Clopidogrel (clopidogrel bisulfate)

Dosage of clopidogrel bisulfate is expressed in terms of clopidogrel.

No dosing information is available for this tab.

There is no enhanced messaging for this drug.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Anticoagulant;Antiplatelet;Thrombolytic/Alipogene Tiparvovec

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Alipogene tiparvovec is given as a one-time series of intramuscular (IM)injections. Depending upon patient weight 27 to 60 injections are given, each at a different site.

CLINICAL EFFECTS: Concurrent use of anticoagulant, antiplatelet, or thrombolytic agents increase bleeding risk at IM injection sites.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Antiplatelet or other anticoagulant agents must not be taken for at least one week prior to alipogene tiparvovec therapy. Assure that abnormal bleeding parameters have been corrected prior to administration. Antiplatelet or anticoagulant therapy may be resumed one day after alipogene tiparvovec administration. If concurrent therapy is deemed medically necessary, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory tests (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: Alipogene tiparvovec is given as a one-time series of intramuscular (IM)injections for the treatment of familial lipoprotein lipase deficiency. Depending upon patient weight 27 to 60 injections are given, each at a different site. Concurrent use of anticoagulant, antiplatelet, or thrombolytic agents increase bleeding risk at IM injection sites.

Anticoagulants; Antiplatelets/Mifepristone

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Anticoagulants may result in excessive bleeding following the abortion.

CLINICAL EFFECTS: The concurrent use of mifepristone with anticoagulants may result in excessive bleeding following the abortion.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: The manufacturer of mifepristone states that mifepristone is contraindicated in patients receiving concurrent anticoagulant therapy.(1) If concurrent therapy is deemed medically necessary, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: The manufacturer of mifepristone states that mifepristone is contraindicated in patients receiving concurrent anticoagulant therapy.(1)

Bcrp Inhibitors/Topotecan

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Inhibitors of the BCRP transporter may increase the intestinal absorption and hepatic uptake of topotecan.(1)

CLINICAL EFFECTS: The concurrent administration of topotecan with an inhibitor of BCRP may result in elevated levels of topotecan and signs of toxicity. These signs may include but are not limited to anemia, diarrhea, and thrombocytopenia.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of topotecan states that the use of topotecan and BCRP inhibitors should be avoided. If concurrent use is warranted, carefully monitor patients for adverse effects.(1)

DISCUSSION: In clinical studies, the combined use of elacridar (100 mg to 1000 mg), a BCRP and P-gp inhibitor, increased the area-under-curve (AUC) of topotecan approximately 2.5-fold.(1) BCRP inhibitors linked to this monograph include: capmatinib, clopidogrel, curcumin, danicopan, dasabuvir, elbasvir, enasidenib, ensitrelvir, febuxostat, fostamatinib, fostemsavir, glecaprevir, grazoprevir, lazertinib, oteseconazole, pacritinib, paritaprevir, pibrentasvir, pirtobrutinib, regorafenib, resmetirom, ritonavir, roxadustat, tafamidis, ticagrelor, tolvaptan, turmeric, vadadustat, velpatasvir, voxilaprevir, and zongertinib.(2,3)

Clopidogrel/Cannabidiol

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Clopidogrel is a prodrug and is converted to its active metabolite via a 2 step process. The first conversion step is mediated by CYP2C19, CYP1A2 and CYP2B6, while the second step is mediated by CYP3A4, CYP2B6 and CYP2C19.(1,2) CYP2C19 contributes to both steps and is thought to be the more important enzyme involved in formation of the pharmacologically active metabolite.(1) Cannabidiol may inhibit the metabolism of clopidogrel to its active form by CYP2C19.(1)

CLINICAL EFFECTS: Concurrent use of cannabidiol may result in decreased clopidogrel effectiveness, resulting in increased risk of adverse cardiac events.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of clopidogrel states that alternatives to clopidogrel should be considered in patients who are poor metabolizers of CYP2C19.(1) It would be prudent to assume that patients taking inhibitors of CYP2C19, such as cannabidiol, are decreased activity of this isoenzyme. Consider alternatives to cannabidiol in patients stabilized on clopidogrel and alternatives to clopidogrel in patients stabilized on cannabidiol. If concurrent therapy is warranted, consider appropriate testing to assure adequate inhibition of platelet reactivity.

DISCUSSION: In an open-label, cross-over study in 8 health male volunteers, a loading dose of clopidogrel (600 mg) was administered alone and after 5 days of fluoxetine (20 mg) (a CYP2C19 inhibitor). The maximum concentration (Cmax) and area-under-curve (AUC) of the active metabolite of clopidogrel were decreased by 25.3% and 20.6%, respectively. There was an average decrease of approximately 25% in the antiplatelet effects of clopidogrel when administered with fluoxetine.(3) However, it is likely that this study significantly underestimates the magnitude of this interaction. Both fluoxetine and its norfluoxetine metabolite inhibit CYP2C19 and have long half-lives of 4 to 9 days and so and is an irreversible inhibitor of CYP2C19. In a randomized, cross-over study in healthy subjects, ketoconazole (another CYP2C19 inhibitor, 400 mg daily) decreased the Cmax of the active metabolite of clopidogrel (300 mg loading dose, followed by 75 mg daily) by 61%. The AUC of the active metabolite of clopidogrel was decreased by 22% following the loading dose and by 29% during maintenance dosing. Clopidogrel-induced inhibition of platelet aggregation was decreased by 28% following the loading dose and by 33% during the maintenance dose.(3) In a cross-over study in 72 healthy subjects, simultaneous administration of omeprazole (another CYP2C19 inhibitor, 80 mg daily) and clopidogrel (300 mg loading dose, followed by 75 mg daily) decreased the AUC of the active metabolite of clopidogrel by 46% following the loading dose and by 42% during maintenance dosing. Clopidogrel-induced inhibition of platelet aggregation was decreased by 47% following the loading dose and by 30% during the maintenance dose. In a cross-over study in 72 healthy subjects, administration of omeprazole (another CYP2C19 inhibitor, 80 mg daily) 12 hours after clopidogrel (300 mg loading dose, followed by 75 mg daily) produced similar effects.(1) A pharmacokinetic modeling study identified cannabidiol as having potent inhibitory effects on CYP2C19 in human cells.(4)

Clopidogrel/Repaglinide

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Repaglinide is primarily metabolized by CYP2C8, and its elimination is facilitated by OATP1B1 transport. A clopidogrel metabolite inhibits both of these pathways.(1)

CLINICAL EFFECTS: Concurrent use of clopidogrel and repaglinide is expected to increase systemic exposure (AUC, area-under-curve) to repaglinide and may result in hypoglycemia.

PREDISPOSING FACTORS: Patients who achieve tight control of blood sugars, or have a history of multiple hypoglycemic episodes may be at greater risk for hypoglycemia with this combination.

PATIENT MANAGEMENT: Based upon results of a published clinical trial, Health Canada and the Canadian manufacturer of repaglinide state that concurrent use of clopidogrel and repaglinide is contraindicated due to the risk for hypoglycemia from unanticipated lowering of serum glucose concentrations.(2) Alternative antiplatelet agents (e.g. prasugrel, ticagrelor) and antidiabetic agents are not known to inhibit CYP2C8 or OATP1B1.(3) The manufacturer of clopidogrel states that when concomitant use is required in a patient maintained on clopidogrel, initiate repaglinide at 0.5 mg with each meal and titrate based on blood glucose levels. Do not exceed a total daily dose of 4 mg. If concomitant use of clopidogrel is required in a patient stabilized on repaglinide, down titrate the dose of repaglinide based on blood glucose levels to not exceed a total daily dose of 4 mg.(4) If concomitant use is deemed medically necessary: - Hypoglycemic risk is greatest when clopidogrel is added to existing repaglinide therapy. Frequent monitoring of serum/blood glucose is needed to monitor patient response as the magnitude of glucose lowering varies between patients. - In patients stabilized on clopidogrel when repaglinide is initiated, increased sensitivity to the hypoglycemic effect of repaglinide would be expected. In addition, because repaglinide half-life is prolonged in the presence of clopidogrel, maximal effects of repaglinide may be delayed - slower than usual dose titration would be prudent. Separating the timing of drug administration would not be expected to decrease interaction risk as the clopidogrel metabolite (clopidogrel acyl-beta-D-glucuronide) is an irreversible inhibitor of CYP2C8.(1)

DISCUSSION: In a drug interaction trial conducted in healthy non-diabetic adults, a clopidogrel 300 mg loading dose increased repaglinide exposure 5.1-fold and a 75 mg maintenance dose increased repaglinide exposure 3.9-fold. Corresponding serum glucose changes: - Clopidogrel 300 mg plus repaglinide decreased minimum glucose concentrations an average of 20 mg/dL (1.1 mmol/L) more than repaglinide alone. - Clopidogrel 300mg X1 dose, followed by 75 mg daily dosing for two days with daily repaglinide resulted in an average decrease in minimum glucose concentrations of 9 mg/dL lower than patients on repaglinide alone.(1)

Clopidogrel/Selected Protease Inhibitors; Cobicistat

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Clopidogrel is a prodrug and is converted to its active metabolite via a 2 step process. The first conversion step is mediated by CYP2C19, CYP1A2 and CYP2B6, while the second step is mediated by CYP3A4, CYP2B6 and CYP2C19.(1,2) CYP2C19 contributes to both steps and is thought to be the more important enzyme involved in formation of the pharmacologically active metabolite.(1) CYP3A4 is responsible for 39.8% of the second step of metabolism. Protease inhibitors that are strong CYP3A4 inhibitors may inhibit the metabolism of clopidogrel to its active form by CYP3A4.(1,3)

CLINICAL EFFECTS: Concurrent use of protease inhibitors that are strong CYP3A4 inhibitors may result in decreased clopidogrel effectiveness, resulting in increased risk of adverse cardiac events.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of clopidogrel does not make specific recommendations for concurrent use with strong CYP3A4 inhibitors. Patient monitoring for adequate inhibition of platelet reactivity with clopidogrel is warranted. HIV treatment guidelines from the US Department of Health and Human Services and the European AIDS Clinical Society, and the University of Liverpool HIV Drug Interactions database all recommend not to coadminister clopidogrel with any protease inhibitor or cobicistat.(4-6) Consider alternatives to protease inhibitors that are strong CYP3A4 inhibitors in patients stabilized on clopidogrel and alternatives to clopidogrel in patients stabilized on protease inhibitors that are strong CYP3A4 inhibitors. If concurrent therapy is warranted, consider appropriate testing to assure adequate inhibition of platelet reactivity.

DISCUSSION: In a randomized, cross-over study in healthy subjects, ketoconazole (400 mg daily) decreased the maximum concentration (Cmax) of the active metabolite of clopidogrel (300 mg loading dose, followed by 75 mg daily) by 61%. The area-under-curve (AUC) of the active metabolite of clopidogrel was decreased by 22% following the loading dose and by 29% during maintenance dosing. Clopidogrel-induced inhibition of platelet aggregation was decreased by 28% following the loading dose and by 33% during the maintenance dose.(7) A randomized cross over study in 12 healthy volunteers and 9 HIV-infected patients evaluated the impact of boosted antiretroviral therapy (ARV) on the pharmacokinetics and efficacy of clopidogrel. Healthy patients had 3.2-fold lower AUC (p=0.02) and Cmax of clopidogrel active metabolite (p=0.03) than HIV patients. Platelet reactivity was also 35% lower in health patients compared to HIV patients (p=0.04). All healthy patients had a platelet reactivity below the cut-off value at 4 hours after clopidogrel dose, while 44% of HIV patients were above the cut-off value of 206.(8) A cross-sectional study in 240 post acute coronary syndrome (ACS) patients compared platelet reactivity under aspirin and P2Y12 inhibitor therapy between HIV and non-HIV patients with first episode ACS on dual antiplatelet therapy. Study evaluated residual platelet aggregation (RPA), P2Y12 assay (PRU), and VASP platelet reactivity index (VASP-PRI). HIV patients were all on ARV therapy, most commonly with protease inhibitors (darunavir, lopinavir, atazanavir, and indinavir in combination with ritonavir in all but two patients). Patients on ARV containing protease inhibitors compared to other combinations had increased platelet reactivity to P2Y12 inhibitors and higher prevalence of high residual platelet reactivity (HPR) (OR 4.4 (95%CI 1.1-18.1) with RPA, P = 0.04; OR 3.1 (95%CI = 0.84-11.5) with VASP-PRI; P = 0.09, and OR 4.3 (95%CI 1.02-18.1) with PRU, P = 0.047). Patients with CD4 T cell count lower than 350/mm3 also had consistently increased platelet reactivity to P2Y12 inhibitors and higher prevalence of HPR (OR 3.41 (95%CI 0.60-19.4) with RPA, P = 0.17; OR 7.1 (95%CI 0.94-54.2) with VASP-PRI, P = 0.06; and OR 7.9 (95%CI 1.42-44.8) with PRU, P = 0.002), although this association was not significant for all three tests.(9) Selected protease inhibitors that are strong CYP3A4 inhibitors linked to this monograph include: atazanavir, cobicistat, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, paritaprevir, saquinavir, and tipranavir.(10)

Moderate Cyp2c8 Inhibitors/Tolebrutinib

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Moderate inhibitors of CYP2C8 may inhibit the metabolism of tolebrutinib.(1-2)

CLINICAL EFFECTS: Concomitant use of a moderate CYP2C8 inhibitor may result in elevated levels and clinical effects of tolebrutinib, including immunosuppression and hepatotoxicity.(1-2)

PREDISPOSING FACTORS: This interaction is expected to be more severe in patients with hepatic impairment.(1)

PATIENT MANAGEMENT: The manufacturer of tolebrutinib states that use of concomitant moderate CYP2C8 inhibitors should be avoided. If the use of moderate CYP2C8 inhibitors will be short-term, treatment with tolebrutinib should be interrupted.(1)

DISCUSSION: The impact of moderate CYP2C8 inhibitors on the pharmacokinetics of tolebrutinib has not been investigated in clinical studies. Moderate CYP2C8 inhibitors are predicted to increase tolebrutinib exposure.(1-2) In a study of healthy participants, concurrent use of gemfibrozil (strong inhibitor of CYP2C8) 600 mg BID for 6 days increased tolebrutinib area-under-curve (AUC) exposure by 8.4-fold.(2) Moderate CYP2C8 inhibitors linked to this monograph include clopidogrel, deferasirox, letermovir, pirtobrutinib, and selpercatinib.(3,4)

P-Gp Or Bcrp Inhibitors/Ubrogepant (> 50 Mg)

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Inhibitors of P-glycoprotein (P-gp) or BCRP may increase the absorption of ubrogepant.(1)

CLINICAL EFFECTS: The concurrent administration of ubrogepant with an inhibitor of P-glycoprotein or BCRP may result in elevated levels of ubrogepant.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer recommends a dosage adjustment of ubrogepant when coadministered with P-gp or BCRP inhibitors. The dose of ubrogepant should not exceed 50 mg for initial dose. If a second dose of ubrogepant is needed, the dose should not exceed 50 mg.(1) For patients on concurrent therapy with vimseltinib and ubrogepant: the manufacturer of vimseltinib states concurrent use with P-gp substrates should be avoided. If concurrent use cannot be avoided, take vimseltinib at least 4 hours prior to ubrogepant.(3) For patients on daraxonrasib, the manufacturer of daraxonrasib states that it should be taken at least 4 hours apart from P-gp substrates.(4)

DISCUSSION: Ubrogepant is a substrate of P-gp and BCRP transporters. Use of P-gp or BCRP inhibitors may increase the exposure of ubrogepant. Clinical drug interaction studies with inhibitors of these transporters were not conducted. The US manufacturer of ubrogepant recommends dose adjustment if ubrogepant is coadministered with P-gp or BCRP inhibitors.(1) BCRP inhibitors linked to this monograph include: belumosudil, clopidogrel, curcumin, eltrombopag, febuxostat, fostemsavir, leniolisib, momelotinib, oteseconazole, regorafenib, resmetirom, ritonavir, rolapitant, roxadustat, tafamidis, oral tedizolid, turmeric, vadadustat, and zongertinib.(2,3,5) P-glycoprotein inhibitors linked to this monograph include: asunaprevir, belumosudil, capmatinib, carvedilol, danicopan, daraxonrasib, daridorexant, imlunestrant, neratinib, osimertinib, propafenone, quinidine, selpercatinib, sofosbuvir/velpatasvir/voxilaprevir, tepotinib, valbenazine, vimseltinib, and voclosporin.(2,3,5)

Select Bcrp Inhibitors/Aumolertinib

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Aumolertinib is a substrate for BCRP. Inhibitors of the BCRP transporter may increase the intestinal absorption and decrease hepatic elimination of aumolertinib.(1)

CLINICAL EFFECTS: Concurrent use with selected BCRP inhibitors may result in higher systemic concentrations of aumolertinib, which may increase the risk for cardiac failure, rhabdomyolysis, thrombosis, elevated LFTs, hyponatremia, hematologic toxicity, and QT prolongation, which may result in potentially life-threatening cardiac arrhythmias like torsade de pointes (TdP).(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2) Patients with risk factors for thrombosis may be at higher risk of adverse events, including those with advanced age, obesity (BMI >30), smoking, prolonged immobilization, heart failure, hypercoagulable state, history of venous thromboembolism, malignancy, and major surgery. The risk for rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of rhabdomyolysis.

