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Contraindicated Medications

Cariprazine is metabolized into 2 pharmacologically active moieties: desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR)1. This metabolism is mediated by the enzymes CYP3A4 and CYP2D62,3. Drugs that alter the activity of these enzymes can also affect the metabolism, potency, efficacy, and safety of cariprazine. As such, concomitant use of cariprazine with a strong CYP3A4 inhibitor increases the exposures of cariprazine and DDCAR compared with the use of cariprazine alone, and should not be used3.  Additionally, CYP3A4 is responsible for the formation and elimination of the active metabolites of cariprazine. The effect of CYP3A4 inducers on the exposure of cariprazine has not been evaluated and the net effect is unclear, so concomitant use of cariprazine with a CYP3A4 inducer is not recommended3.

Medications That Should Be Avoided While Taking Cariprazine3

Class of Drug Drug Names From the REAGILA Package Insert
CYP3A4 inhibitors Boceprevir, clarithromycin, cobicistat, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole, diltiazem, erythromycin, fluconazole verapamil 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 day) co-administration, either if unbound or unbound+bound moieties were 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 or moderate inhibitors of CYP3A4 is contraindicated.
CYP3A4 inducers Carbamazepine, phenobarbital, phenytoin, rifampicin, St.
John’s wort (Hypericum perforatum), bosentan, efavirenz, etravirine, modafinil, nafcillin
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 is contraindicated.

Medications That May Be Affected By Cariprazine and Should Be Closely Monitored3

Class of Drug Drug Names From the REAGILA Package Insert
P-glycoprotein (P-gp) substrates Dabigatran, digoxin Cariprazine is a P-gp inhibitor in vitro at its theoretical maximum intestinal concentration. The clinical consequences of this effect are not fully understood, however the use of P-gp substrates with narrow therapeutic index could require extra monitoring and dose adjustment.
Hormonal contraceptives Examples can be found on the external website It is currently unknown whether cariprazine may reduce the effectiveness of systemically acting hormonal contraceptives, so women using them should add a second barrier method.

Other Considerations When Taking Cariprazine

Cariprazine is a centrally acting medication with primary central nervous system effects, which means it can lower blood pressure and heart rate, and cause drowsiness3. These side effects can be amplified when combined with other centrally acting psychiatric medications, such as other antipsychotics, antidepressants (eg, fluoxetine, citalopram, sertraline), benzodiazepines (eg, alprazolam, diazepam, clonazepam), and mood stabilizers (eg, lithium, valproate). Cariprazine should be used with caution when alcohol and other centrally acting medications are also being used3.

Long-term treatment with some antipsychotics has been shown to cause dopamine supersensitivity by upregulation of D2 receptors4,5. Dopamine supersensitivity can induce psychosis and tardive dyskinesia, characterized by involuntary or repetitive movements of the limbs, tongue, or face6. These effects could be exacerbated when cariprazine is combined with other antipsychotics. In addition, antipsychotics with a high affinity for cholinergic M1 receptors have been linked to cholinergic rebound upon switching or discontinuation.

Cholinergic rebound, which can cause a variety of symptoms7, including nausea, vomiting, and anxiety, could be exacerbated when combining multiple antipsychotics or in an adjunctive treatment regimen with another M1 binding agent8. Although cariprazine has no appreciable affinity for cholinergic muscarinic receptors9, the possibility exists that combining cariprazine with compounds with high M1 receptor affinity could contribute to cholinergic rebound effects. While potential side effects that could occur if cariprazine is combined with other compounds have been briefly discussed here, it is important to mention that cariprazine is intended as a monotherapy medication.

For more information about drug-drug interactions with cariprazine, please also see the following external websites:



  1. Mészáros, G. P., Ágai-Csongor, É. & Kapás, M. Sensitive LC-MS/MS methods for the quantification of RGH-188 and its active metabolites, desmethyl- and didesmethyl-RGH-188 in human plasma and urine. J. Pharm. Biomed. Anal. 48, 388–397 (2008).
  2. Nakamura, T. et al. Clinical pharmacology study of cariprazine (MP-214) in patients with schizophrenia (12-week treatment). Drug Des. Devel. Ther. 10, 327–338 (2016).
  3. Reagila SmPC.
  4. Chouinard, G. et al. Antipsychotic-Induced Dopamine Supersensitivity Psychosis: Pharmacology, Criteria, and Therapy. Psychother. Psychosom. 86, 189–219 (2017).
  5. Yin, J., Barr, A., Ramos-Miguel, A. & Procyshyn, R. Antipsychotic Induced Dopamine Supersensitivity Psychosis: A Comprehensive Review. Curr. Neuropharmacol. 15, 174–183 (2016).
  6. Nakata, Y., Kanahara, N. & Iyo, M. Dopamine supersensitivity psychosis in schizophrenia: Concepts and implications in clinical practice. J. Psychopharmacol. 31, 1511–1518 (2017).
  7. Correll, C. U. From receptor pharmacology to improved outcomes: Individualising the selection, dosing, and switching of antipsychotics. Eur. Psychiatry 25, S12-21 (2010).
  8. Su, J., Barr, A. M. & Procyshyn, R. M. Adverse events associated with switching antipsychotics. J. Psychiatry Neurosci. 37, E1–E2 (2012).
  9. Kiss, B. et al. Cariprazine (RGH-188), a dopamine D3 receptor-preferring, D 3/D2 dopamine receptor antagonist-partial agonist antipsychotic candidate: In vitro and neurochemical profile. J. Pharmacol. Exp. Ther. 333, 328–340 (2010)


(COD: 300020/R12. Submitted to AIFA 16/04/2020) The safety and tolerability of cariprazine was evaluated in all of the clinical studies in the cariprazine



(COD: 300020/R16. Submitted to AIFA 16/04/2020) The ultimate goal in schizophrenia treatment is recovery, which encompasses symptom remission in addition to