Rivaroxaban - Indications, Contraindications, Dosage, and Side Effects

Overview

Rivaroxaban is a novel oral anticoagulant (NOAC) that is used in the treatment and prevention of deep venous thrombosis. FDA approved Rivaroxaban on 1st July 2011. It is a factor Xa inhibitor and is also known as a blood thinner agent. Rivaroxaban is a monocarboxylic acid aromatic amide. It is an organochlorine compound that belongs to thiophenes. Its chemical structure contains Oxazolidinone and is prepared by formal condensing of the carboxyl group present in carboxylic acid with the amino group of Oxazolidinyl-phenyl morpholine. Rivaroxaban exhibits its anticoagulant activity by directly inhibiting clotting Factor Xa.

What Are the Indications of Rivaroxaban?

Rivaroxaban is indicated to treat and manage various venous thromboembolic events such as deep vein thrombosis and pulmonary embolism. It is a newly developed oral anticoagulant and has both FDA-approved as well as off-label clinical indications.

Indications Approved By FDA

• Rivaroxaban is used as a thromboprophylaxis (to prevent the development of thrombosis) in high-risk people who are prone to develop deep venous thrombosis (DVT).

• Its use is indicated in patients who are operated on elective orthopedic surgeries such as knee and hip replacement surgeries and in postoperative thromboprophylaxis.

• To prevent both primary and secondary stroke in people with atrial fibrillation and cardiac arrhythmia.

• To treat acute venous thromboembolism events and recurrent episodes of blood clots.

• Prophylaxis to reduce the persistent risk of venous thromboembolism events in high-risk patients.

• Used as an adjunct anticoagulant in Aspirin and clopidogrel therapy for secondary prevention of acute coronary syndrome (ACS) and peripheral arterial disease (PAD) after stabilizing with initial intervention.

• In hospitalized patients with an existing acute medical ailment and are at risk of developing thromboembolic complications because of restricted mobility or other related risks.

Off-Label Clinical Uses

Off-label uses commonly refer to the use of FDA-approved drugs for unapproved disease conditions by the FDA. It is clinically practiced as FDA has considered the benefits of using the drug in that particular condition by surpassing its potential risks.

• To treat Heparin-induced thrombocytopenia in stable patients who have received initial therapy of Heparin or non-Heparin anticoagulants.

• In patients having nonvalvular atrial fibrillation after initial stabilization following stent placement (post-percutaneous coronary intervention).

• In symptomatic and acute thrombosis of superficial veins.

What Are the Contraindications of Rivaroxaban?

• Pathological active bleeding conditions like active ulcerative gastrointestinal bleeding.

• Severe hypersensitivity reactions to Rivaroxaban.

• In antiphospholipid syndrome (an autoimmune disorder) with triple-positive antibodies.

• In severe hepatic impairment.

• In patients with liver disease and associated coagulopathy.

• In severe renal impairment.

• In patients having atrial fibrillation along with end-stage chronic kidney disease (CKD).

• Rivaroxaban is contraindicated in patients with valvular diseases such as rheumatic heart disease and mitral stenosis (moderate to severe).

• It is not recommended in patients having mechanical values such as prosthetic heart valves.

• Patients with increased risk of bleeding, such as bronchiectasis, vascular retinopathy, and severe uncontrolled arterial hypertension.

• In known cases of bleeding disorders.

Dosage Forms and Strengths

• Rivaroxaban is available in tablet form.

• The tablets are round, light yellow colored, and film-coated.

• Rivaroxaban tablets are available in four different strengths, which are 2.5 mg, 10 mg, 15 mg, and 20 mg tablets.

Dosage and Administration

Rivaroxaban tablets are administered orally, and their dosages widely vary according to the various requirements in deep venous thrombosis therapeutic management.

For Treatment of Deep Venous Thrombosis

• The 15 mg Rivaroxaban tablet is administered orally, two times a day, along with food for the initial 21 days.

• It is followed by the administration of a 20 mg tablet orally once a day, along with food for the remaining duration of treatment.

To Reduce the Risk of Deep Venous Thrombosis in the High-Risk Groups

• A 10 mg Rivaroxaban tablet is given once a day (with or without food) for at least six months following the standard anticoagulant regime.

• The high-risk group refers to the recurrence of deep venous thrombosis and in patients who are at continued risk of developing deep venous thrombosis even after standard anticoagulant therapy.

