HIGHLIGHTS OF PRESCRIBING INFORMATION
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`These highlights do not include all the information needed to use
`XARELTO® (rivaroxaban) safely and effectively. See full prescribing
`XARELTO® (rivaroxaban) safely and effectively. See full prescribing
`information for XARELTO.
`information for XARELTO.
`XARELTO (rivaroxaban) tablets, for oral use
`XARELTO (rivaroxaban) tablets, for oral use
`Initial U.S. Approval: 2011
`Initial U.S. Approval: 2011
`
`WARNING: (A) DISCONTINUING XARELTO IN PATIENTS WITH
`
`
`WARNING: (A) DISCONTINUING XARELTO IN PATIENTS WITH
`NONVALVULAR ATRIAL FIBRILLATION INCREASES RISK OF
`
`NONVALVULAR ATRIAL FIBRILLATION INCREASES RISK OF
`STROKE, and (B) SPINAL/EPIDURAL HEMATOMA
`STROKE, and (B) SPINAL/EPIDURAL HEMATOMA
`See full prescribing information for complete boxed warning
`See full prescribing information for complete boxed warning
`
`DISCONTINUING XARELTO IN PATIENTS WITH NONVALVULAR
`
`DISCONTINUING XARELTO IN PATIENTS WITH NONVALVULAR
`ATRIAL FIBRILLATION
`ATRIAL FIBRILLATION
`Discontinuing XARELTO places patients at an increased risk of
`Discontinuing XARELTO places patients at an increased risk of
`thrombotic events. To reduce this risk, consider administering another
`
`thrombotic events. To reduce this risk, consider administering another
`anticoagulant if XARELTO must be discontinued for a reason other than
`
`anticoagulant if XARELTO must be discontinued for a reason other than
`pathological bleeding (2.3, 5.1, 14.1).
`
`pathological bleeding (23, 5.1, 14.1).
`SPINAL/EPIDURAL HEMATOMA
`SPINAL/EPIDURAL HEMATOMA
`Epidural or spinal hematomas have occurred in patients treated with
`Epidural or spinal hematomas have occurred in patients treated with
`XARELTO who are receiving neuraxial anesthesia or undergoing spinal
`XARELTO who are receiving neuraxial anesthesia or undergoing spinal
`puncture. These hematomas may result in long-term or permanent
`puncture. These hematomas may result in long-term or permanent
`paralysis (5.2, 5.3, 6.2).
`
`paralysis (5.2, 5.3, 6.2).
`Monitor patients frequently for signs and symptoms of neurological
`
`Monitor patients frequently for signs and symptoms of neurological
`impairment and if observed, treat urgently. Consider the benefits and
`
`
`impairment and if observed, treat urgently. Consider the benefits and
`risks before neuraxial intervention in patients who are or who need to be
`risks before neuraxial intervention in patients who are or who need to be
`anticoagulated (5.3).
`
`anticoagulated (5.3).
`----------------------------RECENT MAJOR CHANGES--------------------------
`RECENT MAJOR CHANGES
`Indications and Usage (1)
`11/2012
`
`
`
`11/2012
`Indications and Usage (1)
`Dosage and Administration (2)
` 11/2012
`
`
`
`
`Dosage and Administration (2)
`11/2012
`Contraindications (4)
` 11/2012
`
`
`
`
`Contraindications (4)
`11/2012
`Warnings and Precautions (5)
` 11/2012
`
`
`
`
`11/2012
`Warnings and Precautions (5)
`----------------------------INDICATIONS AND USAGE---------------------------
`
`INDICATIONS AND USAGE
`XARELTO is a factor Xa inhibitor indicated:
`XARELTO is a factor Xa inhibitor indicated:
`
` to reduce the risk of stroke and systemic embolism in patients with
`
`• to reduce the risk of stroke and systemic embolism in patients with
`nonvalvular atrial fibrillation (1.1)
`nonvalvular atrial fibrillation (1.1)
`
` for the treatment of deep vein thrombosis (DVT), pulmonary embolism
`
`• for the treatment of deep vein thrombosis (DVT), pulmonary embolism
`(PE), and for the reduction in the risk of recurrence of DVT and of PE (1.2,
`
`
