4. Drug-Drug Interactions

Patient profiles will be assessed to identify those drug regimens which may result in clinically significant drug-drug interactions. Drug interactions considered clinically relevant for atypical antipsychotics are summarized in Table 5 1-25. Only those drug-drug interactions classified as clinical significance level 1 or those considered life-threatening which have not yet been classified will be reviewed.

Table 5. Select Drug-Drug Interactions for Oral Atypical Antipsychotics1
Target DrugInteracting DrugInteractionRecommendationClinical Significance Level #
AripiprazoleCitalopramIncreased risk of QT prolongation and serotonin syndrome because aripiprazole is a partial agonist of 5-HT1A and citalopram is a selective serotonin reuptake inhibitorAvoid usemajor (CP)
Atypical antipsychotics (AAs)Antihypertensive agentsPotential for enhanced antihypertensive effects due to AA-associated alpha1-adrenergic receptor antagonismUse cautiously together; monitor for amplified hypotensive effectsmoderate (CP)
AAsCNS depressantsPotential for additive CNS effectsUse cautiously together; observe patients for enhanced CNS adverse effectsmoderate (CP)
AAs (except pimavanserin)Drugs affecting seizure threshold (e.g., tramadol)Increased seizure risk as AAs have been associated with seizures (incidence varies)Avoid drug combination if possible; if combination necessary, closely monitor patients for seizure activity and discontinue therapy as indicatedmajor (CP)
AAsMetoclopramideAdjunctive therapy enhances potential for increased extrapyramidal symptoms (EPS) and neuroleptic malignant syndrome (NMS) as both agents block dopamine receptorsCombination contraindicated by metoclopramide manufacturer; if combination necessary, monitor for signs/ symptoms of EPS or NMS-discontinue metoclopramide if symptoms developsevere (CP)
ClozapineMyelopsuppressive (antineoplastic) drugsPotential for additive bone marrow suppressive effectsConcurrent administration contraindicatedsevere (CP)
ClozapineCarbamazepineIncreased risk of additive bone marrow-suppressing effects, including agranulocytosisAvoid concurrent use; choose alternative anticonvulsantmajor (CP)
SamidorphanOpioidsConcurrent use may decrease opioid efficacy and precipitate opioid withdrawalConcurrent administration is contraindicatedsevere (CP)
Select AAs (clozapine, olanzapine)CYP1A2 inducers (e.g., carbamazepine**, phenobarbital, phenytoin, ritonavir*, rifampin)Potential for reduced clozapine, olanzapine serum concentrations and worsening of psychosisMonitor clozapine, olanzapine efficacy in patients; adjust doses as necessary when CYP1A2 inducer added, deleted, or changed to therapeutic regimenmajor (CP)
Select AAs (asenapine, clozapine, olanzapine)CYP1A2 inhibitors (e.g., ciprofloxacin, fluvoxamine)Potential for decreased AA clearance, increased AA serum concentrations and enhanced pharmacologic/ adverse effects (seizures, hypotension) as clozapine, olanzapine metabolized by CYP1A2If drug combination necessary, used reduced clozapine dosages and closely monitor for adverse eventsmajor (CP)
Select AAs (aripiprazole, brexpiprazole, cariprazine, clozapine, iloperidone, pimavanserin, quetiapine, ziprasidone)CYP3A4 inhibitors (e.g., ketoconazole, ritonavir*)Potential for decreased AA clearance, increased AA serum concentrations, and enhanced pharmacologic/ adverse effects as select AAs metabolized by CYP3A4Monitor for enhanced AA pharmacologic/ adverse effects and adjust doses as necessary (50% dose reduction recommended for aripiprazole,  brexpiprazole, iloperidone)major, moderate (CP)
Select AAs (aripiprazole, brexpiprazole, clozapine, olanzapine, pimavanserin,  quetiapine, risperidone, ziprasidone)CYP3A4 inducers (e.g., carbamazepine**, phenytoin)Potential for significant reductions in AA plasma concentrations (by as much as 50%) due to enhanced AA hepatic microsomal metabolismMonitor AA efficacy in patients; adjust doses as necessary when CYP3A4 inducer added, deleted, or changed to therapeutic regimen (brexpiprazole dose should be doubled over 1-2 weeks when prescribed with CYP3A4 inducer)major, moderate (CP)
Select AAs (aripiprazole, brexpiprazole, iloperidone, risperidone)CYP2D6 inhibitors (e.g., quinidine, select SSRIs, ritonavir)Potential for decreased AA clearance and increased AA serum concentrations and enhanced pharmacologic/ adverse effects as select AAs metabolized by CYP2D6Monitor for enhanced AA pharmacologic/ adverse effects and adjust doses as necessary (recommended to reduce aripiprazole, brexpiprazole,  iloperidone doses by 50% when administered in conjunction with CYP2D6 inhibitor)major, moderate (CP)
Select AAs (aripiprazole, asenapine, clozapine, iloperidone, olanzapine, paliperidone, pimavanserin, quetiapine, risperidone, ziprasidone)QTc interval-prolonging medicationsPotential for increased cardiotoxicity (e.g., torsades de pointes, cardiac arrest) due to additive QT interval prolongationAvoid concurrent use; if combination necessary, closely monitor cardiac function; discontinue therapy in patients with QTc measurements greater than 500 msecsevere, major (CP)

Legend:

  • # CP = Clinical Pharmacology
  • * Ritonavir inhibits clozapine metabolism through CYP3A4 inhibition, but induces olanzapine metabolism through CYP1A2 enzyme induction.  
  • ** Carbamazepine induces olanzapine metabolism through CYP1A2 enzyme induction and induces clozapine metabolism through CYP3A4 induction.