RIVAROXABAN Drug Interactions: What You Need to Know

INTERACTIONS Avoid combined P-gp and strong CYP3A inhibitors and inducers ( 7.2 , 7.3 ) Anticoagulants : Avoid concomitant use ( 7.4 )

7.1 General 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 for oral suspension with known combined P-gp and strong CYP3A inhibitors (e.g., ketoconazole and ritonavir) <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.6 ) and Clinical Pharmacology ( 12.3 )]</span> . Although clarithromycin is a combined P-gp and strong CYP3A inhibitor, pharmacokinetic data suggests that no precautions are necessary with concomitant administration with rivaroxaban for oral suspension as the change in exposure is unlikely to affect the bleeding risk <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> . Interaction with Combined P-gp and Moderate CYP3A Inhibitors in Patients with Renal Impairment Rivaroxaban for oral suspension should not be used in patients with CrCl 15 to &lt;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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.4 ) and Clinical Pharmacology ( 12.3 )]</span> .

7.3 Drugs that Induce Cytochrome P450 3A Enzymes and Drug Transport Systems Avoid concomitant use of rivaroxaban for oral suspension with drugs that are combined P-gp and strong CYP3A inducers (e.g., carbamazepine, phenytoin, rifampin, St. John&apos;s wort) <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.6 ) and Clinical Pharmacology ( 12.3 )]</span> .

7.4 Anticoagulants and NSAIDs/Aspirin Coadministration of enoxaparin, warfarin, aspirin, clopidogrel and chronic NSAID use may increase the risk of bleeding <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span>. Avoid concurrent use of rivaroxaban for oral suspension 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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.2 )]</span>.

Rivaroxaban for oral suspension is contraindicated in patients with: active pathological bleeding [see Warnings and Precautions ( 5.2 )] severe hypersensitivity reaction to rivaroxaban for oral suspension (e.g., anaphylactic reactions) [see Adverse Reactions ( 6.2 )] Active pathological bleeding ( 4 ) Severe hypersensitivity reaction to rivaroxaban for oral suspension ( 4 )

AND PRECAUTIONS 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 )

5.1 Increased 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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.3 , 2.4 ) and Clinical Studies ( 14.1 )]</span> .

5.2 Risk 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 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) <span class="opacity-50 text-xs">[see Drug Interactions ( 7.4 )]</span> , 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 <span class="opacity-50 text-xs">[see Drug Interactions ( 7.2 )]</span> . Risk of Hemorrhage in Acutely Ill Medical Patients at High Risk of Bleeding Acutely ill medical patients with the following conditions are at increased risk of bleeding with the use of rivaroxaban tablets for primary VTE prophylaxis: history of bronchiectasis, pulmonary cavitation, or pulmonary hemorrhage, active cancer (i.e., undergoing acute, in-hospital cancer treatment), active gastroduodenal ulcer in the three months prior to treatment, history of bleeding in the three months prior to treatment, or dual antiplatelet therapy. rivaroxaban tablet is not for use for primary VTE prophylaxis in these hospitalized, acutely ill medical patients at high risk of bleeding. 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> . 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.

5.3 Spinal/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 long-term or permanent paralysis <span class="opacity-50 text-xs">[see Boxed Warning]</span> . 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> . Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of rivaroxaban tablet 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 to 45 years and 26 hours in elderly patients aged 60 to 76 years), after the last administration of rivaroxaban tablets <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span>. 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.

5.4 Use in Patients with Renal Impairment Nonvalvular Atrial Fibrillation Periodically assess renal function as clinically indicated (i.e., more frequently in situations in which renal function may decline) and adjust therapy accordingly <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.1 )]</span> . Consider dose adjustment or discontinuation of rivaroxaban tablets in patients who develop acute renal failure while on rivaroxaban tablets <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.6 )]</span>. Treatment of Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), and Reduction in the Risk of Recurrence of DVT and of PE In patients with CrCl &lt;30 mL/min, rivaroxaban exposure and pharmacodynamic effects are increased compared to patients with normal renal function. There are limited clinical data in patients with CrCl 15 to &lt;30 mL/min; therefore, observe closely and promptly evaluate any signs or symptoms of blood loss in these patients. There are no clinical data in patients with CrCl &lt;15 mL/min (including patients on dialysis); therefore, avoid the use of rivaroxaban tablets in these patients. Discontinue rivaroxaban tablets in patients who develop acute renal failure while on treatment <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.6 )]</span> . Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery In patients with CrCl &lt;30 mL/min, rivaroxaban exposure and pharmacodynamic effects are increased compared to patients with normal renal function. There are limited clinical data in patients with CrCl 15 to &lt;30 mL/min; therefore, observe closely and promptly evaluate any signs or symptoms of blood loss in these patients. There are no clinical data in patients with CrCl&lt;15 mL/min (including patients on dialysis); therefore, avoid the use of rivaroxaban tablets in these patients. Discontinue rivaroxaban tablets in patients who develop acute renal failure while on treatment <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.6 )]</span>. Prophylaxis of Venous Thromboembolism in Acutely Ill Medical Patients at Risk for Thromboembolic Complications Not at High Risk of Bleeding In patients with CrCl &lt;30 mL/min, rivaroxaban exposure and pharmacodynamic effects are increased compared to patients with normal renal function. There are limited clinical data in patients with CrCl 15 to &lt;30 mL/min; therefore, observe closely and promptly evaluate any signs or symptoms of blood loss in these patients. There are no clinical data in patients with CrCl &lt;15 mL/min (including patients on dialysis); therefore, avoid the use of rivaroxaban tablets in these patients. Discontinue rivaroxaban tablets in patients who develop acute renal failure while on treatment <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.6 )]</span>.

Pediatric Patients

There are limited clinical data in pediatric patients 1 year or older with moderate or severe renal impairment (eGFR <50 mL/min/1.73 m2); therefore, avoid the use of rivaroxaban tablets in these patients. There are no clinical data in pediatric patients younger than 1 year with serum creatinine results above 97.5th percentile; therefore, avoid the use of rivaroxaban tablets in these patients [see Dosage and Administration (2.2) and Use in Specific Populations ( 8.6 )] .

5.5 Use 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 <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.7 )]</span> . No clinical data are available in pediatric patients with hepatic impairment.

5.6 Use with P-gp and Strong CYP3A Inhibitors or Inducers Avoid concomitant use of rivaroxaban tablets with known combined P-gp and strong CYP3A inhibitors <span class="opacity-50 text-xs">[see Drug Interactions ( 7.2 )]</span>. Avoid concomitant use of rivaroxaban tablets with drugs that are known combined P-gp and strong CYP3A inducers <span class="opacity-50 text-xs">[see Drug Interactions ( 7.3 )]</span> .

5.7 Risk 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) <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.2 ) and Use in Specific Populations ( 8.1 )]</span> .

5.8 Patients with Prosthetic Heart Valves On the basis of the GALILEO study, use of rivaroxaban tablet 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 tablet 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 tablet 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.

5.10 Increased 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 DOACs has been associated with increased rates of recurrent thrombotic events compared with vitamin K antagonist therapy.