WAKIX 4.5mg tablets medication leaflet

Wakix 4.5 mg film-coated tablets

Wakix 18 mg film-coated tablets

Wakix 4.5 mg film-coated tablet

Each tablet contains pitolisant hydrochloride equivalent to 4.45 mg of pitolisant.

Wakix 18 mg film-coated tablet

Each tablet contains pitolisant hydrochloride equivalent to 17.8 mg of pitolisant.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet)

Wakix 4.5 mg film-coated tablet

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

Wakix 18 mg film-coated tablet

White, round, biconvex film-coated tablet, 7.5 mm diameter marked with “20” on one side.

Wakix is indicated in adults, adolescents and children from the age of 6 years for the treatment ofnarcolepsy with or without cataplexy (see also section 5.1).

Treatment should be initiated by a physician experienced in the treatment of sleep disorders.

Wakix should be used at the lowest effective dose, depending on individual patient response andtolerance, 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 during breakfast.

Maintenance of efficacy

As long-term efficacy data are limited (see section 5.1), the continued efficacy of treatment should beregularly evaluated by the physician.

Limited data are available in elderly. Therefore, dosing should be adjusted according to their renal andhepatic status.

In patients with renal impairment, the maximum daily dose should be 18 mg.

In patients with moderate hepatic impairment (Child-Pugh B) two weeks after initiation of treatment,the daily dose can be increased without exceeding a maximal dose of 18 mg (see section 5.2).

Pitolisant is contra-indicated in patients with severe hepatic impairment (Child-Pugh C) (see section4.3).

No dosage adjustment is required in patients with mild hepatic impairment.

Wakix should be used at the optimal dose, depending on individual patient response and tolerance,according to an up-titration scheme, without exceeding the dose of 36 mg/day (18 mg/day in childrenweighing less than 40 kg).

- 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 4.5mg tablets) per day.

- Week 3: the dose may be increased to 18 mg (one 18 mg tablet) per day.

- Week 4: in children weighing 40 kg and above, the dose may be increased to 36 mg (two 18 mgtablets) 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 inchildren weighing 40 kg and above or 18 mg per day in children weighing less than 40 kg) accordingto the physician assessment and the patient’s response.

The total daily dose should be administered as a single dose in the morning during breakfast.

Poor metabolizers

By comparison to CYP2D6 extensive metabolisers, higher systemic exposure (up to 3 fold) isobserved in CYP2D6 poor metabolisers. In the up-titration scheme, dose increment should take intoaccount this higher exposure.

For oral use.

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).

Pitolisant should be administered with caution in patients with history of psychiatric disorders such assevere anxiety or severe depression with suicidal ideation risk. Suicidal ideation has been reported inpatients with psychiatric history treated with pitolisant.

Hepatic or renal impairment

Pitolisant should be administered with caution in patients with either renal impairment or moderatehepatic impairment (Child-Pugh B) and dosing regimen should be adapted according to section 4.2.

Gastric disorders reactions have been reported with pitolisant, therefore it should be administered withcaution in patients with acid related gastric disorders (see section 4.8) or when co-administered withgastric irritants such as corticosteroids or NSAID.

Nutrition disorders

Pitolisant should be administered with caution in patients with severe obesity or severe anorexia (seesection 4.8). In case of significant weight change, treatment should be re-evaluated by the physician.

In two dedicated QT studies, supra-therapeutic doses of pitolisant (3-6-times the therapeutic dose, thatis 108 mg to 216 mg) produced mild to moderate prolongation of QTc interval (10-13 ms). In clinicaltrials, no specific cardiac safety signal was identified at therapeutic doses of pitolisant. Nevertheless,patients with cardiac disease, co-medicated with other QT-prolonging medicinal products or known toincrease the risk of repolarization disorders, or co-medicated with medicinal products that significantlyincrease pitolisant Cmax and AUC ratio (see section 4.5) or patients with severe renal or moderatehepatic impairment (see section 4.4) should be carefully monitored (see section 4.5).

Convulsions were reported at high doses in animal models (see section 5.3). In clinical trials, oneepilepsy aggravation was reported in one epileptic patient. Caution should be taken for patients withsevere epilepsy.

