Rivarox-20

Film coated tablets, round, biconvex, brown red colored, engraved '20' on one face and other face plain.
Rivaroxaban Tablets 20 mg: Each film-coated tablet contains rivaroxaban 20 mg.

Pharmacotherapeutic group: Direct factor Xa inhibitors. ATC code: B01AF01.
Pharmacology: Pharmacodynamics: Rivaroxaban is a highly selective direct factor Xa inhibitor with oral bioavailability.
Pharmacokinetics: Absorption: Rivaroxaban is rapidly absorbed with maximum concentrations (C_max) appearing 2-4 hours after tablet intake.
Oral absorption of rivaroxaban is almost complete and oral bioavailability is high (80-100%) for the 10 mg tablet dose, irrespective of fasting/fed conditions. Intake with food does not affect rivaroxaban AUC or C_max at the 10 mg dose. Rivaroxaban 10 mg tablets can be taken with or without food.
Due to reduced extent of absorption an oral bioavailability of 66% was determined for the 20 mg tablet under fasting conditions. When rivaroxaban 20 mg tablets are taken together with food increases in mean AUC by 39% were observed when compared to tablet under fasting conditions, indicating almost complete absorption and high oral bioavailability. Rivaroxaban 20 mg should be taken with food. Under fed condition rivaroxaban 10 mg, 15 mg and 20 mg tablets demonstrated dose-proportionality.
Variability in rivaroxaban pharmacokinetics is moderate with inter-individual variability (CV%) ranging from 30% to 40%.
Distribution: Plasma protein binding in humans is high at approximately 92% to 95%, with serum albumin being the main binding component. The volume of distribution is moderate with V_ss being approximately 50 L.
Metabolism and Elimination: Of the administered rivaroxaban dose, approximately ²/₃ undergoes metabolic degradation, with half then being eliminated renally and the other half eliminated by the faecal route. The final ¹/₃ of the administered dose undergoes direct renal excretion as unchanged active substance in the urine, mainly via active renal secretion.
Rivaroxaban is metabolised via CYP3A4, CYP2J2 and CYP-independent mechanisms. Oxidative degradation of the morpholinone moiety and hydrolysis of the amide bonds are the major sites of biotransformation. Based on in vitro investigations rivaroxaban is a substrate of the transporter proteins P-gp (P-glycoprotein) and Bcrp (breast cancer resistance protein).
Unchanged rivaroxaban is the most important compound in human plasma, with no major or active circulating metabolites being present. With a systemic clearance of about 10 L/h, rivaroxaban can be classified as a low-clearance substance. Elimination of rivaroxaban from plasma occurs with terminal half-lives of 5 to 9 hours in young individuals, and with terminal half-lives of 11 to 13 hours in the elderly.

Rivaroxaban is indicated for prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation.
Rivaroxaban is indicated for the treatment of Deep Vein Thrombosis (DVT) and for the prevention of recurrent DVT and Pulmonary Embolism (PE) following an acute DVT in adults.
Rivaroxaban is indicated for the treatment of Pulmonary Embolism (PE) and for the prevention of recurrent PE and DVT.

