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. Its molecular formula is C19H18ClN3O5S, and it has a molecular weight of 435.88 g/mol. Rivaroxaban is a pure (S)-enantiomer and appears as a white to yellowish powder. It is soluble in dimethylsulfoxide and is practically insoluble in water. Rivaroxaban for oral suspension is supplied as granules in bottles containing 155 mg of rivaroxaban, which yields a concentration of 1 mg of rivaroxaban per mL after reconstitution. The inactive ingredients include anhydrous citric acid, carboxymethylcellulose sodium, hydroxypropyl methyl cellulose, mannitol, microcrystalline cellulose, sodium benzoate, sucralose, tutti frutti 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

Rivaroxaban for oral suspension is indicated for use in pediatric patients, with specific dosing recommendations available in the Full Prescribing Information (2.2).

The product is supplied as white to off-white granules in a translucent HDPE bottle, containing a total of 155 mg of rivaroxaban. Each package includes two oral dosing syringes for accurate administration.

To prepare the suspension, the granules must be reconstituted with 150 mL of purified water. Following reconstitution, each 1 mL of the suspension will contain 1 mg of rivaroxaban.

It is essential to discard any reconstituted suspension after the "Discard after" date indicated on the bottle to ensure patient safety and medication efficacy.

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 is associated with significant risks that necessitate careful consideration and monitoring by healthcare professionals.

Risk of Bleeding Rivaroxaban can lead to serious and potentially fatal bleeding events. It is essential for healthcare providers to be aware of this risk and to have access to a specific reversal agent for rivaroxaban's anticoagulant effects.

Pregnancy-Related Hemorrhage Caution is advised when prescribing rivaroxaban for oral suspension to pregnant women due to the potential for obstetric hemorrhage and the risk of complications during emergent delivery.

Prosthetic Heart Valves The use of rivaroxaban for oral suspension is not recommended in patients with prosthetic heart valves, as the safety and efficacy in this population have not been established.

Increased Risk of Thrombosis in Patients with Triple Positive Antiphospholipid Syndrome Rivaroxaban for oral suspension is contraindicated in patients with triple positive antiphospholipid syndrome due to an increased risk of thrombosis.

Premature Discontinuation Premature discontinuation of rivaroxaban for oral suspension significantly increases the risk of thrombotic events. Healthcare providers should ensure that patients understand the importance of adherence to their prescribed regimen.

Spinal/Epidural Hematoma There is a risk of epidural or spinal hematomas in patients receiving rivaroxaban for oral suspension who are undergoing neuraxial anesthesia or spinal puncture. Such hematomas can lead to long-term or permanent paralysis.

Monitoring Healthcare professionals should monitor patients closely for signs and symptoms of neurological impairment. If any neurological deficits are observed, urgent treatment is required. Prior to any neuraxial intervention, a thorough assessment of the benefits and risks should be conducted for patients who are currently anticoagulated or who may require anticoagulation.

Side Effects

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

Serious adverse reactions associated with rivaroxaban for oral suspension include the risk of thrombotic events, particularly following premature discontinuation of the medication. It is crucial for healthcare providers to be aware that stopping rivaroxaban prematurely can significantly increase this risk.

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 careful monitoring and consideration of the risks involved in these procedures.

Rivaroxaban for oral suspension is also associated with a risk of serious and potentially fatal bleeding. An agent to reverse the activity of rivaroxaban is available, which may be necessary in cases of significant bleeding. Special caution is advised when prescribing this medication to pregnant women due to the risk of pregnancy-related hemorrhage and the potential for complications during delivery.

Other notable adverse reactions include active pathological bleeding, severe hypersensitivity reactions to rivaroxaban, and complications arising from overdose, which may necessitate discontinuation of the medication and initiation of appropriate therapeutic measures.

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 are also receiving drugs from these categories.

Packaging & NDC

The table below lists all NDC Code configurations of Rivaroxaban Granule, the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

The safety and effectiveness of rivaroxaban for oral suspension 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 for oral suspension has demonstrated safety and effectiveness. This use is supported by evidence from adequate and well-controlled studies in adults, along with data from a multicenter, prospective, open-label, active-controlled study involving 112 pediatric patients. This study evaluated the pharmacokinetic properties of rivaroxaban for oral suspension and its safety and efficacy for thromboprophylaxis over 12 months in children with single ventricle physiology post-Fontan procedure.

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 for this pediatric population.

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

Pregnancy

The available data on rivaroxaban for oral suspension in pregnant women are limited and insufficient to establish a definitive drug-associated risk of adverse developmental outcomes. Caution is advised when prescribing rivaroxaban for oral suspension 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 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 recognized risk factor for venous thromboembolism, with an 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 weighed against the risk of thrombotic events when considering the use of rivaroxaban for oral suspension in this context.

