 mg, 17.8 mg, and 35.6 mg, and is taken once daily in the morning to promote wakefulness without the stimulant-like effects of traditional narcolepsy treatments.^[1]^[2] Pitolisant received initial marketing authorization from the European Medicines Agency (EMA) on March 31, 2016, as an orphan medicine for narcolepsy with or without cataplexy in adults, adolescents, and children from 6 years of age.^[3] In the United States, the Food and Drug Administration (FDA) approved it on August 14, 2019, initially for EDS in adults with narcolepsy, followed by expansion on October 13, 2020, to include cataplexy in adults, and further on June 21, 2024, to cover EDS in pediatric patients 6 years and older.^[1]^[4]^[5] Developed by Bioprojet Pharma and distributed by Harmony Biosciences in the U.S., pitolisant was designated an orphan drug in the EU in 2007 due to the rarity of narcolepsy, which affects approximately 25–50 people per 100,000.^[3] The drug's mechanism involves blocking presynaptic H3 receptors in the brain, which inhibits the negative feedback on histamine release and increases levels of wake-promoting neurotransmitters including histamine, dopamine, norepinephrine, and acetylcholine, thereby reducing EDS and cataplexy symptoms.^[3]^[1] Efficacy was established in phase 3 clinical trials (e.g., HARMONY 1 and HARMONY CTP), where pitolisant significantly improved Epworth Sleepiness Scale scores and reduced weekly cataplexy rates compared to placebo over 8–12 weeks of treatment.^[1] Unlike amphetamines or modafinil, pitolisant has minimal abuse potential and is not a controlled substance, making it a first-in-class option for long-term narcolepsy management.^[2] For adults, dosing begins at 8.9 mg once daily, titrated weekly to 17.8 mg and up to a maximum of 35.6 mg based on efficacy and tolerability, while pediatric patients start at 4.45 mg, with maximum doses adjusted by body weight (17.8 mg for <40 kg, 35.6 mg for ≥40 kg).^[1] It is contraindicated in severe hepatic impairment (Child-Pugh C) and requires dose reductions in moderate hepatic or renal impairment, as well as in CYP2D6 poor metabolizers.^[1] Common side effects affect up to 10% of patients and include insomnia, headache, and nausea, with rare serious risks such as QT interval prolongation necessitating ECG monitoring in at-risk individuals.^[1]^[3] Additionally, pitolisant may decrease the effectiveness of hormonal contraceptives, requiring alternative methods during treatment and for 21 days after discontinuation.^[2]

Medical Uses

Narcolepsy Treatment

Pitolisant, marketed as Wakix, was approved by the U.S. Food and Drug Administration (FDA) in August 2019 for the treatment of excessive daytime sleepiness (EDS) in adult patients with narcolepsy.^[6] This approval was expanded in October 2020 to include the treatment of cataplexy in adults with narcolepsy, making it the first non-scheduled medication approved for both indications.^[7] The drug is indicated for narcolepsy type 1 (with cataplexy) and type 2 (without cataplexy), addressing core symptoms through its action as a histamine H3 receptor inverse agonist to enhance wake-promoting histamine transmission. The recommended dosing regimen for adults begins with 8.9 mg once daily in the morning for the first week, increasing to 17.8 mg once daily for the second week, and then titrated up to a maximum of 35.6 mg once daily from week 3 onward based on clinical response and tolerability.^[6] This flexible titration allows for individualized therapy, with the effective dose range typically between 17.8 mg and 35.6 mg daily to optimize symptom control while minimizing side effects.^[8] Efficacy in reducing EDS was established in the phase 3 HARMONY 1 trial, a randomized, double-blind, placebo-controlled study involving 95 adults with narcolepsy, where pitolisant at doses up to 40 mg daily led to significant improvements in Epworth Sleepiness Scale (ESS) scores compared to placebo, with mean changes of -5.8 points versus -3.4 points for placebo over 8 weeks.^[9] For cataplexy management, the HARMONY CTP trial, another phase 3 randomized, double-blind, placebo-controlled study in 106 patients with narcolepsy type 1, demonstrated that pitolisant (up to 36 mg daily) significantly decreased weekly cataplexy rates by 75% from baseline (from 9.15 to 2.27 episodes per week) compared to a 38% reduction with placebo over 12 weeks.^[10] Long-term efficacy data from an ongoing 5-year prospective observational post-authorization safety study, with interim analysis reported in 2025, indicate sustained reductions in EDS for patients with narcolepsy types 1 and 2, as measured by ESS scores improving by an average of 5-6 points over 42 months of treatment, alongside continued cataplexy suppression and good adherence without new safety signals.^[11] These findings support pitolisant's role in maintaining symptom control over extended periods in real-world settings.