`(PE), and for the reduction in the risk of recurrence of DVT and of PE (1.2,
`1.3, 1.4)
`
`1.3, 1.4)
`
` for the prophylaxis of DVT, which may lead to PE in patients undergoing
`
`
`
`• for the prophylaxis of DVT, which may lead to PE in patients undergoing
`knee or hip replacement surgery (1.5)
`
`knee or hip replacement surgery (1.5)
`-----------------------DOSAGE AND ADMINISTRATION-----------------------
`
`DOSAGE AND ADMINISTRATION
`
`Take 15 mg and 20 mg tablets with food; take 10 mg tablets with or
`
`
`
`Take 15 mg and 20 mg tablets with food; take 10 mg tablets with or
`•
`without food (2.1)
`
`without food (2.1)
`
` 
`1
`1
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`WARNING: (A) DISCONTINUING XARELTO IN PATIENTS
`
`
`
`WARNING: (A) DISCONTINUING XARELTO IN PATIENTS
`WITH NONVALVULAR ATRIAL FIBRILLATION
`
`
`WITH NONVALVULAR ATRIAL FIBRILLATION
`INCREASES RISK OF STROKE,
`INCREASES RISK OF STROKE,
`(B) SPINAL/EPIDURAL HEMATOMA
`
`(B) SPINAL/EPIDURAL HEMATOMA
` 
`INDICATIONS AND USAGE
`INDICATIONS AND USAGE
` 
`1.1 Reduction of Risk of Stroke and Systemic
`1.1 Reduction of Risk of Stroke and Systemic
` 
`Embolism in Nonvalvular Atrial Fibrillation
`Embolism in Nonvalvular Atrial Fibrillation
` 
` 
`Treatment of Deep Vein Thrombosis
`1.2
`1.2 Treatment of Deep Vein Thrombosis
` 
` 
`Treatment of Pulmonary Embolism
`1.3
`1.3 Treatment of Pulmonary Embolism
` 
`1.4 Reduction in the Risk of Recurrence of Deep
`1.4 Reduction in the Risk of Recurrence of Deep
` 
`Vein Thrombosis and of Pulmonary Embolism
`Vein Thrombosis and of Pulmonary Embolism
` 
`1.5 Prophylaxis of Deep Vein Thrombosis Following
`1.5 Prophylaxis of Deep Vein Thrombosis Following
` 
`Hip or Knee Replacement Surgery
`Hip or Knee Replacement Surgery
` 
` 
`2 DOSAGE AND ADMINISTRATION
`
`2 DOSAGE AND ADMINISTRATION
` 
` 
`Important Food Effect Information
`2.1
`2.1
`Important Food Effect Information
` 
` 
`2.2 Switching to and from XARELTO
`2.2 Switching to and from XARELTO
` 
` 
`2.3 Nonvalvular Atrial Fibrillation
`2.3 Nonvalvular Atrial Fibrillation
` 
`Treatment of Deep Vein Thrombosis (DVT),
`2.4
`2.4 Treatment of Deep Vein Thrombosis (DVT),
`Pulmonary Embolism (PE), and Reduction in the
`Pulmonary Embolism (PE), and Reduction in the
` 
`Risk of Recurrence of DVT and of PE
`Risk of Recurrence of DVT and of PE
` 
`2.5 Prophylaxis of Deep Vein Thrombosis Following
`2.5 Prophylaxis of Deep Vein Thrombosis Following
` 
`Hip or Knee Replacement Surgery
`Hip or Knee Replacement Surgery
`
`
`
`Reference ID: 3212129 Reference ID: 3212129
`
`
`
`•
`
`
`
`•
`
`
`Nonvalvular Atrial Fibrillation:
`
`• Nonvalvular Atrial Fibrillation:
`o
`For patients with CrCl >50 mL/min: 20 mg orally, once daily with
`
`
`
`o
`For patients with CrC1 >50 mL/min: 20 mg orally, once daily with
`the evening meal (2.3)
`
`the evening meal (2.3)
`o
`
`For patients with CrCl 15 - 50 mL/min: 15 mg orally, once daily
`
`For patients with CrC1 15 - 50 mL/min: 15 mg orally, once daily
`o
`with the evening meal (2.3)
`with the evening meal (2.3)
`Treatment of DVT, PE, and Reduction in the Risk of Recurrence of
`
`Treatment of DVT, PE, and Reduction in the Risk of Recurrence of
`DVT and of PE: 15 mg orally twice daily with food for the first 21 days
`
`
`DVT and of PE: 15 mg orally twice daily with food for the first 21 days
`for the initial treatment of acute DVT or PE. After the initial treatment
`for the initial treatment of acute DVT or PE. After the initial treatment
`period, 20 mg orally once daily with food for the remaining treatment
`period, 20 mg orally once daily with food for the remaining treatment
`and the long-term reduction in the risk of recurrence of DVT and of PE.
