Rivaroxaban

Description

Rivaroxaban 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 is C19H18ClN3O5S, and it has a molecular weight of 435.89. Rivaroxaban USP is a pure (S)-enantiomer, presented as a non-hygroscopic, white to yellowish powder.

This compound is sparingly soluble in dimethyl formamide and is practically insoluble in water. Rivaroxaban for oral suspension is supplied as granules in bottles, with each bottle containing 155 mg of rivaroxaban, yielding a concentration of 1 mg of rivaroxaban per mL after reconstitution. The formulation includes inactive ingredients such as anhydrous citric acid, hypromellose, mannitol, microcrystalline cellulose, carboxymethylcellulose sodium, sodium benzoate, sucralose, cream/vanilla flavor, and xanthan gum.

Uses and Indications

Rivaroxaban for oral suspension is indicated for the treatment of venous thromboembolism (VTE) and the reduction in the risk of recurrent VTE in pediatric patients from birth to less than 18 years of age. Additionally, it is indicated for thromboprophylaxis in pediatric patients aged 2 years and older who have congenital heart disease following the Fontan procedure.

There are no teratogenic or nonteratogenic effects associated with this medication.

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 recommended prophylactic dosage is 10 mg orally 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 to 100 mg once daily.

For pediatric patients, healthcare professionals should refer to the dosing recommendations provided in the Full Prescribing Information (section 2.2).

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 for oral suspension, as this may lead to serious adverse effects.

Warnings and Precautions

Rivaroxaban for oral suspension carries significant risks that healthcare professionals must consider when prescribing and monitoring treatment.

Risk of Bleeding Rivaroxaban is associated with serious and potentially fatal bleeding events. It is crucial for healthcare providers to be vigilant in monitoring patients for any signs of bleeding. An agent to reverse the anticoagulant effects of rivaroxaban is available and should be utilized in cases of severe bleeding.

Pregnancy-Related Considerations Caution is advised when administering 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 weighed in this population.

Prosthetic Heart Valves and Antiphospholipid Syndrome The use of rivaroxaban is not recommended for patients with prosthetic heart valves or those diagnosed with triple positive antiphospholipid syndrome due to an increased risk of thrombosis.

Premature Discontinuation Risks Premature discontinuation of rivaroxaban significantly heightens the risk of thrombotic events. Additionally, there is a warning regarding the potential for spinal or epidural hematomas in patients receiving neuraxial anesthesia or undergoing spinal puncture. Such hematomas can lead to long-term or permanent paralysis, necessitating urgent intervention if neurological impairment is observed.

Monitoring Recommendations Healthcare professionals should frequently monitor patients for any signs and symptoms of neurological impairment. If any such symptoms are detected, immediate treatment is warranted. The decision to proceed with neuraxial interventions in patients who are or may need to be anticoagulated should be made after careful consideration of the associated benefits and risks.

No specific laboratory tests are required for the safe use of rivaroxaban; however, ongoing clinical assessment is essential to ensure patient safety throughout the treatment process.

Side Effects

Patients receiving rivaroxaban for oral suspension may experience a range of adverse reactions. The most common adverse reactions reported in pediatric patients, occurring in greater than 10% of participants, include bleeding, cough, vomiting, and gastroenteritis.

Serious adverse reactions associated with rivaroxaban for oral suspension include the risk of thrombotic events, particularly with premature discontinuation of the medication. It is crucial to note that discontinuing rivaroxaban prematurely increases the risk of these events. Additionally, patients receiving neuraxial anesthesia or undergoing spinal puncture are at risk for epidural or spinal hematomas, which may lead to long-term or permanent paralysis.

Rivaroxaban for oral suspension can also cause serious and potentially fatal bleeding. An agent to reverse the activity of rivaroxaban is available for managing such bleeding complications. Special caution is advised when administering rivaroxaban to pregnant women due to the risk of pregnancy-related hemorrhage and the potential for obstetric complications during emergent delivery.

Other adverse reactions that may occur include active pathological bleeding and severe hypersensitivity reactions to rivaroxaban for oral suspension. In cases of overdose, patients may experience hemorrhage, necessitating the discontinuation of rivaroxaban and the initiation of appropriate therapeutic measures.

It is important to highlight that the use of rivaroxaban for oral suspension is not recommended in patients with prosthetic heart valves or those with an increased risk of thrombosis, particularly in individuals with triple positive antiphospholipid syndrome.

Drug Interactions

Concomitant use of strong P-glycoprotein (P-gp) inhibitors and inducers with this medication is not recommended due to potential alterations in drug metabolism and efficacy. Clinicians should exercise caution and consider alternative therapies when prescribing medications that are known to significantly affect P-gp and CYP3A pathways.

Additionally, the use of anticoagulants alongside this medication is contraindicated. The combination may lead to an increased risk of adverse effects, including bleeding complications. It is advisable to monitor patients closely and consider alternative anticoagulation strategies to mitigate these risks.

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 has 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 for this population.

