Source: European Medicines Agency (EU) Revision Year: 2025 Publisher: Bioprojet Pharma, 9, rue Rameau, 75002 Paris, France, Tel: +33 (0)1 47 03 66 33, Fax: +33 (0)1 47 03 66 30, e-mail: contact@bioprojet.com
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.
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.
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.
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.
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).
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 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).
The combination of pitolisant with substrates of CYP3A4 and having a narrow therapeutic margin should be avoided (see section 4.5).
No rebound effect was reported during clinical trials. However, treatment discontinuation should be monitored.
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).
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 (H1-receptor antagonists) crossing the haemato-encephalic barrier (e.g. pheniramine maleate, chlorpheniramine, diphenydramine, promethazine, mepyramine, doxylamine) may impair the efficacy of pitolisant.
Combination with pitolisant should be made with a careful monitoring (see section 4.4).
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.
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.
Interaction studies have only been performed in adults.
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).
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.
Animal study has shown excretion of pitolisant/metabolites in milk. Therefore, breastfeeding is contraindicated during treatment with pitolisant (see section 4.3).
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.
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%).
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 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 |
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 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.
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 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.
Not applicable.
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