Rivaroxaban 10/15/20 Adco 10 mg, 15 mg, 20 mg Tablets

RIVAROXABAN ADCO 10 is indicated for:

• Prevention of venous thromboembolism (VTE) in adult patients undergoing major orthopaedic surgery of the lower limbs.

RIVAROXABAN ADCO 15 and RIVAROXABAN ADCO 20 are indicated for:

• Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (SPAF).
• Treatment of deep vein thrombosis (DVT) and for the prevention of recurrent deep vein thrombosis (DVT) and pulmonary embolism (PE).
• Treatment of pulmonary embolism (PE) and for the prevention of recurrent pulmonary embolism (PE) and deep vein thrombosis (DVT).

Posology

During treatment with RIVAROXABAN ADCO, there is no need for the monitoring of coagulation parameters.

RIVAROXABAN ADCO 10: The recommended dose is one RIVAROXABAN ADCO 10 tablet once daily for the prevention of venous thromboembolism (VTE) in major orthopaedic surgery. The initial dose should be taken within 6 u2013 10 hours after surgery provided that haemostasis has been established.

Duration of treatment: The duration of treatment depends on the type of major orthopaedic surgery:

• Patients undergoing major hip surgery, treatment duration of 5 weeks is recommended.
• For patients undergoing major knee surgery, treatment duration of 2 weeks is recommended.

Missed dose

If a dose is missed, the patient should take RIVAROXABAN ADCO 10 immediately and continue on the following day with the once daily intake as before.

Special populations

Patients with hepatic impairment: Prevention of VTE: RIVAROXABAN ADCO 10 is contraindicated in patients with significant hepatic disease which is associated with coagulopathy leading to a clinically relevant bleeding risk. (see section 4.3). No dose adjustment of the 10 mg is necessary in patients with other hepatic diseases.

Patients with renal impairment: Prevention of VTE: No dose adjustment is required if RIVAROXABAN ADCO 10 is administered in patients with mild (creatinine clearance 80 u2013 50 ml/min) or moderate (creatinine clearance < 50 u2013 30 mL/min) renal impairment.

RIVAROXABAN ADCO 15 and RIVAROXABAN ADCO 20: Posology

There is no need for monitoring of coagulation parameters during treatment with RIVAROXABAN ADCO 15 and RIVAROXABAN ADCO 20.

SPAF (Systemic embolism in patients with non-valvular atrial fibrillation) The recommended dose is one RIVAROXABAN ADCO 20 tablet once daily, which is also the recommended maximum dose.

For patients with moderate renal impairment (creatinine clearance < 50 to 30 mL/min) the recommended dose is one RIVAROXABAN ADCO 15 tablet once daily.

SPAF u2013 Duration of treatment: Therapy should be continued as long as risk factors for stroke and systemic embolism persist.

SPAF u2013 Missed dose: If a dose is missed the patient should take RIVAROXABAN ADCO 15 or RIVAROXABAN ADCO 20 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 u2013 Maximum daily dose: The recommended maximum daily dose is one RIVAROXABAN ADCO 20 tablet (20 mg rivaroxaban).

SPAF Special populations: SPAF u2013 Patients with hepatic impairment: RIVAROXABAN ADCO 15 and RIVAROXABAN ADCO 20 are contraindicated in patients with hepatic disease with or without coagulopathy (see section 4.3). Limited clinical data in patients with moderate hepatic impairment (Child Pugh B) indicate a significant increase in the pharmacological activity. No clinical data are available for patients with severe hepatic impairment (Child Pugh C) (see section 4.3 and 5.2).

SPAF u2013 Patients with renal impairment: No dose adjustment is required if RIVAROXABAN ADCO 20 is administered in patients with mild (creatinine clearance u2264 80 to 50 mL/min) renal impairment. For patients with moderate renal impairment (creatinine clearance < 50 to 30 mL/min) the recommended dose is one RIVAROXABAN ADCO 15 once daily. In patients with severe renal impairment (creatinine clearance < 30 to 15 mL/min) rivaroxaban plasma levels are significantly increased. Therefore RIVAROXABAN ADCO 15 must be used with caution in these patients. Use of RIVAROXABAN ADCO is not recommended in patients with creatinine clearance < 15 mL/min (see section 4.4 and 5.2).