Women of childbearing potential have to use effective contraception during treatment and at least upto 21 days after treatment discontinuation (based on pitolisant/metabolites half-life). Pitolisant mayreduce the effectiveness of hormonal contraceptives. Therefore, an alternative method of effectivecontraception should be used if the woman patient is using hormonal contraceptives (see sections 4.5and 4.6).

The combination of pitolisant with substrates of CYP3A4 and having a narrow therapeutic marginshould be avoided (see section 4.5).

Rebound effect

No rebound effect was reported during clinical trials. However, treatment discontinuation should bemonitored.

Drug abuse

Pitolisant showed absence or low abuse potential according to clinical data (specific human abusepotential study at doses from 36 up to 216 mg in adults and observed abuse-related adverse effects inphase 3 studies).

Antidepressants

Tri or tetracyclic antidepressants (e.g. imipramine, clomipramine, mirtazapine) may impair theefficacy of pitolisant because they display histamine H1-receptor antagonist activity and possiblycancel the effect of endogenous histamine released in brain by the treatment.

Anti-histamines

Anti-histamines (H1-receptor antagonists) crossing the haemato-encephalic barrier (e.g. pheniraminemaleate, chlorpheniramine, diphenydramine, promethazine, mepyramine, doxylamine) may impair theefficacy of pitolisant.

QT-prolonging substances or known to increase the risk of repolarization disorders

Combination with pitolisant should be made with a careful monitoring (see section 4.4).

Medicinal products affecting pitolisant metabolism

- Enzyme inducers

Co-administration of pitolisant with rifampicin in multiple doses significantly decreases pitolisantmean Cmax and AUC ratio about 39% and 50%, respectively. Therefore, co-administration of pitolisantwith potent CYP3A4 inducers (e.g. rifampicin, phenobarbital, carbamazepine, phenytoin) should bedone with caution. With St John’s Wort (Hypericum Perforatum), due to its strong CYP3A4 inducingeffect, caution should be exercised when taken concurrently with pitolisant. A clinical monitoringshould be made when both active substances are combined and, eventually a dosage adjustment duringthe combination and one week after the inducer treatment.

In a clinical multiple dose study, the combination of pitolisant with probenecid decreases the AUC ofpitolisant by about 34%.

- CYP2D6 inhibitors

Co-administration of pitolisant with paroxetine significantly increases pitolisant mean Cmax and

AUC0—72h ratio about 47% and 105%, respectively. Given the 2-fold increase of pitolisant exposure, itscoadministration with CYP2D6 inhibitors (e.g. paroxetine, fluoxetine, venlafaxine, duloxetine,bupropion, quinidine, terbinafine, cinacalcet) should be done with caution. A dosage adjustmentduring the combination could eventually be considered.

Medicinal products that pitolisant may affect metabolism

- CYP3A4 and CYP2B6 substrates

Based on in vitro data, pitolisant and its main metabolites may induce CYP3A4 and CYP2B6 attherapeutic concentrations and by extrapolation, CYP2C, UGTs and P-gp. No clinical data on themagnitude of this interaction are available. Therefore, the combination of pitolisant with substrates of

CYP3A4 and having a narrow therapeutic margin (e.g. immunosuppressants, docetaxel, kinaseinhibitors, 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) substrates, caution should bemade with a clinical monitoring of their efficacy.

With oral contraceptives, the combination with pitolisant should be avoided and a further reliablecontraceptive method used.

- Substrates of OCT1

Pitolisant shows greater than 50% inhibition towards OCT1 (organic cation transporters 1) at1.33 µM, the extrapolated IC50 of pitolisant is 0.795 µM.

Even if the clinical relevance of this effect is not established, caution is advised when pitolisant isadministered with a substrate of OCT1 (e.g. metformin (biguanides)) (see section 5.2).

The combination of pitolisant with modafinil or sodium oxybate, usual treatments of narcolepsy wasevaluated in healthy volunteers, at therapeutic doses. No clinically relevant pharmacokinetic drug-druginteraction was evidenced either with modafinil or with sodium oxybate.

