Rivaxab^® (Tablets) Instructions for Use

Marketing Authorization Holder

Mylan Laboratories, Limited (India)

ATC Code

B01AF01 (Rivaroxaban)

Active Substance

Rivaroxaban (Rec.INN registered by WHO)

Dosage Forms

	Rivaxab®	Film-coated tablets 15 mg: 14, 28, 42, 98 or 100 pcs.
		Film-coated tablets 20 mg: 14, 28, 98 or 100 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets round, biconvex, with bevelled edges, coated with a brownish-red film coating, with the inscription “RX” embossed on one side and “3” on the other.

Excipients: microcrystalline cellulose (type 101), lactose monohydrate, croscarmellose sodium, hypromellose, sodium lauryl sulfate, magnesium stearate.

Film coating – ready-made pink film coating Instamoistshield Aqua II Pink (A22E01115): polyvinyl alcohol, polyethylene glycol (macrogol), talc, titanium dioxide, red iron oxide dye.

10 pcs. – PVC/PVdC/Aluminum blisters (10) – cardboard packs.
14 pcs. – PVC/PVdC/Aluminum blisters (1) – cardboard packs.
14 pcs. – PVC/PVdC/Aluminum blisters (2) – cardboard packs.
14 pcs. – PVC/PVdC/Aluminum blisters (3) – cardboard packs.
14 pcs. – PVC/PVdC/Aluminum blisters (7) – cardboard packs.

Film-coated tablets round, biconvex, with bevelled edges, coated with a film coating from light pink to pink, with the inscription “RX” embossed on one side and “4” on the other.

Excipients: microcrystalline cellulose (type 101), lactose monohydrate, croscarmellose sodium, hypromellose, sodium lauryl sulfate, magnesium stearate.

Film coating – ready-made pink film coating Instamoistshield Aqua II Pink (A22E01116): polyvinyl alcohol, polyethylene glycol (macrogol), talc, titanium dioxide, red iron oxide dye.

10 pcs. – PVC/PVdC/Aluminum blisters (10) – cardboard packs.
14 pcs. – PVC/PVdC/Aluminum blisters (1) – cardboard packs.
14 pcs. – PVC/PVdC/Aluminum blisters (2) – cardboard packs.
14 pcs. – PVC/PVdC/Aluminum blisters (7) – cardboard packs.

Clinical-Pharmacological Group

Anticoagulant – direct factor Xa inhibitor

Pharmacotherapeutic Group

Antithrombotic agents; direct factor Xa inhibitors

Pharmacological Action

A selective direct inhibitor of factor Xa for oral administration. The activation of factor X to form factor Xa via the intrinsic and extrinsic pathways plays a central role in the coagulation cascade.

Rivaroxaban has a dose-dependent effect on prothrombin time and is characterized by a high correlation with plasma concentration when analyzed using the Neoplastin kit (results will differ when using other reagents).

Rivaroxaban also dose-dependently increases aPTT and the HepTest result, however, these parameters are not recommended for assessing the pharmacodynamic effects of rivaroxaban.

Pharmacokinetics

After oral administration, Rivaroxaban is rapidly absorbed; the absolute bioavailability is high and amounts to 80-100%. C_max in plasma is reached in 2-4 hours. Food intake does not affect the AUC and C_max of rivaroxaban.
The pharmacokinetics of rivaroxaban is characterized by moderate variability; individual variability (coefficient of variation) is 30-40%, except for the day of surgery and the day after surgery, when variability is high (70%).

Plasma protein binding, predominantly with albumin, is 92-95%. V_d is about 50 L.
Rivaroxaban is excreted primarily as metabolites (approximately 2/3 of the dose), with half excreted by the kidneys and the other half in the feces. 1/3 of the administered dose undergoes direct renal excretion as unchanged substance, believed to be primarily via active renal secretion. The metabolism of rivaroxaban occurs with the participation of isoenzymes CYP3A4, CYP2J2, as well as enzymes independent of the cytochrome P450 system. The main participant in biotransformation is the morpholine group, undergoing oxidative decomposition, and the amide groups, undergoing hydrolysis.

According to in vitro data, Rivaroxaban is a substrate for the transporter proteins P-gp (P-glycoprotein) and BCR-P (breast cancer resistance protein). Unchanged Rivaroxaban is the most significant compound in human plasma; no active circulating metabolites were detected in plasma. The systemic clearance of rivaroxaban is about 10 L/h. The terminal T_1/2 in young patients is 5-9 hours, in elderly patients – 11-13 hours.