SPAF u2013 Converting from warfarin to RIVAROXABAN ADCO 15 or RIVAROXABAN ADCO 20: Warfarin treatment should be stopped and RIVAROXABAN ADCO 15 or RIVAROXABAN ADCO 20 therapy should be initiated when the (International Normalized Ratio) INR is u2264 3,0. When converting patients from warfarin to RIVAROXABAN ADCO 15 or RIVAROXABAN ADCO 20, INR values will be falsely elevated after the intake of RIVAROXABAN ADCO 15 or RIVAROXABAN ADCO 20. The INR is not valid to measure the anticoagulant activity of RIVAROXABAN ADCO 15 or RIVAROXABAN ADCO 20, and therefore should not be used (see section 4.5).

SPAF u2013 Converting from RIVAROXABAN ADCO 15 or RIVAROXABAN ADCO 20 to warfarin: There is a potential for inadequate anticoagulation during the transition from RIVAROXABAN ADCO 15 or RIVAROXABAN ADCO 20 to warfarin. Continuous adequate anticoagulation should be ensured during any transition to an alternate anticoagulant. It should be noted that RIVAROXABAN ADCO 15 and RIVAROXABAN ADCO 20 can contribute to an elevated INR. In patients converting from rivaroxaban to warfarin, warfarin should be given concurrently until the INR is u2265 2,0.

For the first two days of the conversion period, standard initial dosing of warfarin should be used followed by warfarin dosing, as guided by INR testing. While patients are on both rivaroxaban and warfarin the INR should not be tested earlier than 24 hours after the previous dose but prior to the next dose of rivaroxaban. Once RIVAROXABAN ADCO is discontinued INR testing may be done reliably at least 24 hours after the last dose.

SPAF u2013 Converting from parenteral anticoagulants to RIVAROXABAN ADCO 15 or RIVAROXABAN ADCO 20: For patients currently receiving a parenteral anticoagulant, start RIVAROXABAN ADCO 15 or RIVAROXABAN ADCO 20, 0 to 2 hours before the time that the next scheduled administration of the parenteral medicine (e.g. low molecular weight heparins - LMWH) or at the time of discontinuation of a continuously administered parenteral medicine (e.g. intravenous unfractionated heparin).

SPAF u2013 Converting from RIVAROXABAN ADCO 15 or RIVAROXABAN ADCO 20 to parenteral anticoagulants: Discontinue RIVAROXABAN ADCO 15 or RIVAROXABAN ADCO 20 and give the first dose of parenteral anticoagulant at the time that the next RIVAROXABAN ADCO 15 or RIVAROXABAN ADCO 20 dose would have been taken.

SPAF u2013 Children and adolescents (from birth to 18 years): The safety and efficacy have not been established in children and adolescents below 18 years.

SPAF u2013 Body weight: No dose adjustment is required based on body weight.

DVT and PE treatment u2013 Recommended usual dose and frequency of administration: The recommended dose for the initial treatment of acute DVT and PE is one RIVAROXABAN ADCO 15 tablet twice daily for the first three weeks followed by one RIVAROXABAN ADCO 20 tablet once daily for the continued treatment and the prevention of recurrent DVT and PE. RIVAROXABAN ADCO 15 and RIVAROXABAN ADCO 20 tablets should be taken with food.

DVT and PE treatment u2013 Duration of treatment: Therapy should be continued as long as the VTE (venous thromboembolism) risk persists.

