Rivaxored

RIVAXORED (Rivaroxaban Tablets 10 mg): Light Pink colored, round biconvex film coated tablets, engraved with '10' on one side and plain on other side.
Each film-coated tablet contains 10 mg rivaroxaban.
RIVAXORED (Rivaroxaban Tablets 15 mg): Red colored, round biconvex film coated tablets, engraved with '15' on one side and plain on other side.
Each film-coated tablet contains 15 mg rivaroxaban.
RIVAXORED (Rivaroxaban Tablets 20 mg): Dark red colored, round biconvex film coated tablets, engraved with '20' on one side and plain on other side.
Each film-coated tablet contains 20 mg rivaroxaban.
Excipients: Each 10 mg, 15 mg and 20 mg film-coated tablet contain lactose monohydrate, see Precautions.
Excipients/Inactive Ingredients: Microcrystalline cellulose; Lactose Monohydrate; Croscarmellose Sodium; Hypromellose 5 CPS; Sodium Lauryl Sulfate; Magnesium Stearate and Opadry Pink 04F540025 (10 mg), Opadry Brown 04F565014 (15 mg), Opadry Red 04F550002 (20 mg).

Pharmacotherapeutic group: Antithrombotic agents, direct factor Xa inhibitors. ATC code: B01AF01.
Pharmacology: Pharmacodynamics: Mechanism of action: Rivaroxaban is a highly selective direct factor Xa inhibitor with oral bioavailability. Inhibition of factor Xa interrupts the intrinsic and extrinsic pathway of the blood coagulation cascade, inhibiting both thrombin formation and development of thrombi. Rivaroxaban does not inhibit thrombin (activated factor II) and no effects on platelets have been demonstrated.
Pharmacodynamic effects: Dose-dependent inhibition of factor Xa activity was observed in humans. Prothrombin time (PT) is influenced by rivaroxaban in a dose dependent way with a close correlation to plasma concentrations (r value equals 0.98) if Neoplastin is used for the assay. Other reagents would provide different results. The readout for PT is to be done in seconds, because the INR is only calibrated and validated for coumarins and cannot be used for any other anticoagulant.
The 3-factor PCC reduced mean Neoplastin PT values by approximately 1.0 second within 30 minutes, compared to reductions of approximately 3.5 seconds observed with the 4-factor PCC. In contrast, the 3-factor PCC had a greater and more rapid overall effect on reversing changes in endogenous thrombin generation than the 4-factor PCC (see Overdosage).
The activated partial thromboplastin time (aPTT) and HepTest are also prolonged dose-dependently; however, they are not recommended to assess the pharmacodynamic effect of rivaroxaban. There is no need for monitoring of coagulation parameters during treatment with rivaroxaban in clinical routine. However, if clinically indicated rivaroxaban levels can be measured by calibrated quantitative anti-factor Xa tests (see Pharmacokinetics as follows).
10 mg: In patients undergoing major orthopaedic surgery, the 5/95 percentiles for PT (Neoplastin) 2-4 hours after tablet intake (i.e. at the time of maximum effect) ranged from 13 to 25 s (baseline values before surgery 12 to 15 s).
15 mg and 20 mg: In patients receiving rivaroxaban for treatment of DVT and PE and prevention of recurrence, the 5/95 percentiles for PT (Neoplastin) 2-4 hours after tablet intake (i.e. at the time of maximum effect) for 15 mg rivaroxaban twice daily ranged from 17 to 32 s and for 20 mg rivaroxaban once daily from 15 to 30 s. At trough (8-16 h after tablet intake) the 5/95 percentiles for 15 mg twice daily ranged from 14 to 24 s and for 20 mg once daily (18-30 h after tablet intake) from 13 to 20 s.
In patients with non-valvular atrial fibrillation receiving rivaroxaban for the prevention of stroke and systemic embolism, the 5/95 percentiles for PT (Neoplastin) 1-4 hours after tablet intake (i.e. at the time of maximum effect) in patients treated with 20 mg once daily ranged from 14 to 40 s and in patients with moderate renal impairment treated with 15 mg once daily from 10 to 50 s. At trough (16-36 h after tablet intake) the 5/95 percentiles in patients treated with 20 mg once daily ranged from 12 to 26 s and in patients with moderate renal impairment treated with 15 mg once daily from 12 to 26 s.
Paediatric population: The European Medicines Agency has deferred the obligation to submit the data with Rivaroxaban in one or more subsets of the paediatric population in the treatment of thromboembolic events. The European Medicines Agency has waived the obligation to submit data or the results of studies with Rivaroxaban in all subsets of the paediatric population in the prevention of thromboembolic events (see Dosage & Administration for information on paediatric use).
Pharmacokinetics: Absorption: Rivaroxaban is rapidly absorbed with maximum concentrations (Cmax) appearing 2-4 hours after tablet intake.
Oral absorption of rivaroxaban is almost complete and oral bioavailability is high for the 2.5 mg and 10 mg tablet dose, irrespective of fasting/fed conditions. Intake with food does not affect rivaroxaban AUC or Cmax at the 2.5 mg and 10 mg dose.
Rivaroxaban pharmacokinetics are approximately linear up to about 15 mg once daily (in fasting state for 15 mg and 20 mg). Under fed conditions Rivaxored 10 mg, 15 mg and 20 mg tablets demonstrated dose-proportionality. At higher doses rivaroxaban displays dissolution limited absorption with decreased bioavailability and decreased absorption rate with increased dose. This is more marked in fasting state than in fed state (for 10 mg).
Variability in rivaroxaban pharmacokinetics is moderate, (with apart from on the day of surgery and the following day when variability in exposure is high for 10 mg only).
