Aziriv Tablets

AZIRIV 10 is indicated for the prevention of venous thromboembolism (VTE) in patients undergoing major orthopaedic surgery of the lower limbs. AZIRIV 15 & 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

There is no need for monitoring of coagulation parameters during treatment with AZIRIV.

VTE u2013 Recommended usual dose and frequency of administration:

The recommended dose is one AZIRIV 10 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 AZIRIV 10 immediately and continue on the following day with the once daily intake as before.

VTE u2013 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.

VTE u2013 Special patient populations

VTE u2013 Elderly (above 65 years), Gender and Body Weight: No dose adjustment is required for these patient populations.

VTE u2013 Children (up to 18 years of age) The safety and efficacy of AZIRIV 10 has not been established in children. No clinical data is available for children.

VTE u2013 Patients with impaired liver function

AZIRIV 10 is contraindicated in patients with significant hepatic disease which is associated with coagulopathy leading to a clinically relevant bleeding risk (see section 4.3). No dose adjustment 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.

VTE u2013 Patients with impaired renal function

No dose adjustment is required if AZIRIV 10 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 AZIRIV 10 must be used with caution in these patients (see section 4.4).

VTE u2013 Ethnic differences

No dose adjustment is required based on ethnic differences.

SPAF u2013 Recommended usual dose and frequency of administration:

The recommended dose is one AZIRIV 20 tablet once daily. For patients with moderate renal impairment (creatinine clearance < 50 to 30 ml/min) the recommended dose is one AZIRIV 15 tablet once daily. AZIRIV tablets should be taken with food.

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 AZIRIV 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 AZIRIV 20 tablet (20 mg rivaroxaban).

SPAF u2013 Additional information on special populations:

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

SPAF u2013 Patients with renal impairment: No dose adjustment is required if AZIRIV 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 AZIRIV 15 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 AZIRIV 15 must be used with caution in these patients. Use of AZIRIV is not recommended in patients with creatinine clearance < 15 ml/min (see section 4.4 & section 5.2).

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

SPAF u2013 Converting from AZIRIV to warfarin: There is a potential for inadequate anticoagulation during the transition from AZIRIV to warfarin. Continuous adequate anticoagulation should be ensured during any transition to an alternate anticoagulant. It should be noted that AZIRIV can contribute to an elevated INR. In patients converting from AZIRIV 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 AZIRIV and warfarin, the INR should not be tested earlier than 24 hours (after the previous dose but prior to the next dose of AZIRIV). Once AZIRIV 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 AZIRIV: For patients currently receiving a parenteral anticoagulant, start AZIRIV, 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).

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

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

SPAF u2013 Body weight: No dose adjustment is required based on body weight (see section 5.2).

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 AZIRIV 15 tablet twice daily for the first three weeks followed by one AZIRIV 20 tablet once daily for the continued treatment and the prevention of recurrent DVT and PE. AZIRIV tablets should be taken with food.

DVT and PE treatment u2013 Duration of treatment:

Therapy should be continued as long as the VTE risk persists.

DVT and PE treatment u2013 Missed dose:

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

DVT and PE treatment u2013 Maximum daily dose:

The recommended maximum daily dose is 30 mg during the first 3 weeks of treatment. In the following treatment phase the recommended maximum daily dose is 20 mg.

DVT and PE treatment u2013 Additional information on special populations:

DVT and PE treatment u2013 Patients with hepatic impairment: AZIRIV 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 section 4.3 and section 5.2).

DVT and PE treatment u2013 Patients with renal impairment: No dose adjustment is required if AZIRIV is administered in patients with mild (creatinine clearance u2264 80 to 50 ml/min) or moderate (creatinine clearance < 50 to 30 ml/min) renal impairment (see section 5.2). 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, AZIRIV must be used with caution in these patients. Use of AZIRIV is not recommended in patients with creatinine clearance < 15 ml/min (see section 4.4 and section 5.2).

DVT and PE treatment u2013 Converting from warfarin to AZIRIV 15: Warfarin treatment should be stopped and AZIRIV 15 therapy should be initiated once the INR is u2264 2,5. When converting patients from warfarin to AZIRIV 15, INR values will be falsely elevated after the intake of AZIRIV 15. The INR is not valid to measure the anticoagulant activity of AZIRIV 15, and therefore should not be used (see section 4.5).

DVT and PE treatment u2013 Converting from AZIRIV to warfarin: There is a potential for inadequate anticoagulation during the transition from AZIRIV to warfarin. Continuous adequate anticoagulation should be ensured during any transition to an alternate anticoagulant. It should be noted that AZIRIV can contribute to an elevated INR. In patients converting from AZIRIV 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 AZIRIV and warfarin, the INR should not be tested earlier than 24 hours (after the previous dose but prior to the next dose of AZIRIV). Once AZIRIV is discontinued INR testing may be done reliably 24 hours after the last dose (see section 4.5).

