XARELTO (rivaroxaban)

There are 6 contraindications. These drug combinations generally should not be dispensed or administered to the same patient. A manufacturer label warning that indicates the contraindication warrants inclusion of a drug combination in this category, regardless of clinical evidence or lack of clinical evidence to support the contraindication.

Drug Interaction	Drug Names
Mifepristone/Anticoagulants; Antiplatelets 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)	MIFEPREX, MIFEPRISTONE
Rivaroxaban/P-gp and Strong CYP3A4 Inhibitors 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: Adagrasib, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, paritaprevir, posaconazole, telaprevir, telithromycin, and tucatinib may inhibit the metabolism of rivaroxaban by CYP3A4 and by P-glycoprotein.(1-3) CLINICAL EFFECTS: Concurrent use of an agent that is both an inhibitor of P-gp and a strong inhibitor of CYP3A4 may result in elevated levels of and clinical effects of rivaroxaban,(1-3) including 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: The Canadian manufacturer of rivaroxaban states that the concurrent use of agents that are both an inhibitor of P-gp and a strong inhibitor of CYP3A4 with rivaroxaban is contraindicated.(1) The US manufacturer states that concurrent use of these agents should be avoided.(2) The UK manufacturer states that concurrent use is not recommended.(3) The US manufacturer of itraconazole states concurrent use with rivaroxaban is not recommended during and two weeks after itraconazole treatment.(5) Agents that are not strong inhibitors of both CYP3A4 and P-glycoprotein, including fluconazole, are expected to increase rivaroxaban levels to a lesser extent and can be used with rivaroxaban with caution(3) in patients with normal renal function.(6) 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. DISCUSSION: Concurrent use of rivaroxaban with ketoconazole (400 mg daily) increased rivaroxaban AUC and Cmax by 2.6-fold and 1.7-fold, respectively. There were also significant increases in pharmacodynamic effects.(1-3) Clarithromycin increased the Cmax and AUC of a single dose of rivaroxaban by 40% and 50%, respectively and is not expected to affect bleeding risk.(2) Agents that are not strong inhibitors of both CYP3A4 and P-glycoprotein, including fluconazole, are expected to increase rivaroxaban levels to a lesser extent and can be used with rivaroxaban with caution(2) in patients with normal renal function.(3)	ITRACONAZOLE, ITRACONAZOLE MICRONIZED, KETOCONAZOLE, KRAZATI, NOXAFIL, POSACONAZOLE, RECORLEV, SPORANOX, TOLSURA, TUKYSA, ZOKINVY
Rivaroxaban/HIV 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: Rivaroxaban is metabolized by CYP3A4 and is a substrate of the P-glycoprotein (P-gp) efflux transport protein.(1-3) HIV protease inhibitors are CYP3A4 and P-gp inhibitors and may increase the absorption and decrease the elimination of rivaroxaban.(1-4) CLINICAL EFFECTS: Concurrent use of protease inhibitors may result in elevated levels and clinical effects of rivaroxaban, including an increased 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: Recommendations for concurrent use of rivaroxaban and HIV protease inhibitors vary in different regions. The Australian(1) and Canadian(2) manufacturers of rivaroxaban state that the concurrent use of strong inhibitors of both P-gp and CYP3A4 with rivaroxaban is contraindicated. The UK manufacturer of rivaroxaban states that concurrent use of these agents is not recommended.(3) The US manufacturer of rivaroxaban states that concurrent use should be avoided.(4) The US manufacturer of atazanavir states that coadministration of atazanavir with ritonavir is not recommended. Coadministration of atazanavir alone should be monitored closely.(5) If concurrent therapy is warranted, 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. 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: Concurrent use of rivaroxaban with ritonavir (600 mg twice daily) increased rivaroxaban area-under-curve (AUC) and maximum concentration (Cmax) by 2.5-fold and 1.6-fold, respectively. There were also significant increases in pharmacodynamic effects.(1,2) HIV protease inhibitors linked to this monograph are: atazanavir, cobicistat, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, saquinavir, and tipranavir.	APTIVUS, ATAZANAVIR SULFATE, DARUNAVIR, EVOTAZ, FOSAMPRENAVIR CALCIUM, GENVOYA, KALETRA, LOPINAVIR-RITONAVIR, PREZCOBIX, PREZISTA, REYATAZ, STRIBILD, SYMTUZA, TYBOST, VIRACEPT
