Wakix 4.5 mg film-coated tablets

Film-coated tablet (tablet) White, round, biconvex film-coated tablet, 3.7 mm diameter, marked with “5” on one side.

4.1 Therapeutic indications Wakix is indicated:

• in adults for the treatment of narcolepsy with or without cataplexy (see also section 5.1).
• to improve wakefulness and reduce excessive daytime sleepiness (EDS) in adult patients with obstructive sleep apnoea (OSA) whose EDS has not been satisfactorily treated by, or who have not tolerated, OSA primary therapy, such as continuous positive airway pressure (CPAP).4.2 Posology and method of administration Treatment should be initiated by a physician experienced in the treatment of sleep disorders or in the treatment of OSA and cardiovascular risk. OSA disease should be annually reassessed. Wakix is not a therapy for the underlying airway obstruction in patients with OSA. Primary OSA therapy should be maintained or periodically rechallenged in patients not tolerating primary OSA therapy. **Posology** *Narcolepsy* Pitolisant should be used at the lowest effective dose, depending on individual patient response and tolerance, according to an up-titration scheme, without exceeding the dose of 36 mg/day:
• Week 1: initial dose of 9 mg (two 4.5 mg tablets) per day.
• Week 2: the dose may be increased to 18 mg (one 18 mg tablet) per day or decreased to 4.5 mg (one 4.5 mg tablet) per day.
• Week 3: the dose may be increased to 36 mg (two 18 mg tablets) per day. At any time the dose can be decreased (down to 4.5 mg per day) or increased (up to 36 mg per day) according to the physician assessment and the patient's response. The total daily dose should be administered as a single dose in the morning upon wakening. *Improving wakefulness and reduce excessive daytime sleepiness (EDS)* *in OSA patients* Pitolisant should be used at the lowest effective dose, depending on individual patient response and tolerance, according to an up-titration scheme, without exceeding the dose of 18 mg/day:
• Week 1: initial dose of 4.5 mg (one 4.5 mg tablet) per day.
• Week 2: the dose may be increased to 9 mg (two 4.5 mg tablets) per day.
• Week 3: the dose may be increased to 18 mg (one 18 mg tablet) per day or decreased to 4.5 mg (one 4.5 mg tablet) per day. At any time, the dose can be decreased (down to 4.5 mg per day) or increased (up to 18 mg per day) according to the physician assessment and the patient's response. The total daily dose should be administered as a single dose in the morning upon wakening. *Maintenance of efficacy* As long-term efficacy data are limited (see section 5.1), the continued efficacy of treatment should be regularly evaluated by the physician. **Special populations** *Elderly* Limited data are available in elderly. Therefore, dosing should be adjusted according to their renal, hepatic status, individual response and tolerance. Insomnia has been reported in higher rate in the elderly and dosing should be adjusted accordingly (see section 4.8). *Renal impairment* In patients with renal impairment, the maximum daily dose should be 18 mg. *Hepatic impairment* No dosage adjustment is required in patients with mild hepatic impairment. In patients with moderate hepatic impairment (Child-Pugh B) the titration period should be two week up-titration steps instead of one after initiation of treatment, due to expected longer half-life and higher exposure, and a dosage adjustment in patients with moderate hepatic impairment could eventually be considered depending on individual response and tolerance. The daily dose can be increased without exceeding a maximal dose of 18 mg (see section 5.2). Pitolisant is contraindicated in patients with severe hepatic impairment (Child-Pugh C) (see section 4.3). *Paediatric population* The safety and efficacy of pitolisant in children aged from 0 to 18 years old have not yet been established. No data are available. *Poor metabolizers* By comparison to CYP2D6 extensive metabolisers, higher systemic exposure (up to 3 fold) is observed in CYP2D6 poor metabolisers and lower exposure (by 0.8-fold) is observed in CYP2D6 ultra-rapid metabolizers. No differences in systemic exposure is observed between CYP2D6 extensive and intermediate metabolizers. In the up-titration scheme, dose increment should take into account this higher exposure in CYP2D6 poor metabolizers, and a dosage adjustment in patients with known poor CYP2D6 metabolizer genotype could be considered depending on individual response and tolerance (see section 5.2). Furthermore, no dose recommendation can currently be given for CYP2D6 ultra-rapid metabolizers taking a CYP3A inducer, because the PK is currently unknown in this subpopulation. **Method of administration** For oral use.4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Severe hepatic impairment (Child-Pugh C). Breastfeeding (see section 4.6).4.4 Special warnings and precautions for use **Psychiatric disorders** Pitolisant should be administered with caution in patients with history of psychiatric disorders such as severe anxiety or severe depression with suicidal ideation risk. Suicidal ideation has been reported in patients with psychiatric history treated with pitolisant. **Hepatic or renal impairment** Pitolisant should be administered with caution in patients with either renal impairment or moderate hepatic impairment (Child-Pugh B) and dosing regimen should be adapted according to section 4.2. **Gastrointestinal disorders** Gastric disorders reactions have been reported with pitolisant, therefore it should be administered with caution in patients with acid related gastric disorders (see section 4.8) or when co-administered with gastric irritants such as corticosteroids or NSAID. **Nutrition disorders** Pitolisant should be administered with caution in patients with severe obesity or severe anorexia (see section 4.8). In case of significant weight change, treatment should be re-evaluated by the physician. **Cardiac disorders** In two dedicated QT studies, supra-therapeutic doses of pitolisant (3-6-times the therapeutic dose, that is 108 mg to 216 mg) produced mild to moderate prolongation of QTc interval (10-13 ms). In clinical trials, no specific cardiac safety signal was identified at therapeutic doses of pitolisant. Nevertheless, patients with