Rivaroxaban

Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular Atrial Fibrillation

Rivaroxaban is indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

There are limited data on the relative effectiveness of Rivaroxaban and warfarin in reducing the risk of stroke and systemic embolism when warfarin therapy is well-controlled.

Treatment of Deep Vein Thrombosis

Rivaroxaban is indicated for the treatment of deep vein thrombosis (DVT).

Treatment of Pulmonary Embolism

Rivaroxaban is indicated for the treatment of pulmonary embolism (PE).

Reduction in the Risk of Recurrence of Deep Vein Thrombosis and of Pulmonary Embolism

Rivaroxaban is indicated for the reduction in the risk of recurrence of deep vein thrombosis and of pulmonary embolism following initial 6 months treatment for DVT and/or PE.

Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery

Rivaroxaban is indicated for the prophylaxis of DVT, which may lead to PE in patients undergoing knee or hip replacement surgery.

Rivaroxaban is used to treat and prevent deep venous thrombosis, a condition in which harmful blood clots form in the blood vessels of the legs. These blood clots can travel to the lungs and can become lodged in the blood vessels of the lungs, causing a condition called pulmonary embolism. Rivaroxaban is used for several days after hip or knee replacement surgery while you are unable to walk. It is during this time that blood clots are most likely to form.

Rivaroxaban is also used to prevent stroke and blood clots in patients with certain heart rhythm problem (eg, nonvalvular atrial fibrillation).

Rivaroxaban is a factor Xa inhibitor, an anticoagulant. It works by decreasing the clotting ability of the blood and helps preventing harmful clots from forming in the blood vessels.

Rivaroxaban is available only with your doctor's prescription.

Important Food Effect Information

The 15 mg and 20 mg Rivaroxaban tablets should be taken with food, while the 10 mg tablet can be taken with or without food.

In the nonvalvular atrial fibrillation efficacy study Rivaroxaban was taken with the evening meal.

Switching to and from Rivaroxaban

Switching from Warfarin to Rivaroxaban - When switching patients from warfarin to Rivaroxaban, discontinue warfarin and start Rivaroxaban as soon as the International Normalized Ratio (INR) is below 3.0 to avoid periods of inadequate anticoagulation.

Switching from Rivaroxaban to Warfarin - No clinical trial data are available to guide converting patients from Rivaroxaban to warfarin. Rivaroxaban affects INR, so INR measurements made during coadministration with warfarin may not be useful for determining the appropriate dose of warfarin. One approach is to discontinue Rivaroxaban and begin both a parenteral anticoagulant and warfarin at the time the next dose of Rivaroxaban would have been taken.

Switching from Rivaroxaban to Anticoagulants other than Warfarin - For patients currently taking Rivaroxaban and transitioning to an anticoagulant with rapid onset, discontinue Rivaroxaban and give the first dose of the other anticoagulant (oral or parenteral) at the time that the next Rivaroxaban dose would have been taken.

Switching from Anticoagulants other than Warfarin to Rivaroxaban - For patients currently receiving an anticoagulant other than warfarin, start Rivaroxaban 0 to 2 hours prior to the next scheduled evening administration of the drug (e.g., low molecular weight heparin or non-warfarin oral anticoagulant) and omit administration of the other anticoagulant. For unfractionated heparin being administered by continuous infusion, stop the infusion and start Rivaroxaban at the same time.

Nonvalvular Atrial Fibrillation

For patients with creatinine clearance (CrCl) >50 mL/min, the recommended dose of Rivaroxaban is 20 mg taken orally once daily with the evening meal. For patients with CrCl 15 to 50 mL/min, the recommended dose is 15 mg once daily with the evening meal.

Treatment of Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), and Reduction in the Risk of Recurrence of DVT and of PE

The recommended dose of Rivaroxaban for the initial treatment of acute DVT and/or PE is 15 mg taken orally twice daily with food for the first 21 days. After this initial treatment period, the recommended dose of Rivaroxaban is 20 mg taken orally once daily with food, at approximately the same time each day. The recommended dose of Rivaroxaban for reduction in the risk of recurrence of DVT or PE is 20 mg taken orally once daily with food at approximately the same time each day.

Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery

The recommended dose of Rivaroxaban is 10 mg taken orally once daily with or without food. The initial dose should be taken 6 to 10 hours after surgery provided that hemostasis has been established.

• For patients undergoing hip replacement surgery, treatment duration of 35 days is recommended.
• For patients undergoing knee replacement surgery, treatment duration of 12 days is recommended.

Discontinuation for Surgery and other Interventions

If anticoagulation must be discontinued to reduce the risk of bleeding with surgical or other procedures, Rivaroxaban should be stopped at least 24 hours before the procedure to reduce the risk of bleeding. In deciding whether a procedure should be delayed until 24 hours after the last dose of Rivaroxaban, the increased risk of bleeding should be weighed against the urgency of intervention. Rivaroxaban should be restarted after the surgical or other procedures as soon as adequate hemostasis has been established, noting that the time to onset of therapeutic effect is short. If oral medication cannot be taken during or after surgical intervention, consider administering a parenteral anticoagulant.

Missed Dose

If a dose of Rivaroxaban is not taken at the scheduled time, administer the dose as soon as possible on the same day as follows:

• For patients receiving 15 mg twice daily: The patient should take Rivaroxaban immediately to ensure intake of 30 mg Rivaroxaban per day. In this particular instance, two 15 mg tablets may be taken at once. The patient should continue with the regular 15 mg twice daily intake as recommended on the following day.
• For patients receiving 20 mg, 15 mg or 10 mg once daily: The patient should take the missed Rivaroxaban dose immediately.

Administration Options

For patients who are unable to swallow whole tablets, 10 mg, 15 mg or 20 mg Rivaroxaban tablets may be crushed and mixed with applesauce immediately prior to use and administered orally. After the administration of a crushed Rivaroxaban 15 mg or 20 mg tablet, the dose should be immediately followed by food.

Administration via nasogastric (NG) tube or gastric feeding tube: After confirming gastric placement of the tube, 10 mg, 15 mg or 20 mg Rivaroxaban tablets may be crushed and suspended in 50 mL of water and administered via an NG tube or gastric feeding tube. Since Rivaroxaban absorption is dependent on the site of drug release, avoid administration of Rivaroxaban distal to the stomach which can result in reduced absorption and thereby, reduced drug exposure. After the administration of a crushed Rivaroxaban 15 mg or 20 mg tablet, the dose should then be immediately followed by enteral feeding.

Crushed 10 mg, 15 mg or 20 mg Rivaroxaban tablets are stable in water and in applesauce for up to 4 hours. An in vitro compatibility study indicated that there is no adsorption of Rivaroxaban from a water suspension of a crushed Rivaroxaban tablet to PVC or silicone nasogastric (NG) tubing.

See also:
What is the most important information I should know about Rivaroxaban?

Patients with hypersensitivity to Rivaroxaban or any of the excipients of Rivaroxaban; clinically significant active bleeding (eg, intracranial and gastrointestinal bleeding); hepatic disease which is associated with coagulopathy leading to a clinically relevant bleeding risk.

Use in pregnancy: No human data are available on the use of Rivaroxaban in pregnant women.

In rats and rabbits, Rivaroxaban showed pronounced maternal toxicity with placental changes related to its pharmacological mode of action (eg, hemorrhagic complications). No primary teratogenic potential was identified. Data from animals showed a pronounced maternal toxicity of Rivaroxaban related to its pharmacological mode of action (eg, hemorrhagic complications) leading to reproductive toxicity. Due to the intrinsic risk of bleeding and the evidence that Rivaroxaban passes the placenta, Rivaroxaban is contraindicated in pregnancy.

Women of Childbearing Potential: Rivaroxaban should be used in women of childbearing potential only with effective contraception.

Use in lactation: No human data on the use of Rivaroxaban in nursing mothers are available. In rats, Rivaroxaban is secreted into breast milk. Therefore, Rivaroxaban may only be administered after breastfeeding is discontinued.

