WARNING
(A) PREMATURE DISCONTINUATION OF XARELTO INCREASES THE RISK OF THROMBOTIC EVENTS,
(B) SPINAL/EPIDURAL HEMATOMA
A. PREMATURE DISCONTINUATION OF XARELTO INCREASES THE RISK OF THROMBOTIC EVENTS
PREMATURE DISCONTINUATION OF ANY ORAL ANTICOAGULANT, INCLUDING XARELTO, INCREASES THE RISK OF THROMBOTIC EVENTS. IF ANTICOAGULATION WITH XARELTO IS DISCONTINUED FOR A REASON OTHER THAN PATHOLOGICAL BLEEDING OR COMPLETION OF A COURSE OF THERAPY, CONSIDER COVERAGE WITH ANOTHER ANTICOAGULANT [SEE DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS, AND CLINICAL STUDIES]
B. SPINAL/EPIDURAL HEMATOMA
EPIDURAL OR SPINAL HEMATOMAS HAVE OCCURRED IN PATIENTS TREATED WITH XARELTO WHO 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
" OPTIMAL TIMING BETWEEN THE ADMINISTRATION OF XARELTO AND NEURAXIAL PROCEDURES IS NOT KNOWN [SEE WARNINGS AND PRECAUTIONS AND ADVERSE REACTIONS].
MONITOR PATIENTS FREQUENTLY FOR SIGNS AND SYMPTOMS OF NEUROLOGICAL IMPAIRMENT. IF NEUROLOGICAL COMPROMISE IS NOTED, URGENT TREATMENT IS NECESSARY [SEE WARNINGS AND PRECAUTIONS].
CONSIDER THE BENEFITS AND RISKS BEFORE NEURAXIAL INTERVENTION IN PATIENTS ANTICOAGULATED OR TO BE ANTICOAGULATED FOR THROMBOPROPHYLAXIS [SEE WARNINGS AND PRECAUTIONS].
FACEBOOK TWITTER EMAIL PRINT
DRUG DESCRIPTION
RIVAROXABAN, A FXA 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-5YL}METHYL)-2-THIOPHENECARBOXAMIDE. THE MOLECULAR FORMULA OF RIVAROXABAN IS C19H18CLN3O5S AND THE MOLECULAR WEIGHT IS 435.89. THE STRUCTURAL FORMULA IS:
RIVAROXABAN IS A PURE (AN 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, 15 MG, OR 20 MG OF RIVAROXABAN. THE INACTIVE INGREDIENTS OF XARELTO ARE: CROSCARMELLOSE SODIUM, HYPROMELLOSE, LACTOSE MONOHYDRATE, MAGNESIUM STEARATE, MICROCRYSTALLINE CELLULOSE, AND SODIUM LAURYL SULFATE. ADDITIONALLY, THE PROPRIETARY FILM COATING MIXTURE USED FOR XARELTO 10 MG TABLETS IS OPADRY® PINK AND FOR XARELTO 15 MG TABLETS IS OPADRY® RED, BOTH CONTAINING FERRIC OXIDE RED, HYPROMELLOSE, POLYETHYLENE GLYCOL 3350, AND TITANIUM DIOXIDE, AND FOR XARELTO 20 MG TABLETS IS OPADRY® II DARK RED, CONTAINING FERRIC OXIDE RED, POLYETHYLENE GLYCOL 3350, POLYVINYL ALCOHOL (PARTIALLY HYDROLYZED), TALC, AND TITANIUM DIOXIDE.
WHAT ARE THE POSSIBLE SIDE EFFECTS OF RIVAROXABAN (XARELTO)?
GET EMERGENCY MEDICAL HELP IF YOU HAVE ANY OF THESE SIGNS OF AN ALLERGIC REACTION: HIVES; DIFFICULT BREATHING; SWELLING OF YOUR FACE, LIPS, TONGUE, OR THROAT.
STOP USING RIVAROXABAN AND CALL YOUR DOCTOR AT ONCE IF YOU HAVE A SERIOUS SIDE EFFECT SUCH AS:
" EASY BRUISING, UNUSUAL BLEEDING (NOSE, MOUTH, VAGINA, OR RECTUM), BLEEDING FROM WOUNDS OR NEEDLE INJECTIONS, ANY BLEEDING THAT WILL NOT STOP;
" HEAVY MENSTRUAL PERIODS;
" HEADACHE, DIZZINESS, WEAKNESS, FEELING LIKE YOU MIGHT PASS OUT;
" RED OR PINK URINE;
" BLACK OR BLOODY STOOLS, COUGHING UP...