Absorption of rivaroxaban is dependent on the site of its release in the gastrointestinal tract. A decrease in AUC and Cmax compared to tablet was reported when rivaroxaban granulate is released in the proximal small intestine. Exposure is further reduced when rivaroxaban is released in the distal small intestine, or ascending colon. Therefore, administration of rivaroxaban distal to the stomach should be avoided since this can result in reduced absorption and related rivaroxaban exposure.
Bioavailability (AUC and Cmax) was comparable for 20 mg rivaroxaban administered orally as a crushed tablet mixed in apple puree, or suspended in water and administered via a gastric tube followed by a liquid meal, compared to a whole tablet. Given the predictable, dose-proportional pharmacokinetic profile of rivaroxaban, the bioavailability data/results are likely applicable to lower rivaroxaban doses.
10 mg: Rivaroxaban 10 mg tablets can be taken with or without food.
15 mg and 20 mg: Due to a reduced extent of absorption an oral bioavailability was determined for the 20 mg tablet under fasting conditions. When Rivaxored 20 mg tablets are taken together with food increases in mean AUC were observed when compared to tablet intake under fasting conditions, indicating almost complete absorption and high oral bioavailability. Rivaxored 15 mg and 20 mg are to be taken with food (see Dosage & Administration).
Distribution: Plasma protein binding in humans is high, with serum albumin being the main binding component. The volume of distribution is moderate with Vss being approximately 50 litres.
Biotransformation 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. 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. The elimination half-life is about 4.5 hours. After oral administration the elimination becomes absorption rate limited. 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.
Special populations: Gender: There were no clinically relevant differences in pharmacokinetics and pharmacodynamics between male and female patients.
Elderly population: Elderly patients exhibited higher plasma concentrations than younger patients, with mean AUC values being higher, mainly due to reduced (apparent) total and renal clearance. No dose adjustment is necessary.
Different weight categories: Extremes in body weight (<50 kg or >120 kg) had only a small influence on rivaroxaban plasma concentrations. No dose adjustment is necessary.
Inter-ethnic differences: No clinically relevant inter-ethnic differences among Caucasian, African-American, Hispanic, Japanese or Chinese patients were observed regarding rivaroxaban pharmacokinetics and pharmacodynamics.
Hepatic impairment: Cirrhotic patients with mild hepatic impairment (classified as Child Pugh A) exhibited only minor changes in rivaroxaban pharmacokinetics (increase in rivaroxaban AUC on average), nearly comparable to their matched healthy patients. In cirrhotic patients with moderate hepatic impairment (classified as Child Pugh B), rivaroxaban mean AUC was significantly increased compared to healthy patients. Unbound AUC was increased. These patients also had reduced renal elimination of rivaroxaban, similar to patients with moderate renal impairment. There are no data in patients with severe hepatic impairment.
The inhibition of factor Xa activity was increased in patients with moderate hepatic impairment as compared to healthy patients; prolongation of PT was similarly increased. Patients with moderate hepatic impairment were more sensitive to rivaroxaban resulting in a steeper PK/PD relationship between concentration and PT.
Rivaxored is contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk, including cirrhotic patients with Child Pugh B and C (see Contraindications).
Renal impairment: There was an increase in rivaroxaban exposure correlated to decrease in renal function, as assessed via creatinine clearance measurements. In patients with mild (creatinine clearance 50-80 ml/min), moderate (creatinine clearance 30-49 ml/min) and severe (creatinine clearance 15-29 ml/min) renal impairment, rivaroxaban plasma concentrations (AUC) were increased. Corresponding increases in pharmacodynamic effects were more pronounced. In individuals with mild, moderate and severe renal impairment the overall inhibition of factor Xa activity was increased respectively as compared to healthy patients; prolongation of PT was similarly increased. There are no data in patients with creatinine clearance <15 ml/min.
Due to the high plasma protein binding rivaroxaban is not expected to be dialysable.
Use is not recommended in patients with creatinine clearance <15 ml/min. Rivaxored is to be used with caution in patients with creatinine clearance 15-29 ml/min (see Precautions).
Pharmacokinetic/pharmacodynamic relationship: The relationship between rivaroxaban concentration and factor Xa activity is best described by an Emax model. For PT, the linear intercept model generally described the data better. Depending on the different PT reagents used, the slope differed considerably. When Neoplastin PT was used, baseline PT was about 13 s and the slope was around 3 to 4 s/(100 mcg/l). The results of the PK/PD analyses were consistent with the data established in healthy patients.
10 mg: In patients, baseline factor Xa and PT were influenced by the surgery resulting in a difference in the concentration-PT slope between the day post- surgery and steady state.
15 mg and 20 mg: The pharmacokinetic/pharmacodynamic (PK/PD) relationship between rivaroxaban plasma concentration and several PD endpoints (factor Xa inhibition, PT, aPTT, Heptest) has been evaluated after administration of a wide range of doses (5-30 mg twice a day).
Paediatric population: Safety and efficacy have not been established for children and adolescents up to 18 years.

