Boxed warningThe FDA label of this medicine carries a boxed warning, the strongest warning the FDA gives. Read it under warnings and precautions.
Indications
Rivaroxaban Tablets is a factor Xa inhibitor indicated: to reduce the risk of major cardiovascular events in patients with coronary artery disease (CAD) ( 1.7 ) to reduce the risk of major thrombotic vascular events in patients with peripheral artery disease (PAD), including patients after recent lower extremity revascularization due to symptomatic PAD ( 1.8 )
1.7 Reduction of Risk of Major Cardiovascular Events in Patients with Coronary Artery Disease (CAD) Rivaroxaban Tablets, in combination with aspirin, is indicated to reduce the risk of major cardiovascular events (cardiovascular death, myocardial infarction, and stroke) in adult patients with coronary artery disease.
1.8 Reduction of Risk of Major Thrombotic Vascular Events in Patients with Peripheral Artery Disease (PAD), Including Patients after Lower Extremity Revascularization due to Symptomatic PAD Rivaroxaban Tablets, in combination with aspirin, is indicated to reduce the risk of major thrombotic vascular events (myocardial infarction, ischemic stroke, acute limb ischemia, and major amputation of a vascular etiology) in adult patients with PAD, including patients who have recently undergone a lower extremity revascularization procedure due to symptomatic PAD.
Contraindications
Rivaroxaban tablets are contraindicated in patients with: active pathological bleeding [see Warnings and Precautions ( 5.2 )] severe hypersensitivity reaction to Rivaroxaban Tablets (e.g., anaphylactic reactions) [see Adverse Reactions ( 6.2 )] Active pathological bleeding ( 4 ) Severe hypersensitivity reaction to Rivaroxaban Tablets ( 4 )
Risk of bleeding: Rivaroxaban Tablets can cause serious and fatal bleeding. An agent to reverse the activity of rivaroxaban is available. ( 5.2 ) Pregnancy-related hemorrhage: Use Rivaroxaban Tablets with caution in pregnant women due to the potential for obstetric hemorrhage and/or emergent delivery. ( 5.7 , 8.1 ) Prosthetic heart valves: Rivaroxaban Tablets use not recommended. ( 5.8 ) Increased Risk of Thrombosis in Patients with Triple Positive Antiphospholipid Syndrome: Rivaroxaban Tablets use not recommended.
( 5.10 )
5.1Increased Risk of Thrombotic Events after Premature Discontinuation
Premature discontinuation of any oral anticoagulant, including Rivaroxaban Tablets, in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from Rivaroxaban Tablets to warfarin in clinical trials in atrial fibrillation patients. If Rivaroxaban Tablets are discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant [see Dosage and Administration ( 2.3 , 2.4 ) and Clinical Studies ( 14.1 )].
5.2Risk of Bleeding Rivaroxaban
Tablets increases the risk of bleeding, including in any organ, and can cause serious or fatal bleeding. In deciding whether to prescribe Rivaroxaban Tablets to patients at increased risk of bleeding, the risk of thrombotic events should be weighed against the risk of bleeding. Promptly evaluate any signs or symptoms of blood loss and consider the need for blood replacement. Discontinue Rivaroxaban Tablets in patients with active pathological hemorrhage.
The terminal elimination half-life of rivaroxaban is 5 to 9 hours in healthy subjects aged 20 years to 45 years. Concomitant use of other drugs that impair hemostasis increases the risk of bleeding. These include aspirin, P2Y12 platelet inhibitors, dual antiplatelet therapy, other antithrombotic agents, fibrinolytic therapy, non-steroidal anti-inflammatory drugs (NSAIDs) [see Drug Interactions ( 7.4) ] , selective serotonin reuptake inhibitors, and serotonin norepinephrine reuptake inhibitors.
Concomitant use of drugs that are known combined P-gp and strong CYP3A inhibitors increases rivaroxaban exposure and may increase bleeding risk [see Drug Interactions ( 7.2 )]. Reversal of Anticoagulant Effect An agent to reverse the anti-factor Xa activity of rivaroxaban is available. Because of high plasma protein binding, rivaroxaban is not dialyzable [see Clinical Pharmacology ( 12.3 )]. Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban.
