Myoroxa 10 mg/15 mg/20 mg FC tablets

MYOROXA 10 is indicated for:

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

MYOROXA 15 and MYOROXA 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

Prevention of VTE in patients undergoing major orthopaedic surgery of the lower limbs

The recommended dose is one MYOROXA 10 tablet (10 mg rivaroxaban) taken orally once daily. 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 MYOROXA 10 immediately and then continue the following day with once daily intake as before.

The duration of treatment depends on the type of major 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.

Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (SPAF)

The recommended dose is one MYOROXA 20 tablet (20 mg rivaroxaban) once daily, which is also the recommended maximum dose. For patients with moderate renal impairment (creatinine clearance 30 to < 50 ml/min) the recommended dose is one MYOROXA 15 tablet (15 mg rivaroxaban) once daily. Therapy should be continued as long as risk factors for stroke and systemic embolism persist.

If a dose is missed the patient should take MYOROXA 20 or MYOROXA 15 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 Converting from warfarin to MYOROXA 15 or MYOROXA 20

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

SPAF u2013 Converting from MYOROXA 15 or MYOROXA 20 to warfarin

There is a potential for inadequate anticoagulation during the transition from MYOROXA 15 or MYOROXA 20 to warfarin. Continuous adequate anticoagulation should be ensured during any transition to an alternate anticoagulant. It should be noted that MYOROXA 15 and MYOROXA 20 can contribute to an elevated INR.

In patients converting from MYOROXA 15 or MYOROXA 20 to warfarin, warfarin should be given concurrently until the INR is u2265 2,0. For the first two days of the conversion period, standard warfarin dosing should be used followed by warfarin dosing guided by INR testing. While patients are on both MYOROXA 15 or MYOROXA 20 and warfarin, the INR should not be tested earlier than 24 hours (after the previous dose but prior to the next dose of MYOROXA 15 or MYOROXA 20). Once MYOROXA 15 or MYOROXA 20 is discontinued INR testing may be done reliably 24 hours after the last dose (see section 4.5).

SPAF u2013 Converting from parenteral anticoagulants to MYOROXA 15 or MYOROXA 20

For patients currently receiving a parenteral anticoagulant, start MYOROXA 20 or MYOROXA 15, 0 to 2 hours before the time of the next scheduled administration of the parenteral medicine (e.g., low molecular weight heparins) or at the time of discontinuation of a continuously administered parenteral medicine (e.g., intravenous unfractionated heparin).

SPAF u2013 Converting from MYOROXA 15 or MYOROXA 20 to parenteral anticoagulants

Discontinue MYOROXA 15 or MYOROXA 20 and give the first dose of parenteral anticoagulant at the time that the next MYOROXA 15 or MYOROXA 20 dose would have been taken.

Treatment of DVT and PE, and prevention of recurrent DVT and PE

The recommended dose for the initial treatment of acute DVT and PE is one MYOROXA 15 tablet twice daily for the first three weeks followed by one MYOROXA 20 tablet once daily for the continued treatment and the prevention of recurrent DVT and PE. Therapy should be continued as long as the VTE risk persists. 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. It is essential to adhere to the dosage schedule provided.

If a dose is missed during the MYOROXA 15 twice daily treatment phase the patient should take MYOROXA 15 immediately to ensure intake of 30 mg per day. In this case two MYOROXA 15 tablets may be taken at once. The patient should continue with the regular one MYOROXA 15 twice daily intake as recommended on the following day.

If a dose is missed during the MYOROXA 20 once daily treatment phase the patient should take MYOROXA 20 immediately to ensure intake of 20 mg per day. The patient should continue with the regular one MYOROXA 20 once daily intake as recommended on the following day.

DVT and PE u2013 Converting from warfarin to MYOROXA 15

Warfarin treatment should be stopped and MYOROXA 15 therapy should be initiated when the INR is u2264 2,5. When converting patients from warfarin to MYOROXA 15, INR values will be falsely elevated after the intake of MYOROXA 15. The INR is not valid to measure the anticoagulant activity of MYOROXA 15, and therefore should not be used (see section 4.5).

DVT and PE u2013 Converting from MYOROXA 15 or MYOROXA 20 to warfarin

There is a potential for inadequate anticoagulation during the transition from MYOROXA 15 or MYOROXA 20 to warfarin. Continuous adequate anticoagulation should be ensured during any transition to an alternate anticoagulant. It should be noted that MYOROXA 15 and MYOROXA 20 can contribute to an elevated INR.

In patients converting from MYOROXA 15 or MYOROXA 20 to warfarin, warfarin should be given concurrently until the INR is u2265 2,0. For the first two days of the conversion period, standard warfarin dosing should be used followed by warfarin dosing guided by INR testing. While patients are on both MYOROXA 15 or MYOROXA 20 and warfarin, the INR should not be tested earlier than 24 hours (after the previous dose but prior to the next dose of MYOROXA 15 or MYOROXA 20). Once MYOROXA 15 or MYOROXA 20 is discontinued INR testing may be done reliably 24 hours after the last dose (see section 4.5).

