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 435.88. Rivaroxaban, USP is a pure (S)-enantiomer and appears as a white to yellowish powder. It is soluble in dimethyl sulfoxide and is practically insoluble to very slightly soluble in acetone and water.

Each rivaroxaban tablet, USP contains 2.5 mg, 10 mg, 15 mg, or 20 mg of rivaroxaban, USP. The inactive ingredients in rivaroxaban tablets, USP include colloidal silicon dioxide, croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. The proprietary film coating mixture for the rivaroxaban 2.5 mg tablet is Opadry Yellow, which contains D&C yellow #10 aluminium lake, hypromellose, iron oxide red, iron oxide yellow, polyethylene glycol 6000, and titanium dioxide. The film coating for the rivaroxaban 10 mg tablet is Opadry Pink, consisting of hypromellose, iron oxide red, polyethylene glycol 6000, talc, and titanium dioxide. The film coating for the rivaroxaban 15 mg and 20 mg tablets is Opadry Brown, which includes hypromellose, iron oxide black, iron oxide red, polyethylene glycol 8000, and titanium dioxide.

Uses and Indications

Rivaroxaban tablet is indicated for the following conditions:

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.

The drug is indicated for the prophylaxis of DVT, which may lead to PE, in patients undergoing knee or hip replacement surgery. It is also 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.

No specific teratogenic or nonteratogenic effects have been mentioned.

Dosage and Administration

For the management of nonvalvular atrial fibrillation, the recommended dosage is 15 mg or 20 mg administered orally 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.

For the reduction in the risk of recurrence of DVT and/or PE in patients who remain at continued risk, a dosage of 10 mg orally 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 prophylaxis of DVT following hip or knee replacement surgery, the recommended dosage is 10 mg orally once daily, which can be taken with or without food.

In acutely ill medical patients at risk for thromboembolic complications who are not at high risk of bleeding, the prophylactic dosage is 10 mg orally once daily, with or without food, during hospitalization and after discharge, for a total recommended 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 to 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 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 and should be utilized 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.

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

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. Therefore, it is essential to monitor these patients closely for any signs or symptoms of neurological impairment. If such symptoms 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

Patients receiving rivaroxaban tablets may experience a range of adverse reactions, which can be categorized by frequency and seriousness.

Common adverse reactions observed in adult patients include bleeding, occurring in more than 5% of subjects. 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 the use of rivaroxaban tablets include the risk of premature discontinuation, which significantly increases the likelihood of thrombotic events. Additionally, patients undergoing neuraxial anesthesia or spinal puncture are at risk for spinal or epidural hematomas, which may lead to long-term or permanent paralysis.

Rivaroxaban tablets carry a risk of serious and potentially fatal bleeding. An agent to reverse the activity of rivaroxaban is available for managing such events. 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 for patients with prosthetic heart valves or those with triple positive antiphospholipid syndrome due to an increased risk of thrombosis. Other contraindications include active pathological bleeding and a severe hypersensitivity reaction to rivaroxaban tablets.

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.

Anticoagulants are contraindicated for use alongside this medication. The combination may result in significant interactions that could compromise the safety and effectiveness of anticoagulation therapy. Monitoring of coagulation parameters is advised 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

The safety and effectiveness of rivaroxaban tablets 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, dosing cannot be reliably determined or recommended for 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 had a body weight of less than 2.6 kg.

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

While not all adverse reactions observed in the adult population 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 tablets, 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 (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 elderly patients. Therefore, careful monitoring for these events is recommended in this population. Healthcare providers should consider these factors when prescribing rivaroxaban to geriatric patients and may need to implement appropriate dose adjustments or increased surveillance to ensure patient safety.

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 the mother and potential risks to 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 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 population.

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 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 the breastfed child 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 with 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 tablets and any potential adverse effects on the breastfed infant from rivaroxaban or from the underlying maternal condition.

Renal Impairment

Rivaroxaban tablets should be used with caution in patients with renal impairment. Dosage adjustments may be necessary based on renal function, and renal function tests should be monitored regularly in patients receiving rivaroxaban. It is contraindicated in patients with a creatinine clearance of less than 30 mL/min. For patients with significant renal impairment, alternative anticoagulants should be considered.

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, healthcare professionals should be vigilant for potential complications, particularly hemorrhage. If bleeding complications arise, it is imperative to discontinue rivaroxaban immediately 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, the risk of overdose-related effects may plateau at higher doses.

In cases of overdose, the administration of activated charcoal may be considered to reduce further absorption of rivaroxaban. However, due to the drug's high plasma protein binding, it is important to note that rivaroxaban is not amenable to dialysis as a means of removal from the system.

