Direct oral anticoagulants (factor Xa inhibitors)
ATC code: B01AF01 (Rivaroxaban)
Brand names
Xarelto
Selective reversible direct factor Xa inhibitor. Blocks the final step of the coagulation cascade upstream of thrombin formation. Unlike apixaban, the maintenance phase uses once-daily dosing, improving adherence but making missed doses more impactful. Half-life is 5–13 hours depending on age and renal function.
First line
First-line DOAC for stroke prevention in non-valvular AF per 2024. The ROCKET-AF trial showed non-inferiority versus warfarin for stroke and systemic embolism. Bleeding profile: fewer intracranial, slightly more GI bleeds than warfarin. Standard dose 20 mg once daily with food. At eGFR 15–49 mL/min/1.73 m², 15 mg once daily.
First line
First-line treatment of DVT and PE in outpatients without contraindications. Loading 15 mg twice daily for 21 days, then 20 mg once daily for up to 6 months. Long-term secondary prevention: 10 mg once daily. In active cancer, DOAC evidence (apixaban, rivaroxaban, edoxaban) accumulated through SELECT-D, Hokusai-VTE Cancer, and ADAM-VTE: non-inferior to LMWH, but GI and genitourinary tumors carry an increased bleeding risk.
Individual decision
The COMPASS trial (over 27,000 patients with chronic CAD or peripheral artery disease) showed that rivaroxaban 2.5 mg twice daily plus aspirin 100 mg reduced MACE (vascular death, MI, stroke) by 24 % compared with aspirin alone, at the cost of a 70 % increase in major bleeding. Use is justified in patients at high ischemic and low hemorrhagic risk. The decision is individualized using , age, and comorbidities.
Low «vascular» dose 2.5 mg twice daily combined with aspirin 100 mg.
The drug is promoted for these uses outside international guidelines. Each entry below is analyzed against AEMPS, FDA, EMA, Cochrane and major RCTs.
Not recommended
After the COVID-19 pandemic some patients took up the habit of taking rivaroxaban, apixaban, and other DOACs at the first symptoms of an upper respiratory infection «for thrombosis prevention». International guidelines do not support this. Outpatient viral URI is self-limiting, clinically meaningful thromboembolism risk is not elevated, and major bleeding risk on rivaroxaban remains the same. , , ASH, and ISTH do not mention anticoagulants for outpatient URI. Evidence-based management is rest, hydration, symptomatic measures; antivirals (oseltamivir, nirmatrelvir/ritonavir) are reserved for confirmed influenza or COVID-19 in high-risk patients.
Not recommended
For mild and moderate outpatient COVID-19, rivaroxaban and other DOACs are not prescribed for thrombosis prophylaxis. The ACTIV-4B RCT (Connors et al., JAMA 2021) compared aspirin, prophylactic-dose apixaban, therapeutic-dose apixaban, and placebo in symptomatic outpatients – the trial was stopped early for futility at very low event rates. Anticoagulants did not reduce hospitalisations, thromboses, or mortality, while bleeding events rose. The updated ASH 2024 living guideline (Blood Advances) issued a conditional recommendation against routine post-discharge thromboprophylaxis in COVID-19; the Therapeutics Living Guideline and NG191 do not support routine DOAC use in outpatients. Non-severe hospitalised patients benefit from low-molecular-weight heparin under supervision, not oral DOACs. One exception is MICHELLE (Ramacciotti et al., Lancet 2022): post-discharge rivaroxaban 10 mg for 35 days reduced VTE in high-thrombotic-risk patients (IMPROVE-DD ≥ 4 or ≥ 2 with D-dimer ≥ 500 ng/mL). ISTH 2023 discusses this tactic only for that selected post-discharge cohort. This narrow scenario does not justify self-administered Xarelto «just in case» for outpatient COVID-19.
17 pairs found. Sorted from critical to minor.
Mechanism
Apixaban and rivaroxaban are both direct factor Xa inhibitors. Their effects are additive without therapeutic gain. Risk of major bleeding rises sharply.
