Rivaroxaban

Description

Rivaroxaban USP is a factor Xa (FXa) inhibitor, with the active ingredient being 5-Chloro-N-({(5S)-2-oxo-3-4-(3-oxo-4-morpholinyl)phenyl-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide. The molecular formula of rivaroxaban 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. It 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 either 2.5 mg, 10 mg, 15 mg, or 20 mg of rivaroxaban. The inactive ingredients in the rivaroxaban tablets USP include croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. The proprietary film coating mixture for the 2.5 mg tablets is Opadry Yellow, which contains HPMC 2910/hypermellose 15 mpass, titanium dioxide, macrogol 4000/PEG 3350, and iron oxide yellow. The 10 mg tablets are coated with Opadry Pink, while the 15 mg tablets use Opadry Red. The 20 mg tablets are also coated with Opadry Red, which includes HPMC 2910/hypermellose 15 mpass, titanium dioxide, macrogol 4000/PEG 3350, and iron oxide red.

Uses and Indications

Rivaroxaban tablets are indicated for the following conditions:

Rivaroxaban is indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. It is also indicated for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE). Additionally, rivaroxaban is indicated for the reduction in the risk of recurrence of DVT or PE.

For patients undergoing knee or hip replacement surgery, rivaroxaban is indicated for the prophylaxis of DVT, which may lead to PE. It is further indicated for the prophylaxis of venous thromboembolism (VTE) in acutely ill medical patients.

In patients with coronary artery disease (CAD), rivaroxaban is indicated to reduce the risk of major cardiovascular events. It is also 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.

Rivaroxaban is indicated for the treatment of VTE and the reduction in the risk of recurrent VTE in pediatric patients from birth to less than 18 years of age. Furthermore, it is indicated for thromboprophylaxis in pediatric patients aged 2 years and older with congenital heart disease following the Fontan procedure.

No specific teratogenic or nonteratogenic effects have been mentioned.

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.

To reduce 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, after a minimum of 6 months of standard anticoagulant therapy.

For the 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 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 75-100 mg once daily.

For pediatric patients, healthcare professionals should refer to the Full Prescribing Information for specific dosing recommendations.

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 are associated with a significant risk of serious and potentially fatal bleeding. Healthcare professionals should be aware that an agent to reverse the activity of rivaroxaban is available and should be prepared to utilize it in cases of severe 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 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 tablets heightens 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 the completion of a prescribed treatment course.

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 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, a thorough assessment of the benefits and risks should be conducted for patients who are currently anticoagulated or who may require anticoagulation.

Side Effects

In clinical trials and postmarketing experiences, the most common adverse reactions associated with rivaroxaban include bleeding, which occurs in more than 5% of adult patients and exceeds 10% in pediatric patients. Other notable adverse reactions in pediatric patients include cough, vomiting, and gastroenteritis, each occurring in more than 10% of this population.

Serious adverse reactions have been identified, including the risk of serious and fatal bleeding. Patients receiving rivaroxaban should be monitored closely for signs of bleeding, and an agent to reverse the activity of rivaroxaban is available. Additionally, premature discontinuation of rivaroxaban has been associated with an increased risk of thrombotic events.

Warnings regarding the use of rivaroxaban include the potential for spinal or epidural hematomas, particularly in patients undergoing neuraxial anesthesia or spinal puncture. These hematomas may lead to long-term or permanent paralysis. Caution is advised when prescribing rivaroxaban to pregnant women due to the risk of obstetric hemorrhage and/or emergent delivery.

Rivaroxaban is not recommended for patients with prosthetic heart valves or those with Triple Positive Antiphospholipid Syndrome due to an increased risk of thrombosis. Active pathological bleeding and severe hypersensitivity reactions to rivaroxaban tablets have also been reported. In cases of overdose, there is a risk of hemorrhage; therefore, rivaroxaban should be discontinued, and appropriate therapy should be initiated if bleeding complications arise.

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 contraindicated. The combination may increase the risk of bleeding complications, necessitating careful consideration and monitoring of alternative therapeutic options.

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 tablets 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. In pediatric patients aged 2 years and older with congenital heart disease who have undergone the Fontan procedure, rivaroxaban has also been shown to be effective.

Dosing for rivaroxaban tablets has been supported by clinical studies, with available dosages of 10 mg, 15 mg, and 20 mg for pediatric patients. However, rivaroxaban 2.5 mg tablets are not recommended for use in this population due to insufficient safety, efficacy, pharmacokinetic, and pharmacodynamic data.

It is important to note that 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 had a body weight of less than 2.6 kg; therefore, dosing cannot be reliably determined or recommended for these patients.

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 when treating pediatric patients.

Geriatric Use

In clinical trials involving rivaroxaban, 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 aged 65 years and older was found to be comparable to that observed in younger patients under 65 years of age.

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 potential adverse events is recommended, and consideration should be given to 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 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 2–4% and 15–20%, 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 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

Rivaroxaban tablets are not adequately studied in lactating mothers, and there is limited data regarding their excretion in breast milk. The available information does not provide sufficient evidence to determine the potential effects on breastfed infants. Caution is advised when considering the use of rivaroxaban in lactating mothers due to the potential risks associated with anticoagulation therapy.

The anticoagulant effect of rivaroxaban cannot be reliably monitored with standard laboratory testing, which may complicate management in breastfeeding situations. Healthcare professionals should weigh the benefits and risks of rivaroxaban for the mother against any potential risks to the nursing infant when prescribing this medication.

