4. Drug-Drug Interactions

Patient profiles will be assessed to identify those drug regimens that may result in clinically significant drug-drug interactions. Major drug-drug interactions considered clinically significant for platelet aggregation inhibitors are summarized in Table 5. Only those drug-drug interactions classified as clinical significance level of contraindicated or those considered life threatening which have not yet been classified will be reviewed.

Table 5:  Major Platelet Aggregation Inhibitor Drug-Drug Interactions [1]

Target Drug	Interacting Drug	Interaction	Recommendation	Clinical Significance Level
aspirin	cidofovir	concurrent use increases the risk of nephrotoxicity	discontinue aspirin 7 days prior to starting cidofovir	contraindicated
aspirin	ketorolac	concurrent use increases the risk of serious NSAID related adverse events	concurrent use is contraindicated	contraindicated
aspirin	probenecid	salicylates inhibit uricosuric actions of probenecid	concurrent use is contraindicated	contraindicated
aspirin	methotrexate (MTX)	potential for increased MTX serum levels, risk of enhanced pharmacologic/ toxic effects as NSAIDs can reduce MTX clearance	avoid concurrent aspirin use within 10 days of high-dose MTX; otherwise, use cautiously together; monitor for increased myelosuppressive, GI adverse effects; may consider using longer leucovorin rescue	major (DrugReax) 1-severe (CP)
cilostazol, dipyridamole	riociguat (Adempas)	concurrent administration may result in increased hypotension risk	avoid concurrent use	contraindicated (dipyridamole) moderate (cilostazol)
cilostazol, ticagrelor	strong CYP3A4 inhibitors (e.g., itraconazole)	co-administration may result in elevated serum concentrations of select platelet aggregation inhibitors (PAIs) and potential bleeding complications as cilostazol, and ticagrelor metabolized by CYP3A4	avoid use; ticagrelor therapy should not be initiated for at least 2 weeks after itraconazole discontinuation; if adjunctive administration necessary, use cautiously and monitor patient closely for enhanced pharmacologic/ adverse effects, especially bleeding	major
clopidogrel	CYP2C19 inhibitors (e.g., omeprazole, esomeprazole, fluvoxamine))	strong CYP2C19 inhibitor (e.g. omeprazole) may result in reduced plasma concentrations of clopidogrel active metabolite and diminish antiplatelet activity	Avoid concurrent use. Consider alternate therapies	major
clopidogrel	CYP2C19 inducers (e.g., apalutamide, rifampin)	concomitant use may increase active metabolite concentrations of clopidogrel and increase platelet inhibition	avoid concurrent use	major
PAIs	abrocitinib	concurrent use during the first 3 months of abrocitinib therapy may increase the risk of bleeding with thrombocytopenia	concurrent use is contraindicated during the first 3 months of abrocitinib therapy. Aspiring greater than 81 mg daily is contraindicated during the first 3 months of abrocitinib therapy	contraindicated
PAIs	defibrotide	increased risk of hemorrhage when used adjunctively with  antithrombotic/ fibrinolytic drugs like PAIs	avoid concurrent use	contraindicated
PAIs, including aspirin	low molecular weight heparins	potential for additive bleeding adverse effects; PAIs inhibit platelet aggregation and have increased bleeding risk, prolonged bleeding time	avoid concurrent therapy, if possible; if drug combination necessary, use cautiously, monitor for signs/symptoms of bleeding	moderate
PAIs, including aspirin	selective serotonin reuptake inhibitors (SSRIs)/,  serotonin norepinephrine reuptake inhibitors (SNRIs)	increased bleeding risk with combined therapy;  SSRIs/SNRIs deplete platelet serotonin, which may impair platelet aggregation	monitor for signs/symptoms of bleeding; may consider substituting tricyclic antidepressant for SSRI/SNRI	moderate
PAIs, including aspirin	anticoagulants	combined administration may increase bleeding risk, due to additive effects	if combined therapy necessary, monitor patients closely for bleeding signs/symptoms	moderate
PAIs	nonsteroidal anti-inflammatory drugs (NSAIDs)	concurrent use may increase risk for bleeding especially with chronic NSAID use	monitor for signs of bleeding with concurrent use	moderate
ticagrelor	strong CYP3A inducers (e.g., rifampin)	strong inducers substantially reduce ticagrelor, vorapaxar exposure and efficacy as both are CYP3A4 substrates	avoid use	major
ticagrelor	simvastatin, lovastatin	adjunctive use may increase lovastatin, simvastatin serum levels as ticagrelor is CYP3A4 inhibitor and lovastatin and simvastatin are metabolized by CYP3A4	avoid lovastatin, simvastatin doses higher than 40 mg; observe for adverse effects if combined use necessary	moderate