OZAWADE Film-coated tablet Ref.[27832] Active ingredients: Pitolisant

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 (ChildPugh 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 C_max 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 significantly increases pitolisant mean C_max and AUC_0—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.

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 C_max 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

CYP3A inhibitors will most likely have an effect on the pharmacokinetic of pitolisant in CYP2D6 poor metabolizers and their effect in this population is currently unknown.

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. However, based on the biotransformation pathway caution should be exercised in subjects that are CYP2D6 poor metabolizers 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.

Summary of the safety profile

The most frequent adverse reactions are headache 12.4%, insomnia (all types) 8.9%, nausea 3.3%, anxiety 2.2%, abdominal pain 2.8%, vertigo 1.7% and diarrhoea 1%.

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:

Description of selected adverse reactions

Headache and insomnia

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 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.

Not applicable.