Interaction studies have only been performed in adults.

Women of childbearing potential have to use effective contraception during treatment and at least upto 21 days after treatment discontinuation (based on pitolisant/metabolites half-life).

Pitolisant/metabolites may reduce the effectiveness of hormonal contraceptives. Therefore, analternative method of effective contraception should be used if the woman is using hormonalcontraceptives (see section 4.5).

There are no or limited amount of data from the use of pitolisant in pregnant women. Studies inanimals have shown reproductive toxicity, including teratogenicity. In rats, pitolisant/metabolites wereshown to cross the placenta (see section 5.3).

Pitolisant should not be used during pregnancy unless the potential benefit outweighs the potential riskfor foetus.

Animal study has shown excretion of pitolisant/metabolites in milk. Therefore, breastfeeding iscontraindicated during treatment with pitolisant (see section 4.3).

Study in animals has shown effects on semen parameters, without a significant impact on reproductiveperformance in males and reduction on the percentage of live foetuses in treated females (see section5.3).

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 ofwakefulness may not return to normal. Patients with excessive daytime sleepiness, including thosetaking pitolisant should be frequently reassessed for their degree of sleepiness and, if appropriate,advised to avoid driving or any other potentially dangerous activity.

The most frequent adverse drug reactions (ADRs) reported with pitolisant in adult patients wereinsomnia (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 mostserious ADRs are abnormal weight decrease (0.09%) and abortion spontaneous (0.09%).

The following adverse reactions have been reported with pitolisant during clinical studies innarcolepsy and other indications and are listed below as MedDRA preferred term by system organclass 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 eachfrequency group, adverse reactions are presented in order of decreasing seriousness:

MedDRA System Organ Common Uncommon Rare

Class

Metabolism and nutrition Decreased appetite Anorexiadisorders Increased appetite Hyperphagia

Fluid retention Appetite disorder

Psychiatric disorders Insomnia Agitation Abnormal behaviour

Anxiety Hallucination Confusional state

Irritability Hallucination visual, Depressed mood

Depression auditory Excitability

Sleep disorder Affect lability Obsessive thoughts

Abnormal dreams Dysphoria

Dyssomnia Hypnopompic

Middle insomnia hallucination

Initial insomnia Depressive symptom

Terminal insomnia Hypnagogic

Nervousness hallucination

Tension Mental impairment

Apathy

Nightmare

Restlessness

Panic Attack

Libido decreased

Libido increased

Suicidal ideation

Nervous system disorders Headache Dyskinesia Loss of consciousness

Dizziness Balance disorder Tension headache

Tremor Cataplexy Memory impairment

Disturbance in attention Poor sleep quality

Dystonia

On and off phenomenon

Hypersomnia

Migraine

Psychomotorhyperactivity

Restless Legs Syndrome

Somnolence

Bradykinesia

Paresthesia

Eye disorders Visual acuity reduced

Blepharospasm

Ear and labyrinth disorders Vertigo Tinnitus

Cardiac disorders Extrasystoles

Bradycardia

Vascular disorders Hypertension

Hot flush

Respiratory, thoracic and Yawningmediastinal disorders

Gastrointestinal disorders Nausea Dry mouth Abdominal distension

Vomiting Abdominal pain Dysphagia

Dyspepsia Diarrhoea Flatulence

Abdominal discomfort Odynophagia

Abdominal pain upper Enterocolitis

Gastroesophagealreflux disease

Gastritis

Gastrointestinal pain

Hyperacidity

Paraesthesia oral

Stomach discomfort

Skin and subcutaneous Erythema Toxic skin eruptiontissue disorders Pruritus Photosensitivity

Hyperhidrosis

Sweating

Musculoskeletal and Arthralgia Neck painconnective tissue disorders Back pain Musculoskeletal chest

Muscle rigidity pain

Muscular weakness

Musculoskeletal pain

Myalgia

Pain in extremity

Renal and urinary disorders Pollakiuria

Pregnancy, puerperium and Abortion spontaneousperinatal conditions

Reproductive system and Metrorrhagiabreast disorders

General disorders and Fatigue Asthenia Painadministration site Chest Pain Night sweatsconditions Feeling Abnormal Sense of oppression