DVT and PE treatment u2013 Missed dose: It is essential to adhere to the dosage schedule provided. If a dose is missed during the RIVAROXABAN ADCO 15 twice daily treatment phase, the patient should take RIVAROXABAN ADCO 15 immediately to ensure intake of 30 mg per day. In this case two RIVAROXABAN ADCO 15 tablets may be taken at once. The patient should continue with the regular one RIVAROXABAN ADCO 15 twice daily intake as recommended on the following day. If a dose is missed during the RIVAROXABAN ADCO 20 once daily treatment phase the patient should take RIVAROXABAN ADCO 20 immediately to ensure intake of 20 mg per day. The patient should continue with the regular one RIVAROXABAN ADCO 20 once daily intake as recommended on the following day.

DVT and PE treatment u2013 Maximum daily dose: The recommended maximum daily dose is 30 mg during the first 3 weeks of treatment. In the following treatment phase the recommended maximum daily dose is 20 mg.

DVT and PE treatment Special populations

DVT and PE treatment u2013 Patients with hepatic impairment: RIVAROXABAN ADCO 15 and RIVAROXABAN ADCO 20 are contraindicated in patients with hepatic disease with or without coagulopathy (see section 4.3). Limited clinical data in patients with moderate hepatic impairment (Child Pugh B) indicate a significant increase in the pharmacological activity. No clinical data are available for patients with severe hepatic impairment (Child Pugh C) (see section 4.3 and 5.2).

DVT and PE treatment u2013 Patients with renal impairment: No dose adjustment is required if RIVAROXABAN ADCO 15 and RIVAROXABAN ADCO 20 is administered in patients with mild (creatinine clearance u2264 80 to 50 m L/min) or moderate (creatinine clearance< 50 to 30 mL/min) renal impairment (see section 5.2).

RIVAROXABAN ADCO are contraindicated in patients with:

• Hypersensitivity to rivaroxaban or any of the excipients of RIVAROXABAN ADCO listed in section 6.1.
• Clinically significant active bleeding. (e.g. intracranial bleeding, gastro bleeding)
• Known existing inherited bleeding disorders.
• Hepatic disease with or without coagulopathy, and clinically relevant bleeding risk including cirrhotic patients with Child Pugh B and C.
• Pregnancy and lactation (see section 4.6).
• 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 or when UFH is given at doses necessary to maintain an open central venous or arterial catheter.

Clinical surveillance in line with anticoagulation practice is recommended throughout the treatment period.

Haemorrhagic risk

As with other anticoagulants, patients taking RIVAROXABAN ADCO are to be carefully observed for signs of bleeding. It is recommended to be used with caution in conditions with increased risk of haemorrhage. Administration of RIVAROXABAN ADCO should be discontinued if severe haemorrhage occurs.

Several sub-groups of patients are at increased risk of bleeding (see section 4.8). These patients are to be carefully monitored for signs and symptoms of bleeding complications and anaemia after initiation of treatment. Any unexplained fall in haemoglobin or blood pressure should lead to a search for a bleeding site.

In addition to adequate clinical surveillance, laboratory testing of haemoglobin/haematocrit could be of value to detect occult bleeding.

Although treatment with RIVAROXABAN ADCO 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.

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. RIVAROXABAN ADCO should 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 sections 4.2 and 5.2).

RIVAROXABAN ADCO should be used with caution in patients with renal impairment concomitantly receiving other medicines which increase rivaroxaban plasma concentrations (see section 4.5).

No dose adjustment is necessary in patients with mild (creatinine clearance 50 u2013 80 ml/min) or moderate (creatinine clearance < 50 to 30 mL/min) renal impairment. No clinical data are available for patients with severe renal impairment (creatinine clearance< 15 mL/min). Therefore, the use of RIVAROXABAN ADCO is not recommended in these patients (see sections 4.2, 5.1 and 5.2).

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.

Concomitant medication

RIVAROXABAN ADCO is not recommended in patients receiving concomitant systemic treatment with azole-antimycotics (e.g. ketoconazole, itraconazole, voriconazole and posaconazole) or HIV protease inhibitors (e.g. ritonavir). These medicines are strong inhibitors of both CYP3A4 and P-gp. Therefore, these medicines may increase rivaroxaban plasma concentrations to a clinically relevant degree which may lead to an increased bleeding risk (see sections 4.5).

