Rivaroxaban

Description

Rivaroxaban, USP, is a factor Xa (FXa) inhibitor and serves as the active ingredient in rivaroxaban film-coated tablets, USP. The chemical name for rivaroxaban is 5-Chloro-N-({(5S)-2-oxo-3-4-(3-oxo-4-morpholinyl)phenyl-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide. Its molecular formula is C19H18ClN3O5S, with a molecular weight of 435.88. Rivaroxaban is characterized as a pure (S)-enantiomer and appears as a non-hygroscopic, white to off-white powder.

The compound exhibits slight solubility in acetone and polyethylene glycol 400, while being practically insoluble in water. Each film-coated tablet contains 2.5 mg of rivaroxaban, USP. The inactive ingredients include anhydrous lactose, colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, and poloxamer. The film-coating mixture comprises ferric oxide yellow, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. It is important to note that the FDA-approved dissolution test method and specifications differ from those of the USP.

Uses and Indications

Rivaroxaban tablets are indicated to reduce the risk of major cardiovascular events in patients with coronary artery disease (CAD). Additionally, these tablets are indicated to reduce the risk of major thrombotic vascular events in patients with peripheral artery disease (PAD), including those who have recently undergone lower extremity revascularization due to symptomatic PAD.

There are no teratogenic or nonteratogenic effects associated with the use of rivaroxaban tablets.

Dosage and Administration

For the treatment of coronary artery disease (CAD) or peripheral artery disease (PAD), the recommended dosage is 2.5 mg administered orally twice daily. This 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, administered orally once daily.

Healthcare professionals should ensure that patients adhere to the prescribed dosing schedule, taking the medication consistently at the same times each day to maintain optimal therapeutic levels.

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 carry a significant risk of serious and potentially fatal bleeding. Healthcare professionals should be aware that an agent is available to reverse the activity of rivaroxaban in the event of such 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 for patients with prosthetic heart valves or those with triple positive antiphospholipid syndrome, as these conditions may increase the risk of thrombosis.

Premature discontinuation of rivaroxaban tablets can elevate the risk of thrombotic events, necessitating careful management of treatment duration. Additionally, there have been reports of epidural or spinal hematomas in patients receiving neuraxial anesthesia or undergoing spinal puncture while on rivaroxaban. These hematomas can lead to long-term or permanent paralysis, underscoring the need for vigilance in monitoring patients undergoing such procedures.

In clinical trials involving rivaroxaban, a substantial proportion of participants were elderly, with 64 percent aged 65 years and older and 27 percent aged 75 years and older. While the efficacy of rivaroxaban in this demographic was comparable to that in younger patients, both thrombotic and bleeding event rates were notably higher among older adults. Therefore, healthcare providers should exercise caution and closely monitor this population for adverse events.

Healthcare professionals are advised to monitor patients frequently for signs and symptoms of neurological impairment. If any such symptoms are observed, urgent treatment should be initiated. Prior to any neuraxial intervention in patients who are or need to be anticoagulated, a thorough assessment of the benefits and risks should be conducted.

Side Effects

The most common adverse reaction observed in adult patients treated with rivaroxaban tablets was bleeding, occurring in more than 5% of participants.

Serious adverse reactions include the risk of serious and potentially fatal bleeding, which necessitates careful monitoring. Patients should be informed that premature discontinuation of rivaroxaban tablets significantly increases the risk of thrombotic events. Additionally, there is a warning regarding the occurrence of epidural or spinal hematomas in patients receiving neuraxial anesthesia or undergoing spinal puncture. Such hematomas may lead to long-term or permanent paralysis.

Other important considerations include the potential for pregnancy-related hemorrhage; therefore, rivaroxaban tablets should be used with caution in pregnant women due to the risk of obstetric hemorrhage and/or the need for emergent delivery. The use of rivaroxaban is not recommended in patients with prosthetic heart valves or those with triple positive antiphospholipid syndrome due to an increased risk of thrombosis.

Additional adverse reactions may include active pathological bleeding, severe hypersensitivity reactions to rivaroxaban tablets, and complications arising from overdose, which may lead to hemorrhage. In cases of overdose, it is advised to discontinue rivaroxaban tablets and initiate appropriate therapeutic measures to manage any bleeding complications.

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.

Additionally, 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

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

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

Geriatric Use

In clinical trials involving rivaroxaban tablets, a significant proportion of the adult patient population was comprised of elderly individuals, with 64 percent of the 64,943 patients being 65 years of age or older, and 27 percent being 75 years or older. The efficacy of rivaroxaban in geriatric patients (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, 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, 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 regardless of maternal health or medication use. The estimated background risk of major birth defects and miscarriage in the U.S. general population is approximately 2 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.

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 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 thromboembolic events and bleeding.