Malaise

Oedema

Peripheral oedema

Investigations Weight increased Creatine

Weight decreased phosphokinase

Hepatic enzymes increasedincreased General physical

Electrocardiogram QT condition abnormalprolonged Electrocardiogram

Heart rate increased repolarisation

Gamma- abnormalityglutamyltransferase Electrocardiogram Tincreased wave inversion

Headache and insomnia

During clinical studies, episodes of headache and insomnia have been reported (7.7 % to 8.4%). Mostof these adverse reactions were mild to moderate. If symptoms persist a reduced daily dose ordiscontinuation should be considered.

Gastric disorders

Gastric disorders caused by hyperacidity have been reported during clinical studies in 3.5% of thepatients receiving pitolisant. These effects were mostly mild to moderate. If they persist a correctivetreatment with proton pump inhibitor could be initiated.

Paediatric population (Age 6 to 17)

The paediatric population has been studied in a double-blind multicentre randomized placebo-controlled trial; a total of 73 children and adolescents with narcolepsy with or without cataplexy weretreated with pitolisant for 8 weeks.

Frequency, type and severity of adverse reactions in children and adolescents were similar to that ofadults. The most frequent related adverse drug reactions (ADRs) reported in this population wereheadache (11%), insomnia (5.5%), hypertension (2.7%).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Symptoms of Wakix overdose may include headache, insomnia, irritability, nausea and abdominalpain.

In case of overdose, hospitalisation and monitoring of the vital functions are recommended. There isno clearly identified antidote.

Pharmacotherapeutic group: Other nervous system drugs, ATC code: N07XX11.

Pitolisant is a potent, orally active histamine H3-receptor antagonist/inverse agonist which, via itsblockade of histamine auto-receptors enhances the activity of brain histaminergic neurons, a majorarousal system with widespread projections to the whole brain. Pitolisant also modulates variousneurotransmitter systems, increasing acetylcholine, noradrenaline and dopamine release in the brain.

However no increase in dopamine release in the striatal complex including nucleus accumbens wasevidenced for pitolisant.

In narcoleptic patients with or without cataplexy, pitolisant improves the level and duration ofwakefulness 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)).

Adult population

Narcolepsy (with or without cataplexy) is a chronic condition. The effectiveness of pitolisant up to36 mg once a day, for the treatment of narcolepsy with or without cataplexy was established in twomain, 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 mgonce a day. Long-term safety data of Wakix in this indication are available in the open label long-termstudy 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 withpitolisant, 30 with placebo and 33 with modafinil). Dosage was initiated at 9 mg once a day and wasincreased, according to efficacy response and tolerance to 18 mg or 36 mg once a day per 1-weekinterval. Most patients (60%) reached the 36 mg once a day dosage. To assess the efficacy of pitolisanton Excessive Daytime Sleepiness (EDS), Epworth Sleepiness Scale (ESS) score was used as primaryefficacy 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 theresults in the modafinil group (mean difference: 0.12; 95%CI [-2.5 to 2.7]). The waking effect of thetwo active substances was established at similar rates (Figure 1).

Figure 1: Changes in Epworth Sleepiness Scale Score (ESS) (mean ± SEM) from Baseline toweek 8 in Harmony 1 study

The effect on Epworth was supported in two laboratory tests of vigilance and attention (Maintenanceof 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 (geometricmeans) was 0.52 at baseline and 0.18 at final visit for pitolisant and 0.43 at baseline and 0.39 at finalvisit 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 withplacebo and 65 with modafinil). The study design was similar to study Harmony I except that themaximum 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 groupingof sites, the most conservative approach showed non-significant ESS score decrease with pitolisantcompared to placebo (pitolisant-placebo=-1.94 with p=0.065). Results from cataplexy rate at 18 mgonce 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 pitolisantwas significant versus placebo (p=0.009 and p=0.002 respectively) and non-significant versusmodafinil (p=0.713 and p=0.294 respectively).

