Xarelto Information
Xarelto () Indications And Usage
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
Xarelto () Dosage And Administration
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 .
Xarelto () Contraindications
Xarelto () is contraindicated in patients with:
Xarelto () Warnings And Precautions
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 .
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. 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 . 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 evaluated in clinical trials.
Concomitant use of drugs affecting hemostasis increases the risk of bleeding. These include aspirin, P2Y platelet inhibitors, other antithrombotic agents, fibrinolytic therapy, and non-steroidal anti-inflammatory drugs (NSAIDs)
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 .
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 .
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.
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 () .
Xarelto () Adverse Reactions
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).
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:
Gastrointestinal disorders:
Hepatobiliary disorders:
Immune system disorders:
Nervous system disorders:
Skin and subcutaneous tissue disorders:
Xarelto () 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.
In drug interaction studies evaluating the concomitant use with drugs that are combined P-gp and CYP3A4 inhibitors, increases in rivaroxaban exposure and pharmacodynamic effects (i.e., factor Xa inhibition and PT prolongation) were observed. Significant increases in rivaroxaban exposure may increase bleeding risk.
Avoid concomitant administration of Xarelto () with combined P-gp and strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, lopinavir/ritonavir, ritonavir, indinavir/ritonavir, and conivaptan), which cause significant increases in rivaroxaban exposure that may increase bleeding risk.
In a drug interaction study, co-administration of Xarelto () (20 mg single dose with food) with a drug that is a combined P-gp and strong CYP3A4 inducer (rifampicin titrated up to 600 mg once daily) led to an approximate decrease of 50% and 22% in AUC and C, respectively. Similar decreases in pharmacodynamic effects were also observed. These decreases in exposure to rivaroxaban may decrease efficacy.
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).
In ROCKET AF, concomitant aspirin use (almost exclusively at a dose of 100 mg or less) during the double-blind phase was identified as an independent risk factor for major bleeding. NSAIDs are known to increase bleeding, and bleeding risk may be increased when NSAIDs are used concomitantly with Xarelto () . In a single-dose drug interaction study there were no pharmacokinetic or pharmacodynamic interactions observed after concomitant administration of naproxen or aspirin (acetylsalicylic acid) with Xarelto () .
Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with aspirin, other platelet aggregation inhibitors, or NSAIDs .
In two drug interaction studies where clopidogrel (300 mg 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 pharmacokinetics of either drug.
Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with clopidogrel .
Based on simulated pharmacokinetic data, patients with renal impairment receiving full dose Xarelto () in combination with drugs classified as combined P-gp and weak or moderate CYP3A4 inhibitors (e.g., amiodarone, diltiazem, verapamil, quinidine, ranolazine, dronedarone, felodipine, erythromycin, and azithromycin) may have significant increases in exposure compared with patients with normal renal function and no inhibitor use, since both pathways of rivaroxaban elimination are affected.
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 combined P-gp and 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
Xarelto () Use In Specific Populations
The safety and pharmacokinetics of single-dose Xarelto () (10 mg) were evaluated in a study in healthy subjects [CrCl ≥80 mL/min (n=8)] and in subjects with varying degrees of renal impairment (see ). Compared to healthy subjects with normal creatinine clearance, rivaroxaban exposure increased in subjects with renal impairment. Increases in pharmacodynamic effects were also observed.
Patients with renal impairment taking P-gp and weak to moderate CYP3A4 inhibitors may have significant increases in exposure which may increase bleeding risk .
The safety and pharmacokinetics of single-dose Xarelto () (10 mg) were evaluated in a study in healthy subjects (n=16) and subjects with varying degrees of hepatic impairment (see ). No patients with severe hepatic impairment (Child-Pugh C) were studied. Compared to healthy subjects with normal liver function, significant increases in rivaroxaban exposure were observed in subjects with moderate hepatic impairment (Child-Pugh B). Increases in pharmacodynamic effects were also observed.
Avoid the 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 .
Xarelto () Overdosage
Overdose of Xarelto () may lead to hemorrhage. A specific antidote for rivaroxaban is not available. Rivaroxaban systemic exposure is not further increased at single doses >50 mg due to limited absorption. Discontinue Xarelto () and initiate appropriate therapy if bleeding complications associated with overdosage occur. The use of activated charcoal to reduce absorption in case of Xarelto () overdose may be considered. Due to the high plasma protein binding, rivaroxaban is not expected to be dialyzable .
Xarelto () Description
Rivaroxaban, a factor Xa 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-5-yl}methyl)-2-thiophenecarboxamide. The molecular formula of rivaroxaban is CHClNOS and the molecular weight is 435.89. The structural formula is:
Rivaroxaban is a pure ()-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 Xarelto () 15 mg tablets is Opadry Red, 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.