In elderly patients, plasma concentrations of rivaroxaban are higher than in young patients, the mean AUC is approximately 1.5 times higher than the corresponding values in young patients, mainly due to reduced total and renal clearance.

In patients with mild (CrCl ≤80-50 ml/min), moderate (CrCl ≤50-30 ml/min) or severe (CrCl ≤30-15 ml/min) renal impairment, AUC values were 1.4, 1.5 and 1.6 times higher, respectively, than in healthy volunteers. The corresponding increase in pharmacodynamic effect was more pronounced.

Indications

Adults: prevention of stroke and systemic thromboembolism in patients with non-valvular atrial fibrillation; treatment of deep vein thrombosis and pulmonary embolism and prevention of recurrent DVT and PE.

Children: treatment of venous thromboembolism (VTE) and prevention of recurrent VTE in children and adolescents under 18 years of age weighing 30 kg or more after at least 5 days of initial parenteral anticoagulant therapy.

ICD codes

Dosage Regimen

Administer the dose individually based on the specific indication, patient weight, and renal function.

For stroke prevention in non-valvular atrial fibrillation: Take 20 mg once daily with the evening meal.

For treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE): Take 15 mg twice daily with food for the first 21 days, then switch to 20 mg once daily with food.

For prevention of recurrent DVT and PE: Take 20 mg once daily with food.

For pediatric patients (≥30 kg) for VTE treatment and recurrence prevention: Administer the 15 mg tablet once daily after at least 5 days of initial parenteral anticoagulation.

Take tablets with food to ensure adequate absorption.

Do not break or crush the tablets.

In patients with moderate renal impairment (CrCl 30-49 ml/min) and concomitant use of drugs that increase rivaroxaban plasma levels, use with caution.

Contraindicated in patients with severe renal impairment (CrCl <15 ml/min).

For patients unable to swallow whole tablets, the 15 mg and 20 mg tablets may be crushed and mixed with applesauce or water immediately prior to administration; follow the crushed mixture with food.

For surgical procedures, discontinue rivaroxaban at least 24 hours before the intervention, considering the clinical urgency and patient’s bleeding risk.

Resume therapy after the procedure once adequate hemostasis is established.

Adverse Reactions

Given the pharmacological mechanism of action, the use of rivaroxaban may be associated with an increased risk of occult or overt bleeding from any organ or tissue, which may lead to post-hemorrhagic anemia. The signs, symptoms and severity (including the possibility of a fatal outcome) will vary depending on the location and severity or duration of bleeding. The risk of bleeding may be increased in certain patient groups, such as patients with uncontrolled severe arterial hypertension and/or in patients taking drugs that affect hemostasis. Hemorrhagic complications may manifest as weakness, asthenia, pallor, dizziness, headache, or edema of unknown etiology. Therefore, when assessing the condition of a patient receiving anticoagulants, the likelihood of bleeding should be assessed.

From the blood and lymphatic system: often – anemia; sometimes – thrombocythemia.

From the cardiovascular system: often – postprocedural hemorrhages (including postoperative anemia and wound bleeding); sometimes – tachycardia, arterial hypotension (including hypotension during procedures), hemorrhage (including hematomas and rare cases of muscle hemorrhages), gastrointestinal hemorrhages (including hematemesis, gum bleeding, rectal bleeding, hematuria, bloody discharge from the genital tract, nosebleeds).

From the digestive system: often – nausea; rarely – constipation, diarrhea, abdominal pain, stomach discomfort, dyspeptic symptoms, dry mouth, vomiting; rarely – impaired liver function.

Other sometimes – localized or peripheral edema, fatigue, weakness, asthenia, fever.

Allergic reactions: sometimes – urticaria (including cases of generalized urticaria); rarely – allergic dermatitis.

From the CNS: sometimes – dizziness, headache, syncope.

From the musculoskeletal system: sometimes – limb pain.

Dermatological reactions: sometimes – itching (including cases of generalized itching), skin rashes.

From the urinary system: sometimes – renal failure (increased blood levels of creatinine, urea).