Obstructive Sleep Apnea Treatment

Pitolisant, marketed as Ozawade in the European Union, received marketing authorization from the European Medicines Agency on September 1, 2021, for the treatment of excessive daytime sleepiness (EDS) in adult patients with obstructive sleep apnea (OSA).^[12] This approval targets individuals whose EDS persists despite continuous positive airway pressure (CPAP) therapy or who cannot tolerate CPAP, positioning pitolisant as an adjunctive option to promote wakefulness without directly addressing the underlying airway obstruction.^[12] By acting as a histamine H3 receptor inverse agonist, pitolisant enhances histaminergic transmission in the brain to improve alertness in this population.^[13] The recommended dosing regimen for OSA follows a gradual titration to optimize efficacy and minimize side effects, beginning at 4.5 mg once daily in the morning with breakfast during week 1.^[13] The dose may then be increased to 9 mg in week 2 and up to 18 mg in week 3, with further adjustments possible based on individual response and tolerability, reaching a maximum of 36 mg once daily.^[13] This flexible approach allows for personalization, particularly in patients with renal or hepatic impairment, where the maximum dose is limited to 18 mg daily.^[13] Supporting evidence for pitolisant's efficacy in OSA derives from two pivotal phase 3 randomized, double-blind, placebo-controlled trials involving over 500 adults with moderate to severe OSA and baseline Epworth Sleepiness Scale (ESS) scores indicating significant EDS.^[12] In the first trial, which enrolled 244 CPAP-adherent patients with residual EDS, pitolisant (up to 20 mg daily) reduced mean ESS scores by 5.5 points after 12 weeks compared to 2.8 points with placebo, alongside improvements in objective measures like maintenance of wakefulness test latency.^[14] The second trial, with 268 patients refusing CPAP, showed a mean ESS reduction of 6.3 points with pitolisant (up to 40 mg daily) versus 3.6 points for placebo, demonstrating benefits even without CPAP use. These reductions highlight pitolisant's role in alleviating EDS, with effect sizes establishing clinical relevance for daily functioning.^[12] In Japan, a phase 3 double-blind trial completed in early 2025 evaluated pitolisant in 120 OSA patients with residual EDS despite CPAP therapy, reporting a statistically significant ESS reduction (p=0.007) after 12 weeks compared to placebo.^[15] These positive results, consistent with global data, support Aculys Pharma's planned new drug application to Japan's Pharmaceuticals and Medical Devices Agency, potentially expanding access for this indication in the region.^[15]

Pediatric Indications

In June 2024, the U.S. Food and Drug Administration (FDA) approved pitolisant (Wakix) for the treatment of excessive daytime sleepiness (EDS) in pediatric patients aged 6 years and older with narcolepsy, marking the first non-scheduled treatment option for this indication in children.^[1]^[16] This approval expands access to a histamine-3 receptor inverse agonist previously authorized only for adults with narcolepsy. Dosing in pediatric patients is weight-based and administered once daily in the morning, with gradual titration to minimize adverse effects. For children weighing less than 40 kg, treatment begins at 4.45 mg once daily for one week, increases to 8.9 mg for the second week, and then to 17.8 mg for week three and beyond, which is the maximum recommended dose for this group. For those weighing 40 kg or more, the regimen follows the same initial steps but may be further increased to 35.6 mg starting in week four if tolerated and needed for efficacy.^[1]^[17] The approval was supported by data from the HARMONY 4 trial (NCT02611687), a multicenter, randomized, double-blind, placebo-controlled study involving 110 pediatric patients aged 6 to 17 years with narcolepsy. In this 8-week trial, pitolisant significantly improved EDS as measured by the Pediatric Daytime Sleepiness Scale (PDSS), with a least squares mean difference of -3.41 points (95% CI: -5.52 to -1.31) compared to placebo. An open-label extension of the trial, involving up to 105 patients treated for 12 months, demonstrated sustained efficacy and a safety profile comparable to that observed in adults, with most patients reaching target doses (69% at 17.8 mg for <40 kg and 72% at 35.6 mg for ≥40 kg).^[1]