Use Rivaroxaban as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Rivaroxaban comes with an extra patient information sheet called a Medication Guide. Read it carefully. Read it again each time you get Rivaroxaban refilled.
• Take Rivaroxaban by mouth with or without food, as directed by your doctor.
• Taking Rivaroxaban at the same time each day will help you remember to take it.
• Be sure to take Rivaroxaban for the full course of treatment. If you do not, you may be at increased risk of developing blood clots. Keep taking it even if you feel well.
• If you miss a dose of Rivaroxaban, take it as soon as possible on the same day you missed the dose then go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Rivaroxaban.

Rivaroxaban is used to prevent blood clots from forming due to a certain irregular heartbeat (atrial fibrillation) or after hip or knee replacement surgery. It is also used to treat blood clots (such as in deep vein thrombosis-DVT or pulmonary embolus-PE) and to prevent the blood clots from forming again.

Rivaroxaban is an anticoagulant that works by blocking certain clotting proteins in your blood.

How to use Rivaroxaban

Read the Medication Guide provided by your pharmacist before you start taking Rivaroxaban and each time you get a refill. If you have any questions, ask your doctor or pharmacist.

Take this medication by mouth as directed by your doctor. If you are taking this medication to prevent blood clots after knee or hip replacement surgery, the dose is usually taken once a day. If you are taking this drug to prevent strokes and blood clots that may form due to an irregular heartbeat, the dose is usually taken once a day with the evening meal. If you are taking Rivaroxaban to treat blood clots, the dose is usually taken twice a day for the first 3 weeks, and then once a day. Carefully follow your doctor's directions. Do not increase your dose, take it more often, or stop taking it unless you are told to do so by your doctor.

The 10 milligrams tablet may be taken with or without food. The 15 milligrams and 20 milligrams tablet should be taken with food. If you have any questions about how to take Rivaroxaban, ask your doctor or pharmacist.

If you are unable to swallow whole tablets, you may crush the tablet and mix it with applesauce. Eat the entire mixture right away. Do not prepare a supply for future use.

If you are giving this medication through a tube into the stomach (nasogastric or gastric tube), ask your health care professional for detailed instructions on how to properly mix and give it.

The dosage and length of treatment is based on your medical condition and response to treatment.

Use this medication regularly to get the most benefit from it. To help you remember, take it at the same time(s) each day.

See also:
What other drugs will affect Rivaroxaban?

Pharmacokinetic Interactions: Rivaroxaban is cleared mainly via cytochrome P-450 mediated (CYP3A4, CYP2J2) hepatic metabolism and renal excretion of the unchanged drug, involving the P-gp/Bcrp transporter systems.

CYP Inhibition or Induction: Rivaroxaban does not inhibit or induce CYP3A4 or any other major CYP isoforms.

Effects on Rivaroxaban: The concomitant use of Rivaroxaban with strong CYP3A4 and P-gp inhibitors may lead to both reduced hepatic and renal clearance and thus significantly increased systemic exposure.

Co-administration of Rivaroxaban with the azole-antimycotic ketoconazole (400 mg once daily), a strong CYP3A4 and P-gp inhibitor, led to a 2.6-fold increase in mean Rivaroxaban steady-state AUC and a 1.7-fold increase in mean Rivaroxaban C_max with significant increases in its pharmacodynamic effects.

Co-administration of Rivaroxaban with the HIV protease inhibitor ritonavir (600 mg twice daily), a strong CYP3A4 and P-gp inhibitor, led to a 2.5-fold increase in mean Rivaroxaban AUC and a 1.6-fold increase in mean Rivaroxaban C_max with significant increases in its pharmacodynamic effects.

Therefore, Rivaroxaban is not recommended in patients receiving concomitant systemic treatment with azole-antimycotics or HIV-protease inhibitors.

Other active substances strongly inhibiting only 1 of the Rivaroxaban elimination pathways, either CYP3A4 or P-gp, are expected to increase Rivaroxaban plasma concentrations to a lesser extent (Rivaroxaban 15 and 20 mg).

Clarithromycin (500 mg twice daily), considered as strong CYP3A4 inhibitor and moderate P-gp inhibitor, led to a 1.5-fold increase in mean Rivaroxaban AUC and a 1.4-fold increase in C_max. This increase which is close to the magnitude of the normal variability of AUC and C_max, is considered as clinically not relevant.