Use of procoagulant reversal agents, such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate or recombinant factor VIIa, may be considered but has not been evaluated in clinical efficacy and safety studies. Monitoring for the anticoagulation effect of rivaroxaban using a clotting test (PT, INR or aPTT) or anti-factor Xa (FXa) activity is not recommended.
5.3Spinal/Epidural Anesthesia or Puncture
When neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture is employed, patients treated with anticoagulant agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma which can result in longterm or permanent paralysis [see Boxed Warning]. To reduce the potential risk of bleeding associated with the concurrent use of Rivaroxaban Tablets and epidural or spinal anesthesia/ analgesia or spinal puncture, consider the pharmacokinetic profile of Rivaroxaban Tablets [see Clinical Pharmacology ( 12.3 )].
Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of Rivaroxaban Tablets is low; however, the exact timing to reach a sufficiently low anticoagulant effect in each patient is not known. An indwelling epidural or intrathecal catheter should not be removed before at least 2 half-lives have elapsed (i.e., 18 hours in young patients aged 20 years to 45 years and 26 hours in elderly patients aged 60 years to 76 years), after the last administration of Rivaroxaban Tablets [see Clinical Pharmacology ( 12.3 )].
The next Rivaroxaban Tablets dose should not be administered earlier than 6 hours after the removal of the catheter. If traumatic puncture occurs, delay the administration of Rivaroxaban Tablets for 24 hours. Should the physician decide to administer anticoagulation in the context of epidural or spinal anesthesia/analgesia or lumbar puncture, monitor frequently to detect any signs or symptoms of neurological impairment, such as midline back pain, sensory and motor deficits (numbness, tingling, or weakness in lower limbs), bowel and/or bladder dysfunction.
Instruct patients to immediately report if they experience any of the above signs or symptoms. If signs or symptoms of spinal hematoma are suspected, initiate urgent diagnosis and treatment including consideration for spinal cord decompression even though such treatment may not prevent or reverse neurological sequelae.
5.4Use in Patients with Renal Impairment Discontinue Rivaroxaban Tablets
in patients who develop acute renal failure while on treatment [ see Use in Specific Populations ( 8.6 )].
5.5Use in Patients with Hepatic Impairment
No clinical data are available for adult patients with severe hepatic impairment. Avoid use of Rivaroxaban Tablets in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy since drug exposure and bleeding risk may be increased [see Use in Specific Populations ( 8.7 )].
5.6Use with P-gp and Strong CYP3A Inhibitors or Inducers
Avoid concomitant use of Rivaroxaban Tablets with known combined P-gp and strong CYP3A inhibitors [see Drug Interactions ( 7.2 )]. Avoid concomitant use of Rivaroxaban Tablets with drugs that are known combined P-gp and strong CYP3A inducers [see Drug Interactions ( 7.3 )].
5.7Risk of Pregnancy-Related Hemorrhage
In pregnant women, Rivaroxaban Tablets should be used only if the potential benefit justifies the potential risk to the mother and fetus. Rivaroxaban Tablets dosing in pregnancy has not been studied. The anticoagulant effect of Rivaroxaban Tablets cannot be monitored with standard laboratory testing. Promptly evaluate any signs or symptoms suggesting blood loss (e.g., a drop in hemoglobin and/or hematocrit, hypotension, or fetal distress) [see Warnings and Precautions ( 5.2 ) and Use in Specific Populations ( 8.1 )].
5.8 Patients with Prosthetic Heart Valves On the basis of the GALILEO study, use of Rivaroxaban Tablets is not recommended in patients who have had transcatheter aortic valve replacement (TAVR) because patients randomized to Rivaroxaban Tablets experienced higher rates of death and bleeding compared to those randomized to an anti-platelet regimen. The safety and efficacy of Rivaroxaban Tablets have not been studied in patients with other prosthetic heart valves or other valve procedures.
Use of Rivaroxaban Tablets is not recommended in patients with prosthetic heart valves.
5.9 Acute PE in Hemodynamically Unstable Patients or Patients Who Require Thrombolysis or Pulmonary Embolectomy Initiation of Rivaroxaban Tablets is not recommended acutely as an alternative to unfractionated heparin in patients with pulmonary embolism who present with hemodynamic instability or who may receive thrombolysis or pulmonary embolectomy.
