Rivaroxaban

Description

Rivaroxaban USP is a factor Xa (FXa) inhibitor with the chemical name 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 435.89 g/mol. Rivaroxaban USP is a pure (S)-enantiomer, presented as an odorless, non-hygroscopic, white or off-white 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 is available in strengths of 2.5 mg, 10 mg, 15 mg, or 20 mg of rivaroxaban. The inactive ingredients include croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. The proprietary film coating mixture for rivaroxaban 2.5 mg tablets is Opadry White, which contains hypromellose, polyethylene glycol 4000, and titanium dioxide. The 10 mg tablets are coated with Opadry Pink. The 15 mg tablets utilize Opadry Red, which includes ferric oxide red, hypromellose, polyethylene glycol 3350, and titanium dioxide. The 20 mg tablets are coated with Opadry Light Yellow, containing ferric oxide yellow, hypromellose, polyethylene glycol 3350, and titanium dioxide.

Uses and Indications

Rivaroxaban is indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. It is also indicated for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE). Additionally, rivaroxaban is indicated for the reduction in the risk of recurrence of DVT or PE.

For patients undergoing knee or hip replacement surgery, rivaroxaban is indicated for the prophylaxis of DVT, which may lead to PE. It is further indicated for the prophylaxis of venous thromboembolism (VTE) in acutely ill medical patients.

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

In pediatric patients, rivaroxaban is indicated for the treatment of VTE and for the reduction in the risk of recurrent VTE in patients from birth to less than 18 years of age. It is also indicated for thromboprophylaxis in pediatric patients aged 2 years and older with congenital heart disease following the Fontan procedure.

Dosage and Administration

For the management of nonvalvular atrial fibrillation, the recommended dosage is 15 mg or 20 mg administered once daily with food.

In the treatment of deep vein thrombosis (DVT) and/or pulmonary embolism (PE), the initial dosage is 15 mg orally twice daily with food for the first 21 days. Following this period, the dosage should be adjusted to 20 mg orally once daily with food for the remainder of the treatment duration.

To reduce the risk of recurrence of DVT and/or PE in patients who remain at continued risk, a dosage of 10 mg once daily is recommended, which may be taken with or without food, and should be initiated after at least 6 months of standard anticoagulant treatment.

For the prophylaxis of DVT following hip or knee replacement surgery, a dosage of 10 mg orally once daily is advised, which can be taken with or without food.

In acutely ill medical patients at risk for thromboembolic complications but not at high risk of bleeding, the recommended prophylactic dosage is 10 mg once daily, with or without food, during hospitalization and after discharge, for a total duration of 31 to 39 days.

For patients with coronary artery disease (CAD) or peripheral artery disease (PAD), the recommended dosage is 2.5 mg orally twice daily with or without food, in conjunction with aspirin at a dosage of 75–100 mg once daily.

For pediatric patients, healthcare professionals should refer to the dosing recommendations provided in the Full Prescribing Information.

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 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 prescribed therapy course, healthcare providers should consider bridging therapy with another anticoagulant to mitigate this risk.

Additionally, there is a risk of epidural or spinal hematomas in patients receiving rivaroxaban who are undergoing neuraxial anesthesia or spinal puncture. Such hematomas can lead to long-term or permanent paralysis. It is essential to monitor patients closely for any signs or symptoms of neurological impairment. If any neurological deficits are observed, urgent treatment is warranted. Prior to any neuraxial intervention, healthcare professionals should carefully weigh the benefits against the risks in patients who are currently anticoagulated or require anticoagulation.

Side Effects

In clinical trials and postmarketing experiences, various adverse reactions have been reported in patients treated with rivaroxaban.

Common adverse reactions observed in adult patients include bleeding, which occurs in more than 5% of this population. In pediatric patients, the incidence of bleeding is greater than 10%, along with other common reactions such as cough, vomiting, and gastroenteritis, each also exceeding 10%.

Serious warnings associated with rivaroxaban include the risk of premature discontinuation, which significantly increases the likelihood of thrombotic events. Additionally, there is a risk of spinal or epidural hematoma in patients receiving neuraxial anesthesia or undergoing spinal puncture. Such hematomas can lead to long-term or permanent paralysis; therefore, it is crucial to monitor patients closely for any signs of neurological impairment and to provide urgent treatment if symptoms arise.