cardiac disease, hypertension, at risk of major adverse cardiovascular events (MACE), co-medicated with other QT-prolonging medicinal products or known to increase the risk of repolarization disorders, or co-medicated with medicinal products that significantly increase pitolisant Cmax and AUC ratio (see section 4.5) or patients with severe renal or moderate hepatic impairment (see section 4.4) should be carefully monitored (see section 4.5). **Epilepsy** Convulsions were reported at high doses in animal models (see section 5.3). In clinical trials, one epilepsy aggravation was reported in one epileptic patient. Caution should be taken for patients with severe epilepsy. **Women of childbearing potential** Women of childbearing potential have to use effective contraception during treatment and at least up to 21 days after treatment discontinuation (based on pitolisant/metabolites half-life). Pitolisant may reduce the effectiveness of hormonal contraceptives. Therefore, an alternative method of effective contraception should be used if the woman patient is using hormonal contraceptives (see sections 4.5 and 4.6). **Drug-drug interactions** The combination of pitolisant with substrates of CYP3A4 and having a narrow therapeutic margin should be avoided (see section 4.5). **Rebound effect** No rebound effect was reported during clinical trials. However, treatment discontinuation should be monitored. **Drug abuse** Pitolisant showed absence or low abuse potential according to clinical data (specific human abuse potential study at doses from 36 up to 216 mg, and observed abuse-related adverse effects in phase 3 studies).4.5 Interaction with other medicinal products and other forms of interaction **Antidepressants** Tri or tetracyclic antidepressants (e.g. imipramine, clomipramine, mirtazapine) may impair the efficacy of pitolisant because they display histamine H1-receptor antagonist activity and possibly cancel the effect of endogenous histamine released in brain by the treatment and alternative should be used. **Anti-histamines** Anti-histamines (H1-receptor antagonists) crossing the haemato-encephalic barrier (e.g. pheniramine maleate, chlorpheniramine, diphenydramine, promethazine, mepyramine, doxylamine) may impair the efficacy of pitolisant and alternative should be used. **QT-prolonging substances or known to increase the risk of repolarization disorders** (e.g. haloperidol, risperidone, erythromycine, clarithromycine, roxithromycine, loratadine, sildenafil) Combination with pitolisant should be made with a careful monitoring (see section 4.4). **Pharmacokinetic interactions** In subjects that are CYP2D6 intermediate, extensive (normal) or ultra-rapid metabolizers, CYP2D6 is the main enzyme involved in the biotransformation of pitolisant, CYP3A is involved to a lesser extent. In subjects that are CYP2D6 poor metabolizers or are CYP2D6 intermediate, extensive or ultra-rapid metabolizers taking CYP3A inducers, CYP3A is significantly involved in the biotransformation of pitolisant and CYP2D6 is involved to a lesser extent. *Medicinal products affecting pitolisant metabolism*
• Enzyme inducers CYP3A inducers will most likely have an effect on the pharmacokinetics of pitolisant in CYP2D6 poor metabolizers and CYP2D6 ultra-rapid metabolizers and their effect in these populations is currently unknown. A clinical monitoring should be made when both active substances are combined and, eventually a dosage adjustment during the combination and one week after the inducer treatment. Co-administration of pitolisant with rifampicin in multiple doses significantly decreases pitolisant mean Cmax and AUC ratio about 0.6 fold and 0.5 fold, respectively. Therefore, co-administration of pitolisant with potent CYP3A4 inducers (e.g. rifampicin, phenobarbital, carbamazepine, phenytoin) should be done with caution. With St John's Wort (Hypericum Perforatum), due to its strong CYP3A4 inducing effect, caution should be exercised when taken concurrently with pitolisant. A clinical monitoring should be made when both active substances are combined and, eventually a dosage adjustment during the combination and one week after the inducer treatment.
• CYP2D6 inhibitors CYP2D6 inhibitors will most likely have an effect on the pharmacokinetics of pitolisant in subjects that are CYP2D6 intermediate, extensive metabolizers or ultra-rapid metabolizers and taking no CYP3A inducers, but not in subjects that are CYP2D6 poor metabolizers or intermediate, extensive metabolizers or CYP2D6 ultra-rapid metabolizers and taking CYP3A inducers. A dosage adjustment during the combination could eventually be considered depending on individual response and tolerance. Co-administration of pitolisant with paroxetine significantly increases pitolisant mean Cmax and AUC0—72h ratio about 1.5 fold and 2 fold, respectively. Given the 2-fold increase of pitolisant exposure, its coadministration with CYP2D6 inhibitors (e.g. paroxetine, fluoxetine, venlafaxine, duloxetine, bupropion, quinidine, terbinafine, cinacalcet) should be done with caution. A dosage adjustment during the combination could eventually be considered. Other In a clinical multiple dose study, the combination of pitolisant with probenecid decreases the AUC of pitolisant by about 0.7 fold. The underlying mechanism is unknown. A dosage adjustment during the combination could eventually be considered depending on individual response and tolerance. *Medicinal products that pitolisant may affect metabolism*
• CYP3A4 and CYP2B6 substrates A clinical induction study showed that pitolisant is a weak inducer of CYP3A (0.2-fold reduction in midazolam exposure). Therefore, the combination of pitolisant with substrates of CYP3A4 and having a narrow therapeutic margin (e.g. immunosuppressants, docetaxel, kinase inhibitors, cisapride, pimozide, halofantrine) should be avoided (see section 4.4). With other CYP3A4, CYP2B6 (e.g. efavirenz, bupropion), CYP2C (e.g. repaglinide, phenytoin, warfarin), P-gp (e.g. dabigatran, digoxin) and UGT (e.g. morphine, paracetamol, irinotecan) susbtrates, caution should be made with a clinical monitoring of their efficacy. Pitolisant might decrease the exposure to oral contraceptives and an additional further reliable contraceptive method should be used (see section 4.6).
