XARELTO® (rivaroxaban) tablets
XARELTO® (rivaroxaban) tablets
XARELTO® (rivaroxaban) tablets
The rates of major bleeding events and any bleeding events observed in
patients in the RECORD clinical trials are shown in Table 4.
Table 4: Bleeding Events* in Patients Undergoing Hip or Knee
Replacement Surgeries (RECORD 1-3)
XARELTO 10 mg Enoxaparin†
Total treated patients
N = 4487
N = 4524
n (%)
n (%)
* Adverse reaction occurring any time following the first dose of doubleblind 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 1-3)
Other clinical trial experience: In an investigational study of acute
medically ill patients being treated with XARELTO 10 mg tablets, cases of
pulmonary hemorrhage and pulmonary hemorrhage with bronchiectasis
were observed.
Postmarketing Experience: The following adverse reactions have been
identified during post-approval use of rivaroxaban. Because these
reactions are reported voluntarily from a population of uncertain size, it
is not always possible to reliably estimate their frequency or establish a
causal relationship to drug exposure.
Blood and lymphatic system disorders: agranulocytosis, thrombocytopenia
Gastrointestinal disorders: retroperitoneal hemorrhage
Hepatobiliary disorders: jaundice, cholestasis, hepatitis (including
hepatocellular injury)
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. These decreases in
exposure to rivaroxaban may decrease efficacy [see Clinical
Pharmacology (12.3) in full Prescribing Information].
Avoid concomitant use of XARELTO with drugs that are combined P-gp
and strong CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin,
St. John’s wort) [see Warnings and Precautions].
Anticoagulants and NSAIDs/Aspirin: Single doses of enoxaparin and
XARELTO given concomitantly resulted in an additive effect on antifactor Xa activity. Single doses of warfarin and XARELTO resulted in an
additive effect on factor Xa (FXa) inhibition and PT. Concomitant aspirin
use has been identified as an independent risk factor for major bleeding
in efficacy trials. NSAIDs are known to increase bleeding, and bleeding
risk may be increased when NSAIDs are used concomitantly with
XARELTO. Coadministration of the platelet aggregation inhibitor
clopidogrel and XARELTO resulted in an increase in bleeding time for
some subjects [see Clinical Pharmacology (12.3) in full Prescribing
Information].
Avoid concurrent use of XARELTO 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].
Drug-Disease Interactions with Drugs that Inhibit Cytochrome P450 3A4
Enzymes and Drug Transport Systems: Results from a pharmacokinetic
trial with erythromycin indicated that patients with renal impairment
coadministered XARELTO with drugs classified as combined P-gp and
moderate CYP3A4 inhibitors (e.g., diltiazem, verapamil, dronedarone, and
erythromycin) have increased exposure compared with patients with
normal renal function and no inhibitor use. Significant increases in
rivaroxaban exposure may increase bleeding risk.
While increases in rivaroxaban exposure can be expected under such
conditions, results from an analysis in the ROCKET AF trial, which allowed
concomitant use with combined P-gp and weak or moderate CYP3A4
inhibitors (e.g., amiodarone, diltiazem, verapamil, chloramphenicol,
cimetidine, and erythromyci