From laboratory tests: often – increased LDH level, increased ALT and AST levels; sometimes – increased levels of lipase, amylase, blood bilirubin, ALP level; rarely – increased level of conjugated bilirubin (with or without concomitant increase in liver transaminases).

Contraindications

Hypersensitivity to rivaroxaban; clinically significant active bleeding (e.g., intracranial bleeding, gastrointestinal bleeding); injury or condition associated with an increased risk of major bleeding, such as existing or recently experienced gastrointestinal ulcer, presence of malignant neoplasms with a high risk of bleeding, recent trauma to the brain or spinal cord, surgery on the brain, spinal cord or eyes, intracranial hemorrhage, diagnosed or suspected esophageal varices, arteriovenous malformations, vascular aneurysms or pathology of the vessels of the brain or spinal cord; concomitant therapy with any other anticoagulants, for example, unfractionated heparin, low molecular weight heparins (including enoxaparin, dalteparin), heparin derivatives (including fondaparinux), oral anticoagulants (including warfarin, apixaban, dabigatran), except when switching from or to Rivaroxaban or when using unfractionated heparin in doses necessary to maintain the function of a central venous or arterial catheter; liver disease accompanied by coagulopathy and the risk of clinically significant bleeding, including patients with liver cirrhosis (Child-Pugh class B and C); severe renal impairment (CrCl <15 ml/min); pregnancy, breastfeeding period; children and adolescents under 18 years of age weighing less than 30 kg – for the 15 mg dose, children and adolescents under 18 years of age weighing less than 50 kg – for the 20 mg dose.

With caution

When treating patients with an increased risk of bleeding (including with congenital or acquired bleeding tendency, uncontrolled severe arterial hypertension, gastric and duodenal ulcer in the acute phase, recently experienced gastric and duodenal ulcer, vascular retinopathy, bronchiectasis or history of pulmonary hemorrhage); when treating patients with moderate renal impairment (CrCl 30-49 ml/min) receiving concomitant drugs that increase the plasma concentration of rivaroxaban; when treating patients with severe renal impairment (CrCl 15-29 ml/min); in children and adolescents with moderate or severe renal impairment (GFR<50 ml/min/1.73 m²); in patients receiving concomitant medications that affect hemostasis, for example, NSAIDs, antiplatelet agents, other antithrombotic agents or selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs); in patients receiving concomitant treatment with systemic azole antifungal drugs (e.g., ketoconazole, itraconazole, voriconazole or posaconazole) or HIV protease inhibitors (e.g., ritonavir).

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and breastfeeding.

Use in Hepatic Impairment

Contraindicated in liver disease accompanied by coagulopathy that increases the risk of clinically significant bleeding, including patients with liver cirrhosis (Child-Pugh class B and C).

Use in Renal Impairment

Contraindicated in patients with severe renal failure (CrCl ≤15 ml/min).

Rivaroxaban should be used with caution in the treatment of patients with moderate renal failure (CrCl 30-49 ml/min) receiving concomitant therapy with drugs that can cause an increase in the plasma concentration of rivaroxaban, as well as in patients with CrCl ≤15-30 ml/min. In patients with severe renal failure, the plasma concentration of rivaroxaban may be significantly increased, which may lead to an increased risk of bleeding.

Patients with severe renal failure with an increased risk of bleeding after starting treatment should be under close observation for the timely detection of hemorrhagic complications. Such monitoring may include regular physical examination of the patient, careful monitoring of surgical wound drainage discharge, and periodic determination of hemoglobin levels.

Pediatric Use

Used in children and adolescents under 18 years of age according to indications.

Contraindicated for use in children and adolescents under 18 years of age weighing less than 30 kg – for the 15 mg dose, in children and adolescents under 18 years of age weighing less than 50 kg – for the 20 mg dose.

Geriatric Use

When used in elderly patients, dose adjustment is not required.

Special Precautions

The use of rivaroxaban is not recommended in patients with severe renal failure (CrCl ≤15 ml/min).

Rivaroxaban should be used with caution in the treatment of patients with moderate renal failure (CrCl 30-49 ml/min) receiving concomitant therapy with drugs that can cause an increase in the plasma concentration of rivaroxaban, as well as in patients with CrCl ≤15-30 ml/min. In patients with severe renal failure, the plasma concentration of rivaroxaban may be significantly increased, which may lead to an increased risk of bleeding.