READ ALL POTENTIAL SIDE EFFECTS AND SEE PICTURES OF XARELTO "
INDICATIONS
REDUCTION OF RISK OF STROKE AND SYSTEMIC EMBOLISM IN NONVALVULAR ATRIAL FIBRILLATION
XARELTO IS INDICATED TO REDUCE THE RISK OF STROKE AND SYSTEMIC EMBOLISM IN PATIENTS WITH NONVALVULAR ATRIAL FIBRILLATION.
THERE ARE LIMITED DATA ON THE RELATIVE EFFECTIVENESS OF XARELTO AND WARFARIN IN REDUCING THE RISK OF STROKE AND SYSTEMIC EMBOLISM WHEN WARFARIN THERAPY IS WELL-CONTROLLED [SEE CLINICAL STUDIES].
TREATMENT OF DEEP VEIN THROMBOSIS
XARELTO IS INDICATED FOR THE TREATMENT OF DEEP VEIN THROMBOSIS (DVT).
TREATMENT OF PULMONARY EMBOLISM
XARELTO IS INDICATED FOR THE TREATMENT OF PULMONARY EMBOLISM (PE).
REDUCTION IN THE RISK OF RECURRENCE OF DEEP VEIN THROMBOSIS AND OF PULMONARY EMBOLISM
XARELTO IS INDICATED FOR THE REDUCTION IN THE RISK OF RECURRENCE OF DEEP VEIN THROMBOSIS AND OF PULMONARY EMBOLISM FOLLOWING INITIAL 6 MONTHS TREATMENT FOR DVT AND/OR PE.
PROPHYLAXIS OF DEEP VEIN THROMBOSIS FOLLOWING HIP OR KNEE REPLACEMENT SURGERY
XARELTO IS INDICATED FOR THE PROPHYLAXIS OF DVT, WHICH MAY LEAD TO PE IN PATIENTS UNDERGOING KNEE OR HIP REPLACEMENT SURGERY.
HOW SUPPLIED
DOSAGE FORMS AND STRENGTHS
" 10 MG TABLETS: 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
" 15 MG TABLETS: ROUND, RED, BICONVEX, AND FILM-COATED WITH A TRIANGLE POINTING DOWN ABOVE A "15" MARKED ON ONE SIDE AND "XA" ON THE OTHER SIDE
" 20 MG TABLETS: TRIANGLE-SHAPED, DARK RED, AND FILM-COATED WITH A TRIANGLE POINTING DOWN ABOVE A "20" MARKED ON ONE SIDE AND "XA" ON THE OTHER SIDE
STORAGE AND HANDLING
XARELTO (RIVAROXABAN) TABLETS ARE AVAILABLE IN THE STRENGTHS AND PACKAGES LISTED BELOW:
" 10 MG TABLETS ARE ROUND, LIGHT RED, BICONVEX FILM-COATED TABLETS MARKED WITH A TRIANGLE POINTING DOWN ABOVE A "10" ON ONE SIDE, AND "XA" ON THE OTHER SIDE. THE TABLETS ARE SUPPLIED IN THE PACKAGES LISTED:
NDC 50458-580-30 BOTTLE CONTAINING 30 TABLETS
NDC 50458-580-10 BLISTER PACKAGE CONTAINING 100 TABLETS (10 BLISTER CARDS CONTAINING 10 TABLETS EACH)
" 15 MG TABLETS ARE ROUND, RED, BICONVEX FILM-COATED TABLETS WITH A TRIANGLE POINTING DOWN ABOVE A "15" MARKED ON ONE SIDE AND "XA" ON THE OTHER SIDE. THE TABLETS ARE SUPPLIED IN THE PACKAGES LISTED:
NDC 50458-578-30 BOTTLE CONTAINING 30 TABLETS
NDC 50458-578-90 BOTTLE CONTAINING 90 TABLETS
NDC 50458-578-10 BLISTER PACKAGE CONTAINING 100 TABLETS (10 BLISTER CARDS CONTAINING 10 TABLETS EACH)
" 20 MG TABLETS ARE TRIANGLE-SHAPED, DARK RED FILM-COATED TABLETS WITH A TRIANGLE POINTING DOWN ABOVE A "20" MARKED ON ONE SIDE AND "XA" ON THE OTHER SIDE. THE TABLETS ARE SUPPLIED IN THE PACKAGES LISTED:
NDC 50458-579-30 BOTTLE CONTAINING 30 TABLETS
NDC 50458-579-90 BOTTLE CONTAINING 90 TABLETS
NDC 50458-579-10 BLISTER PACKAGE CONTAINING 100 TABLETS (10 BLISTER CARDS CONTAINING 10 TABLETS EACH)
" STARTER PACK FOR TREATMENT OF DEEP VEIN THROMBOSIS AND TREATMENT OF PULMONARY EMBOLISM:
NDC 50458-584-51 30-DAY STARTER BLISTER PACK CONTAINING 51 TABLETS: 42 TABLETS OF 15 MG AND 9 TABLETS OF 20 MG
STORE AT 25°C (77°F) OR ROOM TEMPERATURE; EXCURSIONS PERMITTED TO 15°-30°C (59°-86°F) [SEE USP CONTROLLED ROOM TEMPERATURE]. KEEP OUT OF THE REACH OF CHILDREN.
