`
`
` CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`022406Orig1s000
`
`LABELING
`
`
`
`

`

`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use XARELTO®
`(rivaroxaban) safely and effectively. See full prescribing information for
`XARELTO
`XARELTO (rivaroxaban) film-coated oral tablets
`Initial U.S. Approval: 2011
`
`WARNING: SURGICAL SETTINGS--SPINAL/EPIDURAL HEMATOMA
`Epidural or spinal hematomas may occur in patients who are anticoagulated
`and are receiving neuraxial anesthesia or undergoing spinal puncture. These
`hematomas may result in long-term or permanent paralysis. Consider these
`risks when scheduling patients for spinal procedures. Factors that can increase
`the risk of developing epidural or spinal hematomas in these patients include:
`• use of indwelling epidural catheters
`• concomitant use of other drugs that affect hemostasis, such as non-steroidal
`anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants
`• a history of traumatic or repeated epidural or spinal punctures
`• a history of spinal deformity or spinal surgery.
`Monitor patients frequently for signs and symptoms of neurological
`impairment. If neurological compromise is noted, urgent treatment is
`necessary.
`Consider the benefits and risks before neuraxial intervention in patients
`anticoagulated or to be anticoagulated for thromboprophylaxis [see Warnings
`and Precautions (5.1) and Drug Interactions (7)].
`
`----------------------------INDICATIONS AND USAGE---------------------------
`XARELTO is a factor Xa inhibitor indicated for the prophylaxis of deep vein
`thrombosis (DVT) which may lead to pulmonary embolism (PE) in patients
`undergoing knee or hip replacement surgery. (1)
`-----------------------DOSAGE AND ADMINISTRATION-----------------------
`• 10 mg orally, once daily with or without food (2)
`--------------------DOSAGE FORMS AND STRENGTHS----------------------
`Tablet: 10 mg (3)
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`WARNING: SURGICAL SETTINGS—SPINAL/EPIDURAL HEMATOMA
`1 
`INDICATIONS AND USAGE 
`2  DOSAGE AND ADMINISTRATION 
`2.1  Use with P-gp and Strong CYP3A4 Inducers 
`3  DOSAGE FORMS AND STRENGTHS 
`4  CONTRAINDICATIONS 
`5  WARNINGS AND PRECAUTIONS 
`5.1  Spinal/Epidural Anesthesia or Puncture 
`5.2  Risk of Bleeding 
`5.3  Risk of Pregnancy Related Hemorrhage 
`5.4  Renal Impairment 
`5.5  Hepatic Impairment 
`6  ADVERSE REACTIONS 
`6.1  Adverse Reactions in Clinical Trials 
`6.2  Hemorrhage 
`6.3  Other Adverse Reactions 
`6.4  Postmarketing Experience 
`7  DRUG INTERACTIONS 
`7.1  Drugs that Inhibit Cytochrome P450 3A4 Enzymes
`and Drug Transport Systems 
`7.2  Drug-Disease Interactions with Drugs that Inh bit
`Cytochrome P450 3A4 Enzymes and Drug Transport
`Systems 
`7.3  Drugs that Induce Cytochrome P450 3A4 Enzymes
`and Drug Transport Systems 
`7.4  Anticoagulants 
`7.5  NSAIDs/Aspirin 
`7.6  Clopidogrel 
`
`
`
`
`-------------------------------CONTRAINDICATIONS------------------------------
`• Hypersensitivity to XARELTO (4)
`• Active major bleeding (4)
`---------------------------WARNINGS AND PRECAUTIONS--------------------
`• Risk of bleeding: XARELTO can cause serious and fatal bleeding. Promptly
`evaluate signs and symptoms of blood loss. (5.2)
`• Pregnancy related hemorrhage: Use XARELTO with caution in pregnant
`women due to the potential for obstetric hemorrhage and/or emergent
`delivery. Promptly evaluate signs and symptoms of blood loss. (5 3)
`------------------------------ADVERSE REACTIONS------------------------------
`The most common adverse reaction (>5%) was bleeding. (6)
`To report SUSPECTED ADVERSE REACTIONS, contact Janssen
`Pharmaceuticals, Inc. at 1-800-526-7736 or FDA at 1-800-FDA-1088 or
`www.fda.gov/medwatch.
