Formulary
Rivaroxaban: Indications, Dosing, Side Effects and Interactions
Rivaroxaban is a direct inhibitor of activated factor X (factor Xa).
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Rivaroxaban: Indications, Dosing, Side Effects and Interactions
Rivaroxaban is a direct inhibitor of activated factor X (factor Xa).
Drug action
Rivaroxaban is a direct inhibitor of activated factor X (factor Xa).
Indications and dose
**Prophylaxis of venous thromboembolism following knee replacement surgery**
- **Adult** (By Mouth): 10 mg once daily for 2 weeks, to be started 6-10 hours after surgery.
**Prophylaxis of venous thromboembolism following hip replacement surgery**
- **Adult** (By Mouth): 10 mg once daily for 5 weeks, to be started 6-10 hours after surgery.
**Treatment of deep-vein thrombosis,Treatment of pulmonary embolism**
- **Adult** (By Mouth): Initially 15 mg twice daily for 21 days, to be taken with food, then maintenance 20 mg once daily, to be taken with food, for duration of treatment-consult product literature.
**Prophylaxis of recurrent deep-vein thrombosis,Prophylaxis of recurrent pulmonary embolism**
- **Adult** (By Mouth): 10 mg once daily, to be given following completion of at least 6 months of anticoagulant treatment, consider 20 mg once daily, to be taken with food, in those at high risk of recurrence (such as complicated comorbidities, or previous recurrence with rivaroxaban 10 mg once daily).
**Prophylaxis of stroke and systemic embolism in patients with non-valvular atrial fibrillation and with at least one of the following risk factors: congestive heart failure, hypertension, previous stroke or transient ischaemic attack, age 75 years, or diabetes mellitus**
- **Adult** (By Mouth): 20 mg once daily, to be taken with food.
**Prophylaxis of atherothrombotic events following an acute coronary syndrome with elevated cardiac biomarkers (in combination with aspirin alone or aspirin and clopidogrel)**
- **Adult** (By Mouth): 2.5 mg twice daily usual duration 12 months.
**Prophylaxis of atherothrombotic events in patients with coronary artery disease or symptomatic peripheral artery disease at high risk of ischaemic events (in combination with aspirin)**
- **Adult** (By Mouth): 2.5 mg twice daily.
**Treatment of venous thromboembolism, Prophylaxis of recurrent venous thromboembolism for rivaroxaban**
- **Neonate (body-weight 2.6 kg and above)** (By mouth): (consult product literature).
- **Child (body-weight 2.6-2.9 kg)** (By mouth): 0.8 mg 3 times a day for at least 3 months, to be given following completion of at least 5 days of initial parenteral anticoagulant treatment, review dose and body-weight regularly, for dose adjustments before and after invasive procedures, surgical intervention and for duration of treatment for catheter related thrombosis-consult product literature, treatment can be extended up to 12 months if required, taking into account the risk for recurrent thrombosis versus the potential bleeding risk.
- **Child (body-weight 3-3.9 kg)** (By mouth): 0.9 mg 3 times a day for at least 3 months, to be given following completion of at least 5 days of initial parenteral anticoagulant treatment, review dose and body-weight regularly, for dose adjustments before and after invasive procedures, surgical intervention and for duration of treatment for catheter related thrombosis-consult product literature, treatment can be extended up to 12 months if required, taking into account the risk for recurrent thrombosis versus the potential bleeding risk.
- **Child (body-weight 4-4.9 kg)** (By mouth): 1.4 mg 3 times a day for at least 3 months, to be given following completion of at least 5 days of initial parenteral anticoagulant treatment, review dose and body-weight regularly, for dose adjustments before and after invasive procedures, surgical intervention and for duration of treatment for catheter related thrombosis-consult product literature, treatment can be extended up to 12 months if required, taking into account the risk for recurrent thrombosis versus the potential bleeding risk.
- **Child (body-weight 5-6.9 kg)** (By mouth): 1.6 mg 3 times a day for at least 3 months, to be given following completion of at least 5 days of initial parenteral anticoagulant treatment, review dose and body-weight regularly, for dose adjustments before and after invasive procedures, surgical intervention and for duration of treatment for catheter related thrombosis-consult product literature, treatment can be extended up to 12 months if required, taking into account the risk for recurrent thrombosis versus the potential bleeding risk.
