Varoxo 10/15/20 10 mg, 15 mg, 20 mg Tablets

VAROXO 10 is indicated for:

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

VAROXO 15 and VAROXO 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

VAROXO 10: During treatment with VAROXO, there is no need for the monitoring of coagulation parameters. The recommended dose is one VAROXO 10 tablet once daily for the prevention of venous thromboembolism (VTE) in major orthopaedic surgery. The initial dose should be taken within 6 u2013 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:

• Patients undergoing major hip surgery, treatment duration of 5 weeks is recommended.
• For patients undergoing major knee surgery, treatment duration of 2 weeks is recommended.

Missed dose

If a dose is missed, the patient should take VAROXO 10 immediately and continue on the following day with the once daily intake as before.

Special populations

Patients with hepatic impairment: Prevention of VTE: VAROXO 10 is contraindicated in patients with significant hepatic disease which is associated with coagulopathy leading to a clinically relevant bleeding risk including cirrhotic patients with Child Pugh B and C. (see section 4.3 and 5.2). No dose adjustment of the 10 mg is necessary in patients with other hepatic diseases.

Patients with renal impairment: Prevention of VTE: No dose adjustment is required if VAROXO 10 is administered in patients with mild (creatinine clearance 80 to 50 mL/min) or moderate (creatinine clearance < 50 to 30 mL/min) renal impairment.

Paediatric population

The safety and efficacy of VAROXO in children below 18 years have not been established. No data is available.

VAROXO 15 and VAROXO 20: Posology

There is no need for monitoring of coagulation parameters during treatment with VAROXO 15 and VAROXO 20. SPAF (Systemic embolism in patients with non-valvular atrial fibrillation) The recommended dose is one VAROXO 20 tablet once daily, which is also the recommended maximum dose. For patients with moderate renal impairment (creatinine clearance < 50 to 30 mL/min) the recommended dose is one VAROXO 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 VAROXO 15 or VAROXO 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 VAROXO 20 tablet (20 mg rivaroxaban).

VAROXO is contraindicated in patients with:

• Hypersensitivity to rivaroxaban or any of the excipients of VAROXO listed in section 6.1.
• Clinically significant active bleeding. (e.g. intracranial bleeding, gastro bleeding)
• Known existing inherited bleeding disorders.
• Hepatic disease with or without coagulopathy, and clinically relevant bleeding risk including cirrhotic patients with Child Pugh B and C.
• Pregnancy and lactation (see section 4.6).
• Persistent triple positive antiphospholipid syndrome (APS).
• 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 or when UFH is given at doses necessary to maintain an open central venous or arterial catheter.

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

Haemorrhagic risk

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

Mucosal bleedings (i.e., epistaxis, gingival, gastrointestinal, genitourinary including abnormal vaginal or increased menstrual bleeding) and anaemia were reported more frequently during long term VAROXO 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 are at increased risk of bleeding (see section 4.8). These patients are to be carefully monitored for signs and symptoms of bleeding complications and anaemia after initiation of treatment. In patients receiving VAROXO 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.

In addition to adequate clinical surveillance, laboratory testing of haemoglobin/haematocrit could be of value to detect occult bleeding. Although treatment with VAROXO 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.

Renal impairment

DVT and PE treatment - Renal impairment VAROXO should be used with caution in patients with moderate renal impairment (creatinine clearance < 50 to 30 mL/min) concomitantly receiving other medicines which increase 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. VAROXO should be used with caution in patients with creatinine clearance 15 to 29 mL/min. Use is not recommended in patients with creatinine clearance < 15 mL/min (see sections 4.2 and 5.2).

No dose adjustment is necessary in patients with mild (creatinine clearance 50 to 80 mL/min) or moderate (creatinine clearance < 50 to 30 mL/min) renal impairment.

No clinical data is available for patients with severe renal impairment (creatinine clearance <15 mL/min). Therefore, the use of VAROXO is not recommended in these patients (see sections 4.2, 5.1 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.

Pharmacokinetic interactions: Rivaroxaban, as in VAROXO, is cleared mainly via cytochrome P450 mediated (CYP 3A4, CYP 2J2 and CYP-independent mechanisms) hepatic metabolism and renal excretion of the unchanged medicine, involving the P-glycoprotein (P-gp)/breast cancer resistance protein (Bcrp) transporter systems (see section 5.2).