Investigational and Off-Label Uses

Pitolisant received orphan drug designation from the U.S. Food and Drug Administration (FDA) on September 5, 2023, for the treatment of idiopathic hypersomnia (IH), a rare neurological disorder characterized by excessive daytime sleepiness (EDS) despite adequate sleep duration.^[18] This designation aims to encourage development for conditions affecting fewer than 200,000 individuals in the United States, providing incentives such as tax credits and market exclusivity upon approval.^[19] In 2025, an 8-week open-label phase 3 trial (NCT05458128) evaluated pitolisant in adult patients with IH, demonstrating robust improvements in EDS as measured by the Epworth Sleepiness Scale (ESS), alongside reductions in sleep inertia and other hypersomnia symptoms, with approximately 83% of completers classified as responders based on symptom score decreases.^[20] Following a February 2025 FDA refusal-to-file letter for a supplemental new drug application due to prior trial data, Harmony Biosciences announced plans to initiate a new phase 3 registrational trial in the fourth quarter of 2025, targeting a Prescription Drug User Fee Act (PDUFA) date in 2028.^[21] Emerging 2025 data from the same open-label extension further support pitolisant's potential to alleviate IH-specific symptoms, including sleep inertia—the grogginess and difficulty transitioning from sleep to wakefulness—through sustained improvements observed over one year in a subset of participants.^[22] These findings, presented in abstracts from the SLEEP journal, highlight pitolisant's role in addressing multifaceted IH manifestations beyond EDS alone, though full peer-reviewed publication is pending.^[20] Off-label use of pitolisant has been explored in other central hypersomnia disorders, such as subjective hypersomnia, but evidence remains limited to small, observational studies showing modest EDS reductions in drug-resistant cases, with no established dosing or routine clinical recommendations due to insufficient randomized data.^[23] Early-phase trials prior to 2025 investigated pitolisant for excessive daytime sleepiness associated with Parkinson's disease, including a completed phase 2 study (NCT01036139) that assessed safety and efficacy in this population, though results indicated variable improvements and did not lead to further development in this indication.^[24] These exploratory efforts underscore pitolisant's potential in neurodegenerative-related sleep disturbances, but larger confirmatory trials are lacking.^[25]

Safety and Adverse Effects

Contraindications

Pitolisant is contraindicated in patients with known hypersensitivity to the active substance or to any of the excipients, as anaphylaxis has been reported in postmarketing experience.^[1]^[26] The drug is also contraindicated in individuals with severe hepatic impairment (Child-Pugh class C), owing to substantially reduced clearance and increased risk of adverse effects.^[1]^[26] There are limited data on the use of pitolisant in pregnant women. Animal reproduction studies showed developmental toxicity, including malformations and reduced fetal weight, at exposures greater than or equal to 13 times the maximum recommended human dose. No drug-associated risk of major birth defects or miscarriage has been identified in humans based on available data. Use during pregnancy is not recommended unless the potential benefit justifies the possible risk to the fetus, and a pregnancy registry is available to monitor outcomes (contact: 1-800-833-7460).^[1] In the European Union, pitolisant is similarly advised against during pregnancy unless the clinical need outweighs potential risks, with effective contraception recommended during treatment and for 21 days thereafter due to reproductive toxicity observed in animal studies.^[26] Additionally, breastfeeding is contraindicated in the EU due to the absence of data on excretion in human milk and potential effects on the infant, while in the US, it is recommended to consider the developmental and health benefits of breastfeeding against the mother's clinical need and any potential adverse effects on the breastfed infant.^[26]^[1]

Common Adverse Effects

The most frequently reported adverse effects in pivotal clinical trials of pitolisant include insomnia (incidence 6-13%), headache (6-22%), nausea (6-12%), and anxiety (5-6%). In pediatric patients (≥6 years), headache (19%) and insomnia (7%) were the most common adverse reactions.^[25]^[1] These effects are generally mild to moderate and often resolve with continued treatment or adjustment.^[1] The occurrence of these adverse effects exhibits a dose-dependent pattern, with higher incidence rates observed at the maximum recommended dose of 35.6 mg daily.^[25] For instance, insomnia and headache may be more pronounced at elevated doses due to the drug's wakefulness-promoting mechanism via histamine H3 receptor antagonism.^[26] Management of these common effects typically involves dose titration starting at 8.9 mg once daily and increasing gradually to 17.8 mg after 7 days, and up to 35.6 mg after another 7 days, based on tolerability, as well as avoiding administration in the evening to minimize insomnia.^[1]^[26] If symptoms persist, temporary dose reduction or supportive measures, such as over-the-counter analgesics for headache or antiemetics for nausea, may be employed under medical supervision. Weight changes have been reported, including gains in up to 7.8% of patients in some studies. Long-term data indicate weight stability in most patients, with 13.3% experiencing gains >10% of baseline by year 3 and 5.6% experiencing losses.^[27]^[28] This effect may relate to improved alertness and activity levels but warrants monitoring, particularly in patients with low baseline BMI.^[26]

