rivaroxaban (Rx)

1-10%

Hematoma (<3%)

Back pain (2.9%)

Wound secretion (2.8%)

Abdominal pain (2.7%)

Dizziness (2.2%)

Pruritus (2.1-2.2%)

Pain in extremity (1.7%)

Insomnia (1.6%)

Anxiety (1.4%)

Blister (1.4%)

Fatigue (1.4%)

Muscle spasm (1.3%)

Syncope (1.2%)

Muscle spasm (1.2%)

Depression (1.2%)

Major bleeding

• Atrial fibrillation (6%)
• DVT prophylaxis (<1%)
• DVT treatment (1%)
• VTE prophylaxis (0.7%)

Postmarketing Reports

Blood and lymphatic system disorders: Agranulocytosis, thrombocytopenia

Gastrointestinal disorders: Retroperitoneal hemorrhage

Hepatobiliary disorders: Jaundice, cholestasis, hepatitis (including hepatocellular injury)

Immune system disorders: Hypersensitivity, anaphylactic reaction, anaphylactic shock, angioedema

Nervous system disorders: Cerebral hemorrhage, subdural hematoma, epidural hematoma, hemiparesis

Skin and SC tissue disorders: Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS)

Contraindications

Hypersensitivity

Active pathological bleeding

Cautions

Neuraxial anesthesia (see Black Box Warnings)

Risk for thrombotic events increased with premature discontinuation (see Black Box Warnings)

Safety and efficacy not established in patients with prosthetic heart valves

Increases risk of bleeding and can cause serious and fatal bleeding; reports of major hemorrhages, including epidural hematomas, adrenal bleeding, and intracranial, gastrointestinal, and retinal hemorrhages; promptly evaluate S/S of blood loss and consider the need for blood replacement; discontinue with active pathological hemorrhage

Not for use with the following conditions at increased risk of bleeding in patients requiring primary VTE prophylaxis; history of bronchiectasis, pulmonary cavitation, or pulmonary hemorrhage, active cancer (i.e. undergoing acute, in-hospital cancer treatment), active gastroduodenal ulcer in the three months prior to treatment, history of bleeding in the three months prior to treatment, or dual antiplatelet therapy

Not recommended acutely as an alternative to unfractionated heparin in patients with PE who present with hemodynamic instability or who may receive thrombolysis or pulmonary embolectomy

Do not remove an indwelling epidural or intrathecal catheter before at least 2 half-lives have elapsed (ie, 18 hr in patients aged 20-45 years and 26 hr in patients aged 60-76 years), after last administration; do not administer next dose earlier than 6 hr after removal of catheter; if traumatic puncture occurs, delay administration for 24 hr

Periodically assess renal function as clinically indicated (ie, more frequently in situations in which renal function may decline) and adjust therapy accordingly; consider dose adjustment or discontinuation of therapy in patients who develop acute renal failure while on therapy

Not recommended for use in patients with a history of thrombosis who are diagnosed with antiphospholipid syndrome (APS); for patients with APS (especially those who are triple positive [positive for lupus anticoagulant, anticardiolipin, and anti-beta 2-glycoprotein I antibodies]), treatment has been associated with an increased rate of recurrent thrombotic events compared with vitamin K antagonist therapy

Use with caution in pregnant women and only if the potential benefit justifies the potential risk to the mother and fetus (see Pregnancy)

Reversing anticoagulant effect

• Use of procoagulant reversal agents, including prothrombin complex concentrate (PCC), activated prothrombin complex concentrate or recombinant factor VIIa, may be considered when reversal of anticoagulation needed because of life-threatening or uncontrolled bleeding
• Clinical efficacy and safety has not been evaluated
• Monitoring for anticoagulation effect of rivaroxaban using a clotting test (PT, INR or aPTT) or anti-factor Xa (FXa) activity not recommended

Drug interaction overview

• Rivaroxaban is a substrate of CYP3A4/5, CYP2J2, and the P-gp and ATP-binding cassette G2 (ABCG2) transporters
• Avoid concomitant use of P-gp and strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, lopinavir/ritonavir, ritonavir, indinavir/ritonavir, conivaptan); may increase risk of bleeding
• Caution with concomitant use of P-gp and weak or moderate CYP3A4 inhibitors (eg, erythromycin, azithromycin, diltiazem, verapamil, quinidine, ranolazine, dronedarone, amiodarone, felodipine, citalopram, escitalopram, fluoxetine, fluvoxamine, desvenlafaxine, venlafaxine)
• Avoid concomitant use of P-gp and strong CYP3A4 inducers (eg, carbamazepine, phenytoin, rifampin, St. John’s wort); these drugs may decrease the systemic effects and efficacy of rivaroxaban and may increase risk of thromboembolic events
• Concomitant use of other drugs that impair hemostasis increases risk of bleeding; these include aspirin, P2Y12 platelet inhibitors, other antithrombotic agents, fibrinolytic therapy, non-steroidal anti-inflammatory drugs (NSAIDs), selective serotonin reuptake inhibitors, and serotonin norepinephrine reuptake inhibitors
• Clopidogrel: Avoid concomitant use unless the benefit outweighs the bleeding risk; change in bleeding time was found to be approximately twice the maximum increase seen with either drug alone

