Rivaroxaban

Uses and Indications

Rivaroxaban tablet is indicated as a factor Xa inhibitor for the following conditions:

• To reduce the risk of major cardiovascular events in patients with coronary artery disease (CAD).

• To reduce the risk of major thrombotic vascular events in patients with peripheral artery disease (PAD), including those who have undergone recent lower extremity revascularization due to symptomatic PAD.

There are no teratogenic or nonteratogenic effects associated with the use of this drug as per the available data.

Dosage and Administration

The recommended dosage for the management of coronary artery disease (CAD) or peripheral artery disease (PAD) is 2.5 mg administered orally twice daily. This medication may be taken with or without food. It is advised to use this medication in conjunction with aspirin, at a dosage of 75 to 100 mg, which should be taken orally once daily.

Healthcare professionals should ensure that patients adhere to the prescribed dosing schedule to optimize therapeutic outcomes.

Contraindications

Use of this product is contraindicated in patients with active pathological bleeding due to the risk of exacerbating hemorrhagic conditions. Additionally, it is contraindicated in individuals with a severe hypersensitivity reaction to rivaroxaban tablets, as this may lead to serious adverse effects.

Warnings and Precautions

Rivaroxaban is associated with a significant risk of serious and potentially fatal bleeding. Healthcare professionals should be aware that an agent to reverse the activity of rivaroxaban is available for emergency situations.

Caution is advised when prescribing rivaroxaban to pregnant women due to the potential for obstetric hemorrhage and the risk of emergent delivery. Additionally, the use of rivaroxaban is not recommended for patients with prosthetic heart valves or those diagnosed with triple positive antiphospholipid syndrome, as these conditions may increase the risk of thrombosis.

It is critical to note that premature discontinuation of rivaroxaban tablets heightens the risk of thrombotic events. To mitigate this risk, healthcare providers should consider bridging therapy with another anticoagulant if rivaroxaban is discontinued for reasons other than pathological bleeding or the completion of a prescribed treatment course.

Patients receiving rivaroxaban who are undergoing neuraxial anesthesia or spinal puncture are at risk for epidural or spinal hematomas, which can lead to long-term or permanent paralysis. Therefore, it is essential to monitor these patients closely for any signs and symptoms of neurological impairment. If such symptoms are observed, urgent treatment is warranted. Prior to any neuraxial intervention, healthcare professionals should carefully weigh the benefits against the risks in patients who are or may need to be anticoagulated.

Side Effects

In clinical trials and postmarketing experiences, various adverse reactions have been reported in patients receiving rivaroxaban.

Common adverse reactions observed in adult patients include bleeding, which occurs in more than 5% of this population. In pediatric patients, the incidence of bleeding is higher, exceeding 10%, along with other common reactions such as cough, vomiting, and gastroenteritis, each also occurring in more than 10% of this group.

Serious warnings associated with rivaroxaban include the risk of premature discontinuation, which significantly increases the likelihood of thrombotic events. Additionally, patients receiving neuraxial anesthesia or undergoing spinal puncture are at risk for epidural or spinal hematomas, which may lead to long-term or permanent paralysis.

Rivaroxaban is associated with a risk of serious and potentially fatal bleeding. An agent to reverse the activity of rivaroxaban is available for managing such complications. Caution is advised when prescribing rivaroxaban to pregnant women due to the potential for obstetric hemorrhage and/or the need for emergent delivery. The use of rivaroxaban is not recommended in patients with prosthetic heart valves or those with triple positive antiphospholipid syndrome due to an increased risk of thrombosis.

The medication is contraindicated in patients with active pathological bleeding and those with a severe hypersensitivity reaction to rivaroxaban. In cases of overdose, there is a risk of hemorrhage; therefore, it is essential to discontinue rivaroxaban and initiate appropriate therapy if bleeding complications arise.

Drug Interactions

Concomitant use of strong P-glycoprotein (P-gp) inhibitors and inducers with this medication is not recommended due to the potential for significant drug interactions. These interactions may alter the pharmacokinetics of the medication, leading to either increased toxicity or reduced efficacy.

In addition, the use of anticoagulants alongside this medication should be avoided. The combination may increase the risk of bleeding or other adverse effects, necessitating careful consideration of alternative therapies or close monitoring if co-administration is unavoidable.

Packaging & NDC

The table below lists all NDC Code configurations of Rivaroxaban, the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

There are no available safety, efficacy, pharmacokinetic, or pharmacodynamic data to support the use of rivaroxaban 2.5 mg tablets in pediatric patients. Consequently, rivaroxaban 2.5 mg tablets are not recommended for use in this population.

Geriatric Use

In clinical trials involving rivaroxaban, a significant proportion of adult patients were elderly, with 64 percent aged 65 years and older, and 27 percent aged 75 years and older. The efficacy of rivaroxaban in geriatric patients (65 years and older) was found to be comparable to that observed in younger patients.

However, it is important to note that both thrombotic and bleeding event rates were higher in elderly patients. Therefore, careful monitoring for these events is recommended in this population. Healthcare providers should consider these factors when prescribing rivaroxaban to geriatric patients, and appropriate dose adjustments may be necessary based on individual patient characteristics and clinical judgment.

