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-oxo-4-morpholinyl)phenyl-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide, with a molecular formula of C19H18ClN3O5S and a molecular weight of 435.89. Rivaroxaban is a pure (S)-enantiomer, presented as an odorless, non-hygroscopic, white to yellowish powder.

The compound 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. The inactive ingredients include colloidal silicon dioxide, croscarmellose sodium, hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. The proprietary film coating mixture for Rivaroxaban Tablet, USP 2.5 mg is Instacoat® Yellow, which consists of hypromellose, polyethylene glycol, titanium dioxide, and yellow iron oxide. The USP dissolution test is currently pending.

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 the condition. 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 a significant risk of serious and potentially fatal bleeding. Healthcare professionals should be aware that an agent to reverse the activity 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 emergent delivery. The use of rivaroxaban is not recommended in patients with prosthetic heart valves or those with triple positive antiphospholipid syndrome, as these conditions may increase the risk of thrombosis.

Premature discontinuation of rivaroxaban tablets poses a heightened risk of thrombotic events. To mitigate this risk, it is advisable to consider bridging therapy with another anticoagulant if rivaroxaban is discontinued for reasons other than pathological bleeding or the completion of a prescribed treatment course.

Additionally, there is a risk of spinal or epidural hematoma in patients receiving neuraxial anesthesia or undergoing spinal puncture while on rivaroxaban. Such hematomas can lead to long-term or permanent paralysis. Therefore, it is crucial to monitor patients closely for any signs or symptoms of neurological impairment. If any neurological deficits are observed, urgent treatment is warranted. Healthcare providers should carefully weigh the benefits and risks before proceeding with neuraxial interventions in patients who are currently anticoagulated or require anticoagulation.

No specific laboratory tests are recommended for the safe use of rivaroxaban; however, ongoing clinical vigilance is essential 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 participants. In pediatric patients, the most frequently reported adverse reactions, occurring in over 10% of subjects, included bleeding, cough, vomiting, and gastroenteritis.

Serious warnings associated with rivaroxaban tablets include the risk of thrombotic events following premature discontinuation of the medication. Additionally, there is a significant risk of spinal or epidural hematoma in patients receiving neuraxial anesthesia or undergoing spinal puncture, which may lead to long-term or permanent paralysis.

Rivaroxaban tablets can cause serious and potentially fatal bleeding, necessitating the availability of a reversal agent for its anticoagulant effects. 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 notable adverse reactions include active pathological bleeding and severe hypersensitivity reactions to rivaroxaban tablets.

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 effect, 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 dosages may be required if such combinations are inadvertently used.

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

Rivaroxaban 2.5 mg tablets have not been studied in pediatric patients, and there are no available safety, efficacy, pharmacokinetic, or pharmacodynamic data to support their use in this population. Consequently, rivaroxaban 2.5 mg tablets are not recommended for pediatric patients.

While clinical trials in children and adolescents may not have identified all adverse reactions observed in adults, the same warnings and precautions applicable to adults should be considered when treating children and adolescents.

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 total 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 (aged 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. Close monitoring of these patients is recommended to ensure safety and efficacy, and dosage adjustments may be necessary based on individual patient factors and clinical judgment.

Pregnancy

The available data on rivaroxaban tablets 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. 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 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.

Given these considerations, healthcare professionals should exercise caution when prescribing rivaroxaban to pregnant patients and thoroughly evaluate the potential risks and benefits.

Lactation

Rivaroxaban has been detected in human milk; however, there are insufficient data to determine the effects of rivaroxaban on breastfed infants or on milk production. In animal studies, rivaroxaban and/or its metabolites were present in the milk of lactating rats. Following a single oral administration of 3 mg/kg of radioactive ^14C-rivaroxaban to lactating rats between Day 8 to 10 postpartum, the concentration of total radioactivity in milk samples was measured up to 32 hours post-dose, with an estimated 2.1% of the maternal dose excreted in milk within that timeframe.

When considering the use of rivaroxaban in lactating mothers, the developmental and health benefits of breastfeeding should be weighed against the mother's clinical need for rivaroxaban and any potential adverse effects on the breastfed infant from the medication or from the underlying maternal condition.

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 less than 50 mL/min, a reduced dose of rivaroxaban is recommended.

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 require more frequent monitoring of renal function tests. Additionally, adjustments in dosing may be necessary based on any changes in renal function during treatment.

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 cases of overdose with 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.

To mitigate the effects of an 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, making traditional renal clearance methods ineffective.

For managing anticoagulation parameters affected by rivaroxaban overdose, 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 are advised to monitor patients closely and implement these management strategies as necessary to ensure optimal outcomes in cases 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.

In terms of systemic exposure, the highest dose tested in male and female mice (60 mg/kg/day) resulted in unbound drug exposures that were 1- and 2-times, respectively, the human exposure at a clinical dose of 20 mg/day. Similarly, in male and female rats at the same highest dose, systemic exposures were found to be 2- and 4-times, respectively, the human exposure.

Rivaroxaban was also assessed for mutagenicity and clastogenicity. The compound did not exhibit mutagenic effects in bacterial assays (Ames test) and was not found to be clastogenic in V79 Chinese hamster lung cells in vitro, nor in the mouse micronucleus test in vivo.

Furthermore, studies on reproductive toxicity demonstrated no impairment of fertility in male or female rats administered rivaroxaban at doses up to 200 mg/kg/day. This dose 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

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

Patients and/or caregivers should be advised to read the FDA-approved patient labeling (Medication Guide) to understand the important information regarding their treatment. It is essential for patients to report any unusual bleeding or bruising to their physician, as rivaroxaban may cause them to bleed more easily and take longer than usual to stop bleeding.

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

Patients should be instructed to inform their healthcare professional that they are taking rivaroxaban tablets before scheduling any invasive procedures, including dental work. Additionally, patients must notify 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 the evaluation of potential interactions.

It is important for patients to inform their physician immediately if they become pregnant or intend to become pregnant during treatment with rivaroxaban. Pregnant women receiving rivaroxaban should be advised to 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 upon request. It should be stored at a temperature range of 20° to 25°C (68° to 77°F), with permissible excursions between 15° to 30°C (59° to 86°F) in accordance with USP Controlled Room Temperature guidelines.

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

No further data are available.

FDA Insert (PDF)

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

View full prescribing information (PDF)