Rabovix 10 Mg Tablets

RABOVIX 10 mg film-coated tablets are indicated for the prevention of venous thromboembolism (VTE) in patients undergoing major orthopaedic surgery of the lower limbs.

Posology
Recommended dose and frequency of administration: The recommended dose is one RABOVIX 10 mg tablet once daily for the prevention of venous thromboembolism (VTE) in major orthopaedic surgery. The initial dose should be taken within 6 - 10 hours after surgery provided that haemostasis has been established. If a dose is missed the patient should take RABOVIX 10 mg immediately and continue on the following day with the once daily intake as before.
Duration of treatment: The duration of treatment depends on the type of major orthopaedic surgery. After major hip surgery patients should be treated for 5 weeks. After major knee surgery patients should be treated for 2 weeks.
Special patient populations
Elderly (above 65 years), Gender and Body Weight: No dose adjustment is required for these patient populations.
Patients with impaired liver function
RABOVIX 10 mg 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 is necessary in patients with other hepatic diseases. Limited clinical data in patients with moderate hepatic impairment indicate a significant increase in the pharmacological activity. No clinical data are available for patients with severe hepatic impairment.
Patients with impaired renal function
No dose adjustment is required if RABOVIX 10 mg is administered in patients with mild (creatinine clearance 80 u2013 50 mL/min) or moderate (creatinine clearance < 50 - 30 mL/min) renal impairment. Limited clinical data for patients with severe renal impairment (creatinine clearance < 30 mL/min) indicate that rivaroxaban plasma levels are significantly increased in this patient population. Therefore RABOVIX 10 mg must be used with caution in these patients (see section 4.4).
Ethnic differences: No dose adjustment is required based on ethnic differences.
Paediatric population (children up to 18 years of age): The safety and efficacy of RABOVIX 10 mg has not been established in children. No clinical data is available for children.
Method of administration: Oral use. RABOVIX 10 mg may be taken with or without food.

• Hypersensitivity to rivaroxaban or to any of the excipients of RABOVIX (see section 6.1).
• Active clinically significant bleeding (e.g. intracranial bleeding, gastrointestinal 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 section 4.2) or when UFH is given at doses necessary to maintain an open central venous or arterial catheter (see section 4.5).
• Hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic patients with Child Pugh B and C (see section 5.2).
• Pregnancy and lactation (see section 4.6).
• Patients with persistent triple positive antiphospholipid syndrome (APS).

Clinical surveillance in line with anticoagulation practice is recommended throughout the treatment period. Haemorrhagic risk: Patients taking RABOVIX must be carefully observed for signs of bleeding. It is recommended to be used with caution in conditions with increased risk of haemorrhage. RABOVIX administration should be discontinued if severe haemorrhage occurs (see section 4.9). In the clinical studies 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 RABOVIX treatment compared with vitamin K antagonist (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 below, 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 section 4.8). Any unexplained fall in haemoglobin or blood pressure should lead to a search for a bleeding site. Although treatment with RABOVIX 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 sections 5.1 and 5.2).

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. RABOVIX 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 sections 4.2 and 5.2). In patients with moderate renal impairment (creatinine clearance 30 - 49 mL/min) concomitantly receiving other medicines which increase rivaroxaban plasma concentrations RABOVIX is to be used with caution (see section 4.5).

Interaction with other medicines: The use of RABOVIX 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 section 4.5).

Other haemorrhagic risk factors: RABOVIX 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
• recent intracranial or intracerebral haemorrhage
• shortly after brain, spinal or ophthalmological surgery.

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

Patients with antiphospholipid syndrome: Direct acting Oral Anticoagulants (DOACs) including RABOVIX 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 (see section 4.3).

Hip fracture surgery: RABOVIX has not been studied in interventional clinical studies in patients undergoing hip fracture surgery to evaluate efficacy and safety.

