Rivaroxaban

Description

Rivaroxaban USP is a factor Xa (FXa) inhibitor, with the active ingredient characterized by 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 is C19H18ClN3O5S, and it has a molecular weight of 435.88. Rivaroxaban is a pure (S)-enantiomer, presented as an odorless, non-hygroscopic, white to yellowish powder.

The compound exhibits slight solubility in organic solvents such as acetone and polyethylene glycol 400, while being practically insoluble in water and aqueous media. Each rivaroxaban tablet USP contains 2.5 mg of rivaroxaban. The formulation includes inactive ingredients such as croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. The proprietary film coating for the 2.5 mg rivaroxaban tablets USP is Opadry® Yellow, which consists of HPMC 2910/hypermellose 15 mpass, titanium dioxide, macrogol 4000/PEG 3350, and iron oxide yellow.

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 undergone recent lower extremity revascularization due to symptomatic PAD.

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

Dosage and Administration

The recommended dosage for the management of coronary artery disease (CAD) or peripheral artery disease (PAD) 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, which should be taken orally once daily.

Healthcare professionals should ensure that patients adhere to the prescribed dosing schedule to optimize therapeutic outcomes.

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 tablets carry significant risks that healthcare professionals must consider when prescribing and managing treatment.

Risk of Bleeding Rivaroxaban is associated with serious and potentially fatal bleeding events. It is essential to be aware that an agent to reverse the activity of rivaroxaban is available, which may be necessary in cases of severe bleeding.

Pregnancy-Related Hemorrhage Caution is advised when prescribing rivaroxaban to pregnant women due to the risk of obstetric hemorrhage and the potential need for emergent delivery. The benefits and risks should be carefully evaluated in this population.

Prosthetic Heart Valves The use of rivaroxaban is not recommended for patients with prosthetic heart valves.

Increased Risk of Thrombosis in Patients with Triple Positive Antiphospholipid Syndrome Rivaroxaban is also not recommended for patients diagnosed with triple positive antiphospholipid syndrome due to an increased risk of thrombosis.

Warnings Regarding Discontinuation and Neuraxial Procedures Premature discontinuation of rivaroxaban tablets significantly increases the risk of thrombotic events. To mitigate this risk, healthcare providers should consider bridging therapy with another anticoagulant if rivaroxaban is discontinued for reasons other than pathological bleeding or completion of therapy. Additionally, there is a risk of spinal or epidural hematoma in patients receiving neuraxial anesthesia or undergoing spinal puncture while on rivaroxaban. Such hematomas can lead to long-term or permanent paralysis. Therefore, it is crucial to monitor patients closely for any signs or symptoms of neurological impairment and to respond urgently if these symptoms arise. The benefits and risks of neuraxial interventions should be carefully weighed in patients who are or may need to be anticoagulated.

Healthcare professionals are encouraged to remain vigilant and informed about these warnings and precautions to ensure the safe use of rivaroxaban in their patients.

Side Effects

The most common adverse reaction observed in adult patients treated with rivaroxaban was bleeding, occurring in more than 5% of subjects. In pediatric patients, the most frequently reported adverse reactions, occurring in over 10% of participants, included bleeding, cough, vomiting, and gastroenteritis.

Serious warnings associated with rivaroxaban include the risk of thrombotic events following premature discontinuation of the medication. Patients who discontinue rivaroxaban tablets prematurely are at an increased risk for such events. Additionally, there is a significant risk of spinal or epidural hematomas in patients receiving neuraxial anesthesia or undergoing spinal puncture, which may lead to long-term or permanent paralysis.

Rivaroxaban tablets can cause serious and potentially fatal bleeding. An agent to reverse the anticoagulant effects of rivaroxaban is available for use in cases of severe bleeding. Caution is advised when prescribing rivaroxaban to pregnant women due to the potential for pregnancy-related hemorrhage and the risk of complications during 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.

Additional adverse reactions reported include active pathological bleeding and severe hypersensitivity reactions to rivaroxaban. In cases of overdose, patients may experience hemorrhage; therefore, it is crucial to discontinue rivaroxaban tablets and initiate appropriate therapy if bleeding complications arise.

Drug Interactions

Concomitant use of strong CYP3A 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.

In addition, the use of anticoagulants alongside this medication is contraindicated. The combination may heighten the risk of bleeding complications, necessitating careful consideration and monitoring of alternative therapeutic options. It is advisable to assess the patient's medication regimen thoroughly to prevent adverse effects associated with these interactions.

