|
XARELTO (rivaroxaban) tablets, for oral use
|
HIGHLIGHTS OF PRESCRIBING INFORMATION |
These highlights do not include all the information needed to use XARELTO® (rivaroxaban) safely and effectively. See full prescribing information for XARELTO.
XARELTO (rivaroxaban) tablets, for oral use
Initial U.S. Approval: 2011
|
WARNINGS: (A) DISCONTINUING XARELTO IN PATIENTS WITH NONVALVULAR ATRIAL FIBRILLATION INCREASES RISK OF STROKE, (B) SPINAL/EPIDURAL HEMATOMA
See full prescribing information for complete boxed warning
A. DISCONTINUING XARELTO IN PATIENTS WITH NONVALVULAR ATRIAL FIBRILLATION
Discontinuing XARELTO places patients at an increased risk of thrombotic events. If anticoagulation with XARELTO must be discontinued for a reason other than pathological bleeding, consider administering another anticoagulant (2.1, 5.1, 14.1).
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 (5.2, 5.3, 6.2).
Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary (5.3).
Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis (5.3).
|
|
RECENT MAJOR CHANGES
|
|
Boxed Warning |
11/2011 |
|
Indications and Usage (1.1) |
11/2011 |
|
Dosage and Administration (2.1, 2.3) |
11/2011 |
|
Contraindications (4) |
11/2011 |
|
Warnings and Precautions (5.1, 5.2, 5.5) |
11/2011 |
|
|
INDICATIONS AND USAGE
|
|
XARELTO is a factor Xa inhibitor indicated:
-
to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (1.1)
-
for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE) in patients undergoing knee or hip replacement surgery (1.2)
|
|
DOSAGE AND ADMINISTRATION
|
-
Nonvalvular Atrial Fibrillation:
-
For patients with CrCl >50 mL/min: 20 mg orally, once daily with the evening meal (2.1)
-
For patients with CrCl 15 – 50 mL/min: 15 mg orally, once daily with the evening meal (2.1)
-
Avoid use in patients with CrCl <15 mL/min (2.3)
-
Prophylaxis of DVT: 10 mg orally, once daily with or without food (2.2)
-
Hepatic impairment (for nonvalvular AF and prophylaxis of DVT indications):
-
Avoid use in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any degree of hepatic disease associated with coagulopathy (2.3, 8.8).
|
|
DOSAGE FORMS AND STRENGTHS
|
|
Tablets: 10 mg, 15 mg, and 20 mg (3)
|
|
CONTRAINDICATIONS
|
-
Active pathological bleeding (4)
-
Severe hypersensitivity reaction to XARELTO (4)
|
|
WARNINGS AND PRECAUTIONS
|
-
Risk of bleeding: XARELTO can cause serious and fatal bleeding. Promptly eva luate signs and symptoms of blood loss. (5.2)
-
Pregnancy related hemorrhage: Use XARELTO with caution in pregnant women due to the potential for obstetric hemorrhage and/or emergent delivery. Promptly eva luate signs and symptoms of blood loss. (5.4)
|
|
ADVERSE REACTIONS
|
|
The most common adverse reaction (>5%) was bleeding. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Janssen Pharmaceuticals, Inc. at 1-800-526-7736 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
|
|
DRUG INTERACTIONS
|
-
Combined P-gp and strong CYP3A4 inhibitors and inducers: Avoid concomitant use (7.1, 7.2)
-
Prophylaxis of DVT:
-
Anticoagulants: Avoid concomitant use (7.3)
|
|
USE IN SPECIFIC POPULATIONS
|
-
Nursing mothers: discontinue drug or discontinue nursing (8.3)
-
Renal impairment:
-
Prophylaxis of DVT: Avoid use in patients with severe impairment (CrCl <30 mL/min). Use with caution in moderate impairment (CrCl 30 to <50 mL/min) (8.7)
|
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide |
Revised: 12/2011 |
|
FULL PRESCRIBING INFORMATION: CONTENTS* |
|
*
|
|
|
FULL PRESCRIBING INFORMATION
WARNINGS: (A) DISCONTINUING XARELTO IN PATIENTS WITH NONVALVULAR ATRIAL FIBRILLATION INCREASES RISK OF STROKE, (B) SPINAL/EPIDURAL HEMATOMA
A. DISCONTINUING XARELTO IN PATIENTS WITH NONVALVULAR ATRIAL FIBRILLATION
Discontinuing XARELTO places patients at an increased risk of thrombotic events. An increased rate of stroke was observed following XARELTO discontinuation in clinical trials in atrial fibrillation patients. If anticoagulation with XARELTO must be discontinued for a reason other than pathological bleeding, consider administering another anticoagulant [see Dosage and Administration (2.1), Warnings and Precautions (5.1), and Clinical Studies (14.1)].
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
[see Warnings and Precautions (5.2, 5.3) and Adverse Reactions (6.2)].
Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary [see Warnings and Precautions (5.3)].
Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis [see Warnings and Precautions (5.3)].