PATIENT MANAGEMENT: The manufacturer of aumolertinib states concomitant administration of aumolertinib should be avoided with BCRP inhibitors.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Based on in vitro data, aumolertinib is a substrate of BCRP.(1) BCRP inhibitors linked to this monograph include: asciminib, clopidogrel, darolutamide, elbasvir/grazoprevir, eltrombopag, enasidenib, febuxostat, fostemsavir, lazertinib, leniolisib, momelotinib, oteseconazole, regorafenib, rolapitant, roxadustat, tafamidis, ticagrelor, vadadustat, and zongertinib.(3,4)

Selected Inhibitors Of P-Gp Or Bcrp/Pazopanib

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Inhibitors of P-glycoprotein (P-gp) or BCRP may increase the absorption of pazopanib.(1)

CLINICAL EFFECTS: The concurrent administration of pazopanib with an inhibitor of P-glycoprotein or BCRP may result in elevated levels of pazopanib and signs of toxicity.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The US manufacturer of pazopanib states concurrent use of P-gp inhibitors or BCRP inhibitors should be avoided.(1) Monitor patients for increased side effects from pazopanib. The manufacturer of daraxonrasib states P-gp substrates should be administered at least 4 hours apart from daraxonrasib.(5) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Pazopanib is a substrate of P-gp and BCRP. Inhibitors of these transporters are expected to increase pazopanib levels.(1) BCRP inhibitors linked to this monograph include: asciminib, belumosudil, clopidogrel, cyclosporine, curcumin, darolutamide, eltrombopag, enasidenib, febuxostat, fostemsavir, grazoprevir, lazertinib, leflunomide, leniolisib, momelotinib, oteseconazole, pirtobrutinib, regorafenib, resmetirom, ritonavir, rolapitant, roxadustat, tafamidis, teriflunomide, tolvaptan, turmeric, vadadustat, and zongertinib.(1,3-5) P-glycoprotein inhibitors linked to this monograph include: asunaprevir, belumosudil, capmatinib, carvedilol, cyclosporine, danicopan, daraxonrasib, daridorexant, diltiazem, flibanserin, fostamatinib, ginseng, glecaprevir/pibrentasvir, imlunestrant, isavuconazonium, ivacaftor, ledipasvir, neratinib, sofosbuvir/velpatasvir/voxilaprevir, tepotinib, tezacaftor, ticagrelor, valbenazine, verapamil, vimseltinib, and voclosporin.(3,4)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Anticoagulants; Antiplatelets/Inotersen

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Inotersen causes reductions in platelet count that may result in sudden and unpredictable thrombocytopenia.(1)

CLINICAL EFFECTS: Concurrent use of inotersen with anticoagulants and/or antiplatelet agents may result in additive or synergistic effects, including fatal and non-fatal intracranial hemorrhage.(1)

PREDISPOSING FACTORS: The risk for bleeding episodes may also be greater in patients greater than 60 years or have a prior history of major bleeding events. Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Inotersen should be administered with caution in patients receiving anticoagulants and/or antiplatelet agents.(1) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Monitor platelet count frequently. If platelet count is less than 50, stop inotersen treatment and consider discontinuation of any anticoagulant and/or antiplatelet agents. Monitor for signs and symptoms of thrombocytopenia; such as, unusual or prolonged bleeding (petechiae, easy bruising, hematoma, subconjunctival bleeding, gingival bleeding, epistaxis, hemoptysis, irregular or heavier than normal menstrual bleeding, hematemesis, hematuria, hematochezia, melena), neck stiffness, or atypical severe headache.

DISCUSSION: In a clinical study, platelet counts below 100 occurred in 25% of inotersen-treated patients, compared with 2% of patients on placebo. Platelet counts below 75 occurred in 14% of inotersen-treated patients, compared to no patients on placebo. In study 1 and its extension study, 39% of inotersen-treated patients with a baseline platelet count below 200 had a nadir platelet count below 75, compared to 6% of patients with baseline platelet counts 200 or higher. Three inotersen-treated patients (3%) had sudden severe thrombocytopenia (platelet count below 25). One patient experienced a fatal intracranial hemorrhage.(1) Inotersen is only available through a Tegsedi REMS program because of the risk of severe thrombocytopenia and the risk of glomerulonephritis.(1)

Anticoagulants; Antiplatelets; Thrombolytics/Caplacizumab

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Bleeding has been reported with the use of caplacizumab.(1)

CLINICAL EFFECTS: Concurrent use of caplacizumab with anticoagulants, antiplatelets, or thrombolytics may increase the risk of hemorrhage.(1)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. hemophilia, coagulation factor deficiencies). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Avoid the use of caplacizumab with anticoagulants, antiplatelets, and thrombolytics. Interrupt caplacizumab therapy if clinically significant bleeding occurs. Patients may require von Willebrand factor concentrate to rapidly correct hemostasis. If caplacizumab is restarted, closely monitor for signs of bleeding.(1) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory tests (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: Bleeding has been reported with caplacizumab. In clinical studies, severe bleeding adverse reactions of epistaxis, gingival bleeding, upper gastrointestinal hemorrhage, and metrorrhagia were each reported in 1% of patients. Overall, bleeding events occurred in approximately 58% of patients on caplacizumab versus 43% of patients on placebo.(1) In post-marketing reports, cases of life-threatening and fatal bleeding were reported with caplacizumab.(1)

Antiplatelets; Aspirin (> 100 Mg)/Apixaban

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Additive effects on hemostasis.(1-4)

CLINICAL EFFECTS: Concurrent use of apixaban with antiplatelets may increase the risk of bleeding.(1-4)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Patients requiring concurrent therapy with apixaban and an antiplatelet agent should be closely monitored for signs of bleeding. Monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. Discontinue apixaban in patients with active bleeding. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: Concurrent administration of enoxaparin (40 mg single dose) and apixaban (5 mg single dose) resulted in additive effects on anti-Factor Xa activity.(1) Concurrent apixaban and aspirin (325 mg daily) resulted in no pharmacokinetic or pharmacodynamic interactions.(1) Concurrent apixaban with clopidogrel (75 mg daily) or with combination clopidogrel (75 mg daily) and aspirin (162 mg daily) produced no relevant increases in bleeding time, platelet aggregation, or clotting tests (PI, INR, and aPTT) compared either clopidogrel alone or clopidogrel with aspirin without apixaban.(1) Significant bleeding risk was reported with the combination of apixaban, aspirin, and clopidogrel in patients with acute coronary syndrome.(1) A self-controlled case study of 1,622 oral anticoagulant-precipitant drug pairs were reviewed and found 14% of drug pairs were associated with a statistically significant elevated risk of thromboembolism. Concurrent use of apixaban and clopidogrel resulted in a ratio of rate ratios (95% CI) of 1.96 (1.53-2.51).(5) A meta-analysis of 9 studies identified 13,459 patients taking direct oral anticoagulants (DOACs), 1,692 of whom also took an antiplatelet agent. Of the patients on antiplatelet agents, 1,254 took aspirin while the rest was unspecified. Most of the trials restricted patients to use of low-dose aspirin, with the highest allowable dose being 165 mg/day. The use of DOACs with antiplatelet agents was associated with an increased risk of major bleeding (OR 1.89; 95% CI, 1.04-3.44) and clinically relevant non-major bleeding (OR 1.82; 95% CI, 1.50-2.22). There was no difference between groups in the efficacy outcome of symptomatic recurrent venous thromboembolism (VTE) or VTE-related death.(3)

Antiplatelets; Aspirin (> 100 Mg)/Dabigatran

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Dabigatran is a direct thrombin inhibitor and when taken with agents that effect platelet aggregation increased bleeding episodes can occur.(1,2)

CLINICAL EFFECTS: Concurrent use of dabigatran with antiplatelet agents may result in additive or synergistic effects resulting in unwanted bleeding episodes.(1,2)

PREDISPOSING FACTORS: Factors associated with an increase risk for bleeding include renal impairment, concomitant use of P-glycoprotein inhibitors, patient age >74 years, coexisting conditions (e.g. recent trauma) or use of drugs (e.g. NSAIDs) associated with bleeding risk, and patient weight <50 kg.(1-3) The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Patients requiring concurrent therapy with dabigatran and an antiplatelet agent should be closely monitored for signs of bleeding. If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug. Discontinue dabigatran in patients with active bleeding.

DISCUSSION: Dabigatran is a direct thrombin inhibitor and when taken with agents that effect platelet aggregation and/or other clotting factors increased bleeding episodes can occur.(1,2) In the RE-LY trial, 40% of patients were on aspirin at baseline.(1) In the RE-MEDY trial, 7.7% of patients were on aspirin at baseline.(1) In the RE-DUAL PCI trial, patients were randomly assigned to one of three treatments: (A) dual therapy with dabigatran 110 mg twice daily plus either clopidogrel or ticagrelor, (B) dual therapy with dabigatran 150 mg twice daily plus either clopidogrel or ticagrelor, or (C) triple therapy with warfarin (goal INR 2-3) plus aspirin (< or = 100 mg daily) plus either clopidogrel or ticagrelor. The incidence of the first major or clinically relevant non-major (CRNM) bleeding event was 15.4% in group A compared with 26.9% in group C (hazard ratio, 0.52; 95% CI 0.42 to 0.63; p<0.001 for noninferiority; p<0.001 for superiority) and 20.2% in group B compared to 25.7% in corresponding group C (hazard ratio, 0.72; 95% CI 0.58 to 0.88; p<0.001 for noninferiority). For major bleeding as defined by Thrombolysis in Myocardial Infarction (TIMI) criteria, the rate was lower in both dual-therapy groups than in the triple-therapy group: 1.4% in group A compared to 3.8% in group C (hazard ratio, 0.37; 95% CI 0.2 to 0.68; p=0.002) and 2.1% in group B compared to 3.9% in corresponding group C (hazard ratio, 0.51; 95% CI 0.28 to 0.93; p=0.03). Incidence of composite efficacy end point of thromboembolic events (myocardial infarction, stroke, or systemic embolism), death, or unplanned revascularization was 13.7% in groups A and B compared to 13.4% in group C (hazard ratio, 1.04; 95% CI 0.84 to 1.29; p=0.005 for noninferiority).(4) A meta-analysis of 9 studies identified 13,459 patients taking direct oral anticoagulants (DOACs), 1,692 of whom also took an antiplatelet agent. Of the patients on antiplatelet agents, 1,254 took aspirin while the rest was unspecified. Most of the trials restricted patients to use of low-dose aspirin, with the highest allowable dose being 165 mg/day. Compared with DOACs alone, the use of DOACs with antiplatelet agents was associated with an increased risk of major bleeding (OR 1.89; 95% CI, 1.04-3.44) and CRNM bleeding (OR 1.82; 95% CI, 1.50-2.22). There was no difference between groups in the efficacy outcome of symptomatic recurrent venous thromboembolism (VTE) or VTE-related death.(5)

Antiplatelets; Aspirin (> 100 Mg)/Edoxaban

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Anticoagulants and antiplatelet agents have additive effects on hemostasis.(1) In addition, aspirin doses greater than or equal to 325 mg daily increase edoxaban exposure.(1)

CLINICAL EFFECTS: Concurrent use of edoxaban with antiplatelets may increase the risk of bleeding.(1)

PREDISPOSING FACTORS: Bleeding risk may be increased in patients with renal impairment and in patients > 75 years of age.(1) Use of multiple agents which affect hemostasis increases the risk for bleeding. The risk for bleeding episodes may be greater in patient with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Patients requiring concurrent therapy with edoxaban and an antiplatelet agent should be closely monitored for signs of bleeding. Edoxaban and aspirin at dosages of 100 mg or less may be coadministered.(2,3) Monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. Discontinue edoxaban in patients with active bleeding.

DISCUSSION: Concomitant use of edoxaban and antiplatelet agents may increase the risk of bleeding. In edoxaban clinical trials concomitant use of low dose aspirin (< or = 100 mg daily), thienopyridines, and NSAIDs was permitted and resulted in increased rates of clinically relevant bleeding. The rates of major bleeding on edoxaban and warfarin were generally consistent among subgroups. Bleeding rates appeared higher in both treatment arms (edoxaban and warfarin) in patients taking aspirin. Co-administration of aspirin (100 mg or 325 mg) and edoxaban increased bleeding time relative to that seen with either drug alone.(1) About 30% of the population in ENGAGE-AF received concomitant therapy with aspirin because of co-morbid conditions. While aspirin is known to increase risk for bleeds and the annualized event rate for major bleeds was higher than that in patients not receiving aspirin (3.87% vs. 2.13%), the risk for bleeds in patients receiving edoxaban 60 mg on a background of aspirin was lower than that for warfarin on a background of aspirin (HR 0.78 (95%CI 0.65,0.94). Based on these data no dose adjustments/contraindications are required.(4) Edoxaban and aspirin at dosages of 100 mg or less may be coadministered.(2,3) A meta-analysis of 9 studies identified 13,459 patients taking direct oral anticoagulants (DOACs), 1,692 of whom also took an antiplatelet agent. Of the patients on antiplatelet agents, 1,254 took aspirin while the rest was unspecified. Most of the trials restricted patients to use of low-dose aspirin, with the highest allowable dose being 165 mg/day. The use of DOACs with antiplatelet agents was associated with an increased risk of major bleeding (OR 1.89; 95% CI, 1.04-3.44) and clinically relevant non-major bleeding (OR 1.82; 95% CI, 1.50-2.22). There was no difference between groups in the efficacy outcome of symptomatic recurrent venous thromboembolism (VTE) or VTE-related death.(5)

Antiplatelets; Aspirin (> 325 Mg)/Betrixaban

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Betrixaban is a factor Xa inhibitor and when taken with agents that effect platelet aggregation increased bleeding episodes can occur.(1,2)

CLINICAL EFFECTS: Concurrent use of betrixaban with antiplatelet agents may result in additive or synergistic effects resulting in unwanted bleeding episodes.(1,2)

PREDISPOSING FACTORS: Factors associated with an increase risk for bleeding include renal impairment, concomitant use of P-glycoprotein inhibitors, coexisting conditions (e.g. recent trauma) or use of drugs (e.g. NSAIDs) associated with bleeding risk.(1-3) The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Patients requiring concurrent therapy with betrixaban and an antiplatelet agent should be closely monitored for signs of bleeding. If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug. Discontinue betrixaban in patients with active bleeding. The anticoagulant effect of betrixaban is expected to persist for at least 72 hours after the last dose.

DISCUSSION: Betrixaban is a factor Xa inhibitor and when taken with agents that effect platelet aggregation and/or other clotting factors increased bleeding episodes can occur.(1,2) In the APEX trial, if aspirin was required for cardiovascular disease, doses were limited to less than 165mg daily, with the exception of patients who were receiving aspirin for ischemic stroke or TIA indication, who could take 325mg daily. Concomitant use of aspirin and betrixaban resulted in a slightly increased incidence of major/clinically relevant non-major (CRNM) bleeding compared to those who did not use aspirin (3.7% vs. 2.89%). Concomitant use of aspirin with betrixaban resulted in an increased incidence of major bleeding twice as much as those who did not use aspirin with betrixaban (0.93% vs. 0.46%).(2) A meta-analysis of 9 studies identified 13,459 patients taking direct oral anticoagulants (DOACs), 1,692 of whom also took an antiplatelet agent. Of the patients on antiplatelet agents, 1,254 took aspirin while the rest was unspecified. Most of the trials restricted patients to use of low-dose aspirin, with the highest allowable dose being 165 mg/day. The use of DOACs with antiplatelet agents was associated with an increased risk of major bleeding (OR 1.89; 95% CI, 1.04-3.44) and CRNM bleeding (OR 1.82; 95% CI, 1.50-2.22). There was no difference between groups in the efficacy outcome of symptomatic recurrent venous thromboembolism (VTE) or VTE-related death.(3)

Clopidogrel/Abrocitinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Clopidogrel is a prodrug and is converted to its active metabolite via a 2-step process. The first conversion step is mediated by CYP2C19, CYP1A2 and CYP2B6, while the second step is mediated by CYP3A4, CYP2B6 and CYP2C19.(1-3) CYP2C19 contributes to both steps and is thought to be the more important enzyme involved in formation of the pharmacologically active metabolite.(1) Inhibitors of CYP2C19 may decrease the conversion of clopidogrel to its active metabolite.(1) Abrocitinib is a moderate CYP2C19 inhibitor.(4,5) Abrocitinib has been associated with transient, dose-dependent thrombocytopenia. The nadir platelet count occurs at a median of 24 days after receiving abrocitinib 200 mg once daily and a 40% recovery occurs by 12 weeks. Concurrent use with agents that affect platelet aggregation may result in an additive risk of bleeding.(5)

CLINICAL EFFECTS: Concurrent use of CYP2C19 inhibitors may result in decreased clopidogrel effectiveness, resulting in increased risk of adverse cardiac events. Concurrent use of abrocitinib with clopidogrel may increase the risk of bleeding.(5)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. pre-existing thrombocytopenia). Abrocitinib is not recommended for patients with a platelet count less than 150,000/mm3.(5) Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding.