- **Child (body-weight 7-7.9 kg)** (By mouth): 1.8 mg 3 times a day for at least 3 months, to be given following completion of at least 5 days of initial parenteral anticoagulant treatment, review dose and body-weight regularly, for dose adjustments before and after invasive procedures, surgical intervention and for duration of treatment for catheter related thrombosis-consult product literature, treatment can be extended up to 12 months if required, taking into account the risk for recurrent thrombosis versus the potential bleeding risk.
- **Child (body-weight 8-8.9 kg)** (By mouth): 2.4 mg 3 times a day for at least 3 months, to be given following completion of at least 5 days of initial parenteral anticoagulant treatment, review dose and body-weight regularly, for dose adjustments before and after invasive procedures, surgical intervention and for duration of treatment for catheter related thrombosis-consult product literature, treatment can be extended up to 12 months if required, taking into account the risk for recurrent thrombosis versus the potential bleeding risk.
- **Child (body-weight 9-9.9 kg)** (By mouth): 2.8 mg 3 times a day for at least 3 months, to be given following completion of at least 5 days of initial parenteral anticoagulant treatment, review dose and body-weight regularly, for dose adjustments before and after invasive procedures, surgical intervention and for duration of treatment for catheter related thrombosis-consult product literature, treatment can be extended up to 12 months if required, taking into account the risk for recurrent thrombosis versus the potential bleeding risk.
- **Child (body-weight 10-11.9 kg)** (By mouth): 3 mg 3 times a day for at least 3 months, to be given following completion of at least 5 days of initial parenteral anticoagulant treatment, review dose and body-weight regularly, for dose adjustments before and after invasive procedures, surgical intervention and for duration of treatment for catheter related thrombosis-consult product literature, treatment can be extended up to 12 months if required, taking into account the risk for recurrent thrombosis versus the potential bleeding risk.
- **Child (body-weight 12-29.9 kg)** (By mouth): 5 mg twice daily for at least 3 months, to be given following completion of at least 5 days of initial parenteral anticoagulant treatment, for dose adjustments before and after invasive procedures, surgical intervention and for duration of treatment for catheter related thrombosis-consult product literature, treatment can be extended up to 12 months if required, taking into account the risk for recurrent thrombosis versus the potential bleeding risk.
- **Child (body-weight 30-49.9 kg)** (By mouth): 15 mg once daily for at least 3 months, to be given following completion of at least 5 days of initial parenteral anticoagulant treatment, for dose adjustments before and after invasive procedures, surgical intervention and for duration of treatment for catheter related thrombosis-consult product literature, treatment can be extended up to 12 months if required, taking into account the risk for recurrent thrombosis versus the potential bleeding risk.
- **Child (body-weight 50 kg and above)** (By mouth): 20 mg once daily for at least 3 months, to be given following completion of at least 5 days of initial parenteral anticoagulant treatment, for dose adjustments before and after invasive procedures, surgical intervention and for duration of treatment for catheter related thrombosis-consult product literature, treatment can be extended up to 12 months if required, taking into account the risk for recurrent thrombosis versus the potential bleeding risk.
Cautions
General cautions: Anaesthesia with postoperative indwelling epidural catheter (risk of paralysis-monitor neurological signs and wait at least 18 hours after rivaroxaban dose before removing catheter and do not give next dose until at least 6 hours after catheter removal); bronchiectasis; elderly; risk of bleeding; rivaroxaban should not be used as an alternative to heparin in pulmonary embolism in patients with haemodynamic instability, or who may receive thrombolysis or pulmonary embolectomy; severe hypertension; vascular retinopathy Specific cautions: When used for Prophylaxis of atherothrombotic events following an acute coronary syndrome Body-weight less than 60 kg When used for Prophylaxis of atherothrombotic events in patients with coronary artery disease or symptomatic peripheral artery disease Body-weight less than 60 kg Cautions, further information Elderly For factor Xa inhibitors, Screening Tool of Older Persons' potentially inappropriate Prescriptions (STOPP) criteria to aid medication reviews (see Prescribing in the elderly for information). Potentially inappropriate: with concurrent significant bleeding risk, such as uncontrolled severe hypertension, bleeding diathesis or recent non-trivial spontaneous bleeding (high risk of bleeding) for first deep venous thrombosis without continuing provoking risk factors (e.g. thrombophilia) for greater than 6 months (no proven added benefit) for first pulmonary embolus without continuing provoking risk factors for greater than 12 months (no proven added benefit) as part of dual therapy with an antiplatelet agent in patients with stable coronary, cerebrovascular or peripheral arterial disease, without a clear indication for anticoagulant therapy (no added benefit) if eGFR less than 15 mL/min/1.73 m (contra-indicated in kidney failure; risk of bleeding)