DVT and PE u2013 Converting from parenteral anticoagulants to MYOROXA 15

For patients currently receiving a parenteral anticoagulant, start MYOROXA 15, 0 to 2 hours before the time of the next scheduled administration of the parenteral medicine (e.g., low molecular weight heparins) or at the time of discontinuation of a continuously administered parenteral medicine (e.g., intravenous unfractionated heparin).

DVT and PE u2013 Converting from MYOROXA 15 or MYOROXA 20 to parenteral anticoagulants

Discontinue MYOROXA 15 or MYOROXA 20 and give the first dose of parenteral anticoagulant at the time that the next MYOROXA 15 or MYOROXA 20 dose would have been taken.

Special populations

There is no need for monitoring of coagulation parameters during treatment with MYOROXA (see section 5.1).

Hepatic impairment

MYOROXA is 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).

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, MYOROXA must be used with caution in these patients. Use of MYOROXA is not recommended in patients with creatinine clearance < 15 ml/min (see sections 4.4 and 5.2).

In patients with mild and moderate renal impairment the following dose recommendations apply:

• For the prevention of VTE in patients undergoing major orthopaedic surgery of the lower limbs, no dose adjustment is necessary if MYOROXA 10 is administered in patients with mild (creatinine clearance 50-80 ml/min) or moderate (creatinine clearance 30-49 ml/min) renal impairment (see section 5.2).
• For SPAF, no dose adjustment is necessary if MYOROXA 20 is administered in patients with mild (creatinine clearance 50-80 ml/min) renal impairment. For patients with moderate (creatinine clearance 30-49 ml/min) renal impairment the recommended dose is MYOROXA 15 once daily (see section 5.2).
• For DVT and PE, no dose adjustment is required if MYOROXA 15 or MYOROXA 20 is administered in patients with mild (creatinine clearance 50-80 ml/min) or moderate (creatinine clearance 30-49 ml/min) renal impairment (see section 5.2).

Elderly (above 65 years), Gender and Body Weight

No dose adjustment is required for these patient populations.

Ethnic differences

No dose adjustment is required based on ethnic differences.

Paediatric population

The safety and efficacy of MYOROXA in children aged 0 to 18 years have not been established. No data are available.

Method of administration

Oral use.

MYOROXA 10 tablets can be taken with or without food (see section 5.2).

MYOROXA 15 and MYOROXA 20 tablets should be taken with food (see section 5.2).

For patients who are unable to swallow whole tablets, MYOROXA tablet may be crushed and mixed with water or apple puree immediately prior to use and administered orally. After the administration of crushed MYOROXA 15 mg or 20 mg film-coated tablets, the dose should be immediately followed by food. The crushed MYOROXA 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 MYOROXA 15 mg or 20 mg film-coated tablets, the dose should then be immediately followed by enteral feeding (see section 5.2).

• Hypersensitivity to rivaroxaban or to any of the excipients listed in section 6.1.
• Clinically significant active bleeding (e.g., intracranial bleeding, gastrointestinal bleeding).
• Known existing inherited bleeding disorders.
• Persistent triple positive antiphospholipid syndrome (APS).
• Hepatic disease with or without coagulopathy, and clinically relevant bleeding risk including cirrhotic patients with Child Pugh B and C (see section 5.2).
• 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).
• Safety and efficacy of MYOROXA have not been established in pregnant women or breastfeeding mothers. MYOROXA is therefore contraindicated in pregnancy and breastfeeding (see section 4.6).

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

Haemorrhagic risk

As with other concomitant anticoagulants, patients taking MYOROXA are to be carefully observed for signs of bleeding. It is recommended to be used with caution in conditions with increased risk of haemorrhage. MYOROXA administration should be discontinued if severe haemorrhage occurs (see sections 4.3 and 4.9).

Mucosal bleedings (i.e., epistaxis, gingival, gastrointestinal, genito-urinary including abnormal vaginal or increased menstrual bleeding) and anaemia were reported more frequently during long term MYOROXA treatment compared with vitamin K antagonist 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). In patients receiving MYOROXA 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.

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

Although treatment with MYOROXA 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).

Other haemorrhagic risk factors

• MYOROXA should be used with caution in patients with an increased bleeding risk such as:
• acquired bleeding disorders
• uncontrolled severe arterial hypertension
• vascular retinopathy
• bronchiectasis or history of pulmonary bleeding.

DVT and PE treatment - Renal impairment

MYOROXA is to be used with caution in patients with moderate renal impairment (creatinine clearance < 50 to 30 ml/min) receiving co-medications leading to increased rivaroxaban plasma concentrations (see section 4.5).

SPAF, DVT and PE treatment - 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. Due to the underlying disease these patients are at an increased risk of both bleeding and thrombosis.

Due to limited clinical data MYOROXA should be used with caution in patients with creatinine clearance < 30 to 15 ml/min. Use is not recommended in patients with creatinine clearance < 15 ml/min (see sections 4.2 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

The use of MYOROXA 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 medicines 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).

