Ozawade · 4.8 Undesirable effects · 1

HOS-099185 · has-adverse-reaction-information · PDF-Seite 7

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 Alanine aminotransferase increased disorders Blood cholesterol increased Blood pressure increased Blood triglycerides increased Hepatic enzyme increased Transaminase increased Metabolism and nutrition Alcohol intolerance disorders Increased appetite 7  Hypoglycaemia Weight decreased Weight increased Psychiatric disorders Insomnia (all types) Confusional arousal Anxiety disorders Depressed mood disorders and Sleep disorders disturbances Fear Irritability

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HOS-099181 · has-contraindication-information · PDF-Seite 3

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).

HOS-099180 · has-indication-information · PDF-Seite 2

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).

HOS-099183 · has-interaction-information · PDF-Seite 5

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

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HOS-099184 · has-pregnancy-information · PDF-Seite 6

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). 6 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).

HOS-099182 · has-warning-information · PDF-Seite 3

Psychiatric disorders 3 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

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