`
`
`
`and the long-term reduction in the risk of recurrence of DVT and of PE.
`(2.4)
`(2.4)
`Prophylaxis of DVT Following Hip or Knee Replacement Surgery:
`Prophylaxis of DVT Following Hip or Knee Replacement Surgery:
`10 mg orally, once daily with or without food (2.5)
`
`
`10 mg orally, once daily with or without food (2.5)
`--------------------DOSAGE FORMS AND STRENGTHS----------------------
`
`DOSAGE FORMS AND STRENGTHS
`Tablets: 10 mg, 15 mg, and 20 mg (3)
`
`Tablets: 10 mg, 15 mg, and 20 mg (3)
`-------------------------------CONTRAINDICATIONS------------------------------
`
`CONTRAINDICATIONS
`
`Active pathological bleeding (4)
`
`
`
`• Active pathological bleeding (4)
`
`Severe hypersensitivity reaction to XARELTO (4)
`
`
`Severe hypersensitivity reaction to XARELTO (4)
`•
`---------------------------WARNINGS AND PRECAUTIONS-------------------
`
`WARNINGS AND PRECAUTIONS
`
`
`Risk of bleeding: XARELTO can cause serious and fatal bleeding.
`
`
`
`•
`Risk of bleeding: XARELTO can cause serious and fatal bleeding.
`Promptly evaluate signs and symptoms of blood loss. (5.2)
`
`Promptly evaluate signs and symptoms of blood loss. (5.2)
`Pregnancy related hemorrhage: Use XARELTO with caution in pregnant
`
`Pregnancy related hemorrhage: Use XARELTO with caution in pregnant
`women due to the potential for obstetric hemorrhage and/or emergent
`women due to the potential for obstetric hemorrhage and/or emergent
`delivery. Promptly evaluate signs and symptoms of blood loss. (5.7)
`
`
`delivery. Promptly evaluate signs and symptoms of blood loss. (5.7)
`------------------------------ADVERSE REACTIONS------------------------------
` ADVERSE REACTIONS
`The most common adverse reaction (>5%) was bleeding. (6.1)
`
`The most common adverse reaction (>5%) was bleeding. (6.1)
`To report SUSPECTED ADVERSE REACTIONS, contact Janssen
`
`To report SUSPECTED ADVERSE REACTIONS, contact Janssen
`Pharmaceuticals, Inc. at 1-800-526-7736 or FDA at 1-800-FDA-1088 or
`Pharmaceuticals, Inc. at 1-800-526-7736 or FDA at 1-800-FDA-1088 or
`www.fda.gov/medwatch.
`
`www.fda.gov/medwatch.
`---------------------------------DRUG INTERACTIONS----------------------------
`DRUG INTERACTIONS
`
`
`Combined P-gp and strong CYP3A4 inhibitors and inducers: Avoid
`
`•
`Combined P-gp and strong CYP3A4 inhibitors and inducers: Avoid
`
`concomitant use (7.1, 7.2)
`concomitant use (7.1, 7.2)
`
`
`Anticoagulants: Avoid concomitant use (7.3)
`
`• Anticoagulants: Avoid concomitant use (7.3)
`-----------------------USE IN SPECIFIC POPULATIONS-----------------------
`
`USE IN SPECIFIC POPULATIONS
`
`
`Nursing mothers: discontinue drug or discontinue nursing (8.3)
`
`• Nursing mothers: discontinue drug or discontinue nursing (8.3)
`
`
`Renal impairment: Avoid or adjust dose based on CrCl (8.7)
`
`•
`Renal impairment: Avoid or adjust dose based on CrC1 (8.7)
`
`Hepatic impairment: Avoid use in patients with Child-Pugh B and C
`
`• Hepatic impairment: Avoid use in patients with Child-Pugh B and C
`hepatic impairment or with any degree of hepatic disease associated with
`hepatic impairment or with any degree of hepatic disease associated with
`
`coagulopathy (8.8)
`coagulopathy (8.8)
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide.