Apixaban/Anticoagulants; Thrombolytics 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: Additive effects on hemostasis. CLINICAL EFFECTS: Concurrent use of apixaban with anticoagulants or thrombolytics may increase the 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: The long-term use of concurrent therapy with direct oral anticoagulants (DOACs) and other anticoagulants is generally considered contraindicated. However, overlap may be necessary when switching therapy from one agent to another in order to prevent thrombotic events. Manufacturer recommendations concerning overlap (if any) and timing of discontinuation versus initiation vary depending upon which agent is being discontinued and initiated. Refer to current prescribing information for both agents for additional details. Specific recommendations for converting between anticoagulants: - When converting between apixaban and anticoagulants other than warfarin, discontinue the current anticoagulant and begin the new one when next dose is due. - When converting from warfarin to apixaban, discontinue warfarin and begin apixaban when the international normalized ratio (INR) is below 2.0. - Apixaban affects INR. Therefore concurrent administration with warfarin when converting from apixaban to warfarin is not useful in determining target warfarin dose. If continuous anticoagulation is warranted, discontinue apixaban and begin both warfarin and a parenteral anticoagulant when next dose of apixaban is due. Once INR is within range, discontinue the parenteral anticoagulant. The use of concurrent therapy with Direct Oral Anticoagulants (DOACs) and thrombolytics is generally considered contraindicated. The manufacturer of alteplase states that the use of alteplase for an indication of acute ischemic stroke is contraindicated in patients receiving anticoagulants. Concurrent use of alteplase and anticoagulants is dependent on the therapeutic indication. In Acute Ischemic Stroke: - Clinical practice guidelines for acute ischemic stroke state the use of thrombolytic therapy for an indication of acute ischemic stroke is contraindicated in patients who have received thrombin inhibitors or factor Xa inhibitors in the previous 48 hours (in normal renal function) and have abnormal laboratory tests such as activated partial thromboplastin time (aPTT), INR, platelet count, ecarin clotting time (ECT), thrombin time, or direct factor Xa assays at presentation. In Acute Myocardial Infarction: - Patients who are receiving thrombolytics for an indication of acute myocardial infarction should be carefully monitored for signs of bleeding, especially at arterial puncture sites, if apixaban is used concurrently. - The use of thrombolytics in patients with acute myocardial infarction should follow standard management of myocardial infarction, including minimizing arterial and venous puncture; avoid noncompressible arterial puncture; and minimize internal jugular and subclavian venous punctures to decrease bleeding from the noncompressible sites. For all indications: - In the event of serious bleeding, anticoagulants should be discontinued immediately. - 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: Limited overlap of DOACs with other anticoagulants may be required when initiating or discontinuing DOACs in order to prevent thrombotic events. However, long-term concomitant treatment is not recommended because of increased risk of bleeding. Patients who are receiving thrombolytics should be carefully monitored for signs of bleeding if anticoagulants are being used concurrently or have recently been used.	ELIQUIS
Rivaroxaban/Anticoagulants; Thrombolytics 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: Additive effects on hemostasis. CLINICAL EFFECTS: Concurrent use of rivaroxaban with anticoagulants or thrombolytics may increase the 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: The long-term use of concurrent therapy with direct oral anticoagulants (DOACs) and other anticoagulants is generally considered contraindicated. However, overlap may be necessary when switching therapy from one agent to another in order to prevent thrombotic events. Manufacturer recommendations concerning overlap (if any) and timing of discontinuation versus initiation vary depending upon which agent is being discontinued and initiated. Refer to current prescribing information for both agents for additional details. Specific recommendations for converting between anticoagulants: - When converting from rivaroxaban to anticoagulants other than warfarin and switching to an anticoagulant with rapid onset, discontinue rivaroxaban and begin new anticoagulant when next dose of rivaroxaban is due. - When converting from anticoagulants other than warfarin to rivaroxaban, discontinue current anticoagulant and begin rivaroxaban between 0-2 hours before next evening dose of the drug is due. For patients receiving continuous infusion of unfractionated heparin, simultaneously stop the infusion and administer rivaroxaban. - When converting from warfarin to rivaroxaban, discontinue warfarin and begin rivaroxaban once international normalized ratio (INR) is below 3.0 in