Ixarola 15 Mg/20 Mg Film-Coated Tablets

IXAROLA 15 and IXAROLA 20 are indicated for:

• Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation (SPAF) with one or more risk factors, such as congestive heart failure, hypertension, age u2265 75 years, diabetes mellitus, prior stroke or transient ischaemic attack.
• 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

IXAROLA 15 and IXAROLA 20 tablets should be taken with food.

SPAF u2013 Recommended usual dose and frequency of administration: The recommended dose is one IXAROLA 20 tablet once daily. For patients with moderate renal impairment (creatinine clearance < 50 to 30 ml/min) the recommended dose is one IXAROLA 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 IXAROLA 15 or IXAROLA 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 IXAROLA 20 tablet (20 mg rivaroxaban).

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 IXAROLA 15 tablet twice daily for the first three weeks followed by one IXAROLA 20 tablet once daily for the continued treatment and the prevention of recurrent DVT and PE.

Short duration of therapy (at least 3 months) should be considered in patients with DVT or PE provoked by major transient risk factors (i.e. recent major surgery or trauma). Longer duration of therapy should be considered in patients with provoked DVT or PE not related to major transient risk factors, unprovoked DVT or PE, or a history of recurrent DVT or PE.

When extended prevention of recurrent DVT and PE is indicated (following completion of at least 6 months therapy for DVT or PE), the recommended dose is 10 mg once daily. In patients in whom the risk of recurrent DVT or PE is considered high, such as those with complicated comorbidities, or who have developed recurrent DVT or PE on extended prevention with IXAROLA 10 mg once daily, a dose of IXAROLA 20 mg once daily should be considered.

The duration of therapy and dose selection should be individualised after careful assessment of the treatment benefit against the risk for bleeding (see section 4.4).

Time period Dosing schedule Total daily dose Treatment and prevention of recurrent DVT and PE Day 1 - 21 15 mg twice daily 30 mg Day 22 onwards 20 mg once daily 20 mg Prevention of recurrent DVT and PE Following completion of at least 6 months therapy for DVT or PE 10 mg once daily or 20 mg once daily 10 mg or 20 mg

If a dose is missed during the 15 mg twice daily treatment phase (day 1 to 21), the patient should take IXAROLA immediately to ensure intake of 30 mg IXAROLA per day. In this case two 15 mg tablets may be taken at once. The patient should continue with the regular 15 mg twice daily intake as recommended on the following day.

If a dose is missed during the once daily treatment phase, the patient should take IXAROLA immediately, and continue on the following day with the once daily intake as recommended. The dose should not be doubled within the same day to make up for a missed dose.

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

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

Converting from warfarin to IXAROLA 15 or IXAROLA 20: Warfarin treatment should be stopped and IXAROLA 15 or IXAROLA 20 therapy should be initiated when the INR is u2264 3,0. For patients treated for DVT, PE and prevention of recurrence, VKA treatment should be stopped and IXAROLA therapy should be initiated once the INR is u2264 2.5. When converting patients from warfarin to IXAROLA 15 or IXAROLA 20, INR values will be falsely elevated after the intake of IXAROLA 15 or IXAROLA 20. The INR is not valid to measure the anticoagulant activity of IXAROLA 15 or IXAROLA 20, and therefore should not be used (see section 4.5).

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

In patients converting from IXAROLA 15 or IXAROLA 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 IXAROLA 15 or IXAROLA 20 and warfarin, the INR should not be tested earlier than 24 hours (after the previous dose but prior to the next dose of IXAROLA 15 or IXAROLA 20). Once IXAROLA 15 or IXAROLA 20 is discontinued INR testing may be done reliably 24 hours after the last dose (see section 4.5 and 5.2).

Converting from parenteral anticoagulants to IXAROLA 15 or IXAROLA 20: For patients currently receiving a parenteral anticoagulant, start IXAROLA 15 or IXAROLA 20, 0 to 2 hours before the time of the next scheduled administration of the parenteral medicine (e.g. LMWH) or at the time of discontinuation of a continuously administered parenteral medicine (e.g. intravenous unfractionated heparin).

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

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

Additional information on special populations: Patients with hepatic impairment: IXAROLA 15 and IXAROLA 20 are contra-indicated in patients with hepatic disease with coagulopathy and clinically relevant bleeding risk including cirrhotic patients with Child Pugh B and C. (see section 4.3 and 5.2) 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 4.3 and 5.2).

Patients with renal impairment: 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 IXAROLA 15 or IXAROLA 20 must be used with caution in these patients. Use of IXAROLA 15 or IXAROLA 20 is not recommended in patients with creatinine clearance < 15 ml/min (see section 4.4 and 5.2).

No dose adjustment is required if IXAROLA 20 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 IXAROLA 15 once daily.