PATIENT MANAGEMENT: Evaluate medication list or interaction alerts to determine if patient is receiving additional drugs which may also inhibit clopidogrel active metabolite formation. The US manufacturer of clopidogrel states that alternatives to clopidogrel should be considered in patients who are poor metabolizers of CYP2C19.(1) It would be prudent to assume that patients taking strong inhibitors of CYP2C19 are poor metabolizers of this isoenzyme. Moderate or weak inhibitors of CYP2C19 may have less of an effect on this interaction. Consider alternatives to CYP2C19 inhibitors in patients stabilized on clopidogrel and alternatives to clopidogrel in patients stabilized on CYP2C19 inhibitors. If concurrent therapy is warranted, consider appropriate testing to assure adequate inhibition of platelet reactivity. The concurrent use of abrocitinib with antiplatelet agents (except aspirin < or = 81 mg daily) is contraindicated during the first 3 months of abrocitinib therapy.(5) Prior to starting abrocitinib therapy, obtain a complete blood count and recheck at 4 weeks after initiation and 4 weeks after a dose increase. Discontinuation of abrocitinib is required if platelets drop below 50,000/mm3.(5) If concurrent therapy is warranted after the first 3 months of abrocitinib therapy, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms.(5) Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: Clopidogrel is a prodrug and requires conversion to the active metabolite by CYP2C19. Clopidogrel is not a sensitive substrate for CYP2C19 as CYP3A4, CYP2B6 and CYP1A2 also participate in active metabolite formation. Studies have not evaluated this specific drug combination; the actual magnitude of this interaction is not known. Given the possible consequences of clopidogrel treatment failure, it would be prudent to avoid concomitant use of clopidogrel and CYP2C19 inhibitors when possible. Abrocitinib has been associated with transient, dose-dependent thrombocytopenia which is more severe with lower baseline platelet counts. At baseline platelet counts of 170,000/mm3, 220,000/m3 and 270,000/mm3, the nadirs were -41.2%, -33.4%, and -26.5%, respectively. Recovery of platelet count (about 40% recovery by 12 weeks) occurred without discontinuation of the treatment.(5)

Clopidogrel/Asciminib (> 80 Mg)

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Clopidogrel is a prodrug and is converted to its active metabolite via a 2 step process. The first conversion step is mediated by CYP2C19, CYP1A2 and CYP2B6, while the second step is mediated by CYP3A4, CYP2B6 and CYP2C19.(1,2) CYP2C19 contributes to both steps and is thought to be the more important enzyme involved in formation of the pharmacologically active metabolite.(1) Asciminib is a weak CYP2C19 inhibitor and may decrease the conversion of clopidogrel to its active metabolite.(1-4)

CLINICAL EFFECTS: Concurrent use of asciminib may result in decreased clopidogrel effectiveness, resulting in increased risk of adverse cardiac events.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The concurrent use of asciminib and clopidogrel should be approached with caution. CYP2C19 inhibition by asciminib is dose dependent. The US manufacturer of asciminib states that asciminib is predicted to be a weak inhibitor of CYP2C19 at 200 mg twice daily but has no inhibition potential at 80 mg total daily dose.(3) The US manufacturer of clopidogrel states that alternatives to clopidogrel should be considered in patients who are poor metabolizers of CYP2C19.(1) It would be prudent to assume that patients taking strong inhibitors of CYP2C19 are poor metabolizers of this isoenzyme. Moderate or weak inhibitors of CYP2C19 may have less of an effect on this interaction. Consider alternatives to CYP2C19 inhibitors in patients stabilized on clopidogrel and alternatives to clopidogrel in patients stabilized on CYP2C19 inhibitors. If concurrent therapy is warranted, consider appropriate testing to assure adequate inhibition of platelet reactivity.

DISCUSSION: Clopidogrel is a prodrug and requires conversion to the active metabolite by CYP2C19. Clopidogrel is not a sensitive substrate for CYP2C19 as CYP3A4, CYP2B6 and CYP1A2 also participate in active metabolite formation. Studies have not evaluated this specific drug combination; the actual magnitude of this interaction is not known. In a pharmacokinetic simulation, the area under the curve (AUC) of omeprazole (CYP2C19 sensitive substrate) 20 mg twice daily was predicted to be increased by 41% with asciminib 200 mg twice daily.(5) Given the possible consequences of clopidogrel treatment failure, it would be prudent to avoid concomitant use of clopidogrel and asciminib when possible.

Clopidogrel/Efavirenz; Etravirine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Clopidogrel is a prodrug and is converted to its active metabolite via a 2 step process. The first conversion step is mediated by CYP2C19, CYP1A2 and CYP2B6, while the second step is mediated by CYP3A4, CYP2B6 and CYP2C19.(1,2) CYP2C19 contributes to both steps and is thought to be the more important enzyme involved in formation of the pharmacologically active metabolite.(1) Efavirenz and etravirine may inhibit the metabolism of clopidogrel to its active form by CYP2C19.(1-4)

CLINICAL EFFECTS: Concurrent use of efavirenz or etravirine may result in decreased clopidogrel effectiveness, resulting in increased risk of adverse cardiac events.(1-4)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of clopidogrel states that concurrent use of inhibitors of CYP2C19, such as efavirenz or etravirine should be avoided.(1) HIV treatment guidelines from the US Department of Health and Human Services and the University of Liverpool HIV Drug Interactions database recommend not to coadminister clopidogrel with efavirenz or etravirine. Consider alternative antiretroviral or antiplatelet therapy.(4,5) The US manufacturer of etravirine recommends alternative to clopidogrel in patients maintained on etravirine.(2) The US manufacturer of clopidogrel states that alternatives to clopidogrel should be considered in patients who are poor metabolizers of CYP2C19.(1) It would be prudent to assume that patients taking strong inhibitors of CYP2C19 are poor metabolizers of this isoenzyme. Moderate CYP2C19 inhibitors, such as efavirenz or etravirine, may also affect this interaction. Consider alternatives to etravirine in patients stabilized on clopidogrel and alternatives to clopidogrel in patients stabilized on etravirine. If concurrent therapy is warranted, consider appropriate testing to assure adequate inhibition of platelet reactivity.

DISCUSSION: In a randomized, cross-over study in healthy subjects, ketoconazole (another CYP2C19 inhibitor, 400 mg daily) decreased the maximum concentration (Cmax) of the active metabolite of clopidogrel (300 mg loading dose, followed by 75 mg daily) by 61%. The area-under-curve (AUC) of the active metabolite of clopidogrel was decreased by 22% following the loading dose and by 29% during maintenance dosing. Clopidogrel-induced inhibition of platelet aggregation was decreased by 28% following the loading dose and by 33% during the maintenance dose.(6) In a cross-over study in 72 healthy subjects, simultaneous administration of omeprazole (another CYP2C19 inhibitor, 80 mg daily) and clopidogrel (300 mg loading dose, followed by 75 mg daily) decreased the AUC of the active metabolite of clopidogrel by 46% following the loading dose and by 42% during maintenance dosing. Clopidogrel-induced inhibition of platelet aggregation was decreased by 47% following the loading dose and by 30% during the maintenance dose. In a cross-over study in 72 healthy subjects, administration of omeprazole (another CYP2C19 inhibitor, 80 mg daily) 12 hours after clopidogrel (300 mg loading dose, followed by 75 mg daily) produced similar effects.(1)

Clopidogrel/Enzalutamide

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Clopidogrel metabolism to its active metabolite occurs primarily through CYP2C19, with contributions from other CYP enzymes including CYP3A4.(1) Enzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer and may increase the conversion of clopidogrel to its active form.(2)

CLINICAL EFFECTS: Concurrent use of enzalutamide with clopidogrel may increase the effects and toxicity of clopidogrel, including bleeding.(1,2)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patient with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Avoid concurrent use of clopidogrel with enzalutamide. Monitor patients for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Discontinue clopidogrel in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: In a study of 12 healthy volunteers, rifampin (a strong CYP3A4 inducer, 300 mg twice daily for 7 days) increased the maximum concentration (Cmax) and area-under-curve (AUC) of the active metabolite of clopidogrel by approximately 4-fold. In conjunction with this, there was a higher level of P2Y12 receptor blockade by clopidogrel after rifampin pre-treatment. Clopidogrel 600 mg alone decreased the number of unblocked receptors at 4 hours from 248 +/- 40 to 48 +/- 24 per platelet. After rifampin pre-treatment, clopidogrel decreased the number of unblocked receptors from 266 +/- 63 to 4 +/- 2 (p < 0.0001).(3) A study of 10 healthy volunteers found that rifampin 300 mg twice daily for 4 days then combined with clopidogrel 75 mg daily for 6 days led to a significantly greater inhibition of platelet aggregation compared to clopidogrel alone (56% versus 33%, respectively). Three subjects who were initially clopidogrel nonresponders and 1 subject who was a low responder all became responders after treatment with rifampin.(4)

Clopidogrel/Esomeprazole; Omeprazole; Cimetidine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Clopidogrel is a prodrug and is converted to its active metabolite via a 2 step process. The first conversion step is mediated by CYP2C19, CYP1A2 and CYP2B6, while the second step is mediated by CYP3A4, CYP2B6 and CYP2C19.(1,2) CYP2C19 contributes to both steps and is thought to be the more important enzyme involved in formation of the pharmacologically active metabolite.(1) Proton pump inhibitors (PPIs) may inhibit CYP2C19 mediated conversion to the active metabolite of clopidogrel. The magnitude and clinical significance of CYP2C19 inhibition is highly variable between agents.(1)

CLINICAL EFFECTS: Concurrent use of esomeprazole, omeprazole, or cimetidine may result in decreased clopidogrel effectiveness, resulting in increased risk of adverse cardiac events.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Evaluate patient risk for gastrointestinal(GI) bleeding. When PPIs are needed, use dexlansoprazole, lansoprazole, pantoprazole or rabeprazole as they have a lower interaction risk.(1,3) Consider the use of H2 blockers (such as famotidine, nizatidine, or ranitidine) in patients with a low bleeding risk and reserve the use of PPIs for patients at higher risk of GI bleeding. US manufacturers for clopidogrel and omeprazole state concurrent use of clopidogrel esomeprazole and omeprazole should be avoided.(1,4-5) As esomeprazole and omeprazole are irreversible inhibitors of CYP2C19, separating clopidogrel from esomeprazole or omeprazole administration times does not change the magnitude of this interaction.(1,4,6) The US manufacturer of clopidogrel states that alternatives to clopidogrel should be considered in patients who are poor metabolizers of CYP2C19.(1) It would be prudent to assume that patients taking strong inhibitors of CYP2C19 are poor metabolizers of this isoenzyme. Moderate CYP2C19 inhibitors, such as omeprazole, and weak CYP2C19 inhibitors, such as cimetidine, may also affect this interaction. Consider alternatives to esomeprazole, omeprazole, and cimetidine in patients stabilized on clopidogrel and alternatives to clopidogrel in patients stabilized on esomeprazole, omeprazole, and cimetidine. If concurrent therapy is warranted, consider appropriate testing to assure adequate inhibition of platelet reactivity.

DISCUSSION: US manufacturer for clopidogrel states omeprazole and esomeprazole have been shown to reduce antiplatelet activity of clopidogrel and recommends against concomitant use. The antiplatelet effect of clopidogrel is reduced by approximately 40% in patients receiving 80 mg per day of omeprazole. Dexlansoprazole, lansoprazole and pantoprazole are described as having less effect on clopidogrel antiplatelet activity.(1,3) In the primary literature, documentation for this interaction is conflicting. However, both in-vitro and retrospective analyses indicate that omeprazole decreases the effectiveness of clopidogrel. Although the half-lives of esomeprazole and omeprazole (a racemic mixture of R- and esomeprazole) are short, the effect on CYP2C19 is long lasting because esomeprazole is an irreversible inhibitor of CYP2C19.(6) In two studies in healthy subjects, concurrent omeprazole decreased the effects of clopidogrel on platelets.(7-8) Several studies have found coadministration of clopidogrel with omeprazole resulted in increased platelet aggregation compared to clopidogrel with pantoprazole, or no PPI.(9-12) In a study, use of omeprazole was associated with a decreased risk of upper gastrointestinal bleeding in patients receiving dual antiplatelet therapy with clopidogrel and aspirin. There was no significant difference between the groups in rate of cardiovascular events.(12) Three studies found that simultaneous omeprazole with clopidogrel reduced clopidogrel concentrations and effects.(13-15) In a cross-over trial, healthy subjects received clopidogrel (300 mg loading dose/75 mg daily maintenance dose) and esomeprazole (40 mg oral once daily) co-administered for 30 days. Exposure to the active metabolite of clopidogrel was reduced by 35% to 40% over this time period.(16) In a study in 39 healthy subjects, the effects of omeprazole and rabeprazole on clopidogrel in patients with different CYP2C19 genotypes was examined. In rapid 2C19 metabolizers, simultaneous omeprazole and rabeprazole significantly decreased clopidogrel response. In decreased 2C19 responders, there was wide variation in clopidogrel response and simultaneous omeprazole and rabeprazole had no significant effect on overall clopidogrel effects; however, some subjects became low responders to clopidogrel while on PPI therapy. Staggered dosing of omeprazole had no effect on clopidogrel response in rapid metabolizers, but decreased clopidogrel response in decreased metabolizers.(17) Several retrospective studies found that patients who took clopidogrel with a PPI had increased incidence of major cardiovascular events compared to patients who took clopidogrel without a PPI.(18-22) A retrospective cohort study of 20,596 patients in the Tennessee Medicaid program, evaluated both cardiovascular disease event and GI bleed risk in patients prescribed clopidogrel with or without concurrent PPI use. Pantoprazole was prescribed in 62% of PPI patients. Concomitant PPI and clopidogrel use decreased the risk of hospitalization from GI bleeding by 50%. There was no clear-cut increase risk for serious cardiovascular disease events; however, the 95% CI for this was wide.(23) A post-hoc analysis of the PRINCIPLE-TIMI 44 trial and the TRITON-TIMI trial examined the effects of PPI use on the pharmacodynamic effects and clinical efficacy of clopidogrel. The PRINCIPLE-TIMI 44 trial examined 201 patients undergoing cardiac catheterization with planned percutaneous coronary intervention, 53 of which were taking a PPI at randomization. Patients receiving a PPI had significantly lower rates of inhibition of platelet aggregation at 0.5 hours, 2 hours, 6 hours, and 18-24 hours post-loading dose of clopidogrel. After 15 days of maintenance therapy, there were significantly more non-responders in the group receiving PPI (50% versus 7.9%). The TRITON-TIMI trial examined 13,608 patients who underwent cardiac catheterization with planned percutaneous coronary intervention, 4529 of which were taking a PPI at randomization. Patients received clopidogrel treatment for 6-15 months. There were no significant differences in occurrence of cardiovascular death, non-fatal MI, or non-fatal stroke between patients taking PPIs at randomization and those not; however, use of PPIs was only assessed at randomization and not during the study.(24) A retrospective cohort study of 16,064 patients evaluated the impact of MACE events in patients taking clopidogrel with PPIs/PCABs. Patients taking concurrent PPIs or PCABs with clopidogrel had a higher incidence of MACE compared to clopidogrel monotherapy. Among MACE, stroke recurrence was the highest risk with the PPI and PCAB groups. The PPIs studied included esomeprazole, dexlansoprazole, omeprazole, pantoprazole, ilaprazole, and rabeprazole, with esomeprazole resulting in the highest risk of MACE and stroke recurrence.(29)

Clopidogrel/Felbamate; Stiripentol

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Clopidogrel is a prodrug and is converted to its active metabolite via a 2 step process. The first conversion step is mediated by CYP2C19, CYP1A2 and CYP2B6, while the second step is mediated by CYP3A4, CYP2B6 and CYP2C19.(1,2) CYP2C19 contributes to both steps and is thought to be the more important enzyme involved in formation of the pharmacologically active metabolite.(1) Felbamate and stiripentol may inhibit the metabolism of clopidogrel to its active form by CYP2C19.(1,3)

CLINICAL EFFECTS: Concurrent use of felbamate or stiripentol may result in decreased clopidogrel effectiveness, resulting in increased risk of adverse cardiac events.(1,3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of clopidogrel states that concurrent use of inhibitors of CYP2C19, such as felbamate and stiripentol, should be avoided.(1) The US manufacturer of clopidogrel states that alternatives to clopidogrel should be considered in patients who are poor metabolizers of CYP2C19.(1) It would be prudent to assume that patients taking strong inhibitors of CYP2C19 are poor metabolizers of this isoenzyme. Consider alternatives to felbamate or stiripentol in patients stabilized on clopidogrel, or alternatives to clopidogrel in patients stabilized on felbamate or stiripentol. If concurrent therapy is warranted, consider appropriate testing to assure adequate inhibition of platelet reactivity.

