Rivaroxaban

Description

Rivaroxaban, USP is a factor Xa (FXa) inhibitor and serves as the active ingredient in rivaroxaban tablets, USP. The chemical name for rivaroxaban is 5-Chloro-N-({(5S)-2-oxo-3-4-(3-oxomorpholin-4-yl)phenyl-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide. The molecular formula is C19H18ClN3O5S, with a molecular weight of 435.88. Rivaroxaban is a pure (S)-enantiomer, presented as an odorless, non-hygroscopic, white to yellowish powder.

Rivaroxaban exhibits slight solubility in organic solvents such as acetone and polyethylene glycol 400, while being practically insoluble in water and aqueous media. Each rivaroxaban tablet, USP contains 2.5 mg of rivaroxaban, USP. The formulation includes inactive ingredients such as lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hydroxy propyl methyl cellulose, sodium lauryl sulfate, and magnesium stearate. The proprietary film coating mixture for rivaroxaban tablets, USP 2.5 mg, known as Aquarius Prime Yellow, consists of hypromellose, D&C yellow no.10 aluminum lake, polyethylene glycol, and titanium dioxide.

Uses and Indications

Rivaroxaban tablets are a factor Xa inhibitor indicated for the following uses:

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 recently undergone lower extremity revascularization due to symptomatic PAD.

There are no teratogenic or nonteratogenic effects mentioned in the available data.

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 that this medication be used in conjunction with aspirin, at a dosage of 75-100 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. Regular monitoring of the patient's response to treatment and any side effects is recommended 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 tablets are associated with significant risks that necessitate careful consideration and monitoring by healthcare professionals.

Risk of Bleeding Rivaroxaban can lead to serious and potentially fatal bleeding events. It is essential to be aware that an agent is available to reverse the anticoagulant effects of rivaroxaban. Healthcare providers should remain vigilant for signs of bleeding and manage any occurrences promptly.

Pregnancy-Related Considerations Caution is advised when prescribing rivaroxaban to pregnant women due to the risk of obstetric hemorrhage and the potential need for emergent delivery. The benefits and risks should be thoroughly evaluated in this population.

Prosthetic Heart Valves and Antiphospholipid Syndrome The use of rivaroxaban is not recommended in patients with prosthetic heart valves or those diagnosed with triple positive antiphospholipid syndrome due to an increased risk of thrombotic events.

Premature Discontinuation Premature discontinuation of rivaroxaban tablets significantly increases the risk of thrombotic events. Healthcare professionals 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 neuraxial anesthesia or undergoing spinal puncture while on rivaroxaban. These hematomas can lead to long-term or permanent paralysis. Therefore, it is crucial to monitor patients closely for signs and symptoms of neurological impairment. If any neurological deficits are observed, urgent treatment is warranted. The decision to perform neuraxial interventions in patients who are or need to be anticoagulated should be made after careful consideration of the potential benefits and risks.

Monitoring Recommendations While no specific laboratory tests are required for the safe use of rivaroxaban, healthcare providers should maintain a high index of suspicion for complications and monitor patients frequently for any signs of adverse effects, particularly neurological impairment.

Side Effects

The most common adverse reaction observed in adult patients treated with rivaroxaban tablets was bleeding, occurring in more than 5% of participants. Serious adverse reactions associated with the use of rivaroxaban include the risk of thrombotic events, particularly following premature discontinuation of the medication. It is critical to note that discontinuing any oral anticoagulant, including rivaroxaban, increases the risk of such events. To mitigate this risk, healthcare providers should consider transitioning patients to another anticoagulant if rivaroxaban is discontinued for reasons other than pathological bleeding or the completion of a prescribed treatment course.

Additionally, there is a significant risk of spinal or epidural hematomas in patients receiving rivaroxaban who are undergoing neuraxial anesthesia or spinal puncture. These hematomas can lead to long-term or permanent paralysis. Therefore, it is essential to monitor patients closely for any signs or symptoms of neurological impairment and to provide urgent treatment if such symptoms arise. The benefits and risks of neuraxial interventions should be carefully evaluated in patients who are or may need to be anticoagulated.

Rivaroxaban tablets can also cause serious and potentially fatal bleeding. An agent to reverse the anticoagulant effects of rivaroxaban is available, which may be necessary in cases of severe bleeding. 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 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. Other contraindications include active pathological bleeding and severe hypersensitivity reactions to rivaroxaban tablets.

Drug Interactions

Concomitant use of strong inhibitors or inducers of P-glycoprotein (P-gp) and CYP3A should be avoided due to the potential for significant drug interactions. These interactions may alter the pharmacokinetics of the affected drug, leading to either increased toxicity or reduced efficacy.

In the case of anticoagulants, concomitant administration is not recommended. The interaction may enhance the risk of bleeding or alter anticoagulant effectiveness, necessitating careful monitoring and potential dosage adjustments if these agents must be used together.