Harmony CTP, a supportive double blind, randomized, parallel group study of pitolisant versusplacebo, was designed to establish pitolisant efficacy in patients with high frequency cataplexy innarcolepsy. The primary efficacy endpoint was the change in the average number of cataplexy attacksper week between the 2 weeks of baseline and the 4 weeks of stable treatment period at the end ofstudy. 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 dayand was increased, according to efficacy response and tolerance to 9 mg, 18 mg or 36 mg once a dayper 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 withpitolisant were significantly superior to those in the placebo group (p < 0.0001), with a progressive64% decrease from baseline to end of treatment (Figure 2). At baseline, the geometric mean of WRCwas 7.31 (median=6.5 [4.5; 12]) and 9.15 (median=8.5 [5.5; 15.5]) in the placebo and pitolisant groupsrespectively. During the stable period (until the end of treatment), geometric mean WRC decreased to6.79 (median=6 [3; 15]) and 3.28 (median=3 [1.3; 6]) in the placebo and pitolisant groups respectivelyin patients who had experienced at least one episode of cataplexy. The observed WRC in pitolisantgroup was about half of WRC in the placebo group: the effect size of pitolisant compared with placebowas summarized by the ratio rate rR(Pt/Pb), rR=0.512; 95%CI [0.435 to 0.603]; p < 0.0001). Theeffect size of pitolisant compared with placebo based on a model for WRC based on BOCF with centreas 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 thepitolisant group, ESS decreased significantly between baseline and the end of treatment compared toplacebo with an observed mean change of -1.9 ± 4.3 and -5.4 ± 4.3 (mean ± sd) for placebo andpitolisant 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 inthe placebo group.

Figure 3: Changes in Epworth Sleepiness Scale Score (ESS) (mean ± SEM) from Baseline toweek 7 in Harmony CTP study

The open-label, long-term Phase III study (HARMONY III) assessed the long term safety of pitolisantin patients suffering from narcolepsy (with or without cataplexy) over 12 months and with anextension of up to 5 years. 102 narcoleptic patients with or without cataplexy were included in the 12months follow-up period. 68 patients completed the first 12 months period. 45, 38, 34 and 14 patientscompleted 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 oftreatment, improvements in EDS assessed by ESS score of remaining patients is of same magnitude asthose 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, sleepparalysis, cataplexy and hallucinations has been improved.

No major safety concern was identified. The safety results observed were similar to those reported inprevious trials where pitolisant at 36 mg once daily was given for up to 3 months only.

The effectiveness of pitolisant up to 36 mg once a day has been studied for the treatment of narcolepsywith or without cataplexy in children from 6 to less than 18 years old in an 8-week, multicenter,randomized, double-blind, placebo-controlled, parallel group trial. It included 110 patients (72 patientsin the pitolisant group, 38 in the placebo group). Dosage was initiated at 4.5 mg once a day and wasincreased, according to efficacy response and tolerance to 18 mg or 36 mg once a day per 1-weekinterval. Patients weighing less than 40 kg remained at a maximum dose of 18 mg. Most patients(60%) reached the 36 mg once a day dosage. 35 patients (31.8%) were aged 6 to 11 years and75 patients (68.2%) were aged 12 to less than 18 years. To assess the efficacy of pitolisant on

Excessive Daytime Sleepiness (EDS) and cataplexy (CTP), the Ullanlinna Narcolepsy Scale (UNS)total score was used as primary efficacy criterion, assessed as the change from baseline to the end ofdouble-blind period. The estimate LS means difference (SE) [95% CI] of UNS between treatmentgroups (pitolisant minus placebo) was -3.69 (1.37) [-6.38; -0.99], p=0.0073. Secondary endpointsincluded the paediatric daytime sleepiness scale (PDSS), the UNS-cataplexy (CTP) subscore, and theweekly rate of cataplexy (WRC). The estimate LS means difference (SE) [95% CI] of the PDSS totalscore between treatment groups (pitolisant minus placebo) was -3.41 (1.07) [-5.52; -1.31], p=0.0015.