As Prophylaxis for Preventing Deep Venous Thrombosis

• 10 mg of Rivaroxaban tablet is taken orally once a day with or without food.

What Are the Drug Warnings and Precautions?

The warnings and precautionary measures of using Rivaroxaban reflect its increased dosage causing excessive bleeding or inadequate administration prone to the development of thrombotic events. Some of the important warnings and precautions in using Rivaroxaban are as follows:

• Increased risk of bleeding could lead to serious or fatal hemorrhagic complications.

• Signs and symptoms of blood loss should be evaluated promptly.

• Anticoagulant reversal agents to neutralize the anti-factor Xa action of Rivaroxaban should be administered in case of excessive bleeding.

• The use of Rivaroxaban is associated with pregnancy-related hemorrhage.

• It should be administered with caution during pregnancy due to the increased risk of obstetric hemorrhage or emergent delivery.

• Rivaroxaban is not recommended in patients with prosthetic heart valves.

US Boxed Warning

• Premature cessation or discontinuation of Rivaroxaban leads to an increased risk of developing thrombotic events.

• If discontinuation of the drug is initiated for certain clinical reasons other than pathological bleeding or completion of the therapy, alternative or substitution anticoagulant therapy should be followed.

• The chances of developing spinal or epidural hematomas are high during spinal or epidural anesthetic procedures.

• Indwelling epidural catheters and concomitant use of other medications increase the risk of spinal or epidural hematoma and affect the hemostasis in such patients.

• Risk assessment versus benefits becomes mandatory in patients who are under Rivaroxaban therapy before anesthetic procedures.

Use in Specific Populations

Pregnancy

• Rivaroxaban should be used with caution in pregnant women due to its increased risk associated with pregnancy-related hemorrhage.

• Adverse side effects are reported in pregnancy conditions such as miscarriages, emergent delivery, and birth defects.

• Pregnancy is a major risk factor for developing venous thromboembolism in women who have existing thrombotic disorders (hereditary and acquired).

• Thromboembolic disease in pregnant women leads to maternal complications such as preeclampsia.

• Thromboembolic disease in pregnancy also leads to restricted intrauterine growth, placental abruption, and unexpected pregnancy loss.

• The risk of bleeding, other side effects as well as the potential risk of thrombotic events should be assessed before initiating Rivaroxaban therapy in pregnant women.

Lactation

• Rivaroxaban levels are detected in human milk. However, there is no significant data to evaluate its effects on the lactating mother or breastfed child.

• Regular monitoring of both the health benefits of the child and the clinical needs of the mother is recommended during lactation.

Pediatric Use

• No clinical trials have been reported on the use of Rivaroxaban in the pediatric population.

• Hence, no scientific data is available for its safe and effective use in pediatric patients.

Geriatric Use

• Clinical trials report that the efficacy of Rivaroxaban in the elderly ( above 65 years) is similar to that observed in younger patients (less than 65 years).

• Elderly patients have higher concentrations of Rivaroxaban in their plasma than younger patients, which occurs mainly due to decreased clearance of the drug.

Renal Impairment

• Rivaroxaban is mainly eliminated by the kidneys, and it is also a low-clearance drug.

• Use of Rivaroxaban should be avoided, or doses should be adjusted depending on the creatinine clearance (CrCl) and the severity of renal impairment.

Hepatic Impairment

• Rivaroxaban is primarily metabolized in the liver. Moderate hepatic impairment causes increased plasma levels (127 %) of Rivaroxaban.

• Use of Rivaroxaban should be avoided in moderate to severe hepatic impairment and also in hepatic diseases manifesting clotting dysfunction.

For Patients

What Is Deep Venous Thrombosis?

Deep venous thrombosis (DVT) is a clinical condition where clotting of blood occurs in a deep vein, commonly in the lower extremities (legs). It is a form of venous thromboembolism (VTE), which is characterized by the blocking of blood flow in a vein due to the formation of blood clots inside the intact vessel (there is no external cut in the vein). Deep venous thrombosis usually occurs in the deep veins present in the lower legs, thighs, pelvis, and arms. DVT is caused due to impaired venous return (blood flow from the legs back to the heart). This causes endothelial (inner side of the blood vessel) injury and dysfunction, triggering coagulation mechanism and clot formation inside the vein.

Some of the risk factors for developing DVT are as follows:

• Smoking (active and passive).

• Cancers like myeloproliferative neoplasms cause hyperviscosity of the blood.