Patients with severe renal failure with an increased risk of bleeding and patients receiving concomitant systemic therapy with azole antifungal drugs or HIV protease inhibitors, after starting treatment, should be under close observation for the timely detection of hemorrhagic complications. Such monitoring may include regular physical examination of the patient, careful monitoring of surgical wound drainage discharge, and periodic determination of hemoglobin levels.

Rivaroxaban should be used with caution in the treatment of patients with an increased risk of bleeding, including if there are congenital or acquired conditions leading to bleeding; uncontrolled severe hypertension; active peptic ulcer of the gastrointestinal tract; recently experienced peptic ulcer of the gastrointestinal tract; vascular retinopathy; recently experienced intracranial or intracerebral hemorrhage; intraspinal or intracerebral vascular pathology; recently undergone neurosurgical (surgery on the brain, spinal cord) or ophthalmic intervention.

Caution is required when prescribing rivaroxaban to patients receiving medications that affect hemostasis, such as NSAIDs, platelet aggregation inhibitors or other antithrombotic agents.

When it is necessary to use in children according to indications and in the appropriate dosage form, the risk of bleeding should be carefully assessed before and during treatment with rivaroxaban.

Drug Interactions

Concomitant use of rivaroxaban and strong inhibitors of the CYP3A4 isoenzyme and P-glycoprotein may lead to a decrease in renal and hepatic clearance and thus significantly increase the AUC of rivaroxaban.

Concomitant use of rivaroxaban and the azole antifungal drug ketoconazole (400 mg once daily), which is a strong inhibitor of CYP3A4 and P-glycoprotein, resulted in a 2.6-fold increase in the mean steady-state AUC of rivaroxaban and a 1.7-fold increase in the mean C_max of rivaroxaban, accompanied by a significant enhancement of the pharmacodynamic effects of the drug.

Concomitant use of rivaroxaban and the HIV protease inhibitor ritonavir (600 mg twice daily), which is a strong inhibitor of CYP3A4 and P-glycoprotein, resulted in a 2.5-fold increase in the mean steady-state AUC of rivaroxaban and a 1.6-fold increase in the mean C_max of rivaroxaban, accompanied by a significant enhancement of the pharmacodynamic effects of the drug. In this regard, Rivaroxaban should be used with caution in the treatment of patients simultaneously receiving systemic azole antifungal drugs or HIV protease inhibitors.

Clarithromycin (500 mg twice daily), a potent inhibitor of CYP3A4 and a moderate-intensity inhibitor of P-glycoprotein, caused a 1.5-fold increase in mean AUC values and a 1.4-fold increase in C_max of rivaroxaban. This increase in AUC and increase in C_max is within the normal range and is considered clinically insignificant.

Erythromycin (500 mg three times daily), a moderate inhibitor of the CYP3A4 isoenzyme and P-glycoprotein, caused a 1.3-fold increase in mean steady-state AUC and C_max values of rivaroxaban. This increase in AUC and increase in C_max is within the normal range and is considered clinically significant.

Concomitant administration of rivaroxaban and rifampicin, a potent inducer of CYP3A4 and P-glycoprotein, led to an approximately 50% decrease in the mean AUC of rivaroxaban and a parallel decrease in its pharmacodynamic effects. Concomitant use of rivaroxaban with other potent inducers of CYP3A4 (e.g., phenytoin, carbamazepine, phenobarbital or St. John’s wort preparations) may also lead to a decrease in rivaroxaban plasma concentrations. The decrease in rivaroxaban plasma concentration is considered clinically insignificant.

After combined use of enoxaparin (in a single dose of 40 mg) and rivaroxaban (in a single dose of 10 mg), an additive effect on anti-factor Xa activity was observed, which was not accompanied by additional effects on blood coagulation parameters (prothrombin time, aPTT). Enoxaparin did not change the pharmacokinetics of rivaroxaban.

No pharmacokinetic interaction between rivaroxaban and clopidogrel was identified (loading dose of 300 mg followed by a maintenance dose of 75 mg), but a clinically significant increase in bleeding time was detected in a subgroup of patients, which did not correlate with platelet aggregation and the level of P-selectin or GPIIb/IIIa receptor.

After simultaneous administration of rivaroxaban and 500 mg of naproxen, no clinically relevant prolongation of bleeding time was observed. However, a more pronounced pharmacodynamic response is possible in some individuals.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.