• Substrates of OCT1 Pitolisant shows greater than 50% inhibition towards OCT1 (organic cation transporters 1) at 1.33 µM, the extrapolated IC50 of pitolisant is 0.795 µM. Pitolisant may be a clinically relevant inhibitor of OCT1 based on in vitro data and a clinically relevant interaction may occur with substrates of OCT1 (e.g. metformin). Even if the clinical relevance of this effect is not established, caution is advised when pitolisant is administered with a substrate of OCT1 (e.g. metformin (biguanides)) (see section 5.2). **Other** The combination of pitolisant with modafinil or sodium oxybate, usual treatments of narcolepsy was evaluated in healthy volunteers, at therapeutic doses. No clinically relevant pharmacokinetic drug-drug interaction was evidenced either with modafinil or with sodium oxybate and no dose adjustment is necessary when pitolisant is co-administered with those current treatments of OSA symptoms. Pitolisant decreases the olanzapine exposure by 0.3 fold. **Paediatric population** Interaction studies have only been performed in adults.4.6 Fertility, pregnancy and lactation **Women of childbearing potential** Women of childbearing potential have to use effective contraception during treatment and at least up to 21 days after treatment discontinuation (based on pitolisant/metabolites half-life). Pitolisant/metabolites may reduce the effectiveness of hormonal contraceptives. Therefore, an alternative method of effective contraception should be used if the woman is using hormonal contraceptives (see section 4.5). **Pregnancy** There are no or limited amount of data from the use of pitolisant in pregnant women. Studies in animals have shown reproductive toxicity, including teratogenicity. In rats, pitolisant/metabolites were shown to cross the placenta (see section 5.3). Pitolisant should not be used during pregnancy unless the potential benefit outweighs the potential risk for foetus. **Breast-feeding** Animal study has shown excretion of pitolisant/metabolites in milk. Therefore, breastfeeding is contraindicated during treatment with pitolisant (see section 4.3). **Fertility** Study in animals has shown effects on semen parameters, without a significant impact on reproductive performance in males and reduction on the percentage of live foetuses in treated females (see section 5.3).4.7 Effects on ability to drive and use machines Pitolisant has minor influence on the ability to drive and use machines. Patients with abnormal levels of sleepiness who take pitolisant should be advised that their level of wakefulness may not return to normal. Patients with excessive daytime sleepiness, including those taking pitolisant should be frequently reassessed for their degree of sleepiness and, if appropriate, advised to avoid driving or any other potentially dangerous activity.4.8 Undesirable effects **Summary of the safety profile** The most frequent adverse drug reactions (ADRs) reported with pitolisant were insomnia (8.4%), headache (7.7%), nausea (4.8%), anxiety (2.1%), irritability (1.8%), dizziness (1.4%), depression (1.3%), tremor (1.2%), sleep disorders (1.1%), fatigue (1.1%), vomiting (1.0%), vertigo (1.0%), dyspepsia (1.0%), weight increase (0.9%), abdominal pain upper (0.9%). The most serious ADRs are abnormal weight decrease (0.09%) and abortion spontaneous (0.09%). **Tabulated list of adverse reactions** The following adverse reactions have been reported with pitolisant during clinical studies in narcolepsy and other indications and are listed below as MedDRA preferred term by system organ class and frequency; frequencies are defined as: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥ 1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000); within each frequency group, adverse reactions are presented in order of decreasing seriousness: *Narcolepsy and other indications* | | | | | | --- | --- | --- | --- | | | **Common** | **Uncommon** | **Rare** | | Metabolism and nutrition disorders | | Decreased appetite Increased appetite Fluid retention | Anorexia Hyperphagia Appetite disorder | | Psychiatric disorders | Insomnia Anxiety Irritability Depression Sleep disorder | Agitation Hallucination Hallucination visual, auditory Affect lability Abnormal dreams Dyssomnia Middle insomnia Initial insomnia Terminal insomnia Nervousness Tension Apathy Nightmare Restlessness Panic Attack Libido decreased Libido increased Suicidal ideation | Abnormal behaviour Confusional state Depressed mood Excitability Obsessive thoughts Dysphoria Hypnopompic hallucination Depressive symptom Hypnagogic hallucination Mental impairment | | Nervous system disorders | Headache Dizziness Tremor | Dyskinesia Balance disorder Cataplexy Disturbance in attention Dystonia On and off phenomenon Hypersomnia Migraine Psychomotor hyperactivity Restless Legs Syndrome Somnolence Epilepsy Bradykinesia Paresthesia | Loss of consciousness Tension headache Memory impairment Poor sleep quality | | Eye disorders | | Visual acuity reduced Blepharospasm | | | Ear and labyrinth disorders | Vertigo | Tinnitus | | | Cardiac disorders | | Extrasystoles Bradycardia | | | Vascular disorders | | Hypertension Hypotension Hot flush | | | Respiratory, thoracic and mediastinal disorders | | Yawning | | | Gastrointestinal disorders | Nausea Vomiting Dyspepsia | Dry mouth Abdominal pain Diarrhoea Abdominal discomfort Abdominal pain upper Constipation Gastrooesophageal reflux disease Gastritis Gastrointestinal pain Hyperacidity Paraesthesia oral Stomach discomfort | Abdominal distension Dysphagia Flatulence Odynophagia Enterocolitis | | Skin and subcutaneous tissue disorders | | Erythema Pruritus Rash Hyperhidrosis Sweating | Toxic skin eruption Photosensitivity | | Musculoskeletal and connective tissue disorders | | Arthralgia Back pain Muscle rigidity Muscular weakness Musculoskeletal pain Myalgia Pain in extremity | Neck pain Musculoskeletal chest pain | | Renal and urinary disorders | | Pollakiuria | | | Pregnancy, puerperium and perinatal conditions | | | Abortion spontaneous | | Reproductive system and breast disorders | | Metrorrhagia | | | General disorders and administration site conditions | Fatigue | Asthenia Chest Pain Feeling Abnormal Malaise Oedema Peripheral oedema | Pain Night sweats Sense of oppression | | Investigations | | Weight increased Weight decreased Hepatic enzymes increased | Creatine phosphokinase increased | | | | Electrocardiogram QT prolonged Heart rate increased Gamma-glutamyltransferase increased | General physical condition abnormal Electrocardiogram repolarisation abnormality Electrocardiogram T wave inversion | *Obstructive sleep apnoea* | | | | | | --- | --- | --- | --- | | | **Very Common** | **Common** | **Uncommon** | | Infections and infestations | | | Herpes zoster Viral upper respiratory tract infection | | Blood and lymphatic system disorders | | | Alanine aminotransferase increased Blood cholesterol increased Blood pressure increased Blood triglycerides increased Hepatic enzyme increased Transaminase increased | | Metabolism and nutrition disorders | | | Alcohol intolerance Increased appetite Hypoglycaemia Weight decreased Weight increased | | Psychiatric disorders | | Insomnia (all types) Anxiety disorders Sleep disorders | Confusional arousal Depressed mood disorders and disturbances Fear Irritability Nervousness disorders Libido disorders Panic reaction Withdrawal syndrome | | Nervous system disorders | Headache | | Circadian rhythm sleep disorder Dizziness Dysgeusia Psychomotor hyperactivity Migraine Sleep paralysis Hypotonia | | Eye disorders | | | Dry eye Photopsia | | Ear and labyrinth disorders | | Vertigo | Tinnitus | | Cardiac disorders | | | Atrioventricular block first degree Palpitations Tachycardia Ventricular extrasystoles Electrocardiogram QT prolonged Heart rate increased | | Vascular disorders | | Hypertension | Hot flush | | Respiratory, thoracic and mediastinal disorders | | | Yawning Cough Nocturnal dyspnoea | | Gastrointestinal disorders | | Nausea/vomiting Abdominal pain and discomfort Diarrhoea | Constipation Dry mouth Enterocolitis Faeces discoloured Gastrointestinal disorders Breath odour Flatulence Rectal haemorrhage Salivary hypersecretion | | Skin and subcutaneous tissue disorders | | | Rash Hyperhidrosis Pruritus Erythema Cold sweat Night sweats Solar dermatitis | | Musculoskeletal and connective tissue disorders | | | Limb discomfort Muscle spasms Myalgia Arthralgia Tendonitis | | Renal and urinary disorders | | | Pollakiuria | | General disorders and administration site conditions | | Pain and Discomfort | Asthenia Pyrexia Thirst | **Description of selected adverse reactions** *Headache and insomnia* During clinical studies, episodes of headache and insomnia have been reported (7.7 % to 8.4%). Most of these adverse reactions were mild to moderate. If symptoms persist a reduced daily dose or discontinuation should be considered. During clinical studies in OSA indication, episodes of headache and insomnia have been reported (12.4 % and 8.9%) more frequently in women (headache and insomnia) and in elderly (insomnia) patients. Most of these adverse reactions were mild to moderate (see section 4.2). Dosing should be adjusted accordingly. *Gastric disorders* Gastric disorders caused by hyperacidity have been reported during clinical studies in 3.5% of the patients receiving pitolisant. Higher rates of nausea are reported in women. These effects were mostly mild to moderate. If they persist a corrective treatment with proton pump inhibitor could be initiated. *Patients with low/normal Body Mass Index (BMI) (<25)* Headache, insomnia, nausea and anxiety have been reported in higher rates in patients with low/normal BMI. Dosing should be adjusted accordingly. **Reporting of suspected adverse reactions** Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.4.9 Overdose **Symptoms** Symptoms of Wakix overdose may include headache, insomnia, irritability, nausea and abdominal pain. **Management** In case of overdose, hospitalisation and monitoring of the vital functions are recommended. There is no clearly identified antidote.