`
`Guide.
`
`
`
`•
`
`
`
`
`Revised: 11/2012
`Revised: 11/2012
`
`
`
` 
`2.6 Discontinuation for Surgery and other
`
`
`2.6 Discontinuation for Surgery and other
` 
`Interventions
`
`Interventions
` 
` 
`2.7 Missed Dose
`2.7 Missed Dose
` 
` 
`3 DOSAGE FORMS AND STRENGTHS
`3 DOSAGE FORMS AND STRENGTHS
` 
` 
`4 CONTRAINDICATIONS
`4 CONTRAINDICATIONS
` 
` 
`5 WARNINGS AND PRECAUTIONS
`5 WARNINGS AND PRECAUTIONS
` 
`Increased Risk of Stroke after Discontinuation in
`5.1
`Increased Risk of Stroke after Discontinuation in
`5.1
` 
`Nonvalvular Atrial Fibrillation
`Nonvalvular Atrial Fibrillation
` 
` 
`5.2 Risk of Bleeding
`5.2 Risk of Bleeding
` 
` 
`5.3 Spinal/Epidural Anesthesia or Puncture
`5.3 Spinal/Epidural Anesthesia or Puncture
` 
` 
`5.4 Use in Patients with Renal Impairment
`5.4 Use in Patients with Renal Impairment
` 
` 
`5.5 Use in Patients with Hepatic Impairment
`5.5 Use in Patients with Hepatic Impairment
` 
`5.6 Use with P-gp and Strong CYP3A4 Inhibitors or
`5.6 Use with P-gp and Strong CYP3A4 Inhibitors or
` 
`Inducers
`Inducers
` 
` 
`5.7 Risk of Pregnancy Related Hemorrhage
`5.7 Risk of Pregnancy Related Hemorrhage
` 
` 
`6 ADVERSE REACTIONS
`6 ADVERSE REACTIONS
` 
` 
`6.1 Clinical Trials Experience
`6.1 Clinical Trials Experience
` 
` 
`6.2 Postmarketing Experience
`6.2 Postmarketing Experience
` 
` 
`7 DRUG INTERACTIONS
`7 DRUG INTERACTIONS
` 
`7.1 Drugs that Inhibit Cytochrome P450 3A4
`7.1 Drugs that Inhibit Cytochrome P450 3A4
` 
`Enzymes and Drug Transport Systems
`Enzymes and Drug Transport Systems
` 
`7.2 Drugs that Induce Cytochrome P450 3A4
`7.2 Drugs that Induce Cytochrome P450 3A4
` 
`Enzymes and Drug Transport Systems
`Enzymes and Drug Transport Systems
` 
` 
`7.3 Anticoagulants and NSAIDs/Aspirin
`7.3 Anticoagulants and NSAIDs/Aspirin
`
`1
`
`0001
`
`0001
`
`MYLAN - EXHIBIT 1061
`
`

`

`
`
` 
`7.4 Drug-Disease Interactions with Drugs that Inhibit
`
`7.4 Drug-Disease Interactions with Drugs that Inhibit
`Cytochrome P450 3A4 Enzymes and Drug
`
`
`Cytochrome P450 3A4 Enzymes and Drug
` 
`Transport Systems
`
`Transport Systems
` 
` 
`8 USE IN SPECIFIC POPULATIONS
`8 USE IN SPECIFIC POPULATIONS
` 
` 
`8.1 Pregnancy
`
`8.1 Pregnancy
` 
` 
`8.2
`Labor and Delivery
`
`Labor and Delivery
`8.2
` 
` 
`8.3 Nursing Mothers
`
`8.3
`Nursing Mothers
` 
` 
`8.4 Pediatric Use
`
