Rivaroxaban

Description

Rivaroxaban is a factor Xa (FXa) inhibitor and the active ingredient in Rivaroxaban Tablets, USP. Its chemical name 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 of rivaroxaban is C19H18ClN3O5S, with a molecular weight of 435.88. Rivaroxaban is a pure (S)-enantiomer, presented as an odorless, non-hygroscopic, white to off-white powder.

Rivaroxaban is freely soluble in dimethyl sulphoxide and dimethyl formamide, slightly soluble in dichloromethane, and very slightly soluble in acetone and methanol. It is practically insoluble in water, anhydrous ethanol, and heptane. Each Rivaroxaban Tablet, USP contains 2.5 mg of rivaroxaban.

The inactive ingredients in Rivaroxaban Tablets, USP include anhydrous lactose NF, croscarmellose sodium NF, hypromellose USP, magnesium stearate NF, and sodium lauryl sulfate NF. The film coating mixture for the 2.5 mg tablets is Opadry II Beige, which contains polyethylene glycol, polyvinyl alcohol, red iron oxide, talc, titanium dioxide, and yellow iron oxide.

Uses and Indications

Rivaroxaban is indicated to reduce the risk of major cardiovascular events in patients with coronary artery disease (CAD). Additionally, it is 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.

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 medication may be taken with or without food. It is advised to use this medication in conjunction with aspirin, at a dosage of 75 mg to 100 mg, taken once daily.

Healthcare professionals should ensure that patients are informed about the appropriate timing of doses, emphasizing the importance of adherence to the prescribed regimen for optimal therapeutic outcomes.

Contraindications

Use of Rivaroxaban Tablets is contraindicated in patients with active pathological bleeding due to the risk of exacerbating hemorrhagic conditions. Additionally, a severe hypersensitivity reaction to Rivaroxaban Tablets constitutes a contraindication, as it may lead to serious adverse effects.

Warnings and Precautions

Rivaroxaban Tablets carry significant risks that healthcare professionals must consider when prescribing and managing treatment.

Risk of Bleeding Rivaroxaban Tablets 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 in case of emergencies.

Pregnancy-Related Considerations Caution is advised when prescribing Rivaroxaban Tablets to pregnant women due to the risk of obstetric hemorrhage and the potential need for emergent delivery.

Prosthetic Heart Valves and Antiphospholipid Syndrome The use of Rivaroxaban Tablets is not recommended for patients with prosthetic heart valves or those diagnosed with triple positive antiphospholipid syndrome due to an increased risk of thrombosis.

Premature Discontinuation Risks Premature discontinuation of Rivaroxaban Tablets significantly heightens the risk of thrombotic events. Additionally, there is a warning regarding the potential for spinal or epidural hematoma, particularly in patients receiving neuraxial anesthesia or undergoing spinal puncture. Such hematomas can lead to long-term or permanent paralysis.

Monitoring and Neurological Impairment Healthcare professionals should monitor patients frequently for signs and symptoms of neurological impairment. If any symptoms are observed, urgent treatment is warranted. It is crucial to weigh the benefits and risks before proceeding with neuraxial interventions in patients who are currently anticoagulated or may require anticoagulation.

No specific laboratory tests are required for the safe use of Rivaroxaban Tablets; however, ongoing assessment of the patient's clinical status is essential to ensure safety and efficacy during treatment.

Side Effects

The most common adverse reaction observed in adult patients treated with Rivaroxaban Tablets was bleeding, occurring in more than 5% of this population. In pediatric patients, the most frequently reported adverse reactions, occurring in over 10% of subjects, included bleeding, cough, vomiting, and gastroenteritis.

Serious adverse reactions associated with Rivaroxaban Tablets include a significant risk of bleeding, which can be serious and potentially fatal. An agent to reverse the anticoagulant effects of rivaroxaban is available for managing such events. Additionally, caution is advised when administering Rivaroxaban Tablets to pregnant women due to the risk of pregnancy-related hemorrhage and the potential for complications during emergent delivery. The use of Rivaroxaban Tablets is not recommended in patients with prosthetic heart valves or those with triple positive antiphospholipid syndrome due to an increased risk of thrombosis.

Warnings associated with Rivaroxaban Tablets include the risk of premature discontinuation, which increases the likelihood of thrombotic events. 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.

Additional adverse reactions may include active pathological bleeding and severe hypersensitivity reactions to Rivaroxaban Tablets. In cases of overdose, there is a risk of hemorrhage; therefore, Rivaroxaban Tablets should be discontinued, and appropriate therapeutic measures should be initiated 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 exercise caution and consider alternative therapies or closely monitor patients if these interactions 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 available safety, efficacy, pharmacokinetic, or pharmacodynamic data to support the use of Rivaroxaban in pediatric patients. Consequently, Rivaroxaban 2.5 mg tablets are not recommended for use in this population.

Geriatric Use

Elderly patients, defined as those aged 65 years and older, comprised 64 percent of the total adult population (N=64,943 patients) in clinical trials evaluating the approved indications of Rivaroxaban Tablets. Among these, 27 percent were aged 75 years and older.

The efficacy of Rivaroxaban Tablets in geriatric patients 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.

Given these findings, healthcare providers should exercise caution when prescribing Rivaroxaban to geriatric patients. Close monitoring for potential adverse events, particularly bleeding complications, is recommended. Additionally, consideration of dose adjustments may be warranted based on the individual patient's clinical status and risk factors.