Contraindications
General contra-indications: Active bleeding; antiphospholipid syndrome (increased risk of recurrent thrombotic events); arteriovenous malformation; major intraspinal or intracerebral vascular abnormalities; malignant neoplasms at high risk of bleeding; oesophageal varices; prosthetic heart valve (efficacy not established); recent brain or spinal injury; recent brain surgery; recent gastro-intestinal ulcer; recent intracranial haemorrhage; recent ophthalmic surgery; recent spine surgery; significant risk of major bleeding; use with any other anticoagulant ; vascular aneurysm Specific contra-indications: When used for Prophylaxis of atherothrombotic events following an acute coronary syndrome Previous stroke; transient ischaemic attack When used for Prophylaxis of atherothrombotic events in patients with coronary artery disease or symptomatic peripheral artery disease Previous stroke (no information available-consult product literature) Contra-indications, further information Use with any other anticoagulant Concomitant use with any other anticoagulant is contra-indicated, except when switching therapy, or when heparin is given at doses necessary to maintain an open central venous or arterial catheter or for catheter ablation-use with caution. M
Side effects
Common or very common Anaemia; asthenia; constipation; diarrhoea; dizziness; fever; gastrointestinal discomfort; haemorrhage; headache; hypotension; menorrhagia; nausea; oedema; pain in extremity; post procedural anaemia; renal impairment; skin reactions; vomiting; wound complications Uncommon Angioedema; dry mouth; hepatic disorders; hypersensitivity; intracranial haemorrhage; malaise; syncope; tachycardia; thrombocytopenia; thrombocytosis Rare or very rare Severe cutaneous adverse reactions (SCARs); vascular pseudoaneurysm
Interactions
**Severe interactions:**
- CYP3A4 and P-gp inhibitors Co-administration of rivaroxaban with ketoconazole (400 mg once a day) or ritonavir (600 mg twice a day) led to a 2.6 fold / 2.5 fold increase in mean rivaroxaban AUC and...
- The interaction with clarithromycin is likely not clinically relevant in most patients but can be potentially significant in high-risk patients.
- The interaction with erythromycin is likely not clinically relevant in most patients but can be potentially significant in high-risk patients.
- The interaction with fluconazole is likely not clinically relevant in most patients but can be potentially significant in high-risk patients.
- No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when rivaroxaban was co-administered with 500 mg acetylsalicylic acid.
- Other concomitant therapies No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when rivaroxaban was co-administered with midazolam (substrate of CYP3A4), digoxin...
**Other interactions (25):**
- Therefore, the use of Rivaroxaban is not recommended in patients receiving concomitant systemic treatment with azole-antimycotics such as ketoconazole, itraconazole, voriconazole and posaconazole or...
- Active substances strongly inhibiting only one of the rivaroxaban elimination pathways, either CYP3A4 or P-gp, are expected to increase rivaroxaban plasma concentrations to a lesser extent.
- Clarithromycin (500 mg twice a day), for instance, considered as a strong CYP3A4 inhibitor and moderate P-gp inhibitor, led to a 1.5 fold increase in mean rivaroxaban AUC and a 1.4 fold increase in...
- Erythromycin (500 mg three times a day), which inhibits CYP3A4 and P-gp moderately, led to a 1.3 fold increase in mean rivaroxaban AUC and C max .
- In subjects with mild renal impairment erythromycin (500 mg three times a day) led to a 1.8 fold increase in mean rivaroxaban AUC and 1.6 fold increase in C max when compared to subjects with normal...
- In subjects with moderate renal impairment, erythromycin led to a 2.0 fold increase in mean rivaroxaban AUC and 1.6 fold increase in C max when compared to subjects with normal renal function.
Pregnancy
Manufacturer advises avoid-toxicity in animal studies.
Breast feeding
Manufacturer advises avoid-present in milk in animal studies.
Hepatic impairment
Manufacturer advises avoid in hepatic disease with coagulopathy and clinically-relevant bleeding risk including patients with moderate to severe cirrhosis.