In patients with moderate (creatinine clearance 30 - 49 ml/min) or severe (creatinine clearance 15 - 29 ml/min) renal impairment the following dose recommendations apply:

• For the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation, the recommended dose is 15 mg once daily (see section 5.2).
• For the treatment of DVT, treatment of PE and prevention of recurrent DVT and PE: patients should be treated with 15 mg twice daily for the first 3 weeks. Thereafter, when the recommended dose is 20 mg once daily, a reduction of the dose from 20 mg once daily to 15 mg once daily should be considered if the patientu2019s assessed risk for bleeding outweighs the risk for recurrent DVT and PE. The recommendation for the use of 15 mg is based on PK modelling and has not been studied in this clinical setting (see sections 4.4, 5.1 and 5.2).
• When the recommended dose is 10 mg once daily, no dose adjustment from the recommended dose is necessary.

Children and adolescents (from birth to 18 years): Safety and efficacy have not been established in children and adolescents below 18 years in the indication prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation. . No data are available.

Body weight: No dose adjustment is required based on body weight (see section 5.2).

Patients undergoing cardioversion IXAROLA can be initiated or continued in patients who may require cardioversion. For transesophageal echocardiogram (TEE) guided cardioversion in patients not previously treated with anticoagulants, IXAROLA treatment should be started at least 4 hours before cardioversion to ensure adequate anticoagulation (see sections 5.1 and 5.2). For all patients, confirmation should be sought prior to cardioversion that the patient has taken IXAROLA as prescribed. Decisions on initiation and duration of treatment should take established guideline recommendations for anticoagulant treatment in patients undergoing cardioversion into account.

Patients with non-valvular atrial fibrillation who undergo PCI (percutaneous coronary intervention) with stent placement There is limited experience of a reduced dose of 15 mg IXAROLA once daily (or 10 mg IXAROLA once daily for patients with moderate renal impairment [creatinine clearance 30 - 49 ml/min]) in addition to a P2Y12 inhibitor for a maximum of 12 months in patients with non-valvular atrial fibrillation who require oral anticoagulation and undergo PCI with stent placement (see sections 4.4 and 5.1).

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

IXAROLA 15 and IXAROLA 20 are contra-indicated in patients with:

• Hypersensitivity to rivaroxaban or any excipient of the tablets.
• Clinically significant active bleeding (e.g. intracranial bleeding, gastrointestinal bleeding).
• Known existing inherited bleeding disorders.
• Persistent triple positive antiphospholipid syndrome (APS).
• Hepatic disease associated with 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 IXAROLA 15 and IXAROLA 20 have not been established in pregnant women. Animal data show that rivaroxaban crosses the placental barrier. Therefore the use of IXAROLA 15 and IXAROLA 20 are contra-indicated throughout pregnancy (see section 4.6).
• Safety and efficacy of IXAROLA 15 and IXAROLA 20 have not been established in breastfeeding mothers. Animal data indicate that rivaroxaban is secreted into breast milk. Therefore IXAROLA 15 and IXAROLA 20 may only be administered after breastfeeding is discontinued (see section 4.6).

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

Patients with prosthetic valves: IXAROLA 15 and IXAROLA 20 should not be used for thromboprophylaxis in patients having recently undergone transcatheter aortic valve replacement (TAVR). Safety and efficacy of IXAROLA 15 and IXAROLA 20 have not been studied in patients with prosthetic heart valves; therefore, there are no data to support that IXAROLA 20 (IXAROLA 15 in patients with moderate or severe renal impairment) provides adequate anti-coagulation in this patient population. Treatment with IXAROLA 15 and IXAROLA 20 is not recommended.

Patients with antiphospholipid syndrome (APS) Treatment of patients with established APS is not recommended as evidence regarding safety and efficacy, including the benefit/harm balance of rivaroxaban (and DOACs with the same mechanism of action) in APS patients, is inconclusive. There is some evidence that treatment of persistently triple positive APS patients with rivaroxaban is associated with an increased risk of recurrent arterial thrombotic events compared with treatment of these patients with warfarin; a vitamin K antagonist (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 non-valvular 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/ transient ischaemic attack (TIA).

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

Bleeding risk: As with other anticoagulants, patients taking IXAROLA are to be carefully observed for signs of bleeding. It is recommended to be used with caution in conditions with increased risk of haemorrhage. IXAROLA 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 rivaroxaban treatment compared with VKA treatment. Thus, in addition to adequate clinical surveillance, laboratory testing of haemoglobin/haematocrit could be of value to detect occult bleeding and quantify the clinical relevance of overt bleeding, as judged to be appropriate.

Several sub-groups of patients, as detailed above, 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 rivaroxaban does not require routine monitoring of exposure, rivaroxaban levels measured with a calibrated quantitative anti-factor Xa assay may be useful in exceptional situations where knowledge of rivaroxaban exposure may help to inform clinical decisions, e.g. overdose and emergency surgery (see sections 5.1 and 5.2).