Lactation

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

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

Renal Impairment

Patients with renal impairment should be monitored closely when using rivaroxaban tablets, as the medication can cause serious and potentially fatal bleeding. Dosing adjustments may be necessary based on the degree of renal function impairment. It is important to note that an agent to reverse the activity of rivaroxaban is available, which may be utilized in cases of bleeding complications.

Caution is advised when prescribing rivaroxaban tablets to pregnant women due to the risk of obstetric hemorrhage and/or the potential need for emergent delivery. Additionally, the use of rivaroxaban tablets is not recommended in patients with prosthetic heart valves or those with an increased risk of thrombosis associated with triple positive antiphospholipid syndrome. Regular assessment of renal function is essential to ensure safe and effective use of this medication in patients with reduced kidney function.

Hepatic Impairment

Rivaroxaban tablets are contraindicated in patients with severe hepatic impairment (Child-Pugh class C). For patients with moderate hepatic impairment (Child-Pugh class B), the use of rivaroxaban is not recommended due to the potential for increased exposure and an associated risk of bleeding.

In patients with mild hepatic impairment (Child-Pugh class A), no dose adjustment is necessary; however, caution is advised when prescribing rivaroxaban.

Liver function tests should be conducted prior to initiating treatment and periodically monitored during therapy in patients with hepatic impairment to ensure safety and efficacy.

Overdosage

In cases of rivaroxaban tablet overdosage, the primary concern is the potential for hemorrhage. Healthcare professionals should be vigilant for signs of bleeding complications, which necessitate the immediate discontinuation of rivaroxaban therapy and the initiation of appropriate management strategies.

It is important to note that systemic exposure to rivaroxaban does not increase with single doses exceeding 50 mg, as absorption is limited at higher doses. In instances of overdose, the administration of activated charcoal may be considered to reduce further absorption of the drug, provided that it is within the appropriate time frame post-ingestion.

Due to rivaroxaban's high plasma protein binding characteristics, it is not amenable to dialysis as a means of removal from the system. However, partial reversal of anticoagulation effects may be achieved through the use of plasma products, which can help restore normal coagulation parameters.

For more severe cases of overdosage, an agent specifically designed to reverse the anti-factor Xa activity of rivaroxaban is available and should be utilized as part of the management protocol. Healthcare professionals are advised to monitor patients closely and provide supportive care as needed.

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, compared to the human exposure at a dose of 20 mg/day. In male and female rats, systemic exposures at the same highest 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 exposure levels, based on the unbound AUC, that were at least 13 times higher than those observed in humans receiving a daily dose of 20 mg rivaroxaban.

Postmarketing Experience

Postmarketing experience has identified cases of serious bleeding events, including gastrointestinal bleeding and hemorrhagic stroke. Reports of thrombocytopenia (low platelet count) have been documented in patients taking rivaroxaban. Additionally, some patients have experienced elevations in liver enzymes during postmarketing surveillance. Instances of hypersensitivity reactions, including anaphylaxis, have also been reported. There have been cases of spinal or epidural hematoma in patients receiving neuraxial anesthesia or spinal puncture while on rivaroxaban. Furthermore, postmarketing experience has noted occurrences of renal impairment in patients taking rivaroxaban.

Patient Counseling

Patients and/or caregivers should be advised to read the FDA-approved patient labeling (Medication Guide) to ensure they understand the medication's use and safety information. It is important to instruct patients to take rivaroxaban tablets only as directed by their healthcare professional. Patients must be reminded not to discontinue rivaroxaban tablets without first consulting their healthcare provider.

For patients who have difficulty swallowing the tablet whole, they should be informed that they can crush rivaroxaban tablets and mix them with a small amount of applesauce, followed by food. In cases where patients require an NG tube or gastric feeding tube, caregivers should be instructed to crush the rivaroxaban tablet and mix it with a small amount of water before administering it via the tube.

In the event of a missed dose, patients should be advised to follow the instructions provided in the Full Prescribing Information based on their specific dosing schedule. Patients must be encouraged to report any unusual bleeding or bruising to their physician, as it may take longer than usual for them to stop bleeding, and they may experience increased bruising and bleeding while on rivaroxaban tablets.

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

Patients should also be instructed to inform their healthcare professional that they are taking rivaroxaban tablets prior to any scheduled invasive procedures, including dental procedures. It is essential 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 the evaluation of potential interactions.

Finally, patients must be advised to inform their physician immediately if they become pregnant or plan to become pregnant during treatment with rivaroxaban tablets. Pregnant women receiving rivaroxaban should report any bleeding or symptoms of blood loss to their physician without delay.

Storage and Handling

The product is supplied in various package configurations, with specific NDC numbers available upon request. It should be stored at a temperature range of 20°C to 25°C (68°F to 77°F), with permissible excursions between 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. Proper handling and storage conditions must be adhered to in order to maintain the integrity of the product.

Additional Clinical Information

No further data are available.

FDA Insert (PDF)

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

View full prescribing information (PDF)