Serious Adverse Effects

Pitolisant has been associated with a risk of QT interval prolongation, which can lead to serious cardiac arrhythmias such as torsades de pointes. This effect is dose-dependent and may be exacerbated in patients with hepatic or renal impairment due to elevated plasma concentrations of the drug, as well as in those who are CYP2D6 poor metabolizers, where exposure can increase up to 3.6-fold compared to normal metabolizers. Avoid use in patients with known QT prolongation or a history of ventricular arrhythmia. Use caution with concomitant QT-prolonging medications, such as certain antipsychotics or antiarrhythmics, or in individuals with family history of sudden death or significant electrolyte disturbances like hypokalemia or hypomagnesemia; such use further heightens this risk. Electrocardiogram (ECG) monitoring is recommended for patients with moderate to severe hepatic or renal impairment, CYP2D6 poor metabolizers, or those at high risk for QT prolongation, to detect changes in QTc interval early.^[1]^[6]^[16] Rare psychiatric adverse events, including hallucinations, have been reported in clinical trials occurring in approximately 3% of adult patients treated with pitolisant, with post-marketing surveillance identifying additional cases of abnormal behavior, depression, suicidal ideation, and hallucinations at incidences below 2%. These events may require immediate discontinuation of the drug and psychiatric evaluation, particularly in patients with a history of mental health disorders. While common adverse effects like anxiety can sometimes precede these rarer psychiatric manifestations, severe outcomes such as suicide attempts or hospitalizations for psychiatric illness have been noted in post-approval use.^[1]^[29]^[30] Reproductive toxicity data from animal studies indicate potential risks, with oral administration of pitolisant during organogenesis causing maternal toxicity, embryofetal lethality, and increased rates of spontaneous abortion in rats and rabbits at doses equivalent to or above 13 and 28 times the maximum recommended human dose, respectively. In humans, post-marketing reports have documented rare instances of spontaneous abortion (incidence approximately 0.09%), though insufficient data exist to fully characterize the risk of major birth defects, miscarriage, or adverse maternal/fetal outcomes. Pregnant patients should be enrolled in a pregnancy registry to monitor outcomes, and pitolisant use during pregnancy is generally not recommended unless benefits outweigh potential risks.^[1]^[31]^[32] In cases of overdose, symptoms may include severe headache, insomnia, irritability, nausea, and abdominal pain, with agitation and tachycardia reported in some instances; there is no specific antidote, and management involves supportive care such as gastric lavage if ingestion is recent, along with monitoring for QT prolongation and psychiatric symptoms. Hospitalization is advised for symptomatic overdoses to provide cardiovascular and neurological support as needed.^[33]^[26]

Long-Term Safety Data

An interim analysis of a prospective 5-year post-authorization safety study (PASS) involving 370 adults with narcolepsy type 1 or 2, conducted across multiple European centers, reported no new safety signals after a mean treatment duration of 42.6 months. Among the 364 patients in the safety population, 355 treatment-emergent adverse events occurred in 156 individuals (42.9%), with only 3 serious events deemed possibly related, confirming sustained tolerability in real-world use.^[28] Discontinuation rates due to adverse events in long-term studies remain relatively low. In the PASS interim analysis, 12.4% of patients discontinued for safety reasons over the observation period, while the earlier HARMONY III open-label extension (n=104, up to 5 years) showed an 10.6% rate, primarily occurring in the first year. These figures indicate good long-term retention compared to initial trial phases.^[28]^[25] No evidence of tolerance development to pitolisant's therapeutic effects or rebound phenomena upon discontinuation has emerged from extended-use data, including the absence of withdrawal symptoms in the PASS cohort.^[28]^[25] Ongoing monitoring for hepatic function is advised in long-term users, especially those with moderate impairment, as the drug is contraindicated in severe cases and rare elevations in liver enzymes have been noted. Weight fluctuations, with 13.3% of patients experiencing gains exceeding 10% of baseline body weight by year 3 in the PASS study, warrant periodic assessment to manage potential metabolic effects.^[1]^[28]

