Rivaroxaban

Description

Rivaroxaban, USP is the active ingredient with the chemical name 5-Chloro-N-({(5S)-2-oxo-3-4-(3-oxo-4-morpholinyl)phenyl-1,3-oxazolidin-5­-yl}methyl)-2-thiophenecarboxamide. The molecular formula of rivaroxaban is C19H18ClN3O5S, and it has a molecular weight of 435.89 g/mol. Rivaroxaban, USP is a pure (S)-enantiomer and appears as a white to yellowish powder. It is slightly soluble in dimethyl sulfoxide and is practically insoluble in acetone and in water. Each rivaroxaban tablet, USP contains 2.5 mg of rivaroxaban, USP. The inactive ingredients of rivaroxaban tablets, USP include croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, red iron oxide, sodium lauryl sulfate, talc, titanium dioxide, and yellow iron oxide.

Uses and Indications

Rivaroxaban tablets are indicated to reduce the risk of major cardiovascular events in patients with coronary artery disease (CAD). Additionally, these tablets are indicated to reduce the risk of major thrombotic vascular events in patients with peripheral artery disease (PAD), including those who have recently undergone lower extremity revascularization due to symptomatic PAD.

There are no teratogenic or nonteratogenic effects associated with the use of rivaroxaban tablets.

Dosage and Administration

For the treatment of Coronary Artery Disease (CAD) or Peripheral Artery Disease (PAD), the recommended dosage is 2.5 mg administered orally twice daily. This can 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 once daily.

Healthcare professionals should ensure that patients are informed about the importance of adhering to the prescribed dosing schedule and the potential benefits of the combination therapy.

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 several significant warnings and precautions that healthcare professionals must consider to ensure patient safety.

Risk of Bleeding Rivaroxaban can lead to serious and potentially fatal bleeding events. It is crucial for healthcare providers to be aware of this risk and to monitor patients accordingly. An agent is available to reverse the anticoagulant effects of rivaroxaban in the event of a bleeding complication.

Pregnancy-Related Hemorrhage Caution is advised when prescribing rivaroxaban to pregnant women due to the potential for obstetric hemorrhage and the risk of complications during emergent delivery. The benefits and risks should be carefully weighed in this population.

Prosthetic Heart Valves The use of rivaroxaban is not recommended for patients with prosthetic heart valves. This contraindication is essential to prevent adverse outcomes in this patient group.

Increased Risk of Thrombosis in Patients with Triple Positive Antiphospholipid Syndrome Rivaroxaban is not recommended for patients diagnosed with triple positive antiphospholipid syndrome due to an increased risk of thrombosis.

Premature Discontinuation Premature discontinuation of rivaroxaban significantly increases the risk of thrombotic events. Healthcare providers should ensure that patients understand the importance of adherence to their prescribed regimen.

Spinal/Epidural Hematoma There is a risk of epidural or spinal hematomas in patients receiving rivaroxaban who are undergoing neuraxial anesthesia or spinal puncture. These hematomas can lead to long-term or permanent paralysis. It is imperative to monitor patients closely for signs and symptoms of neurological impairment and to treat any observed issues urgently. The decision to perform neuraxial interventions in anticoagulated patients should be made after careful consideration of the benefits and risks.

Monitoring Parameters While no specific laboratory tests are required for the safe use of rivaroxaban, healthcare professionals should maintain vigilant monitoring for any signs of bleeding or neurological impairment in patients receiving this medication.

Side Effects

The most common adverse reaction observed in adult patients treated with rivaroxaban was bleeding, occurring in more than 5% of participants.

Serious adverse reactions associated with rivaroxaban include a significant risk of serious and potentially fatal bleeding. An agent to reverse the activity of rivaroxaban is available for use in such cases. Additionally, pregnancy-related hemorrhage has been noted, necessitating caution when prescribing rivaroxaban to pregnant women due to the risk of obstetric hemorrhage and/or the need for emergent delivery. Other serious reactions include active pathological bleeding and severe hypersensitivity reactions to rivaroxaban tablets.

Warnings associated with the use of rivaroxaban include the risk of thrombotic events following premature discontinuation of the medication. Furthermore, 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. It is essential to monitor these patients closely for signs and symptoms of neurological impairment and to provide urgent treatment if such symptoms are observed.

