Xarelto

Rivaroxaban (Rivaroxaban) instructions
Common name: Rivaroxaban
Trade name: Xarelto
Full names: Rivaroxaban, Xarelto, Rivaroxaban, Xarelto

Indications:
Mainly used to treat venous thrombosis in adults
For adult patients undergoing elective hip or knee replacement surgery to prevent venous thrombosis (VTE).
Indicated to treat venous thrombosis (DVT) in adults and reduce the risk of DVT recurrence and pulmonary embolism (PE) after acute DVT.
For use in adult patients with nonvalvular atrial fibrillation who have one or more risk factors (e.g., congestive heart failure, hypertension, age ≥75 years, diabetes, history of stroke or transient ischemic attack) to reduce the risk of stroke and systemic embolism.

Usage and dosage:
Orally.
Rivaroxaban 10mg can be taken with food or alone.
Rivaroxaban 15mg or 20mg tablets should be taken with food.

Prevention of venous thrombosis in adult patients undergoing elective hip or knee replacement surgery
The recommended dose is oral rivaroxaban 10 mg once daily. If the wound has stopped bleeding, the first dose of medication should be between 6 and 10 hours after surgery.
For patients undergoing major hip surgery, the recommended course of treatment is 35 days.
For patients undergoing major knee surgery, the recommended course of treatment is 12 days.
If a missed dose occurs, the patient should take rivaroxaban immediately and continue taking the drug once daily the next day.

Treat DVT (venous thrombosis) and reduce the risk of acute DVT recurrence and PE
The recommended dose for the initial treatment of acute DVT is 15 mg twice a day for the first three weeks, and then the dose for maintenance treatment and to reduce the risk of DVT recurrence and PE is 20 mg once a day.

For adult patients with non-valvular atrial fibrillation to reduce the risk of stroke and systemic embolism
The recommended dose is 20 mg once a day, which is also the maximum recommended dose. For patients with low body weight and advanced age (>75 years old), doctors can use 15 mg once a day as appropriate based on the patient's condition.

Adverse reactions:
>10%
Hematology and oncology: bleeding (5%-28%)
1%-10%
Central nervous system: dizziness (2%), insomnia (2%), anxiety (1%), depression (1%), fatigue (1%), syncope (1%)
Dermatology: wound discharge (3%), itching (2%) ), skin blisters (1%)
Gastrointestinal tract: abdominal pain (3%)
Hematology and oncology: major bleeding (≤4%)
Liver: elevated serum aminotransferases (>3xULN (upper limit of reference value): 2%)
Neuromuscular and skeletal: back pain (3%), limb pain (2%), muscle cramps (1%)
Frequency not defined: Respiratory: bronchiectasis, pulmonary hemorrhage
< 1%
Post-marketing or case reports: agranulocytosis, anaphylactic shock, anaphylaxis, angioedema, intracerebral hemorrhage, cholestasis, decreased hemoglobin, DRESS syndrome (drug eruption with eosinophilia and systemic symptoms), injection site hematoma, hemiplegia, hematuria, Hepatitis, liver injury, allergic reaction, intracranial hemorrhage, jaundice, retroperitoneal hemorrhage, spinal hematoma, Stevens-Johnson syndrome, subdural hematoma, thrombocytopenia

Contraindications:
Severe hypersensitivity to rivaroxaban or any of its components.
Patients with clinically apparent active bleeding.
Patients with liver disease who have coagulation abnormalities and clinically relevant bleeding risks.
Contraindicated for pregnant and lactating women.

