INFORMTION
`HIGHLIGHTS
`OF PRESCRIING
`ThesehighUghts do not include all the information needed to ,use XAL TO~
`(rivaroxaban) safely and effectively. See ful prescribing information for
`XARELTO
`
`XA'L TO (rivaroxllban)
`t1-coated
`I"itial U.S. Approval: 2011
`
`oral tablets
`
`WARNING: 'SuRGIcAL
`
`Epiduralorspiiial bèmatQmas may Qccur hi patieiitswho are
`
`anticoagulated
`and are receivig neuraxialanestliesia or undergoingspinlll pum:ture. These
`these
`result
`in long-term or permanent paralysis. Consider
`hematomas may
`risks when scheduling patients fQr spinal procedures. FactQrs that can increase
`the risk 'of develQpiig epidural or spinal hematomas in these patients include:
`. use of indweUilig epidural catheters
`. coitconitanl use, of other drugs that affect hemostasis, such as non-steroidal
`inhibitors, other anticoagulants '
`, anti-inflammatory drugs (NSAIDs), platelet
`
`. a history of traunaticQuepeated epidural or spinal punctures
`surgery,
`_ a history ofspinal defornity or spinal
`and symptoms of neurological
`MQnitor patientsfrequentiy for signs
`impaiÌ'ent.If neurological comprQnise is noted, urgenttreatient is '
`, necessary.
`
`before neuraxial interVention inpatients
`Consider thebenelìts and risks
`anticQagulated Qr to be anticoagulated fQr ,thrombQprophylaxis (see Warnings
`
`alldPrectil(tjnns '$.1 alUlprli lnitrraçtlt!!ii 7. '
`
`--____---INDICATIONS AND.USAGE------7-----
`the prophylaxiS of deep vein
`XARLTO is a factor Xa inhibitor indicated for
`thrombosis (DVT)whichmay lead to pulmonaryèmbolism (PE)inpatienis
`undergoingknèe or hip repiåcementsurgery.(I)' ,
`
`----'cc--DOSAGE AND'ADMINISTRATION-~------
`0; i Omgorâlly, once dailywith or without food (2)
`
`-DOSAGE
`
`FORMS AND STRENGTHSc~-~__~-
`
`Tablet: 10 mg(3)
`
`FULL
`
`PRESCRIBING
`
`INFORMATION: èONTENTS*
`
`WARING: SURGICAL 8ETTINGS-PINAL/EPIDURL HEMATOMA
`1 INDICAtiONS AND USAGE
`2 DOSAGEANP ADMINISTRATION
`2.1 Use with P-gp and Strong CYP3A4lnducers
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS" ' '
`5 WARNINGSANDPRECAUTIONS
`5.1 Spinal/Epidural Anesthesia or Puncture
`5.2 ~iskof Bleeding
`5.3 Risk 9fPregnancyReiated Hemorrhage
`5.4 Renal Impairrent
`Impairment
`5:5 Hepatic
`REACTIONS
`6.1 AdverSe Reactions
`6.2 Hemorrhage
`6,3 Other Adverse Reaètions
`6.4 Póstmarketing Experience
`7 DRUG INTERACTIONS
`7,1 "Drugs,thatlnhibilCytochromeP4503A4 Enzymes
`and Drug Transport SystemS
`7.2 Drog7Diseas,elnteractions with
`
`6 ADVERSE
`
`in Clinical TrialS
`
`Drugs that Inhibit
`and ,Drug Transport
`
`Cýtochrome P450 3A4 Enzymes
`Systems
`Induce Cytochrome P450 3A4 Enzymes
`that
`7,3 Drugs
`and Drug Transport Systems
`7.4 AnticoagUlants
`7,5 NSAIDs/Aspirin
`7.6 Clopidögrel
`
`------------------_CONTRANDICATIONSc-__------------
`. Hypersensitivity toXARLTO (4)
`_Active major bleeding (4) ,
`
`------.,-----WAIINGS AND PRECAUTIONS--------'---
`fatal bleediiig.Prompily
`.. Risk of bleeding: XARtTOcancause serious and
`loss, (5,2)
`evaluate signs and symptoms of blood
`.. Pregnancy related hemorrhage: Use XALTO with caution inpregnant
`due to the pptential for obstetric hemorrhage and/or emergent
`women
`delivery, Prompilyevaluate signs and symptomsofblood loss~ (5.3)
`-.,---_---..-ADVERSE REACTIONS-c------------'"-~--
`(:5%) was bieeòing. (6)
`
`The most common adverse
`
`reaction
`
`To repQrtSUSPIiCTEDADVERSEREACTIONS, coRtactJanssen
`FDA at 1-800-FDA-I088 or
`PhaÌ'aceuticals,IRc. at 1-800-526-7736 or
`
`=W,tiØil'l!Kmøc(v
`--__DRUG INTERACTIONs-------.,~
`_ Combined P-gp andstrongCYP3A4 inhibitors: Avoid cpncOl1itant use unless
`(7, i)
`is proven
`the lack ofa significant interaction
`. CombinedWgp and wea or moderateCYl3A4 inhibitors: Avoid concomitant
`use Unless the berefitoutweighs the bleeing risk in patients with renal
`impainnent (7,2)
`
`_ Combined P-gpand strongCYP3A4irtducers: Avoid
`consider an increased dose (2.1, 7.3)
`0; Aniicoagulants: Avoid concomitant use (7.4)
`. Clopidogrel: Avoid concomitant use unlesS the benefit outweighs the bleeding
`risk (7.6)
`
`cpncomitant
`
`use or
`
`--~~~.,--USE IN SPECIFIC POPULATIONS----c-----.-
`. Nursing mothers: discontinue drugotdiscontinue nursing (8.3)
`. Renalimpainnent:Avoid use in patienis with severe impainreiit (CrCI.:30
`caution in moderate impainnent (CrCl 30 to .:50 mUmin)
`mUmin), Use with
`
`(8.7) " , ,
`
`_ Hepatic impainnent: Avoid use in palientswitn moòei'te (Child-Pugh B) or
`severe (Child-Pugh C) hepatic impairment or in patients with any degree of
`hepati~diseaseassociated-withcoagulopathy(8 ,8)
`
`See 17 for PATIENTCOUN~ELING INFORMTION.
`
`Issued: July ion
`
`8 USEJNSPECIFIC POPULATIONS
`8.1 Pregnancy
`8:2 Labor and Delivery
`8.3 NUrsing Mothers
`8A Pediatric Use
`Use
`8.5 Geriatric
`8.6 Females óf Reproductive Potential
`Impairment
`8:7 Renal
`8.8 Hepaticlmpairrent
`10 OVERDOSAGE '
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`of Action
`12:1 Mechanism
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`12.4 aT/aTe Prolongation, ,
`tOXICOLOGY
`13.1 ' Carcinogenesis, Mutagenesis,
`Fertilty
`14 CLlNICALSTlJDIES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENTCOÜNSELINGINFORMATION
`17.1 Instructions forPatient Use
`17.2 BleedingRisks
`17.3 Concomitant Medication and Herbals
`and Pregnancy-Related Hemorrhage
`
`13 NON-CLINICAL
`
`and Impairment of
`
`17.4 Pregnancy
`
`17.5 Nursing ,
`17.6 Females ofRepröductive Potential
`
`.Sections or subsèctions omitted from the full prescribing information are not
`listed
`
`Reference ID: 2968773
`
`

