Product Overview
[Drug Name]
Generic Name: Rivaroxaban Tablets
Trade Name: Lierban Rivaroxaban Tablets 20mg*7 Tablets
Pinyin Full Code: LiErBan LiFaShaBanPian 20mg*7 Tablets
[Main Ingredient]
The main ingredient of this product is rivaroxaban.
[Properties]
This product is a film-coated tablet that appears white or off-white after removal of the coating.
[Indications/Main Functions]
1. For the prevention of venous thrombosis (VTE) in adult patients undergoing elective hip or knee replacement surgery. 2. For the treatment of venous thrombosis (DVT) in adults to reduce the risk of DVT recurrence and pulmonary embolism (PE) after acute DVT. 3. For the reduction of the risk of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation and one or more risk factors (e.g., congestive heart failure, hypertension, age ≥75 years, diabetes, history of stroke or transient ischemic attack).
[Specifications]
20mg x 7 tablets (Rivaroxaban)
[Dosage and Administration]
1. The recommended dose is 10mg of rivaroxaban taken orally once daily. If wound bleeding has stopped, the first dose should be taken between 6 and 10 hours after surgery. The duration of treatment depends on each patient's risk of venous thromboembolism, which is determined by the type of orthopedic surgery they undergo. 2. For patients undergoing major hip surgery, a 5-week treatment course is recommended. For patients undergoing major knee surgery, a 2-week treatment course is recommended. If a dose is missed, the patient should immediately take rivaroxaban and continue taking it once daily the following day. Patients can take rivaroxaban with or without meals.
[Adverse Reactions]
The safety of rivaroxaban 10 mg was evaluated in three Phase 2 studies involving 4,571 patients undergoing major lower extremity orthopedic surgery (total hip replacement or total knee replacement) who received rivaroxaban for up to 39 days. Approximately 14% of treated patients experienced adverse reactions. Bleeding and anemia occurred in approximately 3.3% and 1% of patients, respectively. Other common adverse reactions included nausea, elevated GGT, and elevated transaminases. Adverse reactions should be interpreted in the context of the procedure. Due to its pharmacological mode of action, rivaroxaban may increase the risk of occult or overt bleeding in some tissues or organs, potentially leading to post-hemorrhagic anemia. Signs, symptoms, and severity of bleeding (including potential fatal outcomes) may vary depending on the location, degree, or extent of bleeding. The risk of bleeding may be increased in certain patient groups, such as those with uncontrolled severe arterial hypertension and/or those taking concomitant medications that affect hemostasis. Hemorrhagic complications may manifest as weakness, asthenia, pallor, dizziness, headache, or unexplained swelling. Therefore, the possibility of bleeding should be considered when evaluating patients receiving anticoagulants. Table 1 below lists adverse reactions from three Phase 1 studies by system organ class (MedDRA) and frequency. Frequency definitions are as follows: Common: ≥1/100 to <1/10 Uncommon: ≥1/1,000 to <1/100 Rare: ≥1/10,000 to <1/000 Unknown: No estimate can be made based on available data.
[Contraindications]
Rivaroxaban is contraindicated in the following patients: 1. Patients with hypersensitivity to rivaroxaban or any of the excipients in the tablets. 2. Patients with clinically significant active bleeding. 3. Patients with liver disease with coagulation abnormalities and a clinically relevant risk of bleeding. 4. Pregnant and lactating women.
[Drug Interactions]
CYP3A4 and P-gp Inhibitors: Coadministration of rivaroxaban with ketoconazole (400 mg once daily [od]) or ritonavir (600 mg twice daily [bid]) increased the mean AUC of rivaroxaban by 2.6-fold and 2.5-fold, and the mean Cmax of rivaroxaban by 1.7-fold and 1.6-fold, respectively. This significantly enhances drug efficacy and may increase the risk of bleeding. Therefore, coadministration of rivaroxaban with azole antifungals (such as ketoconazole, itraconazole, voriconazole, and posaconazole) or systemic HIV protease inhibitors is not recommended. These active substances are potent inhibitors of CYP3A4 and P-gp. Fluconazole is expected to have a minimal effect on rivaroxaban plasma concentrations, and coadministration with caution is recommended. Strong inhibitors of one of the two elimination pathways of rivaroxaban (CYP3A4 or P-gp) will slightly increase the plasma concentration of rivaroxaban. For example, clarithromycin (500 mg twice daily), which is considered a strong CYP3A4 inhibitor and a moderate P-gp inhibitor, increased the mean AUC of rivaroxaban by 1.5 times and Cmax by 1.4 times. The above increases are not considered to be clinically relevant. Erythromycin (500 mg three times daily), which moderately inhibits CYP3A4 and P-gp, increased the mean AUC and Cmax of rivaroxaban by 1.3 times. The above increases are not considered to be clinically relevant. The combined use of enoxaparin (40 mg, single dose) and rivaroxaban (10 mg, single dose) has an additive effect on anti-factor Xa activity, but no additive effect on coagulation tests (PT, aPTT). Enoxaparin does not affect the pharmacokinetics of rivaroxaban. If the patient is receiving any other anticoagulant treatment at the same time, special caution should be exercised due to the increased risk of bleeding. Nonsteroidal anti-inflammatory drugs/platelet aggregation inhibitors No clinically significant prolongation of bleeding time was observed when rivaroxaban was used in combination with 500 mg naproxen. However, Some individuals may experience more pronounced pharmacodynamic effects. No clinically significant pharmacokinetic or pharmacodynamic interactions were observed with the co-administration of rivaroxaban and 500 mg acetylsalicylic acid. Clopidogrel (300 mg loading dose followed by 75 mg maintenance dose) did not demonstrate a pharmacokinetic interaction, but an associated prolongation of bleeding time was observed in a subgroup of patients, which was not associated with platelet aggregation, P-selectin, or GPIb/α receptor levels. Salicylic acid) and platelet aggregation inhibitors should be used with caution because these drugs generally increase the risk of bleeding. CYP3A4 inducers Combination use of rivaroxaban with the strong CYP3A4 inducer rifampicin reduces the average AUC of rivaroxaban by about 50%, and the efficacy is also reduced in parallel. Combination use of rivaroxaban with other strong CYP3A4 inducers (such as phenytoin, carbamazepine, phenobarbital or St. John's wort) may also reduce the blood concentration of rivaroxaban. Caution should be exercised when using strong CYP3A4 inducers. Other combined medications will reduce rivaroxaban. No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when rivaroxaban was co-administered with midazolam (CYP3A4 substrate), digoxin (P-gp substrate), or atorvastatin (CYP3A4 and P-gp substrate). Rivaroxaban neither inhibited nor induced any major CYP isoforms (e.g., CYP3A4). No clinically significant interactions with food were observed. Laboratory parameters As expected, coagulation parameters (e.g., PT, aPTT, HepTest) were affected by the mode of action of rivaroxaban tablets.