Note:
Bleeding: The most common complication is hemorrhage; major bleeding (eg, intracranial, gastrointestinal, retinal, epidural hematoma, adrenal hemorrhage) has been reported. Certain patients are at increased risk of bleeding; risk factors include bacterial endocarditis, congenital or acquired bleeding disorders, vascular retinopathy, thrombocytopenia, recent large vessel or organ biopsy, stroke, intracerebral or other neuroaxonal surgery, severe uncontrolled hypertension, and renal impairment. Recent major surgery, recent major bleeding (intracranial, gastrointestinal, intraocular or pulmonary), concurrent use of drugs that affect hemostasis, and advanced age. When used for venous thromboembolism (VTE) prophylaxis in acutely ill patients, rivaroxaban is not recommended in patients with an increased risk of bleeding, including bronchiectasis, pulmonary cavitation or pulmonary hemorrhage, active cancer, or a history of gastroduodenal ulcer within the past 3 months. Have a history of bleeding or dual antiplatelet therapy in the past 3 months. Monitor for signs and symptoms of bleeding (weakness, dizziness, unexplained edema). If there is an unexplained drop in hemoglobin or blood pressure, immediate clinical evaluation should be performed. Andexanet alfa may be used for reversal of rivaroxaban in patients with life-threatening or uncontrolled bleeding. Rivaroxaban is highly protein bound and therefore, hemodialysis is ineffective. Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban. Depending on the severity of the bleeding, oral activated charcoal should be considered if ingested within 1 to 2 hours of the onset of symptoms. Depending on the specific clinical situation, the following alternatives may also be considered: 4-factor unactivated prothrombin concentrate (eg, Kcentra (Human Prothrombin Complex Concentrate)) or 4-factor activated prothrombin complex concentrate (eg, FEIBA (Inhibitor)). Some studies and case reports have shown some success in correcting coagulation tests with some of these drugs; however, correction of coagulation tests does not mean reversal of the anticoagulant effect of the drug.
Thromboembolic Events: As with any oral anticoagulant, premature discontinuation of rivaroxaban may increase the risk of thromboembolic events, including stroke, if adequate alternative anticoagulants are not available. When discontinuing rivaroxaban due to nonpathological bleeding or completion of a course of therapy, consider adding an alternative anticoagulant therapy. In clinical trials in patients with atrial fibrillation (AF), an increased incidence of stroke was observed during the transition from rivaroxaban to warfarin. In a post hoc analysis of the ROCKET AF trial, the risk of stroke or non-CNS embolism was similar with rivaroxaban compared with warfarin in patients who temporarily (>3 days) or permanently discontinued anticoagulation. In patients with nonvalvular atrial fibrillation for acute ischemic stroke who are receiving direct-acting oral anticoagulants (DOACs) (eg, rivaroxaban), guidelines generally support discontinuation of oral anticoagulants within 4 to 14 days after the onset of neurological symptoms (shorter for transient ischemic attack or mild, nondisabling stroke; longer for moderate to severe stroke).
Antiphospholipid Syndrome: Not recommended for use in patients with triple-positive antiphospholipid syndrome; safety and efficacy have not been established. Patients who are positive for all 3 antiphospholipid antibodies (lupus anticoagulant, anticardiolipin, and anti-β2-glycoprotein I) may have an increased incidence of recurrent thrombotic events compared with treatment with vitamin K antagonists.
Altered Absorption: Assess the risks versus benefits of reduced drug absorption when considering alternative anticoagulants; efficacy may be reduced after gastric bypass or sleeve gastrectomy. Absorption of apixaban appears to occur primarily in the small intestine. When released in the distal small intestine, the peak concentration and total AUC of apixaban were reduced by 60% and further decreased to 90%; when released in the ascending colon, the peak concentration and total AUC were reduced by 84%.
Rivaroxaban: When released into the proximal small intestine and further reduced in the distal small intestine or colon, peak concentration and AUC were reduced by 56% and 29%, respectively. There are a small number of patient reports and case reports of significant changes in the gastrointestinal tract. Existing data are conflicting regarding changes in absorption from small populations: individuals receiving direct oral anticoagulants and those undergoing surgery.
Hepatic Impairment: Avoid use in patients with moderate to severe hepatic impairment (Child-Pugh Class B, C) or liver disease related to coagulation disorders.
Renal impairment: Use with caution in patients with moderate renal impairment (CrCl (creatinine clearance) 30 to 50 ml/min), including patients receiving concurrent drug therapy, as it may increase systemic exposure to rivaroxaban and worsen renal function. Monitor for signs or symptoms of blood loss. Avoid use for deep vein thrombosis/pulmonary embolism and venous thromboembolism prophylaxis in patients with CRCL <30 mL/min. Discontinue use in patients who develop acute renal failure. Some experts recommend against the use of rivaroxaban in patients with end-stage renal disease requiring hemodialysis; if rivaroxaban is used, use caution while closely monitoring bleeding. Dose reduction may be considered in patients with nonvalvular atrial fibrillation and moderate to severe chronic kidney disease (chronic kidney disease; CrCl ≤50 mL/min); rivaroxaban is not recommended in patients with atrial fibrillation and end-stage chronic kidney disease or in patients on hemodialysis.
Valvular disease: Not recommended for patients with artificial heart valves or severe rheumatic heart disease. Avoid the use of DOACs (newer anticoagulants) in patients with mechanical valves or moderate to severe mitral stenosis. However, when anticoagulation is required, DOACs can be used in patients with atrial fibrillation and primary aortic valve disease, tricuspid valve disease, or mitral regurgitation.
Drug-Drug Interactions: Significant interactions may exist that may require dose or frequency adjustment, additional monitoring, or the selection of alternative therapies.
Elderly: Use with caution in the elderly. Elderly patients exhibit higher rivaroxaban concentrations compared with younger patients, primarily due to reduced clearance. Overall, the efficacy of rivaroxaban in the elderly (over 65 years of age) was similar to that in patients under 65 years of age. Both thrombotic and bleeding events were higher in older adults; however, the risk of benefit was favorable in all age groups.
Lactose Intolerance: May contain lactose; not recommended for patients with lactose or galactose intolerance (e.g., Lapp lactase deficiency, glucose-galactose malabsorption).
Spinal or epidural hematoma: Spinal or epidural hematoma can occur during spinal tap in patients undergoing neuraxial anesthesia (epidural or spinal anesthesia) or anticoagulation; may result in long-term or permanent paralysis. In patients with a history of trauma or repeated epidural or spinal taps, or in patients with a history of spinal deformity or spinal surgery, use of an epidural catheter along with other medications that affect hemostasis (e.g., nonsteroidal anti-inflammatory drugs, platelet inhibitors, other anticoagulants) increases the risk of spinal/epidural hematoma. Monitor for signs of neurological damage (e.g., low back pain, leg numbness/weakness, bowel/bladder dysfunction); and seek prompt diagnosis and treatment. Assess the risks versus benefits before neurointervention in patients on anticoagulation or pharmacological prophylaxis. The optimal timing between rivaroxaban and neuroaxon therapy is unclear. When rivaroxaban is less effective as an anticoagulant, placement or removal of an epidural catheter or lumbar puncture is preferable. European guidelines recommend waiting at least 22 to 26 hours after the last dose of rivaroxaban when using prophylactic doses (e.g., 10 mg daily) before catheter placement or lumbar puncture. When using higher doses (such as 20 mg daily), some recommend avoiding neuraxial surgery for at least 48 hours. In patients receiving ceramide anesthesia concurrently receiving rivaroxaban (usually in patients undergoing knee or hip replacement surgery), avoid removal of the epidural catheter for at least 18 hours after the last dose of rivaroxaban; avoid use of rivaroxaban for at least 6 hours after epidural catheter removal; and if traumatic puncture occurs, avoid use of rivaroxaban for at least 24 hours. In addition to these and other clinical variables, renal function and patient age should be considered (rivaroxaban has a prolonged half-life [11 to 13 hours] in older patients). Canadian labeling recommends that patients with postoperative indwelling epidural catheters avoid doses greater than 10 mg.