Symptoms
Gum bleeding, epistaxis, bruising without trauma, blood in urine or stool, menorrhagia. Severe cases include gastrointestinal or intracranial haemorrhage, gross haematuria with renal colic, spontaneous retroperitoneal haematomas. Symptoms may appear within days of co-prescription.
Management
The combination is not prescribed. When switching between DOACs, stop the first agent and start the second at the time of the next scheduled dose, with no overlap. If a patient inadvertently takes both, observe in hospital for at least 24 hours with haemoglobin and creatinine monitoring.
Mechanism
Rivaroxaban blocks factor Xa; dabigatran blocks thrombin. Different targets but additive anticoagulation with no therapeutic benefit.
Symptoms
Gum bleeding, epistaxis, bruising without trauma, blood in urine or stool, menorrhagia. Severe cases include gastrointestinal or intracranial haemorrhage, gross haematuria with renal colic, spontaneous retroperitoneal haematomas. Symptoms may appear within days of co-prescription.
Management
The combination is not prescribed. When switching DOACs, stop the first and start the second at the next scheduled dose without overlap. For high thrombotic risk with renal impairment, bridge with a parenteral anticoagulant (low molecular weight heparin).
Mechanism
Ketoconazole is a potent inhibitor of hepatic CYP3A4 and the P-glycoprotein transporter. Rivaroxaban uses both for clearance. Rivaroxaban plasma levels rise 2.6-fold. The lists the combination as an absolute contraindication.
Symptoms
Gum bleeding, epistaxis, bruising without trauma, blood in urine or stool, menorrhagia. Severe cases include gastrointestinal or intracranial haemorrhage, gross haematuria with renal colic, spontaneous retroperitoneal haematomas. Symptoms may appear within days of co-prescription.
Management
The combination is not prescribed. Alternative antifungals: terbinafine (no CYP3A4 use) for dermatophytosis, echinocandins for systemic mycoses. If a short ketoconazole course is required, switch rivaroxaban to a parenteral anticoagulant temporarily.
Sources
Mechanism
Ritonavir strongly inhibits CYP3A4 and P-glycoprotein – the clearance routes of rivaroxaban. Rivaroxaban plasma levels rise several-fold. The lists the combination as an absolute contraindication.
Symptoms
Gum bleeding, epistaxis, bruising without trauma, blood in urine or stool, menorrhagia. Severe cases include gastrointestinal or intracranial haemorrhage, gross haematuria with renal colic, spontaneous retroperitoneal haematomas. Symptoms may appear within days of co-prescription.
Management
The combination is not prescribed. For HIV patients, anticoagulate with warfarin under INR control or short-course low molecular weight heparin.
Mechanism
Warfarin blocks vitamin K-dependent clotting factor synthesis; rivaroxaban directly inhibits factor Xa. Effects are additive with risk of major bleeding.
Symptoms
Gum bleeding, epistaxis, bruising without trauma, blood in urine or stool, menorrhagia. Severe cases include gastrointestinal or intracranial haemorrhage, gross haematuria with renal colic, spontaneous retroperitoneal haematomas. Symptoms may appear within days of co-prescription.
Management
The combination is not prescribed. Switching from warfarin to rivaroxaban: stop warfarin, wait for INR below 3.0, then start rivaroxaban. Reverse switch: overlap with INR monitoring, stop rivaroxaban once INR exceeds 2.0.
Mechanism
Aspirin irreversibly blocks platelet cyclooxygenase; rivaroxaban directly inhibits factor Xa. Dual antithrombotic action raises major bleeding risk roughly 1.5- to 2-fold versus rivaroxaban alone.
Symptoms
Gum bleeding, epistaxis, bruising without trauma, blood in urine or stool, menorrhagia. Severe cases include gastrointestinal or intracranial haemorrhage. Risk rises in patients over 65 and with prior peptic ulcer disease.
Management
Combine only for strict indications. Limit aspirin to 75–100 mg/day and dual therapy to 1–6 months. PPI cover with pantoprazole is mandatory.
Mechanism
Amiodarone moderately blocks CYP3A4 and P-glycoprotein – two rivaroxaban clearance routes. Rivaroxaban plasma levels rise by about 50%; bleeding risk rises moderately.