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

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

Patients with prosthetic valves

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

Patients with antiphospholipid syndrome (APS)

Direct acting Oral Anticoagulants (DOACs) including MYOROXA 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 warfarin; a vitamin K antagonist therapy (see section 4.3).

Hip fracture surgery

The use of MYOROXA to prevent VTE has not been studied in patients undergoing hip fracture surgery to evaluate efficacy and safety.

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 non-valvular atrial fibrillation who undergo PCI with stent placement. Data on efficacy in this population are limited. No data are available for such patients with a history of stroke/transient ischaemic attack (TIA).

Haemodynamically unstable PE patients or patients who require thrombolysis or pulmonary embolectomy

MYOROXA 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 MYOROXA have not been established in these clinical situations.

Neuraxial (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 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 doctor 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 MYOROXA 15 or MYOROXA 20 in these situations.

To reduce the potential risk of bleeding associated with the concurrent use of MYOROXA 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 and should be weighed against the urgency of a diagnostic procedure.

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 adult patients and 26 hours in elderly patients should elapse after the last administration of MYOROXA (see section 5.2). Following removal of the catheter, at least 6 hours should elapse before the next MYOROXA dose is administered.

If traumatic puncture occurs the administration of MYOROXA should be delayed for 24 hours.

Surgery and interventions

If an invasive procedure or surgical intervention other than elective hip or knee replacement surgery is required, MYOROXA 10 should be stopped at least 24 hours before the intervention, if possible and based on the clinical judgement of the doctor.

If an invasive procedure or surgical intervention is required, MYOROXA 15 or MYOROXA 20 should be stopped at least 24 hours before the intervention, if possible and based on the clinical judgement of the doctor.

If the procedure cannot be delayed the increased risk of bleeding should be assessed against the urgency of the intervention. MYOROXA 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 doctor (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 MYOROXA (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. MYOROXA 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.

QTc prolongation

No QTc prolonging effect was observed with MYOROXA.

Information about excipients

MYOROXA tablets contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take MYOROXA.

MYOROXA contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially u201csodium free.

Pharmacokinetic interactions: Rivaroxaban is cleared mainly via cytochrome P450-mediated (CYP 3A4, CYP 2J2) hepatic metabolism and renal excretion of the unchanged drug, involving the P-glycoprotein (P-gp)/breast cancer resistance protein (Bcrp) transporter systems (see u201cPharmacokineticsu201d).

CYP inhibition: Rivaroxaban does not inhibit CYP 3A4 or any other major CYP isoforms.

CYP induction: Rivaroxaban does not induce CYP 3A4 or any other major CYP isoforms.

Effects on MYOROXA: The concomitant use of MYOROXA with strong CYP 3A4 and P-gp inhibitors, may lead to both reduced hepatic and renal clearance and thus significantly increased systemic exposure. Co-administration of MYOROXA with the azole-antimycotic ketoconazole (400 mg once a day) a strong CYP 3A4 and P-gp inhibitor, led to a 2,6 fold increase in mean rivaroxaban AUC and a 1,7 fold increase in mean rivaroxaban C max, with significant increases in pharmacodynamic effects which may lead to an increased bleeding risk (see section 4.4).

Co-administration of MYOROXA with the HIV protease inhibitor ritonavir (600 mg twice daily), a strong CYP 3A4 and P-gp inhibitor, led to a 2,5 fold increase in mean rivaroxaban AUC and a 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).

Data on the co-administration of MYOROXA with the HIV protease inhibitor ritonavir (100 mg twice daily) is not available.

Women of child-bearing potential

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

Pregnancy

Safety and efficacy of MYOROXA have not been established in pregnant women. Due to the potential reproductive toxicity in animals, the intrinsic risk of bleeding and the evidence that rivaroxaban passes the placenta, MYOROXA is contraindicated during pregnancy (see section 4.3).

Breastfeeding

Safety and efficacy of MYOROXA have not been established in breastfeeding women. Data from animals indicate that rivaroxaban is secreted into milk. Therefore, MYOROXA may only be administered after breastfeeding is discontinued (see section 4.3).

Fertility

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

MYOROXA 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.

System organ class (MedDRA)

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)

Description of selected adverse reactions

Due to the pharmacological mode of action, the use of MYOROXA 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). Mucosal bleedings (i.e., epistaxis, gingival, gastrointestinal, genito-urinary including abnormal vaginal or increased menstrual bleeding) and anaemia have been reported more frequently during long term RALAN treatment compared with vitamin K antagonist 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, impaired renal and hepatic function 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 MYOROXA. 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 rivaroxaban or above.

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

Management of bleeding

Should a bleeding complication arise in a patient receiving MYOROXA, the next 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, administration of 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 MYOROXA. 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 MYOROXA. There is limited experience with tranexamic acid and no experience with aminocaproic acid and aprotinin in adults receiving MYOROXA. There is neither scientific rationale for benefit nor experience with the use of the systemic haemostatic desmopressin in individuals receiving MYOROXA.