`

`/~
`
`
`
`
`
`Reference ID: 2968773
`Reference ID: 2968773
`
`

`

`FULL PRESCRIBING INFORMATION
`
`WARNING: SURGICAL SETTINGS--SPINAL/EPIDURAL HEMATOMA
`
`Epidural or spinalheiiatomas may
`
`occur inpatients
`
`who
`
`receiving neuraxial
`
`anesthesia
`
`or undergoing spinal puncture.
`
`result in
`
`long-term
`
`or permanent
`
`paralysis.
`
`Consider these
`
`for spinal pròcedures. Factors that
`
`can increase the risk of developing
`
`are anticoagulated
`
`and are
`These hematomas may
`risks when scheduling patients
`or spinal
`
`epidural
`
`hematomas in these patients' include:
`catheters
`
`. use of indwelling epidural
`
`. concomitant use of other drugs that affect
`
`hemostasis, such as
`
`non-steroidal
`drugs ,(NSAIDs), platelet iiihibitors, otheranticoaguia:nts
`or spinal punctures
`spinal deformity orspinalsurgery.
`
`. a history oftrauriaticor repeated
`
`epidural
`
`inflammatory
`
`.. a
`
`history of
`
`Monitor
`
`patients
`
`frequently for
`
`signs
`
`neurologicalcompromiseis noted,'urgent treatment
`
`and symptoms of neurological
`is necessary.
`
`Consider the, benefits and
`
`to be anticoagulated forthrombopropbylaxis (see
`
`risks beforeneuraxialintervention in, patieiîtsanticoagulated or
`Warnings and Precautions (5.1)and Drug
`
`Interactions (7)).
`
`1 INDICATIONS AND USAGE
`
`XARELTO(rivaroxaban) Tablets are
`
`(DVT), which may lead to
`
`replacement surgery.
`
`indicated for the prophylaxis of deep vein thrombosis
`embolism (PE) in patients undergoing knee or hip
`
`pulmonar
`
`2 DOSAGE AND ADMINISTRATION
`
`The recommende.d dose of XARELTO is '10' ing taken
`
`The initiaLdose should be taken
`
`at least
`
`6 to 1 o
`
`hours
`
`established,
`
`orally
`
`once
`
`daily with or without food.-
`after surgeryonceheinostasis has been
`
`. For patients undergoing
`
`hip replacement surgery,
`
`treatment
`
`duration of 35 days is
`
`recommended.
`.. Forpàtients undergoing knee replacement surgery, treatinentdtiration of 12 days is
`recommended.
`
`If adoseöfXARELTO:is not taken aUhe
`
`scheduled
`
`tiine, the
`
`possible on the same
`
`day and continued on the following
`
`recommended.
`
`dose should betaken as soon as
`Olicedailyintake as
`
`day with the
`
`Reference ID: 2968773
`
`