IXAROLA 15 and IXAROLA 20 should be used with caution in patients with an increased bleeding risk such as:

• Congenital or acquired bleeding disorders
• Uncontrolled severe arterial hypertension
• 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.
• other gastrointestinal disease without active ulceration that can potentially lead to bleeding complications (e.g. inflammatory bowel disease, oesophagitis, gastritis and gastroesophageal reflux disease)

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

Surgery and interventions: If an invasive procedure or surgical intervention is required, IXAROLA 15 and IXAROLA 20 should be stopped at least 24 hours before the intervention, if possible and based on clinical judgement of the medical practitioner. If the procedure cannot be delayed the increased risk of bleeding should be assessed against the urgency of the intervention. IXAROLA 15 and IXAROLA 20 should be restarted after the invasive procedure or surgical intervention as soon as possible provided the clinical situation allows and adequate haemostasis has been established (see section 5.2).

Bleeding during antithrombotic treatment may unmask underlying yet unknown malignancy, in particular in the gastrointestinal or genitourinary tract. Patients with malignant disease may simultaneously be at higher risk of bleeding and thrombosis. The individual benefit of antithrombotic treatment should be weighed against risk for bleeding in patients with active cancer dependent on tumor location, antineoplastic therapy and stage of disease.

Neuraxial (epidural/spinal) anaesthesia or puncture: When neuraxial (epidural/spinal) anaesthesia or spinal puncture is performed patients treated with antithrombotics for prevention of thromboembolic complications are at risk for development of an epidural or spinal haematoma, which may result in long-term or permanent paralysis. The risk of these events is further increased by 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 punctures. Patients should be frequently monitored for signs and symptoms of neurological impairment (e.g., numbness or weakness of the legs, bowel or bladder dysfunction). If neurological deficits are noted, urgent diagnosis and treatment is necessary. The medical practitioner should consider the potential benefit versus the risk before neuraxial intervention in patients who are anticoagulated or considered to be anticoagulated for thromboprophylaxis. There is no clinical experience with the use of IXAROLA 15 and IXAROLA 20 in these situations. To reduce the potential risk of bleeding associated with the concurrent use of IXAROLA 15 and IXAROLA 20 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 adult patients and 26 hours in elderly patients should elapse after the last administration of IXAROLA 15 and IXAROLA 20 (see section 5.2). Following removal of the catheter, at least 6 hours should elapse before the next rivaroxaban dose is administered. If a traumatic puncture occurs, the administration of IXAROLA 15 or IXAROLA 20 should be delayed for 24 hours.

DVT and PE treatment u2013 Renal impairment: IXAROLA 15 and IXAROLA 20 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 u2013 Renal impairment: In patients with severe renal impairment (creatinine clearance < 30 ml/min) rivaroxaban plasma levels may be significantly elevated (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.

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 IXAROLA: The concomitant use of IXAROLA 15 or IXAROLA 20 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 IXAROLA with the azole-antimycotic ketoconazole (400 mg once daily) a strong CYP 3A4 and P-gp inhibitor, led to a 2.6-fold increase in mean rivaroxaban steady state AUC and a 1.7-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)

Co-administration of IXAROLA 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 IXAROLA with the HIV protease inhibitor ritonavir (100 mg twice daily) is not available. Therefore IXAROLA 15 and IXAROLA 20 are not recommended in patients receiving concomitant systemic treatment with azole-antimycotics or HIV-protease inhibitors (see section 4.4).

Other active substances strongly inhibiting only one of the rivaroxaban elimination pathways, either CYP 3A4 or P-gp, are expected to increase rivaroxaban plasma concentrations to a lesser extent. Clarithromycin (500 mg twice daily), considered a strong CYP 3A4 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 daily), which inhibits CYP 3A4 and P-gp moderately, led to a 1.3-fold increase in mean rivaroxaban AUC and C max. This increase is within the magnitude of the normal variability of AUC and C max and is considered as clinically not relevant.

Fluconazole (400 mg once daily), considered a moderate CYP 3A4 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 rivaroxaban should be avoided.

CYP3A4 inducers Co-administration of IXAROLA with the strong CYP 3A4 and P-gp inducer rifampicin led to an approximate 50 % decrease in mean rivaroxaban AUC, with parallel decreases in its pharmacodynamic effects (see section 5.2). The concomitant use of IXAROLA 15 or IXAROLA 20 with other strong CYP 3A4 inducers (e.g. phenytoin, carbamazepine, phenobarbitone or St. Johnu2019s Wort (Hypericum perforatum)) may also lead to a decreased rivaroxaban plasma concentration. Strong CYP 3A4 inducers should be co-administered with caution.

