XARELTO ® ( rivaroxaban ) tablets XARELTO ® ( rivaroxaban ) tablets XARELTO ® ( rivaroxaban ) tablets
Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery : In the RECORD clinical trials , the overall incidence rate of adverse reactions leading to permanent treatment discontinuation was 3.7 % with XARELTO .
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 (%)
N = 4524 n (%)
Major bleeding event |
14 ( 0.3 ) |
9 ( 0.2 ) |
Fatal bleeding |
1 (< 0.1 ) |
0 |
Bleeding into a critical organ |
2 (< 0.1 ) |
3 ( 0.1 ) |
Bleeding that required re-operation |
7 ( 0.2 ) |
5 ( 0.1 ) |
Extra-surgical site bleeding requiring |
4 ( 0.1 ) |
1 (< 0.1 ) |
transfusion of > 2 units of whole blood or packed cells |
|
|
Any bleeding event ‡ |
261 ( 5.8 ) |
251 ( 5.6 ) |
Hip Surgery Studies |
N = 3281 n (%) |
N = 3298 n (%) |
Major bleeding event |
7 ( 0.2 ) |
3 ( 0.1 ) |
Fatal bleeding |
1 (< 0.1 ) |
0 |
Bleeding into a critical organ |
1 (< 0.1 ) |
1 (< 0.1 ) |
Bleeding that required re-operation |
2 ( 0.1 ) |
1 (< 0.1 ) |
Extra-surgical site bleeding requiring |
3 ( 0.1 ) |
1 (< 0.1 ) |
transfusion of > 2 units of whole blood or packed cells |
|
|
Any bleeding event ‡ |
201 ( 6.1 ) |
191 ( 5.8 ) |
Knee Surgery Study |
N = 1206 n (%) |
N = 1226 n (%) |
Major bleeding event |
7 ( 0.6 ) |
6 ( 0.5 ) |
Fatal bleeding |
0 |
0 |
Bleeding into a critical organ |
1 ( 0.1 ) |
2 ( 0.2 ) |
Bleeding that required re-operation |
5 ( 0.4 ) |
4 ( 0.3 ) |
Extra-surgical site bleeding requiring |
1 ( 0.1 ) |
0 |
transfusion of > 2 units of whole blood or packed cells |
|
|
Any bleeding event ‡ |
60 ( 5.0 ) |
60 ( 4.9 ) |
* Bleeding events occurring any time following the first dose of double-blind |
study medication ( which may have been prior to administration of active |
drug ) until two days after the last dose of double-blind study medication . |
Patients may have more than one event . |
|
†
Includes the placebo-controlled period for RECORD 2 , enoxaparin dosing
|
was 40 mg once daily ( RECORD 1-3 ) |
‡ Includes major bleeding events |
Following XARELTO treatment , the majority of major bleeding complications |
( ≥60 %) occurred during the first week after surgery . |
Other Adverse Reactions : Non-hemorrhagic adverse reactions reported in |
≥1 % of XARELTO-treated patients in the EINSTEIN Extension study are shown |
in Table 5 . |
Table 5 : Other Adverse Reactions * Reported by ≥1 % of XARELTO-Treated |
Patients in EINSTEIN Extension Study |
System Organ Class Preferred Term
XARELTO N = 598 n (%)
Placebo N = 590 n (%)
Gastrointestinal disorders Abdominal pain upper |
10 ( 1.7 ) |
1 ( 0.2 ) |
Dyspepsia |
8 ( 1.3 ) |
4 ( 0.7 ) |
Toothache |
6 ( 1.0 ) |
0 |
|
General disorders and administration site conditions
Fatigue
|
6 ( 1.0 ) |
3 ( 0.5 ) |
Infections and infestations Sinusitis |
7 ( 1.2 ) |
3 ( 0.5 ) |
Urinary tract infection |
7 ( 1.2 ) |
3 ( 0.5 ) |
|
Musculoskeletal and connective tissue disorders
Back pain
|
22 ( 3.7 ) |
7 ( 1.2 ) |
Osteoarthritis |
10 ( 1.7 ) |
5 ( 0.8 ) |
Respiratory , thoracic and mediastinal disorders Oropharyngeal pain |
6 ( 1.0 ) |
2 ( 0.3 ) |
* Adverse reaction ( with Relative Risk > 1.5 for XARELTO versus placebo ) |
occurred after the first dose and up to 2 days after the last dose of study |
drug . Incidences are based on the number of patients , not the number of |
events . Although a patient may have had 2 or more clinical adverse |
reactions , the patient is counted only once in a category . The same patient |
may appear in different categories . |
Non-hemorrhagic adverse reactions reported in ≥1 % of XARELTO-treated |
patients in RECORD 1-3 studies are shown in Table 6 . |
Table 6 : Other Adverse Drug Reactions * Reported by ≥1 % of XARELTO- |
Treated Patients in RECORD 1-3 Studies |
System / Organ Class |
Enoxaparin † |
Adverse Reaction |
XARELTO 10 mg N = 4487 n (%)
N = 4524 n (%)
Injury , poisoning and procedural complications Wound secretion |
125 ( 2.8 ) |
89 ( 2.0 ) |
|