`8.4 Pediatric Use
` 
` 
`8.5 Geriatric Use
`
`8.5 Geriatric Use
` 
` 
`8.6
`Females of Reproductive Potential
`
`8.6 Females of Reproductive Potential
` 
` 
`8.7 Renal Impairment
`
`8.7 Renal Impairment
` 
` 
`8.8 Hepatic Impairment
`
`8.8 Hepatic Impairment
` 
` 
`10 OVERDOSAGE
`10 OVERDOSAGE
` 
` 
`11 DESCRIPTION
`11 DESCRIPTION
` 
` 
`12 CLINICAL PHARMACOLOGY
`12 CLINICAL PHARMACOLOGY
` 
` 
`12.1 Mechanism of Action
`
`12.1 Mechanism of Action
` 
` 
`12.2 Pharmacodynamics
`
`12.2 Pharmacodynamics
` 
` 
`12.3 Pharmacokinetics
`
`12.3 Pharmacokinetics
` 
` 
`12.6 QT/QTc Prolongation
`
`12.6 QT/QTc Prolongation
`
`
`
`
`
`
`
` 
` 
`13 NON-CLINICAL TOXICOLOGY
`13 NON-CLINICAL TOXICOLOGY
` 
`13.1 Carcinogenesis, Mutagenesis, Impairment of
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of
` 
`Fertility
`
`Fertility
` 
` 
`14 CLINICAL STUDIES
`14 CLINICAL STUDIES
` 
` 
`14.1 Stroke Prevention in Nonvalvular Atrial Fibrillation
`
`14.1 Stroke Prevention in Nonvalvular Atrial Fibrillation
` 
`14.2 Treatment of Deep Vein Thrombosis (DVT),
`
`14.2 Treatment of Deep Vein Thrombosis (DVT),
`Pulmonary Embolism (PE), and Reduction in the
`
`Pulmonary Embolism (PE), and Reduction in the
` 
`Risk of Recurrence of DVT and of PE
`
`Risk of Recurrence of DVT and of PE
` 
`14.3 Prophylaxis of Deep Vein Thrombosis Following
`
`14.3 Prophylaxis of Deep Vein Thrombosis Following
` 
`Hip or Knee Replacement Surgery
`
`Hip or Knee Replacement Surgery
` 
` 
`16 HOW SUPPLIED/STORAGE AND HANDLING
`16 HOW SUPPLIED/STORAGE AND HANDLING
` 
` 
`17 PATIENT COUNSELING INFORMATION
`
`17 PATIENT COUNSELING INFORMATION
` 
` 
`17.1
`Instructions for Patient Use
`
`17.1
`Instructions for Patient Use
` 
` 
`17.2 Bleeding Risks
`
`17.2 Bleeding Risks
` 
` 
`17.3
`Invasive or Surgical Procedures
`
`17.3
`Invasive or Surgical Procedures
` 
` 
`17.4 Concomitant Medication and Herbals
`
`17.4 Concomitant Medication and Herbals
` 
` 
`17.5 Pregnancy and Pregnancy-Related Hemorrhage
`
`
`17.5 Pregnancy and Pregnancy-Related Hemorrhage
` 
` 
`17.6 Nursing
`
`17.6 Nursing
` 
` 
`17.7 Females of Reproductive Potential
`
`17.7 Females of Reproductive Potential
`
`
`*Sections or subsections omitted from the full prescribing information are not
`
`
`*Sections or subsections omitted from the full prescribing information are not
`listed.
`listed.