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. REVISED: JAN 2015
DOSAGE AND ADMINISTRATION
INDICATION DOSAGE
REDUCTION IN RISK OF STROKE IN NONVALVULAR ATRIAL FIBRILLATION CRCL > 50 ML/MIN: 20 MG ONCE DAILY WITH THE EVENING MEAL
CRCL 15 TO 50 ML/MIN: 15 MG ONCE DAILY WITH THE EVENING MEAL
TREATMENT OF DVT
TREATMENT OF PE 15 MS TWICE DAILY WITH FOOD, FOR FIRST 21 DAYS
? AFTER 21 DAYS, TRANSITION TO ?
20 MG ONCE DAILY WITH FOOD, FOR REMAINING TREATMENT
REDUCTION IN THE RISK OF RECURRENCE OF DVT AND OF PE 20 MG ONCE DAILY WITH FOOD
PROPHYLAXIS OF DVT FOLLOWING HIP OR
KNEE REPLACEMENT SURGERY HIP REPLACEMENT: 10 MG ONCE DAILY FOR 35 DAYS
KNEE REPLACEMENT: 10 MG ONCE DAILY FOR 12 DAYS
IMPORTANT FOOD EFFECT INFORMATION
THE 15 MG AND 20 MG XARELTO TABLETS SHOULD BE TAKEN WITH FOOD, WHILE THE 10 MG TABLET CAN BE TAKEN WITH OR WITHOUT FOOD [SEE CLINICAL PHARMACOLOGY].
IN THE NONVALVULAR ATRIAL FIBRILLATION EFFICACY STUDY XARELTO WAS TAKEN WITH THE EVENING MEAL.
SWITCHING TO AND FROM XARELTO
SWITCHING FROM WARFARIN TO XARELTO
WHEN SWITCHING PATIENTS FROM WARFARIN TO XARELTO, DISCONTINUE WARFARIN AND START XARELTO AS SOON AS THE INTERNATIONAL NORMALIZED RATIO (INR) IS BELOW 3.0 TO AVOID PERIODS OF INADEQUATE ANTICOAGULATION.
SWITCHING FROM XARELTO TO WARFARIN
NO CLINICAL TRIAL DATA ARE AVAILABLE TO GUIDE CONVERTING PATIENTS FROM XARELTO TO WARFARIN. XARELTO AFFECTS INR, SO INR MEASUREMENTS MADE DURING COADMINISTRATION WITH WARFARIN MAY NOT BE USEFUL FOR DETERMINING THE APPROPRIATE DOSE OF WARFARIN. ONE APPROACH IS TO DISCONTINUE XARELTO AND BEGIN BOTH A PARENTERAL ANTICOAGULANT AND WARFARIN AT THE TIME THE NEXT DOSE OF XARELTO WOULD HAVE BEEN TAKEN.
SWITCHING FROM XARELTO TO ANTICOAGULANTS OTHER THAN WARFARIN
FOR PATIENTS CURRENTLY TAKING XARELTO AND TRANSITIONING TO AN ANTICOAGULANT WITH RAPID ONSET, DISCONTINUE XARELTO AND GIVE THE FIRST DOSE OF THE OTHER ANTICOAGULANT (ORAL OR PARENTERAL) AT THE TIME THAT THE NEXT XARELTO DOSE WOULD HAVE BEEN TAKEN [SEE DRUG INTERACTIONS].
SWITCHING FROM ANTICOAGULANTS OTHER THAN WARFARIN TO XARELTO
FOR PATIENTS CURRENTLY RECEIVING AN ANTICOAGULANT OTHER THAN WARFARIN, START XARELTO 0 TO 2 HOURS PRIOR TO THE NEXT SCHEDULED EVENING ADMINISTRATION OF THE DRUG (E.G., LOW MOLECULAR WEIGHT HEPARIN OR NON-WARFARIN ORAL ANTICOAGULANT) AND OMIT ADMINISTRATION OF THE OTHER ANTICOAGULANT. FOR UNFRACTIONATED HEPARIN BEING ADMINISTERED BY CONTINUOUS INFUSION, STOP THE INFUSION AND START XARELTO AT THE SAME TIME.