`

`Riyaroxabanabsorption is dependent on the site of
`
`(gastnc
`
`versus
`
`small intestine). When administenng XARELTOasa crushed tablet
`
`tube, confirmgastncplacement of the
`
`tube (see Clinical Pharmacology (12.3)).
`
`drug release inthe gastrointestinal (GI)tract
`via a feeding
`
`2~ 1 Use
`
`with P-gp
`
`Concomitant useofXARELTO with drugs
`
`and Strong CYP3A41nducers
`that are combined P~gp and strongCYP3A4inducers
`be ayoided. A XARELTO
`drugs mus~be
`
`(e;g" carbamazepine, phenytoin,rifampin, St.John's wort) should
`
`dose increase to 20 mg (i.e., two 10 mgtablets) should be considered if these
`
`coadministered. The 20 mg dose should be taken with food (see Drug Interactions (7.3) and
`Clinical Pharmacology (12.3)J.
`
`3 DOSAGE FORMS AND STRENGTHS
`r
`light red, biconyexand film-coatedwith a tnanglepointing
`other side.
`
`XARELTO lOingtablets are
`
`round,
`
`down aboye
`
`a
`
`"10"
`
`rnarkedononeside
`
`and ~~Xa~'on the
`
`4 CONTRAINDICATIONS
`XARELTO is contraindicated inpatients with:
`
`. hypersensitivity to XARELTO
`
`. actiye major
`
`bleeding (see
`
`Warnings and Precautions
`
`(5.2)J
`
`5 WARNINGS AND
`
`5.1 Spinal/Epidural Anesthesia
`
`PRECAUTIONS
`or Puncture
`
`Whenneuraxial anesthesia (spinallepiduralanesthesia) or spinal
`
`treated with
`
`anticoagulant agents for preyention of thromboembolic
`
`developing
`
`an epidural
`
`or
`
`spinal hematoma
`
`which can result
`
`(seeBoxedWarningJ .
`
`puncture
`
`is
`
`employed,
`
`patients
`areatnskof
`in long-teim or permanent paralysis
`
`complications
`
`An epidural catheter should not be removed earlier than 1 8
`
`XARELTO. The next XARELTO dose is not to be
`
`removal of the catheter. If traumatic puncture
`
`delayedfor 24hours.
`
`5.2
`
`Risk of
`
`Bleeding
`
`hours
`
`administered
`
`after the last administration of
`hours after the
`be
`
`earlier than 6
`
`occurs, the administration ofXARELTO is to
`
`XARELTO increases the risk of bleeding and
`
`can cause serous and fatal bleeding.
`
`hemorrhages ,.including intracranial, ,epidural' hematoma" gastrointestinal, retinal, and
`
`Major
`adrenal
`been reported. UseXARELTOwith caution in conditions with increased risk of
`
`4
`
`bleeding
`
`have
`
`hemorrhage.
`
`Reference ID: 2968773
`
`

`

`Concomitant use of drugs affecting hemostasis increases, the risk of bleeding. These include
`other antithrombotic agents, fibrinolytic therapy, thienopyrdines
`anti-inflammatory drugs (NSAIDs) ¡see Drug Interactions
`
`and chronic use of non-steroidal
`
`platelet aggregation inhibitors,
`
`(7.4), (7.5), (7.6)).
`
`Bleeding can occur at any site durng therapy with XARELTO. An unexplained fall in
`hematocrit or blood pressure should lead to a search for a bleeding site. Promptly eyaluate any
`blood loss.
`
`signs or symptoms of
`
`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. XAREL TO dosing in pregnancy has not been
`studied. The anticoagulant effect of XAEL TO cannot, be monitored with standard laboratory
`testing nor readily reversed~ Promptly eyaluate any signs or symptoms suggesting blood loss
`(e.g., a drop in hemoglobin and/or hematocrit, hypotension, or fetal distress).
`
`5.4
`
`Renal Impairment
`A yoid the use of XAELTO in patients with severe renal impairment (creatinine clearance
`-:30-mh!min~due-tÐ---e*peGted-inGrease-in-rivarm~aban-€xp()8ur€-and-pharmac()d~amic-effects
`in this patient population.
`
`Obsere closely and promptly evaluate any signs or symptoms of blood loss in patients with
`moderate renal impainnent (CrCl 30 to .:50 mLlmin). Patients who develop acute renal failure
`(8. 7)).
`
`while on XAREL TO should discontinue the treatment ¡see Use in Specifc Populations
`
`5.5 Hepatic Impairment
`
`Clinical data in patients with moderate hepatic impairment indicate a significant increase in
`riyaroxaban exposure and phannacodynamic effects. No clinical data are available for patients
`(Child-Pugh
`B) or seyere (Child-Pugh C) hepatic impairment or with any hepatic disease associated with
`(8.8)J.
`
`with severe hepatic impainneht. Ayoid use ofXARELTO in patients with moderate
`
`coagulopathy ¡see Use in Specifc Populations
`
`surgery, 4487
`
`6 ADVERSEREACTIONS
`6.1 Adverse Reactions in Clinical Trials
`In three randomized, controlled clinical trials (RECORD 1-3) in electiye joint replacement
`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 XAREL TO
`were Caucasian. Twenty-seyen percent (1206) of
`
`group
`
`was 64 years, 59% were female and 82%
`
`Reference ID: 2968773
`
`