DISCUSSION: In a randomized, cross-over study in healthy subjects, ketoconazole (another CYP2C19 inhibitor, 400 mg daily) decreased the maximum concentration (Cmax) of the active metabolite of clopidogrel (300 mg loading dose, followed by 75 mg daily) by 61%. The area-under-curve (AUC) of the active metabolite of clopidogrel was decreased by 22% following the loading dose and by 29% during maintenance dosing. Clopidogrel-induced inhibition of platelet aggregation was decreased by 28% following the loading dose and by 33% during the maintenance dose.(3) In a cross-over study in 72 healthy subjects, simultaneous administration of omeprazole (another CYP2C19 inhibitor, 80 mg daily) and clopidogrel (300 mg loading dose, followed by 75 mg daily) decreased the AUC of the active metabolite of clopidogrel by 46% following the loading dose and by 42% during maintenance dosing. Clopidogrel-induced inhibition of platelet aggregation was decreased by 47% following the loading dose and by 30% during the maintenance dose. In a cross-over study in 72 healthy subjects, administration of omeprazole (another CYP2C19 inhibitor, 80 mg daily) 12 hours after clopidogrel (300 mg loading dose, followed by 75 mg daily) produced similar effects.(1)

Clopidogrel/Fluconazole; Ketoconazole; Voriconazole

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Clopidogrel is a prodrug and is converted to its active metabolite via a 2 step process. The first conversion step is mediated by CYP2C19, CYP1A2 and CYP2B6, while the second step is mediated by CYP3A4, CYP2B6 and CYP2C19.(1,2) CYP2C19 contributes to both steps and is thought to be the more important enzyme involved in formation of the pharmacologically active metabolite.(1) Fluconazole, ketoconazole, and voriconazole may inhibit the metabolism of clopidogrel to its active form by CYP2C19 and CYP3A4.(1)

CLINICAL EFFECTS: Concurrent use of fluconazole, ketoconazole, or voriconazole may result in decreased clopidogrel effectiveness, resulting in increased risk of adverse cardiac events.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of clopidogrel states that concurrent use of inhibitors of CYP2C19, such as fluconazole, ketoconazole, and voriconazole should be avoided.(1) The US manufacturer of clopidogrel states that alternatives to clopidogrel should be considered in patients who are poor metabolizers of CYP2C19.(1) It would be prudent to assume that patients taking strong inhibitors of CYP2C19, such as fluconazole, are poor metabolizers of this isoenzyme. Voriconazole is a moderate CYP2C19 inhibitor. Ketoconazole and voriconazole are strong inhibitors of CYP3A4. Fluconazole is a moderate inhibitor of CYP3A4. Consider alternatives to fluconazole, ketoconazole, and voriconazole in patients stabilized on clopidogrel and alternatives to clopidogrel in patients stabilized on fluconazole, ketoconazole, and voriconazole. If concurrent therapy is warranted, consider appropriate testing to assure adequate inhibition of platelet reactivity.

DISCUSSION: In a randomized, cross-over study in healthy subjects, ketoconazole (400 mg daily) decreased the maximum concentration (Cmax) of the active metabolite of clopidogrel (300 mg loading dose, followed by 75 mg daily) by 61%. The area-under-curve (AUC) of the active metabolite of clopidogrel was decreased by 22% following the loading dose and by 29% during maintenance dosing. Clopidogrel-induced inhibition of platelet aggregation was decreased by 28% following the loading dose and by 33% during the maintenance dose.(3)

Clopidogrel/Fluoxetine; Fluvoxamine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Clopidogrel is a prodrug and is converted to its active metabolite via a 2 step process. The first conversion step is mediated by CYP2C19, CYP1A2 and CYP2B6, while the second step is mediated by CYP3A4, CYP2B6 and CYP2C19.(1,2) CYP2C19 contributes to both steps and is thought to be the more important enzyme involved in formation of the pharmacologically active metabolite.(1) Fluoxetine and fluvoxamine may inhibit the metabolism of clopidogrel to its active form by CYP2C19.(1)

CLINICAL EFFECTS: Concurrent use of fluoxetine and fluvoxamine may result in decreased clopidogrel effectiveness, resulting in increased risk of adverse cardiac events.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of clopidogrel states that alternatives to clopidogrel should be considered in patients who are poor metabolizers of CYP2C19.(1) It would be prudent to assume that patients taking strong inhibitors of CYP2C19, such as fluoxetine and fluvoxamine, are poor metabolizers of this isoenzyme. Consider alternatives to fluoxetine and fluvoxamine in patients stabilized on clopidogrel and alternatives to clopidogrel in patients stabilized on fluoxetine or fluvoxamine. If concurrent therapy is warranted, consider appropriate testing to assure adequate inhibition of platelet reactivity.

DISCUSSION: In an open-label, cross-over study in 8 health male volunteers, a loading dose of clopidogrel (600 mg) was administered alone and after 5 days of fluoxetine (20 mg). The maximum concentration (Cmax) and area-under-curve (AUC) of the active metabolite of clopidogrel were decreased by 25.3% and 20.6%, respectively. There was an average decrease of approximately 25% in the antiplatelet effects of clopidogrel when administered with fluoxetine.(2) However, it is likely that this study significantly underestimates the magnitude of this interaction. Both fluoxetine and its norfluoxetine metabolite inhibit CYP2C19 and have long half-lives of 4 to 9 days and so and is an irreversible inhibitor of CYP2C19. In a randomized, cross-over study in healthy subjects, ketoconazole (another CYP2C19 inhibitor, 400 mg daily) decreased the Cmax of the active metabolite of clopidogrel (300 mg loading dose, followed by 75 mg daily) by 61%. The AUC of the active metabolite of clopidogrel was decreased by 22% following the loading dose and by 29% during maintenance dosing. Clopidogrel-induced inhibition of platelet aggregation was decreased by 28% following the loading dose and by 33% during the maintenance dose.(4) In a cross-over study in 72 healthy subjects, simultaneous administration of omeprazole (another CYP2C19 inhibitor, 80 mg daily) and clopidogrel (300 mg loading dose, followed by 75 mg daily) decreased the AUC of the active metabolite of clopidogrel by 46% following the loading dose and by 42% during maintenance dosing. Clopidogrel-induced inhibition of platelet aggregation was decreased by 47% following the loading dose and by 30% during the maintenance dose. In a cross-over study in 72 healthy subjects, administration of omeprazole (another CYP2C19 inhibitor, 80 mg daily) 12 hours after clopidogrel (300 mg loading dose, followed by 75 mg daily) produced similar effects.(1)

Clopidogrel/Isoniazid

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Clopidogrel is a prodrug and is converted to its active metabolite via a 2 step process. The first conversion step is mediated by CYP2C19, CYP1A2 and CYP2B6, while the second step is mediated by CYP3A4, CYP2B6 and CYP2C19.(1,2) CYP2C19 contributes to both steps and is thought to be the more important enzyme involved in formation of the pharmacologically active metabolite.(1) Isoniazid may inhibit the metabolism of clopidogrel to its active metabolite via inhibition of CYP2C19.

CLINICAL EFFECTS: Concurrent use of isoniazid and clopidogrel may result in decreased clopidogrel effectiveness, resulting in increased risk of adverse cardiac events.

PREDISPOSING FACTORS: Patients who are 'slow acetylators' of NAT2, the enzyme which metabolizes isoniazid, may have substantially (e.g. 2 to 7-fold) higher isoniazid concentrations than 'fast acetylators'. Higher isoniazid levels may have greater inhibition of the CYP2C19 metabolism of clopidogrel to its active metabolite.

PATIENT MANAGEMENT: Evaluate the medication list or interaction alerts to determine if patient is receiving additional drugs which may also inhibit clopidogrel active metabolite formation. Whenever possible, convert patient to non-interacting medication(s). If potential interacting medication(s) cannot be changed, consider alternative antiplatelet therapy or testing to assure adequate on-treatment inhibition of platelet reactivity. The US manufacturer of clopidogrel states that alternatives to clopidogrel should be considered in patients who are poor metabolizers of CYP2C19.(1) It would be prudent to assume that patients taking strong inhibitors of CYP2C19 are poor metabolizers of this isoenzyme. Consider alternatives to isoniazid in patients stabilized on clopidogrel and alternatives to clopidogrel in patients stabilized on isoniazid. If concurrent therapy is warranted, consider appropriate testing to assure adequate inhibition of platelet reactivity.

DISCUSSION: In pharmacogenomic studies and clinical trials, patients with a CYP2C19 poor metabolizer phenotype have decreased active metabolite exposure, diminished antiplatelet effects, and a higher rate of cardiovascular events compared with extensive metabolizers.(1,3) Studies have not evaluated this specific drug combination; the actual magnitude of this interaction is not known. Given the possible consequences of clopidogrel treatment failure, it would be prudent to avoid concomitant use of clopidogrel and isoniazid when possible.

Clopidogrel/Nirmatrelvir-Ritonavir

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Clopidogrel is a prodrug and is converted to its active metabolite via a 2 step process. The first conversion step is mediated by CYP2C19, CYP1A2 and CYP2B6, while the second step is mediated by CYP3A4, CYP2B6 and CYP2C19.(1,2) CYP2C19 contributes to both steps and is thought to be the more important enzyme involved in formation of the pharmacologically active metabolite.(1) CYP3A4 is responsible for 39.8% of the second step of metabolism. Protease inhibitors that are strong CYP3A4 inhibitors may inhibit the metabolism of clopidogrel to its active form by CYP3A4.(1,2)

CLINICAL EFFECTS: Concurrent use of protease inhibitors that are strong CYP3A4 inhibitors may result in decreased clopidogrel effectiveness, resulting in increased risk of adverse cardiac events.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of clopidogrel as well as the US and Canadian manufacturers of nirmatrelvir-ritonavir do not make specific recommendations for concurrent use of clopidogrel and nirmatrelvir-ritonavir. Patient monitoring for adequate inhibition of platelet reactivity with clopidogrel is warranted.(1,4-5) The Australian manufacturer of nirmatrelvir-ritonavir states that concomitant use of clopidogrel should be avoided.(6) The Journal of American College of Cardiology (JACC) states use of nirmatrelvir-ritonavir with clopidogrel should be avoided in patients with a recent percutaneous coronary intervention (PCI) (at least within previous 6 weeks) or history of high-risk PCI. If use of nirmatrelvir-ritonavir is deemed necessary, consider switching to prasugrel with a loading dose while on nirmatrelvir-ritonavir.(7) The JACC states concurrent use of nirmatrelvir-ritonavir with clopidogrel is considered safe to co-administer in other low-risk patients.(7) HIV treatment guidelines from the US Department of Health and Human Services and the European AIDS Clinical Society, and the University of Liverpool HIV Drug Interactions database all recommend not to coadminister clopidogrel with any protease inhibitor or cobicistat.(8-10) Consider alternatives to protease inhibitors that are strong CYP3A4 inhibitors in patients stabilized on clopidogrel and alternatives to clopidogrel in patients stabilized on protease inhibitors that are strong CYP3A4 inhibitors. If concurrent therapy is warranted, consider appropriate testing to assure adequate inhibition of platelet reactivity.

DISCUSSION: In a randomized, cross-over study in healthy subjects, ketoconazole (400 mg daily) decreased the maximum concentration (Cmax) of the active metabolite of clopidogrel (300 mg loading dose, followed by 75 mg daily) by 61%. The area-under-curve (AUC) of the active metabolite of clopidogrel was decreased by 22% following the loading dose and by 29% during maintenance dosing. Clopidogrel-induced inhibition of platelet aggregation was decreased by 28% following the loading dose and by 33% during the maintenance dose.(11) A randomized cross over study in 12 healthy volunteers and 9 HIV-infected patients evaluated the impact of boosted antiretroviral therapy (ARV) on the pharmacokinetics and efficacy of clopidogrel. Healthy patients had 3.2-fold lower AUC (p=0.02) and Cmax of clopidogrel active metabolite (p=0.03) than HIV patients. Platelet reactivity was also 35% lower in health patients compared to HIV patients (p=0.04). All healthy patients had a platelet reactivity below the cut-off value at 4 hours after clopidogrel dose, while 44% of HIV patients were above the cut-off value of 206.(12) A cross-sectional study in 240 post acute coronary syndrome (ACS) patients compared platelet reactivity under aspirin and P2Y12 inhibitor therapy between HIV and non-HIV patients with first episode ACS on dual antiplatelet therapy. Study evaluated residual platelet aggregation (RPA), P2Y12 assay (PRU), and VASP platelet reactivity index (VASP-PRI). HIV patients were all on ARV therapy, most commonly with protease inhibitors (darunavir, lopinavir, atazanavir, and indinavir in combination with ritonavir in all but two patients). Patients on ARV containing protease inhibitors compared to other combinations had increased platelet reactivity to P2Y12 inhibitors and higher prevalence of high residual platelet reactivity (HPR) (OR 4.4 (95%CI 1.1-18.1) with RPA, P = 0.04; OR 3.1 (95%CI = 0.84-11.5) with VASP-PRI; P = 0.09, and OR 4.3 (95%CI 1.02-18.1) with PRU, P = 0.047). Patients with CD4 T cell count lower than 350/mm3 also had consistently increased platelet reactivity to P2Y12 inhibitors and higher prevalence of HPR (OR 3.41 (95%CI 0.60-19.4) with RPA, P = 0.17; OR 7.1 (95%CI 0.94-54.2) with VASP-PRI, P = 0.06; and OR 7.9 (95%CI 1.42-44.8) with PRU, P = 0.002), although this association was not significant for all three tests.(13)

Clopidogrel/Selected Cyp2c19 Inhibitors

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Clopidogrel is a prodrug and is converted to its active metabolite via a 2 step process. The first conversion step is mediated by CYP2C19, CYP1A2 and CYP2B6, while the second step is mediated by CYP3A4, CYP2B6 and CYP2C19.(1,2) CYP2C19 contributes to both steps and is thought to be the more important enzyme involved in formation of the pharmacologically active metabolite.(1) Inhibitors of CYP2C19 may decrease the conversion of clopidogrel to its active metabolite.(1)

CLINICAL EFFECTS: Concurrent use of CYP2C19 inhibitors may result in decreased clopidogrel effectiveness, resulting in increased risk of adverse cardiac events.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Evaluate medication list or interaction alerts to determine if patient is receiving additional drugs which may also inhibit clopidogrel active metabolite formation. The US manufacturer of clopidogrel states that alternatives to clopidogrel should be considered in patients who are poor metabolizers of CYP2C19.(1) It would be prudent to assume that patients taking strong inhibitors of CYP2C19 are poor metabolizers of this isoenzyme. Moderate or weak inhibitors of CYP2C19 may have less of an effect on this interaction. Consider alternatives to CYP2C19 inhibitors in patients stabilized on clopidogrel and alternatives to clopidogrel in patients stabilized on CYP2C19 inhibitors. If concurrent therapy is warranted, consider appropriate testing to assure adequate inhibition of platelet reactivity.