NONVALVULAR ATRIAL FIBRILLATION
FOR PATIENTS WITH CREATININE CLEARANCE (CRCL) > 50 ML/MIN, THE RECOMMENDED DOSE OF XARELTO IS 20 MG TAKEN ORALLY ONCE DAILY WITH THE EVENING MEAL. FOR PATIENTS WITH CRCL 15 TO 50 ML/MIN, THE RECOMMENDED DOSE IS 15 MG ONCE DAILY WITH THE EVENING MEAL [SEE USE IN SPECIFIC POPULATIONS].
TREATMENT OF DEEP VEIN THROMBOSIS (DVT), PULMONARY EMBOLISM (PE), AND REDUCTION IN THE RISK OF RECURRENCE OF DVT AND OF PE
THE RECOMMENDED DOSE OF XARELTO FOR THE INITIAL TREATMENT OF ACUTE DVT AND/OR PE IS 15 MG TAKEN ORALLY TWICE DAILY WITH FOOD FOR THE FIRST 21 DAYS. AFTER THIS INITIAL TREATMENT PERIOD, THE RECOMMENDED DOSE OF XARELTO IS 20 MG TAKEN ORALLY ONCE DAILY WITH FOOD, AT APPROXIMATELY THE SAME TIME EACH DAY. THE RECOMMENDED DOSE OF XARELTO FOR REDUCTION IN THE RISK OF RECURRENCE OF DVT OR PE IS 20 MG TAKEN ORALLY ONCE DAILY WITH FOOD AT APPROXIMATELY THE SAME TIME EACH DAY [SEE CLINICAL STUDIES].
PROPHYLAXIS OF DEEP VEIN THROMBOSIS FOLLOWING HIP OR KNEE REPLACEMENT SURGERY
THE RECOMMENDED DOSE OF XARELTO IS 10 MG TAKEN ORALLY ONCE DAILY WITH OR WITHOUT FOOD. THE INITIAL DOSE SHOULD BE TAKEN 6 TO 10 HOURS AFTER SURGERY PROVIDED THAT HEMOSTASIS HAS BEEN ESTABLISHED [SEE DISCONTINUATION FOR SURGERY AND OTHER INTERVENTIONS].
" 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.
DISCONTINUATION FOR SURGERY AND OTHER INTERVENTIONS
IF ANTICOAGULATION MUST BE DISCONTINUED TO REDUCE THE RISK OF BLEEDING WITH SURGICAL OR OTHER PROCEDURES, XARELTO SHOULD BE STOPPED AT LEAST 24 HOURS BEFORE THE PROCEDURE TO REDUCE THE RISK OF BLEEDING [SEE WARNINGS AND PRECAUTIONS]. IN DECIDING WHETHER A PROCEDURE SHOULD BE DELAYED UNTIL 24 HOURS AFTER THE LAST DOSE OF XARELTO, THE INCREASED RISK OF BLEEDING SHOULD BE WEIGHED AGAINST THE URGENCY OF INTERVENTION. XARELTO SHOULD BE RESTARTED AFTER THE SURGICAL OR OTHER PROCEDURES AS SOON AS ADEQUATE HEMOSTASIS HAS BEEN ESTABLISHED, NOTING THAT THE TIME TO ONSET OF THERAPEUTIC EFFECT IS SHORT [SEE WARNINGS AND PRECAUTIONS]. IF ORAL MEDICATION CANNOT BE TAKEN DURING OR AFTER SURGICAL INTERVENTION, CONSIDER ADMINISTERING A PARENTERAL ANTICOAGULANT.
MISSED DOSE
IF A DOSE OF XARELTO IS NOT TAKEN AT THE SCHEDULED TIME, ADMINISTER THE DOSE AS SOON AS POSSIBLE ON THE SAME DAY AS FOLLOWS:
" FOR PATIENTS RECEIVING 15 MG TWICE DAILY: THE PATIENT SHOULD TAKE XARELTO IMMEDIATELY TO ENSURE INTAKE OF 30 MG XARELTO PER DAY. IN THIS PARTICULAR INSTANCE, TWO 15 MG TABLETS MAY BE TAKEN AT ONCE. THE PATIENT SHOULD CONTINUE WITH THE REGULAR 15 MG TWICE DAILY INTAKE AS RECOMMENDED ON THE FOLLOWING DAY.