[Precautions]
1. Bleeding Risk: As detailed below, some subgroups of patients are at increased risk of bleeding. Following initiation of treatment, these patients should be closely monitored for signs of bleeding complications. This can be achieved through regular physical examinations, close monitoring of surgical wound drainage, and periodic hemoglobin measurement. Any unexplained decrease in hemoglobin or blood pressure should prompt investigation for the source of bleeding.
2. Renal Impairment: In patients with severe renal impairment (creatinine clearance <30 mL/min), rivaroxaban plasma concentrations may be significantly elevated, leading to an increased risk of bleeding. Rivaroxaban is not recommended for patients with a creatinine clearance <15 mL/min. Rivaroxaban should be used with caution in patients with a creatinine clearance of 15-29 mL/min. Patients with moderate renal impairment (creatinine clearance 30-49 mL/min) should use rivaroxaban with caution when taking concomitant medications that may increase rivaroxaban plasma concentrations.
3. Liver damage: In patients with cirrhosis and moderate liver damage (Child Pugh B class), rivaroxaban blood concentrations may increase significantly, leading to an increased risk of bleeding. Rivaroxaban is contraindicated in patients with liver disease accompanied by coagulation abnormalities and clinically relevant bleeding risks. For patients with cirrhosis and moderate liver damage (Child Pugh B class), rivaroxaban can be used with caution if there is no coagulation abnormality.
4. Interactions with other drugs: In the case of azole-antifungal agents (such as ketoconazole, itraconazole, voriconazole and posaconazole).
[Pharmacology and Toxicology]
1. Pharmacological action (1) Rivaroxaban is a highly selective oral drug that directly inhibits factor Xa. By inhibiting factor Xa, it can interrupt the intrinsic and extrinsic pathways of the coagulation cascade, inhibiting the generation of thrombin and thrombosis. Rivaroxaban does not inhibit thrombin (activated factor I) and has not been shown to have an effect on platelets. (2) A dose-dependent inhibitory effect of rivaroxaban on factor Xa activity was observed in humans. The effect of rivaroxaban on prothrombin time (PT) is dose-dependent and closely correlates with plasma concentrations when measured with NeopLastin® (correlation coefficient 0.98). Different results may be obtained using other reagents. The PT should be read within seconds because the international normalized ratio (INR) is only calibrated and validated for coumarins and cannot be used for other anticoagulants. In patients undergoing major orthopedic surgery, 2-4 hours after tablet administration (when the effect is strongest), the PT at the 5/95th percentile is 13-25 seconds (NeopLastin®) (pre-operative baseline value is 12-15 seconds). (3) Prolongation of the activated partial thromboplastin time (aPTT) and HepTest is also dose-dependent; however, their use in evaluating the efficacy of rivaroxaban is not recommended. Rivaroxaban also has an effect on antagonistic factor Xa activity; however, no calibration standard is currently available. Coagulation parameters do not need to be monitored during routine clinical use of rivaroxaban.
2. Toxicology studies (1) Based on traditional safety pharmacology, single-dose toxicity, phototoxicity, and genotoxicity studies, nonclinical data indicate no specific hazard to humans. The effects observed in repeated-dose toxicity studies were primarily due to the extended pharmacodynamic activity of rivaroxaban. In rats, elevated IgG and IgA plasma concentrations were observed at clinically relevant plasma concentrations. (2) Animal studies have shown reproductive toxicity related to the pharmacological mechanism of action of rivaroxaban (e.g., bleeding complications). Embryo-fetal toxicity (post-implantation loss, delayed/progressive ossification, multiple pale spots on the liver) and increased incidence of common malformations and placental changes were observed at clinically relevant plasma concentrations. In prenatal and postnatal studies in rats, reduced offspring viability was observed at maternally toxic doses.