Storage:
Store at 25°C (77°F); deviations from 15°C to 30°C (59°F to 86°F) allowed.

Mechanism of action:
Rivaroxaban is an oral, bioavailable factor Xa inhibitor that selectively blocks the active site of factor Xa and does not require cofactors (such as antithrombin III) to exert activity. Factor X is activated into factor Xa (FXa) through endogenous and exogenous pathways, which plays an important role in the coagulation cascade.
Rivaroxaban inhibits the activity of Factor Anti-factor Xa activity is also affected by rivaroxaban.

Safety and efficacy:
Eisenberg MJ et al. meta-analysed five randomized controlled studies (a total of 23,063 patients were included, all taking rivaroxaban for ≥1 month, including 14,264 cases of non-valvular atrial fibrillation, 3967 cases of deep vein thrombosis, and 3967 cases of acute symptomatic pulmonary embolism). The results found that compared with vitamin K antagonists, rivaroxaban did not increase the composite endpoint of major bleeding and clinically relevant bleeding (RR: 0.99, confidence interval: 0.93 - 1.06), and fatal bleeding events were significantly reduced in the rivaroxaban group (RR: 0.48, CI: 0.31 – 0.74).
For patients with acute coronary syndrome, the ATLAS ACS 2–TIMI 51 trial (included 15,526 patients, divided into 2 groups: rivaroxaban 2.5 mg twice/day and 5 mg twice/day, The dosage of aspirin in each group (75-100mg/day) showed that rivaroxaban in the two groups significantly reduced primary endpoints including cardiovascular death, myocardial infarction and stroke, while rivaroxaban in the low-dose group reduced secondary endpoints including cardiovascular death and all-cause death.
Compared with warfarin, rivaroxaban has the advantages of convenience to take, rapid onset of action, definite efficacy, wide indications and no need for routine detection of coagulation indicators.