In the subgroup of patients with type 1 narcolepsy, who had no minimum level of cataplexy requiredat inclusion (N=61 in the pitolisant group; N=29 in the placebo group), the estimate LS meansdifference (SE) [95% CI] of the UNS-CTP subscore between treatment groups (pitolisant minusplacebo) was -1.77 (0.78) [-3.29; -0.24], p=0.0229, and the rate ratio between the WRC in thepitolisant group and the WRC in the placebo group, adjusted for baseline, was in favor of pitolisant(0.42 [95% CI: 0.18; 1.01], p=0.0540).

Table 1: overview of efficacy results after 8 weeks in phase 3 paediatric study

Placebo (n= 38) Pitolisant (n= 72)

Ullanlinna Narcolepsy Scale (UNS)

Total score

Baseline mean (SD) 23.68 (9.08) 24.63 (7.80)

End of treatment mean (SD) 21.77 (9.25) 18.23 (8.14)

LS mean (SE) - change from baseline -2.60 (1.35) -6.29 (1.14)

Estimate, 95% CI -3.69 (-6.38; -0.99)p-value 0.0073

Paediatric Daytime Sleepiness Score

Baseline mean (SD) 20.00 (3.49) 20.16 (3.64)

End of treatment mean (SD) 17.96 (5.60) 14.57 (5.37)

LS mean (SE) - change from baseline -2.11 (0.89) -5.53 (0.66)

Estimate, 95% CI -3.41 (-5.52; -1.31)p-value 0.0015

Placebo (n= 29) Pitolisant (n= 61)

UNS-Cataplexy Subscore*

Baseline mean (SD) 9.03 (4.33) 8.93 (3.96)

End of treatment mean (SD) 8.07 (4.62) 6.02 (4.00)

LS mean (SE) - change from baseline -1.12 (0.64) -2.88 (0.44)

Estimate, 95% CI -1.77 (-3.29; -0.24)p-value 0.0229

Weekly cataplexy rate*

Baseline mean (SD) 13.44 (26.92) 8.63 (17.73)

LS mean (SE) 5.05 (0.37) 2.14 (0.27)

Estimate, 95% CI 0.42 (0.18; 1.01)p-value 0.0540

*only measured in patients with type I narcolepsy

Figure 4 Change in the Mean Ullanlinna Narcolepsy Scale Total Score (mean ± SEM) from

Baseline to the End of Treatment (Full Analysis Set)

Placebo24 24.63 Pitolisant23.6821.7718.23

Baseline End of Treatment

Baseline=[V1 score (D-14) + V2 score (D0)]/2

End of treatment=[V6 score (D49) + V7 score (D56)]/2

SEM=standard error of the mean

The exposure to pitolisant in healthy volunteers was assessed in studies involving more than 200subjects that received doses of pitolisant in single administration up to 216 mg and for a duration up to28 days.

Pitolisant is well and rapidly absorbed with peak plasma concentration reached approximately threehours after administration.

Total score [Mean ± SEM]

Pitolisant exhibits high serum protein binding (>90%) and demonstrates approximately equaldistribution between red blood cells and plasma.

The metabolisation of pitolisant in humans is fully characterized. The major non-conjugatedmetabolites are hydroxylated derivatives in several positions and cleaved forms of pitolisant leading toinactive major carboxylic acid metabolite found in urine and serum. They are formed under the actionof 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 ketonemetabolite of monohydroxy desaturated pitolisant.

On liver microsomes, pitolisant and its major metabolites do not significantly inhibit the activities ofthe cytochromes CYP1A2, CYP2C9, CYP2C19, CYP2C8, CYP2B6, CYP2E1 or CYP3A4 and ofuridine 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 withtherapeutic 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 areexpected with CYP3A4 and CYP2B6 substrates and by extrapolation, UGTs, CYP2C and P-gpsubstrates (see section 4.5).

In vitro studies indicate that pitolisant is neither a substrate nor an inhibitor of human P-glycoproteinand 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 section4.5).

Pitolisant has a plasma half-life of 10-12 hours. Upon repeated administrations, the steady state isachieved after 5-6 days of administration leading to an increased serum level around 100%. Interindividual variability is rather high, some volunteers showing outlier high profile (without toleranceissues).