" FOR PATIENTS RECEIVING 20 MG, 15 MG OR 10 MG ONCE DAILY: THE PATIENT SHOULD TAKE THE MISSED XARELTO DOSE IMMEDIATELY.
ADMINISTRATION OPTIONS
FOR PATIENTS WHO ARE UNABLE TO SWALLOW WHOLE TABLETS, 10 MG, 15 MG OR 20 MG XARELTO TABLETS MAY BE CRUSHED AND MIXED WITH APPLESAUCE IMMEDIATELY PRIOR TO USE AND ADMINISTERED ORALLY. AFTER THE ADMINISTRATION OF A CRUSHED XARELTO 15 MG OR 20 MG TABLET, THE DOSE SHOULD BE IMMEDIATELY FOLLOWED BY FOOD [SEE IMPORTANT FOOD EFFECT INFORMATION, NONVALVULAR ATRIAL FIBRILLATION, TREATMENT OF DEEP VEIN THROMBOSIS (DVT), PULMONARY EMBOLISM (PE), AND REDUCTION IN THE RISK OF RECURRENCE OF DVT AND OF PE AND CLINICAL PHARMACOLOGY].
ADMINISTRATION VIA NASOGASTRIC (NG) TUBE OR GASTRIC FEEDING TUBE
AFTER CONFIRMING GASTRIC PLACEMENT OF THE TUBE, 10 MG, 15 MG OR 20 MG XARELTO TABLETS MAY BE CRUSHED AND SUSPENDED IN 50 ML OF WATER AND ADMINISTERED VIA AN NG TUBE OR GASTRIC FEEDING TUBE. SINCE RIVAROXABAN ABSORPTION IS DEPENDENT ON THE SITE OF DRUG RELEASE, AVOID ADMINISTRATION OF XARELTO DISTAL TO THE STOMACH WHICH CAN RESULT IN REDUCED ABSORPTION AND THEREBY, REDUCED DRUG EXPOSURE. AFTER THE ADMINISTRATION OF A CRUSHED XARELTO 15 MG OR 20 MG TABLET, THE DOSE SHOULD THEN BE IMMEDIATELY FOLLOWED BY ENTERAL FEEDING [SEE CLINICAL PHARMACOLOGY].
CRUSHED 10 MG, 15 MG OR 20 MG XARELTO TABLETS ARE STABLE IN WATER AND IN APPLESAUCE FOR UP TO 4 HOURS. AN IN VITRO COMPATIBILITY STUDY INDICATED THAT THERE IS NO ADSORPTION OF RIVAROXABAN FROM A WATER SUSPENSION OF A CRUSHED XARELTO TABLET TO PVC OR SILICONE NASOGASTRIC (NG) TUBING.
SIDE EFFECTS
THE FOLLOWING ADVERSE REACTIONS ARE ALSO DISCUSSED IN OTHER SECTIONS OF THE LABELING:
" INCREASED RISK OF STROKE AFTER DISCONTINUATION IN NONVALVULAR ATRIAL FIBRILLATION [SEE BOXED WARNING AND WARNINGS AND PRECAUTIONS]
" BLEEDING RISK [SEE WARNINGS AND PRECAUTIONS]
" SPINAL/EPIDURAL HEMATOMA [SEE BOXED WARNING AND WARNINGS AND PRECAUTIONS]
CLINICAL TRIALS EXPERIENCE
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.
DURING CLINICAL DEVELOPMENT FOR THE APPROVED INDICATIONS, 16326 PATIENTS WERE EXPOSED TO XARELTO. THESE INCLUDED 7111 PATIENTS WHO RECEIVED XARELTO 15 MG OR 20 MG ORALLY ONCE DAILY FOR A MEAN OF 19 MONTHS (5558 FOR 12 MONTHS AND 2512 FOR 24 MONTHS) TO REDUCE THE RISK OF STROKE AND SYSTEMIC EMBOLISM IN NONVALVULAR ATRIAL FIBRILLATION (ROCKET AF); 4728 PATIENTS WHO RECEIVED EITHER XARELTO 15 MG ORALLY TWICE DAILY FOR THREE WEEKS FOLLOWED BY 20 MG ORALLY ONCE DAILY (EINSTEIN DVT, EINSTEIN PE) OR 20 MG ORALLY ONCE DAILY (EINSTEIN EXTENSION) TO TREAT DVT, PE, AND TO REDUCE THE RISK OF RECURRENCE OF DVT AND OF PE; AND 4487 PATIENTS WHO RECEIVED XARELTO 10 MG ORALLY ONCE DAILY FOR PROPHYLAXIS OF DVT FOLLOWING HIP OR KNEE REPLACEMENT SURGERY (RECORD 1-3).