10 mg: Prevention of venous thromboembolism (VTE) in adult patients undergoing elective hip or knee replacement surgery.
15 mg and 20 mg: Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation with one or more risk factors, such as congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, prior stroke or transient ischaemic attack.
Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults. (See Precautions for haemodynamically unstable PE patients.)

Posology: 10 mg: The recommended dose is 10 mg rivaroxaban taken orally once daily. The initial dose should be taken 6 to 10 hours after surgery, provided that haemostasis has been established.
The duration of treatment depends on the individual risk of the patient for venous thromboembolism which is determined by the type of orthopaedic surgery.
For patients undergoing major hip surgery, a treatment duration of 5 weeks is recommended.
For patients undergoing major knee surgery, a treatment duration of 2 weeks is recommended.
If a dose is missed the patient should take Rivaxored immediately and then continue the following day with once daily intake as before.
15 mg and 20 mg: Prevention of stroke and systemic embolism: The recommended dose is 20 mg once daily, which is also the recommended maximum dose.
Therapy with Rivaxored should be continued long term provided the benefit of prevention of stroke and systemic embolism outweighs the risk of bleeding (see Precautions).
If a dose is missed the patient should take Rivaxored immediately and continue on the following day with the once daily intake as recommended. The dose should not be doubled within the same day to make up for a missed dose.
Treatment of DVT, treatment of PE and prevention of recurrent DVT and PE: The recommended dose for the initial treatment of acute DVT or PE is 15 mg twice daily for the first three weeks followed by 20 mg once daily for the continued treatment and prevention of recurrent DVT and PE, as indicated in the table as follows. (See Table 1.)