• Estrogen-receptor modulating agents such as Tamoxifen and Raloxifene.

• Heart failure.

• Hypercoagulability disorders such as antiphospholipid antibody syndrome.

• Antithrombin deficiency.

• Heparin-induced thrombocytopenia.

• Hereditary fibrinolytic deficiency.

• Hyperhomocysteinemia.

• Prolonged immobilization due to surgeries or illness.

• Indwelling central venous catheters.

• Trauma in lower extremities.

• Oral contraceptives or estrogen therapy.

• Pregnancy and associated postpartum complications.

DVT causes pain, tenderness, and swelling in the affected extremity. It could remain asymptomatic or lead to complications like pulmonary embolism (PE). Imaging techniques like ultrasound (US) can help in diagnosing DVT. The use of anticoagulants is the most effective line of treatment in the management of deep venous thrombosis.

What Is Rivaroxaban?

Rivaroxaban is a newly developed oral anticoagulant drug used for the treatment of venous thromboembolic events (VTE), such as deep vein thrombosis (DVT). Rivaroxaban inhibits Factor Xa directly in the clotting cascade mechanism and prevents the formation of the clot (thrombus). It is also used in patients following orthopedic surgery to prevent thrombus formation (postoperative thromboprophylaxis). Rivaroxaban prevents the occurrence of stroke in patients having non-valvular atrial fibrillation (irregular heartbeats). It is used as an add-on drug in acute coronary syndrome and peripheral arterial disease to prevent secondary development.

How to Use Rivaroxaban?

Rivaroxaban is an orally administered drug and is effectively metabolized in the body. It does not require any special monitoring. However, precautions should be taken in case of conditions like kidney or liver problems, pregnancy, and the use of other drugs. Also, patients should be aware of the adverse reactions of the drug and report immediately if any signs of side effects occur.

• The recommended dose for treating DVT is 15 mg Rivaroabxan tablet two times daily for the first three weeks and then followed by 20 mg once a day.

• 15 mg and 20 mg tablets should always be taken along with food and not on empty stomachs. Food increases the absorption of the drug, and the effectiveness of Rivaroxaban is attained.

• The duration of Rivaroxaban treatment is recommended for three months and is continued as an extended therapy till the condition improves.

What Are the Adverse Side Effects of Rivaroxaban?

Hemorrhage or increased risk of bleeding is the most frequently occurring adverse effect of Rivaroxaban use. Some of the adverse effects of Rivaroxaban are as follows:

• Hemorrhage at various sites like intracranial, retinal, gastrointestinal, and adrenal bleeding.

• Decrease in hemoglobin (anemia).

• Reduced blood pressure.

• Dizziness.

• Insomnia.

• Fatigue.

• Depression.

• Anxiety.

• Syncope.

• Wound healing is delayed.

• Pruritus.

• Skin blisters.

• Abdominal pain.

• Increased liver enzymes like serum transaminases.

• Pain in the back and limbs.

• Muscle spasms or cramps.

• Bronchiectasis (pulmonary hemorrhage).

• Injection site hematoma (epidural hematoma).

• Jaundice.

• Retroperitoneal hemorrhage.

• Subdural hematoma.

• Thrombocytopenia.

What Are the Precautions to Be Followed While Using Rivaroxaban?

Rivaroxaban is a potent anticoagulant and is currently considered the drug of choice in treating deep venous thrombosis. Some of the precautions to be taken while using the drug are as follows:

• Rivaroxaban (15 mg and 25 mg) should not be taken on an empty stomach. It should always be taken with food.

• Hypersensitivity reactions should be reported immediately to the doctor.

• Use of Rivaroxaban in pregnant women should be done with caution and requires a complete risk assessment before starting the treatment.

• Patients should inform the doctor prior to any surgical procedures or dental extractions about undergoing Rivaroxaban therapy to prevent bleeding complications.

• The presence of liver problems should be reported before starting Rivaroxaban therapy.

• The development of clinical symptoms related to its adverse reactions should be promptly reported to a medical professional. Rivaroxaban tablets must not be stopped on the patient’s own decision.

• Discontinuation of Rivaroxaban could lead to recurrent thrombotic events. Hence, patients should continue the full regime.

• Excessive dosages or missed doses must be reported immediately to the doctor, and patients must not self-adjust the missing doses.

• Rivaroxaban is stored at room temperature between 15 to 30 degrees centigrades and must be kept out of reach of children.