Bleeding complications were the most frequently reported adverse reactions in clinical trials. In the ROCKET AF trial, the rate of major bleeding was 3.6% for rivaroxaban compared to 3.5% for warfarin, with specific events including intracranial hemorrhage (0.5% for rivaroxaban vs. 0.7% for warfarin) and gastrointestinal bleeding (2.0% for rivaroxaban vs. 1.2% for warfarin). Fatal bleeding events were reported at a rate of 0.2% for rivaroxaban and 0.5% for warfarin.

In the EINSTEIN DVT and PE studies, major bleeding events occurred in 1.0% of patients receiving rivaroxaban compared to 1.7% for enoxaparin/VKA, with fatal bleeding rates of less than 0.1% for rivaroxaban versus 0.2% for enoxaparin/VKA. The EINSTEIN CHOICE study reported major bleeding events at rates of 0.4% for rivaroxaban 10 mg and 0.3% for aspirin 100 mg. The RECORD trials indicated a major bleeding event rate of 0.3% for rivaroxaban 10 mg compared to 0.2% for enoxaparin. In the MAGELLAN study, major bleeding occurred in 0.7% of rivaroxaban patients versus 0.5% for enoxaparin, with fatal bleeding rates of less than 0.1% for both treatments. The COMPASS trial reported modified ISTH major bleeding rates of 1.6% for rivaroxaban compared to 0.9% for placebo.

Other non-hemorrhagic adverse reactions reported in at least 1% of rivaroxaban-treated patients include abdominal pain, which occurred in 2.7% of patients receiving rivaroxaban 20 mg compared to 1.5% for enoxaparin/VKA.

Drug Interactions

Concomitant use of strong P-glycoprotein (P-gp) inhibitors and inducers with this medication should be avoided due to potential alterations in drug metabolism and transport, which may lead to increased toxicity or reduced efficacy.

In the case of anticoagulants, the use of this medication alongside these agents is contraindicated. The combination may result in significant interactions that could compromise patient safety and therapeutic outcomes. 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

The safety and effectiveness of rivaroxaban have been established in pediatric patients from birth to less than 18 years for the treatment of venous thromboembolism (VTE) and the reduction in the risk of recurrent VTE. However, rivaroxaban tablets have not been studied in children less than 6 months of age who were born at less than 37 weeks of gestation, had less than 10 days of oral feeding, or weighed less than 2.6 kg; therefore, dosing cannot be reliably determined or recommended in this population.

For pediatric patients aged 2 years and older with congenital heart disease who have undergone the Fontan procedure, the safety and effectiveness of rivaroxaban have been established. Clinical studies support the use of rivaroxaban 10 mg, 15 mg, and 20 mg tablets in pediatric patients. Conversely, there are no safety, efficacy, pharmacokinetic, or pharmacodynamic data to support the use of rivaroxaban 2.5 mg tablets in pediatric patients; thus, these tablets are not recommended for this population.

While not all adverse reactions identified in the adult population have been observed in clinical trials involving children and adolescents, the same warnings and precautions applicable to adults should be considered for pediatric patients.

Geriatric Use

In clinical trials involving rivaroxaban, a significant proportion of participants were elderly, with 64 percent of the total 64,943 adult 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 of age.

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 potential adverse events is recommended, and consideration should be given to possible dose adjustments based on individual patient factors, including renal function and the presence of comorbidities.

Pregnancy

The limited available data on rivaroxaban 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 alongside potential risks to 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 2–4% and 15–20%, respectively, although the specific background risk for the indicated populations remains unknown. 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 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 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 approximately four times the human exposure based on AUC comparisons. In rats, significant fetal body weight reductions and peripartal maternal bleeding, along with maternal and fetal death, were observed at doses corresponding to approximately 14 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. In the ROCKET AF trial, patients with creatinine clearance (CrCl) of 30 to 50 mL/min were administered rivaroxaban tablets 15 mg once daily, resulting in serum concentrations and clinical outcomes similar to those in patients with better renal function receiving rivaroxaban tablets 20 mg once daily. Patients with CrCl <30 mL/min were not studied; however, administration of rivaroxaban tablets 15 mg once daily is expected to yield serum concentrations similar to those in patients with moderate renal impairment.

Clinical efficacy and safety studies did not enroll patients with end-stage renal disease (ESRD) on dialysis. In patients with ESRD maintained on intermittent hemodialysis, administration of rivaroxaban tablets 15 mg once daily is anticipated to result in concentrations and pharmacodynamic activity similar to those observed in the ROCKET AF study. It remains unknown whether these concentrations will lead to similar stroke reduction and bleeding risk in patients with ESRD on dialysis.

