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| __NOTOC__
| | #REDIRECT [[Rivaroxaban#Pharmacology]] |
| {{Rivaroxaban}}
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| {{CMG}}; {{AE}} {{AZ}}
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| == CLINICAL PHARMACOLOGY==
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| === Mechanism of Action===
| | [[Category: Cardiovascular Drugs]] |
| XARELTO is a selective inhibitor of [[FXa]]. It does not require a cofactor (such as [[Anti-thrombin III]]) for activity. Rivaroxaban inhibits free FXa and [[prothrombinase ]]activity. Rivaroxaban has no direct effect on platelet aggregation, but indirectly inhibits platelet aggregation induced by [[thrombin]]. By inhibiting [[FXa]], rivaroxaban decreases thrombin generation.
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| ===Pharmacodynamics===
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| Dose-dependent inhibition of FXa activity was observed in humans and the Neoplastin® [[prothrombin time]] ([[PT]]), [[activated partial thromboplastin time]] (aPTT) and HepTest® are prolonged dose-dependently. Anti-[[factor Xa]] activity is also influenced by rivaroxaban.
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| === Pharmacokinetics===
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| ====Absorption====
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| The absolute bioavailability of rivaroxaban is dose-dependent. For the 10 mg dose, it is estimated to be 80% to 100% and is not affected by food. XARELTO 10 mg tablets can be taken with or without food. For the 20 mg dose in the fasted state, the absolute bioavailability is approximately 66%. Coadministration of XARELTO with food increases the bioavailability of the 20 mg dose (mean AUC and Cmax increasing by 39% and 76% respectively with food). XARELTO 15 mg and 20 mg tablets should be taken with food [see Dosage and Administration (2.1)].
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| The maximum concentrations (Cmax) of rivaroxaban appear 2 to 4 hours after tablet intake. The pharmacokinetics of rivaroxaban were not affected by drugs altering gastric pH. Coadministration of XARELTO (30 mg single dose) with the H2-receptor antagonist ranitidine (150 mg twice daily), the antacid aluminum hydroxide/magnesium hydroxide (10 mL) or XARELTO (20 mg single dose) with the PPI omeprazole (40 mg once daily) did not show an effect on the bioavailability and exposure of rivaroxaban.
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| Absorption of rivaroxaban is dependent on the site of drug release in the GI tract. A 29% and 56% decrease in AUC and Cmax compared to tablet was reported when rivaroxaban granulate is released in the proximal small intestine. Exposure is further reduced when drug is released in the distal small intestine, or ascending colon. Avoid administration of rivaroxaban distal to the stomach which can result in reduced absorption and related drug exposure.
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| In a study with 44 healthy subjects, both mean AUC and Cmax values for 20 mg rivaroxaban administered orally as a crushed tablet mixed in applesauce were comparable to that after the whole tablet. However, for the crushed tablet suspended in water and administered via an NG tube followed by a liquid meal, only mean AUC was comparable to that after the whole tablet, and Cmax was 18% lower.
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| ====Distribution====
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| Plasma protein binding of rivaroxaban in human plasma is approximately 92% to 95%, with albumin being the main binding component. The steady-state volume of distribution in healthy subjects is approximately 50 L.
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| ===Metabolism===
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| Approximately 51% of an orally administered [14C]-rivaroxaban dose was recovered as inactive metabolites in urine (30%) and feces (21%). Oxidative degradation catalyzed by [[CYP3A4]]/[[CYP3A%|5]] and [[CYP2J2]] and [[hydrolysis]] are the major sites of biotransformation. Unchanged rivaroxaban was the predominant moiety in plasma with no major or active circulating metabolites.
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| ===Excretion===
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| Following oral administration, approximately one-third of the absorbed dose is excreted unchanged in the urine, with the remaining two-thirds excreted as inactive metabolites in both the urine and feces. In a Phase 1 study, following the administration of a [14C]-rivaroxaban dose, 66% of the radioactive dose was recovered in urine (36% as unchanged drug) and 28% was recovered in feces (7% as unchanged drug). Unchanged drug is excreted into urine, mainly via active tubular secretion and to a lesser extent via glomerular filtration (approximate 5:1 ratio). Rivaroxaban is a substrate of the efflux transporter proteins P-gp and ABCG2 (also abbreviated Bcrp). Rivaroxaban's affinity for influx transporter proteins is unknown.
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| Rivaroxaban is a low-clearance drug, with a systemic clearance of approximately 10 L/hr in healthy volunteers following intravenous administration. The terminal elimination half-life of rivaroxaban is 5 to 9 hours in healthy subjects aged 20 to 45 years.
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| ===Specific Populations===
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| ====Gender ====
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| Gender did not influence the pharmacokinetics or pharmacodynamics of XARELTO.
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| ====Race ====
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| Healthy Japanese subjects were found to have 20 to 40% on average higher exposures compared to other ethnicities including Chinese. However, these differences in exposure are reduced when values are corrected for body weight.
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| ====Elderly ====
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| In clinical studies, elderly subjects exhibited higher rivaroxaban plasma concentrations than younger subjects with mean AUC values being approximately 50% higher, mainly due to reduced (apparent) total body and renal clearance. Age related changes in renal function may play a role in this age effect. The terminal elimination half-life is 11 to 13 hours in the elderly [see Use in Specific Populations (8.5)].
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| ====Body Weight ====
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| Extremes in body weight (<50 kg or >120 kg) did not influence (less than 25%) rivaroxaban exposure.