HEMORRHAGE
THE MOST COMMON ADVERSE REACTIONS WITH XARELTO WERE BLEEDING COMPLICATIONS [SEE WARNINGS AND PRECAUTIONS].
NONVALVULAR ATRIAL FIBRILLATION
IN THE ROCKET AF TRIAL, THE MOST FREQUENT ADVERSE REACTIONS ASSOCIATED WITH PERMANENT DRUG DISCONTINUATION WERE BLEEDING EVENTS, WITH INCIDENCE RATES OF 4.3% FOR XARELTO VS. 3.1% FOR WARFARIN. THE INCIDENCE OF DISCONTINUATIONS FOR NON-BLEEDING ADVERSE EVENTS WAS SIMILAR IN BOTH TREATMENT GROUPS.
TABLE 1 SHOWS THE NUMBER OF PATIENTS EXPERIENCING VARIOUS TYPES OF BLEEDING EVENTS IN THE ROCKET AF TRIAL.
TABLE 1: BLEEDING EVENTS IN ROCKET AF*
PARAMETER XARELTO
N = 7111 N (%) EVENT RATE (PER 100 PT-YRS) WARFARIN
N = 7125 N (%) EVENT RATE (PER 100 PT-YRS)
MAJOR BLEEDING† 395 (5.6) 3.6 386 (5.4) 3.5
BLEEDING INTO A CRITICAL ORGAN‡ 91 (1.3) 0.8 133 (1.9) 1.2
FATAL BLEEDING 27 (0.4) 0.2 55 (0.8) 0.5
BLEEDING RESULTING IN TRANSFUSION OF ?2 UNITS OF WHOLE BLOOD OR PACKED RED BLOOD CELLS 183 (2.6) 1.7 149 (2.1) 1.3
GASTROINTESTINAL BLEEDING 221 (3.1) 2.0 140 (2.0) 1.2
* FOR ALL SUB-TYPES OF MAJOR BLEEDING, SINGLE EVENTS MAY BE REPRESENTED IN MORE THAN ONE ROW, AND INDIVIDUAL PATIENTS MAY HAVE MORE THAN ONE EVENT.
† DEFINED AS CLINICALLY OVERT BLEEDING ASSOCIATED WITH A DECREASE IN HEMOGLOBIN OF ?2 G/DL, TRANSFUSION OF ?2 UNITS OF PACKED RED BLOOD CELLS OR WHOLE BLOOD, BLEEDING AT A CRITICAL SITE, OR WITH A FATAL OUTCOME. HEMORRHAGIC STROKES ARE COUNTED AS BOTH BLEEDING AND EFFICACY EVENTS. MAJOR BLEEDING RATES EXCLUDING STROKES ARE 3.3 PER 100 PT-YRS FOR XARELTO VS. 2.9 PER 100 PT-YRS FOR WARFARIN.
‡ THE MAJORITY OF THE EVENTS WERE INTRACRANIAL, AND ALSO INCLUDED INTRASPINAL, INTRAOCULAR, PERICARDIAL, INTRAARTICULAR, INTRAMUSCULAR WITH COMPARTMENT SYNDROME, OR RETROPERITONEAL.
TREATMENT OF DEEP VEIN THROMBOSIS (DVT), PULMONARY EMBOLISM (PE), AND TO REDUCE THE RISK OF RECURRENCE OF DVT AND OF PE
EINSTEIN DVT AND EINSTEIN PE STUDIES
IN THE POOLED ANALYSIS OF THE EINSTEIN DVT AND EINSTEIN PE CLINICAL STUDIES, THE MOST FREQUENT ADVERSE REACTIONS LEADING TO PERMANENT DRUG DISCONTINUATION WERE BLEEDING EVENTS, WITH XARELTO VS. ENOXAPARIN/VITAMIN K ANTAGONIST (VKA) INCIDENCE RATES OF 1.7% VS. 1.5%, RESPECTIVELY. THE MEAN DURATION OF TREATMENT WAS 208 DAYS FOR XARELTO-TREATED PATIENTS AND 204 DAYS FOR ENOXAPARIN/VKA-TREATED PATIENTS.
TABLE 2 SHOWS THE NUMBER OF PATIENTS EXPERIENCING MAJOR BLEEDING EVENTS IN THE POOLED ANALYSIS OF THE EINSTEIN DVT AND EINSTEIN PE STUDIES.