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 tablets, a significant proportion of the adult patient population was comprised of elderly individuals, with 64 percent of the 64,943 patients being 65 years of age or older, and 27 percent being 75 years or 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, healthcare providers should exercise caution when prescribing rivaroxaban to this population. Close monitoring for potential adverse events is recommended, and consideration should be given to possible dose adjustments based on individual patient factors 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 both the mother and the fetus.

Adverse outcomes in pregnancy can occur irrespective of maternal health or medication use. The estimated background risk of major birth defects and miscarriage in the U.S. general population is approximately 2–4% and 15–20%, respectively. Pregnancy itself is a known 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 population.

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 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 and maternal and fetal deaths were observed at doses corresponding to about 14 times and six times the maximum human exposure, respectively.

Given these findings, healthcare professionals should exercise caution when considering rivaroxaban for use in pregnant patients, weighing the potential risks to both the mother and the fetus.

Lactation

There are no adequate or well-controlled studies of rivaroxaban tablet in nursing mothers, and dosing for nursing mothers has not been established. The potential for excretion in breast milk is unknown. Caution should be exercised when rivaroxaban tablet is administered to a nursing mother due to the potential for adverse effects in the breastfed infant.

Renal Impairment

Rivaroxaban tablets are 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 49 mL/min, a reduced dose of rivaroxaban is recommended.

It is essential to assess renal function prior to initiating rivaroxaban therapy and to monitor it periodically throughout treatment, particularly in patients with renal impairment. Caution should be exercised when administering rivaroxaban to these patients, as they may have an increased risk of bleeding.

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 outlined 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 an overdose of rivaroxaban tablets, significant clinical concerns arise, primarily the risk of hemorrhage. Healthcare professionals should be vigilant for signs of bleeding complications, which necessitate immediate intervention.

Upon confirmation of an overdose, it is imperative to discontinue rivaroxaban tablets and initiate appropriate therapeutic measures to manage any bleeding complications that may occur. The systemic exposure to rivaroxaban does not increase with single doses exceeding 50 mg, as absorption is limited beyond this threshold.

In cases of overdose, the administration of activated charcoal may be considered to reduce further absorption of rivaroxaban. However, due to the high plasma protein binding characteristics of rivaroxaban, it is important to note that the drug is not dialyzable, which limits the effectiveness of dialysis as a treatment option.

For managing anticoagulation effects, partial reversal of laboratory parameters may be achieved through the use of plasma products. Additionally, an agent specifically designed to reverse the anti-factor Xa activity of rivaroxaban is available, providing a targeted approach to counteract the effects of overdose.

Healthcare professionals are advised to monitor patients closely and implement these management strategies as necessary 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 did not exhibit carcinogenic properties in either species. At the highest tested dose of 60 mg/kg/day, systemic exposures (AUCs) of unbound rivaroxaban were found to be 1- and 2-times higher in male and female mice, respectively, compared to the human exposure at a dose of 20 mg/day. In male and female rats, systemic exposures at the same dose were 2- and 4-times higher, respectively, than the human exposure.

In terms of mutagenicity, rivaroxaban demonstrated no mutagenic effects 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 activity.

Assessment of reproductive toxicity revealed no impairment of fertility in male or female rats administered rivaroxaban at doses up to 200 mg/kg/day. 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 of rivaroxaban.

Postmarketing Experience

No specific postmarketing experience details are available. As such, there are no additional adverse events or rare case reports to summarize at this time.

Patient Counseling

Healthcare providers should advise patients and/or caregivers to read the FDA-approved patient labeling, specifically the Medication Guide, to ensure they understand the medication's use and safety information. Patients should be instructed to take rivaroxaban tablets only as directed and to avoid discontinuing 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 must be informed to report any unusual bleeding or bruising to their physician, as rivaroxaban may cause prolonged bleeding times and increased susceptibility to bruising.

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

Healthcare providers should instruct patients to inform their healthcare professional that they are taking rivaroxaban tablets prior to any scheduled invasive procedures, including dental work. Additionally, patients should be encouraged to disclose any prescription or over-the-counter medications, as well as herbal supplements, to their physicians and dentists to evaluate potential drug interactions.

Patients should also 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.

Storage and Handling

The product is supplied in various package configurations, with specific NDC numbers available for identification. It should be stored at room temperature, ideally between 20°C to 25°C (68°F to 77°F). Temporary excursions are permissible within the range of 15°C to 30°C (59°F to 86°F), in accordance with USP Controlled Room Temperature guidelines.

Additionally, it is essential to keep the product out of the reach of children to ensure safety.

Additional Clinical Information

Monitoring for the anticoagulation effect of rivaroxaban using clotting tests such as PT, INR, or aPTT, or by assessing anti-factor Xa (FXa) activity is not recommended. Clinicians should counsel patients to promptly report any signs or symptoms indicative of neurological impairment, which may include midline back pain, sensory and motor deficits (such as numbness, tingling, or weakness in the lower limbs), and bowel and/or bladder dysfunction.

FDA Insert (PDF)

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

View full prescribing information (PDF)