Pregnancy

The available data on Rivaroxaban Tablets in pregnant women are limited and insufficient to establish a definitive drug-associated risk of adverse developmental outcomes. Caution is advised when prescribing Rivaroxaban Tablets 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. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is approximately 2% to 4% and 15% to 20%, respectively. Pregnancy itself is a recognized risk factor for venous thromboembolism, with an 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. Therefore, the risk of bleeding must be carefully balanced against the risk of thrombotic events when considering the use of Rivaroxaban Tablets in this population.

Currently, there are no adequate or well-controlled studies of Rivaroxaban Tablets 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, similar effects were observed at doses corresponding to about 14 times the human exposure, with severe outcomes, including maternal and fetal death, occurring at doses approximately six times the maximum human exposure.

Lactation

There are no adequate or well-controlled studies of Rivaroxaban Tablets in nursing mothers. It is not known whether Rivaroxaban is excreted in human milk. Caution should be exercised when Rivaroxaban is administered to a nursing woman.

Renal Impairment

Patients with renal impairment should be monitored closely when using Rivaroxaban Tablets, as the medication can cause serious and potentially fatal bleeding. Dosing adjustments may be necessary based on the degree of renal function impairment. It is important to note that Rivaroxaban Tablets are not recommended for use in patients with prosthetic heart valves or those at increased risk of thrombosis, such as individuals with triple positive antiphospholipid syndrome. Additionally, caution is advised when prescribing Rivaroxaban Tablets to pregnant women due to the risk of obstetric hemorrhage and/or the potential need for emergent delivery. An agent to reverse the activity of rivaroxaban is available, which may be considered in cases of severe bleeding.

Hepatic Impairment

Rivaroxaban Tablets are contraindicated in patients with active bleeding and in those with severe hepatic impairment, classified as Child-Pugh Class C. Given that Rivaroxaban is primarily eliminated through hepatic metabolism, caution is warranted when administering this medication to patients with any degree of hepatic impairment.

For patients with moderate hepatic impairment, classified as Child-Pugh Class B, a reduced dose of Rivaroxaban may be necessary to mitigate the risk of adverse effects. Additionally, liver function tests should be closely monitored in patients with hepatic impairment throughout the duration of treatment with Rivaroxaban.

It is important to note that Rivaroxaban should not be used in patients with hepatic disease that is associated with coagulopathy, as this condition significantly increases the risk of bleeding complications.

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 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 cases 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 characteristics, it is not amenable to dialysis as a means of removal from the system. However, partial reversal of anticoagulation effects may be achieved through the use of plasma products, which can help manage the anticoagulation parameters in affected patients.

For situations requiring more immediate reversal of the anticoagulant effects, an agent specifically designed to reverse the anti-factor Xa activity of Rivaroxaban is available and should be utilized as part of the management strategy.

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 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, greater 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 higher than those observed in humans receiving a daily dose of 20 mg rivaroxaban.

Postmarketing Experience

No specific postmarketing experience details have been reported. 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. 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 tablets and mix them with a small amount of water before administration via the tube.

In the event of a missed dose, healthcare providers should guide patients to follow the instructions outlined in the Full Prescribing Information based on their specific dosing schedule. Patients should be advised to report any unusual bleeding or bruising to their physician, as Rivaroxaban Tablets may increase the time it takes to stop bleeding and may cause patients to bruise and bleed more easily.

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 instructed to contact their physician immediately.

Patients should also be advised to inform their healthcare professional that they are taking Rivaroxaban Tablets prior to any scheduled invasive procedures, including dental work. It is important for patients to disclose any prescription or over-the-counter medications, as well as herbal supplements, to their physicians and dentists to evaluate potential interactions.

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

Finally, healthcare providers should ensure that patients receive the Medication Guide, which can be accessed at: https://sciegenpharm.com/medication-guide/.

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).

It is essential to keep the product out of the reach of children to ensure safety. Proper handling and storage conditions must be adhered to in order to maintain the integrity of the product.

Additional Clinical Information

Patients and caregivers should be advised to read the FDA-approved patient labeling (Medication Guide) for Rivaroxaban Tablets. It is essential for patients to take the medication only as directed and to consult their healthcare professional before discontinuing use. For those who have difficulty swallowing the tablets, they may crush Rivaroxaban Tablets and mix them with a small amount of applesauce, followed by food. Patients requiring an NG tube or gastric feeding tube should crush the tablets and mix them with water prior to administration. In the event of a missed dose, patients should follow the instructions provided in the Full Prescribing Information based on their specific dosing schedule.

Patients should be informed of the increased risk of bleeding while on Rivaroxaban, including the need to report any unusual bleeding or bruising to their physician. They should be particularly vigilant for signs of spinal or epidural hematoma if they have undergone neuraxial anesthesia or spinal puncture, especially if taking NSAIDs or platelet inhibitors. Prior to any invasive procedures, including dental work, patients must inform their healthcare professional about their use of Rivaroxaban. Additionally, patients should disclose any prescription or over-the-counter medications or herbal supplements they are taking to evaluate potential interactions. Pregnant patients or those planning to become pregnant should notify their physician immediately and report any bleeding or symptoms of blood loss. Nursing mothers should discuss the risks and benefits of Rivaroxaban with their physician. Lastly, patients of reproductive potential should engage in discussions about pregnancy planning with their healthcare provider. The Medication Guide can be accessed at: https://sciegenpharm.com/medication-guide/.

FDA Insert (PDF)

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

View full prescribing information (PDF)