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The duration of therapy should be individualised after careful assessment of the treatment benefit against the risk for bleeding (see Precautions). Short duration of therapy (at least 3 months) should be based on transient risk factors (e.g. recent surgery, trauma, immobilisation) and longer durations should be based on permanent risk factors or idiopathic DVT or PE.
If a dose is missed during the 15 mg twice daily treatment phase (day 1-21), the patient should take Rivaxored immediately to ensure intake of 30 mg Rivaxored 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 once daily treatment phase (day 22 and onwards), the patient should take Rivaxored immediately, and continue on the following day with the once daily intake as recommended. The dose should not be doubled within the same day to make up for a missed dose.
Converting from Vitamin K Antagonists (VKA) to Rivaxored: When converting patients from VKAs to Rivaxored, International Normalized Ratio (INR) values will be falsely elevated after the intake of Rivaxored. The INR is not valid to measure the anticoagulant activity of Rivaxored, and therefore should not be used (see Interactions).
15 mg and 20 mg: For patients treated for prevention of stroke and systemic embolism, VKA treatment should be stopped and Rivaxored therapy should be initiated when the International Normalized Ratio (INR) is ≤3.0.
For patients treated for DVT, PE and prevention of recurrence, VKA treatment should be stopped and Rivaxored therapy should be initiated once the INR is ≤2.5.
Converting from Rivaxored to Vitamin K antagonists (VKA): There is a potential for inadequate anticoagulation during the transition from Rivaxored to VKA. Continuous adequate anticoagulation should be ensured during any transition to an alternate anticoagulant. It should be noted that Rivaxored can contribute to an elevated INR.
In patients converting from Rivaxored to VKA, VKA should be given concurrently until the INR is ≥2.0. For the first two days of the conversion period, standard initial dosing of VKA should be used followed by VKA dosing, as guided by INR testing. While patients are on both Rivaxored and VKA the INR should not be tested earlier than 24 hours after the previous dose but prior to the next dose of Rivaxored. Once Rivaxored is discontinued INR testing may be done reliably at least 24 hours after the last dose (see Interactions and Pharmacology: Pharmacokinetics under Actions).
Converting from parenteral anticoagulants to Rivaxored: For patients currently receiving a parenteral anticoagulant, discontinue the parenteral anticoagulant and start Rivaxored 0 to 2 hours before the time that the next scheduled administration of the parenteral medicinal product (e.g. low molecular weight heparins) would be due or at the time of discontinuation of a continuously administered parenteral medicinal product (e.g. intravenous unfractionated heparin).
Converting from Rivaxored to parenteral anticoagulants: Give the first dose of parenteral anticoagulant at the time the next Rivaxored dose would be taken.
Special populations: Renal impairment: Limited clinical data for patients with severe renal impairment (creatinine clearance 15-29 ml/min) indicate that rivaroxaban plasma concentrations are significantly increased. Therefore, Rivaxored is to be used with caution in these patients. Use is not recommended in patients with creatinine clearance <15 ml/min (see Precautions and Pharmacology: Pharmacokinetics under Actions).
No dose adjustment is necessary in patients with mild renal impairment (creatinine clearance 50-80 ml/min) or moderate renal impairment (creatinine clearance 30-49 ml/min) (for 10 mg) (see Pharmacology: Pharmacokinetics under Actions).
15 mg and 20 mg: In patients with moderate (creatinine clearance 30-49 ml/min) or severe (creatinine clearance 15-29 ml/min) renal impairment the following dosage recommendations apply: For the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation, the recommended dose is 15 mg once daily (see Pharmacology: Pharmacokinetics under Actions).
For the treatment of DVT, treatment of PE and prevention of recurrent DVT and PE: Patients should be treated with 15 mg twice daily for the first 3 weeks. Thereafter when, the recommended dose is 20 mg once daily, a reduction of the dose from 20 mg once daily to 15 mg once daily should be considered if the patient's assessed risk for bleeding outweighs the risk for recurrent DVT and PE. The recommendation for the use of 15 mg is based on PK modelling and has not been studied in this clinical setting (see Precautions, Pharmacology: Pharmacodynamics and Pharmacokinetics under Actions). When the recommended dose is 10 mg once daily, no dose adjustment from the recommended dose is necessary.
Hepatic impairment: Rivaxored is contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic patients with Child Pugh B and C (see Contraindications and Pharmacology: Pharmacokinetics under Actions).
Elderly population: No dose adjustment (see Pharmacology: Pharmacokinetics under Actions).
Body weight: No dose adjustment (see Pharmacology: Pharmacokinetics under Actions).
Gender: No dose adjustment (see Pharmacology: Pharmacokinetics under Actions).
Paediatric population: The safety and efficacy of Rivaxored in children aged 0 to 18 years have not been established. No data are available. Therefore, Rivaxored is not recommended for use in children below 18 years of age.
15 mg and 20 mg: Patients undergoing cardioversion: Rivaxored can be initiated or continued in patients who may require cardioversion.
For transesophageal echocardiogram (TEE) guided cardioversion in patients not previously treated with anticoagulants, Rivaxored treatment should be started at least 4 hours before cardioversion to ensure adequate anticoagulation (see Pharmacology: Pharmacodynamics and Pharmacokinetics under Actions). For all patients, confirmation should be sought prior to cardioversion that the patient has taken Rivaxored as prescribed. Decisions on initiation and duration of treatment should take established guideline recommendations for anticoagulant treatment in patients undergoing cardioversion into account.
Patients with non-valvular atrial fibrillation who undergo PCI (percutaneous coronary intervention) with stent placement: There is limited experience of a reduced dose of 15 mg Rivaxored once daily (or 10 mg Rivaxored once daily for patients with moderate renal impairment [creatinine clearance 30-49 ml/min]) in addition to a P2Y12 inhibitor for a maximum of 12 months in patients with non-valvular atrial fibrillation who require oral anticoagulation and undergo PCI with stent placement (see Precautions and Pharmacology: Pharmacodynamics under Actions).
Method of administration: For oral use.
10 mg: Rivaxored can be taken with or without food (see Interactions and Pharmacology: Pharmacokinetics under Actions).
15 mg and 20 mg: The tablets are to be taken with food (see Pharmacology: Pharmacokinetics under Actions).
For patients who are unable to swallow whole tablets, Rivaxored tablet may be crushed and mixed with water or apple puree immediately prior to use and administered orally. After the administration of crushed Rivaxored 15 mg or 20 mg film-coated tablets, the dose should be immediately followed by food.
The crushed Rivaxored tablet may also be given through gastric tubes after confirmation of the correct gastric placement of the tube. The crushed tablet should be administered in a small amount of water via a gastric tube after which it should be flushed with water. After the administration of crushed Rivaxored 15 mg or 20 mg film-coated tablets, the dose should then be immediately followed by enteral feeding (see Pharmacology: Pharmacokinetics under Actions).