`

`patients underwent knee replacement surgery and 73% (3281) underwent hip replacement
`surgery.
`
`Because clinical trials are conducted under widely yaryng conditions, adYerse 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 reflectthe rates observed in clinical practice.
`
`In the RECORD clinical trials, the overall incidence rate of adverse reactions leading to
`discontinuation was 3.7% with XARELTO.
`
`permane~t treatment
`
`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 eyents
`shown in Table 1.
`
`observed inpatients in the RECORD clinical trals are
`
`Reference ID: 2968773
`
`

`

`FollowingXARELTO treatment, the
`
`majority
`
`of major bleeding
`
`during the first
`
`week after surgery.
`
`complications (~60%) occurred
`
`6.3 OtherAdverseReactions
`
`Table 2 shows other
`
`adverse drug reactions
`
`(ADRs)
`
`patients
`
`in the RECORD clinical studies.
`
`reported in~l%of XARELTO-treated
`
`Reference ID: 2968773
`
`

`

`Table 2:
`
`Other Adverse Drug
`
`Reactions. Reported by il
`
`1 % of XALTO-TreatedPatients inREÇORD
`
`XALTO
`10mg
`(N =4487)
`n %
`
`1-3 Studies
`SystemJOrga.nClass '
`Adverse Reaction
`
`Inj ury ,poisoning, and
`rocedural com lications
`W ouIdsecretion
`lVusculoskeletaliiiîd connective
`tissue'disorders
`PaiI in extreinit
`Muscles asii
`NerVous sstem disorders
`S co e
`
`Skin and' subcutaneous
`
`disorders
`
`tissue
`
`PruritusBlister63 1.4 40 0.9
`
`AD:R.occurng any time following thefirst dose
`
`been
`admiiistration of active drug, until twodays at1er the last dose of double~blind study medication.
`
`of doub1e-blindmedicàtion, which
`
`may have
`
`prior to
`
`t Includes the placebo-controlled periodofRECORD2, enoxaparindosing was
`
`40 mgonce daily
`
`(RECORD
`
`(
`
`Thèfollowing ADR occurred in~i % ofXARELTO-treatedpatientsin the clinical studies:
`
`Renal
`
`and urinary disorders:
`
`dysuria
`
`The laboratory abnormalities in Table 3 were observed in clinical studies:
`
`1-3)
`
`Alanine amiIotransferase::3 x ULN
`x ULN
`
`'Aimartateaininotransferase )-3
`
`,
`
`,
`
`,
`
`"
`
`,
`
`' ,
`
`,
`
`c
`.. :.
`i COO S dO
`tu ies
`Laboratorv Abnormalities inRE ORD -3
`¡able
`linical
`3
`XALTO
`Laborátóly Abnorinality
`10 mil '
`11414441 2.6%)
`122/4441 2.8%)
`total bilirbin;:L.SxULN
`140/4442 3.2%
`Gamia-i,diitainvltransferase:: 3x'ULN
`292/4442 6.6%
`Plate1etcounts':100,000!miJ or ':50% of baseline
`116/4425' (2.6%)
`value
`"
`,
`,
`,
`* Includes the placebo-controlledpenodofRECORD2,enoxapanndosmg was40mg once daily(RECORD 1-3)
`
`"
`
`d
`
`,
`
`' Enoxa.parin*
`
`167/4456 3.8%
`152/4456 3.4%
`128/4456 2.9%
`391/4457 8.8%
`131/4447 (3.0%)
`
`,
`
`,
`
`6.4 PostmarkètingExperience
`
`\
`
`The following
`
`additional 'adverse reactions
`
`have
`
`has
`
`been
`
`marketed. BecauSe these reactions are reported voluntarily from
`
`uncertain size, itisI10talways possible
`
`relationship to
`
`drug
`
`exposure.
`
`to reliably estimate their
`
`been reported in countres whereXARELTO
`a population of
`frequency or establish a causal
`
`Blood and lymphatic system disorders: agranulocytosis
`
`Gastrointestinal disorders: retroperitoneal
`
`hemorrhage
`
`Reference ID: 2968773
`
`

