Rivaroxaban

Toxicity

Excessive bleeding. Overdosages should be treated using activated charcoal and supportive measures such as mechanical compression and hemodynamic support. If bleeding is not controlled, the following procoagulants can be administered: activated prothrombin complex concentrate, prothrombin complex concentrate and recombinant factor VIIa. There is also a higher chance of post procedural hemorrhage compared to enoxaparin (1.55% vs. 1.39% respectively).

Description

Rivaroxaban is an orally active, direct inhibitor of Factor Xa (Ki = 0.4 nM), which is a crucial component of the intrinsic and extrinsic pathways of the blood coagulation cascade. It demonstrates >10,000-fold greater selectivity for Factor Xa compared to other related serine proteases (thrombin, trypsin, plasmin, FVIIa, FIXa, FXIa, urokinase, and activated protein C). In various animal arterial and venous thrombosis models, rivaroxaban is reported to inhibit thrombin formation without prolonging bleeding time and has been approved for clinical use as an anticoagulant in the prevention of stroke and the treatment of venous thromboembolisms.

The Uses of Rivaroxaban

Rivaroxaban is a novel antithrombotic agent. It is a novel, oral, selective direct inhibitor of factor Xa developed by Bayer Healthcare. It has been approved by the EMEA and FDA for the prevention ofvenous thromboembolism in adult patients after total hip replacement or total kneereplacement surgery.

Background

Rivaroxaban is an anticoagulant and the first orally active direct factor Xa inhibitor. Unlike warfarin, routine lab monitoring of INR is not necessary. However there is no antidote available in the event of a major bleed. Only the 10 mg tablet can be taken without regard to food. The 15 mg and 20 mg tablet should be taken with food. FDA approved on July 1, 2011.

Indications

Rivaroxaban is indicated for the prevention of venous thromboembolic events (VTE) in patients who have undergone total hips replacements and total knee replacement surgery; prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation; treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE); to reduce risk of recurrent DVT and/or PE. Rivaroxaban is also indicated, in combination with aspirin, for reducing the risk of major cardiovascular events in patients with chronic coronary artery disease or peripheral artery disease. Its use is also not recommended in those with severe renal impairment (<30mL/min).
Rivaroxaban is also indicated for the treatment and prevention of VTE in pediatric patients (from birth to 18 years of age) and for thromboprophylaxis in pediatric patients ≥2 years old with congenital heart disease following the Fontan procedure.

Pharmacokinetics

Rivaroxaban is an oral anticoagulant drug that is rapidly absorbed and reaches peak plasma concentrations within 2-4 hours of oral administration.The bioavailability of a 10 mg dose is greater than 80%. However, if a 15-20 mg dose is taken on an empty stomach, the bioavailability is lower and should be taken with food. Approximately two-thirds of the dose of rivaroxaban is metabolised. It is metabolised by CYP3A4, CYP3A5, CYP2J2 and CYP-dependent mechanisms.

Side Effects

Common side effects of Rivaroxaban include: back pain, headache, bleeding gums, coughing up blood, blood in the stool, bowel or bladder dysfunction, burning, itching, numbness, tingling, "pins and needles" or prickling sensation; difficulty breathing or swallowing, dizziness, increased menstrual flow or vaginal bleeding, prolonged bleeding from cuts, weakness in the legs, urine that is red or dark brown; vomiting blood or a substance that looks like coffee grounds. Occasionally fainting, arm or leg pain, wound discharge. Rare side effects include a burning sensation when passing urine, difficulty or pain in passing urine.

Mechanism of action

Rivaroxaban--the first oral, direct Factor Xa inhibitor--is a small-molecule oxazolidinone derivative that binds directly and reversibly to Factor Xa via the S1 and S4 pockets. Rivaroxaban competitively inhibits Factor Xa and is more than 10,000-fold more selective for Factor Xa than other related serine proteases, and it does not require cofactors (such as antithrombin) to exert its anticoagulant effect. Unlike indirect Factor Xa inhibitors, rivaroxaban inhibits both free and clot-bound Factor Xa, as well as prothrombinase activity, thereby prolonging clotting times.