Pharmacology

Mechanism of Action

Pitolisant functions primarily as a selective inverse agonist and competitive antagonist at histamine H3 autoreceptors, which are predominantly expressed on histaminergic neurons in the tuberomammillary nucleus (TMN) of the posterior hypothalamus. These autoreceptors normally exert negative feedback by inhibiting the synthesis and release of histamine when synaptic levels are elevated; by binding to H3 receptors, pitolisant disrupts this inhibition, leading to increased histamine release from TMN neurons. This enhanced histaminergic tone promotes wakefulness by activating downstream pathways throughout the brain.^[34]^[35]^[36] The released histamine diffuses to postsynaptic sites, where it binds to H1 receptors located on neurons in key wake-promoting regions such as the cortex and hypothalamus. Activation of these H1 receptors depolarizes target neurons, increasing excitability and facilitating arousal states through mechanisms like reduced potassium conductance and enhanced glutamatergic transmission. Unlike traditional stimulants, pitolisant does not directly inhibit dopamine reuptake or significantly elevate dopamine levels in reward-related areas like the nucleus accumbens, thereby minimizing the risk of abuse or dependence.^[37]^[38]^[39] In addition to its primary histaminergic effects, pitolisant exhibits affinity for sigma-1 and sigma-2 receptors in the low nanomolar range, acting as an agonist at sigma-1 and antagonist at sigma-2 sites. Sigma-1 receptor activation supports neuroprotective functions by modulating calcium homeostasis, endoplasmic reticulum stress responses, and neuroplasticity, potentially contributing to pitolisant's broader therapeutic benefits beyond wake promotion.^[40]^[41]

Pharmacokinetics

Pitolisant exhibits rapid and nearly complete absorption after oral administration, with an estimated bioavailability of approximately 90%. The median time to reach peak plasma concentrations (Tmax) is 3.5 hours, with a range of 2 to 5 hours. Food, including high-fat meals, has no clinically significant effect on its absorption or overall exposure, allowing flexible administration with or without meals.^[42] Following repeated dosing, steady-state plasma concentrations of pitolisant are achieved by day 7, accompanied by approximately twofold accumulation compared to single-dose levels. The apparent volume of distribution is around 700 L (equivalent to 5–10 L/kg), indicating extensive distribution into tissues, while plasma protein binding ranges from 91% to 96%, primarily to albumin and alpha-1-acid glycoprotein. The elimination half-life is approximately 20 hours (median; range 7.5–24.2 hours), supporting its suitability for once-daily dosing regimens.^[42] Pitolisant undergoes extensive hepatic metabolism, primarily via the cytochrome P450 enzyme CYP2D6 (accounting for about 60% of metabolism in extensive metabolizers) and to a lesser extent via CYP3A4 (approximately 30%). The resulting metabolites are pharmacologically inactive and undergo further conjugation with glucuronic acid or glycine. Concomitant use with strong inhibitors of CYP2D6 (e.g., paroxetine) or strong inducers of CYP3A4 (e.g., rifampin) necessitates dose adjustments to avoid altered exposure. The apparent oral clearance is 43.9 L/hour.^[42]^[43] Elimination of pitolisant occurs predominantly through the urine, with approximately 90% of the administered dose recovered as metabolites and less than 2% as unchanged parent drug; renal clearance contributes minimally (<2% of total clearance). Fecal excretion accounts for about 2.3% of the dose. No significant accumulation occurs beyond steady-state levels with chronic use.^[42]

Pharmacodynamics

Pitolisant binds with high affinity to the histamine H3 receptor as an inverse agonist (Ki = 1 nM), thereby blocking the autoinhibitory feedback mechanism on histaminergic neurons and promoting the release of histamine in the brain.^[6] At therapeutic doses, this action results in a 3- to 4-fold increase in brain histamine levels, enhancing histaminergic neurotransmission and contributing to wake-promoting effects.^[41] In addition to its primary target, pitolisant exhibits off-target binding to other receptors, including the sigma-1 receptor (Ki ≈ 10 nM), dopamine D3 receptor (Ki = 380 nM), and 5-HT2A receptor (Ki = 544 nM), though these affinities are lower than for the H3 receptor and their clinical relevance remains limited.^[41] The pharmacodynamic response to pitolisant, particularly improvement in excessive daytime sleepiness, shows a dose-response relationship correlating with plasma concentrations exceeding 100 ng/mL, where therapeutic efficacy is more consistently observed.^[44] At standard therapeutic doses, pitolisant demonstrates no significant impact on cardiovascular parameters, such as QTc interval prolongation or blood pressure changes, supporting its safety profile in patients without underlying cardiac conditions.^[6]

Chemistry

Chemical Structure

Pitolisant has the molecular formula C_{17}H_{26}ClNO and a molecular weight of 295.85 g/mol for the free base.^[45] The compound features a central piperidine ring, with the nitrogen atom substituted by a 3-[3-(4-chlorophenyl)propoxy]propyl chain, giving it a non-imidazole structure typical of certain histamine receptor ligands.^[33] In pharmaceutical formulations, pitolisant is employed as its hydrochloride salt (C_{17}H_{27}Cl_{2}NO, molecular weight 332.31 g/mol) to enhance solubility.^[6] The synthesis of pitolisant involves a multi-step process starting from piperidine derivatives, including the base-catalyzed reaction of 3-(piperidin-1-yl)propan-1-ol with 3-(4-chlorophenyl)propyl methanesulfonate, followed by treatment with hydrochloric acid to form the salt.^[46]