`---------------------------------DRUG INTERACTIONS----------------------------
`• Combined P-gp and strong CYP3A4 inhibitors: Avoid concomitant use unless
`the lack of a significant interaction is proven (7.1)
`• Combined P-gp and weak or moderate CYP3A4 inhibitors: Avoid concomitant
`use unless the benefit outweighs the bleeding risk in patients with renal
`impairment (7.2)
`• Combined P-gp and strong CYP3A4 inducers: Avoid concomitant use or
`consider an increased dose (2.1, 7.3)
`• Anticoagulants: Avoid concomitant use (7.4)
`• Clopidogrel: Avoid concomitant use unless the benefit outweighs the bleeding
`risk (7.6)
`-----------------------USE IN SPECIFIC POPULATIONS-----------------------
`• Nursing mothers: discontinue drug or discontinue nursing (8.3)
`• Renal impairment: Avoid use in patients with severe impairment (CrCl <30
`mL/min). Use with caution in moderate impairment (CrCl 30 to <50 mL/min)
`(8.7)
`• Hepatic impairment: Avoid use in patients with moderate (Child-Pugh B) or
`severe (Child-Pugh C) hepatic impairment or in patients with any degree of
`hepatic disease associated with coagulopathy (8.8)
`See 17 for PATIENT COUNSELING INFORMATION.
`
`Issued: July 2011
`
`
`
`
`
`8  USE IN SPECIFIC POPULATIONS 
`8.1  Pregnancy 
`8.2 
`Labor and Delivery 
`8.3  Nursing Mothers 
`8.4  Pediatric Use 
`8.5  Geriatric Use 
`8.6  Females of Reproductive Potential 
`8.7  Renal Impairment 
`8.8  Hepatic Impairment 
`10  OVERDOSAGE 
`11  DESCRIPTION 
`12  CLINICAL PHARMACOLOGY 
`12.1  Mechanism of Action 
`12.2  Pharmacodynamics 
`12.3  Pharmacokinetics 
`12.4  QT/QTc Prolongation 
`13  NON-CLINICAL TOXICOLOGY 
`13.1  Carcinogenesis, Mutagenesis, and Impairment of
`Fertility 
`14  CLINICAL STUDIES 
`16  HOW SUPPLIED/STORAGE AND HANDLING 
`17  PATIENT COUNSELING INFORMATION 
`17.1 
`Instructions for Patient Use 
`17.2  Bleeding Risks 
`17.3  Concomitant Medication and Herbals 
`17.4  Pregnancy and Pregnancy-Related Hemorrhage 
`17.5  Nursing 
`17.6  Females of Reproductive Potential 
`
`
`*Sections or subsections omitted from the full prescribing information are not
`listed
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`2
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`
`FULL PRESCRIBING INFORMATION
`
`WARNING: SURGICAL SETTINGS--SPINAL/EPIDURAL HEMATOMA
`
`Epidural or spinal hematomas may occur in patients who are anticoagulated and are
`receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may
`result in long-term or permanent paralysis. Consider these risks when scheduling patients
`for spinal procedures. Factors that can increase the risk of developing epidural or spinal
`hematomas in these patients include:
`• use of indwelling epidural catheters
`• concomitant use of other drugs that affect hemostasis, such as non-steroidal anti-
`inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants
`• a history of traumatic or repeated epidural or spinal punctures
`• a history of spinal deformity or spinal surgery.
`
`Monitor patients frequently for signs and symptoms of neurological impairment. If
`neurological compromise is noted, urgent treatment is necessary.
