pitolisant: prescribing information – dosing, contraindications, interactions, side effects

Ozawade is indicated 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).

Treatment should be initiated by a healthcare professional experienced in the treatment of OSA and cardiovascular risk. OSA disease should be annually reassessed.

Ozawade 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

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 or 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 be regularly evaluated by the physician.

Special populations

Elderly
Limited data are available in elderly. Therefore, dosing should be adjusted according to their 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) 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 contraindicated in patients with severe hepatic impairment (Child-Pugh C) (see section 4.3).

Paediatric population
There is no relevant use of Ozawade in the paediatric population in Obstructive Sleep Apnoea (OSA).

CYP2D6 metabolizers phenotype (If known)
By comparison to CYP2D6 extensive metabolizers, higher systemic exposure (up to 3-fold) is observed in CYP2D6 poor metabolizers 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 the 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.

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).

Summary of the safety profile

The most frequent adverse reactions are headache 9.5%, insomnia (all types) 8.0%, anxiety 2.7%, nausea 2.3%, abdominal pain 1.9% and vertigo 1.7%.

Tabulated list of adverse reactions

The following adverse reactions have been reported with pitolisant during clinical studies 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:

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

Swelling of eyelid
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

Hot flush
Hypertension
Hypertensive crisis
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
Oedema peripheral

Description of selected adverse reactions

Headache and insomnia
During clinical studies in OSA indication, episodes of headache and insomnia have been reported (9.5 % and 8.0%) 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 presumably 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 national reporting system listed in Appendix V.

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 impairment

Pitolisant should be administered with caution in patients with 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 (see section 4.5).

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 (6-12-times the therapeutic dose, that is 108 mg to 216 mg) produced mild to moderate prolongation of QTc interval (10-13 ms).
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 studies, 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).

Drug abuse, rebound effect

In a specific study, pitolisant showed no or very low signal suggestive of abuse at the current therapeutic dose of 36 mg and at doses up to 216 mg; consequently, potential for drug abuse or recreational drug with pitolisant is very low.

No rebound effect was reported during clinical studies. However, treatment discontinuation should be monitored.

Pharmacodynamic interactions

Antidepressants

Tri or tetracyclic antidepressants with anti-histaminic H1-receptor properties (e.g. imipramine, clomipramine, mirtazapine) may impair the efficacy of pitolisant because they may decrease 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, diphenhydramine, 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
- 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 alone or combined with CY3A4 inhibitors significantly increases to the same extent 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) alone or combined with a CYP3A4 inhibitors (itraconazole, ketonazole) should be done with caution.

- 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.

• CYP3A4 inhibitors

Based on the in vitro biotransformation pathway, CYP3A4 inhibitors may have an impact on the pharmacokinetics of pitolisant and particularly in subjects that are CYP2D6 poor metabolizers.
The combination of pitolisant with grapefruit juice and itraconazole was evaluated in healthy volunteers. No clinically relevant pharmacokinetic drug-drug interaction was evidenced with any of these combinations. In CYP2D6 poor metabolizers, co-administration of pitolisant with paroxetine (a strong CYP2D6 inhibitor) combined with a CYP3A4 inhibitor may moderatly increase the exposure compared with administration with paroxetine alone confirming the minor clinical impact of CYP3A4 inhibition.
However, based on the biotransformation pathway caution should be exercised when pitolisant is co- administered with both CYP2D6 and CYP3A4 inhibitors whatever the CYP2D6 phenotype of the patients due to a significant decrease in clearance and an increase in exposure.

- 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, 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 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 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.

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).

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.

Symptoms

Symptoms of pitolisant 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.
PHARMACOLOGICAL PROPERTIES

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

Mechanism of action

Pitolisant is an 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.

Clinical efficacy

The efficacy of pitolisant in the treatment of Excessive Daytime Sleepiness (EDS) in patients with Obstructive Sleep Apnoea (OSA) has been studied in two pivotal clinical studies: HAROSA I and HAROSA II.

HAROSA I studied the efficacy and safety of pitolisant in the treatment of EDS in patients with Obstructive Sleep Apnoea syndrome (OSA), and treated by Continuous Positive Airway Pressure (CPAP), but still complaining of 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 EDS (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 EDS despite the efforts made beforehand to obtain an efficient nCPAP.

The primary efficacy variable was the change in Epworth Sleepiness Scale (ESS) Score between baseline and end of treatment. During the double-blind phase, the maximum dose prescribed was 18 mg for 79.8% of the patients 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)

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 (91.4-95.2%) 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 metabolism of pitolisant in humans is well characterized and represents the major route of elimination. The major non-conjugated metabolites are cleaved forms of pitolisant leading to inactive major carboxylic acid metabolites, three of which being major and in a lesser extent five hydroxylated/N-oxide derivatives in several positions found in urine and serum. By combining the contribution of enzyme determined in vitro with the exposure of the main metabolites identified in the mass balance study, the estimated overall contribution of CYP enzymes in pitolisant metabolism is of 60% for CYP2D6 and of ~ 30% for CYP3A4/3A5 when CYP2D6 phenotype is extensive metabolizer.

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).

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

Posology

Adults
Wakix 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 during breakfast.

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 and hepatic status.

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

Hepatic impairment
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 section 4.3).
No dosage adjustment is required in patients with mild hepatic impairment.

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.

Poor metabolizers
By comparison to CYP2D6 extensive metabolisers, higher systemic exposure (up to 3 fold) is observed in CYP2D6 poor metabolisers. In the up-titration scheme, dose increment should take into account this higher exposure.

Method of administration

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).

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:

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
Loss of consciousness
Tension headache
Memory impairment
Poor sleep quality

Psychomotor hyperactivity
Restless Legs Syndrome
Somnolence
Epilepsy
Bradykinesia
Paresthesia
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

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.

Gastric disorders
Gastric disorders caused by hyperacidity have been reported during clinical studies in 3.5% of the patients receiving pitolisant. 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)
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 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%).

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 national reporting system listed in Appendix V.

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, 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).

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.

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.

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).

Pharmacokinetic interactions

Medicinal products affecting pitolisant metabolism

- Enzyme inducers
Co-administration of pitolisant with rifampicin in multiple doses significantly decreases pitolisant mean Cmax and AUC ratio about 39% and 50%, 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.
In a clinical multiple dose study, the combination of pitolisant with probenecid decreases the AUC of pitolisant 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, 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.

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 at therapeutic concentrations and by extrapolation, CYP2C, UGTs and P-gp. No clinical data on the magnitude of this interaction are available. 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.

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

- 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.

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).

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.

Paediatric population

Interaction studies have only been performed in adults.

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).

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.

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.
PHARMACOLOGICAL 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

Adult population
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)).

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.

Baseline
End of Treatment