Physical Properties

Pitolisant hydrochloride appears as a white or almost white crystalline powder.^[6] Its melting point ranges from 190°C to 193°C.^[47] The compound exhibits a pKa of 9.67 at the piperidine nitrogen, reflecting its basic character.^[33] It has a logP value of approximately 4.5, which underscores its lipophilicity and supports penetration into the central nervous system, attributable to the structural features including the alkyl chain and aromatic rings.^[33] Pitolisant hydrochloride is soluble in water (greater than 57 mg/mL) and highly soluble in ethanol (greater than 94 mg/mL), while being practically insoluble in cyclohexane.^[6]^[48] Regarding stability, pitolisant hydrochloride is hygroscopic up to 75% relative humidity and sensitive to excessive oxidative conditions, with recommended storage at room temperature (20–25°C) to maintain integrity; protection from light and moisture is advised during handling.^[49]^[6]

History and Development

Preclinical Research

Pitolisant, developed by Bioprojet under the code name BF2.649, underwent extensive preclinical evaluation to assess its wake-promoting potential, primarily through studies in rodent models. In orexin knockout mice, a model of narcolepsy, oral administration of pitolisant at doses of 10–20 mg/kg significantly increased wakefulness duration, reduced slow-wave and paradoxical sleep, and suppressed direct rapid eye movement sleep transitions, effects mediated via enhanced histaminergic neurotransmission and interactions with orexin pathways. Similar wake-promoting activity was observed in wild-type mice and rats, where pitolisant (ED50: 1.6–3 mg/kg orally) elevated brain levels of histamine, noradrenaline, dopamine, and acetylcholine, demonstrating efficacy in promoting vigilance without psychostimulant properties.^[41]^[49]^[50] As a selective histamine H3 receptor inverse agonist, pitolisant's specificity was confirmed in early binding assays, showing high affinity (Ki = 1–2.4 nM) for H3 receptors with over 1000-fold selectivity against other histamine receptor subtypes and minimal off-target binding to receptors like dopamine or serotonin transporters. These assays, conducted prior to 2010, established its targeted mechanism without notable interactions at therapeutically relevant concentrations.^[41]^[49] Toxicological studies revealed no genotoxic potential, with negative results in the Ames bacterial reverse mutation test, mouse lymphoma TK assay, and in vivo micronucleus test in mice at doses up to 150 mg/kg orally. Reproductive toxicity was observed in rats at high doses; in fertility studies, pitolisant at 52–90 mg/kg/day reduced sperm motility and caused morphological alterations, though without impairing overall fertility (NOAEL: 30 mg/kg/day). Embryo-fetal development studies in rats showed increased post-implantation losses, resorptions, and teratogenic effects such as cleft palate and limb flexures at 90 mg/kg/day (approximately 22 times the maximum recommended human dose on a mg/m² basis), with a NOAEL of 30 mg/kg/day. Similar findings in rabbits included delayed ossification at doses ≥16 mg/kg/day, but no effects on maternal toxicity.^[41]^[49] Preclinical pharmacokinetics in rodents indicated good oral absorption and extensive distribution, with pitolisant achieving rapid brain penetration and high concentrations in the central nervous system (e.g., brain Cmax up to 9668 ng/mL in rats at 60 mg/kg). In rats, the plasma half-life ranged from 1.15 to 7.33 hours, comparable in scale to human values of 10–20 hours, supporting once-daily dosing potential; bioavailability was low (~1.5–2% for unchanged drug) due to first-pass metabolism, primarily to inactive metabolites like BP1.2526, with excretion mainly via urine (over 90%). These profiles confirmed adequate CNS exposure for wake-promoting effects while highlighting species-specific metabolic differences.^[41]^[49]