5.1 Pharmacodynamic properties Pharmacotherapeutic group: Other nervous system drugs, ATC code: N07XX11. **Mechanism of action** Pitolisant is a potent, orally active histamine H3-receptor antagonist/inverse agonist which, via its blockade of histamine auto-receptors enhances the activity of brain histaminergic neurons, a major arousal system with widespread projections to the whole brain. Pitolisant also modulates various neurotransmitter systems, increasing acetylcholine, noradrenaline and dopamine release in the brain. However no increase in dopamine release in the striatal complex including nucleus accumbens was evidenced for pitolisant. **Pharmacodynamic effects** In narcoleptic patients with or without cataplexy, pitolisant improves the level and duration of wakefulness and daytime alertness assessed by objective measures of ability to sustain wakefulness (e.g. Maintenance of Wakefulness Test (MWT)) and attention (e.g. Sustained Attention to Response Task (SART)). **Clinical efficacy and safety** Narcolepsy (with or without cataplexy) is a chronic condition. The effectiveness of pitolisant up to 36 mg once a day, for the treatment of narcolepsy with or without cataplexy was established in two main, 8 weeks, multicenter, randomized, double-blind, placebo-controlled, parallel group trials (Harmony I and Harmony CTP). Harmony Ibis, study with a similar design, was limited to 18 mg once a day. Long-term safety data of Wakix in this indication are available in the open label long-term study HARMONY III The pivotal study (Harmony 1), double-blind, randomized, vs placebo and modafinil (400 mg/day), parallel group studies with flexible dose adaptation, included 94 patients (31 patients treated with pitolisant, 30 with placebo and 33 with modafinil). Dosage was initiated at 9 mg once a day and was increased, according to efficacy response and tolerance to 18 mg or 36 mg once a day per 1-week interval. Most patients (60%) reached the 36 mg once a day dosage. To assess the efficacy of pitolisant on Excessive Daytime Sleepiness (EDS), Epworth Sleepiness Scale (ESS) score was used as primary efficacy criterion. The results with pitolisant were significantly superior to those in the placebo group (mean difference: -3.33; 95%CI [-5.83 to -0.83]; p < 0.05) but did not differ significantly from the results in the modafinil group (mean difference: 0.12; 95%CI [-2.5 to 2.7]). The waking effect of the two active substances was established at similar rates (Figure 1). **Figure 1: Changes in Epworth Sleepiness Scale Score (ESS) (mean ± SEM) from Baseline to week 8 in Harmony 1 study** The effect on Epworth was supported in two laboratory tests of vigilance and attention (Maintenance of Wakefulness Test (MWT) (p=0.044) and Sustained Attention to Response (SART) (p=0.053, almost but not significant)). Cataplexy attacks frequency in patients displaying this symptom was decreased significantly (p=0.034) with pitolisant (-65%) compared to placebo (-10%). The daily cataplexy rate (geometric means) was 0.52 at baseline and 0.18 at final visit for pitolisant and 0.43 at baseline and 0.39 at final visit for placebo, with a rate ratio rR=0.38 [0.16 ; 0.93] (p=0.034). The second pivotal study (Harmony Ibis) included 165 patients (67 treated with pitolisant, 33 with placebo and 65 with modafinil). The study design was similar to study Harmony I except that the maximum dose for pitolisant reached by 75% of patients was 18 mg once a day instead of 36 mg in Harmony I. As an important unbalance led to comparison of results with or without cluster grouping of sites, the most conservative approach showed non-significant ESS score decrease with pitolisant compared to placebo (pitolisant-placebo=-1.94 with p=0.065). Results from cataplexy rate at 18 mg once a day were not consistent with those of the first pivotal study (36 mg once a day). Improvement of the two objective tests of wakefulness and attention, MWT and SART, with pitolisant was significant versus placebo (p=0.009 and p=0.002 respectively) and non-significant versus modafinil (p=0.713 and p=0.294 respectively). Harmony CTP, a supportive double blind, randomized, parallel group study of pitolisant versus placebo, was designed to establish pitolisant efficacy in patients with high frequency cataplexy in narcolepsy. The primary efficacy endpoint was the change in the average number of cataplexy attacks per week between the 2 weeks of baseline and the 4 weeks of stable treatment period at the end of study. 105 narcoleptic patients with high frequency weekly cataplexy rates at baseline were included (54 patients treated with pitolisant and 51 with placebo). Dosage was initiated at 4.5 mg once a day and was increased, according to efficacy response and tolerance to 9 mg, 18 mg or 36 mg once a day per 1-week interval. Most patients (65%) reached the 36 mg once a day dosage. On the primary efficacy endpoint, Weekly Rate of Cataplexy episodes (WRC), the results with pitolisant were significantly superior to those in the placebo group (p < 0.0001), with a progressive 64% decrease from baseline to end of treatment (Figure 2). At baseline, the geometric mean of WRC was 7.31 (median=6.5 [4.5; 12]) and 9.15 (median=8.5 [5.5; 15.5]) in the placebo and pitolisant groups respectively. During the stable period (until the end of treatment), geometric mean WRC decreased to 6.79 (median=6 [3; 15]) and 3.28 (median=3 [1.3; 6]) in the placebo and pitolisant groups respectively in patients who had experienced at least one episode of cataplexy. The observed WRC in pitolisant group was about half of WRC in the placebo group: the effect size of pitolisant compared with placebo was summarized by the ratio rate rR(Pt/Pb), rR=0.512; 