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 can 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 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 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 contraindicates their use, 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 Healthcare professionals should be aware that premature discontinuation of Rivaroxaban Tablets significantly increases the risk of thrombotic events. If discontinuation is necessary for reasons other than pathological bleeding or completion of therapy, it is advisable to consider bridging therapy with another anticoagulant to mitigate this risk.

Epidural and Spinal Hematoma Risk Patients receiving Rivaroxaban Tablets who undergo neuraxial anesthesia or spinal puncture are at risk for epidural or spinal hematomas, which may lead to long-term or permanent paralysis. It is crucial to monitor these patients closely for any signs or symptoms of neurological impairment. If such symptoms are observed, urgent treatment is required. The benefits and risks of neuraxial interventions should be carefully evaluated in patients who are or will be anticoagulated.

In summary, the management of patients on Rivaroxaban Tablets requires vigilant monitoring and a thorough understanding of the associated risks to ensure patient safety.

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. Additionally, there is a warning regarding the use of Rivaroxaban in pregnant women, as it may lead to pregnancy-related hemorrhage and complications during emergent delivery. Patients with active pathological bleeding or those experiencing a severe hypersensitivity reaction to Rivaroxaban should also be closely monitored.

It is critical to note that premature discontinuation of Rivaroxaban Tablets increases the risk of thrombotic events. Furthermore, patients receiving neuraxial anesthesia or undergoing spinal puncture are at risk for epidural or spinal hematomas, which may result in long-term or permanent paralysis.

In cases of bleeding complications associated with overdosage, it is advised to discontinue Rivaroxaban Tablets and initiate appropriate therapy, as overdose may lead to hemorrhage.

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.

Additionally, the use of anticoagulants alongside this medication is contraindicated. The combination may increase the risk of bleeding complications, necessitating careful consideration and monitoring of alternative therapeutic options.

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

In clinical trials involving Rivaroxaban Tablets, a significant proportion of the adult patient population (N=64,943) included elderly patients, 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 the elderly population. Therefore, healthcare providers should exercise caution when prescribing Rivaroxaban to geriatric patients, considering the increased risk of adverse events. Monitoring for signs of bleeding and thrombotic complications is recommended, and dose adjustments may be necessary based on individual patient factors and clinical judgment.

Pregnancy

The limited available data on Rivaroxaban Tablets in pregnant women are insufficient to inform a 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 the mother and potential risks to 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 2% to 4% and 15% to 20%, respectively. Pregnancy itself is a 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 Rivaroxaban to cross the placenta, 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 balanced against the risk of thrombotic events when considering the use of Rivaroxaban Tablets 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 corresponding to about four times the human exposure based on AUC comparisons. In rats, decreased fetal body weights were observed at doses corresponding to about fourteen 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

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 mother.

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 an agent to reverse the activity of rivaroxaban is available, which may be relevant in the event of bleeding complications.

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. Additionally, the use of Rivaroxaban Tablets is not recommended for patients with prosthetic heart valves or those with an increased risk of thrombosis associated with triple positive antiphospholipid syndrome. Regular assessment of renal function is essential to ensure safe and effective use of this medication in patients with reduced kidney function.

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 identification 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 the drug. However, due to Rivaroxaban's high plasma protein binding, 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, 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 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-times, respectively, the human exposure at a clinical dose of 20 mg/day. In male and female rats, systemic exposures at the same dose were 2- and 4-times, respectively, the human exposure.

In terms of mutagenicity, rivaroxaban did not demonstrate 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.

Regarding reproductive toxicity, no impairment of fertility was observed in male or female rats administered rivaroxaban at doses up to 200 mg/kg/day. This dose 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 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. 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 may increase the time it takes to stop bleeding and may cause them to bruise or 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. Patients experiencing any of these symptoms should be instructed to contact their physician immediately.

Patients should also be informed to notify their healthcare professional that they are taking Rivaroxaban Tablets prior to any invasive procedures, including dental work. It is important for patients to inform their physicians and dentists about any prescription or over-the-counter medications, as well as herbal supplements they are taking or plan to take, to allow for evaluation of 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.

For further information, healthcare providers should dispense the Medication Guide available at: https://sciegenpharm.com/medication-guide/.

Storage and Handling

The product is supplied in various package configurations, with specific NDC numbers available upon request. 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.

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. Special attention should be given to those who have undergone neuraxial anesthesia or spinal puncture, particularly if they are also taking NSAIDs or platelet inhibitors, as they may be at risk for spinal or epidural hematoma. Patients must inform their healthcare professional about their use of Rivaroxaban before any invasive procedures, including dental work. Additionally, they should disclose any prescription or over-the-counter medications or herbal supplements to evaluate potential interactions. Pregnant patients or those planning to become pregnant should notify their physician immediately, especially if experiencing any bleeding. Nursing mothers should discuss the risks and benefits of Rivaroxaban with their healthcare provider. Lastly, patients of reproductive potential are encouraged to discuss pregnancy planning with their physician. 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 Exelan pharmaceuticals, Inc. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)