The azole anti-mycotic fluconazole, a moderate CYP 3A4 inhibitor, has however less effect on rivaroxaban exposure and can be co-administered (see sections 4.5).

Care is to be taken if patients are treated concomitantly with medicines affecting haemostasis such as non-steroidal anti-inflammatory medicines (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 sections 4.5).

Other haemorrhagic risk factors

RIVAROXABAN ADCO 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
• Other gastrointestinal disease without active ulceration that can potentially lead to bleeding complications (e.g. Inflammatory bowel disease, oesophagitis, gastritis and gastroesophageal reflux disease)
• Recent gastrointestinal ulcerations
• Vascular retinopathy
• Recent intracranial or intracerebral haemorrhage
• lntraspinal or intracerebral vascular abnormalities
• Shortly after brain, spinal or ophthalmological surgery
• Bronchiectasis or history of pulmonary bleeding.

Any unexplained fall in haemoglobin or blood pressure should lead to a search for a bleeding site.

Patients with prosthetic valves

RIVAROXABAN ADCO should not be used for thromboprophylaxis in patients having recently undergone transcatheter aortic valve replacement (TAVR). Safety and efficacy of RIVAROXABAN ADCO have not been studied in patients with prosthetic heart valves. There are therefore no data to support that RIVAROXABAN ADCO provides adequate anticoagulation in this patient population. Treatment with RIVAROXABAN ADCO is not recommended for these patients.

Neuraxial (epidural/spinal) anaesthesia

When neuraxial (epidural/spinal) anaesthesia or spinal puncture is performed patients treated with antithrombotic medicines for prevention of thromboembolic complications are at risk for development of an epidural or spinal haematoma, which may result in long-term paralysis. The risk of these events may be increased by the post-operative use of indwelling epidural catheters or the concomitant use of medicines 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 medical practitioner should consider the potential benefit versus the risk in anticoagulated patients or in patients to be anticoagulated for thromboprophylaxis. There is no clinical experience with the use of 15 mg or 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. At least 18 hours should elapse after the last administration of rivaroxaban, as in RIVAROXABAN ADCO, before removal of an epidural catheter. RIVAROXABAN ADCO should be administered at least 6 hours after the removal of the catheter, or when the anticoagulant effect of RIVAROXABAN ADCO is estimated to be low. If a traumatic puncture occurs, the administration of RIVAROXABAN ADCO should be delayed for 24 hours.

Women of childbearing potential

RIVAROXABAN ADCO should be used in women of childbearing potential only with effective contraception.

QTc prolongation: No QTc prolonging effect is observed with RIVAROXABAN ADCO.

Patient with antiphospholipid syndrome

Direct acting Oral Anticoagulants (DOACs) including RIVAROXABAN ADCO 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

RIVAROXABAN ADCO has not been studied in interventional clinical studies in patients undergoing hip fracture surgery to evaluate efficacy and safety.

Patient with non-valvular atrial fibrillation who undergo PCI with stent placement

Evaluation of rivaroxaban as in RIVAROXABAN ADCO was performed in 7750 patients with non-valvular atrial fibrillation from two phase III trials with at least one dose of RIVAROXABAN ADCO 15 or RIVAROXABAN ADCO 20. Due to the pharmacological mode of action, RIVAROXABAN ADCO 15 and RIVAROXABAN ADCO 20 may be associated with an increased risk of occult or overt bleeding from any tissue and organ which may result in post-haemorrhagic anaemia. The risk of bleedings may be increased in certain patient groups e.g. patients with uncontrolled severe arterial hypertension, impaired renal and hepatic function 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 anaemia. 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.

Haemodynamically unstable PE patients or patients who require thrombolysis or pulmonary embolectomy RIVAROXABAN ADCO 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 ADCO have not been established in these clinical situations.

Elderly population Increasing age may increase haemorrhagic risk (see section 5.2).