Musculoskeletal 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 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 , conducted in subjects with normal renal function , evaluating the concomitant use with drugs that are combined P-gp and CYP3A4 inhibitors ( ketoconazole , ritonavir , clarithromycin , and erythromycin ) or a moderate CYP3A4 inhibitor ( 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 anti-factor 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 either weak ( e . g ., amiodarone ) or moderate CYP3A4 inhibitors ( e . g ., diltiazem , verapamil , and erythromycin ), did not show an increase in bleeding in patients with CrCl 30 to < 50 mL / min [ Hazard Ratio ( 95 % CI ): 1.05 ( 0.77 , 1.42 )] [ see Use in Specific Populations ].
XARELTO should not be used in patients with CrCl 15 to < 80 mL / min who are receiving concomitant combined P-gp and moderate CYP3A4 inhibitors ( e . g ., diltiazem , verapamil , dronedarone , and erythromycin ) unless the potential benefit justifies the potential risk [ see Clinical Pharmacology ( 12.3 ) in full Prescribing Information ].
USE IN SPECIFIC POPULATIONS Pregnancy : Pregnancy Category C : There are no adequate or well-controlled studies of XARELTO in pregnant women , and dosing for pregnant women has not been established . Use XARELTO with caution in pregnant patients because of the potential for pregnancy related hemorrhage and / or emergent delivery with an anticoagulant that is not readily reversible . The anticoagulant effect of XARELTO cannot be reliably monitored with standard laboratory testing . Animal reproduction studies showed no increased risk of structural malformations , but increased post-implantation pregnancy loss occurred in rabbits . XARELTO should be used during pregnancy only if the potential benefit justifies the potential risk to mother and fetus [ see Warnings and Precautions ].
Rivaroxaban crosses the placenta in animals . Animal reproduction studies have shown pronounced maternal hemorrhagic complications in rats and an increased incidence of post-implantation pregnancy loss in rabbits . Rivaroxaban increased fetal toxicity ( increased resorptions , decreased number of live fetuses , and decreased fetal body weight ) when pregnant rabbits were given oral doses of ≥10 mg / kg rivaroxaban during the period of organogenesis . This dose corresponds to about 4 times the human exposure of unbound drug , based on AUC comparisons at the highest recommended human dose of 20 mg / day . Fetal body weights decreased when pregnant rats were given oral doses of 120 mg / kg . This dose corresponds to about 14 times the human exposure of unbound drug .
Labor and Delivery : Safety and effectiveness of XARELTO during labor and delivery have not been studied in clinical trials . However , in animal studies maternal bleeding and maternal and fetal death occurred at the rivaroxaban dose of 40 mg / kg ( about 6 times maximum human exposure of the unbound drug at the human dose of 20 mg / day ).
Nursing Mothers : It is not known if rivaroxaban is excreted in human milk . Rivaroxaban and / or its metabolites were excreted into the milk of rats . Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from rivaroxaban , a decision should be made whether to discontinue nursing or discontinue XARELTO , taking into account the importance of the drug to the mother .
Pediatric Use : Safety and effectiveness in pediatric patients have not been established .
Geriatric Use : Of the total number of patients in the RECORD 1-3 clinical studies evaluating XARELTO , about 54 % were 65 years and over , while about 15 % were > 75 years . In ROCKET AF , approximately 77 % were 65 years and over and about 38 % were > 75 years . In the EINSTEIN DVT , PE and Extension clinical studies approximately 37 % were 65 years and over and about 16 % were > 75 years . In clinical trials the efficacy of XARELTO in the elderly ( 65 years or older ) was similar to that seen in patients younger than 65 years . Both thrombotic and bleeding event rates were higher in these older patients , but the risk-benefit profile was favorable in all age groups [ see Clinical Pharmacology ( 12.3 ) and Clinical Studies ( 14 ) in full Prescribing Information ].
