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 Antipsychotics

Target Drug Interacting Drug Interaction Recommendation Clinical Significance Level #
Aripiprazole Citalopram Increased risk of QT prolongation and serotonin syndrome because aripiprazole is a partial agonist of 5-HT1A and citalopram is a selective serotonin reuptake inhibitor Avoid use Major (DrugReax) 2-major(CP)
Atypical antipsychotics (AAs) Antihypertensive agents Potential for enhanced antihypertensive effects due to AA-associated alpha1-adrenergic receptor antagonism Use cautiously together; monitor for amplified hypotensive effects 3-moderate (CP)
AAs CNS depressants Potential for additive CNS effects Use cautiously together; observe patients for enhanced CNS adverse effects Major (DrugReax) 3-moderate (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 indicated Major (DrugReax) 2-major (CP)
AAs Metoclopramide Adjunctive therapy enhances potential for increased extrapyramidal symptoms (EPS) and neuroleptic malignant syndrome (NMS) as both agents block dopamine receptors Combination contraindicated by metoclopramide manufacturer; if combination necessary, monitor for signs/ symptoms of EPS or NMS-discontinue metoclopramide if symptoms develop Contraindicated (DrugReax) 1-severe (CP)
Clozapine Myelopsuppressive (antineoplastic) drugs Potential for additive bone marrow suppressive effects Concurrent administration contraindicated 1-severe (CP)
Clozapine Carbamazepine Increased risk of additive bone marrow-suppressing effects, including agranulocytosis Avoid concurrent use; choose alternative anticonvulsant Major (DrugReax) 2-major (CP)
Samidorphan Opioids Concurrent use may decrease opioid efficacy and precipitate opioid withdrawal Concurrent administration is contraindicated Contraindicated (DrugReax) 1-severe (CP)
Select AAs (clozapine, olanzapine) CYP1A2 inducers (e.g., carbamazepine**, phenobarbital, phenytoin, ritonavir*, rifampin) Potential for reduced clozapine, olanzapine serum concentrations and worsening of psychosis Monitor clozapine, olanzapine efficacy in patients; adjust doses as necessary when CYP1A2 inducer added, deleted, or changed to therapeutic regimen Moderate (DrugReax) 2-major (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 CYP1A2 If drug combination necessary, used reduced clozapine dosages and closely monitor for adverse events Moderate (DrugReax) 2-major (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 CYP3A4 Monitor for enhanced AA pharmacologic/ adverse effects and adjust doses as necessary (50% dose reduction recommended for aripiprazole,  brexpiprazole, iloperidone) Moderate (DrugReax) 2-major, 3-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 metabolism Monitor 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) Moderate (DrugReax) 2-major, 3-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 CYP2D6 Monitor 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) Moderate (DrugReax) 2-major, 3-moderate (CP)
Select AAs (aripiprazole, asenapine, clozapine, iloperidone, olanzapine, paliperidone, pimavanserin, quetiapine, risperidone, ziprasidone) QTc interval-prolonging medications Potential for increased cardiotoxicity (e.g., torsades de pointes, cardiac arrest) due to additive QT interval prolongation Avoid concurrent use; if combination necessary, closely monitor cardiac function; discontinue therapy in patients with QTc measurements greater than 500 msec Major (DrugReax) 1-severe, 2-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.