Stroke prevention in atrial fibrillation (SPAF): SPAF: Recommended usual dose: The recommended dose is 20 mg one tablet once daily, maximum daily dose is 20 mg.
For patients with moderate renal impairment (creatinine clearance (CrC): <50-30 mL/min) the recommended dose is 15 mg once daily.
SPAF: Missed Dose: If a dose is missed the patient should take rivaroxaban immediately and continue with the once daily intake as recommended on the following day. The dose should not be doubled to make up for a missed dose within the same day.
SPAF: Additional information on special populations: Patients with hepatic impairment: Rivaroxaban is contraindicated in patients with hepatic disease which is associated with coagulopathy leading to a clinically relevant bleeding risk.
No dose adjustment is necessary in patients with other hepatic diseases.
Limited clinical data in patients with moderate hepatic impairment indicate a significant increase in the pharmacological activity.
No clinical data are available for patients with severe hepatic impairment.
Patients with renal impairment: No dose adjustment is required if Rivaroxaban is administered in patients with mild renal impairment.
For patients with moderate renal impairment the recommended dose is 15 mg once daily.
Limited clinical data for patients with severe renal impairment indicate that rivaroxaban plasma levels are significantly increased in this patient population.
Therefore, rivaroxaban 15 mg must be used with caution in these patients.
Use of rivaroxaban is not recommended in patients with CrC <15 mL/min.
Cardioversion: Rivaroxaban can be initiated or continued in patients who may require cardioversion.
For transesophageal echocardiogram (TEE) guided cardioversion in patients not previously treated with anticoagulants, rivaroxaban treatment should be started at least 4 hours before cardioversion to ensure adequate anticoagulation.
Patients who Undergo PCI (Percutaneous Coronary Intervention) with Stent Placement: Patients with non-valvular atrial fibrillation who undergo PCI with stent placement should receive reduced dose of 15 mg rivaroxaban once daily (or 10 mg rivaroxaban once daily for patients with moderate renal impairment [CrCl <50-30 mL/min]) in addition to a P2Y12 inhibitor. This treatment regimen is recommended for a maximum of 12 months after PCI with stent placement. Rivaroxaban dosage should be increased to the standard dose for patients with non-valvular atrial fibrillation.
Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE) treatment: DVT/PE: Recommended usual dose: The recommended dose for the initial treatment of acute DVT and PE is 15 mg rivaroxaban twice daily (maximum daily dose is 30 mg) for the first three weeks followed by 20 mg rivaroxaban once daily (maximum daily dose is 20 mg) for the continued treatment and the prevention of recurrent DVT and PE.
DVT/PE: Missed Dose: It is essential to adhere to the dosage schedule provided.
If a dose is missed during the 15 mg twice daily treatment phase the patient should take rivaroxaban immediately to ensure intake of 30 mg rivaroxaban per day. In this case 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.
If a dose is missed during the 20 mg once daily treatment phase the patient should take rivaroxaban immediately to ensure intake of 20 mg per day. The patient should continue with the regular 20 mg once daily intake as recommended on the following day.
Patients with hepatic impairment: Rivaroxaban is contraindicated in patients with hepatic disease which is associated with coagulopathy leading to a clinically relevant bleeding risk.
No dose adjustment is necessary in patients with other hepatic diseases.
Limited clinical data in patients with moderate hepatic impairment indicate a significant increase in the pharmacological activity.
No clinical data are available for patients with severe hepatic impairment.
Patients with renal impairment: No dose adjustment is required if rivaroxaban is administered in patients with mild or moderate renal impairment.
Limited clinical data for patients with severe renal impairment indicate that rivaroxaban plasma levels are significantly increased in this patient population.
Therefore rivaroxaban must be used with caution in these patients.
Use of rivaroxaban is not recommended in patients with CrC: <15 mL/min.
Additional information on special populations (SPAF, DVT and PE Treatment): Converting from Vitamin K Antagonists (VKA) to Rivaroxaban: For SPAF: VKA treatment should be stopped and rivaroxaban therapy should be initiated when the INR is ≤3.0.
For DVT and PE treatment: VKA treatment should be stopped and rivaroxaban therapy should be initiated when the INR is ≤2.5.
When converting patients from VKAs to rivaroxaban, INR values will be falsely elevated after the intake of rivaroxaban. The INR is not valid to measure the anticoagulant activity of rivaroxaban, and therefore should not be used.
Converting from Rivaroxaban to Vitamin K antagonists (VKA): There is a potential for inadequate anticoagulation during the transition from rivaroxaban to VKA. Continuous adequate anticoagulation should be ensured during any transition to an alternate anticoagulant. It should be noted that rivaroxaban can contribute to an elevated INR.
In patients converting from rivaroxaban to VKA, VKA should be given concurrently until the INR is ≥2.0. For the first two days of the conversion period, standard VKA dosing should be used followed by VKA dosing guided by INR testing. While patients are on both rivaroxaban and VKA, the INR should not be tested earlier than 24 hours (after the previous dose but prior to the next dose of rivaroxaban). Once rivaroxaban is discontinued INR testing maybe done reliably 24 hours after the last dose.
Converting from parenteral anti-coagulants to Rivaroxaban: For patients currently receiving a parenteral anticoagulant, start rivaroxaban 0 to 2 hours before the time of the next scheduled administration of the parenteral drug (e.g. LMWH) or at the time of discontinuation of a continuously administered parenteral drug (e.g. intravenous unfractionated heparin).
Converting from Rivaroxaban to parenteral anti-coagulants: Discontinue rivaroxaban and give the first dose of parenteral anticoagulant at the time that the next rivaroxaban dose would be taken.
Children and adolescents (from birth to 16 or 18 years depending on local law): Safety and efficacy have not been established in children and adolescents below 18 years.
Geriatric patients, gender, body weight, ethnic: No dose adjustment is required based on age, gender, body weight and ethnic differences.
Mode of Administration: Oral use, rivaroxaban 20 mg tablets should be taken with food.