95%CI [0.435 to 0.603]; p < 0.0001). The effect size of pitolisant compared with placebo based on a model for WRC based on BOCF with centre as a fixed effect was 0.581, 95%CI [0.493 to 0.686]; p<0.0001. **Figure 2: Changes in weekly cataplexy episodes (geometric mean) from Baseline to week 7 in Harmony CTP study** \*p<0.0001 vs placebo The effect of pitolisant on EDS was also assessed in this population using the ESS score. In the pitolisant group, ESS decreased significantly between baseline and the end of treatment compared to placebo with an observed mean change of -1.9 ± 4.3 and -5.4 ± 4.3 (mean ± sd) for placebo and pitolisant respectively, (p<0.0001) (Figure 3). This effect on EDS was confirmed by the results on Maintenance of Wakefulness Test (MWT). The geometric mean of the ratios (MWTFinal/MWTBaseline) was 1.8 (95%CI 1.19; 2.71, p=0.005). The MWT value in the pitolisant group was 80% higher than in the placebo group. **Figure 3: Changes in Epworth Sleepiness Scale Score (ESS) (mean ± SEM) from Baseline to week 7 in Harmony CTP study** The open-label, long-term Phase III study (HARMONY III) assessed the long term safety of pitolisant in patients suffering from narcolepsy (with or without cataplexy) over 12 months and with an extension of up to 5 years. 102 narcoleptic patients with or without cataplexy were included in the 12 months follow-up period. 68 patients completed the first 12 months period. 45, 38, 34 and 14 patients completed the 2, 3, 4 and 5 year follow-up periods, respectively. The maximal dose received during the study was 36 mg / day in 85% of patients. After 12 months of treatment, improvements in EDS assessed by ESS score of remaining patients is of same magnitude as those observed in the other trials conducted in narcoleptic patients. The decrease in mean ESS score (SD) was -3.62 (4.63) after 1 year. After 12 months of treatment with pitolisant, frequency of symptoms such as sleep attacks, sleep paralysis, cataplexy and hallucinations has been improved. No major safety concern was identified. The safety results observed were similar to those reported in previous trials where pitolisant at 36 mg once daily was given for up to 3 months only. The efficacy of pitolisant in the treatment of Excessive Daytime Sleepiness (EDS) in patients with Obstructive Sleep Apnea (OSA) has been studied in two pivotal clinical trials: HAROSA I and HAROSA II. HAROSA I studied the efficacy and safety of pitolisant in the treatment of Excessive Daytime Sleepiness in patients with Obstructive Sleep Apnea syndrome (OSA), and treated by Continuous Positive Airway Pressure (CPAP), but still complaining of Excessive Daytime Sleepiness (EDS). This was a prospective, multicenter, randomized, double-blind study of pitolisant versus placebo, 12-week double-blind phase. 244 patients were analyzed (183 pitolisant, 61 placebo), 83% male, average of 53 years old, 12% over 65 years. Patients had excessive daytime sleepiness (an Epworth Sleepiness Scale [ESS] score greater than or equal to 12) and were submitted to nCPAP therapy for a minimum period of 3 months and still complaining of Excessive Daytime Sleepiness despite the efforts made beforehand to obtain an efficient nCPAP. The primary efficacy variable was the change in Epworth Scale Score (ESS) between baseline and end of treatment. During the double-blind phase, the maximum dose prescribed was 18 mg for 79.8% of the patient in the active treatment group and for 88.5% of the patients in the placebo group. The maximum dose is reached after a three-week titration, starting with 4.5 mg. After 12 weeks DB treatment, a significant improvement of the ESS was reported with pitolisant compared to placebo (table 1). **Table 1: overview of Efficacy results after 12 weeks in HAROSA I** | | | | | | | | | --- | --- | --- | --- | --- | --- | --- | | **Parameters** | **Treatment group (n)** | **Baseline score (at V2)** | **Final score (at V6)** | **Change** | **Difference from placebo** **95% CI** | **P-value** | | **ESS (SD)** | Placebo (61) | 14.6 (2.8) | 12.1 (6.4) | -2.75 | 2.6[-3.9;-1.4] | P<0.001 | | Pitolisant (183) | 14.9 (2.7) | 9 (4.8) | -5.52 | **Figure 1 Changes in Epworth sleepiness scale (ESS) score in P09-08 studyDouble-Blind Phase - ITT Population (N=244)** HAROSA II studied the efficacy and safety of pitolisant in the treatment of Excessive Daytime Sleepiness in patients with Obstructive Sleep Apnoea syndrome (OSA) refusing the Continuous Positive Airway Pressure (CPAP) therapy. This was a prospective, multicenter, randomized, double-blind study of pitolisant versus placebo, 12-week double-blind phase followed by a 40-week open-label extension phase. 268 patients were analyzed (201 pitolisant, 67 placebo), 75% male, average of 52 years, 12% over 65 years. Patients had an Epworth Sleepiness Scale [ESS] score greater than or equal to 12 and were refusing to be treated by nCPAP therapy, and still complaining of Excessive Daytime Sleepiness. The primary efficacy variable was the change in Epworth Scale Score (ESS) between baseline and end of treatment. During the double-blind phase, the maximum dose prescribed was 18 mg for 82.5% of the patient in the active treatment group and for 86.6% of the patients in the placebo group. After 12 weeks DB treatment, a significant improvement of the ESS was reported with pitolisant compared to placebo (ANCOVA model adjusting for ESS and BMI at V2 and study center as random effect) (Table 2). **Table 2: overview of Efficacy results after 12 weeks in HAROSA II** | | | | | | | | | --- | --- | --- | --- | --- | --- | --- | | **Parameters** | **Treatment group (n)** | **Baseline score (at V2)** | **Final score (at V6)** | **Change** | **Difference from placebo** **95% CI** | **P-value** | | **ESS (SD)** | Placebo (67) | 15.7 (3.6) | 12.2 (6.1) | -3.6 | -2.8 [-4.0;-1.5] | P<0.001 | | Pitolisant (201) | 15.7 (3.1) | 9.1 (4.7) | -6.3 | **Figure 2 Changes in Epworth sleepiness scale (ESS) score in P09-09 studyDouble-Blind Phase - ITT Population (N=268)** In an extended analysis the two HAROSA trials were compared and combined, showing significant improvements by pitolisant compared with placebo on the main parameters (ESS, OSleR test, Pichot Fatigue Scale and CGI). **Table 3: Main efficacy results in pooled analysis HAROSA I – HAROSA II** | | | | | | --- | --- | --- | --- | | | **Mean** | **95% CI** | **p** | | **OSleR Test (1)** | 1.18 | 1.02, 1.35 | P=0.022 | | **Pichot fatigue scale (2)** | -1.27 | -2.30, -0.23 | P=0.017 | | **CGI (3)** | -0.63 | -0.84, -0.47 | P<0.001 |