DISCUSSION: Clopidogrel is a prodrug and requires conversion to the active metabolite by CYP2C19. Clopidogrel is not a sensitive substrate for CYP2C19 as CYP3A4, CYP2B6 and CYP1A2 also participate in active metabolite formation. Studies have not evaluated this specific drug combination; the actual magnitude of this interaction is not known. Given the possible consequences of clopidogrel treatment failure, it would be prudent to avoid concomitant use of clopidogrel and CYP2C19 inhibitors when possible. Selected CYP2C19 inhibitors include: armodafinil, berotralstat, cenobamate, elagolix, enasidenib, eslicarbazepine, fedratinib, fexinidazole, givosiran, lonafarnib, moclobemide, modafinil, obeticholic acid, osilodrostat, piperine, pirtobrutinib, rolapitant, rucaparib, tecovirimat, treosulfan, and triclabendazole.(4,5)

Clopidogrel/Selected Strong Cyp2c19 Inducers

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Clopidogrel is a prodrug and is converted to its active metabolite via a 2 step process. The first conversion step is mediated by CYP2C19, CYP1A2 and CYP2B6, while the second step is mediated by CYP3A4, CYP2B6 and CYP2C19.(1-3) As CYP2C19 contributes to both steps, it is thought to be the more important enzyme involved in formation of the pharmacologically active metabolite. Strong inducers of CYP2C19 may increase the conversion of clopidogrel to its active metabolite.(1,2)

CLINICAL EFFECTS: Concurrent use of strong CYP2C19 inducers with clopidogrel may increase the effects and toxicity of clopidogrel, including bleeding.(1,2)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patient with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: The manufacturer of clopidogrel states that concomitant use of strong CYP2C19 inducers should be avoided.(1,2) If concurrent therapy cannot be avoided, monitor patients for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Discontinue clopidogrel in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: In a study of 12 healthy volunteers, rifampin (300 mg twice daily for 7 days) increased the maximum concentration (Cmax) and area-under-curve (AUC) of the active metabolite of clopidogrel by approximately 4-fold. In conjunction with this, there was a higher level of P2Y12 receptor blockade by clopidogrel after rifampin pre-treatment. Clopidogrel 600 mg alone decreased the number of unblocked receptors at 4 hours from 248 +/- 40 to 48 +/- 24 per platelet. After rifampin pre-treatment, clopidogrel decreased the number of unblocked receptors from 266 +/- 63 to 4 +/- 2 (p < 0.0001).(4) A study of 10 healthy volunteers found that rifampin 300 mg twice daily for 4 days then combined with clopidogrel 75 mg daily for 6 days led to a significantly greater inhibition of platelet aggregation compared to clopidogrel alone (56% versus 33%, respectively). Three subjects who were initially clopidogrel nonresponders and 1 subject who was a low responder all became responders after treatment with rifampin.(5) Strong CYP2C19 inducers linked to this monograph include: apalutamide, rifabutin and rifampin.(6,7)

Clopidogrel/Selected Strong Cyp3a4 Inhibitors

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Clopidogrel is a prodrug and is converted to its active metabolite via a 2 step process. The first conversion step is mediated by CYP2C19, CYP1A2 and CYP2B6, while the second step is mediated by CYP3A4, CYP2B6 and CYP2C19.(1,2) CYP2C19 contributes to both steps and is thought to be the more important enzyme involved in formation of the pharmacologically active metabolite.(1) CYP3A4 is responsible for 39.8% of the second step of metabolism. Strong CYP3A4 inhibitors may inhibit the metabolism of clopidogrel to its active form by CYP3A4.(1,3)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may result in decreased clopidogrel effectiveness, resulting in increased risk of adverse cardiac events.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of clopidogrel does not make specific recommendations for concurrent use with strong CYP3A4 inhibitors. Patient monitoring for adequate inhibition of platelet reactivity with clopidogrel is warranted. Consider alternatives to strong CYP3A4 inhibitors in patients stabilized on clopidogrel and alternatives to clopidogrel in patients stabilized on strong CYP3A4 inhibitors. If concurrent therapy is warranted, consider appropriate testing to assure adequate inhibition of platelet reactivity.

DISCUSSION: In a randomized, cross-over study in healthy subjects, ketoconazole (400 mg daily) decreased the maximum concentration (Cmax) of the active metabolite of clopidogrel (300 mg loading dose, followed by 75 mg daily) by 61%. The area-under-curve (AUC) of the active metabolite of clopidogrel was decreased by 22% following the loading dose and by 29% during maintenance dosing. Clopidogrel-induced inhibition of platelet aggregation was decreased by 28% following the loading dose and by 33% during the maintenance dose.(4) A randomized cross over study in 12 healthy volunteers and 9 HIV-infected patients evaluated the impact of boosted antiretroviral therapy (ARV) on the pharmacokinetics and efficacy of clopidogrel. Healthy patients had 3.2-fold lower AUC (p=0.02) and Cmax of clopidogrel active metabolite (p=0.03) than HIV patients. Platelet reactivity was also 35% lower in health patients compared to HIV patients (p=0.04). All healthy patients had a platelet reactivity below the cut-off value at 4 hours after clopidogrel dose, while 44% of HIV patients were above the cut-off value of 206.(5) A cross-sectional study in 240 post acute coronary syndrome (ACS) patients compared platelet reactivity under aspirin and P2Y12 inhibitor therapy between HIV and non-HIV patients with first episode ACS on dual antiplatelet therapy. Study evaluated residual platelet aggregation (RPA), P2Y12 assay (PRU), and VASP platelet reactivity index (VASP-PRI). HIV patients were all on antiretroviral (ARV) therapy, most commonly with protease inhibitors (darunavir, lopinavir, atazanavir, and indinavir in combination with ritonavir in all but two patients). Patients on ARV containing protease inhibitors compared to other combinations had increased platelet reactivity to P2Y12 inhibitors and higher prevalence of high residual platelet reactivity (HPR) (OR 4.4 (95%CI 1.1-18.1) with RPA, P = 0.04; OR 3.1 (95%CI = 0.84-11.5) with VASP-PRI; P = 0.09, and OR 4.3 (95%CI 1.02-18.1) with PRU, P = 0.047). Patients with CD4 T cell count lower than 350/mm3 also had consistently increased platelet reactivity to P2Y12 inhibitors and higher prevalence of HPR (OR 3.41 (95%CI 0.60-19.4) with RPA, P = 0.17; OR 7.1 (95%CI 0.94-54.2) with VASP-PRI, P = 0.06; and OR 7.9 (95%CI 1.42-44.8) with PRU, P = 0.002), although this association was not significant for all three tests.(6) Selected strong CYP3A4 inhibitors linked to this monograph include: adagrasib, boceprevir, ceritinib, clarithromycin, ensitrelvir, idelalisib, itraconazole, josamycin, levoketoconazole, mibefradil, nefazodone, posaconazole, relacorilant, ribociclib, telaprevir, telithromycin, tucatinib, and troleandomycin.(7)

Clopidogrel/Ticlopidine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Clopidogrel is a prodrug and is converted to its active metabolite via a 2 step process. The first conversion step is mediated by CYP2C19, CYP1A2 and CYP2B6, while the second step is mediated by CYP3A4, CYP2B6 and CYP2C19.(1,2) CYP2C19 contributes to both steps and is thought to be the more important enzyme involved in formation of the pharmacologically active metabolite.(1) Ticlopidine may inhibit the metabolism of clopidogrel to its active form by CYP2C19.(1)

CLINICAL EFFECTS: Concurrent use of ticlopidine may result in decreased clopidogrel effectiveness, resulting in increased risk of adverse cardiac events.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of clopidogrel states that concurrent use of inhibitors of CYP2C19, such as ticlopidine, should be avoided.(1) The US manufacturer of clopidogrel states that alternatives to clopidogrel should be considered in patients who are poor metabolizers of CYP2C19.(1) It would be prudent to assume that patients taking strong inhibitors of CYP2C19, such as ticlopidine, are poor metabolizers of this isoenzyme. Consider alternatives to ticlopidine in patients stabilized on clopidogrel and alternatives to clopidogrel in patients stabilized on ticlopidine. If concurrent therapy is warranted, consider appropriate testing to assure adequate inhibition of platelet reactivity.

DISCUSSION: In a randomized, cross-over study in healthy subjects, ketoconazole (another CYP2C19 inhibitor, 400 mg daily) decreased the maximum concentration (Cmax) of the active metabolite of clopidogrel (300 mg loading dose, followed by 75 mg daily) by 61%. The area-under-curve (AUC) of the active metabolite of clopidogrel was decreased by 22% following the loading dose and by 29% during maintenance dosing. Clopidogrel-induced inhibition of platelet aggregation was decreased by 28% following the loading dose and by 33% during the maintenance dose.(3) In a cross-over study in 72 healthy subjects, simultaneous administration of omeprazole (another CYP2C19 inhibitor, 80 mg daily) and clopidogrel (300 mg loading dose, followed by 75 mg daily) decreased the AUC of the active metabolite of clopidogrel by 46% following the loading dose and by 42% during maintenance dosing. Clopidogrel-induced inhibition of platelet aggregation was decreased by 47% following the loading dose and by 30% during the maintenance dose. In a cross-over study in 72 healthy subjects, administration of omeprazole (another CYP2C19 inhibitor, 80 mg daily) 12 hours after clopidogrel (300 mg loading dose, followed by 75 mg daily) produced similar effects.(1)

Clopidogrel/Vonoprazan

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Clopidogrel is a prodrug and is converted to its active metabolite via a 2 step process. The first conversion step is mediated by CYP2C19, CYP1A2 and CYP2B6, while the second step is mediated by CYP3A4, CYP2B6 and CYP2C19.(1,2) CYP2C19 contributes to both steps and is thought to be the more important enzyme involved in formation of the pharmacologically active metabolite.(1) Vonoprazan may inhibit CYP2C19 mediated conversion to the active metabolite of clopidogrel.(7-10)

CLINICAL EFFECTS: Concurrent use of vonoprazan may result in decreased clopidogrel effectiveness, resulting in increased risk of adverse cardiac events.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of vonoprazan states concurrent use should be carefully monitored. Monitor patients closely for clopidogrel efficacy and consider alternative antiplatelet agents.(7,8) Evaluate patient risk for gastrointestinal (GI) bleeding. When PPIs are needed, use dexlansoprazole, lansoprazole, pantoprazole or rabeprazole as they have a lower interaction risk.(1,11) Consider the use of H2 blockers (such as famotidine, nizatidine, or ranitidine) in patients with a low bleeding risk and reserve the use of PPIs for patients at higher risk of GI bleeding. The US manufacturer of clopidogrel states that alternatives to clopidogrel should be considered in patients who are poor metabolizers of CYP2C19.(1) It would be prudent to assume that patients taking strong inhibitors of CYP2C19 are poor metabolizers of this isoenzyme. Moderate CYP2C19 inhibitors, such as omeprazole, and weak CYP2C19 inhibitors, such as cimetidine, may also affect this interaction. Consider alternatives to vonoprazan in patients stabilized on clopidogrel and alternatives to clopidogrel in patients stabilized on vonoprazan. If concurrent therapy is warranted, consider appropriate testing to assure adequate inhibition of platelet reactivity.

DISCUSSION: In a study in 7 healthy subjects, concurrent use of vonoprazan resulted in an increase and decrease in the area under the plasma concentration-time curve (AUC) of proguanil and cycloguanil, respectively. The AUC ratio of cycloguanil/proguanil was reduced to 0.507-fold (95% CI 0.409-0.605) with concurrent vonoprazan.(9) In a study in 12 healthy subjects, the inhibition of platelet aggregation was decreased with daily and every other day use of vonoprazan with clopidogrel (21.8% and 25%, respectively) compared to clopidogrel alone (40.8%).(10) A retrospective cohort study of 16,064 patients evaluated the impact of MACE events in patients taking clopidogrel with PPIs/PCABs. Patients taking concurrent PPIs or PCABs with clopidogrel had a higher incidence of MACE compared to clopidogrel monotherapy. Among MACE, stroke recurrence was the highest risk with the PPI and PCAB groups. The PPIs studied included esomeprazole, dexlansoprazole, omeprazole, pantoprazole, ilaprazole, and rabeprazole, with esomeprazole resulting in the highest risk of MACE and stroke recurrence.(12)

Moderate Cyp2c8 Inhibitors/Tovorafenib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Moderate inhibitors of CYP2C8 may inhibit the metabolism of tovorafenib.(1)

CLINICAL EFFECTS: Concomitant use of a moderate CYP2C8 inhibitor may increase tovorafenib plasma concentrations, which may increase the risk of tovorafenib toxicity, including hepatotoxicity, bleeding, and photosensitivity.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of tovorafenib recommends avoiding concomitant use of tovorafenib with moderate CYP2C8 inhibitors.(1)

DISCUSSION: Moderate CYP2C8 inhibitors are predicted to increase tovorafenib exposure.(1) Moderate CYP2C8 inhibitors linked to this monograph include clopidogrel, deferasirox, leflunomide, letermovir, mifepristone (chronic therapy), and teriflunomide.(2)

Selected Antiplatelets; Aspirin (> 100 Mg)/Rivaroxaban

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Additive effects on hemostasis.(1)

CLINICAL EFFECTS: Concurrent use of rivaroxaban with anticoagulants, antiplatelets, or thrombolytics may increase the risk of bleeding.(1)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Avoid concurrent use of rivaroxaban and higher doses of aspirin unless the benefit is expected to outweigh the increased risk of bleeding. In the ROCKET AF trial, concomitant use of low dose aspirin (almost exclusively at less than or equal to 100 mg daily) was identified as an independent risk factor for bleeding.(1) If the benefit of concurrent use of rivaroxaban with other antiplatelets is expected to outweigh the increased risk of bleeding, closely monitor patients for signs or symptoms of bleeding.(1) The UK manufacturer of rivaroxaban states that rivaroxaban 2.5 mg twice daily is indicated with aspirin 75 - 100 mg with or without clopidogrel 75 mg or standard dose ticlopidine for post-acute coronary syndrome and in patients with CAD and PAD, weighing the risk for ischemic events against the bleeding risks. Long-term dual antiplatelet therapy should be avoided. Clinical monitoring is recommended throughout treatment.(2) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: In two clinical trials in healthy subjects, concurrent clopidogrel (300 mg loading dose, then 75 mg daily) and rivaroxaban (15 mg single dose) increased bleeding time to 45 minutes in 45% and 30% of subjects. This was twice the maximum increase in bleeding time seen with either agent alone.(1) In the ROCKET AF trial, concomitant aspirin use (almost exclusively at < or = to 100 mg daily) was identified as an independent risk factor for bleeding.(1) In a study, concurrent enoxaparin (40 mg) and rivaroxaban (10 mg) resulted in additive effects on anti-factor Xa activity with no effects on the pharmacokinetics of rivaroxaban.(1) In a study, concurrent warfarin (15 mg) and rivaroxaban (5 mg) resulted in additive effects on factor Xa inhibition and PT with no effects on the pharmacokinetics of rivaroxaban.(1) In a single dose study, there were no pharmacokinetic or pharmacodynamic interactions between rivaroxaban and aspirin.(1) A self-controlled case study of 1,622 oral anticoagulant-precipitant drug pairs were reviewed and found 14% of drug pairs were associated with a statistically significant elevated risk of thromboembolism. Concurrent use of rivaroxaban and dipyridamole resulted in a ratio of rate ratios (95% CI) of 3.49 (1.08-6.64); and rivaroxaban and aspirin ratio of rate ratios 2.19 (1.21-2.95).(3) A meta-analysis of 9 studies identified 13,459 patients taking direct oral anticoagulants (DOACs), 1,692 of whom also took an antiplatelet agent. Of the patients on antiplatelet agents, 1,254 took aspirin while the rest was unspecified. Most of the trials restricted patients to use of low-dose aspirin, with the highest allowable dose being 165 mg/day. The use of DOACs with antiplatelet agents was associated with an increased risk of major bleeding (OR 1.89; 95% CI, 1.04-3.44) and clinically relevant non-major bleeding (OR 1.82; 95% CI, 1.50-2.22). There was no difference between groups in the efficacy outcome of symptomatic recurrent venous thromboembolism (VTE) or VTE-related death.(4)

Selected Inhibitors Of Bcrp/Cladribine Oral

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Inhibitors of BCRP may increase the absorption of cladribine.(1-2)

CLINICAL EFFECTS: The concurrent administration of cladribine with an inhibitor of BCRP may result in elevated levels of cladribine and signs of toxicity.(1-2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of cladribine states concurrent use of BCRP inhibitors should be avoided during the 4- to 5-day cladribine treatment.(1-2) Selection of an alternative concurrent medication with no or minimal transporter inhibiting proprieties should be considered. If this is not possible, dose reduction to the minimum mandatory dose of the BCRP inhibitor, separation in timing of administration, and careful patient monitoring is recommended.(1-2) Monitor for signs of hematologic toxicity. Lymphocyte counts should be monitored.