Rare cases of overdose up to 600 mg have been reported without bleeding complications or other adverse reactions. Due to limited absorption a ceiling effect with no further increase in average plasma exposure is expected at supratherapeutic doses of 50 mg rivaroxaban or above.
A specific antidote antagonising the pharmacodynamic effect of rivaroxaban is not available.
The use of activated charcoal may be considered to reduce absorption of rivaroxaban overdose.
Due to plasma protein binding rivaroxaban is not expected to be dialyzable.
Management of Bleeding: Should a bleeding complication arise in a patient receiving rivaroxaban, the next rivaroxaban administration should be delayed or treatment should be discontinued as appropriate. Rivaroxaban has half-life approximately 5 to 13 hours.
Management should be individualised according to the severity and location of the haemorrhage. Appropriate symptomatic treatment could be used as needed, such as mechanical compression (e.g. for severe epistaxis), surgical haemostasis with bleeding control procedures, fluid replacement and haemodynamic support, blood products (packed red cells or fresh frozen plasma, depending on associated anaemia or coagulopathy) or platelets.
If bleeding cannot be controlled by the previously mentioned measures, administration of a specific procoagulant reversal agent should be considered, such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (APCC) or recombinant factor VIIa (r-FVII a). However, there is currently very limited clinical experience with the use of these products in individuals receiving rivaroxaban.
Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban. There is limited experience with tranexamic acid and no experience with aminocaproic acid and aprotinin in individuals receiving rivaroxaban. There is neither scientific rationale for benefit nor experience with the use of the systemic haemostatic desmopressin in individuals receiving rivaroxaban.

Rivaroxaban is contraindicated in patients with hypersensitivity to rivaroxaban or any excipient of the tablet; patients with clinically significant active bleeding (e.g., intracranial bleeding, gastrointestinal bleeding); patients with hepatic disease which is associated with coagulopathy leading to a clinically relevant bleeding risk.
Use in Pregnancy & Lactation: Pregnancy women, safety and efficacy of rivaroxaban have not been established in pregnant women. Animal data show that rivaroxaban crosses the placental barrier. Therefore use of rivaroxaban is contraindicated throughout pregnancy.
Breastfeeding, safety and efficacy of rivaroxaban have not been established in nursing mothers. Animal data indicate that rivaroxaban is secreted into breast milk. Therefore rivaroxaban may only be administered after breastfeeding is discontinued.