`
`
`
`
`
`
`
`
`
`Reference ID: 3212129 Reference ID: 3212129
`
`2
`2
`
`0002
`
`0002
`
`

`

`
`FULL PRESCRIBING INFORMATION
`
`FULL PRESCRIBING INFORMATION
`WARNING: (A) DISCONTINUING XARELTO IN PATIENTS WITH NONVALVULAR
`
`WARNING: (A) DISCONTINUING XARELTO IN PATIENTS WITH NONVALVULAR
`ATRIAL FIBRILLATION INCREASES RISK OF STROKE,
`ATRIAL FIBRILLATION INCREASES RISK OF STROKE,
`(B) SPINAL/EPIDURAL HEMATOMA
`(B) SPINAL/EPIDURAL HEMATOMA
`
`
`
`A. DISCONTINUING XARELTO IN PATIENTS WITH NONVALVULAR ATRIAL
`A. DISCONTINUING XARELTO IN PATIENTS WITH NONVALVULAR ATRIAL
`FIBRILLATION
`FIBRILLATION
`Discontinuing XARELTO places patients at an increased risk of thrombotic events. An
`Discontinuing XARELTO places patients at an increased risk of thrombotic events. An
`increased rate of stroke was observed following XARELTO discontinuation in clinical
`increased rate of stroke was observed following XARELTO discontinuation in clinical
`trials
`in atrial fibrillation patients. If anticoagulation with XARELTO must be
`trials in atrial fibrillation patients. If anticoagulation with XARELTO must be
`discontinued for a reason other than pathological bleeding, consider administering another
`discontinued for a reason other than pathological bleeding, consider administering another
`anticoagulant [see Dosage and Administration (2.3), Warnings and Precautions (5.1), and
`anticoagulant [see Dosage and Administration (2.3), Warnings and Precautions (5.1), and
`Clinical Studies (14.1)].
`Clinical Studies (14.1)].
`
`
`B. SPINAL/EPIDURAL HEMATOMA
`B. SPINAL/EPIDURAL HEMATOMA
`Epidural or spinal hematomas have occurred in patients treated with XARELTO who are
`Epidural or spinal hematomas have occurred in patients treated with XARELTO who are
`receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may
`receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may
`
`result in long-term or permanent paralysis. Consider these risks when scheduling patients
`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
`for spinal procedures. Factors that can increase the risk of developing epidural or spinal
`hematomas in these patients include:
`hematomas in these patients include:
`
` use of indwelling epidural catheters
`• use of indwelling epidural catheters
`
` concomitant use of other drugs that affect hemostasis, such as non-steroidal anti-
`•
`concomitant use of other drugs that affect hemostasis, such as non-steroidal anti-
`inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants
`inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants
`
` a history of traumatic or repeated epidural or spinal punctures
`• a history of traumatic or repeated epidural or spinal punctures
`
` a history of spinal deformity or spinal surgery
`• a history of spinal deformity or spinal surgery
`[see Warnings and Precautions (5.2, 5.3) and Adverse Reactions (6.2)].
`[see Warnings and Precautions (5.2, 5.3) and Adverse Reactions (6.2)1
`
`
`Monitor patients frequently for signs and symptoms of neurological impairment. If
`Monitor patients frequently for signs and symptoms of neurological impairment. If
`neurological compromise is noted, urgent treatment is necessary [see Warnings and
`
`neurological compromise is noted, urgent treatment is necessary [see Warnings and
`Precautions (5.3)].
`Precautions (5.3)].
`
`Consider the benefits and risks before neuraxial intervention in patients anticoagulated or
`Consider the benefits and risks before neuraxial intervention in patients anticoagulated or
`to be anticoagulated for thromboprophylaxis [see Warnings and Precautions (5.3)].
`to be anticoagulated for thromboprophylaxis [see Warnings and Precautions (5.3)].
`
`
`1
`INDICATIONS AND USAGE
`1 INDICATIONS AND USAGE
`1.1 Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular Atrial
`1.1 Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular Atrial
`Fibrillation
`Fibrillation
`XARELTO is indicated to reduce the risk of stroke and systemic embolism in patients with
`XARELTO is indicated to reduce the risk of stroke and systemic embolism in patients with
`nonvalvular atrial fibrillation.
`nonvalvular atrial fibrillation.
`
`
`
`Reference ID: 3212129 Reference ID: 3212129
`
`3
`3
`
`0003
`
`0003
`
`

`

`
`There are limited data on the relative effectiveness of XARELTO and warfarin in reducing the
`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
`
`risk of stroke and systemic embolism when warfarin therapy is well-controlled [see Clinical
`Studies (14.1)].
`
`Studies (14.1)] .
`
`1.2 Treatment of Deep Vein Thrombosis
`1.2 Treatment of Deep Vein Thrombosis
`XARELTO is indicated for the treatment of deep vein thrombosis (DVT).