In the EINSTEIN trials, patients with CrCl values <30 mL/min at screening were excluded. Administration of rivaroxaban tablets in this population is expected to result in serum concentrations similar to those in patients with moderate renal impairment (CrCl 30 to <50 mL/min). Close monitoring for signs or symptoms of blood loss is advised in patients with CrCl 15 to <30 mL/min, and rivaroxaban tablets should be avoided in patients with CrCl <15 mL/min.

The combined analysis of the RECORD 1–3 clinical efficacy studies did not indicate an increased bleeding risk for patients with CrCl 30 to 50 mL/min, although a possible increase in total venous thromboemboli was reported. Patients with CrCl <30 mL/min were excluded from these trials, but administration of rivaroxaban tablets 10 mg once daily is expected to yield serum concentrations similar to those in patients with moderate renal impairment. Similar precautions regarding monitoring for blood loss apply to this group.

Patients with CrCl values <30 mL/min were also excluded from the MAGELLAN study. In this population, a dose of rivaroxaban tablets 10 mg once daily is expected to result in serum concentrations akin to those in patients with moderate renal impairment. Monitoring for blood loss is essential in patients with CrCl 15 to <30 mL/min, and rivaroxaban tablets should not be used in patients with CrCl <15 mL/min.

For patients with a CrCl <15 mL/min, limited data are available, and they were excluded from the COMPASS and VOYAGER studies. In patients with CrCl <30 mL/min, a dose of 2.5 mg rivaroxaban tablets twice daily is expected to provide exposure similar to that in patients with moderate renal impairment, 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 ESRD on dialysis, as these patients were not enrolled in COMPASS or VOYAGER. In patients with ESRD maintained on intermittent hemodialysis, administration of rivaroxaban tablets 2.5 mg twice daily is expected to yield concentrations and pharmacodynamic activity similar to those observed in moderate renal impairment patients in the COMPASS study, though it is uncertain whether these concentrations will result in similar cardiovascular risk reduction and bleeding risk.

No dosage adjustment is required in patients aged 1 year or older with mild renal impairment (eGFR 50 to ≤ 80 mL/min/1.73 m²). Due to limited clinical data, the use of rivaroxaban tablets is not recommended in pediatric patients aged 1 year or older with moderate or severe renal impairment (eGFR <50 mL/min/1.73 m²) or in those younger than 1 year with serum creatinine results above the 97.5th percentile.

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 tablets 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). 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 an overdose of rivaroxaban tablets, 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 to manage the situation effectively.

Rivaroxaban exhibits a unique pharmacokinetic profile, wherein systemic exposure does not increase with single doses exceeding 50 mg due to its limited absorption characteristics. This aspect 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, due to the high plasma protein binding of rivaroxaban, it is important to note that the drug is not dialyzable, which limits the effectiveness of dialysis as a treatment option.

In cases where laboratory anticoagulation parameters indicate significant anticoagulation, 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 encouraged 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 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-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 include eosinophilic pneumonia.

Skin and subcutaneous tissue disorders consist of 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 that premature discontinuation of any oral anticoagulant, including rivaroxaban, significantly increases the risk of thrombotic events. If rivaroxaban is discontinued for reasons other than pathological bleeding or the completion of a prescribed course of therapy, it is important to consider bridging therapy with another anticoagulant.

Patients should be informed about the risk of epidural or spinal hematomas, which have been reported in individuals receiving rivaroxaban who are undergoing neuraxial anesthesia or spinal puncture. These hematomas can lead to long-term or permanent paralysis, and healthcare providers should carefully evaluate these risks when planning spinal procedures.

It is essential to discuss factors that may elevate the risk of developing epidural or spinal hematomas, including the use of indwelling epidural catheters, concomitant administration of medications that affect hemostasis (such as non-steroidal anti-inflammatory drugs, platelet inhibitors, or other anticoagulants), a history of traumatic or repeated epidural or spinal punctures, and any history of spinal deformity or spinal surgery. The optimal timing for the administration of rivaroxaban in relation to neuraxial procedures remains uncertain.

Healthcare providers should monitor patients closely for any signs or symptoms of neurological impairment. If any neurological compromise is observed, urgent medical intervention is warranted. It is crucial to weigh the benefits and risks of neuraxial interventions in patients who are currently anticoagulated or are to be anticoagulated for thromboprophylaxis.

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), in accordance 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.