Interactions : אינטראקציות

4.5     Interaction with other medicinal products and other forms of interaction

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 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.

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
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.