Rivaroxaban

Description

Rivaroxaban, USP, 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. The molecular formula of rivaroxaban, USP is C19H18ClN3O5S, and it has a molecular weight of 435.89. Rivaroxaban, USP 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 croscarmellose sodium, hydroxypropyl cellulose, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. The film coating mixture for rivaroxaban 2.5 mg tablets, USP consists of ferric oxide yellow, ferrosoferric oxide, hypromellose, lactose monohydrate, polyethylene glycol 3350, and titanium dioxide.

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 that this medication be used in conjunction with aspirin, at a dosage of 75 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 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 is 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.

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.

It is critical to note that premature discontinuation of rivaroxaban tablets heightens the risk of thrombotic events. This warning extends to all oral anticoagulants; therefore, if rivaroxaban is discontinued for reasons other than pathological bleeding or the completion of a treatment course, healthcare providers should consider bridging therapy with another anticoagulant to mitigate this risk.

Patients receiving rivaroxaban who are undergoing neuraxial anesthesia or spinal puncture are at risk for epidural or spinal hematomas, which can lead to long-term or permanent paralysis. Continuous monitoring for signs and symptoms of neurological impairment is essential, and any such symptoms should be treated urgently. Prior to any neuraxial intervention, a careful assessment of the benefits and risks in patients who are or need to be anticoagulated is warranted.

Side Effects

The most common adverse reaction observed in adult patients treated with rivaroxaban is bleeding, occurring in more than 5% of participants. Clinical trial data, particularly from the COMPASS trial, indicate that bleeding complications were the primary reason for permanent drug discontinuation, with incidence rates of 2.7% for rivaroxaban 2.5 mg twice daily compared to 1.2% for placebo.

Serious warnings associated with rivaroxaban include the risk of thrombotic events following premature discontinuation of the medication. It is crucial to consider bridging therapy with another anticoagulant if rivaroxaban is stopped for reasons other than pathological bleeding or the completion of a treatment course. Additionally, there is a significant risk of epidural or spinal hematomas in patients receiving neuraxial anesthesia or undergoing spinal puncture, which may lead to long-term or permanent paralysis. Patients should be monitored closely for neurological impairment, and any signs should be treated urgently.

Postmarketing experience has revealed additional adverse reactions across various systems. Blood and lymphatic system disorders may include agranulocytosis and thrombocytopenia. Hepatobiliary disorders reported include jaundice, cholestasis, and hepatitis, including hepatocellular injury. Immune system disorders may manifest as hypersensitivity reactions, anaphylactic reactions, anaphylactic shock, and angioedema. Nervous system disorders have included hemiparesis, while renal disorders may present as anticoagulant-related nephropathy. Respiratory complications such as eosinophilic pneumonia have also been noted. Skin and subcutaneous tissue disorders can include Stevens-Johnson syndrome and drug reaction with eosinophilia and systemic symptoms (DRESS). Furthermore, there have been reports of atraumatic splenic rupture.

Rivaroxaban carries a risk of serious and potentially fatal bleeding, and an agent to reverse its anticoagulant activity is available. Caution is advised when prescribing rivaroxaban to pregnant women due to the potential for obstetric hemorrhage and/or the need for emergent delivery. Other contraindications include active pathological bleeding and severe hypersensitivity reactions to rivaroxaban.

Drug Interactions

Concomitant use of strong P-glycoprotein (P-gp) inhibitors and inducers with this medication is not recommended due to potential alterations in drug metabolism and transport, which may lead to increased toxicity or reduced efficacy.

In the case of anticoagulants, the concurrent administration of this medication is contraindicated. The combination may result in significant interactions that could compromise the safety and effectiveness of anticoagulant therapy. Monitoring of anticoagulant levels and clinical effects is advised if such combinations are considered, although avoidance is the preferred strategy.

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 not all adverse reactions observed in adults have been reported in clinical trials involving children and adolescents, the same warnings and precautions applicable to adults should be considered when treating pediatric patients.

Geriatric Use

In clinical trials involving rivaroxaban, a significant proportion of adult patients were elderly, 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.

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 this population. Close monitoring for adverse events is recommended, and consideration should be given to potential dose adjustments based on individual patient factors and overall health status.

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 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 approximately 2 to 4% and 15 to 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.

Given the pharmacologic activity of Factor Xa inhibitors and the potential for placental transfer, there is a risk of bleeding 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 carefully balanced against the risk of thrombotic events when considering the use of rivaroxaban 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 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.

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 was measured in milk samples collected up to 32 hours post-dose. The estimated amount of radioactivity excreted in milk within 32 hours after administration was 2.1% of the maternal dose.

The developmental and health benefits of breastfeeding should be considered alongside the mother's clinical need for rivaroxaban and any potential adverse effects on the breastfed infant from rivaroxaban or from the underlying maternal condition.

Renal Impairment

In pharmacokinetic studies, rivaroxaban exposure increased by approximately 44 to 64% in adult subjects with renal impairment compared to healthy adult subjects with normal creatinine clearance. Increases in pharmacodynamic effects were also observed.

Patients with a creatinine clearance (CrCl) of less than 15 mL/min at screening were excluded from the COMPASS and VOYAGER studies, and limited data are available for patients with a CrCl of 15 to 30 mL/min. For patients with CrCl less than 30 mL/min, a dose of 2.5 mg rivaroxaban twice daily is expected to provide an exposure similar to that in patients with moderate renal impairment (CrCl 30 to <50 mL/min), whose efficacy and safety outcomes were comparable to those with preserved renal function.