`
`Consider the benefits and risks before neuraxial intervention in patients anticoagulated or
`to be anticoagulated for thromboprophylaxis [see Warnings and Precautions (5.1) and Drug
`Interactions (7)].
`
`INDICATIONS AND USAGE
`1
`XARELTO (rivaroxaban) Tablets are indicated for the prophylaxis of deep vein thrombosis
`(DVT), which may lead to pulmonary embolism (PE) in patients undergoing knee or hip
`replacement surgery.
`
`2 DOSAGE AND ADMINISTRATION
`The recommended dose of XARELTO is 10 mg taken orally once daily with or without food.
`The initial dose should be taken at least 6 to 10 hours after surgery once hemostasis has been
`established.
`
`• For patients undergoing hip replacement surgery, treatment duration of 35 days is
`recommended.
`• For patients undergoing knee replacement surgery, treatment duration of 12 days is
`recommended.
`If a dose of XARELTO is not taken at the scheduled time, the dose should be taken as soon as
`possible on the same day and continued on the following day with the once daily intake as
`recommended.
`
`Administration via GI feeding tube:
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`Rivaroxaban absorption is dependent on the site of drug release in the gastrointestinal (GI) tract
`(gastric versus small intestine). When administering XARELTO as a crushed tablet via a feeding
`tube, confirm gastric placement of the tube [see Clinical Pharmacology (12.3)].
`
`2.1 Use with P-gp and Strong CYP3A4 Inducers
`Concomitant use of XARELTO with drugs that are combined P-gp and strong CYP3A4 inducers
`(e.g., carbamazepine, phenytoin, rifampin, St. John’s wort) should be avoided. A XARELTO
`dose increase to 20 mg (i.e., two 10 mg tablets) should be considered if these drugs must be
`coadministered. The 20 mg dose should be taken with food [see Drug Interactions (7.3) and
`Clinical Pharmacology (12.3)].
`
`3 DOSAGE FORMS AND STRENGTHS
`XARELTO 10 mg tablets are round, light red, biconvex and film-coated with a triangle pointing
`down above a “10” marked on one side and “Xa” on the other side.
`
`4 CONTRAINDICATIONS
`XARELTO is contraindicated in patients with:
`
`• hypersensitivity to XARELTO
`• active major bleeding [see Warnings and Precautions (5.2)]
`
`5 WARNINGS AND PRECAUTIONS
`5.1 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
`[see Boxed Warning].
`
`An epidural catheter should not be removed earlier than 18 hours after the last administration of
`XARELTO. The next XARELTO dose is not to be administered earlier than 6 hours after the
`removal of the catheter. If traumatic puncture occurs, the administration of XARELTO is to be
`delayed for 24 hours.
`
`5.2 Risk of Bleeding
`XARELTO increases the risk of bleeding and can cause serious and fatal bleeding. Major
`hemorrhages including intracranial, epidural hematoma, gastrointestinal, retinal, and adrenal
`bleeding have been reported. Use XARELTO with caution in conditions with increased risk of
`hemorrhage.
`
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`Concomitant use of drugs affecting hemostasis increases the risk of bleeding. These include
`platelet aggregation inhibitors, other antithrombotic agents, fibrinolytic therapy, thienopyridines
`and chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) [see Drug Interactions
`(7.4), (7.5), (7.6)].
`
`Bleeding can occur at any site during therapy with XARELTO. An unexplained fall in
`hematocrit or blood pressure should lead to a search for a bleeding site. Promptly evaluate any
`signs or symptoms of blood loss.
`
`5.3 Risk of Pregnancy Related Hemorrhage
`XARELTO should be used with caution in pregnant women and only if the potential benefit
`justifies the potential risk to the mother and fetus. XARELTO dosing in pregnancy has not been
`studied. The anticoagulant effect of XARELTO cannot be monitored with standard laboratory
`testing nor readily reversed. Promptly evaluate any signs or symptoms suggesting blood loss
`(e.g., a drop in hemoglobin and/or hematocrit, hypotension, or fetal distress).