For pediatric patients aged 2 years and older with congenital heart disease who have undergone the Fontan procedure, rivaroxaban is supported by evidence from adequate and well-controlled studies in adults, as well as data from a multicenter, prospective, open-label, active-controlled study involving 112 pediatric patients. This study evaluated the pharmacokinetic properties of rivaroxaban and its safety and efficacy for thromboprophylaxis over 12 months in children with single ventricle physiology post-Fontan procedure.

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 adult patients were elderly, with 64 percent aged 65 years and older, and 27 percent aged 75 years and older. The efficacy of rivaroxaban in geriatric patients (65 years and older) was found to be comparable to that observed in younger patients.

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 appropriate dose adjustments may be warranted based on individual patient characteristics and clinical judgment.

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.

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.

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.

Given these considerations, healthcare professionals should exercise caution and thoroughly evaluate the risks and benefits when prescribing rivaroxaban to pregnant patients.

Lactation

There are no adequate or well-controlled studies of rivaroxaban 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 rivaroxaban is administered to a nursing mother due to the potential for adverse effects in the breastfed infant.

Renal Impairment

Rivaroxaban for oral suspension 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 less than 50 mL/min, a reduced dose of rivaroxaban for oral suspension is recommended.

Prior to initiating treatment, renal function should be assessed, and it is advisable to monitor renal function periodically throughout the course of therapy. Patients with renal impairment may necessitate more frequent monitoring due to the increased risk of bleeding associated with the use of rivaroxaban for oral suspension in this population. Caution is therefore warranted when prescribing this medication to patients 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. Healthcare professionals should be vigilant for signs of bleeding complications, which necessitate immediate action. Upon confirmation of an overdose, rivaroxaban should be discontinued, and appropriate therapeutic measures should be initiated to manage any bleeding events.

It is important to note that systemic exposure to rivaroxaban does not increase with single doses below 50 mg, as absorption is limited at these levels. In instances of overdose, the administration of activated charcoal may be considered to reduce further absorption of the drug, provided that it is within an 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. Additionally, there is a specific agent available that can reverse the anti-factor Xa activity of rivaroxaban, which may be utilized in the management of severe overdosage cases.

Healthcare professionals are advised to monitor patients closely for any signs of bleeding and to implement the necessary interventions promptly to mitigate the risks associated with rivaroxaban overdosage.

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 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 did not demonstrate 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.

Regarding reproductive toxicity, no impairment of fertility was observed 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, intracranial hemorrhage, and other bleeding complications. Reports have also indicated the occurrence of spinal or epidural hematoma in patients receiving rivaroxaban who have undergone neuraxial anesthesia or spinal puncture. Additionally, cases of thrombocytopenia have been documented in the postmarketing setting. Elevations in liver enzymes have been reported in patients taking rivaroxaban. Other adverse reactions noted include hypersensitivity reactions, such as rash, pruritus, and angioedema.

Patient Counseling

Healthcare providers should advise patients and/or caregivers to read the FDA-approved patient labeling, including the Medication Guide and Instructions for Use, to ensure proper understanding of the medication. It is important to instruct patients to take rivaroxaban for oral suspension only as directed and to not discontinue the medication without first consulting their healthcare professional.

Caregivers should be informed that they are responsible for administering the dose and should utilize the syringes provided in the original carton. Providers should clarify whether the dose needs to be taken with food. In the event that 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 but 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 who are unable to swallow whole tablets, rivaroxaban for oral suspension is an appropriate alternative. In cases of missed doses, healthcare providers should guide patients according to the instructions in the Full Prescribing Information based on their specific dosing schedule.

Patients should be instructed to report any unusual bleeding or bruising to their physician, as treatment with rivaroxaban for oral suspension may result in prolonged bleeding and increased susceptibility to bruising. Additionally, if patients have undergone neuraxial anesthesia or spinal puncture, particularly if they are taking concomitant 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. Should any of these symptoms arise, patients must contact their physician immediately.

Patients should also be reminded to inform their healthcare professional that they are taking rivaroxaban for oral suspension prior to any invasive procedures, including dental work. It is essential for patients to disclose any prescription or over-the-counter medications, as well as herbal supplements, to their physicians and dentists to evaluate potential interactions.

Finally, patients should be advised to notify their physician immediately if they become pregnant or plan to become pregnant during treatment with rivaroxaban for oral suspension. Pregnant women receiving this medication should report any bleeding or symptoms of blood loss to their physician without delay.

Storage and Handling

The product is supplied in a configuration that includes specific NDC numbers, which should be referenced for accurate identification. It is essential to store the product at room temperature, maintaining a range between 20°C to 25°C (68°F to 77°F). Temporary excursions are permissible within a range of 15°C to 30°C (59°F to 86°F).

Freezing of the granules or the reconstituted suspension is strictly prohibited. Additionally, any reconstituted suspension must be discarded after the “Discard after” date indicated on the bottle. To ensure safety, the product should be kept out of the reach of children.

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 Ascend Laboratories, LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)