`

`Hepatobilary disorders: jaundice,cholestasis,cytolytic hepatitis
`
`Immune system disorder: hypersensitivity, anaphylactic reaction, aiiaphylacticshock
`
`Nervous
`
`system disorders: cerebral hemorrhage, subdural hematoma, epidural
`
`hemiparesis
`
`hematoma,
`
`Ski and
`
`subcutaneous tissue
`
`disorders: Stevens-Johnson syndrome
`
`7 DRUG
`
`INTERACTIONS
`Rivaroxaban isa substrate of CYP3A4/5, CYP2J2, and the P-gpand ATP-bindiiig cassette 02
`or transporters may
`
`(ABCG2) transporters. Inhibitors and inducers of these CYP450
`
`enzymes
`
`result
`
`in changes in rivaroxaban exposure.
`
`7.1 Drugs that Inhibit Cytochrome P4503A4Enzymes and Drug
`
`Systems
`
`Transport
`
`In drug interaction studies evaluating the concomitant use with drugs that are
`
`CYP3A4 inhibitors, increases'inrivaroxabanexposure and
`
`pharmacodynamic effects
`
`combined p-.gp and
`(i.e., factor
`Xainhibitiol1 andPT prolongation) were obsered. Significant increases inriyaroxaban exposure
`
`ma.y-incr€ase~bl€eding-c1"sk ----- - --- --- - -
`
`.. Ketoconazole (combined P-gp and strong CYP3A4inhibitor): Steady-state riyaroxaban AUC
`in pharmacodynamic
`
`andCmaxincreased bY,'160%ánd70%, respectiyely. Similar increases
`
`effects were alsoobsered~
`
`.. Ritonavir(combinedP-gp and strongCYP3A4inhibitor): Single-doserivaroxaban AUe and
`by 150% and 60%, respectiyely. Similar increases in phannacodynamic
`observed.
`
`effects were also
`
`Cmax increased
`
`AUC 'and Cmax increased
`
`by 50%
`
`. Clarithromycin (combined P-gp and strongCYP3A4 inhibitor): Single-dose riyaroxaban
`increases in exposure
`obseryedfor clarthromycin compared to ketoconazole orritonavir may be due to the relative
`difference in P-gp inhibition.
`
`and
`
`40%, respectively. The
`
`smaller
`
`. Erythromycin (combined P-gp and moderate CYP3A4 inhibitor): Both the single-dose
`rivaroxaban AUe andCmàx increased by 30%.
`
`Ayoid concomitant administration of XARELTO with
`
`combined P-gp and strong CYP3A4
`inhibitors (e.g., ketoconazole, itraconazole, lopinayir/ritonayir, ritonavir,indinavir/ritonayir, and
`increases in rivaroxaban expOSure that may increase
`
`conivaptan) which cause significant
`
`bleeding
`
`risk.
`
`Reference ID: 2968773
`
`

`

`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
`are combined P-gp and CYP3A4 inhibitors.
`
`that
`
`7.2
`
`Drug-Disease Interactions with Drugs
`
`that Inhibit Cytochrome P450 3A4
`Enzymes and'DrugTransportSystems
`
`Based on
`
`simulated pharmacokinetic data, patients
`
`with
`
`renal
`
`impairment receiying XARELTO
`
`with drgs that are combined P-gp and weak or moderate CYP3A4 inhibitors
`
`( e.g.,
`
`amiodarone, and felodipine), inayhave significant increases
`
`in
`
`exposure
`
`coinpared with
`
`erythromycin, azithromycin,diltiazei, verapamil, quinidine, ranolazine,dronedarone,
`patients
`pathways of rivaroxabanelimination
`risk, useXARELTO in this situation
`only if the ,potential benefit justifies the'potential risk (see "Use in Specifc Populations ,(8.7)1.
`
`with normal renal fuction
`
`and no inhibitor use, since
`
`both
`
`are
`
`affected.
`
`Since these increases may increase
`
`bleeding
`
`7.3 Drugs
`
`that Induce CytochromeP450 3A4 Enzymes
`
`Systems
`
`and
`
`Drug
`
`Transport
`
`In a drug
`
`interaction study, co-administration
`
`ofXARELTO(20
`
`mgsingle
`
`.a drug that is a combinedP'-gpandstrongCYl3A4 inducer
`
`(rifampicin titrated
`
`dose ,with food) with
`up to 600 mg
`of50% and 22% in AVC andCrrax, respectiyely.
`decreases in pharmacodynamic emèctswere alsoobseryed. Tliese,decreasesin bxposure
`to riyaroxaban may decrease efficacy.
`
`once daily) led
`
`to an
`
`approximate
`
`decrease
`
`Similar
`
`AvoidconcomÌtant useofXARELTO with
`
`inducers(e.g.,carbamàzepine, phenytoin,rifampin, St. John;s wort).
`
`drugs that are combinedP-gp and strong CYP3A4
`the
`co administered (seeDosageandAdministration(2.1)).
`
`Consider increasing
`
`XARELTO dose ifthes~ drugs must be
`
`7.4 ,Antic:oagulants
`
`In adrug interaction
`
`study,
`
`single doses ofenoxaparin(4Qmg subcutaneous) and XARELTQ
`resulted in an additive effect on anti-factorXaactiyity. Enoxaparin
`another study, single doses of warfarin
`PT.
`
`(lOmg) given concomitantly
`
`did
`
`not affect
`
`the
`
`pharmacokinetics of riyaroxaban. In
`
`(15 mg) and xARELTO J5mg) resuitedin an additive effect
`
`on factor Xa inhibition and
`
`Warfarin did not affect the phartacokineticsofriyaroxaban. The safetyot. long-term
`studied.
`
`concomitant
`
`use ofthese drugs has
`
`not
`
`been
`
`Avoid concurrentuseofXARELTO with
`
`other
`
`anticoagulants
`
`due to the increased bleeding
`
`other than
`
`during therapeutic
`
`transition
`
`Promptly eyaluateanysigns or symptoms of
`
`risk
`be obseryed closely.
`blood 10ssiseeWarnings and Precautions (5.2)).
`
`periods where patients
`
`should
`
`Reference ID: 2968773
`
`10
`
`