Patients with prosthetic valves: Safety and efficacy of rivaroxaban, have not been studied in patients with prosthetic heart valves; therefore, there are no data to support that rivaroxaban 20 mg provides adequate anticoagulation in this patient population.
Patients with high risk triple positive antiphospholipid syndrome: Rivaroxaban is not recommended for patients with a history of thrombosis who are diagnosed with antiphospholipid syndrome and are persistently triple positive (for lupus anticoagulant, anticardiolipin antibodies, and anti-beta 2-glycoprotein I antibodies) as treatment with rivaroxaban is associated with an increased rate of recurrent thrombotic events compared with vitamin K antagonists (VKA).
Concomitant medication: Rivaroxaban is not recommended in patients receiving concomitant systemic treatment with azole-antimycotics (e.g. ketoconazole) or HIV protease inhibitors (e.g. ritonavir). These drugs are strong inhibitors of both CYP 3A4 and P-gp. Therefore, these drugs may increase rivaroxaban plasma concentrations to a clinically relevant degree (2.6-fold on average) which may lead to an increased bleeding risk. The Azole antimycotic fluconazole, a moderate CYP 3A4 inhibitor has however less effect on rivaroxaban exposure and can be co-administered.
DVT and PE Treatment in renal impairment: Rivaroxaban is to be used with caution in patients with moderate renal impairment receiving co-medications leading to increased rivaroxaban plasma concentrations.
SPAF, DVT and PE treatment in renal impairment: In patients with severe renal impairment rivaroxaban plasma levels may be significantly elevated (1.6-fold on average) which may lead to an increased bleeding risk.
Due to limited clinical data rivaroxaban should be used with caution in patients with CrC <30-15 mL/min.
No clinical data are available for patients with severe renal impairment. Therefore use of rivaroxaban is not recommended in these patients.
Patients with severe renal impairment or increased bleeding risk and patients receiving concomitant systemic treatment with azole-antimycotics or HIV protease inhibitors are to be carefully monitored for signs of bleeding complications after initiation of treatment.
Bleeding risk: Rivaroxaban like other antithrombotic should be used with caution in patients with an increased bleeding risk such as: Congenital or acquired bleeding disorders; Uncontrolled severe arterial hypertension; Active ulcerative gastrointestinal disease; Recent gastrointestinal ulcerations; Vascular retinopathy; Recent intracranial or intracerebral haemorrhage; Intraspinal or intracerebral vascular abnormalities; Recent brain, spinal or ophthalmological surgery; Bronchiectasis or history of pulmonary bleeding.
Care should be taken if patients are treated concomitantly with drugs affecting haemostasis such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet aggregation inhibitors, or other antithrombotics, or selective serotonin reuptake inhibitors (SSRI), and serotonin norepinephrine reuptake inhibitors (SNRls). For patients at risk of ulcerative gastrointestinal disease an appropriate prophylactic treatment may be considered. Any unexplained fall in haemoglobin or blood pressure should lead to a search for a bleeding site.
Surgery and intervention: If an invasive procedure or surgical intervention is required, rivaroxaban should be stopped at least 24 hours before the intervention, if possible and based on clinical judgment of the physician.
If the procedure cannot be delayed, the increased risk of bleeding should be assessed against the urgency of the intervention.
Rivaroxaban should be restarted as soon as possible after the invasive procedure or surgical intervention provided the clinical situation allows and adequate haemostasis has been established.
Neuraxial (epidural/spinal) Anesthesia: When neuraxial (epidural/spinal) anesthesia or spinal puncture is performed patients treated with antithrombotic for prevention of thromboembolic complications are at risk for development of an epidural or spinal hematoma which may result in long-term paralysis.
The risk of these events is even further increased by use of indwelling epidural catheters or the concomitant use of drugs affecting haemostasis. The risk may also be increased by traumatic or repeated epidural or spinal puncture. Patients should be frequently monitored for signs and symptoms of neurological impairment (e.g., numbness or weakness of the legs, bowel or bladder dysfunction). If neurological deficits are noted, urgent diagnosis and treatment is necessary.
The physician should consider the potential benefit versus the risk before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis.
An epidural catheter should not be withdrawn earlier than 18 hours in young adult patients and 26 hours in elderly patients after the last administration of rivaroxaban.
Rivaroxaban should be administered at earliest 6 hours after the removal of the catheter. If traumatic puncture occurs the administration of rivaroxaban should be delayed for 24 hours.
DVT and PE treatment in Haemodynamically unstable PE patients or patients who require thrombolysis or pulmonary embolectomy: Rivaroxaban is not recommended as an alternative to unfractionated heparin in patients with pulmonary embolism who are haemodynamically unstable or may receive thrombolysis or pulmonary embolectomy since the safety and efficacy of rivaroxaban have not been established in these clinical situations.
Effects on ability to drive or use machines: Syncope and dizziness have been reported and may affect the ability to drive and use machines. Patients experiencing these adverse reactions should not drive or use machines.
Use in Pregnancy: See Use in Pregnancy & Lactation section for further information.