`
`5.4 Renal Impairment
`Avoid the use of XARELTO in patients with severe renal impairment (creatinine clearance
`<30 mL/min) due to an expected increase in rivaroxaban exposure and pharmacodynamic effects
`in this patient population.
`
`Observe closely and promptly evaluate any signs or symptoms of blood loss in patients with
`moderate renal impairment (CrCl 30 to <50 mL/min). Patients who develop acute renal failure
`while on XARELTO should discontinue the treatment [see Use in Specific Populations (8.7)].
`
`5.5 Hepatic Impairment
`Clinical data in patients with moderate hepatic impairment indicate a significant increase in
`rivaroxaban exposure and pharmacodynamic effects. No clinical data are available for patients
`with severe hepatic impairment. Avoid use of XARELTO in patients with moderate (Child-Pugh
`B) or severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with
`coagulopathy [see Use in Specific Populations (8.8)].
`
`6 ADVERSE REACTIONS
`6.1 Adverse Reactions in Clinical Trials
`In three randomized, controlled clinical trials (RECORD 1-3) in elective joint replacement
`surgery, 4487 patients received XARELTO 10 mg orally once daily. The mean duration of
`XARELTO treatment was 11.9 days in the total knee replacement study and 33.4 days in the
`total hip replacement studies. Overall, the mean age of the patients studied in the XARELTO
`group was 64 years, 59% were female and 82% were Caucasian. Twenty-seven percent (1206) of
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`patients underwent knee replacement surgery and 73% (3281) underwent hip replacement
`surgery.
`
`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.
`
`In the RECORD clinical trials, the overall incidence rate of adverse reactions leading to
`permanent treatment discontinuation was 3.7% with XARELTO.
`
`6.2 Hemorrhage
`The most common adverse reactions with XARELTO were bleeding complications [see
`Warnings and Precautions (5.2)]. The rates of major bleeding events and any bleeding events
`observed in patients in the RECORD clinical trials are shown in Table 1.
`
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`

`Bleeding Events* in Patients Undergoing Hip or Knee Replacement Surgeries (RECORD1-3)
`Enoxaparin†
`XARELTO 10 mg
`
`
`
`N = 4487
`N = 4524
`n (%)
`n (%)
`14 (0.3)
`9 (0.2)
`1 (<0.1)
`0
`2 (<0.1)
`3 (0.1)
`7 (0.2)
`5 (0.1)
`4 (0.1)
`1 (<0.1)
`
`
`Table 1:
`
`Total treated patients
`
`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‡
`Hip Surgery Studies
`
`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‡
`Knee Surgery Study
`
`261 (5.8)
`N = 3281
`n (%)
`7 (0.2)
`1 (<0.1)
`1 (<0.1)
`2 (0.1)
`3 (0.1)
`
`251 (5.6)
`N = 3298
`n (%)
`3 (0.1)
`0
`1 (<0.1)
`1 (<0.1)
`1 (<0.1)
`
`201 (6.1)
`N = 1206
`n (%)
`7 (0.6)
`0
`1 (0.1)
`5 (0.4)
`1 (0.1)
`
`191 (5.8)
`N = 1226
`n (%)
`6 (0.5)
`0
`2 (0.2)
`4 (0.3)
`0
`
`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‡
`60 (4.9)
`60 (5.0)
`* 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.
`
`6.3 Other Adverse Reactions
`Table 2 shows other adverse drug reactions (ADRs) reported in ≥1% of XARELTO-treated
`patients in the RECORD clinical studies.