1. mean ratio P20/placebo
2. treatment effect
3. difference P20-placebo Open-label data Patients who participated in the double-blind 12 weeks period of HAROSA I and HAROSA II studies, could participate in the 40 week open-label phase. The primary objective of the open-label phase was long-term safety and effectiveness of pitolisant up to 18 mg/day. Maintenance of effect of pitolisant in EDS in OSA patients has not been established in blinded, placebo-controlled trials. In HAROSA I, 1.5% of patients discontinued study participation during the open-label phase, due to lack of efficacy and 4.0% due to adverse events. In HAROSA II, 1.3% of patients discontinued study participation during the open-label phase due to lack of efficacy and 2.5% due to adverse events. **Paediatric population** The European Medicines Agency has deferred the obligation to submit the results of studies with Wakix in one or more subsets of the paediatric population in narcolepsy with or without cataplexy (see section 4.2 for information on paediatric use).5.2 Pharmacokinetic properties The exposure to pitolisant in healthy volunteers was assessed in studies involving more than 200 subjects that received doses of pitolisant in single administration up to 216 mg and for a duration up to 28 days. **Absorption** Pitolisant is well and rapidly absorbed with peak plasma concentration reached approximately three hours after administration. The steady-state (geometric mean, CV%) Cmax and AUC of the therapeutic dose (18 mg) is 35.5 ng/mL (59.2%) and 378 ng x h/mL (86.3%), respectively. Upon repeated administrations, the steady state is achieved after 5-6 days of administration leading to an increased serum level around 2-fold. Inter individual variability is rather high (Geom CV% of 59.2 and 86.3 for Cmax and AUC0-24h respectively), some volunteers showing outlier high profile (without tolerance issues). The pharmacokinetics of pitolisant is not influenced by concomitant food intake. **Distribution** Pitolisant exhibits high serum protein binding (>90%) and demonstrates approximately equal distribution between red blood cells and plasma. Pitolisant is widely distributed with an apparent volume of distribution of 5-10 L/kg. **Biotransformation** The metabolisation of pitolisant in humans is fully characterized. The major non-conjugated metabolites are hydroxylated derivatives in several positions and cleaved forms of pitolisant leading to inactive major carboxylic acid metabolite found in urine and serum. They are formed under the action of CYP3A4 and CYP2D6. Several conjugated metabolites were identified, the major ones (inactive) being two glycine conjugates of the acid metabolite of pitolisant and a glucuronide of a ketone metabolite of monohydroxy desaturated pitolisant. On liver microsomes, pitolisant and its major metabolites do not significantly inhibit the activities of the cytochromes CYP1A2, CYP2C9, CYP2C19, CYP2C8, CYP2B6, CYP2E1 or CYP3A4 and of uridine diphosphate glucuronosyl transferases isoforms UGT1A1, UGT1A4, UGT1A6, UGT1A9 and UGT2B7 up to the concentration of 13.3 µM, a level considerably higher than the levels achieved with therapeutic dose. Pitolisant is an inhibitor of CYP2D6 with moderate potency (IC50 = 2.6 µM). Pitolisant induces CYP3A4, CYP1A2 and CYP2B6 *in vitro*. Clinically relevant interactions are expected with CYP3A4 and CYP2B6 substrates and by extrapolation, UGTs, CYP2C and P-gp substrates (see section 4.5). *In vitro* studies indicate that pitolisant is neither a substrate nor an inhibitor of human P-glycoprotein and breast cancer resistance protein (BCRP). Pitolisant is not a substrate of OATP1B1, OATP1B3. Pitolisant is not a significant inhibitor of OAT1, OAT3, OCT2, OATP1B1, OATP1B3, MATE1, or MATE2K at the tested concentration. Pitolisant shows greater than 50% inhibition towards OCT1 (organic cation transporters 1) at 1.33 µM, the extrapolated IC50 of pitolisant is 0.795 µM (see section 4.5). **Elimination** Pitolisant has a plasma half-life of 10-12 hours. Upon repeated administrations, the steady state is achieved after 5-6 days of administration leading to an increased serum level around 100%. Inter individual variability is rather high, some volunteers showing outlier high profile (without tolerance issues). The elimination is mainly achieved via urine (approximately 63%) through an inactive non conjugated metabolite (BP2.951) and a glycine conjugated metabolite. 