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| ====Renal Impairment ====
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| 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 Table 7). Compared to healthy subjects with normal creatinine clearance, rivaroxaban exposure increased in subjects with renal impairment. Increases in pharmacodynamic effects were also observed
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| {|
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| |[[image:riva10.png|600px|thumb]]
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| ====Hepatic Impairment====
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| 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 Table 8). 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.
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| {|
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| |[[image:riva11.png|600px|thumb]]
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| ===Drug Interactions===
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| In vitro studies indicate that rivaroxaban neither inhibits the major [[cytochrome P450]] enzymes [[CYP1A2]], 2C8, 2C9, 2C19, 2D6, 2J2, and 3A4 nor induces CYP1A2, 2B6, 2C19, or 3A4. In vitro data also indicates a low rivaroxaban inhibitory potential for P-gp and ABCG2 transporters.
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| ====Drugs that Inhibit Cytochrome P450 3A4 Enzymes and Drug Transport Systems ====
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| In drug interaction studies evaluating the concomitant use with drugs that are combined P-gp and CYP3A4 inhibitors the following increases in rivaroxaban exposure were observed. Similar increases in pharmacodynamic effects (i.e., factor Xa inhibition and PT prolongation) were also observed. Significant increases in rivaroxaban exposure may increase bleeding risk.
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| '''•[[Ketoconazole]]''' (combined P-gp and strong CYP3A4 inhibitor): Steady-state rivaroxaban AUC and Cmax increased by 160% and 70%, respectively. Similar increases in pharmacodynamic effects were also observed.
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| '''•[[Ritonavir]]''' (combined P-gp and strong CYP3A4 inhibitor): Single-dose rivaroxaban AUC and Cmax increased by 150% and 60%, respectively. Similar increases in pharmacodynamic effects were also observed.
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| '''•[[Clarithromycin]]''' (combined P-gp and strong CYP3A4 inhibitor): Single-dose rivaroxaban AUC and Cmax increased by 50% and 40%, respectively. The smaller increases in exposure observed for [[clarithromycin]] compared to [[ketoconazole]] or ritonavir may be due to the relative difference in P-gp inhibition.
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| '''•[[Erythromycin]]''' (combined P-gp and moderate CYP3A4 inhibitor): Both the single-dose rivaroxaban AUC and Cmax increased by 30%.
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| '''•[[Fluconazole]]''' (moderate CYP3A4 inhibitor): Single-dose rivaroxaban AUC and Cmax increased by 40% and 30%, respectively.
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| ====Drugs that Induce Cytochrome P450 3A4 Enzymes and Drug Transport Systems ====
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| In a drug interaction study, coadministration 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 Cmax, respectively. Similar decreases in pharmacodynamic effects were also observed. These decreases in exposure to rivaroxaban may decrease efficacy.
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| ====Anticoagulants ====
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| In a drug interaction study, single doses of [[enoxaparin]] (40 mg subcutaneous) and XARELTO (10 mg) given concomitantly resulted in an additive effect on anti-factor Xa activity. Enoxaparin did not affect the pharmacokinetics of rivaroxaban. In another study, single doses of [[warfarin]] (15 mg) and XARELTO (5 mg) resulted in an additive effect on [[factor Xa]] inhibition and [[PT]]. [[Warfarin]] did not affect the pharmacokinetics of rivaroxaban.
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| ====NSAIDs/Aspirin ====
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| 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.
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| ====Clopidogrel ====
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| 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 coadministered 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.
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| ====Drug-Disease Interactions with Drugs that Inhibit Cytochrome P450 3A4 Enzymes and Drug Transport Systems ====
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| In a pharmacokinetic trial, XARELTO was administered as a single dose in subjects with mild (CrCl = 50 to 79 mL/min) or moderate [[renal impairment]] (CrCl = 30 to 49 mL/min) receiving multiple doses of [[erythromycin ]](a combined P-gp and moderate [[CYP3A4 ]]inhibitor). Compared to XARELTO administered alone in subjects with normal renal function ([[CrCl ]]>80 mL/min), subjects with mild and moderate renal impairment concomitantly receiving [[erythromycin ]]reported a 76% and 99% increase in AUCinf and a 56% and 64% increase in Cmax, respectively. Similar trends in pharmacodynamic effects were also observed.
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| ====Drugs that are Substrates of CYP3A4 and/or Drug Transport Systems ====
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| In addition, there were no significant pharmacokinetic interactions observed in studies comparing concomitant rivaroxaban 20 mg and 7.5 mg single dose of [[midazolam]] (substrate of CYP3A4), 0.375 mg once-daily dose of [[digoxin]] (substrate of P-gp), or 20 mg once daily dose of [[atorvastatin]] (substrate of [[CYP3A4]] and P-gp) in healthy volunteers.
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| === QT/QTc Prolongation===
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| In a thorough QT study in healthy men and women aged 50 years and older, no [[QTc prolonging]] effects were observed for XARELTO (15 mg and 45 mg, single-dose).<ref name="dailymed.nlm.nih.gov">{{Cite web | last = | first = | title = XARELTO (RIVAROXABAN) TABLET, FILM COATED [JANSSEN PHARMACEUTICALS, INC.] |url = http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=10db92f9-2300-4a80-836b-673e1ae91610 | publisher = | date = | accessdate = }}</ref>
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| ==References==
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| {{Reflist}}
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| {{FDA}}
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| [[Category:Drugs]]
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