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 reversal agent (andexanet alfa) antagonising the pharmacodynamic effect of rivaroxaban is available (refer to the Summary of Product Characteristics of andexanet alfa).
The use of activated charcoal to reduce absorption in case of rivaroxaban overdose may be considered.
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 a half-life of approximately 5 to 13 hours (see Pharmacology: Pharmacokinetics under Actions). 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 above measures, either the administration of a specific factor Xa inhibitor reversal agent (andexanet alfa), which antagonises the pharmacodynamic effect of rivaroxaban, or a specific procoagulant reversal agent, such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (APCC) or recombinant factor VIIa (r-FVIIa), should be considered. However, there is currently very limited data with the use of these medicinal products in individuals receiving rivaroxaban. The recommendation is also based on limited nonclinical data. Re-dosing of recombinant factor VIIa shall be considered and titrated depending on improvement of bleeding. Depending on local availability, a consultation with a coagulation expert should be considered in case of major bleedings (see Pharmacology: Pharmacodynamics under Actions).
Protamine sulphate 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. Due to the high plasma protein binding rivaroxaban is not expected to be dialysable.

Hypersensitivity to the active substance or to any of the excipients listed in Description.
Active clinically significant bleeding.
Lesion or condition, if considered to be a significant risk for major bleeding. This may include current or recent gastrointestinal ulceration, presence of malignant neoplasms at high risk of bleeding, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial haemorrhage, known or suspected oesophageal varices, arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities.
Concomitant treatment with any other anticoagulants, e.g. unfractionated heparin (UFH), low molecular weight heparins (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux, etc.), oral anticoagulants (warfarin, dabigatran etexilate, apixaban, etc.) except under specific circumstances of switching anticoagulant therapy (see Dosage & Administration) or when UFH is given at doses necessary to maintain an open central venous or arterial catheter (see Interactions).
Hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic patients with Child Pugh B and C (see Pharmacology: Pharmacokinetics under Actions).
Pregnancy and breast-feeding (see Use in Pregnancy & Lactation).