`

`7.5 NSAIDs/Aspirin
`In a single-dose drug interaction study there were no pharacokinetic or pharmacodynamic
`interactions obsered after concomitant administration of naproxen or aspirin (acetylsalicylic
`acid) with XARELTO. The safety of long-ter concomitant use of these drugs has not been
`studied.
`
`NSAIDs/aspirin are known to increase bleeding, and bleeding risk may be increased when these
`drgs are used concomitantly with XARELTO.
`
`Promptly evaluate any signs or symptoms of
`
`blood loss ifpatients 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 c1opidogrel (300mg 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
`pharmaeøkineties-øf'eithe¡-drug.
`
`A void concurrent administration of c1opidogrel 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
`
`because of
`
`anticoagulant that is not
`
`There are no adequate or well-controlled studies of XAEL TO in pregnant women, and dosing
`for pregnant women has not been established. Use XARELTO with caution in pregnant patients
`the potential for pregnancy related hemorrhage and/or emergent deliyer with an
`'readily reyerSible. The anticoagulant effect of XARELTO canot 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. Riyaroxaban increased fetal toxicity (increased
`live fetuses, and decreased fetal body weight) when pregnant
`
`resorptions, decreased number of
`
`11
`
`Reference ID: 2968773
`
`

`

`rabbits were giyen oral dosesof~lO mg/g riyaroxabanduringtheperiodoforganogenesis. This
`based on AVC
`body weights
`
`comparisons at the maximum recommended
`
`human dose
`
`of 10 mg/day. Fetal
`
`dose
`
`corresponds to about 11
`
`times thehumarexposure of unboutd drug,
`
`decreased'when pregnant rats were giyen oral doses of 120mg/g. This
`
`about 40tiines the
`
`human exposure of
`
`unbound drug.
`
`dose
`
`corresponds to
`
`Safety
`
`and effectiveness ofriyaroxabanduring labor and delivery have not
`
`clinical trials. lIoweyer, in
`
`animal
`
`occurred
`
`at the riyaroxaban dose of 40 mg/g (about 17 times maximum human
`
`unbound drug at the humandoseoflO mg/day).
`
`8~3Nursirig Mothers
`
`been studied in
`studies maternal bleeding and matemaland fetal death
`exposure of the
`
`It
`
`is not
`
`known ifriyaroxaban is
`
`of
`
`excreted in human milk. Rivaroxabanandlorits metabolites
`were excreted into themilkofrats. Because many drugs areexcretêd in humaumilk and because
`the potential for serious adverse reactions in nursing infants fromriyaroxaban,a decision.
`taking into account the
`
`should
`
`be made whether to
`
`discontinue nursing or
`
`discontinue the drug,
`
`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 nuinber of
`
`patients
`
`in the RECORD
`
`"1-3
`
`clinical
`
`53% were 65
`
`years and over, while about 15%were::75 years. In
`
`XARELTO in the
`
`elderly (65 years or older) was
`
`years.
`
`studies evaluating XARELTO, about
`of
`65
`
`clinical
`
`trials the effcacy
`
`similar to thatseenin patients younger than
`
`Elderly' subj ects exhibited ,an, incre,ase in ,exposure ,that' may be caused
`
`renal fuction. For patients 65 years of
`
`age and
`
`older, consideration should be
`
`by age related, changes in
`given to
`function prior to staring therapy with XARELTO. Promptlyeyaluate any
`(12.3)l.
`
`assessment of renal
`
`signs orsymptoins of
`
`blood loss (see
`
`Clinical Pharmacology
`
`8.6 Females of
`
`Reproductive
`
`Potential
`
`Females of reproductive
`
`potential
`
`requiring anticoagulation
`
`should discuss pregnancy planning
`
`with their physician.
`
`Reference ID: 2968773
`
`12
`
`