Erythromycin (500 mg thrice daily), which inhibits CYP3A4 and P-gp moderately, led to a 1.3-fold increase in mean Rivaroxaban AUC and C_max. This increase is within the magnitude of the normal variability of AUC and C_max and is considered as clinically not relevant.

Fluconazole (400 mg once daily), considered as moderate CYP3A4 inhibitor, led to a 1.4-fold increase in mean Rivaroxaban AUC and a 1.3-fold increase in mean C_max. This increase is within the magnitude of the normal variability of AUC and C_max and is considered as clinically not relevant.

Co-administration of Rivaroxaban with the strong CYP3A4 and P-gp inducer rifampicin led to an approximate 50% decrease in mean Rivaroxaban AUC, with parallel decreases in its pharmacodynamic effects.

The concomitant use of Rivaroxaban with other strong CYP3A4 inducers (eg, phenytoin, carbamazepine, phenobarbitone or St. John's wort) may also lead to a decreased Rivaroxaban plasma concentration. The decrease in Rivaroxaban plasma concentrations is considered as clinically not relevant (Rivaroxaban 10 mg). Strong CYP3A4 inducers should be co-administered with caution (Rivaroxaban 15 and 20 mg).

Pharmacodynamic Interactions: After combined administration of enoxaparin (40 mg single dose) with Rivaroxaban (10 mg single dose), an additive effect on anti-factor Xa activity was observed without any additional effects on clotting tests (PT, aPTT). Enoxaparin did not affect the pharmacokinetics of Rivaroxaban.

Clopidogrel (300 mg loading dose followed by 75 mg maintenance dose) did not show a pharmacokinetic interaction (with Rivaroxaban 15 mg) but a relevant increase in bleeding times was observed in a subset of patients which was not correlated to platelet aggregation, P-selectin or GPIIb/IIIa receptor levels.

No clinically relevant prolongation of bleeding time was observed after concomitant administration of Rivaroxaban 15 mg and naproxen 500 mg. Nevertheless, there may be individuals with more pronounced pharmacodynamic response.

Converting patients from the vitamin K antagonist warfarin (INR 2-3) to Rivaroxaban 20 mg or from Rivaroxaban 20 mg to warfarin (INR 2-3) increased prothrombin time/INR (Neoplastin) more than additively (individual INR values up to 12 may be observed), whereas effects on aPTT, inhibition of factor Xa activity and endogenous thrombin potential were additive.

If it is desired to test the pharmacodynamic effects of Rivaroxaban during the conversion period, anti-factor Xa activity, PiCT and HepTest can be used as these tests were not affected by warfarin. On the 4th day after the last dose of warfarin, all tests (including PT, aPTT, inhibition of factor Xa activity and ETP) reflected only the effect of Rivaroxaban.

If it is desired to test the pharmacodynamic effects of warfarin during the conversion period, INR measurement can be used at the C_trough of Rivaroxaban (24 hrs after the previous intake of Rivaroxaban) as this test is minimally affected by Rivaroxaban at this time point.

No pharmacokinetic interaction was observed between warfarin and Rivaroxaban.

Food and Dairy Products: Rivaroxaban can be taken with or without food.

Interactions Shown Not to Exist: There were no mutual pharmacokinetic interactions between Rivaroxaban and midazolam (substrate of CYP3A4), digoxin (substrate of P-gp) or atorvastatin (substrate of CYP3A4 and P-gp).

Co-administration of the proton-pump inhibitor omeprazole, the H₂-receptor antagonist ranitidine, the antacid aluminum hydroxide/magnesium hydroxide, naproxen, clopidogrel or enoxaparin did not affect Rivaroxaban bioavailability and pharmacokinetics.

No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when Rivaroxaban was co-administered with acetylsalicylic acid 500 mg.

Interactions with Laboratory Parameters: Clotting parameter tests (PT, aPTT, Hep Test) are affected as expected by the mode of action of Rivaroxaban.

Laboratory Parameters: Clotting parameters (eg, PT, aPTT, HepTest) are affected as expected by the mode of action of Rivaroxaban.

Incompatibilities: None Known.

See also:
What are the possible side effects of Rivaroxaban?