Clinical surveillance in line with anticoagulation practice is recommended throughout the treatment period.
Haemorrhagic risk: As with other anticoagulants, patients taking Rivaxored are to be carefully observed for signs of bleeding. It is recommended to be used with caution in conditions with increased risk of haemorrhage. Rivaxored administration should be discontinued if severe haemorrhage occurs (see Overdosage).
Mucosal bleedings (i.e. epistaxis, gingival, gastrointestinal, genito urinary including abnormal vaginal or increased menstrual bleeding) and anaemia were seen more frequently during long term rivaroxaban treatment compared with VKA treatment. Thus, in addition to adequate clinical surveillance, laboratory testing of haemoglobin/haematocrit could be of value to detect occult bleeding and quantify the clinical relevance of overt bleeding, as judged to be appropriate.
Several sub-groups of patients, as detailed as follows, are at increased risk of bleeding. These patients are to be carefully monitored for signs and symptoms of bleeding complications and anaemia after initiation of treatment (see Adverse Reactions).
Any unexplained fall in haemoglobin or blood pressure should lead to a search for a bleeding site.
Although treatment with rivaroxaban does not require routine monitoring of exposure, rivaroxaban levels measured with a calibrated quantitative anti-factor Xa assay may be useful in exceptional situations where knowledge of rivaroxaban exposure may help to inform clinical decisions, e.g. overdose and emergency surgery (see Pharmacology: Pharmacodynamics and Pharmacokinetics under Actions).
10 mg: In patients receiving Rivaxored for VTE prevention following elective hip or knee replacement surgery, this may be done by regular physical examination of the patients, close observation of the surgical wound drainage and periodic measurements of haemoglobin.
Renal impairment: In patients with severe renal impairment (creatinine clearance <30 ml/min) rivaroxaban plasma levels may be significantly increased (1.6 fold on average) which may lead to an increased bleeding risk. Rivaxored is to be used with caution in patients with creatinine clearance 15-29 ml/min. Use is not recommended in patients with creatinine clearance <15 ml/min (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
10 mg: In patients with moderate renal impairment (creatinine clearance 30-49 ml/min) concomitantly receiving other medicinal products which increase rivaroxaban plasma concentrations Rivaxored is to be used with caution (see Interactions).
15 mg and 20 mg: Rivaxored should be used with caution in patients with renal impairment concomitantly receiving other medicinal products which increase rivaroxaban plasma concentrations (see Interactions).
Interaction with other medicinal products: The use of Rivaxored is not recommended in patients receiving concomitant systemic treatment with azole-antimycotics (such as ketoconazole, itraconazole, voriconazole and posaconazole) or HIV protease inhibitors (e.g. ritonavir). These active substances are strong inhibitors of both CYP3A4 and P-gp and therefore may increase rivaroxaban plasma concentrations to a clinically relevant degree (2.6 fold on average) which may lead to an increased bleeding risk (see Interactions).
Care is to be taken if patients are treated concomitantly with medicinal products affecting haemostasis such as non-steroidal anti-inflammatory medicinal products (NSAIDs), acetylsalicylic acid and platelet aggregation inhibitors or selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs). For patients at risk of ulcerative gastrointestinal disease an appropriate prophylactic treatment may be considered (see Interactions).
Other haemorrhagic risk factors: As with other antithrombotics, rivaroxaban is not recommended in patients with an increased bleeding risk such as: congenital or acquired bleeding disorders; uncontrolled severe arterial hypertension; other gastrointestinal disease without active ulceration that can potentially lead to bleeding complications (e.g. inflammatory bowel disease, oesophagitis, gastritis and gastroesophageal reflux disease); vascular retinopathy; bronchiectasis or history of pulmonary bleeding.
Patients with prosthetic valves: Rivaroxaban should not be used for thromboprophylaxis in patients having recently undergone transcatheter aortic valve replacement (TAVR). Safety and efficacy of Rivaroxaban have not been studied or established in patients with prosthetic heart valves; therefore, there are no data to support that Rivaroxaban provides adequate anticoagulation in this patient population. Treatment with Rivaxored is not recommended for these patients.
Patients with antiphospholipid syndrome: Direct acting Oral Anticoagulants (DOACs) including rivaroxaban are not recommended for patients with a history of thrombosis who are diagnosed with antiphospholipid syndrome. In particular for patients that are triple positive (for lupus anticoagulant, anticardiolipin antibodies, and anti-beta 2-glycoprotein I antibodies), treatment with DOACs could be associated with increased rates of recurrent thrombotic events compared with vitamin K antagonist therapy.
Hip fracture surgery: 10 mg: There is no data of Rivaroxaban in patients undergoing hip fracture surgery on it's efficacy and safety.
Patients with non-valvular atrial fibrillation who undergo PCI with stent placement: 15 mg and 20 mg: Data on efficacy in this population are limited (see Dosage & Administration and Pharmacology: Pharmacodynamics under Actions). No data are available for such patients with a history of stroke/TIA.
Haemodynamically unstable PE patients or patients who require thrombolysis or pulmonary embolectomy: Rivaxored 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 Rivaxored have not been established in these clinical situations.
Spinal/epidural anaesthesia or puncture: When neuraxial anaesthesia (spinal/epidural anaesthesia) or spinal/epidural puncture is employed, patients treated with antithrombotic agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal haematoma which can result in long-term or permanent paralysis. The risk of these events may be increased by the post-operative use of indwelling epidural catheters or the concomitant use of medicinal products affecting haemostasis. The risk may also be increased by traumatic or repeated epidural or spinal puncture. Patients are to be frequently monitored for signs and symptoms of neurological impairment (e.g. numbness or weakness of the legs, bowel or bladder dysfunction). If neurological compromise is noted, urgent diagnosis and treatment is necessary. Prior to neuraxial intervention the physician should consider the potential benefit versus the risk in anticoagulated patients or in patients to be anticoagulated for thromboprophylaxis. There is no data with the use of 20 mg rivaroxaban in these situations.
To reduce the potential risk of bleeding associated with the concurrent use of rivaroxaban and neuraxial (epidural/spinal) anaesthesia or spinal puncture, consider the pharmacokinetic profile of rivaroxaban. Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of rivaroxaban is estimated to be low. However, the exact timing to reach a sufficiently low anticoagulant effect in each patient is not known.
For the removal of an epidural catheter and based on the general PK characteristics at least 2x half-life, i.e. at least 18 hours in young patients and 26 hours in elderly patients should elapse after the last administration of rivaroxaban (see Pharmacology: Pharmacokinetics under Actions). Following removal of the catheter, at least 6 hours should elapse before the next rivaroxaban dose is administered.
If traumatic puncture occurs the administration of rivaroxaban is to be delayed for 24 hours.
Dosing recommendations before and after invasive procedures and surgical intervention other than elective hip or knee replacement surgery: If an invasive procedure or surgical intervention is required, Rivaxored 10 mg and 20 mg should be stopped at least 24 hours before the intervention, if possible and based on the clinical judgement of the physician.
If the procedure cannot be delayed the increased risk of bleeding should be assessed against the urgency of the intervention.
Rivaxored 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 as determined by the treating physician (see Pharmacology: Pharmacokinetics under Actions).
Dermatological reactions: Serious skin reactions, including Stevens-Johnson syndrome/toxic epidermal necrolysis and DRESS syndrome, have been reported during post-marketing surveillance in association with the use of rivaroxaban (see Adverse Reactions). Patients appear to be at highest risk for these reactions early in the course of therapy: the onset of the reaction occurring in the majority of cases within the first weeks of treatment. Rivaroxaban should be discontinued at the first appearance of a severe skin rash (e.g. spreading, intense and/or blistering), or any other sign of hypersensitivity in conjunction with mucosal lesions.
Information about excipients: Rivaxored contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Effects on ability to drive and use machines: Rivaxored has minor influence on the ability to drive and use machines. Adverse reactions like syncope (frequency: uncommon) and dizziness (frequency: common) have been reported (see Adverse Reactions). Patients experiencing these adverse reactions should not drive or use machines.
Use in the Elderly: Increasing age may increase haemorrhagic risk (see Pharmacology: Pharmacokinetics under Actions).