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

Spinal/epidural anaesthesia or puncture: When neuraxial anaesthesia (spinal/epidural anaesthesia) or spinal/epidural puncture is performed, patients treated with antithrombotic medicines 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 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 10 mg rivaroxaban in these situations. To reduce the potential risk of bleeding associated with the concurrent use of RABOVIX 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. For the removal of an epidural catheter at least 18 hours should elapse after the last administration of RABOVIX (see section 5.2). Following removal of the catheter, at least 6 hours should elapse before the next RABOVIX dose is administered. If traumatic puncture occurs the administration of RABOVIX is to be delayed for 24 hours.

Dosing recommendations before and after invasive procedures and surgical intervention: If an invasive procedure or surgical intervention is required, RABOVIX 10 mg should be stopped at least 24 hours before the intervention. If the procedure cannot be delayed the increased risk of bleeding should be assessed against the urgency of the intervention. RABOVIX 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 medical practitioner (see section 5.2).

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 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. RABOVIX 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.

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 a 2,6 fold / 2,5 fold increase in mean Rivaroxaban AUC and a 1,7 fold / 1,6 fold increase in mean rivaroxaban C max, with significant increases in pharmacodynamic effects which may lead to an increased bleeding risk. Therefore, the use of RABOVIX 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 section 4.4).
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 a 1,5 fold increase in mean rivaroxaban AUC and a 1,4 fold 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. (For patients with renal impairment: see section 4.4).
Erythromycin (500 mg three times a day), which inhibits CYP3A4 and P-gp moderately, led to a 1,3 fold 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 subjects with mild renal impairment erythromycin (500 mg three times a day) led to a 1,8 fold increase in mean rivaroxaban AUC and 1,6 fold increase in C max when compared to subjects with normal renal function. In subjects with moderate renal impairment, erythromycin led to a 2,0 fold increase in mean rivaroxaban AUC and 1,6 fold increase in C max when compared to subjects with normal renal function. The effect of erythromycin is additive to that of renal impairment (see section 4.4).
Fluconazole (400 mg once daily), considered as a moderate CYP3A4 inhibitor, led to a 1,4 fold increase in mean rivaroxaban AUC and a 1,3 fold increase in mean C max. The interaction with fluconazole is likely not clinically relevant in most patients but can be potentially significant in high-risk patients. (For patients with renal impairment: see section 4.4).
Given the limited clinical data available with dronedarone, co-administration with RABOVIX 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 sections 4.3 and 4.4).
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 medicines typically increase the bleeding risk (see section 4.4).
SSRIs/SNRIs: 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, anti-factor 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. No clinically relevant interaction with food was observed (see section 4.2).

Women of childbearing potential: Women of child-bearing potential should avoid becoming pregnant during treatment with RABOVIX.
Pregnancy: Safety and efficacy of RABOVIX have not been established in pregnant women. Studies in animals have shown reproductive toxicity. Due to the potential reproductive toxicity, the intrinsic risk of bleeding and the evidence that rivaroxaban passes the placenta, RABOVIX is contraindicated during pregnancy (see section 4.3).
Breastfeeding: Safety and efficacy of RABOVIX have not been established in breastfeeding women. Data from animals indicate that rivaroxaban is secreted into milk. Therefore RABOVIX is contraindicated during breastfeeding (see section 4.3).
Fertility: No specific studies with rivaroxaban in humans have been conducted to evaluate effects on fertility.

RABOVIX has minor influence on the ability to drive and use machines. Adverse reactions like syncope and dizziness have been reported (see section 4.8). Patients experiencing these adverse reactions should not drive or use machines.