The safety of Rivaroxaban has been evaluated in 4 phase III studies including 6097 patients exposed to Rivaroxaban 10 mg undergoing major orthopedic surgery of the lower limbs (total hip or total knee replacement) in 3997 hospitalized medically ill patients (Rivaroxaban 15 mg and 20 mg) treated up to 39 days, in Rivaroxaban 10 mg two phase III VTE treatment with 2194 patients and in Rivaroxaban 15 mg and 20 mg three phase III VTE treatment trials with 4556 patients exposed either to Rivaroxaban 15 mg twice daily for 3 weeks followed by 20 mg once daily or to 20 mg once daily treated up to 21 months.

Furthermore, safety of Rivaroxaban has been also evaluated in 7750 patients with nonvalvular atrial fibrillation from 2 phase III trials with at least 1 dose of Rivaroxaban as well as in 10,225 ACS patients with at least 1 dose of either Rivaroxaban 2.5 mg (twice daily) or 5 mg (twice daily) on top of either ASA or ASA plus clopidogrel or ticlopidine.

In total about 67% of patients exposed to at least 1 dose of Rivaroxaban were reported with treatment emergent adverse events. About 22% of patients experienced adverse events considered related to treatment as assessed by investigators. In patients treated with Rivaroxaban 10 mg undergoing hip or knee replacement surgery and in hospitalized medically ill patients, bleeding events occurred in approximately 6.8% and 12.6% of patients, respectively and anemia occurred in approximately 5.9% and 2.1% of patients, respectively. In patients treated with either Rivaroxaban 15 mg twice daily followed by 20 mg once-daily for treatment of DVT or PE, or with 20 mg once-daily for prevention of recurrent DVT and PE, bleeding events occurred in approximately 27.8% of patients and anemia occurred in approximately 2.2% of patients. In patients treated for prevention of stroke and systemic embolism, bleeding of any type or severity was reported with an event rate of 28/100 patient years, and anemia with an event rate of 2.5/100 patient years. In patients treated for prevention of cardiovascular death and myocardial infarction after an acute coronary syndrome (ACS), bleeding of any type or severity was reported with an event rate of 22/100 patient years. Anemia was reported with an event rate of 1.4/100 patient years (Rivaroxaban 15 mg and 20 mg).

Due to the pharmacological mode of action, Rivaroxaban may be associated with an increased risk of occult or overt bleeding from any tissue and organ which may result in posthemorrhagic anemia. The risk of bleedings may be increased in certain patient groups eg, patients with uncontrolled severe arterial hypertension and/or on concomitant medication affecting hemostasis. The signs, symptoms and severity (including possible fatal outcome) will vary according to the location and degree or extent of the bleeding and/or anemia.

Hemorrhagic complications may present as weakness, paleness, dizziness, headache or unexplained swelling, dyspnea and unexplained shock. In some cases as a consequence of anemia, symptoms of cardiac ischemia eg, chest pain or angina pectoris have been observed.

Known complications secondary to severe bleeding eg, compartment syndrome and renal failure due to hypoperfusion have been reported for Rivaroxaban. Therefore, the possibility of a hemorrhage should be considered in evaluating the condition in any anticoagulated patient.

The frequencies of adverse drug reactions reported with Rivaroxaban 10 mg, 15 mg and 20 mg are summarized as follows. Within each frequency grouping, adverse effects are presented in order of decreasing seriousness. Frequencies are defined as: Very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100) and rare (≥1/10,000 to <1/1000).

Adverse drug reactions term representation is based on MedDRA version 13.

Adverse drug reactions term representation is based on MedDRA version 14.1.

10 mg: Adverse Drug Reactions from Other Clinical Trials: Furthermore, on other clinical trials with Rivaroxaban, vascular pseudoaneurysm formation has been reported following percutaneous intervention.

Rivaroxaban also contains the following excipients: Microcrystalline cellulose, croscarmellose sodium, hypromellose 5cP, lactose monohydrate, magnesium stearate and sodium lauryl sulfate. Film-Coating: Red ferric oxide, hypromellose 15cP, macrogol 3350 and titanium dioxide.

Each 15- and 20-mg tablet contains lactose monohydrate 25.4 mg and 22.9 mg, equivalent to lactose 24.1 mg and 21.8 mg, respectively.