Females of Reproductive Potential : Females of reproductive potential requiring anticoagulation should discuss pregnancy planning with their physician .
Renal Impairment : In pharmacokinetic studies , compared to healthy subjects with normal creatinine clearance , rivaroxaban exposure increased by approximately 44 to 64 % in subjects with renal impairment . Increases in pharmacodynamic effects were also observed [ see Clinical Pharmacology ( 12.3 ) in full Prescribing Information ].
Nonvalvular Atrial Fibrillation : In the ROCKET AF trial , patients with CrCl 30 to 50 mL / min were administered XARELTO 15 mg once daily resulting in serum concentrations of rivaroxaban and clinical outcomes similar to those in patients with better renal function administered XARELTO 20 mg once daily . Patients with CrCl 15 to 30 mL / min were not studied , but administration of XARELTO 15 mg once daily is also expected to result in serum concentrations of rivaroxaban similar to those in patients with normal renal function [ see Dosage and Administration ( 2.3 ) and Clinical Pharmacology ( 12.3 ) in full Prescribing Information ].
Patients with End-Stage Renal Disease on Dialysis : Clinical efficacy and safety studies with XARELTO did not enroll patients with end-stage renal disease ( ESRD ) on dialysis . In patients with ESRD maintained on intermittent hemodialysis , administration of XARELTO 15 mg once daily will result in concentrations of rivaroxaban and pharmacodynamic activity similar to those observed in the ROCKET AF study [ see Clinical Pharmacology ( 12.2 , 12.3 ) in full Prescribing Information ]. It is not known whether these concentrations will lead to similar stroke reduction and bleeding risk in patients with ESRD on dialysis as was seen in ROCKET AF .
Treatment of DVT and / or PE , and Reduction in the Risk of Recurrence of DVT and of PE : In the EINSTEIN trials , patients with CrCl values < 30 mL / min at screening were excluded from the studies . Avoid the use of XARELTO in patients with CrCl < 30 mL / min .
Prophylaxis of DVT Following Hip or Knee Replacement Surgery : The combined analysis of the RECORD 1-3 clinical efficacy studies did not show an increase in bleeding risk for patients with CrCl 30 to 50 mL / min and reported a possible increase in total venous thromboemboli in this population . Observe closely and promptly evaluate any signs or symptoms of blood loss in patients with CrCl 30 to 50 mL / min . Avoid the use of XARELTO in patients with CrCl < 30 mL / min .
Hepatic Impairment : In a pharmacokinetic study , compared to healthy subjects with normal liver function , AUC increases of 127 % were observed in subjects with moderate hepatic impairment ( Child-Pugh B ).
The safety or PK of XARELTO in patients with severe hepatic impairment ( Child-Pugh C ) has not been evaluated [ see Clinical Pharmacology ( 12.3 ) in full Prescribing Information ].
Avoid the use of XARELTO in patients with moderate ( Child-Pugh B ) and severe ( Child-Pugh C ) hepatic impairment or with any hepatic disease associated with coagulopathy .
OVERDOSAGE Overdose of XARELTO may lead to hemorrhage . Discontinue XARELTO and initiate appropriate therapy if bleeding complications associated with overdosage occur . A specific antidote for rivaroxaban is not available . Rivaroxaban systemic exposure is not further increased at single doses > 50 mg due to limited absorption . The use of activated charcoal to reduce absorption in case of XARELTO overdose may be considered . Due to the high plasma protein binding , rivaroxaban is not dialyzable [ see Warnings and Precautions and Clinical Pharmacology ( 12.3 ) in full Prescribing Information ]. Partial reversal of laboratory anticoagulation parameters may be achieved with use of plasma products .
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Finished Product Manufactured by : Janssen Ortho , LLC Gurabo , PR 00778
or
Bayer Pharma AG 51368 Leverkusen , Germany
Manufactured for : Janssen Pharmaceuticals , Inc . Titusville , NJ 08560
Licensed from : Bayer HealthCare AG 51368 Leverkusen , Germany
© Janssen Pharmaceuticals , Inc . 2011 052843-160508