• Rivaroxaban tablets should be kept in a cool, dry place away from direct sunlight.

For Doctors

Pharmacodynamics

Rivaroxaban is a potent anticoagulant that directly binds to clotting Factor Xa. Thereby, it effectively interferes with the amplification process of the clotting cascade mechanism and prevents thrombus formation. Rivaroxaban is considered a distinct and unique anticoagulant for three main therapeutic reasons, which are as follows:

• It is the first anticoagulant to be designed for orally-dosed administration. Whereas other frequently used anticoagulants, such as Heparin and its derivatives, are only administered parenterally.

• It does not require antithrombin III (an enzyme that inhibits thrombin) to exert its anticoagulant activity.

• Both the free as well as clot-bound forms of Factor Xa remain active in blood circulation. Rivaroxaban deactivates and inhibits both the forms of Factor Xa and also blocks prothrombinase (an enzyme complex that activates thrombin) activity.

• Thus, Rivaroxaban acts as a potent anticoagulant by directly inhibiting thrombus formation and preventing venous thrombosis.

Mechanism of Action

Clotting Factor Xa is a critical mediator of clotting mechanisms. It is a serine protease enzyme that generates thrombin by cleaving prothrombin. Factor Xa lies at the crosspoints of both extrinsic and intrinsic clotting pathways and is essential for the production of thrombin. Rivaroxaban specifically targets Factor Xa and exerts its mechanism of action in the following ways:

• Rivaroxaban is a small-molecule derivative of Oxazolidinone that binds directly with Factor Xa (this drug does not need cofactors like antithrombin for binding).

• It binds reversibly to clotting factor Xa and inhibits the enzymatic activity of Factor Xa by competitive inhibition.

• The binding of Rivaroxaban to Factor Xa blocks the progression of clotting mechanisms through the common clotting pathway and prevents the generation of thrombin (an important clotting enzyme).

• Thrombin formation is a crucial step as it leads to the final common clotting pathway in the coagulation cascade (fibrin formation). Directly blocking thrombin generation increases the anticoagulant efficacy of Rivaroxaban.

• There is no direct inhibitory effect of Rivaroxaban on platelet aggregation, but it indirectly decreases platelet aggregation that is mediated by thrombin.

Chemical Taxonomy of Rivaroxaban

Kingdom- Organic compounds.

Super Class- Organic Heterocyclic compounds.

Class- Oxazinanes.

Sub Class- Morpholines.

Direct Parent Compound- Phenyl Morpholine.

Alternative Parent Compound- Thiophene carboxamides, 2,5-disubstituted thiophenes, Oxazolidinones, Aryl chlorides, Heteroaromatic compounds.

Substituents- 2-heteroaryl carboxamide, Aromatic heterocyclic compound, Aryl chloride, Benzenoid, Carbamic acid ester.

Molecular Framework- Aromatic heteromonocyclic compounds.

External Descriptors- Oxazolidinone (CHEBI:68579), monocarboxylic acid amide, organochlorine compound, thiophenes, lactam, aromatic amide, morpholines.

Pharmacokinetics

Absorption

• On taking Rivaroxaban orally, it is quickly absorbed into the blood.

• It reaches peak plasma levels within two to four hours.

• The absorption rate of Rivaroxaban depends on the site in the gastrointestinal tract where the drug is released.

• Its peak concentration (Cmax) reduces by 56 % when the drug is released distally to the stomach (proximal and distal small intestine).

Bioavailability

• 92 % to 95 % of Rivaroxaban binds to plasma proteins, where albumin is the predominant binding component.

• In healthy human subjects, its steady-state volume distribution equals 50 L.

• The absolute bioavailability of orally administered Rivaroxaban is dose-dependent.

• Its bioavailability is greater than 80 % in a 10 mg dosage and is not influenced by fasting state or intake of food.

• The bioavailability reduces for 15 mg and 20 mg doses if taken on an empty stomach.

• The absolute bioavailability of a 20 mg dosage in a fasting state is 66 %, and it increases to 76 % when co-administered with food.

• The bioavailability of these doses (15 mg and 20 mg) improves when taken along with food.

Metabolism

• Rivaroxaban is metabolized in the liver by oxidative degradation mediated by cytochrome enzymes (CYP 3A 4/5 and CYP2J2) and subsequent hydrolysis.