Renal impairment
Important safety information For rivaroxaban MHRA/CHM advice: New oral anticoagulants apixaban ( Eliquis ), dabigatran ( Pradaxa ) and rivaroxaban ( Xarelto ) (October 2013) The following contra-indications now apply to all new oral anticoagulants, for all indications and doses: a lesion or condition, if considered a significant risk factor for major bleeding-see Contra-indications for further information; concomitant treatment with any other anticoagulant agent-see Contra-indications for further information. Healthcare professionals are advised to take caution when deciding to prescribe these anticoagulants to patients with other conditions, undergoing other procedures, and on other treatments, which may increase the risk of major bleeding. The renal function of patients should also be considered. MHRA/CHM advice: Rivaroxaban ( Xarelto ) after transcatheter aortic valve replacement: increase in all-cause mortality, thromboembolic and bleeding events in a clinical trial (October 2018) A phase 3 clinical trial showed that the risk of all-cause death and bleeding after transcatheter aortic valve replacement (TAVR) approximately doubled in patients assigned to a rivaroxaban-based anticoagulation strategy compared with those receiving an antiplatelet-based strategy (clopidogrel and aspirin). The MHRA reminds healthcare professionals that rivaroxaban should not be used for thromboprophylaxis in patients with prosthetic heart valves, including patients who have undergone TAVR. Rivaroxaban treatment in patients who undergo TAVR should be stopped and switched to standard care. MHRA/CHM advice: Direct-acting oral anticoagulants (DOACs): increased risk of recurrent thrombotic events in patients with antiphospholipid syndrome (June 2019) A clinical trial has shown an increased risk of recurrent thrombotic events associated with rivaroxaban compared with warfarin, in patients with antiphospholipid syndrome and a history of thrombosis. There may be a similar risk associated with other DOACs. Healthcare professionals are advised that DOACs are not recommended in patients with antiphospholipid syndrome, particularly high-risk patients who test positive for all three antiphospholipid tests-lupus anticoagulant, anticardiolipin antibodies, and anti-beta 2 glycoprotein I antibodies. Continued treatment should be reviewed in these patients to determine if appropriate, and switching to a vitamin K antagonist such as warfarin should be considered. MHRA/CHM advice: Rivaroxaban ( Xarelto ): reminder that 15 mg and 20 mg tablets should be taken with food (July 2019) The MHRA has received a small number of reports suggesting a lack of efficacy (thromboembolic events) in patients taking 15 mg or 20 mg rivaroxaban tablets on an empty stomach. Healthcare professionals are advised to remind patients to take rivaroxaban 15 mg or 20 mg tablets with food. In those who have difficulty swallowing, these tablets can be crushed and mixed with water or apple puree immediately before, and followed by food immediately after, ingestion. MHRA/CHM advice: Direct-acting oral anticoagulants (DOACs): reminder of bleeding risk, including availability of reversal agents (June 2020) The MHRA reminds healthcare professionals to remain vigilant for signs and symptoms of bleeding complications during treatment with rivaroxaban after ongoing reports of serious, potentially fatal bleeds associated with the use of DOACs. Healthcare professionals are also advised to use rivaroxaban with caution in patients with increased bleeding risk, and to ensure that those with renal impairment are dosed appropriately and their renal function monitored during treatment. Patients should be counselled on the signs and symptoms of bleeding, and encouraged to read the patient information leaflet. The rivaroxaban reversal agent andexanet alfa ( Ondexxya ) is available if required; its reversal effects should be monitored using clinical parameters, as anti-FXa assay results may not be reliable. MHRA/CHM advice: Warfarin and other anticoagulants: monitoring of patients during the COVID-19 pandemic (October 2020) Healthcare professionals are reminded that: direct-acting oral anticoagulants (DOACs), such as rivaroxaban, may interact with other medicines (including antibacterials and antivirals)-advice in product literature should be followed to minimise the risk of potential interactions; if patients are switched from warfarin to rivaroxaban, warfarin treatment should be stopped before rivaroxaban treatment is started to reduce the risk of over-anticoagulation and bleeding. MHRA/CHM advice: Direct-acting oral anticoagulants (DOACs): reminder of dose adjustments in patients with renal impairment (May 2023) Healthcare professionals are reminded that: exposure to DOACs, such as rivaroxaban, is increased in patients with renal impairment, and these patients should receive an appropriately adjusted dose-see Renal impairment for further information; such patients should be reviewed regularly during treatment to ensure the dose remains appropriate; renal function should be assessed by calculating creatinine clearance using the Cockcroft and Gault formula.
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**Author:** MedNext Clinical Team. **Clinical reviewer:** Dr Shameer Deen, MBBS, MS, MRCS. **Sources:** BNF, Indian Pharmacopoeia, CIMS India. **Correction:** Report errors at support@mednext.academy.
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