Rexarav 20 Mg/15 mg Tablets

REXARAV 15 mg and REXARAV 20 mg 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

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

SPAF - Recommended usual dose and frequency of administration: The recommended dose is one REXARAV 20 mg tablet once daily. For patients with moderate renal impairment (creatinine clearance < 50 to 30 mL/min) the recommended dose is one REXARAV 15 mg tablet once daily.

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

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

SPAF - Additional information on special populations:

SPAF - Patients with hepatic impairment: REXARAV 15 mg and REXARAV 20 mg 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 sections 4.3 and 5.2).

SPAF - Patients with renal impairment: No dose adjustment is required if REXARAV 20 mg is administered in patients with mild (creatinine clearance u2264 80 to 50 mL/min) renal impairment. For patients with moderate (creatinine clearance < 50 to 30 mL/min) renal impairment the recommended dose is one REXARAV 15 mg once daily. Limited clinical data for patients with severe renal impairment (creatinine clearance < 30 to 15 mL/min) indicate that rivaroxaban plasma levels are significantly increased in this patient population. Therefore REXARAV 15 mg must be used with caution in these patients. Use of REXARAV 15 mg or REXARAV 20 mg is not recommended in patients with creatinine clearance < 15 mL/min (see sections 4.4 and 5.2).

SPAF - Converting from warfarin to REXARAV 15 mg or REXARAV 20 mg: Warfarin treatment should be stopped and REXARAV 15 mg or REXARAV 20 mg therapy should be initiated when the INR is u2264 3.0. When converting patients from warfarin to REXARAV 15 mg or REXARAV 20 mg, INR values will be falsely elevated after the intake of REXARAV 15 mg or REXARAV 20 mg. The INR is not valid to measure the anticoagulant activity of REXARAV 15 mg or REXARAV 20 mg, and therefore should not be used (see section 4.5).

• Hypersensitivity to rivaroxaban or to any of the excipients of REXARAV (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 REXARAV must be carefully observed for signs of bleeding. It is recommended to be used with caution in conditions with increased risk of haemorrhage. REXARAV administration should be discontinued if severe haemorrhage occurs (see section 4.9).

In the clinical studies mucosal bleedings (i.e. epistaxis, gingival, gastrointestinal, genitourinary including abnormal vaginal or increased menstrual bleeding) and anaemia were seen more frequently during long term REXARAV 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 REXARAV 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. REXARAV 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).

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

The use of REXARAV 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).

Care is to be taken if patients are treated concomitantly with medicines affecting haemostasis such as nonsteroidal 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 section 4.5).

Other haemorrhagic risk factors: REXARAV 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
• recent intracranial or intracerebral haemorrhage
• intraspinal or intracerebral vascular abnormalities
• shortly after brain, spinal or ophthalmological surgery
• bronchiectasis or history of pulmonary bleeding.

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

Patients with antiphospholipid syndrome (APS): Direct acting Oral Anticoagulants (DOACs) including REXARAV 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).

Patients with non-valvular atrial fibrillation who undergo PCI with stent placement: Clinical data are available from an interventional study with the primary objective to assess safety in patients with nonvalvular atrial fibrillation who undergo PCI with stent placement. Data on efficacy in this population are limited (see sections 4.2 and 5.1). 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: REXARAV 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 REXARAV 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 20 mg rivaroxaban in these situations.

To reduce the potential risk of bleeding associated with the concurrent use of REXARAV 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 REXARAV (see section 5.2). Following removal of the catheter, at least 6 hours should elapse before the next REXARAV dose is administered. If traumatic puncture occurs the administration of REXARAV is to be delayed for 24 hours.

Women of childbearing potential should avoid becoming pregnant during treatment with REXARAV. Safety and efficacy of REXARAV 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, REXARAV is contraindicated during pregnancy (see section 4.3).

Safety and efficacy of REXARAV have not been established in breastfeeding women. Data from animals indicate that rivaroxaban is secreted into milk. Therefore REXARAV is contraindicated during breastfeeding (see section 4.3).

No specific studies with rivaroxaban in humans have been conducted to evaluate effects on fertility.

REXARAV 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 has been evaluated in four phase III studies including 6097 patients exposed to rivaroxaban 10 mg undergoing major orthopaedic surgery of the lower limbs (total hip replacement or total knee replacement) in 3997 hospitalised medically ill patients treated up to 39 days, and in three phase III VTE treatment trials with 4556 patients exposed either to rivaroxaban 15 mg twice daily for 3 weeks followed by rivaroxaban 20 mg once daily or to rivaroxaban 20 mg once daily treated up to 21 months. Furthermore, safety of rivaroxaban has also been evaluated in 7750 patients with non-valvular atrial fibrillation from two phase III trials with at least one dose of rivaroxaban 15 mg or rivaroxaban 20 mg. Due to the pharmacological mode of action, rivaroxaban 15 mg and rivaroxaban 20 mg 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 (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). 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 rivaroxaban 15 mg and rivaroxaban 20 mg. Therefore, the possibility of a haemorrhage should be considered in evaluating the condition in any anticoagulated patient.

b. Tabulated summary of adverse reactions: The frequencies of adverse reactions reported with REXARAV 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 Anaemia (incl. respective laboratory parameters) Less frequent Thrombocytosis (incl. platelet count increased), thrombocytopenia 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 Haemoptysis, epistaxis 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 Jaundice, bilirubin conjugated increased (with or without concomitant increase of ALT), cholestasis, hepatitis (incl. hepatocellular injury), abnormal hepatic function, hepatic impairment, increased bilirubin, increased blood alkaline phosphatase, increased GGT 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 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), 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, peripheral oedema, decreased general strength and energy (incl. fatigue and asthenia) Less frequent Localised oedema. Feeling unwell (incl. malaise) Investigations Less frequent Increased LDHA, 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.

c. Description of selected adverse reactions: Due to the pharmacological mode of action, the use of REXARAV 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, genitourinary 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). 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 REXARAV. 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 REXARAV or above.

A specific antidote antagonising the pharmacodynamic effect of REXARAV not available. Due to the high plasma protein binding rivaroxaban is not expected to be dialysable. The use of activated charcoal to reduce absorption in case of REXARAV overdose may be considered.

Management of bleeding: Should a bleeding complication arise in a patient receiving REXARAV, the next REXARAV 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 rivaroxaban. Protamine sulphate and vitamin K are not expected to affect the anticoagulant activity of REXARAV. There is limited experience with tranexamic acid and no experience with aminocaproic acid and aprotinin in individuals receiving REXARAV. There is neither scientific rationale for benefit nor experience with the use of the systemic haemostatic desmopressin in individuals receiving REXARAV. Due to the high plasma protein binding REXARAV is not expected to be dialysable.