DVT and PE treatment u2013 Converting from parenteral anticoagulants to AZIRIV 15: For patients currently receiving a parenteral anticoagulant, start AZIRIV 15, 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).

DVT and PE treatment u2013 Converting from AZIRIV to parenteral anticoagulants: Discontinue AZIRIV and give the first dose of parenteral anticoagulant at the time that the next AZIRIV dose would have been taken.

DVT and PE treatment u2013 Children and adolescents (from birth to 18 years): Safety and efficacy have not been established in children and adolescents below 18 years.

DVT and PE treatment u2013 Body weight: No dose adjustment is required based on body weight (see section 5.2).

Method of administration: Oral use. AZIRIV tablets should be taken with food.

AZIRIV are contra-indicated in patients with:

• Hypersensitivity to rivaroxaban or any excipient listed in section 6.1.
• Clinically significant active bleeding (e.g. intracranial bleeding, gastrointestinal bleeding).
• Known existing inherited bleeding disorders.
• Hepatic disease with or without coagulopathy.
• Patients with persistent triple positive antiphospholipid syndrome (APS)
• Pregnancy and breastfeeding (see section 4.6).

Patients with prosthetic valves: Safety and efficacy of AZIRIV have not been studied in patients with prosthetic heart valves; therefore, there are no data to support that AZIRIV 20 (AZIRIV 15 in patients with moderate or severe renal impairment) provides adequate anti-coagulation in this patient population.

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 direct acting oral anticoagulants (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).

Bleeding risk: AZIRIV should be used with caution in patients with an increased bleeding risk such as:

• Congenital or acquired bleeding disorders
• Uncontrolled severe arterial hypertension
• Active ulcerative gastrointestinal disease
• Recent gastrointestinal ulcerations
• 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.

Care should be taken if patients are treated concomitantly with medicines affecting haemostasis such as non-steroidal anti-inflammatory medicines (NSAIDs), platelet aggregation inhibitors, or other antithrombotics (see section 4.5). For patients at risk of ulcerative gastrointestinal disease an appropriate prophylactic treatment may be considered (see section 4.5). 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, AZIRIV 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. AZIRIV 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).

Neuraxial (epidural/spinal) anaesthesia: 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 paralysis. The risk of these events is further increased by 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. An epidural catheter should not be withdrawn earlier than 18 hours after the last administration of AZIRIV. AZIRIV should be administered not before 6 hours after the removal of the catheter. If a traumatic puncture occurs, the administration of AZIRIV should be delayed for 24 hours.

DVT and PE treatment u2013 Renal impairment: AZIRIV 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. Due to limited clinical data AZIRIV should be used with caution in patients with creatinine clearance < 30 to 15 ml/min. No clinical data are available for patients with severe renal impairment (creatinine clearance < 15 ml/min). Therefore, the use of AZIRIV is not recommended in these patients (see section 4.2; section 5.1 & 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.

AZIRIV is not recommended in patients receiving concomitant systemic treatment with azole-antimycotics (e.g. ketoconazole) or HIV protease inhibitors (e.g. ritonavir). These medicines are strong inhibitors of both CYP 3A4 and P-gp. Therefore, these medicines may increase rivaroxaban plasma concentrations to a clinically relevant degree which may lead to an increased bleeding risk (see 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).

QTc prolongation: No QTc prolonging effect was observed with AZIRIV.

Lactose The tablets contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take AZIRIV.

Women of childbearing potential: AZIRIV should be used in women of childbearing potential only with effective contraception.

Pregnancy: Safety and efficacy of AZIRIV have not been established in pregnant women. Due to the intrinsic risk of bleeding and the evidence that rivaroxaban passes the placenta, AZIRIV is contra-indicated in pregnancy (see section 4.3).

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

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

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

Due to the pharmacological mode of action, AZIRIV 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. Therefore, the possibility of a haemorrhage should be considered in evaluating the condition in any anticoagulated patient.

Adverse reactions classified by system organ class and MedDRA are presented in the table below (Table 1). Table 1: Tabulated list of adverse reactions (MedDRA) from reported placebo-controlled studies and from post-marketing experience

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. The use of activated charcoal to reduce absorption in case of rivaroxaban overdose may be considered.

Management of bleeding: Should a bleeding complication arise in a patient receiving rivaroxaban, the next rivaroxaban 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 agent (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 medicinal products in individuals receiving rivaroxaban. 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 rivaroxaban. There is limited experience with tranexamic acid and no experience with aminocaproic acid and aprotinin in individuals receiving rivaroxaban. There is neither scientific rationale for benefit nor experience with the use of the systemic haemostatic desmopressin in individuals receiving rivaroxaban. Due to the high plasma protein binding rivaroxaban is not expected to be dialysable.