Xarelto () Clinical Studies
The evidence for the efficacy and safety of Xarelto () was derived from ROCKET AF, a multi-national, double-blind study comparing Xarelto () (at a dose of 20 mg once daily with the evening meal in patients with CrCl >50 mL/min and 15 mg once daily with the evening meal in patients with CrCl 30 to
ROCKET AF was a non-inferiority study designed to demonstrate that Xarelto () preserved more than 50% of warfarin's effect on stroke and non-CNS systemic embolism as established by previous placebo-controlled studies of warfarin in atrial fibrillation.
A total of 14264 patients were randomized and followed on study treatment for a median of 590 days. The mean age was 71 years and the mean CHADS score was 3.5. The population was 60% male, 83% Caucasian, 13% Asian and 1.3% Black. There was a history of stroke, TIA, or non-CNS systemic embolism in 55% of patients, and 38% of patients had not taken a vitamin K antagonist (VKA) within 6 weeks at time of screening. Concomitant diseases of patients in this study included hypertension 91%, diabetes 40%, congestive heart failure 63%, and prior myocardial infarction 17%. At baseline, 37% of patients were on aspirin (almost exclusively at a dose of 100 mg or less) and few patients were on clopidogrel. Patients were enrolled in Eastern Europe (39%); North America (19%); Asia, Australia, and New Zealand (15%); Western Europe (15%); and Latin America (13%). Patients randomized to warfarin had a mean percentage of time in the INR target range of 2.0 to 3.0 of 55%, lower during the first few months of the study.
In ROCKET AF, Xarelto () was demonstrated non-inferior to warfarin for the primary composite endpoint of time to first occurrence of stroke (any type) or non-CNS systemic embolism [HR (95% CI): 0.88 (0.74, 1.03)], but superiority to warfarin was not demonstrated. There is insufficient experience to determine how Xarelto () and warfarin compare when warfarin therapy is well-controlled.
Table 6 displays the overall results for the primary composite endpoint and its components.
Figure 1 is a plot of the time from randomization to the occurrence of the first primary endpoint event in the two treatment arms.
The efficacy of Xarelto () was generally consistent across major subgroups.
The protocol for ROCKET AF did not stipulate anticoagulation after study drug discontinuation, but warfarin patients who completed the study were generally maintained on warfarin. Xarelto () patients were generally switched to warfarin without a period of co-administration of warfarin and Xarelto () , so that they were not adequately anticoagulated after stopping Xarelto () until attaining a therapeutic INR. During the 28 days following the end of the study, there were 22 strokes in the 4637 patients taking Xarelto () vs. 6 in the 4691 patients taking warfarin.
Few patients in ROCKET AF underwent electrical cardioversion for atrial fibrillation. The utility of Xarelto () for preventing post-cardioversion stroke and systemic embolism is unknown.
Xarelto () was studied in 9011 patients (4487 Xarelto () -treated, 4524 enoxaparin-treated patients) in the RECORD 1, 2, and 3 studies.
The two randomized, double-blind, clinical studies (RECORD 1 and 2) in patients undergoing elective total hip replacement surgery compared Xarelto () 10 mg once daily starting at least 6 to 8 hours (about 90% of patients dosed 6 to 10 hours) after wound closure versus enoxaparin 40 mg once daily started 12 hours preoperatively. In RECORD 1 and 2, a total of 6727 patients were randomized and 6579 received study drug. The mean age [± standard deviation (SD)] was 63 ± 12.2 (range 18 to 93) years with 49% of patients ≥65 years and 55% of patients were female. More than 82% of patients were White, 7% were Asian, and less than 2% were Black. The studies excluded patients undergoing staged bilateral total hip replacement, patients with severe renal impairment defined as an estimated creatinine clearance
One randomized, double-blind, clinical study (RECORD 3) in patients undergoing elective total knee replacement surgery compared Xarelto () 10 mg once daily started at least 6 to 8 hours (about 90% of patients dosed 6 to 10 hours) after wound closure versus enoxaparin. In RECORD 3, the enoxaparin regimen was 40 mg once daily started 12 hours preoperatively. The mean age (± SD) of patients in the study was 68 ± 9.0 (range 28 to 91) years with 66% of patients ≥65 years. Sixty-eight percent (68%) of patients were female. Eighty-one percent (81%) of patients were White, less than 7% were Asian, and less than 2% were Black. The study excluded patients with severe renal impairment defined as an estimated creatinine clearance
Xarelto () How Supplied/storage And Handling
Xarelto () (rivaroxaban) Tablets are available in the strengths and packages listed below:
Xarelto () Patient Counseling Information
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