Rivaroxaban

Description

Rivaroxaban, USP is a factor Xa (FXa) inhibitor, with the chemical name 5-Chloro-N-({(5S)-2-oxo-3-4-(3-oxomorpholin-4-yl)phenyl-1,3-oxzolidin-5-yl}methyl)thiophene-2-carboxamide. The molecular formula of rivaroxaban is C19H18ClN3O5S, and it has a molecular weight of 435.88. Rivaroxaban is a pure (S)-enantiomer, presented as an odorless, non-hygroscopic, white to yellowish powder. It is only slightly soluble in organic solvents, such as acetone and polyethylene glycol 400, and is practically insoluble in water and aqueous media. Each rivaroxaban tablet, USP contains 2.5 mg of rivaroxaban, USP. The inactive ingredients in rivaroxaban tablets, USP include 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 is Aquarius Prime Yellow, which contains hypromellose, D&C yellow no.10 aluminum lake, polyethylene glycol, and titanium dioxide.

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 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 Healthcare professionals should be aware that premature discontinuation of rivaroxaban increases the risk of thrombotic events. Patients should be counseled on 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 anticoagulated should be made after careful consideration of the potential benefits and risks.

General Monitoring 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 adverse effects.

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 warnings associated with rivaroxaban include the risk of thrombotic events following premature discontinuation of the medication. It is critical to consider transitioning to another anticoagulant if rivaroxaban is discontinued for reasons other than pathological bleeding or the completion of a prescribed therapy course.

Additionally, there is a significant risk of spinal or epidural hematomas in patients receiving neuraxial anesthesia or undergoing spinal puncture while on rivaroxaban. These hematomas can lead to long-term or permanent paralysis, necessitating close monitoring for neurological impairment. Urgent treatment should be initiated if any signs of neurological issues are observed. 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 lead to serious and potentially fatal bleeding events. An agent is available to reverse the anticoagulant effects of rivaroxaban. Caution is advised when prescribing rivaroxaban to pregnant women due to the risk of obstetric hemorrhage and the potential 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. Other contraindications include active pathological bleeding and severe hypersensitivity reactions to rivaroxaban.

Drug Interactions

Concomitant use of strong CYP3A inhibitors and inducers with this medication should be avoided due to potential alterations in drug metabolism and efficacy. The interaction may lead to either increased toxicity or reduced therapeutic effects, necessitating careful consideration of alternative therapies.

In addition, the use of anticoagulants alongside this medication is contraindicated. The combination may heighten the risk of bleeding complications, and therefore, it is advised to avoid their concurrent administration. Monitoring for signs of bleeding and adjusting anticoagulant therapy may be necessary if such a combination cannot be avoided.

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 patients, with 64 percent being 65 years of age or older and 27 percent being 75 years of age or older. The efficacy of rivaroxaban in this geriatric population was found to be comparable to that observed in patients younger than 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 geriatric patients, considering the increased risk of adverse events. Close monitoring of these patients is recommended to ensure safety and efficacy, and dosage adjustments may be necessary based on individual patient factors.

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 regardless of maternal health or medication use. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies 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 number of live fetuses, and decreased 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.

In summary, the use of rivaroxaban in pregnant patients requires careful consideration of the potential risks and benefits, with an emphasis on monitoring and managing the associated risks of bleeding and thromboembolic events.

Lactation

Rivaroxaban is not adequately studied in lactating mothers, and there are no well-controlled studies to establish its safety during breastfeeding. The limited data available do not provide sufficient information to assess the risk of adverse effects in breastfed infants.

Given the pharmacologic activity of rivaroxaban as a Factor Xa inhibitor, it is important to consider the potential for the drug to cross into breast milk. While specific data on excretion in human breast milk are lacking, caution is advised when prescribing rivaroxaban to lactating mothers due to the potential risks to the nursing infant.

Healthcare professionals should weigh the benefits of rivaroxaban for the mother against any possible risks to the breastfed infant when making treatment decisions. Monitoring for any adverse effects in the infant may be warranted if rivaroxaban is used during lactation.

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, healthcare professionals should be vigilant for potential complications, particularly hemorrhage. If bleeding complications arise, it is imperative to discontinue rivaroxaban immediately and initiate appropriate therapeutic measures.

Rivaroxaban exhibits a unique pharmacokinetic profile, where systemic exposure does not increase with single doses exceeding 50 mg due to its limited absorption characteristics. Therefore, doses above this threshold may not result in heightened systemic effects.

In cases of rivaroxaban overdose, the administration of activated charcoal may be considered to reduce further absorption of the drug. However, due to rivaroxaban's high plasma protein binding, it is important to note that the drug is not amenable to dialysis.

For managing anticoagulation parameters, partial reversal may 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 can be utilized in the management of overdose situations.

Healthcare professionals should remain informed about these management strategies to ensure optimal patient care in the event of 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 rats, the systemic exposures of unbound drug at the same highest dose were 2- and 4-times higher in male and female subjects, 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 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

Postmarketing experience with rivaroxaban tablets has identified several serious side effects associated with their use. Reports indicate an increased risk of blood clots upon discontinuation of the medication. Additionally, there is a noted risk of bleeding, which can be severe and potentially fatal.

Cases of spinal or epidural hematoma have been reported in patients receiving anticoagulant therapy, particularly in those undergoing spinal procedures such as injections or punctures. This condition may lead to long-term or permanent paralysis.

Healthcare professionals are advised to monitor patients closely for signs and symptoms of bleeding, which may include frequent nosebleeds, unusual gum bleeding, heavier than normal menstrual bleeding, severe or uncontrollable bleeding, hematuria (red, pink, or brown urine), melena (bright red or black stools), hemoptysis (coughing up blood), hematemesis (vomiting blood or "coffee grounds"), as well as neurological symptoms such as headaches, dizziness, weakness, and localized pain or swelling at wound sites.

The risk of developing spinal or epidural blood clots is heightened in patients with certain risk factors, including the placement of an epidural catheter, concurrent use of non-steroidal anti-inflammatory drugs (NSAIDs) or other anticoagulants, a history of difficult or repeated spinal procedures, and previous spinal issues or surgeries. It is recommended that patients receiving spinal anesthesia or undergoing spinal puncture while on rivaroxaban be closely monitored for any symptoms indicative of spinal or epidural blood clots.

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 tablets and mixing them 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 advise 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 instructed to contact their physician immediately.

Patients should also be informed to notify their healthcare professional that they are taking rivaroxaban tablets before scheduling any invasive procedures, including dental work. Additionally, they should inform their physicians and dentists of any prescription or over-the-counter medications or herbal products they are taking or plan to take, allowing healthcare professionals to evaluate potential interactions.

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

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 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 or bladder dysfunction.

FDA Insert (PDF)

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

View full prescribing information (PDF)