Dermatological reactions Serious skin reactions, including Stevens-Johnson syndrome/toxic epidermal necrolysis and medicine reaction with eosinophilia and systemic symptoms (DRESS) syndrome, have been reported during post-marketing surveillance in association with the use of rivaroxaban (see section 4.8). 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 ADCO 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.

Lactose Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take RIVAROXABAN ADCO.

Pharmacokinetic interactions: Rivaroxaban, as in RIVAROXABAN ADCO, is cleared mainly via cytochrome P450 mediated (CYP 3A4, CYP 2J2 and CYP-independent mechanisms) hepatic metabolism and renal excretion of the unchanged medicine, involving the P-glycoprotein (P-gp)/breast cancer resistance protein (Bcrp) transporter systems (see section 5.2).

CYP inhibition: Rivaroxaban does not inhibit CYP3A4 or any other major CYP isoforms.

CYP induction: Rivaroxaban does not induce CYP3A4 or any other major CYP isoforms.

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

Co-administration of RIVAROXABAN ADCO with the azole-antimycotic, ketoconazole (400 mg once daily) or ritonavir strong CYP3A4 and P-gp inhibitors, can have a 2,6-fold/2,5-fold increase in mean rivaroxaban, as in RIVAROXABAN ADCO, steady state AUC and a 1,7-fold/1,6-fold increase in mean rivaroxaban C max with significant increases in its pharmacodynamic effects (which may lead to an increased bleeding risk) (see section 4.4). Therefore, the use of RIVAROXABAN ADCO 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.

Medicines that strongly inhibit only one of the rivaroxaban, as in RIVAROXABAN ADCO, elimination pathways, either CYP3A4 or P-gp, are expected to increase its 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, can have (up to a) 1,5-fold increase in mean rivaroxaban, as in RIVAROXABAN ADCO, AUC and a 1,4-fold increase in C max. This increase is not considered clinically relevant. Erythromycin (500 mg three times a day), which inhibits CYP3A4 and P-gp moderately, can have a 1,3-fold increase in mean rivaroxaban, as in RIVAROXABAN ADCO, AUC and C max. This increase is not considered clinically relevant. Fluconazole (400 mg once daily), considered as a moderate CYP3A4 inhibitor, may have a 1,4-fold increase in mean rivaroxaban, as in RIVAROXABAN ADCO, AUC and a 1,3-fold increase in mean C max. This increase is not considered clinically relevant.

Co-administration of RIVAROXABAN ADCO with the strong CYP 3A4 and P-gp inducer rifampicin could lead to a 50 % decrease in mean rivaroxaban AUC, with parallel decreases in its pharmacodynamic effects (see section 5.2). The concomitant use of RIVAROXABAN ADCO with other strong CYP3A4 inducers (e.g. phenytoin, carbamazepine, phenobarbitone or St. John's Wort) may also lead to a decreased rivaroxaban, as in RIVAROXABAN ADCO, plasma concentration. Strong CYP3A4 inducers should be co-administered with caution or avoided, unless the patient is closely observed for signs and symptoms of thrombosis.

Pharmacodynamic interactions: Administration of enoxaparin (40 mg single dose) with rivaroxaban (10 mg single dose) may have an additive effect on anti-factor Xa activity without any additional effects on clotting tests (PT, aPTT). Enoxaparin will not have any effect on the pharmacokinetics of rivaroxaban. Due to the increased bleeding risk care is to be taken if patients are treated concomitantly with any other anticoagulants. Clopidogrel will not have pharmacokinetic interaction with rivaroxaban, as in RIVAROXABAN ADCO but a relevant increase in bleeding time may be observed (not correlated to platelet aggregation, P-selectin or GPIIb/IIIa receptor levels (see section 4.4). Care is to be taken if patients are treated concomitantly with NSAIDs (including acetylsalicylic acid) and platelet aggregation inhibitors because these medicines typically increase the bleeding risk. No clinically relevant prolongation of bleeding time was observed after concomitant administration of RIVAROXABAN ADCO 15 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, as in RIVAROXABAN ADCO, was co-administered with 500 mg acetylsalicylic acid.