Symptoms
Gum bleeding, epistaxis, bruising without trauma, black stools, blood in urine. Severe cases include gastrointestinal or intracranial haemorrhage.
Management
The combination is acceptable in patients with preserved renal function (creatinine clearance above 50 mL/min) and atrial fibrillation. In renal impairment, switch to warfarin or apixaban.
Sources
Mechanism
Carbamazepine induces CYP3A4 and P-glycoprotein – two rivaroxaban clearance routes. Rivaroxaban plasma levels fall by 50%; anticoagulant effect weakens.
Symptoms
The patient feels nothing. Stroke risk in atrial fibrillation rises, as do deep vein thrombosis and pulmonary embolism risks.
Management
Avoid the combination. Alternative anticoagulants: warfarin with INR monitoring or low molecular weight heparin. Alternative anticonvulsants without induction: levetiracetam, lamotrigine.
Mechanism
Clarithromycin blocks CYP3A4 and P-glycoprotein – the two main rivaroxaban clearance routes. Rivaroxaban levels rise by roughly 50%, and bleeding risk grows in patients with renal impairment.
Symptoms
Gum bleeding, epistaxis, bruising without trauma, blood in urine or stool, menorrhagia. Severe cases include gastrointestinal or intracranial haemorrhage. Risk rises in patients over 65 and with prior peptic ulcer disease.
Management
Avoid where possible. Do not prescribe if creatinine clearance is below 30 mL/min. Alternative antibiotics: azithromycin or doxycycline (minimal CYP3A4 and P-glycoprotein interaction).
Mechanism
Clopidogrel blocks the platelet P2Y12 receptor; rivaroxaban directly inhibits factor Xa. The two antithrombotic mechanisms add up, roughly doubling major bleeding risk.
Symptoms
Gum bleeding, epistaxis, bruising without trauma, blood in urine or stool, menorrhagia. Severe cases include gastrointestinal or intracranial haemorrhage. Risk rises in patients over 65 and with prior peptic ulcer disease.
Management
Dual therapy is used after acute coronary syndrome or stenting in atrial fibrillation, generally for no more than 1–6 months. Rivaroxaban dose is adjusted to age and renal function. PPI cover with pantoprazole is mandatory.
Mechanism
Additive GI bleeding risk: anticoagulant (rivaroxaban) + ulcerogenic NSAID (diclofenac). Diclofenac additionally raises cardiovascular risk.
Symptoms
Black or tarry stools (melena), vomiting blood or coffee-ground material, epigastric pain. Risk multiplies in older patients and with prior peptic ulcer disease.
Management
Avoid prolonged combination. If diclofenac is needed for a short course, use the minimum effective dose for 5–7 days under pantoprazole cover. For chronic analgesia: paracetamol, celecoxib (less GI toxicity), or topical NSAIDs.
Mechanism
Additive GI bleeding risk: anticoagulant (rivaroxaban) + ulcerogenic NSAID with antiplatelet effect (ibuprofen).
Symptoms
Black or tarry stools (melena), vomiting blood or coffee-ground material, epigastric pain. Risk multiplies in older patients and with prior peptic ulcer disease.
Management
Avoid prolonged combination. If ibuprofen is needed for a short course, use the minimum effective dose for 5–7 days under pantoprazole cover. For chronic analgesia: paracetamol, celecoxib, or topical NSAIDs.
Mechanism
Ketorolac inhibits platelet aggregation and strongly injures the gastric mucosa. Combined with rivaroxaban (direct factor Xa inhibitor): additive massive GI bleeding risk. Toradol Section 4.3 lists anticoagulants as contraindications.
Symptoms
Black or tarry stools (melena), vomiting blood or coffee-ground material, epigastric pain. Risk multiplies in older patients and with prior peptic ulcer disease.
Management
The combination is not prescribed. For analgesia on rivaroxaban, use paracetamol (up to 3 g/day), metamizole, or a short opioid course. Ketorolac courses never exceed 5 days under any circumstances.
