Axolta Tablets

AXOLTA 10 mg is indicated for:

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

AXOLTA 15 mg and 20 mg is 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).

AXOLTA 10 mg:

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

The recommended dose is one AXOLTA 10 mg tablet once daily for the prevention of venous thromboembolism (VTE) in major orthopaedic surgery. The initial dose should be taken within 6 - 10 hours after surgery provided that haemostasis has been established.

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.

Missed dose: If a dose is missed the patient should take AXOLTA 10 mg immediately and continue on the following day with the once daily intake as before.

Special populations: Patients with hepatic impairment: Prevention of VTE: AXOLTA 10 mg is contra-indicated 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 of the 10 mg is necessary in patient with other hepatic diseases. Limited clinical data in patients with moderate hepatic impairment indicate a significant increase in the pharmacological activity. No clinical data are available for patients with severe hepatic impairment.

Patients with renal impairment: Prevention of VTE: No dose adjustment is required if AXOLTA 10 mg is administered in patients with mild (creatinine clearance 80 u2013 50 mL/min) or moderate (creatinine clearance < 50 - 30 mL/min) renal impairment. Limited clinical data for patients with severe renal impairment (creatinine clearance < 30 mL/min) indicate that rivaroxaban plasma levels are significantly increased in this patient population. Therefore AXOLTA 10 mg must be used with caution in these patients (see section 4.4).

AXOLTA 15 mg and AXOLTA 20 mg: Posology: There is no need for monitoring of coagulation parameters during treatment with AXOLTA 15 mg and AXOLTA 20 mg. Prevention of stroke and systemic embolism (SPAF): The recommended dose is one AXOLTA 20 mg tablet once daily. For patients with moderate renal impairment (creatinine clearance u02c2 50 to 30 mL/min) the recommended dose is one AXOLTA 15 mg tablet once daily.

Duration of treatment: Therapy should be continued as long as risk factors for stroke and systemic embolism persist. Missed dose: If a dose is missed the patient should take AXOLTA 15 mg or AXOLTA 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.

Maximum daily dose: The recommended maximum daily dose is one AXOLTA 20 mg tablet. DVT and PE treatment - Recommended usual dose and frequency of administration: The recommended dose for the initial treatment of acute DVT and PE is one AXOLTA 15 mg tablet twice daily for the first three weeks followed by one AXOLTA 20 mg tablet once daily for the continued treatment and the prevention of recurrent DVT and PE.

DVT and PE treatment - Duration of treatment: Therapy should be continued as long as the VTE risk persists. DVT and PE treatment - Missed dose: It is essential to adhere to the dosage schedule provided. If a dose is missed during the AXOLTA 15 mg twice daily treatment phase the patient should take AXOLTA 15 mg immediately to ensure intake of 30 mg per day. In this case two AXOLTA 15 mg tablets may be taken at once. The patient should continue with the regular one AXOLTA 15 mg twice daily intake as recommended on the following day. If a dose is missed during the AXOLTA 20 mg once daily treatment phase the patient should take AXOLTA 20 mg immediately to ensure intake of 20 mg per day. The patient should continue with the regular one AXOLTA 20 mg once daily intake as recommended on the following day.

DVT and PE treatment - 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.

Special populations: Patients with hepatic impairment: SPAF: AXOLTA 15 mg and AXOLTA 20 mg is contraindicated in patients with hepatic disease with or without coagulopathy (see section 4.3). DVT and PE treatment: AXOLTA 15 mg and AXOLTA 20 mg 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).

Patients with renal impairment: SPAF: No dose adjustment is required if AXOLTA 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 AXOLTA 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 AXOLTA 15 mg must be used with caution in these patients. Use of AXOLTA 15 mg or AXOLTA 20 mg is not recommended in patients with creatinine clearance < 15 mL/min (see sections 4.4 and 5.2).

DVT, PE and post-surgery treatment: No dose adjustment is required if AXOLTA 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 5.1). 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 AXOLTA 15 mg and AXOLTA 20 mg must be used with caution in these patients. Use of AXOLTA 15 mg or AXOLTA 20 mg is not recommended in patients with creatinine clearance < 15 mL/min (see sections 4.4 and 5.2).

SPAF u2013 Converting from warfarin to AXOLTA 15 mg or AXOLTA 20 mg: Warfarin treatment should be stopped and AXOLTA 15 mg or AXOLTA 20 mg therapy should be initiated when the INR is u2264 3,0. When converting patients from warfarin to AXOLTA 15 mg or AXOLTA 20 mg, INR values will be falsely elevated after the intake of AXOLTA 15 mg or AXOLTA 20 mg. The INR is not valid to measure the anticoagulant activity of AXOLTA 15 mg or AXOLTA 20 mg, and therefore should not be used (see section 4.4).

DVT and PE treatment u2013 Converting from warfarin to AXOLTA 15 mg: Warfarin treatment should be stopped and AXOLTA 15 mg or 20 mg therapy should be initiated when the INR is u2264 2,5. When converting patients from warfarin to AXOLTA 15 mg, INR values will be falsely elevated after the intake of AXOLTA 15 mg. The INR is not valid to measure the anticoagulant activity of AXOLTA 15 mg or AXOLTA 20 mg, and therefore should not be used (see section 4.5).

• hypersensitivity to rivaroxaban or to any of the ingredients of AXOLTA.
• clinically significant active bleeding (e.g. intracranial bleeding, gastrointestinal bleeding).
• known existing inherited bleeding disorders.
• hepatic disease with or without coagulopathy leading to a clinically relevant bleeding risk.
• pregnancy and lactation.

