4.1. Therapeutic indications

Wakix is indicated:

- in adults, adolescents and children from the age of 6 years 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

Adults

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.

Paediatric population

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 children weighing 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 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 in children weighing 40 kg and above or 18 mg per day in children weighing less than 40 kg) 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.

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 contra-indicated in patients with severe hepatic impairment (Child-Pugh C) (see section 4.3).

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, co-medicated with other QT-prolonging medicinal products or known to increase the risk of repolarization disorders, hypertension, at risk of major adverse cardiovascular events (MACE), 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 in adults 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) substrates, 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 in adult patients 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

MedDRA System Organ Class

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

Gastroesophageal 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

Electrocardiogram QT prolonged

Heart rate increased

Gamma-glutamyltransferase increased

Creatine phosphokinase 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.

Paediatric population (Age 6 to 17) (see section 5.1)

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

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

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.