No clinical outcome data are available for the use of rivaroxaban with aspirin in patients with end-stage renal disease (ESRD) on dialysis, as these patients were not enrolled in the COMPASS or VOYAGER studies. In patients with ESRD maintained on intermittent hemodialysis, administration of rivaroxaban 2.5 mg twice daily will result in concentrations and pharmacodynamic activity similar to those observed in patients with moderate renal impairment in the COMPASS study. However, it is not known whether these concentrations will lead to similar cardiovascular risk reduction and bleeding risk in patients with ESRD on dialysis as was seen in the COMPASS study.

Hepatic Impairment

Patients with hepatic impairment may experience significant alterations in the pharmacokinetics of rivaroxaban. In a pharmacokinetic study, adult subjects with moderate hepatic impairment (Child-Pugh B) exhibited an increase in the area under the curve (AUC) of 127% compared to healthy adult subjects with normal liver function. Due to these findings, the use of rivaroxaban is contraindicated in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment, as well as in those with any hepatic disease associated with coagulopathy.

Furthermore, the safety and pharmacokinetics of rivaroxaban have not been evaluated in patients with severe hepatic impairment (Child-Pugh C). It is important to note that there are no clinical data available regarding the use of rivaroxaban in pediatric patients with hepatic impairment. Therefore, careful consideration and alternative treatment options should be explored for patients with compromised liver function.

Overdosage

In the event of a rivaroxaban overdose, healthcare professionals should be vigilant for potential complications, particularly hemorrhage. If bleeding complications arise, it is imperative to discontinue rivaroxaban and initiate appropriate therapeutic measures.

Rivaroxaban exhibits a unique pharmacokinetic profile, wherein 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 toxicity.

In cases of overdose, the administration of activated charcoal may be considered to reduce further absorption of rivaroxaban, provided that it is within an appropriate time frame post-ingestion. 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.

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 are advised to monitor patients closely and implement these management strategies as necessary to mitigate the risks associated with 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. 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 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

During post-approval use of rivaroxaban, the following adverse reactions have been identified. These reactions were reported voluntarily from a population of uncertain size, making it challenging to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and lymphatic system disorders include agranulocytosis and thrombocytopenia.

Hepatobiliary disorders reported are jaundice, cholestasis, and hepatitis, which encompasses hepatocellular injury.

Immune system disorders consist of hypersensitivity, anaphylactic reaction, anaphylactic shock, and angioedema.

Nervous system disorders include hemiparesis.

Renal disorders reported include anticoagulant-related nephropathy.

Respiratory, thoracic, and mediastinal disorders feature eosinophilic pneumonia.

Skin and subcutaneous tissue disorders include Stevens-Johnson syndrome and drug reaction with eosinophilia and systemic symptoms (DRESS).

Injury, poisoning, and procedural complications include atraumatic splenic rupture.

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. Patients should be instructed to take rivaroxaban tablets only as directed and to avoid discontinuing 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 must be informed to report any unusual bleeding or bruising to their physician, as rivaroxaban may cause prolonged bleeding and increased susceptibility to bruising.

Healthcare providers should educate patients to be vigilant for signs and symptoms of spinal or epidural hematoma, including back pain, tingling, numbness (especially in the lower limbs), muscle weakness, and stool or urine incontinence. This is particularly important for those who have undergone neuraxial anesthesia or spinal puncture and are taking concomitant NSAIDs or platelet inhibitors.

Patients should be instructed to inform their healthcare professional about their use of rivaroxaban prior to any invasive procedures, including dental work. Additionally, they should 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 should be advised to inform their physician immediately. Pregnant patients receiving rivaroxaban must report any bleeding or symptoms of blood loss to their healthcare provider. Furthermore, patients who are nursing or intend to nurse should discuss the benefits and risks of rivaroxaban treatment with their physician.

Lastly, healthcare providers should encourage patients who can become pregnant to engage in discussions about pregnancy planning with their physician to ensure safe management during anticoagulant therapy.

Storage and Handling

The product is supplied in accordance with the following specifications: it should be stored at a temperature range of 20° to 25°C (68° to 77°F), in compliance with USP Controlled Room Temperature guidelines. It is essential to keep the product out of the reach of children to ensure safety.

Additional Clinical Information

Postmarketing experience has identified several adverse events associated with the use of the medication. Clinicians should be aware of potential blood and lymphatic system disorders, including agranulocytosis and thrombocytopenia. Hepatobiliary disorders such as jaundice, cholestasis, and hepatitis (including hepatocellular injury) have also been reported.

Additionally, immune system disorders may manifest as hypersensitivity reactions, including anaphylactic reactions, anaphylactic shock, and angioedema. Neurological effects such as hemiparesis, renal complications like anticoagulant-related nephropathy, and respiratory issues including eosinophilic pneumonia have been noted. Skin reactions can include Stevens-Johnson syndrome and drug reaction with eosinophilia and systemic symptoms (DRESS). Lastly, there have been reports of atraumatic splenic rupture as an injury-related complication.

FDA Insert (PDF)

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

View full prescribing information (PDF)