Pharmacodynamic interactions: Anticoagulants After combined administration of enoxaparin (40 mg single dose) with IXAROLA 10 (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 (see sections 4.3 and 4.4). 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 Clopidogrel (300 mg loading dose followed by 75 mg maintenance dose) did not show a pharmacokinetic interaction with IXAROLA 15 but a relevant increase in bleeding times was observed in a subset of patients which was not correlated to platelet aggregation, P-selectin or GPIIb/IIIa receptor levels (see u201cWarningsu201d). No clinically relevant prolongation of bleeding time was observed after concomitant administration of IXAROLA 15 and 500 mg naproxen. Nevertheless there may be individuals with more pronounced pharmacodynamic response. No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when IXAROLA was co-administered with 500 mg acetylsalicylic acid. Care is to be taken if patients are treated concomitantly with NSAIDs (including acetylsalicylic acid) and platelet aggregation inhibitors because these medicinal products typically increase the bleeding risk (see section 4.4).

SSRIs/SNRIs As with other anticoagulants the possibility may exist that patients are at increased risk of bleeding in case of concomitant use with SSRIs or SNRIs due to their reported effect on platelets. When concomitantly used in the rivaroxaban clinical programme, numerically higher rates of major or non-major clinically relevant bleeding were observed in all treatment groups.

Warfarin Converting patients from warfarin (INR 2.0 to 3.0) to IXAROLA 20 or from IXAROLA 20 to warfarin (INR 2.0 to 3.0) increased prothrombin time/INR (Neoplastinu00ae) 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 IXAROLA 15 or IXAROLA 20 during the conversion period, anti-Factor Xa activity, prothrombinase-induced clotting time (PiCT), and HepTestu00ae can be used as these tests were not affected by warfarin. From day 4 after stopping warfarin, all tests (including PT, aPTT, inhibition of factor Xa activity and ETP) reflected only the effect of IXAROLA 15 or IXAROLA 20. 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 IXAROLA.

Interactions shown not to exist: There were no mutual pharmacokinetic interactions between IXAROLA and midazolam (substrate of CYP 3A4), digoxin (substrate of P-glycoprotein) or atorvastatin (substrate of CYP 3A4 and P-gp). Co-administration of the proton pump inhibitor omeprazole, the H2 receptor antagonist ranitidine, the antacid aluminium hydroxide/magnesium hydroxide, naproxen, clopidogrel or enoxaparin did not affect rivaroxaban bioavailability and pharmacokinetics.

Interactions with laboratory parameters: Clotting parameter tests (PT, aPTT, HepTestu00ae) are affected as expected by the mode of action of IXAROLA 15 and IXAROLA 20.

Women of childbearing potential: IXAROLA 15 and IXAROLA 20 should be used in women of childbearing potential only with effective contraception.

Pregnancy: Safety and efficacy of IXAROLA 15 and IXAROLA 20 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. No primary teratogenic potential was identified. Due to the intrinsic risk of bleeding and the evidence that rivaroxaban passes the placenta, IXAROLA 15 and IXAROLA 20 is contra-indicated in pregnancy (see section 4.3).

Lactation: Safety and efficacy of IXAROLA 15 and IXAROLA 20 have not been established in nursing mothers. In rats rivaroxaban is secreted into breast milk. Therefore IXAROLA 15 and IXAROLA 20 may only be administered after breastfeeding is discontinued (see section 4.3).

Fertility No specific studies with IXAROLA in humans have been conducted to evaluate effects on fertility. In a study on male and female fertility in rats no effects were seen (see section 5.3).

Syncope and dizziness have been reported and may affect the ability to drive and use machines (see section 4.8). Patients experiencing these adverse reactions should not drive or use machines.

Summary of the safety profile The safety of rivaroxaban has been evaluated in twenty phase III studies including 70,021 patients exposed to rivaroxaban (see Table 1).

Rare cases of overdose up to 1960 mg have been reported. In case of overdose, observe your patient carefully for bleeding complications or other adverse reactions (see section u2018Management of bleedingu2019). Due to limited absorption a ceiling effect with no further increase in average plasma exposure is expected at supratherapeutic doses of 50 mg or above. A specific antidote antagonising the pharmacodynamic effect of IXAROLA 15 and IXAROLA 20 is not available in South Africa. The use of activated charcoal to reduce absorption in case of IXAROLA 15 and IXAROLA 20 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 IXAROLA 15 and IXAROLA 20, 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 factor Xa inhibitor reversal agent (andexanet alfa) should be considered, such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (APCC), or recombinant factor VIIa (r-FVIIa). However, there is currently very limited clinical experience with the use of these products in individuals receiving IXAROLA 15 or IXAROLA 20. 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 IXAROLA 15 or IXAROLA 20.