Converting patients from the vitamin K antagonist warfarin (INR 2,0 to 3,0) to rivaroxaban (20 mg) or from rivaroxaban (20 mg), as in RIVAROXABAN ADCO, to warfarin (INR 2,0 to 3,0) will have an increase in the 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 needed to test the pharmacodynamic effects of rivaroxaban, as in RIVAROXABAN ADCO, during the conversion period, anti-factor Xa activity, prothrombinase-induced clotting time (PiCT), and Heptest u00ae can be used as these tests are 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) will reflect 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 in RIVAROXABAN ADCO. No interactions: No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when rivaroxaban, as in RIVAROXABAN ADCO, was co-administered with midazolam (substrate of CYP3A4), digoxin (substrate of P-gp) or atorvastatin (substrate of CYP3A4 and P-gp). Rivaroxaban, as in RIVAROXABAN ADCO, neither inhibits nor induces any major CYP isoforms like CYP3A4. Co-administration of the proton pump inhibitor omeprazole, H2 receptor antagonist, ranitidine, the antacid aluminium hydroxide/magnesium hydroxide, naproxen, clopidogrel or enoxaparin will not affect the bioavailability and pharmacokinetics of rivaroxaban, as in RIVAROXABAN ADCO.

Interaction with laboratory parameters Clotting parameters (e.g. PT, aPTT, HepTest) will be affected (as expected) by the mode of action of rivaroxaban.

Women of childbearing potential

Women of child-bearing potential should avoid becoming pregnant or use effective contraception during treatment with RIVAROXABAN ADCO. (see section 4.4)

Pregnancy

The use of RIVAROXABAN ADCO is contraindicated in pregnancy. (see section 4.3) 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. haemorrhagic complications), leading to reproductive toxicity. It has been shown that RIVAROXABAN ADCO crosses the placenta and may cause an intrinsic risk of bleeding.

Lactation

Safety and efficacy of RIVAROXABAN ADCO have not been established in lactating mothers. RIVAROXABAN ADCO may only be administered after breastfeeding is discontinued (see section 4.3).

RIVAROXABAN ADCO has minor influence on the ability to drive and use machines. Syncope and dizziness may be experienced. It is therefore recommended that patients experiencing these adverse reactions should not drive or use machines.

a. Summary of the safety profile

There may be an increased risk of occult or overt bleeding from any tissue and organ which may result in post haemorrhagic anaemia due to the pharmacological mode of action of RIVAROXABAN ADCO. The risk of bleedings may be increased in certain patient groups e.g. patients with uncontrolled severe arterial hypertension, impaired renal and hepatic function and/or on concomitant medication affecting haemostasis (see section 4.4). 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 section 4.9). Menstrual bleeding may be intensified and/or prolonged. Haemorrhagic complications may present as weakness, paleness, dizziness, headache or unexplained swelling, dyspnoea and unexplained shock. Symptoms of cardiac ischaemia like chest pain or angina pectoris have been observed in some cases as a consequence of anaemia. Known complications secondary to severe bleeding such as compartment syndrome and renal failure due to hypoperfusion have been reported for RIVAROXABAN ADCO.

b. Tabulated summary of adverse reactions

System Organ Class Frequency Adverse Event

Blood and lymphatic system disorders Frequent Anaemia (including respective laboratory parameters).

Less frequent Thrombocythemia (incl. platelet count increased).

Immune system disorders Less frequent Allergic reaction, allergic dermatitis, angioedema, allergic oedema and anaphylactic reactions including anaphylactic shock

Nervous system disorders Frequent Dizziness and headache.

Less frequent Cerebral and intracranial haemorrhage, syncope.

Eye disorders Frequent Eye haemorrhage (incl. conjunctival haemorrhage).