Clinical Trials

Pitolisant's efficacy and safety in treating excessive daytime sleepiness (EDS) associated with narcolepsy were established through the phase 3 HARMONY trials conducted between 2011 and 2014. The HARMONY 1 trial was a randomized, double-blind, placebo-controlled study involving 94 adult patients with narcolepsy, designed to assess pitolisant's impact on EDS. Patients received pitolisant (up to 35.6 mg/day) or placebo for 8 weeks, with the primary endpoint being the change in Epworth Sleepiness Scale (ESS) score from baseline. Pitolisant resulted in a least-squares mean change of -6.1 points on the ESS compared to -2.3 points for placebo, demonstrating statistically significant improvement (p < 0.001).^[51] The HARMONY CTP trial, also part of the phase 3 program, focused on cataplexy in 106 adult patients with narcolepsy type 1, using a randomized, double-blind, placebo-controlled design over 7 weeks with pitolisant doses up to 35.6 mg/day. Although the primary endpoint was the weekly rate of cataplexy attacks, secondary analyses confirmed benefits on EDS, with a least-squares mean ESS change of -5.0 points for pitolisant versus -1.4 points for placebo (p < 0.001). Pitolisant reduced cataplexy frequency by approximately 75% from baseline, compared to 38% with placebo (rate ratio 0.51; p < 0.0001).^[52] In obstructive sleep apnea (OSA), the HARMONY 3 trial (2013) evaluated pitolisant in 268 adults with moderate to severe OSA and residual EDS, regardless of continuous positive airway pressure use, in a 12-week randomized, double-blind, placebo-controlled study. The primary endpoint was the change in ESS score, where pitolisant (up to 35.6 mg/day) achieved a mean reduction of -6.3 points versus -3.6 points for placebo (difference -2.8; 95% CI -4.0 to -1.5; p < 0.001), alongside improvements in fatigue and patient-reported outcomes.^[53] Pediatric applications were explored in a dedicated phase 3 trial conducted from 2016 to 2021 (NCT02611687), with extensions and analyses through 2024, building on adult data. This randomized, double-blind, placebo-controlled trial in 85 children and adolescents aged 6 years and older with narcolepsy demonstrated pitolisant's efficacy on EDS and cataplexy over 12 weeks, with significant ESS reductions versus placebo (p < 0.05) and a favorable safety profile consistent with adult trials. Long-term open-label extensions up to 1 year confirmed sustained benefits in this population without new safety signals.^[54]^[55] A completed phase 3 trial (NCT05156047) as part of the INTUNE program evaluated pitolisant in approximately 173 adults with idiopathic hypersomnia (IH), featuring an 8-week open-label period followed by a 4-week double-blind randomized withdrawal period. In the open-label period, 80.3% of patients achieved an EDS response (defined as ≥3-point ESS reduction) after treatment up to 35.6 mg/day, with improvements in sleep inertia and cognitive symptoms. Although the primary endpoint in the withdrawal period was not met, ad hoc analyses suggested benefits. In February 2025, the FDA refused to file the supplemental new drug application for IH due to deficiencies; a new phase 3 registrational trial for a higher-dose formulation is planned to initiate in Q4 2025, targeting approval in 2028.^[56]^[57]^[58]

Regulatory Approvals and Designations

Pitolisant received orphan drug designation from the European Medicines Agency (EMA) on July 10, 2007, for the treatment of narcolepsy.^[59] The EMA subsequently granted marketing authorization for pitolisant, marketed as Wakix, on March 31, 2016, for the treatment of narcolepsy with or without cataplexy in adults, adolescents, and children aged 6 years and older.^[3] In the United States, the Food and Drug Administration (FDA) awarded orphan drug designation to pitolisant for narcolepsy in March 2010.^[25] The drug received Fast Track designation in April 2018 for the treatment of excessive daytime sleepiness (EDS) in narcolepsy.^[25] FDA approval followed on August 14, 2019, for the treatment of EDS in adult patients with narcolepsy, marketed as Wakix. This indication was expanded on October 13, 2020, to include the treatment of cataplexy in adults with narcolepsy. In June 2024, the FDA approved an extension to pediatric patients aged 6 years and older for both EDS and cataplexy associated with narcolepsy.^[16] Pitolisant is not scheduled as a controlled substance by the Drug Enforcement Administration.^[47] The EMA expanded pitolisant's indications on September 1, 2021, approving it under the brand name Ozawade for the treatment of EDS in adults with obstructive sleep apnea (OSA) whose sleepiness persists despite primary therapy or who do not tolerate it.^[12] In Japan, Aculys Pharma reported positive topline results from a Phase III trial of pitolisant for EDS in narcolepsy on October 22, 2024, and for residual EDS in OSA on March 24, 2025; following acquisition by Viatris in October 2025, regulatory submissions are planned by end of 2025 and remain pending approval as of November 2025.^[15] Additionally, the FDA granted orphan drug designation to pitolisant for the treatment of idiopathic hypersomnia on September 5, 2023.^[18]