Rivaroxaban is not recommended for use in patients with prosthetic heart valves or those with an increased risk of thrombosis in triple positive antiphospholipid syndrome. In cases of overdose, rivaroxaban may lead to hemorrhage; therefore, it is crucial to discontinue the medication and initiate appropriate therapy if bleeding complications arise.

Drug Interactions

Concomitant use of strong P-glycoprotein (P-gp) inhibitors and inducers with this medication should be avoided 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 is not recommended. The combination may increase the risk of bleeding or other adverse effects, necessitating careful consideration and monitoring if such combinations are deemed necessary.

Healthcare professionals should assess the need for dosage adjustments or enhanced monitoring protocols when managing patients on this medication who may require treatment with drugs from these classes.

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 currently no 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 (under 65 years).

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 may need to implement appropriate dose adjustments or increased surveillance to ensure patient safety.

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.

Rivaroxaban, as a Factor Xa inhibitor, has the potential to cross the placenta, which raises concerns for bleeding at any site in the fetus and/or neonate. All patients receiving anticoagulants, including pregnant women, are at risk for bleeding, a risk that may be exacerbated during labor or delivery. Therefore, the risk of bleeding must be carefully balanced against the risk of thrombotic events when considering the use of rivaroxaban in this context.

Currently, 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 has not provided sufficient data 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 numbers of live fetuses, and reduced fetal body weight in rabbits at doses corresponding to approximately four times the human exposure based on AUC comparisons. In rats, significant fetal body weight reductions were observed at doses corresponding to about 14 times human exposure, and peripartal maternal bleeding, along with maternal and fetal death, occurred at a dose approximately six times the maximum human exposure.

Lactation

Lactating mothers requiring anticoagulation should engage in discussions regarding pregnancy planning with their physician. It is important to assess the risk of clinically significant uterine bleeding, which may necessitate gynecological surgical interventions, particularly in those using oral anticoagulants such as rivaroxaban. This assessment is crucial for females of reproductive potential and those experiencing abnormal uterine bleeding.

Renal Impairment

Rivaroxaban is contraindicated in patients with severe renal impairment, specifically those with a creatinine clearance of less than 30 mL/min. For patients with moderate renal impairment, defined as a creatinine clearance between 30 to less than 50 mL/min, a dose reduction of rivaroxaban is required.

Prior to initiating treatment with rivaroxaban, renal function should be assessed, and it is essential to monitor renal function periodically throughout the course of therapy. Patients with renal impairment may experience an increased risk of bleeding; therefore, caution is advised when prescribing rivaroxaban to this population. Adjustments in dosing may be necessary based on the results of renal function tests.

Hepatic Impairment

Patients with hepatic impairment have not been specifically studied in relation to the use of this medication. Consequently, there are no established dosage adjustments, special monitoring requirements, or precautions for individuals with compromised liver function. It is recommended that healthcare providers exercise caution when prescribing this medication to patients with hepatic impairment, given the lack of data on its safety and efficacy in this population. Regular monitoring of liver function may be prudent in these cases, although specific parameters are not defined in the available information.

Overdosage

In the event of a rivaroxaban overdose, significant clinical considerations must be addressed, particularly the risk of hemorrhage. It is imperative to discontinue rivaroxaban immediately and initiate appropriate therapeutic measures if any bleeding complications arise.

Rivaroxaban exhibits a unique pharmacokinetic profile, wherein systemic exposure does not increase with single doses exceeding 50 mg due to its limited absorption characteristics. Therefore, the potential for overdose effects may be mitigated by this pharmacological behavior.

In cases of overdose, the administration of activated charcoal may be considered to reduce further absorption of rivaroxaban, provided that it is within an appropriate time frame post-ingestion. However, it is important to note that rivaroxaban is not dialyzable due to its high plasma protein binding, which limits the effectiveness of dialysis as a treatment option.

For managing anticoagulation parameters affected by rivaroxaban, partial reversal may be achieved through the use of plasma products. Additionally, a specific agent is available to reverse the anti-factor Xa activity of rivaroxaban, which can be utilized in the management of severe bleeding or overdose situations.