Pregnancy: Due to the potential reproductive toxicity, the intrinsic risk of bleeding and the evidence that rivaroxaban passes the placenta, Rivaxored is contraindicated during pregnancy (see Contraindications).
Women of childbearing potential should avoid becoming pregnant during treatment with rivaroxaban.
Breast-feeding: Safety and efficacy of Rivaroxaban have not been established in breast-feeding women. Rivaxored is contraindicated during breast-feeding (see Contraindications). A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from therapy.
Fertility: No data is available with rivaroxaban to evaluate effects on fertility.

Summary of the safety profile: The most commonly reported adverse reactions in patients receiving Rivaroxaban were bleedings (see Precautions and 'Description of selected adverse reactions' as follows). The most commonly reported bleedings were epistaxis and gastrointestinal tract haemorrhage.
Tabulated list of adverse reactions: The frequencies of adverse reactions reported with Rivaroxaban are summarised in Table 2 as follows by system organ class (in MedDRA) and by frequency.
Frequencies are defined as very common, common, uncommon, rare, very rare or not known. (See Table 2.)

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Description of selected adverse reactions: Due to the pharmacological mode of action, the use of Rivaxored may be associated with an increased risk of occult or overt bleeding from any tissue or organ which may result in post haemorrhagic anaemia. The signs, symptoms, and severity (including fatal outcome) will vary according to the location and degree or extent of the bleeding and/or anaemia (see Management of bleeding under Overdosage). Mucosal bleedings (i.e. epistaxis, gingival, gastrointestinal, genito urinary including abnormal vaginal or increased menstrual bleeding) and anaemia were seen more frequently during long term Rivaroxaban treatment compared with VKA treatment. Thus, in addition to adequate clinical surveillance, laboratory testing of haemoglobin/haematocrit could be of value to detect occult bleeding and quantify the clinical relevance of overt bleeding, as judged to be appropriate. The risk of bleedings may be increased in certain patient groups, e.g. those patients with uncontrolled severe arterial hypertension and/or on concomitant treatment affecting haemostasis (see Haemorrhagic risk under Precautions). Menstrual bleeding may be intensified and/or prolonged. Haemorrhagic complications may present as weakness, paleness, dizziness, headache or unexplained swelling, dyspnoea and unexplained shock. In some cases as a consequence of anaemia, symptoms of cardiac ischaemia 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 Rivaxored. Therefore, the possibility of haemorrhage is to be considered in evaluating the condition in any anticoagulated patient.