DISCUSSION: Cladribine is a substrate of BCRP. Inhibitors of this transporter are expected to increase cladribine levels.(1-2) BCRP inhibitors linked to this monograph include: capmatinib, clopidogrel, curcumin, danicopan, darolutamide, dasabuvir, eltrombopag, enasidenib, ensitrelvir, febuxostat, fostamatinib, fostemsavir, glecaprevir/pibrentasvir, grazoprevir, lazertinib, oteseconazole, pacritinib, paritaprevir, regorafenib, resmetirom, ritonavir, rolapitant, roxadustat, selpercatinib, sofosbuvir/velpatasvir/voxilaprevir, tafamidis, ticagrelor, tolvaptan, turmeric, vadadustat, and zongertinib.(1-4)

Selected Platelet Aggregation Inhibitors/Nsaids; Salicylates

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Abciximab, cangrelor, cilostazol, clopidogrel, dipyridamole, eptifibatide, prasugrel, ticagrelor, vorapaxar and NSAIDs or salicylates inhibit platelet aggregation.

CLINICAL EFFECTS: Concurrent use of platelet aggregation inhibitors and NSAIDs or salicylates may increase the risk of bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with multiple disease-associated factors (e.g. thrombocytopenia, advanced liver disease). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g., anticoagulants, other antiplatelets, corticosteroids, selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs). Risk of GI bleed may be increased in patients who are of older age, in poor health status, or who use alcohol or smoke. Risk may also be increased with longer duration of NSAID use and prior history of peptic ulcer disease and/or GI bleeding. Risk increases as the number of risk factors increases.

PATIENT MANAGEMENT: Use caution when administering platelet aggregation inhibitors with NSAIDs or salicylates.(1-5) It would be prudent to monitor patients more closely during concurrent therapy and to use the lowest NSAID or salicylate dose possible. If concurrent therapy is warranted, monitor patients for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The 2010 ACCF/ACG/AHA Consensus guidelines recommend the use of proton pump inhibitors (PPIs) in patients with multiple risk factors for GI bleeding who require antiplatelet therapy. However, esomeprazole and omeprazole should be avoided with clopidogrel as they are expected to reduce the effectiveness of clopidogrel. Use of other PPIs should be approached with caution, as they may reduce the effectiveness of clopidogrel.

DISCUSSION: Because of the increased risk of bleeding, caution is warranted when using this combination. In a nationwide cohort study, patients were evaluated for thromboembolic cardiovascular and clinically relevant bleeding events with concurrent antithrombotic and ongoing NSAID treatment. A total of 108,232 patients were followed for a mean of 2.3 +/- 1.8 years after diagnosis of myocardial infarction. Concomitant NSAID treatment significantly increased the risk for cardiovascular events (hazard ratio (HR) 6.96; 95% CI 6.24 - 6.77; p<0.001) and bleeding events (HR 4.08; 95% CI 3.51 - 4.73; p<0.001) compared to no NSAID treatment. NSAIDs were further evaluated and revealed the use of celecoxib (HR: 4.65; 95% CI: 3.17 to 6.82; p < 0.001, and 3.44; 95% CI: 2.20 to 5.39; p < 0.001, respectively) and meloxicam (HR: 3.03; 95% CI: 1.68 to 5.47; p < 0.001, and 2.80; 95% CI: 1.40 to 5.60; p < 0.001, respectively) had the lowest risk for cardiovascular and bleeding events, receptively.

Moderate Interaction: Assess the risk to the patient and take action as needed.

Anticoagulant;Antiplatelet;Thrombolytic/Icosapent Ethyl

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: In vitro data suggests that fish oils can competitively inhibit cyclooxygenase which decreases synthesis of thromboxane A1 leading to a decrease in platelet aggregation.(1)

CLINICAL EFFECTS: Concurrent use of anticoagulant, antiplatelet, or thrombolytic agents increase bleeding risks.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: If concurrent therapy is deemed medically necessary, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory tests (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: Specific studies with icosapent ethyl and affects on bleeding risk have not been conducted. Concurrent use of anticoagulant, antiplatelet, or thrombolytic agents may increase bleeding risks by impairing platelet function and prolonging bleeding time.(1) Several case reports have shown increased bleeding time and an increased risk of adverse effects from concurrent therapy.(2,3,4) A randomized placebo controlled study of 40 people taking omega-3 fatty acids and oral anticoagulants showed a significant prolongation in bleeding time.(5)

Anticoagulants; Antiplatelets/Fruquintinib; Surufatinib

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Bleeding has been reported with the use of fruquintinib and surufatinib.(1,2)

CLINICAL EFFECTS: Concurrent use of fruquintinib or surufatinib with either anticoagulants or antiplatelets may increase the risk of hemorrhage.(1,2)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Patients receiving concurrent therapy with fruquintinib and anticoagulants and/or antiplatelets should be closely monitored for changes in platelet count or in International Normalized Ratio (INR). If a serious bleeding event occurs, the manufacturer recommends permanent discontinuation of fruquintinib.(1) Patients receiving concurrent therapy with surufatinib and anticoagulants and/or antiplatelets should be closely monitored for changes in platelet count or in INR.If a serious bleeding event occurs, the manufacturer recommends permanent discontinuation of surufatinib.(2) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory tests (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: Bleeding has been reported with fruquintinib in three randomized, double-blinded, placebo-controlled clinical trials. The incidence of grade 1 and grade 2 bleeding events was 28.2%, including gastrointestinal bleeding (10.9%), hematuria (10.6%), and epistaxis (7.5%). The incidence of grade 3 or higher bleeding events was 2.1% and included gastrointestinal bleeding (1.6%) and hemoptysis (0.5%).(1) Bleeding has been reported with surufatinib in clinical trials. Grade 1 and 2 bleeding events included gastrointestinal bleeding, blood in the urine, and gum bleeding. The incidence of grade 3 or greater bleeding events was 4.5%, including gastrointestinal hemorrhage (1.9%), and cerebral hemorrhage (1.1%). Fatalities due to bleeding were reported in 0.3% of patients. The incidence of permanent discontinuation due to bleeding was 2.6% and the incidence of suspension of surufatinib due to bleeding was 3.8%.(2)

Anticoagulants; Antiplatelets/Mifepristone (Cushing)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Mifepristone is an antagonist at the progesterone receptor which can result in endometrium thickening, cystic dilatation of endometrial glands, or excessive vaginal bleeding. Concurrent use with anticoagulants or antiplatelets may further increase risk.

CLINICAL EFFECTS: The concurrent use of mifepristone with anticoagulants or antiplatelets may result in endometrium thickening, cystic dilatation of endometrial glands, or excessive vaginal bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: The manufacturer of mifepristone states that mifepristone should be used with caution in patients receiving concurrent anticoagulant or antiplatelet therapy.(1) If concurrent therapy is deemed medically necessary, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. Women experiencing vaginal bleeding during concurrent use should be referred to a gynecologist for further evaluation.

DISCUSSION: The manufacturer of mifepristone states that mifepristone should be used with caution in patients receiving concurrent anticoagulant or antiplatelet therapy.(1)

Anticoagulants; Antiplatelets/Obinutuzumab

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Severe and life-threatening thrombocytopenia has been reported during obinutuzumab therapy.(1) Anticoagulants and antiplatelets may have an additive risk of bleeding.

CLINICAL EFFECTS: Concurrent use of obinutuzumab with anticoagulants or antiplatelet agents may result in additive or synergistic effects, including fatal and non-fatal hemorrhage.(1)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Monitor all patients frequently for thrombocytopenia and signs of bleeding. Consider withholding concomitant anticoagulants and antiplatelets, especially during the first cycle of obinutuzumab.(1) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: Obinutuzumab with chemotherapy has been reported to cause severe and life-threatening thrombocytopenia. Fatal hemorrhagic events have occurred in patients with NHL and CLL during obinutuzumab therapy, including during Cycle 1.(1)

Anticoagulants; Antiplatelets/Plasminogen

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Bleeding has been reported with the use of plasminogen.(1)

CLINICAL EFFECTS: Concurrent use of plasminogen with either anticoagulants or antiplatelets may increase the risk of active bleeding during plasminogen therapy, including bleeding from mucosal disease-related lesions that may manifest as gastrointestinal (GI) bleeding, hemoptysis, epistaxis, vaginal bleeding, or hematuria.(1)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Patients receiving concurrent therapy with plasminogen and anticoagulants and/or antiplatelets should be closely monitored during plasminogen therapy for active bleeding from mucosal disease-related lesions, including GI bleeding, hemoptysis, epistaxis, vaginal bleeding, or hematuria.(1) Prior to initiation of treatment with plasminogen, confirm healing of lesions or wounds suspected as a source of a recent bleeding event. Monitor patients during and for 4 hours after infusion when administering plasminogen with concurrent anticoagulants, antiplatelet drugs, or other agents which may interfere with normal coagulation.(1) If patient experiences uncontrolled bleeding (defined as any gastrointestinal bleeding or bleeding from any other site that persists longer than 30 minutes), seek emergency care and discontinue plasminogen immediately.(1) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory tests (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: Plasminogen has not been studied in patients at an increased risk of bleeding. Bleeding has been reported with plasminogen in a two single-arm, open-label clinical trials as well as in compassionate use programs. The incidence of hemorrhage in patients with Plasminogen Deficiency Type 1 was 16% (3/19 patients).(1) One of the bleeding events occurred two days after receiving the second dose of plasminogen in a patient with a recent history of GI bleeding due to gastric ulcers. The patient received plasminogen through a compassionate use program and the dose was 6.6 mg/kg body weight every 2 days. Endoscopy showed multiple ulcers with one actively bleeding ulcer near the pylorus.(1)

Anticoagulants; Antiplatelets/Tisotumab

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Bleeding, including hemorrhage, has been reported with the use of tisotumab.(1)

CLINICAL EFFECTS: Concurrent use of tisotumab with either anticoagulants, antiplatelets, or NSAIDs may increase the risk of hemorrhage.(1)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Patients receiving concurrent therapy with tisotumab and anticoagulants, antiplatelets, and/or NSAIDs should be closely monitored for signs and symptoms of bleeding and changes in platelet count or International Normalized Ratio (INR). For patients experiencing pulmonary or central nervous system (CNS) hemorrhage, permanently discontinue tisotumab. For grade 2 or greater hemorrhage in any other location, withhold until bleeding has resolved, blood hemoglobin is stable, there is no bleeding diathesis that could increase the risk of continuing therapy, and there is no anatomical or pathologic condition that can increase the risk of hemorrhage. After resolution, either resume treatment or permanently discontinue tisotumab.(1) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory tests (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: Hemorrhage occurred in 62% of patients with cervical cancer treated with tisotumab across clinical trials. The most common all grade hemorrhage adverse reactions were epistaxis (44%), hematuria (10%), and vaginal hemorrhage (10%). Grade 3 hemorrhage occurred in 5% of patients.(1)

Anticoagulants; Antiplatelets; Thrombolytics/Drotrecogin

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Drotrecogin, anticoagulants, antiplatelets, and thrombolytics all affect hemostasis.(1)

CLINICAL EFFECTS: Concurrent use of drotrecogin with anticoagulants, antiplatelets, or thrombolytics, including heparin and aspirin, may increase the risk of bleeding.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Drotrecogin should be used with caution with other agents that affect hemostasis, including concurrent heparin for thrombotic or embolic events; recent administration (within 3 days) of thrombolytics; recent administration of oral anticoagulants (within 7 days) or glycoprotein IIb/IIIa inhibitors; or recent administration (within 7 days) of aspirin (greater than 650 mg daily) or other platelet inhibitors.(1) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: Because of the increased risk of bleeding, drotrecogin should be used with caution with other agents that affect hemostasis, including concurrent heparin for thrombotic or embolic events; recent administration (within 3 days) of thrombolytics; recent administration of oral anticoagulants (within 7 days) or glycoprotein IIb/IIIa inhibitors; or recent administration (within 7 days) of aspirin (greater than 650 mg daily) or other platelet inhibitors.(1)

Antiplatelets/Donanemab

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Microhemorrhage has been reported with the use of donanemab. Radiographic changes on brain MRI have been noted as amyloid related imaging abnormalities-hemosiderin deposition (ARIA-H) which included microhemorrhage. In addition, intracerebral hemorrhages (ICH) greater than 1 cm in diameter have occurred in patients treated with donanemab.(1)

CLINICAL EFFECTS: Concurrent use of donanemab with antiplatelets may increase the risk of hemorrhage.(1)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Donanemab should be used with extreme caution in patients treated with antiplatelets. Evaluate the risks and benefits of concurrent use of donanemab with antiplatelets.(1) The manufacturer of donanemab recommends testing for AP0E4 status prior to initiation of treatment.(1) Use of antiplatelet agents in patients who are homozygous for the APOE4 gene, may have an increased risk of ARIA with donanemab therapy.(1-3) Patients receiving concurrent therapy with donanemab and antiplatelets should be closely monitored for signs and symptoms of bleeding and changes in platelet count.(1) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of microhemorrhage, including headache, nausea/vomiting, confusion, dizziness, visual disturbance, gait difficulties, and loss of coordination. General signs of blood loss include decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Instruct patients to report any signs and symptoms of bleeding, such as confusion, headache, dizziness, nausea, visual changes, unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: In a double-blind, placebo-controlled clinical study of 1736 participants randomized to receive donanemab (n = 860) or placebo (n = 876), donanemab was observed to increase amyloid related imaging abnormalities-hemosiderin deposition (ARIA-H), including microhemorrhage and intracerebral hemorrhage (ICH). Radiographic changes were classified as mild (<=4 new incidences), moderate (5 to 9 new incidences), or severe (10 or more new incidences). The maximum severity of ARIA-H microhemorrhage was observed as mild in 17% (143/853), moderate in 4% (34/853), and severe in 5% (40/853) of patients taking donanemab.(1) Baseline use of antithrombotic medications (aspirin, other antiplatelets, or anticoagulants) was allowed. The majority of exposures to antithrombotic medications were to aspirin. The incidence of ARIA-H was 30% (106/349) in patients taking donanemab with a concomitant antithrombotic medication within 30 days compared to 29% (148/504) who did not receive an antithrombotic within 30 days of an ARIA-H event.(1) The incidence of ICH greater than 1 cm in diameter was 0.6% (2/349 patients) in patients taking donanemab with a concomitant antithrombotic medication compared to 0.4% (2/504) in those who did not receive an antithrombotic. One fatal ICH occurred in a patient taking donanemab in the setting of focal neurologic symptoms of ARIA and the use of a thrombolytic agent.(1)

Antiplatelets/Lecanemab

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Microhemorrhage has been reported with the use of lecanemab. Radiographic changes on brain MRI have been noted as amyloid related imaging abnormalities-hemosiderin deposition (ARIA-H) which included microhemorrhage. In addition, intracerebral hemorrhages (ICH) greater than 1 cm in diameter have occurred in patients treated with lecanemab.(1)

CLINICAL EFFECTS: Concurrent use of lecanemab with antiplatelets may increase the risk of hemorrhage.(1)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Lecanemab should be used with extreme caution in patients treated with antiplatelets. Evaluate the risks and benefits of concurrent use of lecanemab with antiplatelets.(1) Appropriate use recommendations for lecanemab state antiplatelets may be used at standard doses if patients meet other criteria for lecanemab therapy. Use of antiplatelet agents in patients who are homozygous for the APOE4 gene may have an increased risk of ARIA with lecanemab therapy.(2) Patients receiving concurrent therapy with lecanemab and antiplatelets should be closely monitored for signs and symptoms of bleeding and changes in platelet count or International Normalized Ratio (INR).(1) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of microhemorrhage, including headache, nausea/vomiting, confusion, dizziness, visual disturbance, gait difficulties, and loss of coordination. General signs of blood loss include decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Instruct patients to report any signs and symptoms of bleeding, such as confusion, headache, dizziness, nausea, visual changes, unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: In clinical studies, lecanemab was observed to increase ARIA-H, including microhemorrhage and intracerebral hemorrhage. Radiographic changes were classified as mild (<=4 new incidences), moderate (5 to 9 new incidences), or severe (10 or more new incidences. Patients were excluded from clinical trials if taking concurrent anticoagulants or anti-platelets.(1) In Studies 1 and 2, the maximum severity of ARIA-H microhemorrhage was mild in 9% (79/898), moderate in 2% (19/898), and severe in 3% (28/898) of patients. Intracerebral hemorrhage greater than 1 cm in diameter was reported in 0.7% (6/898) of patients in Study 2 after treatment with lecanemab compared to 0.1% (1/897) on placebo. Fatal events of intracerebral hemorrhage in patients taking lecanemab have been observed.(1) In Study 2, baseline use of antithrombotic medications (aspirin, other antiplatelets, or anticoagulants) were allowed if patient was on a stable dose. Aspirin was the most common antithrombotic agent. The incidence of ICH was 0.9% (3/328 patients) in patients taking lecanemab with a concomitant antithrombotic medication at the time of the event compared to 0.6% (3/545 patients) in those who did not receive an antithrombotic. Patients taking lecanemab with an anticoagulant alone or combined with an antiplatelet medication or aspirin had an incidence of intracerebral hemorrhage of 2.5% (2/79 patients) compared to none in patients who received placebo.