`XARELTO is indicated for the treatment of deep vein thrombosis (DVT).
`
`1.3 Treatment of Pulmonary Embolism
`1.3 Treatment of Pulmonary Embolism
`XARELTO is indicated for the treatment of pulmonary embolism (PE).
`XARELTO is indicated for the treatment of pulmonary embolism (PE).
`
`1.4 Reduction in the Risk of Recurrence of Deep Vein Thrombosis and of
`1.4 Reduction in the Risk of Recurrence of Deep Vein Thrombosis and of
`Pulmonary Embolism
`Pulmonary Embolism
`
`XARELTO is indicated for the reduction in the risk of recurrence of deep vein thrombosis and of
`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.
`pulmonary embolism following initial 6 months treatment for DVT and/or PE.
`
`1.5 Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement
`1.5 Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement
`Surgery
`Surgery
`XARELTO is indicated for the prophylaxis of DVT, which may lead to PE in patients
`XARELTO is indicated for the prophylaxis of DVT, which may lead to PE in patients
`undergoing knee or hip replacement surgery.
`undergoing knee or hip replacement surgery.
`
`2 DOSAGE AND ADMINISTRATION
`2 DOSAGE AND ADMINISTRATION
`
`
`Indication
`
`Indication
`Reduction in Risk of Stroke in
`Reduction in Risk of Stroke in
`
`
`Nonvalvular Atrial Fibrillation
`Nonvalvular Atrial Fibrillation
`(2.3)
`
`(2.3)
`Treatment of DVT (2.4)
`Treatment of DVT (2.4)
`Treatment of PE (2.4)
`
`Treatment of PE (2.4)
`
`
`CrCl >50 mL/min:
`CrCl >50 mL/min:
`
`Dosage
`
`Dosage
`20 mg once daily with the evening meal
`
`
`20 mg once daily with the evening meal
`
`
`
`CrCl 15 to 50 mL/min:
`CrC115 to 50 mL/min:
`
`15 mg once daily with the evening meal
`
`15 mg once daily with the evening meal
`
`
`15 mg twice daily with food, for first 21 days
`15 mg twice daily with food, for first 21 days
`¤ after 21 days, transition to •
`▼after 21 days, transition to ▼
`
`
`20 mg once daily with food, for remaining treatment
`
`20 mg once daily with food, for remaining treatment
`
`Reduction in the Risk of
`
`Reduction in the Risk of
`Recurrence of DVT and of PE (2.4) 20 mg once daily with food
`20 mg once daily with food
`
`Recurrence of DVT and of PE (2.4)
`Prophylaxis of DVT Following Hip
`Hip replacement:
`10 mg once daily for 35 days
`10 mg once daily for 35 days
`Prophylaxis of DVT Following Hip
`Hip replacement:
`or Knee Replacement Surgery (2.5)
`
`
`or Knee Replacement Surgery (2.5)
`10 mg once daily for 12 days
`10 mg once daily for 12 days
`
`
`Knee replacement:
`Knee replacement:
`
`
`
`
`
`Important Food Effect Information
`2.1
`2.1 Important Food Effect Information
`The 15 mg and 20 mg XARELTO tablets should be taken with food, while the 10 mg tablet can
`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 (12.3)].
`be taken with or without food [see Clinical Pharmacology (12.3)] .
`
`Reference ID: 3212129
`Reference ID: 3212129
`
`4
`4
`
`0004
`
`0004
`
`

`

`
`In the nonvalvular atrial fibrillation efficacy study XARELTO was taken with the evening meal.
`In the nonvalvular atrial fibrillation efficacy study XARELTO was taken with the evening meal.
`
`2.2 Switching to and from XARELTO
`2.2 Switching to and from XARELTO
`Switching from Warfarin to XARELTO - When switching patients from warfarin to 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
`
`discontinue warfarin and start XARELTO as soon as the International Normalized Ratio (INR) is
`
`below 3.0 to avoid periods of inadequate anticoagulation.
`below 3.0 to avoid periods of inadequate anticoagulation.
`
`Switching from XARELTO to Warfarin - No clinical trial data are available to guide converting
`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
`
`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
`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
`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.