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`Table 2: Other Adverse Drug Reactions* Reported by ≥1% of XARELTO-Treated Patients in RECORD
`1-3 Studies
`System/Organ Class
`Adverse Reaction
`
`
`Enoxaparin†
`
`(N = 4524)
`n (%)
`
`Injury, poisoning and
`procedural complications
`Wound secretion
`Musculoskeletal and connective
`tissue disorders
`Pain in extremity
`Muscle spasm
`Nervous system disorders
`Syncope
`Skin and subcutaneous tissue
`disorders
`79 (1.8)
`96 (2.1)
`Pruritus
`40 (0.9)
`63 (1.4)
`Blister
`* ADR 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 1-3)
`
`
`XARELTO
`10 mg
`(N = 4487)
`n (%)
`
`
`125 (2.8)
`
`
`74 (1.7)
`52 (1.2)
`
`55 (1.2)
`
`
`89 (2.0)
`
`55 (1.2)
`32 (0.7)
`
`32 (0.7)
`
`The following ADR occurred in <1% of XARELTO-treated patients in the clinical studies:
`
`Renal and urinary disorders: dysuria
`
`The laboratory abnormalities in Table 3 were observed in clinical studies:
`
`Enoxaparin*
`
`Table 3: Laboratory Abnormalities in RECORD 1-3 Clinical Studies
`Laboratory Abnormality
`XARELTO
`10 mg
`114/4441 (2.6%)
`122/4441 (2.8%)
`140/4442 (3.2%)
`292/4442 (6.6%)
`116/4425 (2.6%)
`
`Alanine aminotransferase >3 x ULN
`Aspartate aminotransferase >3 x ULN
`Total bilirubin >1.5 x ULN
`Gamma-glutamyltransferase >3 x ULN
`Platelet counts <100,000/mm3 or <50% of baseline
`value
`* Includes the placebo-controlled period of RECORD 2, enoxaparin dosing was 40 mg once daily (RECORD 1-3)
`
`6.4 Postmarketing Experience
`The following additional adverse reactions have been reported in countries where XARELTO
`has been marketed. 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.
`
`167/4456 (3.8%)
`152/4456 (3.4%)
`128/4456 (2.9%)
`391/4457 (8.8%)
`131/4447 (3.0%)
`
`Blood and lymphatic system disorders: agranulocytosis
`
`Gastrointestinal disorders: retroperitoneal hemorrhage
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`Hepatobiliary disorders: jaundice, cholestasis, cytolytic hepatitis
`
`Immune system disorder: hypersensitivity, anaphylactic reaction, anaphylactic shock
`
`Nervous system disorders: cerebral hemorrhage, subdural hematoma, epidural hematoma,
`hemiparesis
`
`Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome
`
`7 DRUG INTERACTIONS
`Rivaroxaban is a substrate of CYP3A4/5, CYP2J2, and the P-gp and ATP-binding cassette G2
`(ABCG2) transporters. Inhibitors and inducers of these CYP450 enzymes or transporters may
`result in changes in rivaroxaban exposure.
`
`7.1 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, increases in rivaroxaban exposure and pharmacodynamic effects (i.e., factor
`Xa inhibition and PT prolongation) were observed. Significant increases in rivaroxaban exposure
`may increase bleeding risk.
`
`• Ketoconazole (combined P-gp and strong CYP3A4 inhibitor): Steady-state rivaroxaban AUC
`and Cmax increased by 160% and 70%, respectively. Similar increases in pharmacodynamic
`effects were also observed.
`
`• Ritonavir (combined P-gp and strong CYP3A4 inhibitor): Single-dose rivaroxaban AUC and
`Cmax increased by 150% and 60%, respectively. Similar increases in pharmacodynamic
`effects were also observed.
`
`• Clarithromycin (combined P-gp and strong CYP3A4 inhibitor): Single-dose rivaroxaban
`AUC and Cmax increased by 50% and 40%, respectively. The smaller increases in exposure
`observed for clarithromycin compared to ketoconazole or ritonavir may be due to the relative
`difference in P-gp inhibition.
`
`• Erythromycin (combined P-gp and moderate CYP3A4 inhibitor): Both the single-dose
`rivaroxaban AUC and Cmax increased by 30%.