Cardiac disorders Less frequent Tachycardia

Vascular disorders Frequent Hypotension and haematoma

Respiratory, thoracic and mediastinal disorders Frequent Epistaxis, haemoptysis

Gastrointestinal disorders Frequent Gingival bleeding, gastrointestinal tract haemorrhage (incl. rectal haemorrhage), gastrointestinal and abdominal pains, dyspepsia, nausea, constipation, diarrhoea, vomiting

Less frequent Dry mouth

Hepato-biliary disorders Frequent Increase in transaminases

Less frequent Hepatic impairment, increased bilirubin, increased blood alkaline phosphatase, increased GGT, jaundice, bilirubin conjugated increased (with or without concomitant increase of ALT), cholestasis, hepatitis (incl. hepatocellular injury)

Skin and subcutaneous tissue disorders Frequent Pruritus (incl. uncommon cases of generalised pruritus), rash, ecchymosis, cutaneous and subcutaneous haemorrhage

Less frequent Urticaria, Stevens-Johnson syndrome/ Toxic Epidermal Necrolysis, DRESS syndrome

Musculoskeletal and connective tissue disorders Frequent Pain in extremity

Less frequent Haemarthrosis, muscle haemorrhage, compartment syndrome secondary to a bleeding

Renal and urinary disorders Frequent Urogenital tract haemorrhage (incl. haematuria and menorrhagia), renal impairment (incl. blood creatinine increased, blood urea increased)

Less frequent Renal failure/acute renal failure secondary to a bleeding sufficient to cause hypoperfusion

General disorders and administration site conditions Frequent Fever, peripheral oedema, decreased general strength and energy (incl. fatigue and asthenia)

Less frequent Feeling unwell (incl. malaise), localised oedema

Investigations Frequent Increase GGT, increase in transaminase (incl. ALT increase, AST increase).

Less frequent Increased LDH, increased lipase, increased amylase

Injury, poisoning and procedural complications Frequent Postprocedural haemorrhage (incl. postoperative anaemia, and wound haemorrhage), contusion, wound secretion

Less frequent Vascular pseudoaneurysm

Overdose following administration of RIVAROXABAN ADCO may lead to haemorrhagic complications due to its pharmacodynamic properties. The use of activated charcoal to reduce absorption in case of RIVAROXABAN ADCO overdose may be considered. Administration of activated charcoal up to 8 hours after overdose may reduce the absorption of rivaroxaban.

Due to the high plasma protein binding RIVAROXABAN ADCO is not expected to be dialysable.

Should bleeding occur, management of the haemorrhage may include the following steps:

• Delay of the next RIVAROXABAN ADCO administration or discontinuation of treatment as appropriate. Rivaroxaban, as in RIVAROXABAN ADCO, has a half-life of approximately 5 to 13 hours.
• Appropriate symptomatic treatment, e.g. mechanical compression (e.g., for severe epistaxis), surgical interventions, fluid replacement and haemodynamic support, blood product (packed red cells or fresh frozen plasma, depending on associated anaemia or coagulopathy) or platelets.

If bleeding cannot be controlled by the above measures, consider administration of one of the following procoagulants:

• Specific factor Xa inhibitor reversal agent (andexanet alfa), which antagonises the pharmacodynamic effect of rivaroxaban, as in RIVAROXABAN ADCO
• Activated prothrombin complex concentrate (APCC)
• Prothrombin complex concentrate (PCC)
• Recombinant Factor VIIa (rF VIIa)

However, there is currently very limited clinical experience with the use of these medicines in individuals receiving rivaroxaban, as in RIVAROXABAN ADCO. Protamine Sulphate and Vitamin K are not expected to affect the anticoagulant activity of rivaroxaban as in RIVAROXABAN ADCO. There is no experience with antifibrinolytic medicines (tranexamic acid, aminocaproic acid) in individuals receiving RIVAROXABAN ADCO. There is neither scientific rationale for benefit nor experience with the system haemostatics desmopressin and aprotinin in individuals receiving RIVAROXABAN ADCO.