Pregnancy

The available data on rivaroxaban in pregnant women are limited and insufficient to establish a drug-associated risk of adverse developmental outcomes. Caution is advised when prescribing rivaroxaban to pregnant patients due to the potential for pregnancy-related hemorrhage and/or emergent delivery. The anticoagulant effect of rivaroxaban cannot be reliably monitored with standard laboratory testing, necessitating careful consideration of the benefits and risks for the mother and potential risks to the fetus.

Adverse outcomes in pregnancy can occur regardless of maternal health or medication use. The estimated background risk of major birth defects and miscarriage in the U.S. general population is approximately 2% to 4% and 15% to 20%, respectively, although the specific background risk for the indicated populations remains unknown. Pregnancy itself is a recognized risk factor for venous thromboembolism, with increased risk in women with inherited or acquired thrombophilias. Pregnant women with thromboembolic disease face heightened risks of maternal complications, including pre-eclampsia, as well as increased risks for intrauterine growth restriction, placental abruption, and early and late pregnancy loss.

Given the pharmacologic activity of Factor Xa inhibitors and the potential for placental transfer, there is a risk of bleeding occurring at any site in the fetus and/or neonate. All patients receiving anticoagulants, including pregnant women, are at risk for bleeding, which may be exacerbated during labor or delivery. The risk of bleeding must be carefully balanced against the risk of thrombotic events when considering the use of rivaroxaban in this context.

There are no adequate or well-controlled studies of rivaroxaban in pregnant women, and dosing for this population has not been established. Post-marketing experience is currently insufficient to determine a rivaroxaban-associated risk for major birth defects or miscarriage. Animal studies indicate that rivaroxaban crosses the placenta, with evidence of increased fetal toxicity, including increased resorptions, decreased number of live fetuses, and decreased fetal body weight in pregnant rabbits at doses of ≥10 mg/kg during organogenesis. This dose corresponds to approximately four times the human exposure of unbound drug based on AUC comparisons at the highest recommended human dose of 20 mg/day. Similarly, decreased fetal body weights were observed in pregnant rats at doses of 120 mg/kg, corresponding to about 14 times the human exposure, and peripartal maternal bleeding and maternal and fetal death occurred at a dose of 40 mg/kg, approximately six times the maximum human exposure at the recommended dose.

Lactation

Rivaroxaban is excreted in human milk; however, the effects on breastfed infants and on milk production are unknown. There are no adequate or well-controlled studies of rivaroxaban in nursing mothers, and dosing for this population has not been established.

When prescribing rivaroxaban to lactating mothers, the potential for excretion in breast milk should be considered. Nursing mothers are advised to monitor their infants for any signs of bleeding or other adverse effects.

Renal Impairment

Rivaroxaban is contraindicated in patients with severe renal impairment, specifically those with a creatinine clearance of less than 15 mL/min. For patients with moderate renal impairment, defined as a creatinine clearance between 15 and 49 mL/min, a reduced dose of rivaroxaban is recommended.

Prior to initiating rivaroxaban, renal function should be assessed, and it should be monitored periodically thereafter, particularly in patients with renal impairment. Caution is advised when administering rivaroxaban to this population, as they may be at an increased risk for bleeding.

Hepatic Impairment

Rivaroxaban is contraindicated in patients with active bleeding and in those with severe hepatic impairment, classified as Child-Pugh class C. For patients with moderate hepatic impairment (Child-Pugh class B), rivaroxaban is not recommended due to the potential for increased drug exposure and an associated heightened risk of bleeding.

In patients with mild hepatic impairment (Child-Pugh class A), no dosage adjustment is necessary; however, caution is advised when prescribing rivaroxaban. It is essential that liver function tests be conducted prior to initiating treatment and periodically throughout the course of therapy in patients with hepatic impairment. Additionally, healthcare providers should closely monitor these patients for any signs and symptoms of bleeding, as they may be at an increased risk.

Overdosage

In cases of rivaroxaban overdose, the primary concern is the potential for hemorrhage. Healthcare professionals should be vigilant for signs of bleeding complications, which necessitate the immediate discontinuation of rivaroxaban tablets and the initiation of appropriate therapeutic interventions.

It is important to note that systemic exposure to rivaroxaban does not increase with single doses exceeding 50 mg, as absorption is limited at higher doses. In instances of overdose, the administration of activated charcoal may be considered to reduce further absorption of the drug.

Due to rivaroxaban's high plasma protein binding, it is not amenable to dialysis, which limits the options for removal of the drug from the system. However, partial reversal of laboratory anticoagulation parameters can be achieved through the use of plasma products. Additionally, there is an available agent specifically designed to reverse the anti-factor Xa activity of rivaroxaban, which may be utilized in the management of overdose cases.

Healthcare professionals are advised to monitor patients closely for any signs of bleeding and to implement the necessary interventions promptly to mitigate the risks associated with rivaroxaban overdose.