`
`Avoid concomitant administration of XARELTO with combined P-gp and strong CYP3A4
`inhibitors (e.g., ketoconazole, itraconazole, lopinavir/ritonavir, ritonavir, indinavir/ritonavir, and
`conivaptan) which cause significant increases in rivaroxaban exposure that may increase
`bleeding risk.
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`When clinical 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.
`
`7.2 Drug-Disease Interactions with Drugs that Inhibit Cytochrome P450 3A4
`Enzymes and Drug Transport Systems
`Based on simulated pharmacokinetic data, patients with renal impairment receiving XARELTO
`with drugs that are combined P-gp and weak or moderate CYP3A4 inhibitors (e.g.,
`erythromycin, azithromycin, diltiazem, verapamil, quinidine,
`ranolazine, dronedarone,
`amiodarone, and felodipine), may have significant increases in exposure compared with patients
`with normal renal function and no inhibitor use, since both pathways of rivaroxaban elimination
`are affected. Since these increases may increase bleeding risk, use XARELTO in this situation
`only if the potential benefit justifies the potential risk [see Use in Specific Populations (8.7)].
`
`7.3 Drugs that Induce Cytochrome P450 3A4 Enzymes and Drug Transport
`Systems
`In a drug interaction study, co-administration of XARELTO (20 mg single dose with food) with
`a drug that is a combined P-gp and strong CYP3A4 inducer (rifampicin titrated up to 600 mg
`once daily) led to an approximate decrease of 50% and 22% in AUC and Cmax, respectively.
`Similar decreases in pharmacodynamic effects were also observed. These decreases in exposure
`to rivaroxaban may decrease efficacy.
`
`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). Consider increasing the
`XARELTO dose if these drugs must be coadministered [see Dosage and Administration (2.1)].
`
`7.4 Anticoagulants
`In a drug interaction study, single doses of enoxaparin (40 mg subcutaneous) and XARELTO
`(10 mg) given concomitantly resulted in an additive effect on anti-factor Xa activity. Enoxaparin
`did not affect the pharmacokinetics of rivaroxaban. In another study, single doses of warfarin
`(15 mg) and XARELTO (5 mg) resulted in an additive effect on factor Xa inhibition and PT.
`Warfarin did not affect the pharmacokinetics of rivaroxaban. The safety of long-term
`concomitant use of these drugs has not been studied.
`
`Avoid concurrent use of XARELTO with other anticoagulants due to the increased bleeding risk
`other than during therapeutic transition periods where patients should be observed closely.
`Promptly evaluate any signs or symptoms of blood loss [see Warnings and Precautions (5.2)].
`
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`7.5 NSAIDs/Aspirin
`In a single-dose drug interaction study there were no pharmacokinetic or pharmacodynamic
`interactions observed after concomitant administration of naproxen or aspirin (acetylsalicylic
`acid) with XARELTO. The safety of long-term concomitant use of these drugs has not been
`studied.
`
`NSAIDs/aspirin are known to increase bleeding, and bleeding risk may be increased when these
`drugs are used concomitantly with XARELTO.
`
`Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with
`NSAIDs and/or platelet aggregation inhibitors [see Warnings and Precautions (5.2)].
`
`7.6 Clopidogrel
`In two drug interaction studies where clopidogrel (300 mg loading dose followed by 75 mg daily
`maintenance dose) and XARELTO (15 mg single dose) were co-administered in healthy
`subjects, an increase in bleeding time to 45 minutes was observed in approximately 45% and
`30% of subjects in these studies, respectively. The change in bleeding time was approximately
`twice the maximum increase seen with either drug alone. There was no change in the
`pharmacokinetics of either drug.
`
`Avoid concurrent administration of clopidogrel with XARELTO unless the benefit outweighs the
`risk of increased bleeding [see Warnings and Precautions (5.2)].
`
`8 USE IN SPECIFIC POPULATIONS
`8.1 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.