• Nearly two-thirds of the dose taken in is metabolized.

• Its metabolites are eventually eliminated through renal and biliary or fecal routes.

• No prominent residual circulating metabolites are seen in blood plasma.

Biological Half-Life

• The terminal half-life of Rivaroxaban increases with age.

• It is 11 to 13 hours in elderly individuals.

• In healthy individuals of the age group between 20 to 45 years, Rivaroxaban has a terminal elimination half-life of five to nine hours.

Clearance and Route of Elimination

• Rivaroxaban is a low-clearance drug, where its systemic clearance is nearly 10 L/h, and renal clearance is nearly 3 to 4 L/h.

• Of the two-thirds (66 %) of Rivaroxaban that is excreted into the urine, 36 % is an unchanged drug, and the remaining 30 % is inactive metabolites.

• The rest of the one-third (28 %) administered dose is eliminated through feces ( 7 % as unchanged drug, 21 % as inactive metabolite).

Toxicity

The toxicity of Rivaroxaban is attributed to its overdosage, which eventually leads to hemorrhagic complications. Discontinuation of Rivaroxaban and initiation of appropriate neutralization therapy help in preventing the complications associated with its toxicity. Some of the measures to manage Rivaroaban are as follows:

• Minor episodes of bleeding are managed conservatively by skipping or delaying a single dose of Rivaroxaban.

• In case of major bleeding, antifibrinolytic agents like tranexamic acid are used as hemostatic agents in the initial intervention.

• Epsilon-aminocaproic acid is recommended for major NOAC-induced bleedings.

• Anticoagulant reversal agents such as Andexanet alfa are used in life-threatening bleeding complications.

• Activated oral charcoal is administered within one to two hours of the clinical occurrence of symptoms.

• Andexanet alfa (modified clotting Factor Xa decoy protein) is an anticoagulant reversal agent used as an antidote for Rivaroxaban toxicity.

• Andexanet alfa binds with Rivaroxaban and neutralizes its effect due to its high affinity for the drug.

• Prothrombin complex concentrate (PCC), which is a mixture of coagulation factors, is also used to reverse Rivaroxaban toxicity.

Non-hemorrhagic Toxicities of Rivaroxaban

• Prolonged therapy of Rivaroxaban causes hepatic impairment resulting in elevated hepatic enzymes.

• Acute liver injury with jaundice.

• Skin rashes with fever.

• Anaphylactic shock.

• Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome).

• Acute hepatic necrosis.

Drug-Drug Interactions

Clinically significant drug interactions of Rivaroxaban are minimized by adjusting dosage frequencies, regular monitoring, or substituting with alternative medications.

• Rivaroxaban is metabolized by cytochrome enzymes. Administration of Rivarxoban with potent cytochrome (CYP3A) inhibitors increases its plasma levels, thereby enhancing its adverse side effects.

• Azole-antimycotics and HIV protease inhibitors reduce Rivaroxaban clearance and elimination from the body resulting in its toxicity.

• Its use is avoided with other anticoagulants such as unfractionated Heparin, Enoxaparin, and Warfarin because of the additive effect of Rivaroxaban.

• Concomitant use of Aspirin increases the hemorrhagic risk.

Drug-Disease Interactions

• Rivaroxaban is not recommended for patients with antiphospholipid syndrome (triple-positive antibodies). Recurrent thrombotic events occur if used in such cases.

• Rivaroxaban is not effectively metabolized in patients with existing hepatic dysfunctions and increases the risk of hepatic failure.

• It is not used for patients with acute renal failure because clearance of Rivaroxaban is reduced in such conditions leading to toxic effects.

• Rivaroxaban is not recommended in the case of atrial fibrillation associated with end-stage CKD because it leads to enhanced cardiovascular complications such as stroke.

• Use of Rivaroxaban is not advised in valvular diseases such as rheumatic heart disease and mitral stenosis and also in prosthetic values because Rivaroxaban increases the risk of bleeding in defective values.

• In case of congenital or acquired bleeding disorders, Rivaroban is avoided to reduce increased hemorrhagic episodes.

Conclusion

Rivaroxaban has a wide range of benefits over other anticoagulants like oral administration, faster drug action time, rapid onset of its effects, uncomplicated pharmacokinetics and pharmacodynamics, fewer drug interactions, and improved clinical results. An integrated clinical approach to using Rivaroxaban ensures optimal therapeutic outcomes and minimizes its adverse effects.