TABLE 2: BLEEDING EVENTS* IN THE POOLED ANALYSIS OF EINSTEIN DVT AND EINSTEIN PE STUDIES
PARAMETER XARELTO†
N = 4130 N (%) ENOXAPARIN/ VKA†
N = 4116 N (%)
MAJOR BLEEDING EVENT 40 (1.0) 72 (1.7)
FATAL BLEEDING 3 ( < 0.1) 8 (0.2)
INTRACRANIAL 2 ( < 0.1) 4 ( < 0.1)
NON-FATAL CRITICAL ORGAN BLEEDING 10 (0.2) 29 (0.7)
INTRACRANIAL‡ 3 ( < 0.1) 10 (0.2)
RETROPERITONEAL‡ 1 ( < 0.1) 8 (0.2)
INTRAOCULAR‡ 3 ( < 0.1) 2 ( < 0.1)
INTRA-ARTICULAR‡ 0 4 ( < 0.1)
NON-FATAL NON-CRITICAL ORGAN BLEEDING§ 27 (0.7) 37 (0.9)
DECREASE IN HB ? 2G/DL 28 (0.7) 42 (1.0)
TRANSFUSION OF ?2 UNITS OF WHOLE BLOOD OR PACKED RED BLOOD CELLS 18 (0.4) 25 (0.6)
CLINICALLY RELEVANT NON-MAJOR BLEEDING 357 (8.6) 357 (8.7)
ANY BLEEDING 1169 (28.3) 1153 (28.0)
* BLEEDING EVENT OCCURRED AFTER RANDOMIZATION AND UP TO 2 DAYS AFTER THE LAST DOSE OF STUDY DRUG. ALTHOUGH A PATIENT MAY HAVE HAD 2 OR MORE EVENTS, THE PATIENT IS COUNTED ONLY ONCE IN A CATEGORY.
† TREATMENT SCHEDULE IN EINSTEIN DVT AND EINSTEIN PE STUDIES: XARELTO 15 MG TWICE DAILY FOR 3 WEEKS FOLLOWED BY 20 MG ONCE DAILY; ENOXAPARIN/VKA [ENOXAPARIN: 1 MG/KG TWICE DAILY, VKA: INDIVIDUALLY TITRATED DOSES TO ACHIEVE A TARGET INR OF 2.5 (RANGE: 2.0-3.0)]
‡ TREATMENT-EMERGENT MAJOR BLEEDING EVENTS WITH AT LEAST > 2 SUBJECTS IN ANY POOLED TREATMENT GROUP
§ MAJOR BLEEDING WHICH IS NOT FATAL OR IN A CRITICAL ORGAN, BUT RESULTING IN A DECREASE IN HB ? 2 G/DL AND/OR TRANSFUSION OF ?2 UNITS OF WHOLE BLOOD OR PACKED RED BLOOD CELLS
EINSTEIN EXTENSION STUDY
IN THE EINSTEIN EXTENSION CLINICAL STUDY, THE MOST FREQUENT ADVERSE REACTIONS ASSOCIATED WITH PERMANENT DRUG DISCONTINUATION WERE BLEEDING EVENTS, WITH INCIDENCE RATES OF 1.8% FOR XARELTO VS. 0.2% FOR PLACEBO TREATMENT GROUPS. THE MEAN DURATION OF TREATMENT WAS 190 DAYS FOR BOTH XARELTO AND PLACEBO TREATMENT GROUPS.
TABLE 3 SHOWS THE NUMBER OF PATIENTS EXPERIENCING BLEEDING EVENTS IN THE EINSTEIN EXTENSION STUDY.
TABLE 3: BLEEDING EVENTS* IN EINSTEIN EXTENSION STUDY
PARAMETER XARELTO† 20 MG
N = 598
N (%) PLACEBO†
N = 590
N (%)
MAJOR BLEEDING EVENT‡ 4 (0.7) 0
DECREASE IN HB ?2 G/DL 4 (0.7) 0
TRANSFUSION OF ?2 UNITS OF WHOLE BLOOD OR PACKED RED BLOOD CELLS 2 (0.3) 0
GASTROINTESTINAL 3 (0.5) 0
MENORRHAGIA 1 (0.2) 0
CLINICALLY RELEVANT NON-MAJOR BLEEDING 32 (5.4) 7 (1.2)
ANY BLEEDING 104 (17.4) 63 (10.7)
* BLEEDING EVENT OCCURRED AFTER THE FIRST DOSE AND UP TO 2 DAYS AFTER THE LAST DOSE OF STUDY DRUG. ALTHOUGH A PATIENT MAY HAVE HAD 2 OR MORE EVENTS, THE PATIENT IS COUNTED ONLY ONCE IN A CATEGORY.
