Interactions : אינטראקציות

4.5   Interaction with other medicinal products and other forms of interaction

Potential for other medicinal products to affect cariprazine

Metabolism of cariprazine and its major active metabolites, desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR), is mediated mainly by CYP3A4 with a minor contribution of CYP2D6.

CYP3A4 inhibitors
Ketoconazole, a strong CYP3A4 inhibitor, caused two fold increase in plasma exposure for total cariprazine (sum of cariprazine and its active metabolites) during short-term (4 days) co-administration, either if unbound or unbound+bound moieties considered.
Due to the long half-life of the active moieties of cariprazine a further increase in plasma exposure of total cariprazine can be expected during longer co-administration. Therefore, co-administration of cariprazine with strong CYP3A4 inhibitors (e.g. boceprevir, clarithromycin, cobicistat, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole) is contraindicated (see section 4.3).

Erythromycin (500 mg twice daily), a moderate CYP3A4 inhibitor, caused on average a 1.4-fold (range 1.03-2.32-fold) increase in plasma exposure of total cariprazine after 3 weeks of co-administration.
Therefore, during a period of co-administration of cariprazine with a moderate CYP3A4 inhibitor (e.g., erythromycin, fluconazole, diltiazem, verapamil), monitoring of the individual response and tolerability is recommended and, if needed, the cariprazine dose should be (temporarily) reduced to account for the potential increase in exposure. Because of the long half-life of cariprazine and its active metabolites, starting or stopping a treatment with a moderate CYP3A4 inhibitor or changing the dose will not be fully reflected in plasma drug levels until after several weeks. Patients should be monitored for adverse reactions and treatment response for several weeks after initiating or stopping an interacting drug or after each cariprazine dose change.

Consumption of grapefruit juice should be avoided.

CYP3A4 inducers
Co-administration of cariprazine with strong and moderate inducers of CYP3A4 may result in a significant decrease in total cariprazine exposure, therefore the co-administration of cariprazine and strong or moderate CYP3A4 inducers (e.g. carbamazepine, phenobarbital, phenytoin, rifampicin, St.
John’s wort (Hypericum perforatum), bosentan, efavirenz, etravirine, modafinil, nafcillin) is contraindicated (see section 4.3).

CYP2D6 inhibitors
CYP2D6 mediated pathway plays a minor role in the metabolism of cariprazine, the major pathway is via CYP3A4 (see section 5.2). Therefore CYP2D6 inhibitors are unlikely to have a clinically relevant effect on cariprazine metabolism.

Potential for cariprazine to affect other medicinal products

P-glycoprotein (P-gp) substrates
Cariprazine is a P-gp inhibitor in vitro at its theoretical maximum intestinal concentration. The clinical consequences of this effect is not fully understood, however the use of P-gp substrates with narrow therapeutic index such as dabigatran and digoxin could require extra monitoring and dose adjustment.

Hormonal contraceptives
In a drug interaction study, 28 days of treatment with cariprazine at 6 mg daily had no clinically relevant effect of the pharmacokinetics of oral contraceptives (ethinylestradiol and levonorgestrel).

Pharmacodynamic interactions

Given the primary central nervous system effects of cariprazine, Reagila should be used with caution in combination with other centrally acting medicinal products and alcohol.