5.10Increased Risk of Thrombosis in Patients with Triple Positive Antiphospholipid Syndrome
Direct-acting oral anticoagulants (DOACs), including Rivaroxaban Tablets, are not recommended for use in patients with triple-positive antiphospholipid syndrome (APS). For patients with APS (especially those who are triple positive [positive for lupus anticoagulant, anticardiolipin, and anti- beta 2-glycoprotein I antibodies]), treatment with
Our copy of this section ends here. The full text is in the official label at the FDA. Open Drugs@FDA
Interactions
Avoid combined P-gp and strong CYP3A inhibitors and inducers ( 7.2 , 7.3 ) Anticoagulants: Avoid concomitant use ( 7.4 )
7.1General Inhibition and Induction Properties
Rivaroxaban is a substrate of CYP3A4/5, CYP2J2, and the P-gp and ATP-binding cassette G2 (ABCG2) transporters. Combined P-gp and strong CYP3A inhibitors increase exposure to rivaroxaban and may increase the risk of bleeding. Combined P-gp and strong CYP3A inducers decrease exposure to rivaroxaban and may increase the risk of thromboembolic events.
7.2 Drugs that Inhibit Cytochrome P450 3A Enzymes and Drug Transport Systems Interaction with Combined P-gp and Strong CYP3A Inhibitors Avoid concomitant administration of Rivaroxaban Tablets with known combined P-gp and strong CYP3A inhibitors (e.g., ketoconazole and ritonavir) [see Warnings and Precautions ( 5.6 ) and Clinical Pharmacology ( 12.3 )]. Although clarithromycin is a combined P-gp and strong CYP3A inhibitor, pharmacokinetic data suggests that no precautions are necessary with concomitant administration with Rivaroxaban Tablets as the change in exposure is unlikely to affect the bleeding risk [see Clinical Pharmacology ( 12.3 )].
Interaction with Combined P-gp and Moderate CYP3A Inhibitors in Patients with Renal Impairment Rivaroxaban Tablets should not be used in patients with CrCl 15 to <80 mL/min who are receiving concomitant combined P-gp and moderate CYP3A inhibitors (e.g., erythromycin) unless the potential benefit justifies the potential risk [see Warnings and Precautions ( 5.4 ) and Clinical Pharmacology ( 12.3 )].
7.3 Drugs that Induce Cytochrome P450 3A Enzymes and Drug Transport Systems Avoid concomitant use of Rivaroxaban Tablets with drugs that are combined P-gp and strong CYP3A inducers (e.g., carbamazepine, phenytoin, rifampin, St. John’s wort) [see Warnings and Precautions ( 5.6 ) and Clinical Pharmacology ( 12.3 )].
7.4Anticoagulants and NSAIDs/Aspirin Coadministration
of enoxaparin, warfarin, aspirin, clopidogrel and chronic NSAID use may increase the risk of bleeding [see Clinical Pharmacology ( 12.3 )]. Avoid concurrent use of Rivaroxaban Tablets with other anticoagulants due to increased bleeding risk unless benefit outweighs risk. Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with aspirin, other platelet aggregation inhibitors, or NSAIDs [see Warnings and Precautions ( 5.2 )].
Adverse reactions
The following clinically significant adverse reactions are also discussed in other sections of the labeling: Increased Risk of Stroke After Discontinuation in Nonvalvular Atrial Fibrillation [see Boxed Warning and Warnings and Precautions ( 5.1 )] Bleeding Risk [see Warnings and Precautions ( 5.2 , 5.4 , 5.5 , 5.6 , 5.7 )] Spinal/Epidural Hematoma [see Boxed Warning and Warnings and Precautions ( 5.3 )] The most common adverse reaction (>5%) in adult patients was bleeding.
( 6.1 ) The most common adverse reactions (>10%) in pediatric patients were bleeding, cough, vomiting, and gastro enteritis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact ScieGen Pharmaceuticals, Inc. at (1-855-724-3436) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. During clinical development for the approved indications, 34,947 adult patients were exposed to Rivaroxaban Tablets. Hemorrhage The most common adverse reactions with Rivaroxaban Tablets were bleeding complications [see Warnings and Precautions ( 5.2 )].