Currently, there are no adequate or well-controlled studies of rivaroxaban for oral suspension 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 reductions and maternal and fetal deaths 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 for oral suspension in nursing mothers, and dosing for breastfeeding women has not been established. The potential for excretion in breast milk is unknown. Caution should be exercised when rivaroxaban for oral suspension is administered to a nursing mother due to the potential for adverse effects in the breastfed infant.

Renal Impairment

Patients with renal impairment have not been specifically addressed in the available data regarding dosage adjustments, special monitoring, or safety considerations. Therefore, healthcare professionals should exercise caution when prescribing this medication to patients with reduced kidney function, as the lack of information necessitates careful clinical judgment and monitoring.

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 for oral suspension, healthcare professionals should be vigilant for potential complications, particularly hemorrhage. If bleeding complications arise, it is imperative to discontinue rivaroxaban and initiate appropriate therapeutic measures to manage the situation effectively.

It is important to note that systemic exposure to rivaroxaban does not increase with single doses exceeding 50 mg, as absorption is limited beyond this threshold. In cases of overdose, the administration of activated charcoal may be considered to reduce further absorption of the drug.

Due to the high plasma protein binding of rivaroxaban, it is not amenable to dialysis, which limits the options for removal of the drug from the system. However, partial reversal of laboratory anticoagulation parameters can be achieved through the use of plasma products, which may assist in managing the effects of overdose.

Additionally, there is an available agent specifically designed to reverse the anti-factor Xa activity of rivaroxaban. The use of this reversal agent should be considered in the management of patients experiencing significant bleeding or other severe complications related to 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, 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 orally. 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 for oral suspension has identified several serious side effects. There is an increased risk of blood clots associated with discontinuation of the medication. Additionally, the risk of bleeding is heightened, which can be severe and potentially fatal. Patients with certain medical conditions or those taking other medications that elevate bleeding risk may experience a greater likelihood of bleeding complications.

Healthcare professionals are advised to be vigilant for signs and symptoms of bleeding in patients, and immediate medical attention should be sought if such symptoms arise. Furthermore, spinal or epidural hematomas have been reported in individuals receiving rivaroxaban for oral suspension who undergo spinal or epidural procedures. The risk of these complications is further increased in patients taking non-steroidal anti-inflammatory drugs (NSAIDs) or anticoagulants.

It is important to note that rivaroxaban for oral suspension is contraindicated in individuals with artificial heart valves and those diagnosed with antiphospholipid syndrome (APS), particularly in cases with positive triple antibody testing.

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. Patients should be instructed to take rivaroxaban for oral suspension only as directed and to avoid discontinuing the medication without first consulting their healthcare professional.

It is important for the adult caregiver to administer the dose using the syringes provided in the original carton. Caregivers should be informed 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. If the child vomits or spits up the dose repeatedly, the caregiver should contact the child's doctor immediately. For children who are unable to swallow whole tablets, rivaroxaban for oral suspension may be utilized.

In cases of a missed dose, healthcare providers should advise patients to follow the instructions in the Full Prescribing Information based on their specific dosing schedule. Patients must be informed to report any unusual bleeding or bruising to their physician, as rivaroxaban for oral suspension may prolong bleeding time and increase the likelihood of bruising.

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, including back pain, tingling, numbness (particularly in the lower limbs), muscle weakness, and incontinence of stool or urine. If any of these symptoms arise, patients should contact their physician immediately.

Patients should also be instructed to inform their healthcare professional about their use of 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.

Women who are pregnant or plan to become pregnant during treatment with rivaroxaban for oral suspension should notify their physician immediately. Pregnant women receiving this medication should report any bleeding or symptoms of blood loss to their physician without delay. Additionally, patients should discuss the benefits and risks of rivaroxaban for oral suspension with their physician if they are nursing or intend 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 a configuration that includes a reconstituted suspension. It is essential to discard the reconstituted suspension after the "Discard after" date indicated on the bottle to ensure safety and efficacy.

Storage conditions require the product to be maintained at room temperature, specifically between 20°C and 25°C (68°F and 77°F). Temporary excursions are permissible within a range of 15°C to 30°C (59°F to 86°F). It is critical to avoid freezing both the granules and the reconstituted suspension to preserve their integrity. Additionally, the product should be kept out of the reach of children to prevent accidental ingestion.

Additional Clinical Information

No further data are available.

FDA Insert (PDF)

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

View full prescribing information (PDF)