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

Bleeding risk: AXOLTA 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.

Haemorrhagic risk: Patients taking AXOLTA are to be carefully observed for signs of bleeding. It is recommended to be used with caution in conditions with increased risk of haemorrhage. AXOLTA administration should be discontinued if severe haemorrhage occurs (see section 4.9).

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

Surgery and interventions: If an invasive procedure or surgical intervention is required, AXOLTA 15 mg and AXOLTA 20 mg should be stopped at least 24 hours before the intervention, if possible and based on clinical judgement of the healthcare professional. If the procedure cannot be delayed the increased risk of bleeding should be assessed against the urgency of the intervention. AXOLTA 15 mg and AXOLTA 20 mg 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 healthcare provider should consider the potential benefit versus the risk before neuraxial intervention in patients who are anticoagulated or considered to be anticoagulated for thromboprophylaxis. At least 18 hours should elapse after the last administration of AXOLTA 15 mg and AXOLTA 20 mg before removal of an epidural catheter. Following removal of the catheter, at least 6 hours should elapse before the next AXOLTA 15 mg and AXOLTA 20 mg dose is administered. If a traumatic puncture occurs, the administration of AXOLTA 15 mg and AXOLTA 20 mg should be delayed for 24 hours.

DVT and PE treatment u2013 Renal impairment: AXOLTA 15 mg or AXOLTA 20 mg 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 AXOLTA plasma concentrations (see section 4.5).

SPAF, DVT and PE treatment u2013 Severe 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. Therefore, AXOLTA (all strengths) should be used with caution in patients with severe renal impairment. AXOLTA should also 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).

AXOLTA 15 mg and AXOLTA 20 mg is not recommended in patients receiving concomitant systemic treatment with azole-antimycotics (e.g. ketoconazole, itraconazole, voriconazole and posaconazole) 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).

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).

Women of childbearing potential: AXOLTA should be used in women of childbearing potential only with effective contraception (see section 4.6).

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

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

Hip fracture surgery: AXOLTA has not been studied in interventional clinical studies 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 (see sections 4.2 and 5.1).

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

Dosing recommendations before and after invasive procedures and surgical intervention other than elective hip or knee replacement surgery: If an invasive procedure or surgical intervention is required, AXOLTA should be stopped at least 24 hours before the intervention, if possible and based on the clinical judgement of the healthcare provider. If the procedure cannot be delayed the increased risk of bleeding should be assessed against the urgency of the intervention. AXOLTA 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 in association with the use of AXOLTA (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. AXOLTA 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.

Sugar: AXOLTA contains lactose. Patients with the rare hereditary conditions of galactose intolerance total lactase deficiency or glucose-galactose malabsorption should not take AXOLTA.

Women of childbearing potential / Contraception in males and females: AXOLTA should be used in women of childbearing potential only with effective contraception.

Pregnancy: Safety and efficacy of AXOLTA 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, AXOLTA is contraindicated in pregnancy (see section 4.3).

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

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 AXOLTA has been evaluated in studies including 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 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 (as in AXOLTA), has also been evaluated in patients with non-valvular atrial fibrillation from two phase III trials with at least one dose of either rivaroxaban 15 mg or 20 mg. Due to the pharmacological mode of action, AXOLTA 15 mg and AXOLTA 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 4.2). 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 AXOLTA. Therefore, the possibility of a haemorrhage should be considered in evaluating the condition in any anticoagulated patient.

b). Tabulated summary of adverse reactions:

c). Description of selected adverse reactions: Due to the pharmacological mode of action, the use of AXOLTA 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 conducted, mucosal bleedings (i.e. epistaxis, gingival, gastrointestinal, genito-urinary including abnormal vaginal or increased menstrual bleeding) and anaemia were seen more frequently during long term rivaroxaban treatment compared with VKA treatment. Thus, in addition to adequate clinical surveillance, laboratory testing of haemoglobin/haematocrit could be of value to detect occult bleeding and quantify the clinical relevance of overt bleeding, as judged to be appropriate. The risk of bleedings may be increased in certain patient groups, e.g. those patients with uncontrolled severe arterial hypertension and/or on concomitant treatment affecting haemostasis (see section 4.4 u201cHaemorrhagic risku201d). Menstrual bleeding may be intensified and/or prolonged. Haemorrhagic complications may present as weakness, paleness, dizziness, headache or unexplained swelling, dyspnoea and unexplained shock. In some cases, as a consequence of anaemia, symptoms of cardiac ischaemia like chest pain or angina pectoris have been observed.

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 or above. A specific antidote antagonizing the pharmacodynamic effect of AXOLTA is not available.

Management of overdose: The use of activated charcoal to reduce absorption in case of AXOLTA 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 AXOLTA, the next administration should be delayed, or treatment should be discontinued as appropriate. Rivaroxaban has a half-life of approximately 5 to 13 hours. 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 agent should be considered, such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (APCC), or recombinant factor VIla (r-FVlla). However, there is currently very limited clinical experience with the use of these products in individuals receiving AXOLTA. Protamine sulphate and Vitamin K are not expected to affect the anticoagulant activity of AXOLTA. There is no experience with antifibrinolytic medicines (tranexamic acid, aminocaproic acid) in individuals receiving AXOLTA. There is neither scientific rationale for benefit nor experience with the systemic haemostatics desmopressin and aprotinin in individuals receiving AXOLTA.