1 INDICATIONS AND USAGE
1.1 Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular Atrial Fibrillation
XARELTO (rivaroxaban) 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 (14.1)].
1.2 Prophylaxis of Deep Vein Thrombosis
XARELTO (rivaroxaban) is indicated for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE) in patients undergoing knee or hip replacement surgery.
2 DOSAGE AND ADMINISTRATION
2.1 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 (8.7)].
Switching from or to Warfarin - 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.
No clinical trial data are available to guide converting patients from XARELTO to warfarin. XARELTO affects INR, so INR measurements made during co-administration 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 or to Anticoagulants other than Warfarin - 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.
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 (7.3)].
2.2 Prophylaxis of Deep Vein Thrombosis
The recommended dose of XARELTO is 10 mg taken orally once daily with or without food. The initial dose should be taken at least 6 to 10 hours after surgery once hemostasis has been established.
-
For patients undergoing hip replacement surgery, treatment duration of 35 days is recommended.
-
For patients undergoing knee replacement surgery, treatment duration of 12 days is recommended.
2.3 General Dosing Instructions
Hepatic Impairment
No clinical data are available for patients with severe hepatic impairment. Avoid use of XARELTO in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy [see Use in Specific Populations (8.8)].
Renal Impairment
Nonvalvular Atrial Fibrillation
Avoid the use of XARELTO in patients with CrCl <15 mL/min. Periodically assess renal function as clinically indicated (i.e., more frequently in situations in which renal function may decline) and adjust therapy accordingly. Discontinue XARELTO in patients who develop acute renal failure while on XARELTO [see Use in Specific Populations (8.7)].
Prophylaxis of Deep Vein Thrombosis
Avoid the use of XARELTO in patients with severe renal impairment (CrCl <30 mL/min) due to an expected increase in rivaroxaban exposure and pharmacodynamic effects in this patient population. Observe closely and promptly eva luate any signs or symptoms of blood loss in patients with moderate renal impairment (CrCl 30 to 50 mL/min). Patients who develop acute renal failure while on XARELTO should discontinue the treatment [see Use in Specific Populations (8.7)].
Surgery and Intervention
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. 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. If oral medication cannot be taken 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.
Use with P-gp and Strong CYP3A4 Inhibitors or Inducers
Avoid concomitant use of XARELTO with combined P-gp and strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, lopinavir/ritonavir, ritonavir, indinavir/ritonavir, and conivaptan) [see Drug Interactions (7.1)].
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 Drug Interactions (7.2)].
3 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
4 CONTRAINDICATIONS
XARELTO is contraindicated in patients with:
5 WARNINGS AND PRECAUTIONS
5.1 Increased Risk of Stroke after Discontinuation in Nonvalvular Atrial Fibrillation
Discontinuing 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 must be discontinued for a reason other than pathological bleeding, consider administering another anticoagulant [see Dosage and Administration (2.1) and Clinical Studies (14.1)].
5.2 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 eva luate any signs or symptoms of blood loss. Discontinue XARELTO in patients with active pathological hemorrhage.
A specific antidote for rivaroxaban is not available. Because of high plasma protein binding, rivaroxaban is not expected to be dialyzable [see Clinical Pharmacology (12.3)]. Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban. There is no experience with antifibrinolytic agents (tranexamic acid, aminocaproic acid) in individuals receiving rivaroxaban. There is neither scientific rationale for benefit nor experience with systemic hemostatics (desmopressin and aprotinin) in individuals receiving rivaroxaban. Use of procoagulant reversal agents such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (APCC), or recombinant factor VIIa (rFVIIa) may be considered, but has not been eva luated in clinical trials.
Concomitant use of drugs affecting 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 (7.3), (7.4), (7.5)].
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 (7.1)].
5.3 Spinal/Epidural Anesthesia or Puncture
When neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture is employed, patients treated with anticoagulant agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis [see Boxed Warning].
An epidural catheter should not be removed earlier than 18 hours after the last administration of XARELTO. The next XARELTO dose is not to be administered earlier than 6 hours after the removal of the catheter. If traumatic puncture occurs, the administration of XARELTO is to be delayed for 24 hours.
5.4 Risk of Pregnancy Related Hemorrhage
XARELTO should be used with caution in pregnant women and only if the potential benefit justifies the potential risk to the mother and fetus. XARELTO dosing in pregnancy has not been studied. The anticoagulant effect of XARELTO cannot be monitored with standard laboratory testing nor readily reversed. Promptly eva luate any signs or symptoms suggesting blood loss (e.g., a drop in hemoglobin and/or hematocrit, hypotension, or fetal distress).
5.5 Severe Hypersensitivity Reactions
There were postmarketing cases of anaphylaxis in patients treated with XARELTO to reduce the risk of DVT. Patients who have a history of a severe hypersensitivity reaction to XARELTO should not receive XARELTO [see Adverse Reactions (6.2)].
6 ADVERSE REACTIONS
6.1 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, 11598 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) 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 (5.2)].
Nonvalvular Atrial Fibrillation
In the ROCKET AF trial, the most fr |
|