Society and Culture

Legal Status

Pitolisant is not classified as a controlled substance in the United States, where the Drug Enforcement Administration (DEA) assessed it as having low potential for abuse in 2019, leading to its approval by the Food and Drug Administration (FDA) without scheduling under the Controlled Substances Act.^[60]^[61] Similarly, in the European Union, pitolisant holds marketing authorization from the European Medicines Agency (EMA) since 2016 as an orphan medicinal product for narcolepsy treatment, without designation as a controlled substance.^[3]^[49] As a prescription-only medication worldwide, pitolisant requires a valid prescription from a licensed healthcare provider for dispensing in approved jurisdictions, including the US, EU member states, and other regions where it is authorized, such as Japan and China.^[62]^[3] Regulatory oversight in the US includes FDA-mandated labeling warnings for QT interval prolongation, advising ECG monitoring in patients with risk factors such as hepatic or renal impairment, and avoidance in those with known QT prolongation or concomitant use of QT-prolonging drugs.^[63]^[64] No Risk Evaluation and Mitigation Strategy (REMS) program is required, unlike some other narcolepsy treatments.^[64] Patent protections for pitolisant in the US extend key formulations and methods of use until at least June 2031, delaying generic entry, while orphan drug exclusivity for cataplexy in narcolepsy expires on October 13, 2027.^[65]^[66] In the EU, orphan market exclusivity is set to expire in April 2028.^[67] Import and export of pitolisant are subject to standard international pharmaceutical regulations as a prescription drug, including requirements for prescriptions, declarations, and compliance with customs laws in the US and EU, though it faces no additional restrictions due to its non-controlled status.^[68]

Commercial Availability and Branding

Pitolisant is commercially available under the brand name Wakix in multiple regions worldwide. Developed originally by Bioprojet Pharma, a French pharmaceutical company, it is marketed by various partners depending on the territory. As of the end of 2023, pitolisant had received regulatory approval for the treatment of narcolepsy in 38 countries, including major markets in Europe, North America, and Asia.^[69] In the European Union, Wakix is authorized throughout all member states and marketed by Bioprojet Pharma as the marketing authorization holder. The European Medicines Agency granted marketing authorization on March 31, 2016, for the treatment of narcolepsy with or without cataplexy in adults, with subsequent approval in 2021 for excessive daytime sleepiness in patients with obstructive sleep apnea syndrome (OSAS) who cannot use continuous positive airway pressure therapy. It is available by prescription in tablet form (4.5 mg, 9 mg, 18 mg, and 36 mg strengths) and designated as an orphan medicine.^[3] In the United States, pitolisant is marketed exclusively by Harmony Biosciences under the brand name WAKIX, pursuant to an exclusive license from Bioprojet for development, manufacturing, and commercialization. The U.S. Food and Drug Administration approved WAKIX on August 14, 2019, for excessive daytime sleepiness in adult patients with narcolepsy, followed by approval on June 24, 2024, for excessive daytime sleepiness in pediatric patients aged 6 years and older with narcolepsy. It is available as oral tablets in strengths of 4.45 mg and 17.8 mg pitolisant and is the first and only non-scheduled (non-controlled substance) treatment for these indications in the U.S.^[6]^[16] In China, Wakix is marketed by RareStone Group and was approved by the National Medical Products Administration on July 5, 2023, for excessive daytime sleepiness or cataplexy in adult patients with narcolepsy, marking the first approval for narcolepsy treatment in mainland China. It is positioned as a first-line therapy per national guidelines and is the only non-scheduled option available.^[70] Outside these core markets, pitolisant's availability continues to expand through partnerships. For instance, in October 2025, Viatris completed the acquisition of Aculys Pharma, gaining exclusive rights to develop and commercialize pitolisant in Japan and certain Asia-Pacific regions, with plans to file for marketing approval in Japan by the end of 2025 for narcolepsy and OSAS indications. In India, a generic version by MSN Laboratories has been recommended for market authorization by the Subject Expert Committee, though full approval status remains pending. Globally, Wakix is typically dispensed via specialty pharmacies with patient support programs for access and reimbursement.^[71]

References

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[PDF] WAKIX® (pitolisant) tablets, for oral use - accessdata.fda.gov
Pediatric Patients (6 years and older): EDS (2.2). Week 1 Initiate with a dosage of 4.45 mg once daily. Week 2 Increase dosage to 8.9 mg once daily.
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In stock Rating 5.0 (30) Chemical Properties of Pitolisant hydrochloride ; Formula, C17H27Cl2NO, M.Wt ; Solubility, ≥ 16.6 mg/mL in DMSO, ≥ 94.2 mg/mL in EtOH, ≥ 57.4 mg/mL in Water ...
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