† TREATMENT SCHEDULE: XARELTO 20 MG ONCE DAILY; MATCHED PLACEBO ONCE DAILY
‡ THERE WERE NO FATAL OR CRITICAL ORGAN BLEEDING EVENTS.
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)
TOTAL TREATED PATIENTS XARELTO 10 MG
N = 4487
N (%) ENOXAPARIN†
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 TRANSFUSION OF > 2 UNITS OF WHOLE BLOOD OR PACKED CELLS 4 (0.1) 1 ( < 0.1)
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 TRANSFUSION OF > 2 UNITS OF WHOLE BLOOD OR PACKED CELLS 3 (0.1) 1 ( < 0.1)
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 TRANSFUSION OF > 2 UNITS OF WHOLE BLOOD OR PACKED CELLS 1 (0.1) 0
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 ADVERSE REACTION XARELTO 10 MG
N = 4487
N (%) ENOXAPARIN†
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 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)
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
READ THE XARELTO (RIVAROXABAN FILM-COATED ORAL TABLETS) SIDE EFFECTS CENTER FOR A COMPLETE GUIDE TO POSSIBLE SIDE EFFECTS
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 (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].
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].
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].
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 AN [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 EITHER COMBINED P-GP AND/OR WEAK OR MODERATE CYP3A4 INHIBITORS (E.G., AMIODARONE, DILTIAZEM, VERAPAMIL, CHLORAMPHENICOL, CIMETIDINE, 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)] AN [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].
READ THE XARELTO DRUG INTERACTIONS CENTER FOR A COMPLETE GUIDE TO POSSIBLE INTERACTIONS
PRECAUTIONS
INCREASED RISK OF THROMBOTIC EVENTS AFTER PREMATURE DISCONTINUATION
PREMATURE DISCONTINUATION OF ANY ORAL ANTICOAGULANT, INCLUDING XARELTO, IN THE ABSENCE OF ADEQUATE ALTERNATIVE ANTICOAGULATION INCREASES THE RISK OF THROMBOTIC EVENTS. AN INCREASED RATE OF STROKE WAS OBSERVED DURING THE TRANSITION FROM XARELTO TO WARFARIN IN CLINICAL TRIALS IN ATRIAL FIBRILLATION PATIENTS. IF XARELTO IS DISCONTINUED FOR A REASON OTHER THAN PATHOLOGICAL BLEEDING OR COMPLETION OF A COURSE OF THERAPY, CONSIDER COVERAGE WITH ANOTHER ANTICOAGULANT [SEE DOSAGE AND ADMINISTRATION AND CLINICAL STUDIES].
RISK OF BLEEDING
XARELTO INCREASES THE RISK OF BLEEDING AND CAN CAUSE SERIOUS OR FATAL BLEEDING. IN DECIDING WHETHER TO PRESCRIBE XARELTO TO PATIENTS AT INCREASED RISK OF BLEEDING, THE RISK OF THROMBOTIC EVENTS SHOULD BE WEIGHED AGAINST THE RISK OF BLEEDING.
PROMPTLY EVALUATE ANY SIGNS OR SYMPTOMS OF BLOOD LOSS AND CONSIDER THE NEED FOR BLOOD REPLACEMENT. DISCONTINUE XARELTO IN PATIENTS WITH ACTIVE PATHOLOGICAL HEMORRHAGE. THE TERMINAL ELIMINATION HALF-LIFE OF RIVAROXABAN IS 5 TO 9 HOURS IN HEALTHY SUBJECTS AGED 20 TO 45 YEARS.
CONCOMITANT USE OF OTHER DRUGS THAT IMPAIR HEMOSTASIS INCREASES THE RISK OF BLEEDING. THESE INCLUDE ASPIRIN, P2Y12 PLATELET INHIBITORS, OTHER ANTITHROMBOTIC AGENTS, FIBRINOLYTIC THERAPY, AND NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDS) [SEE DRUG INTERACTIONS].
CONCOMITANT USE OF DRUGS THAT ARE COMBINED P-GP AND CYP3A4 INHIBITORS (E.G., KETOCONAZOLE AND RITONAVIR) INCREASES RIVAROXABAN EXPOSURE AND MAY INCREASE BLEEDING RISK[SEE DRUG INTERACTIONS].