Reduction of Risk of Major Cardiovascular Events in Patients with CAD In the COMPASS trial overall, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 2.7% for Rivaroxaban Tablets 2.5 mg twice daily vs. 1.2% for placebo on background therapy for all patients with aspirin 100 mg once daily. The incidences of important bleeding events in the CAD and PAD populations in COMPASS were similar.
Table 10 shows the number of patients experiencing various types of major bleeding events in the COMPASS trial. Table 10: Major Bleeding Events in COMPASS - On Treatment Plus 2 Days* Parameter Rivaroxaban † N=9134 n(%/year) Placebo† N=9107 n (%/year) Rivaroxabanvs. Placebo HR(95%CI) Modified ISTH Major Bleeding‡ 263 (1.6) 144 (0.9) 1.8 (1.5, 2.3) - Fatal bleeding event Intracranial hemorrhage (ICH) Non-intracranial 12 (<0.1) 6 (<0.1) 6 (<0.1) 8 (<0.1) 3 (<0.1) 5 (<0.1) 1.5 (0.6, 3.7) 2.0 (0.5, 8.0) 1.2 (0.4, 4.0) - Symptomatic bleeding in critical organ (non-fatal) - ICH (fatal and non-fatal) Hemorrhagic Stroke Other ICH 58 (0.3) 23 (0.1) 18 (0.1) 6 (<0.1) 43 (0.3) 21 (0.1) 13 (<0.1) 9 (<0.1) 1.4 (0.9, 2.0) 1.1 (0.6, 2.0) 1.4 (0.7, 2.8) 0.7 (0.2, 1.9) - Bleeding into the surgical site requiring reoperation (non-fatal, not in critical organ) 7 (<0.1) 6 (<0.1) 1.2 (0.4, 3.5) - Bleeding leading to hospitalization (non-fatal, not in critical organ, not requiring reoperation) 188 (1.1) 91 (0.5) 2.1 (1.6, 2.7) Major GI bleeding 117 (0.7) 49 (0.3) 2.4 (1.7, 3.4) * Major bleeding events within each subcategory were counted once per patient, but patients may have contributed events to multiple subcategories.
These events occurred during treatment or within 2 days of stopping treatment in the safety analysis set in COMPASS patients. † Treatment schedule: Rivaroxaban Tablets 2.5 mg twice daily or placebo. All patients received background therapy with aspirin 100 mg once daily. ‡ Defined as i) fatal bleeding, or ii) symptomatic bleeding in a critical area or organ, such as intraarticular, intramuscular with compartment syndrome, intraspinal, intracranial, intraocular, respiratory, pericardial, liver, pancreas, retroperitoneal, adrenal gland or kidney; or iii) bleeding into the surgical site requiring reoperation, or iv) bleeding leading to hospitalization.
CI: confidence interval; HR: hazard ratio; ISTH: International Society on Thrombosis and Hemostasis Reduction of Risk of Major Thrombotic Vascular Events in Patients with Peripheral Artery Disease (PAD), Including Patients after Lower Extremity Revascularization due to Symptomatic PAD The incidence of premature permanent discontinuation due to bleeding events for Rivaroxaban Tablets 2.5 mg twice daily vs. placebo on background therapy with aspirin 100 mg once daily in VOYAGER was 4.1% vs. 1.6% and in COMPASS PAD was 2.7% vs. 1.3%, respectively.
Table 11 shows the number of patients experiencing various types of TIMI (Thrombolysis in Myocardial Infarction) major bleeding events in the VOYAGER trial. The most common site of bleeding was gastrointestinal. Table 11: Major Bleeding Events* in VOYAGER- On Treatment Plus 2 Days Rivaroxaban † N=3256 Placebo† N=3248 Rivaroxaban vs. Placebo Parameter n (%) Event rate %/year n (%) Event rate %/year HR (95 % CI) TIMI Major Bleeding (CABG/non-CABG) 62 (1.9) 0.96 44 (1.4) 0.67 1.4 (1.0, 2.1) Fatal bleeding 6 (0.2) 0.09 6 (0.2) 0.09 1.0 (0.3, 3.2) Intracranial bleeding 13 (0.4) 0.20 17 (0.5) 0.26 0.8 (0.4, 1.6) Clinically overt signs of hemorrhage associated with a drop in hemoglobin of ≥5 g/dL or drop in hematocrit of ≥15% 46 (1.4) 0.71 24 (0.7) 0.36 1.9 (1.2, 3.2) CABG: Coronary artery bypass graft; CI: confidence interval; HR: hazard ratio; TIMI: Thrombolysis in Myocardial Infarction Bleeding Criteria * Major bleeding events within each subcategory were counted once per patient, but patients may have contributed events to multiple subcategories. † Treatment schedule: Rivaroxaban Tablets 2.5 mg twice daily or placebo.