`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
`
`Switching from XARELTO to Anticoagulants other than Warfarin - For patients currently taking
`XARELTO and transitioning to an anticoagulant with rapid onset, discontinue XARELTO and
`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
`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 (7.3)]
`
`XARELTO dose would have been taken [see Drug Interactions (7.3)1
`
`Switching from Anticoagulants other than Warfarin to XARELTO - For patients currently
`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
`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-
`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
`warfarin oral anticoagulant) and omit administration of the other anticoagulant. For
`unfractionated heparin being administered by continuous infusion, stop the infusion and start
`unfractionated heparin being administered by continuous infusion, stop the infusion and start
`XARELTO at the same time.
`XARELTO at the same time.
`
`2.3 Nonvalvular Atrial Fibrillation
`2.3 Nonvalvular Atrial Fibrillation
`For patients with creatinine clearance (CrCl) >50 mL/min, the recommended dose of XARELTO
`For patients with creatinine clearance (CrC1) >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,
`is 20 mg taken orally once daily with the evening meal. For patients with CrC1 15 to 50 mL/min,
`the recommended dose is 15 mg once daily with the evening meal [see Use in Specific
`the recommended dose is 15 mg once daily with the evening meal [see Use in Specific
`Populations (8.7)].
`Populations (8.7)1 .
`
`2.4 Treatment of Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), and
`2.4 Treatment of Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), and
`Reduction in the Risk of Recurrence of DVT and of PE
`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
`
`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
`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
`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
`
`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
`
`recurrence of DVT or PE is 20 mg taken orally once daily with food at approximately the same
`time each day [see Clinical Studies (14.2)].
`time each day [see Clinical Studies (14.2)1.
`
`
`
`Reference ID: 3212129 Reference ID: 3212129
`
`5
`5
`
`0005
`
`0005
`
`

`

`
`2.5 Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement
`2.5 Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement
`Surgery
`Surgery
`The recommended dose of XARELTO is 10 mg taken orally once daily with or without food.
`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
`The initial dose should be taken at least 6 to 10 hours after surgery once hemostasis has been
`established [see Dosage and Administration (2.6)].
`established [see Dosage and Administration (2.6)1 .
`
`
` For patients undergoing hip replacement surgery, treatment duration of 35 days is
`• For patients undergoing hip replacement surgery, treatment duration of 35 days is
`recommended.
`recommended.
`
` For patients undergoing knee replacement surgery, treatment duration of 12 days is
`• For patients undergoing knee replacement surgery, treatment duration of 12 days is
`recommended.
`recommended.
`2.6 Discontinuation for Surgery and other Interventions
`2.6 Discontinuation for Surgery and other Interventions
`If anticoagulation must be discontinued to reduce the risk of bleeding with surgical or other
`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
`procedures, XARELTO should be stopped at least 24 hours before the procedure to reduce the
`risk of bleeding [see Warnings and Precautions (5.2)]. In deciding whether a procedure should
`risk of bleeding [see Warnings and Precautions (5.2)1. In deciding whether a procedure should
`
`be delayed until 24 hours after the last dose of XARELTO, the increased risk of bleeding 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
`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
`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 (5.1)]. If oral medication
`onset of therapeutic effect is short [see Warnings and Precautions (5.1)1. If oral medication
`cannot be taken during or after surgical intervention, consider administering a parenteral
`cannot be taken during or after surgical intervention, consider administering a parenteral
`anticoagulant.
`anticoagulant.
`
`2.7 Missed Dose
`2.7 Missed Dose
`If a dose of XARELTO is not taken at the scheduled time, administer the dose as soon as
`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:
`possible on the same day as follows:
`
`
` For patients receiving 15 mg twice daily: The patient should take XARELTO
`• 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,
`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
`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.
`15 mg twice daily intake as recommended on the following day.
`
` For patients receiving 20, 15 or 10 mg once daily: The patient should take the missed
`• For patients receiving 20, 15 or 10 mg once daily: The patient should take the missed
`XARELTO dose immediately.
`XARELTO dose immediately.
`
`3 DOSAGE FORMS AND STRENGTHS
`3 DOSAGE FORMS AND STRENGTHS
`
` 10 mg tablets: Round, light red, biconvex and film-coated with a triangle p