Rivaroxaban

BRAND NAMES

Xarelto: It contains the active ingredient rivaroxaban. It is available in the form of tablets with strengths of 2.5 mg, 10 mg, 15 mg, and 20 mg.

MECHANISM OF ACTION

It was a small-molecule derivative of oxazolidinone called rivaroxaban that was the first oral direct Factor Xa inhibitor. Through the S1 and S4 pockets, it binds to Factor Xa directly and reversibly. With a selectivity more than 10,000 times that of other serine proteases of a similar kind, rivaroxaban competitively inhibits Factor Xa. Its anticoagulant effects can be achieved without the need for cofactors like antithrombin. By stopping the coagulation cascade from moving on to the last common route, this action prevents the production of thrombin. In both its circulatory and clot-bound forms, factor Xa is functional. Rivaroxaban inhibits prothrombinase activity and both free and clot-bound Factor Xa, in contrast to indirect Factor Xa inhibitors such as fondaparinux or heparin, which cause prolonged clotting times.

PHARMACOKINETICS

Absorption

Rivaroxaban is quickly absorbed after oral treatment and achieves maximal plasma concentration in 2-4 hours. Over 80% of the 10 mg dosage is bioavailable. However, if taken without food, the 15-20 mg dosage has a decreased bioavailability and should thus be given with meals.

Distribution

50 L is the steady-state volume of distribution.

Metabolism

About two-thirds of the dosage is metabolized. It is metabolized by CYP-3A4, CYP-3A5, CYP-2J2, and CYP-independent processes.

Elimination

Approximately two-thirds of rivaroxaban is eliminated in the urine (by active tubular secretion, with approximately 36% unaltered drug and 30% inactive metabolism). The remaining third of the supplied dosage is eliminated in feces, which contain 7% unaltered medication and 21% inactive metabolites. The terminal half-life in humans is 5–9 hours, but in the elderly, it is 11–13 hours.

PHARMACODYNAMICS

Rivaroxaban is an anticoagulant that interacts directly with factor Xa. Following that, it efficiently inhibits the amplification of the coagulation cascade, inhibiting the development of a thrombus. Rivaroxaban is a unique anticoagulant for two reasons. First and foremost, it does not rely on antithrombin III to produce anticoagulant effects. Second, it is an oral drug, as opposed to the extensively used unfractionated and low molecular weight heparins, which are exclusively administered intravenously. Although the activated partial thromboplastin time and HepTest (a low molecular weight heparin assay) are dose-dependently extended, neither test is suggested for evaluating rivaroxaban's pharmacodynamic effects. Anti-Xa activity and inhibition of anti-Xa activity monitoring are also not recommended, even though rivaroxaban influences both.

DOSAGE AND ADMINISTRATION

Rivaroxaban is taken orally and has a half-life of 5 to 9 hours. The dosage varies from 2.5 mg twice daily to 20 mg once daily and does not require monitoring. Rivaroxaban is heavily protein-bound. The medicine is often administered at a set dose without monitoring, and no therapeutic range has been determined.

The dosage for the most prevalent indications of rivaroxaban is:

• Non-valvular atrial fibrillation—stroke prevention: 20 mg once a day with the evening meal.
• Acute VTE treatment: 15 mg twice a day with food for three weeks, followed by 20 mg once daily with food.
• VTE primary prevention: 10 mg per day, with or without meals.

Rivaroxaban should be stopped at least 24 hours before the surgical procedure. The International Society on Thrombosis and Haemostasis (ISTH) 2016 recommends avoiding rivaroxaban in individuals with a BMI >40 kg/m or weight >120 kg due to a lack of clinical data in this cohort. If administered in a patient with a BMI >40 kg/m or weight >120 kg, ISTH recommends evaluating peak and trough levels with an anti-factor Xa test or mass spectrometry.

CONTRAINDICATIONS

Allery: Severe hypersensitivity to rivaroxaban (or any component of the formulation) may occur. 
Haematologic: Active pathological bleeding is a contraindication to rivaroxaban usage.

DRUG INTERACTIONS

Severe interactions may need adjusting the dosage or frequency, further monitoring, and consideration of other medicines. Consult a database for further details on drug interactions. Strong CYP3A and P-glycoprotein inhibitors, as well as multi-pathway rivaroxaban clearance and elimination inhibitors, such as Bcrp inhibitors (mainly azole-antimycotics, apart from fluconazole and HIV protease inhibitors), interact with DOACs like rivaroxaban. Additionally, it should not be used in conjunction with other anticoagulants such as fondaparinux, warfarin, apixaban, dabigatran, low molecular weight heparins (such as enoxaparin), unfractionated heparin, or dabigatran, with the exception of transitioning to or off rivaroxaban treatment. When using rivaroxaban in conjunction with ASA and clopidogrel (or other thienopyridines, such as ticlopidine or prasugrel) or with another adenosine diphosphate (ADP) P2Y12 receptor antagonist, like ticagrelor, it is best to avoid using both simultaneously.

SIDE EFFECTS

The common side effects of rivaroxaban include

• Central nervous system: syncope, sadness, anxiety, weariness, and dizziness
• Dermatologic: Skin blisters, pruritus, and wound secretion 
• Intestinal: pain in the abdomen 
• Skeletal and neuromuscular disorders: muscle spasms, limb discomfort, and back pain

TOXICITY

Patients with minimal bleeding are treated conservatively, and a single anticoagulant dosage is omitted or postponed. Patients with substantial bleeding are initially treated with antifibrinolytic drugs such as tranexamic acid. Epsilon-aminocaproic acid is used off-label as a haemostatic medication in major NOAC-associated bleeds; however, there is insufficient data on its effectiveness. For individuals with life-threatening bleeding caused by direct factor Xa inhibitor anticoagulation, andexanet alfa or an unactivated 4-factor PCC may be utilized. Activated oral charcoal might also be utilized if the consumption happened within 1 to 2 hours after presentation.