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

There are currently no safety, efficacy, pharmacokinetic, or pharmacodynamic data available to support the use of rivaroxaban 2.5 mg tablets in pediatric patients. Consequently, rivaroxaban 2.5 mg tablets are not recommended for use in this population.

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 total 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, 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 limited available data on rivaroxaban tablets 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 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 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 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 of ≥10 mg/kg during organogenesis. This dose corresponds to approximately four times the human exposure of unbound drug based on AUC comparisons at the highest recommended human dose of 20 mg/day. Additionally, decreased fetal body weights were observed in pregnant rats at doses of 120 mg/kg, corresponding to about 14 times the human exposure, and peripartal maternal bleeding and maternal and fetal death occurred at a dose of 40 mg/kg, approximately six times the maximum human exposure at the recommended dose.

Lactation

There are no adequate or well-controlled studies of rivaroxaban tablets in nursing mothers, and dosing for nursing mothers has not been established. The potential for excretion of rivaroxaban in breast milk is unknown. Caution should be exercised when administering rivaroxaban tablets 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 tablets are 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 essential to monitor renal function periodically throughout the course of therapy. Additionally, patients with renal impairment may experience an increased risk of bleeding; therefore, caution is advised when prescribing rivaroxaban to this population.

Hepatic Impairment

Rivaroxaban is contraindicated in patients with active bleeding and in those with severe hepatic impairment, classified as Child-Pugh class C. For patients with moderate hepatic impairment, classified as Child-Pugh class B, rivaroxaban is not recommended due to the potential for increased drug exposure and an associated risk of bleeding.

Prior to the initiation of rivaroxaban therapy, liver function tests should be conducted, and these tests should be performed periodically throughout the course of treatment. Additionally, patients with hepatic impairment may require careful monitoring for signs and symptoms of bleeding to ensure their safety while on this medication.

Overdosage

In the event of an overdose of rivaroxaban tablets, significant clinical concerns arise, primarily the risk of hemorrhage. Healthcare professionals should be vigilant for signs of bleeding complications, which necessitate immediate intervention.

Upon confirmation of an overdose, it is imperative to discontinue rivaroxaban tablets and initiate appropriate therapeutic measures. The systemic exposure to rivaroxaban does not increase with single doses exceeding 50 mg, as absorption is limited beyond this threshold. Therefore, the management of overdose should focus on mitigating the effects of the drug already absorbed.

To reduce further absorption of rivaroxaban in cases of overdose, the administration of activated charcoal may be considered, provided that it is within an appropriate time frame post-ingestion. However, due to rivaroxaban's high plasma protein binding, it is important to note that the drug is not dialyzable, which limits the effectiveness of dialysis as a treatment option.

For patients exhibiting altered anticoagulation parameters, partial reversal may be achieved through the use of plasma products. Additionally, an agent specifically designed to reverse the anti-factor Xa activity of rivaroxaban is available and should be utilized as part of the management strategy in cases of significant overdose.

Healthcare professionals are advised to monitor patients closely for any signs of bleeding and to implement supportive care as necessary.

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 exposure levels, based on unbound AUC, that were at least 13 times higher than those observed in humans receiving a daily dose of 20 mg rivaroxaban.

Postmarketing Experience

No specific postmarketing experience details are available in the extracted data. As such, there are no reported adverse events or case reports to summarize at this time.

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 tablets 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 tablets and mix them 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 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.

Patients who have undergone neuraxial anesthesia or spinal puncture, especially those taking concomitant NSAIDs or platelet inhibitors, should be informed to monitor 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 incontinence of stool or urine. If any of these symptoms occur, patients should be advised to contact their physician immediately.

Healthcare providers should instruct patients to inform their healthcare professional that they are taking rivaroxaban tablets prior to any scheduled invasive procedures, including dental work. Additionally, patients should be encouraged to disclose any prescription or over-the-counter medications, as well as herbal supplements, to their physicians and dentists to evaluate potential interactions.

Patients should also 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 be instructed to 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 room temperature, ideally between 20ºC to 25ºC (68ºF to 77ºF). Temporary excursions are permissible within the range of 15ºC to 30ºC (59ºF to 86ºF), 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

No further data are available.

FDA Insert (PDF)

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

View full prescribing information (PDF)