Pregnancy

Limited available data in pregnant women are insufficient to inform a drug-associated risk of adverse developmental outcomes

Use with caution in pregnant patients because of the potential for pregnancy related hemorrhage and/or emergent delivery; anticoagulant effect cannot be reliably monitored with standard laboratory testing

Consider benefits and risks for the mother and possible risks to the fetus when prescribing to a pregnant woman

Females of reproductive potential requiring anticoagulation should discuss pregnancy planning

Clinical considerations

• Pregnancy is a risk factor for VTE and risk increases in women with inherited or acquired thrombophilias; pregnant women with thromboembolic disease have an increased risk of maternal complications (eg, pre-eclampsia); maternal thromboembolic disease increases the risk for intrauterine growth restriction, placental abruption, and early and late pregnancy loss
• Based on pharmacologic activity of Factor Xa inhibitors and the potential to cross the placenta, bleeding may occur at any site in the fetus and/or neonate
• All patients receiving anticoagulants, including pregnant women, are at risk for bleeding and this risk may be increased during labor or delivery; risk of bleeding should be balanced with the risk of thrombotic events when considering the use in this setting

Lactation

Drug detected in human milk

Insufficient data available to determine effects on breastfed child or on milk production; drug and/or its metabolites were present in milk of rats

Consider developmental and health benefits of breastfeeding along with mother’s clinical need for therapy and any potential adverse effects on breastfed infant from therapy or from underlying maternal condition

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Factor Xa inhibitor that inhibits platelet activation by selectively blocking the active site of factor Xa without requiring a cofactor (eg, antithrombin III) for activity

Blood coagulation cascade is dependent on the activation of factor X to factor Xa via the intrinsic and extrinsic pathways, which play a central role in the blood coagulation cascade

Dose-dependent inhibition of factor Xa activity observed; antifactor Xa activity is also influenced by rivaroxaban; prolongs PT and aPTT and HepTest

Absorption

Bioavailability: 80-100%

Peak plasma time: 2-4 hr

AUC: 29-56% decrease when released in proximal small intestine compared with gastric absorption

Distribution

Protein bound: 92-95% (mainly albumin)

Vd: 50 L

Metabolism

Metabolized by oxidative degradation catalyzed by CYP3A4/5 and CYP2J2; also metabolized by hydrolysis

Unchanged rivaroxaban is the predominant moiety in plasma with no major or active circulating metabolites (50% higher in patients of Japanese descent)

Substrate of P-gp and ABCG2 (Bcrp) efflux transporter proteins

Elimination

Half-life: 5-9 hr; 11-13 hr (elderly)

Total body clearance: 10 L/hr (following IV administration)

Excretion: feces (21% as metabolites; 28% unchanged), urine (30% as metabolites; 36% unchanged)

Oral Administration

2.5 mg or 10 mg tablets: May take with or without food (bioavailability not significantly affected in fasted state)

15 mg or 20 mg tablets: Take with food (bioavailability improves when taken with food)

Patients unable to swallow whole tablets

• Crush tablets and mix with applesauce immediately before use
• After administration of a crushed 15-mg or 20-mg tablet, dose should be
• immediately followed with food

Feeding tube administration

• Crush tablets and suspend in 50 mL of water and administered via NG or gastric feeding tube
• Absorption dependent on site of drug release in the gastrointestinal tract (gastric vs small intestine); avoid administrating distal to the stomach which can result in reduced absorption and thereby, reduced drug exposure
• When administering as a crushed tablet via a feeding tube, confirm gastric placement of tube
• After administration of a crushed 15-mg or 20-mg tablet, dose should be immediately followed by enteral feeding

Missed dose

• 2.5 mg PO BID: If a dose is missed, take a single 2.5-mg dose as recommended at the next scheduled time
• 15 mg PO BID: Take immediately to ensure intake of 30 mg/day; in this instance, two 15-mg tablets may be taken at once; continue with regular 15 mg q12hr on the following day
• If taking 10, 15, or 20 mg PO qDay: Take missed dose immediately; do not double dose within the same day to make up for a missed dose

Storage

Tablets: Store at room temperature, 25ºC (77ºF); excursions permitted to 15-30ºC (59-86ºF)

Crushed tablets in water or applesauce: Store at room temperature, 25ºC (77ºF) for up to 4 hr