CYP inhibition: Rivaroxaban does not inhibit CYP3A4 or any other major CYP isoforms.

CYP induction: Rivaroxaban does not induce CYP3A4 or any other major CYP isoforms.

Effects on VAROXO: The concomitant use of VAROXO with strong CYP3A4 and P-gp inhibitors, may lead to both reduced hepatic and renal clearance and thus significantly increased systemic exposure. Co-administration of VAROXO with the azole-antimycotic, ketoconazole (400 mg once daily) or ritonavir, strong CYP3A4 and P-gp inhibitors, can have a 2,6-fold/2,5-fold increase in mean rivaroxaban, as in VAROXO, steady state AUC and a 1,7-fold/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).

Therefore, the use of VAROXO is not recommended in patients receiving concomitant systemic treatment with azole-antimycotics such as ketoconazole, itraconazole, voriconazole and posaconazole or HIV protease inhibitors. These medicines are strong inhibitors of both CYP3A4 and P-gp (see section 4.4).

Co-administration of VAROXO 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 VAROXO with the HIV protease inhibitor ritonavir (100 mg twice daily) is not available.

Medicines that strongly inhibit only one of the rivaroxaban, as in VAROXO, elimination pathways, either CYP3A4 or P-gp, are expected to increase its plasma concentrations to a lesser extent. Clarithromycin (500 mg twice a day), for instance, considered as a strong CYP3A4 inhibitor and moderate P-gp inhibitor, can have (up to a) 1,5-fold increase in mean rivaroxaban, as in VAROXO, AUC and a 1,4-fold increase in C max. This increase is not considered clinically relevant.

Erythromycin (500 mg three times a day), which inhibits CYP3A4 and P-gp moderately, can have a 1,3-fold increase in mean rivaroxaban, as in VAROXO, AUC and C max. This increase is not considered clinically relevant in most patients but can be potentially significant in high-risk patients. In subjects with mild renal impairment erythromycin (500 mg three times a day) led to a 1,8 fold increase in mean rivaroxaban AUC and 1,6 fold increase in C max when compared to subjects with normal renal function. In subjects with moderate renal impairment, erythromycin led to a 2,0 fold increase in mean rivaroxaban AUC and 1,6 fold increase in C max when compared to subjects with normal renal function. The effect of erythromycin is additive to that of renal impairment (see section 4.4).

Fluconazole (400 mg once daily), considered as a moderate CYP3A4 inhibitor, may have a 1,4-fold increase in mean rivaroxaban, as in VAROXO, AUC and a 1,3-fold increase in mean C max. This increase is not considered clinically relevant. 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).

Co-administration of VAROXO with the strong CYP3A4 and P-gp inducer rifampicin could lead to a 50 % decrease in mean rivaroxaban AUC, with parallel decreases in its pharmacodynamic effects (see section 5.2).

The concomitant use of VAROXO with other strong CYP3A4 inducers (e.g. phenytoin, carbamazepine, phenobarbitone or St. John's Wort) may also lead to a decreased rivaroxaban, as in VAROXO, plasma concentration. Strong CYP3A4 inducers should be co-administered with caution or avoided, unless the patient is closely observed for signs and symptoms of thrombosis.

Given the limited clinical data available with dronedarone, co-administration with rivaroxaban should be avoided.

Pharmacodynamic interactions: Anticoagulants Administration of enoxaparin (40 mg single dose) with rivaroxaban (10 mg single dose) may have an additive effect on anti-factor Xa activity without any additional effects on clotting tests (PT, aPTT). Enoxaparin will not have any effect on the pharmacokinetics of rivaroxaban.

Due to the increased bleeding risk care is to be taken if patients are treated concomitantly with any other anticoagulants.

NSAIDs/platelet aggregation inhibitors Clopidogrel will not have pharmacokinetic interaction with rivaroxaban, as in VAROXO but a relevant increase in bleeding time may be observed (not correlated to platelet aggregation, P-selectin or GPIIb/IIIa receptor levels (see section 4.4). Care is to be taken if patients are treated concomitantly with NSAIDs (including acetylsalicylic acid) and platelet aggregation inhibitors because these medicines typically increase the bleeding risk. No clinically relevant prolongation of bleeding time was observed after concomitant administration of VAROXO 15 and 500 mg naproxen. Nevertheless, there may be individuals with a more pronounced pharmacodynamic response. No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when rivaroxaban, as in VAROXO, was co-administered with 500 mg acetylsalicylic acid.

