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. Its molecular formula 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. The compound 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, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. The proprietary film coating mixture for rivaroxaban tablets, USP 2.5 mg is Opadry® Yellow, which contains hypromellose, titanium dioxide, polyethylene glycol 3350, and iron oxide yellow.

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 can 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 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 elevates 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 neuraxial anesthesia or undergoing spinal puncture while on rivaroxaban. 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 and to respond urgently if these symptoms arise. Prior to any neuraxial intervention, healthcare professionals should carefully weigh the benefits against the risks in patients who are currently anticoagulated or may require anticoagulation.

Side Effects

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

Serious warnings associated with rivaroxaban include the risk of thrombotic events upon premature discontinuation of the medication. To mitigate this risk, it is advised to consider transitioning to another anticoagulant if rivaroxaban is discontinued for reasons other than pathological bleeding or the completion of a prescribed therapy course. Additionally, there is a significant risk of epidural or spinal hematomas in patients receiving neuraxial anesthesia or undergoing spinal puncture while on rivaroxaban. Such hematomas may 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 such symptoms arise. The benefits and risks of neuraxial interventions should be carefully evaluated in patients who are or may need to be anticoagulated.

Rivaroxaban can cause 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 risk of obstetric hemorrhage and the potential 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. Other notable adverse reactions include active pathological bleeding and severe hypersensitivity reactions to rivaroxaban.

Drug Interactions

Concomitant use of strong CYP3A inhibitors and inducers with this medication should be avoided due to potential alterations in drug metabolism and efficacy. The interaction may lead to either increased toxicity or reduced therapeutic effect, necessitating careful consideration of alternative therapies.

In addition, the use of anticoagulants alongside this medication is contraindicated. The combination may heighten the risk of bleeding complications, and therefore, it is advised to avoid their concurrent administration. Monitoring for signs of bleeding and adjusting anticoagulant therapy may be required if such a combination is inadvertently initiated.

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

Elderly patients, defined as those aged 65 years and older, comprised 64 percent of the total adult population (N=64,943 patients) in clinical trials evaluating the approved indications of rivaroxaban. Among these, 27 percent were aged 75 years and older.

The efficacy of rivaroxaban in geriatric patients 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.

Given these findings, healthcare providers should exercise caution when prescribing rivaroxaban to geriatric patients. Close monitoring for potential adverse events, particularly bleeding complications, is recommended. Additionally, consideration of dose adjustments may be warranted based on individual patient factors, including renal function and the presence of comorbidities.

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.

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 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 reduction and maternal and fetal death were observed at doses corresponding to about 14 times and six times the maximum human exposure, respectively.

Lactation

There are no adequate or well-controlled studies of rivaroxaban in nursing mothers, and dosing for breastfeeding women has not been established. The potential for excretion of rivaroxaban in breast milk is unknown. Caution should be exercised when rivaroxaban is administered to a nursing mother due to the potential for adverse effects in the breastfed infant. Additionally, the risk of clinically significant uterine bleeding, which may require gynecological surgical interventions, should be assessed in females of reproductive potential and those with abnormal uterine bleeding.

Renal Impairment

Rivaroxaban is contraindicated in patients with severe renal impairment, specifically those with a creatinine clearance of less than 30 mL/min. For patients with moderate renal impairment, defined as a creatinine clearance between 30 to 49 mL/min, a reduced dose of rivaroxaban is recommended.

Prior to initiating treatment with rivaroxaban, renal function should be assessed, and it is advisable to monitor renal function periodically throughout the course of therapy, particularly in patients with renal impairment. Caution is warranted when administering rivaroxaban to this population due to an increased risk of bleeding associated with reduced kidney function.

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 cases of rivaroxaban overdosage, the primary concern is the potential for hemorrhage. It is imperative to discontinue rivaroxaban immediately and initiate appropriate therapeutic measures if any bleeding complications arise.

Rivaroxaban exhibits limited absorption at single doses exceeding 50 mg, which indicates that systemic exposure does not increase significantly beyond this threshold. In instances of overdose, the administration of activated charcoal may be considered to reduce further absorption of the drug.

Due to rivaroxaban's high plasma protein binding characteristics, it is important to note that the drug is not amenable to dialysis. However, 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 vigilant for signs of bleeding and manage the situation according to established protocols for anticoagulant overdose.

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 was not carcinogenic 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 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 higher than those observed in humans receiving a daily dose of 20 mg rivaroxaban.

Postmarketing Experience

Postmarketing experience with rivaroxaban tablets has identified several adverse events reported voluntarily or through surveillance programs. The most frequently reported side effect in adults is bleeding. In pediatric patients, common side effects include bleeding, cough, vomiting, and inflammation of the stomach and gut.

Serious side effects associated with rivaroxaban tablets may include an increased risk of blood clots upon discontinuation of the medication and a heightened risk of bleeding, which can be severe and potentially fatal. Patients and caregivers are advised to seek immediate medical attention if any signs or symptoms of bleeding occur, such as unexpected or prolonged bleeding, severe bleeding that is uncontrollable, red, pink, or brown urine, bright red or black stools, coughing up blood or blood clots, vomiting blood or vomit resembling "coffee grounds," headaches, dizziness, weakness, pain, swelling, or new drainage at wound sites, and abdominal pain in the left upper quadrant or diffuse discomfort.

Additionally, spinal or epidural hematomas have been reported in individuals receiving rivaroxaban who undergo spinal or epidural procedures. The risk of developing such hematomas is increased in patients with an epidural catheter, those taking non-steroidal anti-inflammatory drugs (NSAIDs) or anticoagulants, individuals with a history of difficult or repeated spinal punctures, and those with prior spinal issues or surgeries.

Patients are encouraged to inform their healthcare provider immediately if they experience back pain, muscle weakness (particularly in the legs and feet), tingling, loss of bowel or bladder control, or numbness.

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 should be informed to report any unusual bleeding or bruising to their physician, as rivaroxaban may cause prolonged bleeding and increased susceptibility to bruising.

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. Patients experiencing any of these symptoms should contact their physician immediately.

Patients should be instructed to inform their healthcare professional that they are taking rivaroxaban prior to any scheduled invasive procedures, including dental work. Additionally, patients should notify their physicians and dentists of any prescription or over-the-counter medications, as well as herbal supplements they are taking or plan to take, to allow for evaluation of potential interactions.

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

Storage and Handling

The product is supplied in various package configurations, with specific NDC numbers available for identification. It should be stored at room temperature, ideally between 20°C to 25°C (68°F to 77°F). Temporary excursions in temperature are permissible, provided they remain within the range of 15°C to 30°C (59°F to 86°F).

To ensure safety, the product must be kept out of the reach of children. Proper handling and storage conditions are essential 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 Novadoz Pharmaceuticals LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)