`
`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
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`
`rabbits were given oral doses of ≥10 mg/kg rivaroxaban during the period of organogenesis. This
`dose corresponds to about 11 times the human exposure of unbound drug, based on AUC
`comparisons at the maximum recommended human dose of 10 mg/day. Fetal body weights
`decreased when pregnant rats were given oral doses of 120 mg/kg. This dose corresponds to
`about 40 times the human exposure of unbound drug.
`
`8.2 Labor and Delivery
`Safety and effectiveness of rivaroxaban 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 17 times maximum human exposure of the
`unbound drug at the human dose of 10 mg/day).
`
`8.3 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 the drug, taking into account the
`importance of the drug to the mother.
`
`8.4 Pediatric Use
`Safety and effectiveness in pediatric patients have not been established.
`
`8.5 Geriatric Use
`Of the total number of patients in the RECORD 1-3 clinical studies evaluating XARELTO, about
`53% were 65 years and over, while about 15% 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.
`
`Elderly subjects exhibited an increase in exposure that may be caused by age related changes in
`renal function. For patients 65 years of age and older, consideration should be given to
`assessment of renal function prior to starting therapy with XARELTO. Promptly evaluate any
`signs or symptoms of blood loss [see Clinical Pharmacology (12.3)].
`
`8.6 Females of Reproductive Potential
`Females of reproductive potential requiring anticoagulation should discuss pregnancy planning
`with their physician.
`
`12
`
`

`

`
`8.7 Renal Impairment
`The safety and pharmacokinetics of single-dose XARELTO (10 mg) were evaluated in a study in
`healthy subjects [CrCl ≥80 mL/min (n=8)] and in subjects with varying degrees of renal
`impairment (see Table 4). Compared to healthy subjects with normal creatinine clearance,
`rivaroxaban exposure
`increased
`in
`subjects with
`renal
`impairment.
`Increases
`in
`pharmacodynamic effects were also observed.
`
`Table 4:
`
`Parameter
`
`Percent Increase of Rivaroxaban PK and PD Parameters from Normal in Subjects with Renal
`Insufficiency from a Dedicated Renal Impairment Study
`Renal Impairment Class
`[CrCl (mL/min)]
`Severe
`Moderate
`Mild
`[15 to 29]
`[30 to 49]
`[50 to 79]
`N=8
`N=8
`N=8
`AUC
`Exposure
`64
`52
`44
`Cmax
`(% increase relative to normal)
`26
`12
`28
`AUC
`FXa Inhibition
`100
`86
`50
`Emax
`(% increase relative to normal)
`12
`10
`9
`AUC
`PT Prolongation
`144
`116
`33
`Emax
`(% increase relative to normal)
`20
`17
`4
`PT = Prothrombin time; FXa = Coagulation factor Xa; AUC = Area under the concentration or effect curve;
`Cmax = maximum concentration; Emax = maximum effect; and CrCl = creatinine clearance
`
`
`Patients with any degree of renal impairment with concurrent use of P-gp and weak to moderate
`CYP3A4 inhibitors may have significant increases in exposure which may increase bleeding risk
`[see Drug Interactions (7.2)].
`
`The combined analysis of the RECORD 1-3 clinical efficacy studies did not show an increase in
`bleeding risk for patients with moderate renal impairment and reported a possible increase in
`total VTE in this population. Observe closely and promptly evaluate any signs or symptoms of
`blood loss in patients with moderate renal impairment (CrCl 30 to <50 mL/min). Avoid the use
`of XARELTO in patients with severe renal impairment (CrCl <30 mL/min) [see Warnings and
`Precautions (5.2, 5.4)].
`
`8.8 Hepatic Impairment
`The safety and pharmacokinetics of single-dose XARELTO (10 mg) were evaluated in a study in
`healthy subjects (n=16) and subjects with varying degrees of hepatic impairment (see Table 5).
`No patients with severe hepatic impairment (Child-Pugh C) were studied. Compared to healthy
`subjects with normal liver function, significant increases in rivaroxaban exposure were observed
`in subjects with moderate hepatic impairment (Child-Pugh B). Increases in pharmacodynamic
`effects were also observed.