Clopidogrel/Asciminib (<= 80 Mg)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Clopidogrel is a prodrug and is converted to its active metabolite via a 2 step process. The first conversion step is mediated by CYP2C19, CYP1A2 and CYP2B6, while the second step is mediated by CYP3A4, CYP2B6 and CYP2C19.(1,2) CYP2C19 contributes to both steps and is thought to be the more important enzyme involved in formation of the pharmacologically active metabolite.(1) Asciminib is a weak CYP2C19 inhibitor and may decrease the conversion of clopidogrel to its active metabolite.(1-4)

CLINICAL EFFECTS: Concurrent use of asciminib may result in decreased clopidogrel effectiveness, resulting in increased risk of adverse cardiac events.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The concurrent use of asciminib and clopidogrel should be approached with caution. CYP2C19 inhibition by asciminib is dose dependent. The US manufacturer of asciminib states that asciminib is predicted to be a weak inhibitor of CYP2C19 at 200 mg twice daily but has no inhibition potential at 80 mg total daily dose.(3) The US manufacturer of clopidogrel states that alternatives to clopidogrel should be considered in patients who are poor metabolizers of CYP2C19.(1) It would be prudent to assume that patients taking strong inhibitors of CYP2C19 are poor metabolizers of this isoenzyme. Moderate or weak inhibitors of CYP2C19 may have less of an effect on this interaction. Consider alternatives to CYP2C19 inhibitors in patients stabilized on clopidogrel and alternatives to clopidogrel in patients stabilized on CYP2C19 inhibitors. If concurrent therapy is warranted, consider appropriate testing to assure adequate inhibition of platelet reactivity.

DISCUSSION: Studies have not evaluated this specific drug combination; the actual magnitude of this interaction is not known. In a pharmacokinetic simulation, the area under the curve (AUC) of omeprazole (CYP2C19 sensitive substrate) 20 mg twice daily was predicted to be increased by 41% with asciminib 200 mg twice daily.(5) Although the 80 mg daily dose of asciminib demonstrated no inhibitory potential, the lack of clinical data, and given the possible consequences of clopidogrel treatment failure, it would be prudent to evaluate the risk vs benefit of concurrent use and monitor accordingly.

Clopidogrel/Selected Ssris; Snris

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Serotonin release by platelets plays a role in hemostasis.(1,2) The increased risk of bleeding may be a result of a decrease in serotonin reuptake by platelets.

CLINICAL EFFECTS: Concurrent use of a selective serotonin reuptake inhibitor(1-5) or a serotonin-norepinephrine reuptake inhibitor(7-9) and agents that affect coagulation may result in bleeding.(12)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Renal impairment has been associated with an elevated risk of GI bleed in patients on SSRIs.(13) Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Selective serotonin reuptake inhibitors(1-5) or serotonin-norepinephrine reuptake inhibitors(6-8) and agents that affect coagulation should be used concurrently with caution. If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Discontinue antiplatelet agents in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: In a retrospective review of 5 years of data from the Pharmaco-Epidemiologic Prescription Database, hospitalizations for upper gastro-intestinal bleeding in antidepressant users were compared to those in non-antidepressant users. The risk of a bleed in a patient using an NSAID only based on an observed-expected ratio was 4.5 and in a patient using low-dose aspirin only was 2.5. Concurrent use of a selective serotonin reuptake inhibitor with NSAIDs or low-dose aspirin increased the risk of bleeding to 12.2 and 5.2, respectively.(9) In another study, there were 16 cases of upper gastrointestinal bleeding in patients receiving concurrent therapy with selective serotonin reuptake inhibitors and NSAIDs. Adjusted relative risk of bleeding with NSAIDs, selective serotonin reuptake inhibitors, or both were 3.7, 2.6, or 15.6, respectively.(10)

Clopidogrel; Prasugrel/Cangrelor

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Cangrelor blocks the active metabolite of clopidogrel or prasugrel from binding to the platelet P2Y12 receptor when cangrelor occupies the receptor.(1-4)

CLINICAL EFFECTS: Doses of clopidogrel and prasugrel administered during cangrelor infusion will not be effective.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Clopidogrel and prasugrel should not be administered during the cangrelor infusion. When transitioning to clopidogrel or prasugrel, administer these agents immediately after the discontinuation of cangrelor infusion.(1)

DISCUSSION: The expected effects of loading doses of clopidogrel (600 mg) and prasugrel (60 mg) were blocked when these agents were administered during infusion of cangrelor.(1) There was no effect on loading doses of ticagrelor.(1) The active metabolite of clopidogrel or prasugrel is blocked from binding to the platelet P2Y12 receptor when cangrelor occupies the receptor.(2-4) Cangrelor is a direct, selective, and reversible P2Y12 platelet receptor inhibitor. Clopidogrel and prasugrel are irreversible P2Y12 platelet inhibitors.(1-4)

Cyp2b6 Inhibitors/Levomethadone; Methadone

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Methadone is metabolized primarily by CYP2B6. Inhibitors of CYP2B6 may decrease the metabolism of methadone.(1-3) Levomethadone is the active (R)-enantiomer of methadone.(4)

CLINICAL EFFECTS: Concurrent administration of CYP2B6 inhibitors may result in increased levels and clinical effects of levomethadone or methadone, which may result in QTc prolongation and life-threatening arrhythmias. Elevated levels can also cause profound sedation, respiratory depression, coma, and/or death. The discontinuation of CYP2B6 inhibitors in patients maintained on levomethadone or methadone may result in symptoms of opiate withdrawal. Levomethadone and methadone have been associated with serotonin syndrome. Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(3)

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(5) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(5)

PATIENT MANAGEMENT: If concomitant use of levomethadone or methadone and CYP2B6 inhibitors is necessary, closely monitor the patient when a CYP2B6 inhibitor is initiated or withdrawn. The dosage of levomethadone or methadone may need to be adjusted.(3) If concurrent therapy is deemed medically necessary, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with agents that may increase opioid drug levels.(6) If concurrent use is necessary, monitor patients for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness. If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea. Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(7)

DISCUSSION: In a clinical study, oral voriconazole (400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 4 days, a CYP2B6 inhibitor) increased the maximum concentration (Cmax) and area-under-curve (AUC) of (R)-methadone by 31% and 47%, respectively, in subjects receiving a methadone maintenance dose of 30 mg to 100 mg daily. The Cmax and AUC of (S)-methadone increased by 65% and 103%, respectively.(3) In healthy subjects, ticlopidine (250 mg twice daily for 4 days, a CYP2B6 inhibitor) increased the dose-adjusted AUC of (R)-methadone and (S)-methadone by about 20% and 60%, respectively.(8) Inhibitors of CYP2B6 linked to this monograph include: clopidogrel, disulfiram, prasugrel, rolapitant, and ticlopidine.(9)

Cyp2b6 Inhibitors/Naltrexone-Bupropion

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: CYP2B6 inhibitors may inhibit the metabolism of naltrexone-bupropion. Bupropion is primarily metabolized to active metabolites by CYP2B6.(1-2)

CLINICAL EFFECTS: Coadministration of CYP2B6 inhibitors may cause an increase in naltrexone-bupropion levels and effects, including increased risk of seizures.(1)

PREDISPOSING FACTORS: The risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants an anorectics; a total daily dose of bupropion greater than 450 mg or single doses greater than 150 mg; rapid escalation of bupropion dosage; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antidepressants, theophylline, systemic steroids).(1)

PATIENT MANAGEMENT: The US manufacturer of naltrexone-bupropion states that the dose of naltrexone-bupropion should not exceed two tablets (one tablet each morning and evening) during concurrent use with CYP2B6 inhibitors .(1)

DISCUSSION: Repeated administration of ticlopidine (250 mg twice daily for 4 days, a inhibitor of CYP2B6) increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of bupropion by 38% and 85%, respectively. Cmax and AUC of the metabolite hydroxybupropion decreased 78% and 84%.(1) Repeated administration of clopidogrel(75 mg twice daily for 4 days, a inhibitor of CYP2B6) increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of bupropion by 40% and 60%, respectively. Cmax and AUC of the metabolite hydroxybupropion decreased 50% and 52%.(1) Inhibitors of CYP2B6 include: clopidogrel, disulfiram, prasugrel, rolapitant, ticlopidine.(2-3)

Cyp3a4; Cyp2c8; P-Glycoprotein (P-Gp) Inhibitors/Loperamide

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Inhibitors of CYP3A4, CYP2C8, and/or P-gp may increase loperamide systemic absorption and facilitate entry into central nervous system (CNS).(1)

CLINICAL EFFECTS: Concurrent use of inhibitors of CYP3A4, CYP2C8, and/or P-gp may increase levels of loperamide, resulting in respiratory depression.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Use loperamide with caution in patients receiving inhibitors of CYP3A4, CYP2C8, and/or P-gp. Consider lower doses of loperamide in these patients and monitor for adverse effects. The manufacturer of lonafarnib recommends starting loperamide at a dose of 1 mg and slowly increasing the dose as needed.(2)

DISCUSSION: In a randomized, cross-over study in 12 healthy subjects, itraconazole (100 mg twice daily for 5 days - first dose 200 mg), gemfibrozil (600 mg twice daily), and the combination of itraconazole and gemfibrozil (same dosages) increased the area-under-curve (AUC) of single doses of loperamide (4 mg) by 2.9-fold, 1.6-fold, and 4.2-fold, respectively.(3) In a study of healthy subjects, lonafarnib (100 mg twice daily for 5 days) increased the AUC and maximum concentration (Cmax) of single dose loperamide (2 mg) by 299% and 214%, respectively.(3) In a study in 18 healthy males, quinidine increased the AUC of a single dose of loperamide by 2.2-fold and markedly decreased pupil size.(4) In a study in 8 healthy subjects, subjects experienced respiratory depression when a single dose of loperamide (16 mg) was administered with a single dose of quinidine (600 mg) but not when loperamide was administered alone.(6) Loperamide plasma levels increased 2-fold to 3-fold.(5) Coadministration of trofinetide 12,000 mg twice daily with 4 mg of loperamide increased the AUC of loperamide by 1.73-fold and the Cmax by 1.95-fold. Administration of trofinetide 2 hours prior to loperamide increased the AUC of loperamide by 1.22-fold and the Cmax by 1.44-fold.(7)

Moderate Cyp2c8 Inhibitors/Resmetirom

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Moderate inhibitors of CYP2C8 may inhibit the metabolism of resmetirom.(1)

CLINICAL EFFECTS: Concomitant use of a moderate CYP2C8 inhibitor may increase resmetirom plasma concentrations, which may increase the risk of resmetirom toxicity, including hepatotoxicity.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concomitant use of resmetirom with moderate CYP2C8 inhibitors is not recommended. If concurrent use is warranted, reduce the dose of resmetirom based on the patient's weight. -If <100 kg, reduce the dose of resmetirom to 60 mg once daily; -If >=100 kg, reduce the dose of resmetirom to 80 mg once daily.(1)

DISCUSSION: Multiple doses of resmetirom 100 mg daily were given with clopidogrel, a moderate CYP2C8 inhibitor, and the resmetirom area-under-curve (AUC) and maximum concentration (Cmax) increased 1.7-fold and 1.3-fold, respectively.(1) Moderate CYP2C8 inhibitors linked to this monograph include: clopidogrel, deferasirox, leflunomide, mifepristone (chronic therapy), pirtobrutinib, selpercatinib, and teriflunomide.(2)

Moderate Cyp2c8 Inhibitors/Selexipag

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Moderate CYP2C8 inhibitors may inhibit the metabolism of selexipag.(1)

CLINICAL EFFECTS: Concurrent use of a moderate CYP2C8 inhibitor may increase levels and effects of selexipag, including headache, diarrhea, jaw pain, nausea, myalgia, vomiting, pain in extremity, flushing, decreased hemoglobin, and hyperthyroidism.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: When co-administered with a moderate inhibitor of CYP2C8, reduce the dose of selexipag to once daily. If the moderate CYP2C8 inhibitor is discontinued, increase the dose of selexipag to twice daily.(1) If concurrent use is warranted, monitor patients closely for increased effects of selexipag, including headache, diarrhea, jaw pain, nausea, myalgia, vomiting, pain in extremity, flushing, decreased hemoglobin, and hyperthyroidism.

DISCUSSION: Clopidogrel (300 mg for 1 day then 75 mg daily, a moderate CYP2C8 inhibitor) had no effect on exposure to selexipag but increased the area-under-curve (AUC) of selexipag's active metabolite by 2.7-fold.(1) A study in healthy subjects evaluated concurrent therapy with selexipag 200 mcg twice daily with clopidogrel 300 mg single does or 75 mg daily. The AUC and the maximum concentration (Cmax) of ACT-333679, the major contributor to the drug effect, increased 2.25-fold (90% confidence interval (CI) 2.06, 2.46) and 1.69-fold (90% CI 1.55, 1.84), respectively with clopidogrel 300 mg and 2.70-fold (90% CI 2.45, 2.96) and 1.90-fold (90% CI 1.72, 2.11), respectively with clopidogrel 75 mg.(2) Moderate CYP2C8 inhibitors linked include: clopidogrel, deferasirox, leflunomide, letermovir, selpercatinib, and teriflunomide.(3-4)

P-Gp Or Bcrp Inhibitors/Ubrogepant (<= 50 Mg)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Inhibitors of P-glycoprotein (P-gp) or BCRP may increase the absorption of ubrogepant.(1)

CLINICAL EFFECTS: The concurrent administration of ubrogepant with an inhibitor of P-glycoprotein or BCRP may result in elevated levels of ubrogepant.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer recommends a dosage adjustment of ubrogepant when coadministered with P-gp or BCRP inhibitors. The dose of ubrogepant should not exceed 50 mg for initial dose. If a second dose of ubrogepant is needed, the dose should not exceed 50 mg.(1) For patients on concurrent therapy with vimseltinib and ubrogepant: The manufacturer of vimseltinib states concurrent use with P-gp substrates should be avoided. If concurrent use cannot be avoided, take vimseltinib at least 4 hours prior to ubrogepant.(3) For patients on daraxonrasib, the manufacturer of daraxonrasib states that it should be taken at least 4 hours apart from P-gp substrates.(4)

DISCUSSION: Ubrogepant is a substrate of P-gp and BCRP transporters. Use of P-gp or BCRP inhibitors may increase the exposure of ubrogepant. Clinical drug interaction studies with inhibitors of these transporters were not conducted. The US manufacturer of ubrogepant recommends dose adjustment if ubrogepant is coadministered with P-gp or BCRP inhibitors.(1) BCRP inhibitors linked to this monograph include: belumosudil, clopidogrel, curcumin, eltrombopag, febuxostat, fostemsavir, leniolisib, momelotinib, oteseconazole, regorafenib, resmetirom, ritonavir, rolapitant, roxadustat, tafamidis, oral tedizolid, turmeric, vadadustat, and zongertinib.(2,3,5,6) P-glycoprotein inhibitors linked to this monograph include: asunaprevir, belumosudil, capmatinib, carvedilol, danicopan, daraxonrasib, daridorexant, imlunestrant, neratinib, osimertinib, propafenone, quinidine, selpercatinib, sofosbuvir/velpatasvir/voxilaprevir, tepotinib, valbenazine, vimseltinib, and voclosporin.(2,3,5,6)

Platelet Aggregation Inhibitors/Eptifibatide

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Eptifibatide reversibly inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive ligands to GP IIb/IIIa.(1) Platelet aggregation inhibitors, such as clopidogrel, inhibit aggregation by inhibiting the binding of ADP to its platelet receptor.(2)

CLINICAL EFFECTS: Concurrent use of eptifibatide and platelet aggregation inhibitors may cause additive effects and increase the risk of bleeding.(1)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: The manufacturer of eptifibatide recommends employing caution when using eptifibatide with other drugs that affect hemostasis, such as eptifibatide.(1) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: The ESPRIT study observed the use of eptifibatide and clopidogrel or ticlopidine and found that when patients were carefully monitored there was no increase in risk of bleeding;(1) however, caution is still warranted.