`

`8.7 Renal
`
`Impairment
`
`The safety
`
`and
`
`pharmacokinetics
`
`healthy subjects (CrCl~80 mLimih (n=8)J and
`
`of single-dose XARELTQ (10 mg)were evaluated in asmdy in
`in subjects with varying degrees of renal
`(see Table 4). Compared to healthy subjects with normal creatinine clearance,
`riyaroxaban exposure increased in subjects with renal impaillent. Increases in
`pharmacodynamic effects were âlso observed.
`
`impairment
`
`Table 4: PercenUncrease of Riviiroxaban PK and PD Parameters
`
`from Normalin Subjects with
`
`Renàl
`
`InsuffCienci; from, a Dedicated Reiiii1 ImpairmenfStudi;
`, ' , ' Renal Inipairment Class
`(CrÇl(mL!itn))
`Parameter ' Mild Moderate ' Severe
`, (50 to 79) (30 to 49) (15 to29)
`, N~8 N=8 ,N=8
`Exposure AUC 44 52 64
`(%increiise reliitiveto normal)Cmax 28 12 26
`FXa Inhibition AUC 50 86 100
`(%increase relative to normal)Emax 9 10 12
`PT Prolongation AUC 33 116 144
`
`(o/increiiserelativetoiiormill) ,Emnf, ',".. 4, , ,',", 17 , ,', ' ", ,,' " ' 20
`time; FXa,=CoagtlationfactorXa; Aue == Area under the ,concentration or effect cile;
`PT= Prothrombin
`creatinne clearance
`
`Cmax = maximum concentratioh;Emax = maximum effect; and CrCI =
`
`Patients with any degree of renal impairment with concurrent use of P-gp and weak to moderate
`risk
`
`CYP3A4 inhibitors
`
`may have significant increases
`
`in exposure
`
`which
`
`may
`
`increase
`
`bleeding
`
`¡see Drug Interactions (7,2)).
`
`The combined
`
`analysis
`
`of
`
`the RECORD 1-3 clinical effcacy
`
`studies
`
`did
`
`not
`
`bleeding
`
`risk for patients with moderate renal impaiffentand reported a possible
`
`increase
`
`show an increase in
`in
`any signs or syiptomsof
`renal impaimient (CrCl30 to -:50mLlmin). Avoid the use
`Warnings and
`
`total VTE in this
`
`population. Observe closely
`
`blood
`
`loss
`
`in patients with moderate
`
`of XARELTOin patients with seyere renal
`
`Precautions (52, 5.4)J;
`
`8.8 Hepatic Impairmeht
`
`'and
`
`promptly
`
`eyaluate
`
`impairment (CrCl-:30mLlmin) ¡see
`
`The safety
`
`and
`
`pharacokinetics ofsingle~dose XARELTO (10 rng) were
`
`healthy subjects
`
`(n=l 6) and
`
`evaluated in a study in
`subjects with varing, dègrees ofhepatìcimpairment(see Table 5).
`to healthy
`,liver function, significant increases in rivaroxaban exposure wereobsèrved
`in subjects with moderate hepaticimpaillent (Child-Pugh B). Increases inphaffacodynamic
`effects were also obsered.
`
`No patients with
`
`severe hepatic impaiffenf (Child-Pugh C) were
`
`studied. Compared
`
`subjects with normal
`
`Reference ID: 2968773
`
`:13
`
`

`

`Table' 5: Percent Increase of Rivaroxabao PKand PDParameters from N ormalin Subjects with Hepatic
`Insuffciency from a Dedicated Hepatic ImpairinentStudy
`Hepatic Impairment Class
`(Child-Pugh'Class)
`
`(Child-Pugh B)
`N=8
`
`(%increase relative
`
`(%inctease relative
`
`Parameter Moderate
`Exposure AUC 127
`to normal) emax 27
`FXa Inhibition AUC 159
`to normal) Emax 24
`PTProlongation AUC 114
`
`(%lncrease relatiyeto normal) " , ,Emax,' ,,',.."",',' 2, '",' ,".',,'..,,'.', 41
`Coagulation factorXa; AUC == Area under the concentration or effect curVe;
`time; FXa =
`PT = Prothombin
`Cinx == maximum concentration; Emax= maximum effect
`
`Avoid theu~e of XARELTOin patients with moderate (Child-Pugh E) or severe (Child-Pugh C)
`impairment or withanyhepatic disease associated withcoagulopathy ¡see Warnings,and
`Precautions (5.2, 5.5)1.
`
`hepatic
`
`10 OVERDOSAGE
`
`Overdose ofXARELTO may lead to hemorrhage. A specific antidote of rivaroxaban is
`
`not
`available. Discontinue XARELTO and initiate appropriate therapy if bleeding ,complications
`The use af aciÍva1èdcharcoal to reduceåbsorptionTn-càse-oC
`plasma protein binding,riyaroxaban is
`not expected to be dialyzable ¡see Clinical Pharmacology (12.3)J.
`
`associatetfwitho-verdosage- occur.
`
`XARELTOoverdose may beconsidered. Due to the high
`
`11 DESCRIPTION
`
`Riyaroxaban, a factor Xa inhibitor, is the actiye ingredient in XARELTO Tablets with
`
`chemical
`
`the
`name 5-Chloro- N -(t(5S)-2-oxo- 3,;(4-(3 -oxo-4-mOrpholinyl)phenyl)-1 ,3-oxazolidin-5-
`yl )methyl)-2-thiophenecarboxamide. The molecular formula ofrivaroxabanis C19HlSClN30SS
`is:
`
`and the molecular weight is 435.89. The
`
`strctural formula
`
`Reference ID: 2968773
`
`14
`
`