CYP3A4 and P-gp inhibitors: Co-administration of rivaroxaban with ketoconazole (400 mg once a day) or ritonavir (600 mg twice a day) led to an increase in mean rivaroxaban AUC and an increase in mean rivaroxaban C_max, with significant increases in pharmacodynamic effects which may lead to an increased bleeding risk.
Therefore, the use of Rivaxored is not recommended in patients receiving concomitant systemic treatment with azole-antimycotics such as ketoconazole, itraconazole, voriconazole and posaconazole or HIV protease inhibitors. These active substances are strong inhibitors of both CYP3A4 and P-gp (see Precautions).
Active substances strongly inhibiting only one of the rivaroxaban elimination pathways, either CYP3A4 or P-gp, are expected to increase rivaroxaban plasma concentrations to a lesser extent.
Clarithromycin (500 mg twice a day), for instance, considered as a strong CYP3A4 inhibitor and moderate P-gp inhibitor, led to an increase in mean rivaroxaban AUC and an increase in C_max. The interaction with clarithromycin is likely not clinically relevant in most patients but can be potentially significant in high-risk patients. (See Precautions for patients with renal impairment.)
Erythromycin (500 mg three times a day), which inhibits CYP3A4 and P-gp moderately, led to an increase in mean rivaroxaban AUC and C_max. The interaction with erythromycin is likely not clinically relevant in most patients but can be potentially significant in high-risk patients.
In patient with mild renal impairment erythromycin (500 mg three times a day) led to an increase in mean rivaroxaban AUC and increase in C_max when compared to patients with normal renal function. In patients with moderate renal impairment, erythromycin led to an increase in mean rivaroxaban AUC and increase in C_max when compared to patients with normal renal function. The effect of erythromycin is additive to that of renal impairment (see Precautions).
Fluconazole (400 mg once daily), considered as a moderate CYP3A4 inhibitor, led to an increase in mean rivaroxaban AUC and an increase in mean Cmax. The interaction with fluconazole is likely not clinically relevant in most patients but can be potentially significant in high-risk patients. (See Precautions for patients with renal impairment.)
Given the limited clinical data available with dronedarone, co-administration with rivaroxaban should be avoided.
Anticoagulants: 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.
Due to the increased bleeding risk care is to be taken if patients are treated concomitantly with any other anticoagulants (see Contraindications and Precautions).
NSAIDs/platelet aggregation inhibitors: 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 a more pronounced pharmacodynamic response.
No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when rivaroxaban was co-administered with 500 mg acetylsalicylic acid.
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 time was observed in a subset of patients which was not correlated to platelet aggregation, P-selectin or GPIIb/IIIa receptor levels.
Care is to be taken if patients are treated concomitantly with NSAIDs (including acetylsalicylic acid) and platelet aggregation inhibitors because these medicinal products typically increase the bleeding risk (see Precautions).
SSRIs/SNRIs: 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 programme, numerically higher rates of major or non-major clinically relevant bleeding were observed in all treatment groups.
Warfarin: Converting patients from the vitamin K antagonist 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, antifactor Xa activity, PiCT, and Heptest can be used as these tests were not affected by warfarin. On the fourth 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 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.
CYP3A4 inducers: Co-administration of rivaroxaban with the strong CYP3A4 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 (e.g. phenytoin, carbamazepine, phenobarbital or St. John's Wort (Hypericum perforatum) may also lead to reduced rivaroxaban plasma concentrations. Therefore, concomitant administration of strong CYP3A4 inducers should be avoided unless the patient is closely observed for signs and symptoms of thrombosis.
Other concomitant therapies: No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when rivaroxaban was co-administered with midazolam (substrate of CYP3A4), digoxin (substrate of P-gp), atorvastatin (substrate of CYP3A4 and P-gp) or omeprazole (proton pump inhibitor). Rivaroxaban neither inhibits nor induces any major CYP isoforms like CYP3A4.
10 mg: No clinically relevant interaction with food was observed (see Dosage & Administration).
Laboratory parameters: Clotting parameters (e.g. PT, aPTT, HepTest) are affected as expected by the mode of action of rivaroxaban (see Pharmacology: Pharmacodynamics under Actions).

Incompatibilities: Not applicable.

Store below 30 Celcius.
Shelf life: 36 months.

Anticoagulants, Antiplatelets & Fibrinolytics (Thrombolytics)

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

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