Platelet Aggregation Inhibitors/Lepirudin

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Lepirudin is a highly specific direct inhibitor of thrombin.(1) Platelet aggregation inhibitors enhance the effects of lepirudin.

CLINICAL EFFECTS: Concurrent use of lepirudin and platelet aggregation inhibitors may increase the risk of bleeding complications and may enhance the effect of lepirudin on aPTT prolongation.(1)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: The manufacturer recommends close monitoring of patients taking this combination.(1) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: A study using lepirudin in combination with platelet aggregation inhibitors concluded that caution should be exercised when using this combination because of the increased risk of bleeding complications.(2)

Platelet Inhibitors/Selected Anticoagulants; Thrombolytics

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Platelet aggregation inhibitors work by irreversibly modifying the platelet ADP receptor and inhibiting the activation of GP IIb/IIIa complex.(1) Concurrent use with anticoagulants may result in additive effects on the clotting cascade.

CLINICAL EFFECTS: The concurrent use of platelet aggregation inhibitors and anticoagulants may result in an increased risk of bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Use caution when administering platelet aggregation inhibitors concurrently with anticoagulants.(1) Careful monitoring of appropriate laboratory values for the patient's anticoagulant (e.g. PTT for heparin, anti Xa levels for low-molecular weight heparins, INR for warfarin) as well as signs and symptoms of bleeding is warranted. If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: Although a study in patients on long-term warfarin therapy found that the stable anticoagulation status was unaffected by concurrent clopidogrel use,(2) careful monitoring would be prudent. A self-controlled case study of 1,622 oral anticoagulant-precipitant drug pairs were reviewed and found 14% of drug pairs were associated with a statistically significant elevated risk of thromboembolism. Concurrent use of warfarin and dipyridamole resulted in a ratio of rate ratios (95% CI) of 2.07 (1.65-2.6); and warfarin and clopidogrel ratio of rate ratios 1.69 (1.56-1.84). A large systematic review was performed on 72 warfarin drug-drug interactions studies that reported on bleeding, thromboembolic events, or death. Most studies were retrospective cohorts. A meta-analysis of 38 of those studies found a higher rate of clinically significant bleeding in patients on warfarin and antiplatelets (OR=1.74; 95% CI 1.56-1.94). Increased bleeding risk was also seen in subgroup analyses with aspirin (OR=1.50; 95% CI 1.29-1.74), clopidogrel (OR=3.55; 95% CI 2.78-4.54), and aspirin plus clopidogrel or ticlopidine (OR=2.07, 95% CI 1.33-3.21).(4)

Selected Anticoagulants; Antiplatelets/Ibrutinib

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Ibrutinib administration lowers platelet count in the majority of patients.(1,2) In addition, ibrutinib has been shown to inhibit collagen-mediated platelet aggregation.(3-4) Bleeding has been reported with the use of ibrutinib,(1-4) anticoagulants, or antiplatelets alone.

CLINICAL EFFECTS: Concurrent use of ibrutinib with either anticoagulants or antiplatelets may increase the risk of hemorrhage.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: The Canadian product monograph for ibrutinib recommends concurrent use with anticoagulants or antiplatelets should be approached with caution. If therapeutic anticoagulation is required, consider temporarily withholding ibrutinib therapy until stable anticoagulation in achieved.(2) The US prescribing information for ibrutinib states patients receiving concurrent therapy with ibrutinib and anticoagulants and/or antiplatelets should be closely monitored for changes in platelet count or in International Normalized Ratio (INR). Carefully weigh the risks vs. benefits of concurrent therapy in patients with significant thrombocytopenia. If a bleeding event occurs, follow manufacturer instructions for ibrutinib dose adjustment.(1) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory tests (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: Bleeding has been reported with ibrutinib alone.(1-3) Across 27 clinical trials, grade 3 or higher bleeding events, e.g. subdural hematoma, gastrointestinal bleeding or hematuria, have occurred in up to 4% of patients, with 0.4% fatality. Grade 3 or 4 thrombocytopenia occurred in 5-19% of patients. Bleeding events of any grade occurred in 39% of patients treated with ibrutinib.(1) Concurrent use of anticoagulants or antiplatelets has been reported to increase the risk for major bleeding. In clinical trials, major bleeding occurred in 3.1% of patients taking ibrutinib without concurrent anticoagulants or antiplatelets, 4.4% of patients on concurrent antiplatelets with or without anticoagulants, and 6.1% of patients on concurrent anticoagulants with or without antiplatelets.(1) In an open-label, phase 2 trial of patients with relapsed/refractory mantle cell lymphoma on ibrutinib, 61 patients (55%) on concurrent anticoagulants or antiplatelets had a higher rate of bleeding (69% any grade, 8% grade 3-4) than patients not on anticoagulants or antiplatelets (28% any grade, 4% grade 3-4).(5) A retrospective trial found a hazard ratio of 20 (95% CI, 2.1-200) for patients on ibrutinib with concurrent anticoagulants and antiplatelets. There was a trend towards an increased bleeding risk in patients on either anticoagulants or antiplatelets, but this was not statistically significant on multivariate analysis.(6) A case report of 2 patients with chronic lymphocytic leukemia (CLL) on ibrutinib and dabigatran demonstrated no stroke nor bleeding events during the mean 11.5 month follow-up.(7) A case report of 4 patients with lymphoproliferative disease on concurrent dabigatran and ibrutinib demonstrated no stroke nor major bleeding events. 1 patient experienced grade 2 conjunctival hemorrhage whilst on both ibrutinib and dabigatran. The anticoagulant was withheld and successfully re-initiated at a lower dose with no further bleeding events.(8)

Selected Bcrp Inhibitors/Atorvastatin

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Atorvastatin is a substrate of the BCRP transporter.(1) Inhibitors of this transporter may increase intestinal absorption and hepatic uptake of BCRP substrates atorvastatin.(1)

CLINICAL EFFECTS: Administration of atorvastatin with BCRP inhibitors may result in elevated levels of atorvastatin, which could result in rhabdomyolysis.(1)

PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis.

PATIENT MANAGEMENT: Concurrent use of atorvastatin with BCRP inhibitors may result in increased risk of side effects associated with atorvastatin. Close monitoring would be prudent for statin related side effects including rhabdomyolysis. If concurrent therapy is deemed medically necessary, monitor patients for signs and symptoms of myopathy/rhabdomyolysis, including muscle pain/tenderness/weakness, fever, unusual tiredness, changes in the amount of urine, and/or discolored urine.

DISCUSSION: Atorvastatin is a BCRP substrate.(1) BCRP inhibitors linked to this monograph include: capmatinib, clopidogrel, curcumin, danicopan, encorafenib, fostamatinib, lazertinib, leflunomide, momelotinib, oteseconazole, pacritinib, pirtobrutinib, regorafenib, ritonavir, rolapitant, roxadustat, selpercatinib, sofosbuvir/velpatasvir/voxilaprevir, tafamidis, teriflunomide, tolvaptan, turmeric, vadadustat, velpatasvir, and zongertinib.(2,3)

Selected Bcrp Inhibitors/Rosuvastatin

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Rosuvastatin is a substrate of the BCRP transporter.(1,2) Inhibitors of this transporter may increase intestinal absorption and hepatic uptake of BCRP substrates rosuvastatin.(1-8)

CLINICAL EFFECTS: Simultaneous use of BCRP inhibitors may result in increased levels and side effects from rosuvastatin, including rhabdomyolysis.(2,4)

PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. Patients on rosuvastatin with ABCG2 polymorphisms leading to decreased or poor BCRP transporter function may have increased rosuvastatin concentrations and risk of myopathy.

PATIENT MANAGEMENT: Concurrent use of rosuvastatin with BCRP inhibitors may result in increased risk of side effects associated with rosuvastatin. If concurrent therapy is warranted, close monitoring would be prudent for statin related side effects including rhabdomyolysis. The Canadian manufacturer of clopidogrel states that the dose of rosuvastatin should not exceed 20 mg daily when used concomitantly with clopidogrel.(5) There is no recommendation for rosuvastatin dose adjustments from the Australian and US manufacturers of clopidogrel.(6,7) The Australian manufacturer of rosuvastatin states that the starting dose of rosuvastatin should not exceed 5 mg daily when used with agents that increase rosuvastatin exposure by 2-fold or more (e.g., clopidogrel, lopinavir-ritonavir, roxadustat). The maximum daily dose should be adjusted so that the expected rosuvastatin exposure does not exceed that obtained with the usual maximum daily dose.(8) Educate the patient of signs and symptoms of rhabdomyolysis.

DISCUSSION: Rosuvastatin is a BCRP substrate.(1,2) In a clinical study of 20 patients with stable coronary heart disease, single-dose clopidogrel 300 mg (a BCRP inhibitor) increased the area-under-curve (AUC) and maximum concentration (Cmax) of rosuvastatin by 2-fold and 1.3-fold, respectively. Multiple doses of clopidogrel 75 mg daily for 7 days increased rosuvastatin AUC by 1.4-fold but did not affect the Cmax.(4) In a pharmacokinetic study, concomitant use of lazertinib increased rosuvastatin Cmax by 2.2-fold and AUC by 2-fold.(3) BCRP inhibitors linked to this monograph include: clopidogrel, curcumin, encorafenib, lazertinib, ritonavir, rolapitant, roxadustat, tolvaptan, turmeric, and zongertinib.(2-9)

Selected Strong And Moderate Cyp2c8 Inhibitors/Paclitaxel

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Inhibitors of CYP2C8 may inhibit paclitaxel metabolism by this pathway. Clopidogrel and gemfibrozil are strong inhibitors of CYP2C8. Deferasirox is a moderate inhibitor of CYP2C8.(1-3)

CLINICAL EFFECTS: Concurrent use of CYP2C8 inhibitors and paclitaxel may result in elevated levels and clinical effects of paclitaxel.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturers of paclitaxel recommend combination use CYP2C8 inhibitors with caution. If concomitant use is necessary, paclitaxel dose reduction may be required.(1,2)

DISCUSSION: The US manufacturer of paclitaxel recommends use with CYP2C8 inhibitors with caution.(1,2)

Strong And Moderate Cyp2c8 Inhibitors/Etrasimod

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong and moderate inhibitors of CYP2C8 may impair the CYP2C8-mediated metabolism of etrasimod.(1) Etrasimod is metabolized by CYP2C8, CYP2C9, and CYP3A4.(1)

CLINICAL EFFECTS: In patients who are poor metabolizers of CYP2C9, concurrent use of a strong or moderate inhibitor of CYP2C8 may result in elevated levels of and clinical effects from etrasimod including immunosuppression, decreased lung function, bradycardia, and AV conduction delays.

PREDISPOSING FACTORS: CYP2C9 poor metabolizers (e.g., *2/*3, *3/*3) may have decreased clearance of etrasimod when etrasimod is used concomitantly with strong or moderate inhibitors of CYP2C8.(1)

PATIENT MANAGEMENT: Concomitant use of etrasimod with strong or moderate CYP2C8 inhibitors in patients who are CYP2C9 poor metabolizers is not recommended.(1)

DISCUSSION: CYP2C9 activity is decreased in individuals with genetic variants such as CYP2C9*2 and CYP2C9*3 alleles. The impact of CYP2C9 genetic variants on the pharmacokinetics of etrasimod has not been directly evaluated. Increased exposure of etrasimod in patients who are CYP2C9 poor metabolizers is expected with concomitant use of strong or moderate inhibitors of CYP2C8.(1) Concomitant use of etrasimod with steady-state fluconazole (a moderate CYP2C9 and CYP3A4 inhibitor) increased etrasimod area-under-curve (AUC) by 84%.(1) Strong inhibitors of CYP2C8 include: clopidogrel and gemfibrozil.(2,3) Moderate inhibitors of CYP2C8 include: deferasirox.(2,3)

*Active pathological bleeding (e.g., peptic ulcer, intracranial hemorrhage).

*Known hypersensitivity to clopidogrel or any ingredient in the formulation.

• Cerebral amyloid angiopathy
• CYp2c19 poor metabolizer
• Deep peripheral nerve block
• Deep plexus block
• Dissection of aorta
• Gastrointestinal hemorrhage
• Hemorrhage
• Intracranial bleeding
• Invasive procedure on spine
• Neuraxial anesthesia
• Placement of indwelling epidural catheter

• Arterial dissection
• CYp2c19 intermediate metabolizer
• Gastrointestinal ulcer
• Increased risk of bleeding due to coagulation disorder
• Invasive surgical procedure
• Thrombotic thrombocytopenic purpura

• Chronic kidney disease stage 3A (moderate) GFR 45-59 ml/min
• Chronic kidney disease stage 3B (moderate) GFR 30-44 ml/min
• Chronic kidney disease stage 5 (failure) GFr<15 ml/min
• Increased risk of bleeding

Bleeding, including life-threatening and fatal bleeding, is the most commonly reported adverse effect of clopidogrel.

More Frequent

• Hemorrhage

Less Frequent

• Gastrointestinal hemorrhage

Rare or Very Rare

• Abnormal hepatic function tests
• Acquired coagulation factor inhibitor disorder
• Acute generalized exanthematous pustulosis
• Acute hepatic failure
• Agranulocytosis
• Anaphylaxis
• Angioedema
• Aplastic anemia
• Bleeding from wound
• Bronchospastic pulmonary disease
• Colitis
• Conjunctival hemorrhage
• DRESS syndrome
• Duodenal ulcer
• Eosinophilia
• Eosinophilic pneumonia
• Erythema multiforme
• Exfoliative dermatitis
• Gastric ulcer
• Hemothorax
• Hepatitis
• Hypersensitivity drug reaction
• Hypotension
• Insulin autoimmune syndrome
• Interstitial pneumonitis
• Intracranial bleeding
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Leukopenia
• Maculopapular rash
• Ocular hemorrhage
• Pancreatitis
• Pancytopenia
• Respiratory tract hemorrhage
• Retinal hemorrhage
• Retroperitoneal hemorrhage
• Serum sickness
• Stevens-johnson syndrome
• Thrombocytopenic disorder
• Thrombotic thrombocytopenic purpura
• Toxic epidermal necrolysis
• Vasculitis

More Frequent

• Arthralgia
• Headache disorder

Less Frequent

• Eczema
• Epistaxis
• Pruritus of skin
• Skin rash

Rare or Very Rare

• Acute cognitive impairment
• Arthritis
• Bruising
• Bullous dermatitis
• Diarrhea
• Dizziness
• Dysgeusia
• Edema
• Erythema
• Fever
• Gynecomastia
• Hallucinations
• Hematoma
• Hematuria
• Lichen planus
• Loss of taste
• Menorrhagia
• Myalgia
• Stomatitis
• Urticaria

No enhanced messaging available.

Safety and efficacy of clopidogrel have not been established in pediatric patients. However, the drug has been used in neonates and infants+ with certain cardiac conditions that predispose them to arterial thrombosis.

Available data from case reports and postmarketing surveillance have not suggested any risks of major birth defects, miscarriage, or adverse fetal outcomes with clopidogrel use in pregnant women. In animal studies, no evidence of fetotoxicity was observed when clopidogrel was administered to pregnant rats and rabbits during organogenesis at doses up to 78 times to recommended daily human dose.

MI and stroke present risks to both the pregnant woman and fetus. Use of clopidogrel during labor or delivery increases the risk of maternal bleeding and hemorrhage. Neuraxial blockade during clopidogrel use should be avoided because of the risk of spinal hematoma. When possible, clopidogrel should be discontinued 5-7 days prior to labor, delivery, or neuraxial blockade.

Clopidogrel is distributed into milk in rats; it is not known whether the drug is distributed into milk in humans. The benefits of breast-feeding should be considered along with the importance of the drug to the mother and any potential adverse effects on the infant from the drug or underlying maternal condition.

No difference in platelet aggregation has been observed in patients 75 years of age or older compared with younger healthy individuals. In the CURE trial, geriatric patients (65 years of age or older) were at greater risk for thrombotic events and major bleeding compared with younger patients. However, in the COMMIT study evaluating patients with ST-segment-elevation MI (STEMI), the efficacy and safety of clopidogrel in preventing ischemic events was independent of age. Dosage adjustment based solely on age does not appear to be necessary in geriatric patients.