Nonclinical Toxicology

Rivaroxaban was evaluated for its carcinogenic potential in long-term studies involving oral gavage administration to mice and rats for a duration of up to 2 years. The results indicated that rivaroxaban was not carcinogenic in either species. At the highest tested dose of 60 mg/kg/day, systemic exposures (AUCs) of unbound rivaroxaban in male and female mice were found to be 1- and 2-fold, respectively, compared to the human exposure at a dose of 20 mg/day. In male and female rats, systemic exposures at the same highest dose were 2- and 4-fold, respectively, higher than the human exposure.

In terms of mutagenicity, rivaroxaban did not exhibit mutagenic properties in bacterial assays (Ames test) and was not found to be clastogenic in V79 Chinese hamster lung cells in vitro. Additionally, results from the mouse micronucleus test in vivo confirmed the absence of mutagenic effects.

Assessment of reproductive toxicity revealed no impairment of fertility in male or female rats administered rivaroxaban at doses up to 200 mg/kg/day orally. This dosage resulted in exposure levels, based on the unbound AUC, that were at least 13 times greater than those observed in humans receiving a daily dose of 20 mg rivaroxaban.

Postmarketing Experience

Epidural or spinal hematomas have been reported in patients treated with rivaroxaban tablets who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may lead to long-term or permanent paralysis. It is recommended that patients be monitored frequently for signs and symptoms of neurological impairment, and urgent treatment should be initiated if neurological compromise is observed.

Before performing neuraxial interventions in patients who are anticoagulated or will be anticoagulated for thromboprophylaxis, careful consideration of the benefits and risks is advised.

Premature discontinuation of rivaroxaban, in the absence of adequate alternative anticoagulation, has been associated with an increased risk of thrombotic events. Clinical trials in patients with atrial fibrillation indicated a higher rate of stroke during the transition from rivaroxaban to warfarin. If rivaroxaban is discontinued for reasons other than pathological bleeding or completion of therapy, it is advisable to consider coverage with another anticoagulant.

Rivaroxaban is known to increase the risk of bleeding, which can occur in any organ and may result in serious or fatal outcomes. When prescribing rivaroxaban to patients at increased risk of bleeding, the potential for thrombotic events should be weighed against the bleeding risk.

The concomitant use of other medications that impair hemostasis, such as aspirin, P2Y12 platelet inhibitors, dual antiplatelet therapy, other antithrombotic agents, fibrinolytic therapy, non-steroidal anti-inflammatory drugs (NSAIDs), selective serotonin reuptake inhibitors, and serotonin norepinephrine reuptake inhibitors, has been shown to increase the risk of bleeding. Additionally, the use of drugs that are known combined P-glycoprotein and strong CYP3A inhibitors may elevate rivaroxaban exposure and further increase bleeding risk.

An agent to reverse the anti-factor Xa activity of rivaroxaban is available; however, due to high plasma protein binding, rivaroxaban is not dialyzable. Protamine sulfate and vitamin K are not expected to influence the anticoagulant activity of rivaroxaban. The use of procoagulant reversal agents, such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate, or recombinant factor VIIa, may be considered, although their clinical efficacy and safety have not been thoroughly evaluated. Monitoring the anticoagulation effect of rivaroxaban using clotting tests (PT, INR, or aPTT) or anti-factor Xa (FXa) activity is not recommended.

The most frequently reported adverse reaction in adult patients was bleeding, occurring in more than 5% of cases. In pediatric patients, the most common adverse reactions, occurring in more than 10% of cases, included bleeding, cough, vomiting, and gastroenteritis.

Patient Counseling

Healthcare providers should advise patients that premature discontinuation of rivaroxaban tablets can significantly increase the risk of thrombotic events. To mitigate this risk, it is important to consider transitioning to another anticoagulant if rivaroxaban is discontinued for reasons other than pathological bleeding or the completion of a prescribed therapy course.

Providers should inform patients about the potential risk of epidural or spinal hematomas associated with the use of rivaroxaban, particularly in those receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas can lead to long-term or permanent paralysis. Therefore, it is essential to monitor patients closely for any signs and symptoms of neurological impairment. Should any neurological compromise be observed, urgent treatment must be initiated.

Before proceeding with any neuraxial interventions in patients who are currently anticoagulated or will be anticoagulated for thromboprophylaxis, healthcare providers should carefully weigh the benefits against the risks involved.

Patients should be instructed to report immediately any signs or symptoms indicative of neurological impairment. This includes midline back pain, sensory and motor deficits such as numbness, tingling, or weakness in the lower limbs, as well as any bowel and/or bladder dysfunction. If there is a suspicion of spinal hematoma, urgent diagnostic measures and treatment should be initiated, which may include consideration for spinal cord decompression.

Storage and Handling

The product is supplied in accordance with the following specifications: it should be stored at a temperature range of 20ºC to 25ºC (68ºF to 77ºF), in compliance with USP Controlled Room Temperature guidelines. It is essential to keep the product out of the reach of children to ensure safety.

Additional Clinical Information

No further data are available.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Rivaroxaban as submitted by Dr. Reddy's Laboratories, Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)