Healthcare professionals should remain vigilant in monitoring patients for signs of hemorrhage and should be prepared to implement the aforementioned interventions as necessary.

Nonclinical Toxicology

Rivaroxaban was evaluated for its carcinogenic potential in long-term studies involving oral gavage administration to mice and rats for up to 2 years. The results indicated that rivaroxaban did not exhibit carcinogenic properties in either species.

In terms of systemic exposure, male and female mice receiving the highest tested dose of 60 mg/kg/day demonstrated unbound rivaroxaban AUCs that were 1- and 2-times, respectively, the human exposure at a clinical dose of 20 mg/day. Similarly, male and female rats at the same dose exhibited systemic exposures that were 2- and 4-times, respectively, the human exposure.

Rivaroxaban was assessed for mutagenicity and clastogenicity and was found to be non-mutagenic in bacterial assays (Ames test) and non-clastogenic in V79 Chinese hamster lung cells in vitro. Additionally, results from the mouse micronucleus test in vivo confirmed the absence of mutagenic effects.

Fertility studies conducted in male and female rats revealed no impairment when administered rivaroxaban at doses up to 200 mg/kg/day orally. This dosage resulted in unbound AUC exposure levels that were at least 13 times greater than those observed in humans receiving a daily dose of 20 mg.

Postmarketing Experience

Postmarketing experience has identified cases of serious bleeding events, including gastrointestinal bleeding and hemorrhagic stroke. Reports have also indicated occurrences of thrombocytopenia (low platelet count) in patients receiving rivaroxaban. Additionally, some patients have experienced elevations in liver enzymes during treatment with rivaroxaban. Rare cases of hypersensitivity reactions, including anaphylaxis, have been documented. Furthermore, there have been reports of spinal or epidural hematoma in patients who received neuraxial anesthesia or spinal puncture while on rivaroxaban.

Patient Counseling

Healthcare providers should advise patients and/or caregivers to read the FDA-approved patient labeling (Medication Guide) thoroughly. It is essential to instruct patients to take rivaroxaban tablets only as directed and to emphasize that they should not discontinue the medication without first consulting their healthcare professional.

For patients who have difficulty swallowing the tablet whole, healthcare providers should recommend crushing the rivaroxaban tablet and mixing it with a small amount of applesauce, followed by food. In cases where patients require an NG tube or gastric feeding tube, they should be instructed to crush the rivaroxaban tablet and mix it with a small amount of water before administration via the tube.

In the event of a missed dose, healthcare providers should advise patients to follow the instructions outlined in the Full Prescribing Information based on their specific dosing schedule. Patients should be informed to report any unusual bleeding or bruising to their physician, as it may take longer than usual for them to stop bleeding, and they may experience increased bruising and bleeding while on rivaroxaban tablets.

For patients who have undergone neuraxial anesthesia or spinal puncture, particularly those taking concomitant NSAIDs or platelet inhibitors, healthcare providers should caution them to monitor for signs and symptoms of spinal or epidural hematoma. Symptoms to watch for include back pain, tingling, numbness (especially in the lower limbs), muscle weakness, and stool or urine incontinence. If any of these symptoms occur, patients should be advised to contact their physician immediately.

Patients should also be instructed to inform their healthcare professional that they are taking rivaroxaban tablets prior to any invasive procedures, including dental work. It is important for patients to disclose to their physicians and dentists any prescription or over-the-counter medications, as well as herbal supplements they are taking or plan to take, to allow for an evaluation of potential interactions.

Additionally, patients should be advised to inform their physician immediately if they become pregnant or plan to become pregnant during treatment with rivaroxaban tablets. Pregnant women receiving rivaroxaban should report any bleeding or symptoms of blood loss to their physician without delay. Patients who are nursing or intend to nurse should discuss the benefits and risks of rivaroxaban tablets for both the mother and child with their physician. Finally, patients who can become pregnant should be encouraged to discuss pregnancy planning with their healthcare provider.

Storage and Handling

The product is supplied in accordance with the following specifications: it should be stored at a temperature range of 20° to 25°C (68° to 77°F), 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 Aurobindo Pharma Limited. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)