25% of the dose is excreted through expired air and a small fraction (<3%) recovered in faeces where the amount of pitolisant or BP2.951 was negligible. **Linearity/non-linearity** When pitolisant dose is doubled from 27 to 54 mg, AUC0-∞ is increased by about 2.3. **Special populations** *Elderly* In 68 to 80 years old patients the pharmacokinetics of pitolisant is not different compared to younger patients (18 to 45 years of age). Above 80 years old, kinetics show a slight variation without clinical relevance. Limited data are available in elderly. Therefore, dosing should be adjusted according to their renal hepatic status (see section 4.2 and 4.4). *Renal impairment* In patients with impaired renal function (stages 2 to 4 according to the international classification of chronic kidney disease, i.e. creatinine clearance between 15 and 89 ml/min), Cmax and AUC tended to be increased by a factor of 2.5 without any impact on half-life (see section 4.2). *Hepatic impairment* In patients with mild hepatic impairment (Child-Pugh A), there was no significant changes in pharmacokinetics compared with normal healthy volunteers. In patients with moderate hepatic impairment (Child-Pugh B), AUC increased by a factor 2.4, while half-life doubled (see section 4.2). Pitolisant pharmacokinetics after repeated administration in patients with hepatic impairment has not been evaluated yet. *CYP2D6 poor metabolizers* The exposure to Pitolisant was higher in the CYP2D6 poor metabolisers after a single dose and at steady state; Cmax and AUC(0-tau) was approximately 2.7-fold and 3.2-fold greater on Day 1 and 2.1-fold and 2.4-fold on Day 7. The serum Pitolisant half-life was longer in CYP2D6 poor metabolisers compared to the extensive metabolisers. In subjects that are CYP2D6 intermediate, extensive (normal) or ultra-rapid metabolizers, CYP2D6 is the main enzyme involved in the biotransformation of pitolisant, CYP3A is involved to a lesser extent. CYP3A4 and CYP3A5 genetic polymorphisms are unlikely to have significant effect on the pharmacokinetic of pitolisant. In these subjects, CYP2D6 inhibitors will have an effect on the pharmacokinetic of pitolisant, not CYP3A inhibitors. In subjects that are CYP2D6 ultra-rapid metabolizers, CYP3A inducers may lead to an even more rapid elimination of pitolisant and lower exposures compared to the other subgroups. This may result in exposures below therapeutic concentrations. In subjects that are CYP2D6 poor metabolizers or are CYP2D6 intermediate, extensive or ultra-rapid metabolizers taking CYP3A inducers, CYP3A is significantly involved in the biotransformation of pitolisant and CYP2D6 is involved to a lesser extent. Only under these conditions, genetic polymorphisms in CYP3A4 and 3A5 may have a significant effect on the pharmacokinetic of pitolisant. In subjects that are CYP2D6 poor metabolizers, CYP3A inhibitors and inducers will have an effect on the pharmacokinetic of pitolisant and CYP2D6 inhibitors to a much lesser extent. In subjects that are CYP2D6 intermediate, extensive or ultra-rapid metabolizers taking a CYP3A inducer, a CYP3A inhibitor will lead to a decrease in the contribution of CYP3A to the overall metabolism. However, the exposure is most likely similar to that in subjects that are not taking a CYP3A inducer. Thus, in this subpopulation, CYP3A inhibition is unlikely to affect the pharmacokinetic of pitolisant. *Race* The effect of race on metabolism of pitolisant has not been evaluated.5.3 Preclinical safety data After 1 month in mice, 6 months in rats and 9 months in monkeys, no adverse effect level (NOAEL) were 75, 30 and 12 mg/kg/day, p.o., respectively, providing safety margins of 9, 1 and 0.4, respectively when compared to the drug exposure at therapeutic dose in human. In rats, transient reversible convulsive episodes occurred at Tmax , that may be attributable to a metabolite abundant in this species but not in humans. In monkeys, at the highest doses, transient CNS related clinical signs including emesis, tremors and convulsions were reported. At the highest doses, no histopathological changes were recorded in monkeys and rats presented some limited histopathological changes in some organs (liver, duodenum, thymus, adrenal gland and lung). Pitolisant was neither genotoxic nor carcinogenic. Teratogenic effect of pitolisant was observed at maternally toxic doses (teratogenicity safety margins < 1 in rats and in rabbits). At high doses, pitolisant induced sperm morphology abnormalities and decreased motility without any significant effect on fertility indexes in male rats and it decreased the percentage of live conceptuses and increased post-implantation loss in female rats (safety margin of 1). It caused a delay in post-natal development (safety margin of 1). Pitolisant/metabolites were shown to cross the placenta barrier in animals. Juvenile toxicity studies in rats revealed that the administration of pitolisant at high doses induced a dose related mortality and convulsive episode that may be attributable to a metabolite abundant in rats but not in humans. Pitolisant blocked hERG channel with an IC50 exceeding therapeutic concentrations and induced a slight QTc prolongation in dogs. In preclinical studies, drug dependence and drug abuse liability studies were conducted in mice, monkeys and rats. However, no definitive conclusion could be drawn on tolerance, dependence and self-administration studies.

6.1 List of excipients **Tablet core** Microcrystalline cellulose Crospovidone type A Talc Magnesium stearate Colloidal anhydrous silica **Coating** Poly(vinyl alcohol) Titanium dioxide (E171) Macrogol 3350 Talc6.2 Incompatibilities Not applicable.6.3 Shelf life 3 years6.4 Special precautions for storage This medicinal product does not require any special storage conditions.6.5 Nature and contents of container High density polyethylene (HDPE) bottle with a tamper evident, child-resistant, polypropylene screw cap fitted with desiccant (silica gel). Bottle of 30 film-coated tablets. Available in packs containing 1 bottle of 30 tablets. Not all pack sizes may be marketed.6.6 Special precautions for disposal and other handling No special requirements.