All patients received background therapy with aspirin 100 mg once daily. Other Adverse Reactions Non-hemorrhagic adverse reactions reported in ≥1% of Rivaroxaban-treated patients in the EINSTEIN DVT and EINSTEIN PE studies are shown in Table 12. Table 12: Other Adverse Reactions* Reported by ≥1% of Rivaroxaban-Treated Patients in EINSTEIN DVT and EINSTEIN PE Studies Body System Adverse Reaction EINSTEINDVT Study Rivaroxaban Tablets 20 mg N=1718 n (%) Enoxaparin/VKA N=1711 n (%) Gastrointestinaldisorders Abdominal pain 46 (2.7) 25 (1.5) Generaldisordersandadministration site conditions Fatigue 24 (1.4) 15 (0.9) Musculoskeletaland connective tissue disorders Back pain 50 (2.9) 31 (1.8) Muscle spasm 23 (1.3) 13 (0.8) Nervous system disorders Dizziness 38 (2.2) 22 (1.3) Psychiatric disorders Anxiety 24 (1.4) 11 (0.6) Depression 20 (1.2) 10 (0.6) Insomnia 28 (1.6) 18 (1.1) EINSTEIN PE Study Rivaroxaban Tablets 20 mg N=2412 n (%) Enoxaparin/VKA N=2405 n (%) Skin and subcutaneous tissue disorders Pruritus 53 (2.2) 27 (1.1) * Adverse reaction with Relative Risk >1.5 for Rivaroxaban Tablets versus comparator Non-hemorrhagic adverse reactions reported in ≥1% of Rivaroxaban-treated patients in RECORD 1–3 studies are shown in Table 13.
Table 13: Other Adverse Drug Reactions* Reported by ≥1% of Rivaroxaban-Treated Patients in RECORD 1-3 Studies Body System Adverse Reaction Rivaroxaban 10 mg N=4487 n (%) Enoxaparin† N=4524 n (%) Injury,poisoning and procedural complications Wound secretion 125 (2.8) 89 (2.0) Musculo skeletal and connective tissue disorders Pain in extremity 74 (1.7) 55 (1.2) Muscle spasm 52 (1.2) 32 (0.7) Nervous system disorders Syncope 55 (1.2) 32 (0.7) Skin and subcutaneous tissue disorders Pruritus 96 (2.1) 79 (1.8) Blister 63 (1.4) 40 (0.9) * Adverse reaction occurring any time following the first dose of double-blind medication, which may have been prior to administration of active drug, until two days after the last dose of double-blind study medication † Includes the placebo-controlled period of RECORD 2, enoxaparin dosing was 40 mg once daily (RECORD 1 to 3) Non-bleeding adverse reactions reported in ≥5% of Rivaroxaban-treated patients are shown in Table 17.
Table 17: Other Adverse Reactions* Reported by ≥5% of Rivaroxaban-Treated Patients in UNIVERSE Study (Part B) Adverse Reaction Rivaroxaban N=64 n (%) Aspirin N=34 n (%) Cough 10 (15.6) 3 (8.8) Vomiting 9 (14.1) 3 (8.8) Gastroenteritis† 8 (12.5) 1 (2.9) Rash † 6 (9.4) 2 (5.9) * Adverse reaction with Relative Risk >1.5 for Rivaroxaban versus aspirin. † The following terms were combined: Gastroenteritis: gastroenteritis, ga
Our copy of this section ends here. The full text is in the official label at the FDA. Open Drugs@FDA
Composition
Active ingredients
RIVAROXABAN 15MG
Strengths and forms
The FDA lists each strength of a product separately; these pages share one label.
Prognia shows this product information for reference and learning. It is not treatment advice and can lag behind the official text. Always check the current product information and local protocols before prescribing.