For managing the anticoagulation effects of rivaroxaban, partial reversal of laboratory anticoagulation parameters can 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 alert to these considerations and act promptly 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 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-fold, respectively, higher than the human exposure associated with a daily dose of 20 mg. In male and female rats, systemic exposures at the same dose were 2- and 4-fold, respectively, greater than 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 unbound AUC exposure levels that were at least 13 times higher than those observed in humans receiving a daily dose of 20 mg of rivaroxaban.

Postmarketing Experience

Postmarketing experience with rivaroxaban tablets has identified several serious side effects reported voluntarily or through surveillance programs.

There is an increased risk of blood clots associated with discontinuation of rivaroxaban, particularly in individuals with non-valvular atrial fibrillation, which may lead to stroke or other serious complications. Additionally, rivaroxaban is associated with a heightened risk of bleeding, which can be severe and potentially fatal due to its anticoagulant properties. Patients may experience increased bruising and prolonged bleeding times during treatment.

Certain medical conditions and concomitant medications can further elevate the risk of bleeding in patients taking rivaroxaban. These include the use of aspirin, non-steroidal anti-inflammatory drugs (NSAIDs), warfarin, heparin, clopidogrel, and selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs).

Patients are advised to seek immediate medical attention if they experience signs of bleeding, such as frequent nosebleeds, unusual gum bleeding, heavy menstrual or vaginal bleeding, severe or uncontrollable bleeding, hematuria, melena, hemoptysis, or hematemesis. Symptoms indicating potential splenic rupture, such as left upper abdominal pain or diffuse abdominal discomfort, should also prompt urgent medical evaluation.

The risk of spinal or epidural hematoma is a concern for patients receiving spinal anesthesia or undergoing spinal puncture while on rivaroxaban. This risk is heightened in individuals with an epidural catheter, those taking NSAIDs or other anticoagulants, or those with a history of spinal issues. Close monitoring for symptoms of spinal or epidural blood clots, including back pain, muscle weakness, tingling, incontinence, or numbness, is recommended.

Rivaroxaban tablets are contraindicated in patients with artificial heart valves and those diagnosed with antiphospholipid syndrome, particularly those with positive triple antibody testing.

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 with atrial fibrillation, healthcare providers should recommend taking rivaroxaban tablets once daily with the evening meal. In cases of initial treatment for deep vein thrombosis (DVT) and/or pulmonary embolism (PE), patients should be advised to take rivaroxaban 15 mg or 20 mg tablets with food at approximately the same time every day. For those at continued risk of recurrent DVT and/or PE after at least six months of initial treatment, a dose of 10 mg once daily with or without food is recommended.

Patients who have difficulty swallowing the tablets should be instructed to crush the rivaroxaban tablets and mix them with a small amount of applesauce, followed by food. For patients requiring a nasogastric (NG) tube or gastric feeding tube, the healthcare provider should instruct the patient or caregiver 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 in the Full Prescribing Information based on their specific dosing schedule. For pediatric patients, the adult caregiver should administer the dose and be informed whether it needs to be taken with food. It is important to communicate that the tablet must not be split to provide a fraction of a tablet dose. If a child vomits or spits up the dose within 30 minutes of administration, a new dose should be given. However, if vomiting occurs more than 30 minutes after the dose, the caregiver should not re-administer the dose and should continue with the next scheduled dose. Caregivers should be advised to contact the child’s doctor if vomiting or spitting up occurs repeatedly. For children unable to swallow whole tablets, rivaroxaban oral suspension may be utilized.

Patients should be instructed to report any unusual bleeding or bruising to their physician, as rivaroxaban may cause prolonged bleeding and increased susceptibility to bruising. If patients have undergone neuraxial anesthesia or spinal puncture, particularly if they are taking concomitant non-steroidal anti-inflammatory drugs (NSAIDs) or platelet inhibitors, they should be vigilant for signs and symptoms of spinal or epidural hematoma, such as back pain, tingling, numbness (especially in the lower limbs), muscle weakness, and stool or urine incontinence. Patients experiencing any of these symptoms should contact their physician immediately.

Patients must inform their healthcare professional that they are taking rivaroxaban tablets before scheduling any invasive procedures, including dental work. They should also disclose any prescription or over-the-counter medications, as well as herbal supplements, to their physicians and dentists to evaluate potential interactions.

Women who become pregnant or intend to become pregnant during treatment with rivaroxaban tablets should inform their physician immediately. Pregnant women receiving rivaroxaban 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 plan to nurse during anticoagulant treatment. Those who can become pregnant should also engage in discussions about pregnancy planning with their healthcare provider.

Storage and Handling

The product is supplied in well-closed containers to ensure its integrity. It should be stored at a temperature of 25°C (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 this product out of the reach of children to ensure safety.

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 Alembic Pharmaceuticals Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)