`

`Rivaroxaban is a pure
`
`powder. Riyaroxaban is only slightly
`
`(S)-enantiomer. It is an odorless, non-hygroscopic, white to yellowish
`(e.g., acetone, polyethylene
`
`soluble in organic solvents
`
`glycol 400) and is practically insoluble in water and aqueous media.
`
`EachJCARELTOtablet contains 10 mg ofrivaroxaban. The inactive
`
`magnesium stearate,
`
`sodium
`
`ingredients ofXARELTO
`are: Microcrystallne cellulose, croscarmellose sodium" hypromellose,lactose monohydrate,
`Jauryl sulfate, and Opadry~Pink, a proprietaryfilmcoating mixtue
`red,
`
`containing
`
`polyethylene
`
`glycol 3350,hypromellose,titaniui dioxide,
`
`and
`
`ferric oxide
`
`12.1 Mechanism
`
`XARELTO is
`
`12 CLINICAL PHARMACOLOGY
`of Action
`an orally bioayailable factor Xainhibitorthat selectively blocks' the active site of
`III) foractiyity. Actiyationof
`pathways plays a central role in the
`
`, factor Xa and does not require a
`
`cofactor (such as
`
`Anti-thrombin
`
`factor
`
`X to factor Xa (FXa) Yia the
`
`intrnsic and
`
`extrinsic
`
`cascade of
`
`blood
`
`coagulation.
`
`12.2 Pharmacodynamics
`Dose-dependent inhibition offactor Xaactiyitywas observed in humansandtheNeoplastin~
`prothrembin--time-EPcT),-aetivated--partial-thremÐeplastin--time--EaP-T+)-and-HepTest~are~-----~~
`prolonged dose-dependently. Anti-factor Xa activityis alsoinfiuencedby rivaroxaban.There are
`no data on the usëof the International Normalized Ratio (INR).The predictiye yalUe of these
`for bleeding risk or efficacy has not been established.
`
`coagulation parameters
`
`12.3 Pharmacokinetics
`Absorption
`
`The absolutebioavailabilty ofrivaroxaban is high
`
`dose. Rivaroxaban is rapidly absorbed with
`
`maximum
`
`hours
`
`after tablet intake.
`
`(estimated to
`
`be 80% to 100%) for
`
`the 10 mg
`concentrations (Cmax) appearing 2 to 4
`
`Rivaroxabanpharacokinetics are linear with no relevant accumulation
`
`after multiple doses. Intake
`
`with food
`
`does
`
`beyond steady-state
`not affect riyaroxaban AUGor Cmax at the 10 mg
`
`dose.
`
`Coadministration of XARELTO(30 mgsinglerlose) with the
`
`The pharmacokinetics ofrivaroxaban were not affected by drugs altering g!1stricpH.
`Ez-receptor antagonist ranitidine
`(150 mg twicedaily)ortheantacirla.luminum hydroxide/magnesium hydroxiden 0 tnL) did not
`an effect onthe bioayailabilityand exposureofriyaroxaban.
`
`show
`
`Absorption ofrivaroxaban is
`
`dependent on the site
`
`of drug release in the attract. A 29%
`
`56% decrease in AUC
`
`andCmax
`
`compared to tablet wasreportedwhenriyaroxaban granulate
`
`and
`is
`
`15
`
`Reference ID: 2968773
`
`

`

`Excretion, "
`
`Fóllowingoraladministration of a e4q-rivaroxaban dose,
`
`66%
`
`released in proximal small intestine, Exposure is
`
`further reduced
`
`distal
`
`small intestine"or
`
`ascending
`
`colon. Ayoidadministrationofrivaroxaban via a
`
`could deposit. drug direct1 y into the proximal small, intestine , (e.g., feeding, tube) which
`
`when drug is released in the
`method that
`can result
`
`in reduced absorption and related drugexposureIsee DosageandAdministration (2)).
`
`Distribution
`
`Plasma protein
`
`albumin beingthe main binding
`
`subjects is approximately
`
`50 L.
`
`binding of rivaroxaban in human plasma is approximately 92% to 95%, with
`of distribution in healthy
`
`component.
`
`The steadyo:state volume
`
`Metabolism
`
`Approximately 51%
`
`metabolites in urine (30%)
`
`CYP2J2andhydrolysis are
`
`predominant moiety
`
`of an
`
`orally
`
`administered (14q-rivaroxaban dose
`
`was recovered
`
`and
`
`as
`feces (21%). Oxidative degradationçatalyzed byCYl3A4/5 and
`the major sitesofbiotransfonnation. Unchangedriyaroxaban was the
`in plasma with no inajor or actiye circulating metabolites.
`
`of the radioactive dose was
`as unchangpd drug)' and. 28~was, recove!edjn ,feces (7~' as _ unch~nged ~_
`secretion and to a lesser
`Rivaroxabanis a substrate of the efflux
`proteins P-gp andABCG2 (also abbreviated Bcrp). 'Rivaroxaban's affinity fodnflux
`proteins is unkown.
`
`recovere