Detailed View: Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research (CDER)
WARNINGS AND PRECAUTIONS
Risk of Bleeding
- Addition of selective serotonin reuptake inhibitors, and serotonin norepinephrine reuptake inhibitors to the paragraph beginning with Concomitant use of other drugs.
Use in Patients with Renal Impairment
Nonvalvular Atrial Fibrillation (replace paragraph)
- Periodically assess renal function as clinically indicated (i.e., more frequently in situations in which renal function may decline) and adjust therapy accordingly. Consider dose adjustment or discontinuation of XARELTO in patients who develop acute renal failure while on XARELTO.
USE IN SPECIAL POPULATIONS
Patients with End-Stage Renal Disease on Dialysis (addition)
- Clinical efficacy and safety studies with XARELTO did not enroll patients with end-stage renal disease (ESRD) on dialysis. In patients with ESRD maintained on intermittent hemodialysis, administration of XARELTO 15 mg once daily will result in concentrations of rivaroxaban and pharmacodynamic activity similar to those observed in the ROCKET AF study. It is not known whether these concentrations will lead to similar stroke reduction and bleeding risk in patients with ESRD on dialysis as was seen in ROCKET AF.
XARELTO can cause bleeding (add the following to the bulleted list)
- selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs)
- other medicines to treat blood clots
- *Table 1 modified (Bleeding events)
* addition of “thrombocytopenia” as an adverse reaction and replaces the adverse reaction term “cytolytic hepatitis” with “hepatitis (including hepatocellular injury)”
- optimal timing between the administration of XARELTO and neuraxial procedures is not known
WARNINGS AND PRECAUTIONS
Spinal/Epidural Anesthesia or Puncture
- To reduce the potential risk of bleeding associated with the concurrent use of rivaroxaban and epidural or spinal anesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of rivaroxaban [see Clinical Pharmacology (12.3)]. Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of rivaroxaban is low; however, the exact timing to reach a sufficiently low anticoagulant effect in each patient is not known.
- Should the physician decide to administer anticoagulation in the context of epidural or spinal anesthesia/analgesia or lumbar puncture, monitor frequently to detect any signs or symptoms of neurological impairment, such as midline back pain, sensory and motor deficits (numbness, tingling, or weakness in lower limbs), bowel and/or bladder dysfunction. Instruct patients to immediately report if they experience any of the above signs or symptoms. If signs or symptoms of spinal hematoma are suspected, initiate urgent diagnosis and treatment including consideration for spinal cord decompression even though such treatment may not prevent or reverse neurological sequelae.
- Study results added… “An Open-Label Study to Estimate the Effect of Multiple Doses of Erythromycin on the Pharmacokinetics, Pharmacodynamics and Safety of a Single Dose of Rivaroxaban in Subjects with Renal Impairment and Normal Renal Function.”
5 WARNINGS AND PRECAUTIONS
5.2 Risk of Bleeding
- Promptly evaluate any signs or symptoms of blood loss and consider the need for blood replacement. Discontinue .....
Reversal of Anticoagulant Effect:
- 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 ......The use of other procoagulant reversal agents like activated prothrombin complex concentrate (APCC) or recombinant factor VIIa (rFVIIa) has not been evaluated.
5.6 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, 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)].
5.8 Patients with Prosthetic Heart Valves
- The safety and efficacy of XARELTO have not been studied in patients with prosthetic heart valves. Therefore, use of XARELTO is not recommended in these patients.
5.9 Acute PE in Hemodynamically Unstable Patients or Patients Who Require Thrombolysis or Pulmonary Embolectomy
- Initiation of XARELTO is not recommended acutely as an alternative to unfractionated heparin in patients with pulmonary embolism who present with hemodynamic instability or who may receive thrombolysis or pulmonary embolectomy.
- Premature discontinuation of Xarelto increases the risk of thrombotic events, and spinal/epidural hematoma…
WARNINGS AND 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…
- Patients with Prosthetic Heart Valves - The safety and efficacy of Xarelto have not been studied in patients with prosthetic heart valves. Therefore, use of Xarelto is not recommended in these patients.