Given the pharmacologic activity of Factor Xa inhibitors and the potential for rivaroxaban to cross biological barriers, including the placenta, there is a theoretical risk of bleeding in the infant. Therefore, careful consideration is warranted when prescribing rivaroxaban to lactating mothers, particularly in the context of the mother's health and the infant's safety.

Renal Impairment

Rivaroxaban tablets should be used with caution in patients with renal impairment. Dosage adjustments may be necessary based on renal function, and renal function tests should be monitored regularly in patients receiving Rivaroxaban. Patients with a creatinine clearance of less than 30 mL/min should not use Rivaroxaban. Additionally, a reduced dose may be required for patients with moderate renal impairment, specifically those with a creatinine clearance of 30-49 mL/min.

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 tablets, healthcare professionals should be vigilant for potential hemorrhagic complications. It is imperative to discontinue rivaroxaban immediately and initiate appropriate therapeutic measures if any bleeding occurs.

Rivaroxaban exhibits a ceiling effect in systemic exposure; therefore, single doses exceeding 50 mg do not result in increased absorption. This characteristic should be taken into account when assessing the severity of an overdose.

To mitigate the effects of an overdose, the administration of activated charcoal may be considered to reduce further absorption of rivaroxaban. However, it is important to note that rivaroxaban is not dialyzable due to its high plasma protein binding, which limits the effectiveness of dialysis as a treatment option.

In cases where laboratory anticoagulation parameters indicate significant anticoagulation, 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 may be utilized in the management of overdose situations.

Healthcare professionals are advised to monitor patients closely and provide supportive care as necessary, tailoring interventions based on the clinical presentation and severity of the 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 serious side effects. There is an increased risk of blood clots associated with discontinuation of the medication. Additionally, rivaroxaban may lead to serious bleeding events, which can be fatal. The risk of bleeding is heightened when rivaroxaban is used concurrently with other medications that also increase bleeding risk, such as aspirin, non-steroidal anti-inflammatory drugs (NSAIDs), warfarin sodium, heparin-containing products, clopidogrel, selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs).

Healthcare professionals are advised to monitor patients for signs and symptoms of bleeding, which may include unexpected or prolonged bleeding, frequent nosebleeds, unusual gum bleeding, heavier than normal menstrual bleeding, severe or uncontrollable bleeding, red or brown urine, bright red or black stools, coughing up blood, vomiting blood or resembling "coffee grounds," headaches, dizziness, weakness, pain or swelling at wound sites, and abdominal pain indicative of potential spleen rupture.

There have also been reports of spinal or epidural hematomas in patients receiving rivaroxaban who undergo spinal procedures, such as injections or punctures. The risk of developing such hematomas is increased in patients with an epidural catheter, those taking NSAIDs or anticoagulants, individuals with a history of difficult spinal procedures, or those with prior spinal issues or surgeries. Close monitoring for symptoms of spinal or epidural blood clots is recommended for patients receiving spinal anesthesia or punctures while on rivaroxaban.

Rivaroxaban 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 (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 with atrial fibrillation, it is important to emphasize that rivaroxaban tablets should be taken once daily with the evening meal. In cases of initial treatment for deep vein thrombosis (DVT) and/or pulmonary embolism (PE), patients should take rivaroxaban tablets in either 15 mg or 20 mg doses with food at approximately the same time each day. For those at continued risk of recurrent DVT and/or PE after at least six months of initial treatment, a daily dose of 10 mg rivaroxaban should be taken with or without food.

Patients who have difficulty swallowing the tablets should be advised that they can crush the rivaroxaban tablets and mix them with a small amount of applesauce, followed by food. For patients requiring an NG tube or gastric feeding tube, caregivers should be instructed to crush the tablets and mix them with a small amount of water before administration via the tube.

In the event of a missed dose, patients should follow the instructions provided in the Full Prescribing Information based on their specific dosing schedule. Caregivers should utilize the syringes included in the original carton for pediatric patients and be informed whether the dose needs to be taken with food. It is crucial to advise caregivers that the tablet must not be split to provide a fraction of a tablet dose.

If 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 continue with the next scheduled dose. Caregivers should be instructed to contact the child's doctor if vomiting or spitting up occurs repeatedly.

Patients should be encouraged to report any unusual bleeding or bruising to their physician, as rivaroxaban may increase the time it takes to stop bleeding and may cause easier bruising. 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 incontinence. Patients experiencing any of these symptoms should contact their physician immediately.

Patients must inform their healthcare professional that they are taking rivaroxaban tablets before scheduling any invasive procedures, including dental work. They should also disclose any prescription or over-the-counter medications, as well as herbal supplements, to their physicians and dentists to evaluate potential interactions.

Women who become pregnant or intend to become pregnant during treatment with rivaroxaban tablets should notify their physician immediately. Pregnant women receiving rivaroxaban should report any bleeding or symptoms of blood loss to their physician without delay. Patients who are nursing or plan to nurse should discuss the benefits and risks of rivaroxaban treatment with their physician. Additionally, patients who can become pregnant should engage in discussions about pregnancy planning with their healthcare provider.

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 20°C to 25°C (68°F to 77°F). Temporary excursions are permissible within the range of 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.

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 Indoco Remedies Limited. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)