XARELTO® (rivaroxaban) tablets
Table 4: Bleeding Events* in Patients Undergoing Hip or Knee Replacement Surgeries (RECORD 1-3) (continued) XARELTO 10 mg Enoxaparin† Knee Surgery Study Major bleeding event Fatal bleeding Bleeding into a critical organ Bleeding that required re-operation Extra-surgical site bleeding requiring transfusion of >2 units of whole blood or packed cells Any bleeding event‡
*
XARELTO® (rivaroxaban) tablets
Hepatobiliary disorders: jaundice, cholestasis, cytolytic hepatitis Immune system disorders: hypersensitivity, anaphylactic reaction, anaphylactic shock, angioedema Nervous system disorders: cerebral hemorrhage, subdural hematoma, epidural hematoma, hemiparesis Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome DRUG INTERACTIONS Rivaroxaban is a substrate of CYP3A4/5, CYP2J2, and the P-gp and ATPbinding cassette G2 (ABCG2) transporters. Inhibitors and inducers of these CYP450 enzymes or transporters (e.g., P-gp) may result in changes in rivaroxaban exposure. Drugs that Inhibit Cytochrome P450 3A4 Enzymes and Drug Transport Systems: In drug interaction studies evaluating the concomitant use with drugs that are combined P-gp and CYP3A4 inhibitors (ketoconazole, ritonavir, clarithromycin, erythromycin and fluconazole), increases in rivaroxaban exposure and pharmacodynamic effects (i.e., factor Xa inhibition and PT prolongation) were observed. The increases in exposure ranged from 30% to 160%. Significant increases in rivaroxaban exposure may increase bleeding risk [see Clinical Pharmacology (12.3) in full Prescribing Information]. When data suggest a change in exposure is unlikely to affect bleeding risk (e.g., clarithromycin, erythromycin), no precautions are necessary during coadministration with drugs that are combined P-gp and CYP3A4 inhibitors. Avoid concomitant administration of XARELTO with combined P-gp and strong CYP3A4 inhibitors [see Warnings and Precautions]. Drugs that Induce Cytochrome P450 3A4 Enzymes and Drug Transport Systems: Results from drug interaction studies and population PK analyses from clinical studies indicate coadministration of XARELTO with a combined P-gp and strong CYP3A4 inducer (e.g., rifampicin, phenytoin) decreased rivaroxaban exposure by up to 50%. Similar decreases in pharmacodynamic effects were also observed. 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