`
`13
`
`

`

`
`Table 5:
`
`Percent Increase of Rivaroxaban PK and PD Parameters from Normal in Subjects with Hepatic
`Insufficiency from a Dedicated Hepatic Impairment Study
`Hepatic Impairment Class
`(Child-Pugh Class)
`
`Parameter
`
`Moderate
`Mild
`(Child-Pugh B)
`(Child-Pugh A)
`N=8
`N=8
`AUC
`Exposure
`127
`15
`Cmax
`(% increase relative to normal)
`27
`0
`AUC
`FXa Inhibition
`159
`8
`Emax
`(% increase relative to normal)
`24
`0
`AUC
`PT Prolongation
`114
`6
`Emax
`(% increase relative to normal)
`41
`2
`PT = Prothrombin time; FXa = Coagulation factor Xa; AUC = Area under the concentration or effect curve;
`Cmax = maximum concentration; Emax = maximum effect
`
`
`Avoid the use of XARELTO in patients with moderate (Child-Pugh B) or severe (Child-Pugh C)
`hepatic impairment or with any hepatic disease associated with coagulopathy [see Warnings and
`Precautions (5.2, 5.5)].
`
`10 OVERDOSAGE
`Overdose of XARELTO may lead to hemorrhage. A specific antidote of rivaroxaban is not
`available. Discontinue XARELTO and initiate appropriate therapy if bleeding complications
`associated with overdosage occur. 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 expected to be dialyzable [see Clinical Pharmacology (12.3)].
`
`11 DESCRIPTION
`Rivaroxaban, a factor Xa inhibitor, is the active ingredient in XARELTO Tablets with the
`chemical name 5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-
`yl}methyl)-2-thiophenecarboxamide. The molecular formula of rivaroxaban is C19H18ClN3O5S
`and the molecular weight is 435.89. The structural formula is:
`
`
`
`
`
`14
`
`

`

`
`Rivaroxaban is a pure (S)-enantiomer. It is an odorless, non-hygroscopic, white to yellowish
`powder. Rivaroxaban is only slightly soluble in organic solvents (e.g., acetone, polyethylene
`glycol 400) and is practically insoluble in water and aqueous media.
`
`Each XARELTO tablet contains 10 mg of rivaroxaban. The inactive ingredients of XARELTO
`are: Microcrystalline cellulose, croscarmellose sodium, hypromellose, lactose monohydrate,
`magnesium stearate, sodium lauryl sulfate, and Opadry® Pink, a proprietary filmcoating mixture
`containing polyethylene glycol 3350, hypromellose, titanium dioxide, and ferric oxide red.
`
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`XARELTO is an orally bioavailable factor Xa inhibitor that selectively blocks the active site of
`factor Xa and does not require a cofactor (such as Anti-thrombin III) for activity. Activation of
`factor X to factor Xa (FXa) via the intrinsic and extrinsic pathways plays a central role in the
`cascade of blood coagulation.
`
`12.2 Pharmacodynamics
`Dose-dependent inhibition of factor Xa activity was observed in humans and the Neoplastin®
`prothrombin time (PT), activated partial thromboplastin time (aPTT) and HepTest® are
`prolonged dose-dependently. Anti-factor Xa activity is also influenced by rivaroxaban. There are
`no data on the use of the International Normalized Ratio (INR). The predictive value of these
`coagulation parameters for bleeding risk or efficacy has not been established.
`
`12.3 Pharmacokinetics
`Absorption
`The absolute bioavailability of rivaroxaban is high (estimated to be 80% to 100%) for the 10 mg
`dose. Rivaroxaban is rapidly absorbed with maximum concentrations (Cmax) appearing 2 to 4
`hours after tablet intake.
`
`Rivaroxaban pharmacokinetics are linear with no relevant accumulation beyond steady-state
`after multiple doses. Intake with food does not affect rivaroxaban