adults and below 2.5 in pediatric patients. - When converting from rivaroxaban to warfarin in adults, rivaroxaban affects INR. Therefore concurrent administration with warfarin is not useful in determining target warfarin dose. If continuous anticoagulation is warranted, discontinue rivaroxaban and begin both warfarin and a parenteral anticoagulant when the next dose of rivaroxaban is due. Once INR is within range, discontinue the parenteral anticoagulant. - When converting from rivaroxaban to warfarin in pediatrics, continue rivaroxaban for at least 2 days after the first dose of warfarin. After two days, INR should be measured just prior to the next scheduled dose of rivaroxaban. Once a stable INR = or > 2.0 is achieved, rivaroxaban should be discontinued and warfarin continued. The use of concurrent therapy with Direct Oral Anticoagulants (DOACs) and thrombolytics is generally considered contraindicated. The manufacturer of alteplase states that the use of alteplase for an indication of acute ischemic stroke is contraindicated in patients receiving anticoagulants. Concurrent use of alteplase and anticoagulants is dependent on the therapeutic indication. In Acute Ischemic Stroke: - Clinical practice guidelines for acute ischemic stroke state the use of thrombolytic therapy for an indication of acute ischemic stroke is contraindicated in patients who have received thrombin inhibitors or factor Xa inhibitors in the previous 48 hours (in normal renal function) and have abnormal laboratory tests such as activated partial thromboplastin time (aPTT), INR, platelet count, ecarin clotting time (ECT), thrombin time, or direct factor Xa assays at presentation. In Acute Myocardial Infarction: - Patients who are receiving thrombolytics for an indication of acute myocardial infarction should be carefully monitored for signs of bleeding, especially at arterial puncture sites, if rivaroxaban is used concurrently. - The use of thrombolytics in patients with acute myocardial infarction should follow standard management of myocardial infarction, including minimizing arterial and venous puncture; avoid noncompressible arterial puncture; and minimize internal jugular and subclavian venous punctures to decrease bleeding from the noncompressible sites. For all indications: - In the event of serious bleeding, anticoagulants should be discontinued immediately. - 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: Patients who are receiving thrombolytics should be carefully monitored for signs of bleeding if anticoagulants are being used concurrently or have recently been used.	ACD-A, ACTIVASE, ANISINDIONE, ARGATROBAN, ARGATROBAN-0.9% NACL, ARIXTRA, BIVALIRUDIN, CATHFLO ACTIVASE, CITRATE PHOSPHATE DEXTROSE, DABIGATRAN ETEXILATE, DEFITELIO, DICUMAROL, ENOXAPARIN SODIUM, ENOXILUV, FONDAPARINUX SODIUM, FRAGMIN, HEPARIN SODIUM, HEPARIN SODIUM IN 0.45% NACL, HEPARIN SODIUM-0.45% NACL, HEPARIN SODIUM-0.9% NACL, HEPARIN SODIUM-D5W, JANTOVEN, LMD 10% WITH 0.9% SOD CHLORIDE, LMD 10% WITH 5% DEXTROSE, LOVENOX, PHENINDIONE, PRADAXA, SAVAYSA, TNKASE, WARFARIN SODIUM
Rivaroxaban/Nirmatrelvir-Ritonavir 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: Nirmatrelvir-ritonavir may inhibit the metabolism of rivaroxaban by CYP3A4 and by P-glycoprotein.(1-5) CLINICAL EFFECTS: Concurrent use of an agent that is both an inhibitor of P-gp and a strong inhibitor of CYP3A4 may result in elevated levels of and clinical effects of rivaroxaban,(1-3) including 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: The US manufacturer of nirmatrelvir-ritonavir states concurrent use with rivaroxaban should be avoided.(4) The Canadian manufacturer of nirmatrelvir-ritonavir states use with rivaroxaban should not be used concomitantly.(5) The Journal of American College of Cardiology states use of nirmatrelvir-ritonavir with rivaroxaban should be avoided. Use of rivaroxaban cannot be safely adjusted or interrupted. If nirmatrelvir-ritonavir is deemed necessary, withhold rivaroxaban for 24-36 hours before starting nirmatrelvir-ritonavir. Use of an alternative anticoagulant is recommended for a total of 8 days. Rivaroxaban may be restarted on day 9.(6) 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. DISCUSSION: Concurrent use of rivaroxaban with ketoconazole (400 mg daily) increased rivaroxaban AUC and Cmax by 2.6-fold and 1.7-fold, respectively. There were also significant increases in pharmacodynamic effects.(1-3) Clarithromycin increased the Cmax and AUC of a single dose of rivaroxaban by 40% and 50%, respectively and is not expected to affect bleeding risk.(2) Agents that are not strong inhibitors of both CYP3A4 and P-glycoprotein, including fluconazole, are expected to increase rivaroxaban levels to a lesser extent and can be used with rivaroxaban with caution(2) in patients with normal renal function.(3)	PAXLOVID