Mechanism
Direct oral anticoagulant (rivaroxaban) + NSAID (meloxicam) – additive GI bleeding risk via combined anticoagulation, mucosal injury, and platelet dysfunction.
Symptoms
Black or tarry stools, vomiting blood, epigastric pain. Risk multiplies in older patients and with prior peptic ulcer disease.
Management
Avoid prolonged combination. If meloxicam is needed for a short course, use the minimum effective dose for 5–7 days under pantoprazole cover. For chronic analgesia: paracetamol or celecoxib.
Mechanism
Direct oral anticoagulant (rivaroxaban) + NSAID (naproxen) – additive GI bleeding risk.
Symptoms
Black or tarry stools, vomiting blood, epigastric pain. Risk multiplies in older patients and with prior peptic ulcer disease.
Management
Avoid prolonged combination. If naproxen is needed for a short course, use the minimum effective dose for 5–7 days under pantoprazole cover. For chronic analgesia: paracetamol or celecoxib.
Mechanism
Rifampicin strongly induces CYP3A4 and P-glycoprotein – two rivaroxaban clearance routes. Rivaroxaban plasma levels fall by 50%; anticoagulant effect weakens.
Symptoms
The patient feels nothing. Thromboembolic risk rises: stroke in atrial fibrillation, deep vein thrombosis, pulmonary embolism.
Management
The combination is not prescribed. Alternative anticoagulants: warfarin with INR monitoring (rifampicin also weakens warfarin, but titration is easier) or low molecular weight heparin for short courses. Induction persists for 2 weeks after rifampicin stops.
Mechanism
Azithromycin is a weak P-glycoprotein inhibitor; rivaroxaban is a P-glycoprotein substrate. Rivaroxaban plasma levels may rise modestly, raising bleeding risk.
Symptoms
Gum bleeding, epistaxis, bruising without trauma, black or tarry stools. Higher risk in older patients and chronic kidney disease.
Management
For short azithromycin courses (3–5 days), the combination is acceptable without dose change. In older patients and creatinine clearance below 50 mL/min: monitor for bleeding signs. Alternative antibiotics without P-glycoprotein effect: a cephalosporin, amoxicillin-clavulanate, doxycycline.
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Boxed warning
FDA boxed warning: premature discontinuation increases the risk of thrombotic events. With neuraxial anesthesia (epidural or spinal), the risk of epidural hematoma is increased — careful timing and monitoring are required.
FDA categories were retired in 2015. The drug crosses the placenta. The manufacturer label states a contraindication. LMWHs are the standard for anticoagulation in pregnancy.
Excreted in breast milk. The manufacturer states a contraindication. Switch breastfeeding patients to LMWH or warfarin (compatible per LactMed).
Reference information, not a clinical decision. Discuss feeding pauses or changes with your physician or an IBCLC.
Rivaroxaban is evaluated for the following indications with varying evidence strength: Venous thromboembolism (evidence tier A), Stroke prevention in non-valvular atrial fibrillation (evidence tier A), Established ASCVD, secondary prevention (evidence tier B). See the full indication matrix with dosing and citations above on this page.
Common side effects of Rivaroxaban (≥ 1 in 100): Epistaxis, gum bleeding, Gastrointestinal bleeding (somewhat more frequent than other DOACs), Hematuria, Bruising, Anemia. See the Safety section for uncommon and serious reactions.
FDA category C. FDA categories were retired in 2015. The drug crosses the placenta. The manufacturer label states a contraindication. LMWHs are the standard for anticoagulation in pregnancy.
Excreted in breast milk. The manufacturer states a contraindication. Switch breastfeeding patients to LMWH or warfarin (compatible per LactMed).
Rivaroxaban is contraindicated in: Active clinically significant bleeding; Lesion or condition at high risk of major bleeding; Concomitant anticoagulant therapy; Severe hepatic impairment (Child-Pugh B and C); Pregnancy and breastfeeding (per manufacturer). Full list in the Safety section.
FDA boxed warning: premature discontinuation increases the risk of thrombotic events. With neuraxial anesthesia (epidural or spinal), the risk of epidural hematoma is increased — careful timing and monitoring are required.