The elimination is mainly achieved via urine (approximately 63%) through an inactive non conjugatedmetabolite (BP2.951) and a glycine conjugated metabolite. 25% of the dose is excreted throughexpired air and a small fraction (<3%) recovered in faeces where the amount of pitolisant or BP2.951was negligible.

When pitolisant dose is doubled from 27 to 54 mg, AUC0-∞ is increased by about 2.3.

In 68 to 80 years old patients the pharmacokinetics of pitolisant is not different compared to youngerpatients (18 to 45 years of age). Above 80 years old, kinetics show a slight variation without clinicalrelevance. Limited data are available in elderly. Therefore, dosing should be adjusted according totheir renal hepatic status (see section 4.2 and 4.4).

In patients with impaired renal function (stages 2 to 4 according to the international classification ofchronic kidney disease, i.e. creatinine clearance between 15 and 89 ml/min), Cmax and AUC tended tobe increased by a factor of 2.5 without any impact on half-life (see section 4.2).

In patients with mild hepatic impairment (Child-Pugh A), there was no significant changes inpharmacokinetics compared with normal healthy volunteers. In patients with moderate hepaticimpairment (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 notbeen evaluated yet.

CYP2D6 poor metabolizers

The exposure to Pitolisant was higher in the CYP2D6 poor metabolisers after a single dose and atsteady 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 metaboliserscompared to the extensive metabolisers.

The effect of race on metabolism of pitolisant has not been evaluated.

The pharmacokinetics of pitolisant at the dose of 18 mg in children from 6 to less than 18 years withnarcolepsy has been studied in a multi-centre, single dose trial. By comparison to adult patientsexposure, in a Population PK analysis with a body weight-dependent model, systemic exposure topitolisant at the dose of 18 mg as estimated by Cmax and AUC0-10h are roughly 3-fold higher in childrenwith a body weight below 40 kg and 2-fold higher in adolescents with a body weight above 40 kgcompared to adults. Therefore, the dose titration should be initiated at the lowest dose of 4.5 mg andlimited to 18 mg in children weighing less than 40 kg (see section 4.2).

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, transientreversible convulsive episodes occurred at Tmax , that may be attributable to a metabolite abundant inthis species but not in humans. In monkeys, at the highest doses, transient CNS related clinical signsincluding emesis, tremors and convulsions were reported. At the highest doses, no histopathologicalchanges were recorded in monkeys and rats presented some limited histopathological changes in someorgans (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 anddecreased motility without any significant effect on fertility indexes in male rats and it decreased thepercentage of live conceptuses and increased post-implantation loss in female rats (safety margin of1). 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 adose related mortality and convulsive episode that may be attributable to a metabolite abundant in ratsbut not in humans.

Pitolisant blocked hERG channel with an IC50 exceeding therapeutic concentrations and induced aslight 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 andself-administration studies.

Microcrystalline cellulose

Crospovidone type A

Talc

Magnesium stearate

Colloidal anhydrous silica

Poly(vinyl alcohol)

Titanium dioxide (E171)

Macrogol 3350

Talc

Not applicable.

Wakix 4.5 mg tablet3 years

Wakix 18 mg tablet3 years

This medicinal product does not require any special storage conditions.

High density polyethylene (HDPE) bottle with a tamper evident, child-resistant, polypropylene screwcap fitted with desiccant (silica gel).

Bottle of 30 or 90 film-coated tablets.

Wakix 4.5 mg

Available in packs containing 1 bottle of 30 tablets.

Wakix 18 mg

Available in packs containing 1 bottle of 30 tablets or packs containing 1 bottle of 90 tablets or multi-packs containing 90 (3 bottles of 30) tablets.

Not all pack sizes may be marketed.

No special requirements.

Bioprojet Pharma9, rue Rameau75002 Paris

France

Tel: +33 (0)1 47 03 66 33

Fax: +33 (0)1 47 03 66 30e-mail: contact@bioprojet.com

EU/1/15/1068/001

EU/1/15/1068/002

EU/1/15/1068/003

EU/1/15/1068/004

Date of first authorisation: 31/03/2016

Date of latest renewal: 17/12/2020

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.