Drug contraindication overview.

*Active pathologic bleeding. *Severe hypersensitivity reaction to rivaroxaban.

Adverse reaction overview.

The most common adverse effect (>5%) of rivaroxaban in adults is bleeding. The most common adverse effects (>10%) of rivaroxaban in pediatric patients are bleeding, cough, vomiting, and gastroenteritis.

Safety and efficacy of rivaroxaban for VTE treatment and the reduction in risk of recurrent VTE in children from birth to <18 years of age are supported by controlled clinical trials in adults with additional pharmacokinetic, safety, and efficacy data from a multicenter, prospective, open-label, active-controlled randomized study in 500 pediatric patients. Children <6 months who were <37 weeks of gestation at birth, had <10 days of oral feeding, or had a body weight of <2.6 kg were not studied and rivaroxaban is not recommended in these patients because dosing cannot be reliably determined.

Safety and efficacy of rivaroxaban for thromboprophylaxis following the Fontan procedure in children >=2 years old with congenital heart disease are supported by evidence from adequate controlled studies of rivaroxaban in adults with additional data from a multicenter, prospective, open-label, active controlled study in 112 pediatric patients; the study evaluated the single- and multiple dose pharmacokinetic properties and safety and efficacy of rivaroxaban when used for thromboprophylaxis for 12 months in children with single ventricle physiology who had the Fontan procedure. The 10 mg, 15 mg, and 20 mg rivaroxaban tablets may be used in children due to clinical studies that evaluated safety, efficacy, pharmacokinetic, and pharmacodynamic data in this patient population. Safety, efficacy, pharmacokinetic, and pharmacodynamic data do not exist for rivaroxaban 2.5

mg tablets and they are not recommended for use in children. Although the manufacturer states that not all adverse reactions identified in the adult population have been observed in clinical trials of children and adolescent patients, the same warnings and precautions for adults should be considered for children and adolescents.

Contraindicated

None

Severe Precaution

None

Management or Monitoring Precaution

None