a. Summary of the safety profile: The safety of rivaroxaban 10 mg has been evaluated in three phase III studies including 4571 patients undergoing major orthopaedic surgery of the lower limbs (total hip replacement or total knee replacement) treated up to 39 days. The adverse reactions are presented within each frequency grouping and system organ classes; the adverse reactions should be interpreted within the surgical setting.
b. Tabulated summary of adverse reactions: The frequencies of adverse reactions reported in phase III clinical trials or through post-marketing use with rivaroxaban 10 mg are summarised in the table below by system organ class (in MedDRA) and by frequency.
MedDRA system organ class Frequency Adverse reactions
Blood and lymphatic system disorders Frequent Thrombocytosis (incl. platelet count increased) A, thrombocytopenia, anaemia (incl. respective laboratory parameters)
Immune system disorders Less frequent Anaphylactic reactions including anaphylactic shock Allergic reaction, dermatitis allergic, angioedema and allergic oedema
Nervous system disorders Frequent Dizziness, 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, 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 A, diarrhoea, vomiting A
Less frequent Dry mouth
Hepato - biliary disorders Frequent Increase in transaminases
Less frequent Jaundice, bilirubin conjugated increased (with or without concomitant increase of ALT), cholestasis, hepatitis (incl. hepatocellular injury), hepatic impairment, increased bilirubin, increased blood alkaline phosphatase A, increased GGT A
Skin and subcutaneous tissue disorders Frequent Pruritus (incl. uncommon cases of generalised pruritus), rash, ecchymosis, cutaneous and subcutaneous haemorrhage
Less frequent Stevens-Johnson syndrome/toxic epidermal necrolysis, DRESS syndrome, urticaria
Musculoskeletal and connective tissue disorders Frequent Pain in extremity A
Less frequent Muscle haemorrhage, haemarthrosis
Frequency Unknown Compartment syndrome secondary to a bleeding
Renal and urinary disorders Frequent Urogenital tract haemorrhage (incl. haematuria and menorrhagia B), renal impairment (incl. blood creatinine increased, blood urea increased)
Frequency Unknown Renal failure/acute renal failure secondary to a bleeding sufficient to cause hypoperfusion
General disorders and administration site conditions Frequent Fever A, peripheral oedema, decreased general strength and energy (incl. fatigue and asthenia)
Less frequent Localised oedema A Feeling unwell (incl. malaise)
Investigations Less frequent Increased LDH A, increased lipase A, increased amylase A
Injury, poisoning and procedural complications Frequent Postprocedural haemorrhage (incl. postoperative anaemia, and wound haemorrhage), contusion, wound secretion A
Less frequent Vascular pseudoaneurysm C
A: observed in prevention of VTE in adult patients undergoing elective hip or knee replacement surgery. B: observed in treatment of DVT, PE and prevention of recurrence as very common in women < 55 years. C: observed as uncommon in prevention of atherothrombotic events in patients after an ACS (following percutaneous coronary intervention). * A pre-specified selective approach to adverse event collection was applied. As incidence of adverse reactions did not increase and no new adverse reaction was identified, COMPASS study data were not included for frequency calculation in this table.
c. Description of selected adverse reactions: Due to the pharmacological mode of action, the use of RABOVIX 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 section 4.9 u201cManagement of bleedingu201d). In the clinical studies 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 section 4.4 u201cHaemorrhagic risku201d). 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 RABOVIX. Therefore, the possibility of haemorrhage is to be considered in evaluating the condition in any anticoagulated patient.

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 RABOVIX or above. A specific reversal medicine (andexanet alfa) antagonising the pharmacodynamic effect of Rivaroxaban is available (refer to the professional information of andexanet alfa). The use of activated charcoal to reduce absorption in case of RABOVIX overdose may be considered. Management of bleeding: Should a bleeding complication arise in a patient receiving RABOVIX, the next RABOVIX administration should be delayed or treatment should be discontinued as appropriate. Rivaroxaban has a half-life of approximately 5 to 13 hours (see section 5.2). 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 medicine (andexanet alfa), which antagonises the pharmacodynamic effect of rivaroxaban, or a specific procoagulant reversal medicine, 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 clinical experience with the use of these medicines in individuals receiving RABOVIX. The recommendation is also based on limited non-clinical 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 section 5.1). Protamine sulphate and vitamin K are not expected to affect the anticoagulant activity of RABOVIX. There is limited experience with tranexamic acid and no experience with aminocaproic acid and aprotinin in individuals receiving RABOVIX. There is neither scientific rationale for benefit nor experience with the use of the systemic haemostatic desmopressin in individuals receiving RABOVIX. Due to the high plasma protein binding RABOVIX is not expected to be dialysable.