1.2 Pharmacokinetics - absorption:

1. what is biovailability?

2. what is maximum plasma concentration cmax?

1. dose dependent: 10 mg dose 80 to 100% not affected by food. 20 mg approximately 66% in fasted state; co admin w/ food increases bioavailability therefore 15 and 20 mg doses take with evening meal.
2. 2 to 4 hours after tablet intake

• ~51% of an orally admin riva dose was recovered as metabolites in urine (30%) and feces (21%)
• the metabolic pathway was catalyzed by cytochrome p450 3a4/5 and cyp2J2 enzymes
• unchanged riva was predominant in plasma with no major or active irculating metabolites

Half-Life?

How is it excreted?

• half life is 5 to 9 hours in healthy subjects aged 20 to 45
• eliminated primarily via urine

• to reduce the risk of stroke and systemic embolism in patients with NVAF; there are limited data on the relative effectiveness of X and warf in reducing the risk of stroke and systemic embolism when warf therapy is well controlled
• for the prohpylaxis of dvt, which may lead to PE in patients undergoing knee or hip replacement surgery

• X taken QD w/ evening meal
• dose based on CRCL:
• crcl > 50 = 20 mg qd
• crcl 15 to 50 = 15 mg qd
• crcl < 15 avoid use
• renal function should be periodically assessed as indicated. x should be discontinued in patients with acute renal failure.

• patients switching from warf to X should discontinue warf and start X as soon as INR is below 3 to avoid periods of inadequate anticoagulation.
• no clinical data are available to guide converting patients from X to warf. X affects inr so inr measurements made during coadministration with warf may not be useful for determining the appropriate dose of warf. One approach is to discontinue X and begin both a parenteral anticoagulant and warfarin at the time of the next dose of X would have been taken.

• patients currently receiving an anticoagulant other than warf should start X 0 to 2 hours prior to the next scheduled evening dose and omit administration of the other anticoagulant. If unfractionated heparin is being administered by continuous infusion, the infusion should be stopped at the time X is started

• X 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 X, weigh risks.
• restart as soon as adequate hemostasis has been established.

avoid use with p-gp and strong cyp3a4 inhibitors (eg, ketoconazole, itraconazole, lopinavir/ritonavir, ritonavir, indinavir/ritonavir, and conivaptan.

X should be avoided with drugs that are combinded p-gp and strong cyp3a4 inducers like carbamazepine, phenytoin, rifampin, st. john's wort.

• discontinuing X in pateints with NVAF - increased rate of stroke observed following x discontinuation.
• spinal/epidural hematoma: have occurred in patients treated with X who are receiving neuraxial anesthesia or undergoing spinal puncture.

• active pathological bleeding
• history of a serious hypersensitivity reaction to X

• Increased risk of stroke after discontinuation in NVAF
• risk of bleeding
• spinal/epidural anesthesia or puncture
• risk of pregnancy related hemorrhage
• severe hypersensitivity reactions

• bleeding complications (pg 11)
• In ROCKET AF 4.3% X vs. 3.1% warf.

Major : 5.6% X vs. 5.4% warf.

Bleeding into critical organ: 1.3% X vs. 1.9% warf.

fatal bleeding: 0.4%X vs. 0.8% warf

bleeding resulting in transfusion of ≥ 2 units of whole blood or packed red blood cells: 2.6% X vs. 2.1% W

GI bleeding: 3.1% X vs. 2.0% W

• drugs that inhibit cyp3a4 enzymes and drug transport systems - avoid concomitant admin
• drugs that induce cyp3a4 enzymes and drug transport systems - avoid concomitant use
• anticoagulants - prophylaxis of DVT: avoid concurrent use of X with other anticoagulants
• NSAIDS/ASA - in ROCKET AF concomitant asa use dose less than 100 id'd as independent risk factor for major bleeding
• clopidogrel - in drug interaction studies where plavix and X were coadmin in healthy subjects an increase in bleeding time to 45 minutes was observed

• Pregnancy Category C - no adequate studies
• labor and delivery - not studied
• Nursing: unknown if excreted in human milk
• Pediatric - not established
• geriatric use: ROCKET AF approx 77% were 65 and older. about 38% were >75. risk benefit favorable in all age groups though bleeding risk increases with age.
• females of reproductive potential: consult your physician regarding pregnancy planning
• renal impairment: avoid use of X in sever renal impairment crcl<30ml/min.  or observe closely and promptly evaluate any signs or symptoms of blood loss in patients with moderate renal impairment crcl 30 to <50 ml/min
• hepatic impairment: no patients were studied, avoid use of X in patients with moderate (child-pugh B) and severe (child-pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy.

• multinational, double-blind published in NEJM August 2011.
• noninferiority study designed to demonstrate that rivaroxaban preserved more than 50% of the effect of warfarin on stroke and non-CNS systemic embolism as established by previous placebo controlled studies of warf in AF.
• 20 mg QD with evening meal in pts w crcl > 50
• 15 mg QD w/ evening meal in pts w/ crcl 30 to 50
• warf. titrated to INR 2.0 - 3.0

one or more of the following additional risk factors for stroke.

• a prior stroke ischemic or unknown type, tia or non cns systemic embolism, or
• 2 or more of the following risk factors
• age ≥75 years
• hypertension
• chf or lvef ≤35%
• diabetes mellitus

Patient characteristics in ROCKET AF

• 14264 patients. for median 590 days
• mean percentage of time in INR target range of 2 to 3 of 55%
• mean age: 71
• mean chads: 3.5
• 60% male
• 55% had history of stroke, TIA or non-CNS systemic embolism
• 38% of patients had not taken a vitamin K antagonist within 6 weeks at time of screening
• 91% of patients had hypertension, 40% had diabetes, 63% had CHF and 17% had a pervious MI
• 37% of patients were on asa and a few patients were on plvx.

Overall RESULTS of ROCKET AF

• non inferior to warf was demonstrated.
• superiority to warf not demonstrated.
• insufficient experience to determine how rivaroxaban and warf compare when warf therapy is well controlled.

• PCE 3.8% X vs. 4.3% W (HR 0.88)
• stroke: 3.6% X vs. 4.0% W
• Hemorrhagic stroke: .5% X vs .8% w
• Ischemic Stroke: 2.9% X vs. 2.9% W
• unknown stroke: .3% X vs. .3% W
• non cns systemic embolism: .3% X vs. 0.4% W
• generally consistent across subgroups.