Rivaroxaban

Description

Rivaroxaban is a factor Xa (FXa) inhibitor, with the active ingredient being 5-Chloro-N-({(5S)-2-oxo-3-4-(3-oxo-4-morpholinyl) phenyl-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide. 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. The inactive ingredients in rivaroxaban tablets include croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. The proprietary film coating mixture for rivaroxaban tablets, USP 2.5 mg consists of Opadry® Yellow, which contains hypromellose, iron oxide yellow, macrogol/PEG, and titanium dioxide.

Uses and Indications

Rivaroxaban is 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.

Limitations of Use: There are no teratogenic or nonteratogenic effects mentioned in the provided data.

Dosage and Administration

The recommended dosage for the management of coronary artery disease (CAD) or peripheral artery disease (PAD) 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 to 100 mg, which should be taken orally once daily.

Healthcare professionals should ensure that patients adhere to the prescribed dosing schedule, maintaining the twice-daily frequency for the primary medication and the once-daily frequency for aspirin.

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, 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 is available to reverse the anticoagulant effects of rivaroxaban in the event of a bleeding complication.

In pregnant women, the use of rivaroxaban requires caution due to the risk of obstetric hemorrhage and the potential need for emergent delivery. It is essential to weigh the benefits against the risks when considering rivaroxaban for this population.

The use of rivaroxaban is not recommended for patients with prosthetic heart valves or those diagnosed with triple positive antiphospholipid syndrome, as these conditions may increase the risk of thrombotic events.

Premature discontinuation of rivaroxaban tablets poses a warning, as it significantly increases the risk of thrombotic events. Therefore, healthcare providers should ensure that patients are adequately informed about the importance of adherence to their prescribed regimen.

Additionally, there is a critical warning regarding the 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. It is imperative to monitor patients closely for any signs and symptoms of neurological impairment. If any neurological deficits are observed, urgent treatment should be initiated. Prior to any neuraxial intervention, healthcare professionals must carefully consider the benefits and risks associated with anticoagulation therapy in their patients.

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 adverse reactions associated with rivaroxaban include the risk of serious and potentially fatal bleeding. It is important to note that premature discontinuation of rivaroxaban tablets significantly increases the risk of thrombotic events. Additionally, 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.

Pregnant women should use rivaroxaban with caution due to the potential for pregnancy-related hemorrhage and the risk of complications during emergent delivery. Other notable adverse reactions include active pathological bleeding and severe hypersensitivity reactions to rivaroxaban. In cases of overdose, patients may experience hemorrhage; therefore, it is crucial to discontinue rivaroxaban tablets and initiate appropriate therapy if bleeding complications arise. An agent to reverse the activity of rivaroxaban is available for managing such situations.

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 assess the need for dosage adjustments or enhanced monitoring protocols when managing patients on this medication who may require treatment with drugs from these classes.

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 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. Close monitoring for potential adverse events is recommended, and consideration should be given to dose adjustments based on individual patient factors, including renal function and the presence of concomitant medications that may increase the risk of bleeding.

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 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 known 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.

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 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, 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 recommended for use in lactating mothers due to insufficient data regarding its excretion in human breast milk and the potential effects on breastfed infants. 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 information to determine a rivaroxaban-associated risk for major birth defects or miscarriage. However, animal studies indicate that rivaroxaban crosses the placenta and has been associated with increased fetal toxicity, including increased resorptions, decreased number of live fetuses, and decreased fetal body weight when administered to pregnant rabbits at doses of ≥10 mg/kg during organogenesis. This dose corresponds to approximately four times the human exposure of unbound drug based on AUC comparisons at the highest recommended human dose of 20 mg/day.

In pregnant rats, doses of 120 mg/kg during organogenesis resulted in decreased fetal body weights, corresponding to about 14 times the human exposure of unbound drug. Additionally, peripartal maternal bleeding and maternal and fetal death were observed in rats at a dose of 40 mg/kg, which is about six times the maximum human exposure of unbound drug at the human dose of 20 mg/day. Given these findings, healthcare professionals should exercise caution when considering the use of rivaroxaban in lactating mothers.

Renal Impairment

Patients with renal impairment have not been specifically addressed in the available data regarding dosage adjustments, special monitoring, or safety considerations. Therefore, healthcare professionals should exercise caution when prescribing this medication to patients with reduced kidney function, as the lack of information necessitates careful clinical judgment and monitoring of these patients.

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 indicated 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 aware of the potential for serious complications, particularly hemorrhage. It is imperative to discontinue rivaroxaban immediately and initiate appropriate therapeutic measures if any bleeding complications arise.

Rivaroxaban exhibits a ceiling effect in systemic exposure; therefore, single doses exceeding 50 mg do not result in increased absorption. This characteristic should be taken into account when assessing the severity of an overdose.

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

In cases where laboratory anticoagulation parameters are significantly altered, 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 may be utilized in the management of overdose situations.

Healthcare professionals should remain vigilant and prepared to implement these management strategies in the event of rivaroxaban overdose to ensure patient safety and optimal outcomes.

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 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 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. There is an increased risk of blood clots associated with discontinuation of rivaroxaban therapy. Additionally, rivaroxaban may lead to serious bleeding events, which can be fatal. The risk of bleeding may be heightened when rivaroxaban is used concurrently with other medications that also increase bleeding risk, including aspirin and aspirin-containing products, long-term use of non-steroidal anti-inflammatory drugs (NSAIDs), warfarin sodium (Coumadin®, Jantoven®), heparin-containing medications, clopidogrel (Plavix®), selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), and other anticoagulants.

Patients are advised to seek immediate medical attention if they experience signs or symptoms of bleeding, such as unexpected or prolonged bleeding, severe bleeding that is difficult to control, red, pink, or brown urine, bright red or black stools, coughing up blood or blood clots, vomiting blood or material resembling "coffee grounds," headaches, dizziness, weakness, pain or swelling at wound sites, or abdominal pain that may indicate splenic rupture.

There have also been reports of spinal or epidural hematomas in patients receiving rivaroxaban who undergo spinal or epidural procedures. This risk is particularly elevated in individuals with an epidural catheter in place, those taking NSAIDs or other anticoagulants, and those with a history of difficult or repeated spinal procedures or spinal surgery. Patients receiving spinal anesthesia or undergoing spinal puncture while on rivaroxaban should be closely monitored for symptoms of spinal or epidural blood clots, including back pain, tingling, numbness, muscle weakness (especially in the legs and feet), and loss of bowel or bladder control (incontinence).

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 tablets 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, providers should instruct the patient or caregiver 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 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 to stop bleeding, and they may experience increased bruising and bleeding while on rivaroxaban.

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 advised to inform their healthcare professional that they are taking rivaroxaban tablets before scheduling any invasive procedures, including dental work. It is important for patients to disclose to their physicians and dentists any prescription or over-the-counter medications, as well as herbal supplements they are taking or plan to take, to allow for an evaluation of potential interactions.

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

Storage and Handling

The product is supplied in accordance with the following specifications. It should be stored at a temperature of 25°C (77°F) or at room temperature, with permissible excursions between 15°C to 30°C (59°F to 86°F) as defined by 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 and efficacy 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 Lupin Pharmaceuticals, Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)