Women of childbearing potential/Contraception: Rivaroxaban should be used in women of childbearing potential only with effective contraception.
Pregnancy: Safety and efficacy of rivaroxaban have not been established in pregnant women.
In rats and rabbits rivaroxaban showed pronounced maternal toxicity with placental changes related to its pharmacological mode of action (e.g. hemorrhagic complications) leading to reproductive toxicity. No primary teratogenic potential was identified. Due to the intrinsic risk of bleeding and the evidence that rivaroxaban passes the placenta, rivaroxaban is contraindicated in pregnancy.
Lactation: Safety and efficacy of rivaroxaban have not been established in nursing mothers. In rats rivaroxaban is secreted into breast milk.
Therefore rivaroxaban may only be administered after breastfeeding is discontinued.

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 post hemorrhagic anemia. The risk of bleedings may be increased in certain patient groups e.g. patients with uncontrolled severe arterial hypertension and/or on concomitant medication affecting haemostasis.
The signs, symptoms, and severity (including 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, dyspnoea, and unexplained shock. In some cases as a consequence of anemia, symptoms of cardiac ischemia like chest pain or angina pectoris have been observed.
Known complications secondary to severe bleeding such as compartment syndrome and renal failure due to hypoperfusion have been reported for rivaroxaban. Therefore the possibility of a haemorrhage should be considered in evaluating the condition in any anticoagulated patient.
The frequencies of ADRs reported with rivaroxaban are summarized in the table as follows. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies are defined as: Very common (≥1/10); Common (≥1/100 to <1/10); Uncommon (≥1/1,000 to <1/100); Rare (≥1/10,000 to <1/1,000). (See table.)

Click on icon to see table/diagram/image

Post marketing observations: The following adverse reactions have been reported post-marketing in temporal association with the use of rivaroxaban.
Immune system disorders: Angioedema and allergic oedema.
Hepatobiliary disorders: Cholestasis, Hepatitis (incl. hepatocellular injury).
Blood and lymphatic system disorders: Thrombocytopenia.

Pharmacokinetic interactions: Rivaroxaban is cleared mainly via cytochrome P450-mediated (CYP 3A4, CYP 2J2) hepatic metabolism and renal excretion of the unchanged drug, involving the P-glycoprotein (P-gp)/breast cancer resistance protein (Bcrp) transporter systems.
CYP Inhibition: Rivaroxaban does not inhibit CYP 3A4 or any other major CYP isoforms.
CYP Induction: Rivaroxaban does not induce CYP 3A4 or any other major CYP isoforms.
Effects on rivaroxaban: The concomitant use of rivaroxaban with strong CYP 3A4 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 CYP 3A4 and P-gp inhibitor, led to a 2.6-fold increase in mean rivaroxaban steady state AUC and 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 CYP 3A4 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.
Clarithromycin (500 mg twice daily), considered as strong CYP 3A4 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 three times daily), which inhibits CYP 3A4 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 CYP 3A4 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 CYP 3A4 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 CYP 3A4 inducers (e.g., phenytoin, carbamazepine, phenobarbitone or St. John's wort) may also lead to a decreased rivaroxaban plasma concentration. Strong CYP 3A4 inducers should be co-administrated with caution.
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 500 mg naproxen.
Nevertheless there may be individuals with more pronounced pharmacodynamics response.
Converting patients from warfarin (INR 2.0 to 3.0) to rivaroxaban (20 mg) or from rivaroxaban (20 mg) to warfarin (INR 2.0 to 3.0) 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. From day 4 after stopping warfarin onwards, 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 hours 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.
As with other anticoagulants the possibility may exist that patients are at increased risk of bleeding in case of concomitant use with SSRIs or SNRIs due to their reported effect on platelets. When concomitantly used in the rivaroxaban clinical program, numerically higher rates of major or non-major clinically relevant bleeding were observed in all treatment groups.
Food and dairy products: 20 mg rivaroxaban should be taken with food.
Interactions with laboratory parameters: Clotting parameter tests (PT, aPTT, and HepTest) are affected as expected by the mode of action of rivaroxaban.

Store below 30°C.

Anticoagulants, Antiplatelets & Fibrinolytics (Thrombolytics)

B01AF01 - rivaroxaban ; Belongs to the class of direct factor Xa inhibitors. Used in the treatment of thrombosis.

D