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 with VAROXO, numerically higher rates of major or non-major clinically relevant bleeding were observed in all treatment groups during clinical studies.

Warfarin Converting patients from the vitamin K antagonist warfarin (INR 2,0 to 3,0) to rivaroxaban (20 mg) or from rivaroxaban (20 mg), as in VAROXO, to warfarin (INR 2,0 to 3,0) will have an increase in the prothrombin time/INR (Neoplastin) 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 needed to test the pharmacodynamic effects of rivaroxaban, as in VAROXO, during the conversion period, anti-factor Xa activity, prothrombinase-induced clotting time (PiCT), and Heptestu00ae can be used as these tests are not affected by warfarin. On the fourth day after the last dose of warfarin, all tests (including PT, aPTT, inhibition of factor Xa activity and ETP) will reflect only the effect of rivaroxaban. 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 rivaroxaban, as in VAROXO.

CYP3A4 inducers Co-administration of VAROXO with the strong CYP3A4 inducer rifampicin led to an approximate 50 % decrease in mean rivaroxaban AUC, with parallel decreases in its pharmacodynamic effects. The concomitant use of VAROXO with other strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, phenobarbital, or St. Johnu2019s Wort (Hypericum perforatum)) may also lead to reduced rivaroxaban plasma concentrations. Therefore, concomitant administration of strong CYP3A4 inducers should be avoided unless the patient is closely observed for signs and symptoms of thrombosis.

No interactions: No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when rivaroxaban, as in VAROXO, was co-administered with midazolam (substrate of CYP3A4), digoxin (substrate of P-gp) or atorvastatin (substrate of CYP3A4 and P-gp). Rivaroxaban, as in VAROXO, neither inhibits nor induces any major CYP isoforms like CYP3A4. Co-administration of the proton pump inhibitor, omeprazole, H2 receptor antagonist, ranitidine, the antacid, aluminium hydroxide/magnesium hydroxide, naproxen, clopidogrel or enoxaparin, will not affect the bioavailability and pharmacokinetics of rivaroxaban, as in VAROXO.

Interaction with laboratory parameters Clotting parameters (e.g. PT, aPTT, HepTest) will be affected (as expected) by the mode of action of rivaroxaban.

Women of childbearing potential should avoid becoming pregnant or use effective contraception during treatment with VAROXO. (see section 4.4)

Pregnancy

The use of VAROXO is contraindicated in pregnancy. (see section 4.3) Safety and efficacy of rivaroxaban 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. It has been shown that VAROXO crosses the placenta and may cause an intrinsic risk of bleeding.

Lactation

Safety and efficacy of VAROXO have not been established in lactating mothers. VAROXO may only be administered after breastfeeding is discontinued (see section 4.3).

Fertility: No data available.

VAROXO has minor influence on the ability to drive and use machines. Syncope and dizziness may be experienced. It is, therefore, recommended that patients experiencing these adverse reactions should not drive or use machines.

a. Summary of the safety profile

There may be an increased risk of occult or overt bleeding from any tissue and organ which may result in post haemorrhagic anaemia due to the pharmacological mode of action of VAROXO. 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). Menstrual bleeding may be intensified and/or prolonged. Haemorrhagic complications may present as weakness, paleness, dizziness, headache or unexplained swelling, dyspnoea, and unexplained shock. Symptoms of cardiac ischaemia like chest pain or angina pectoris have been observed in some cases as a consequence of anaemia. Known complications secondary to severe bleeding such as compartment syndrome and renal failure due to hypoperfusion have been reported for VAROXO. Therefore, the possibility of haemorrhage is to be considered in evaluating the condition in any anticoagulated patient.

b. Tabulated summary of adverse reactions

System Organ Class Frequency Adverse Event

• Blood and lymphatic system disorders Frequent Anaemia (including respective laboratory parameters). Less frequent Thrombocythemia (incl. platelet count increased), thrombocytopenia
• Immune system disorders Less frequent Allergic reaction, allergic dermatitis, angioedema, allergic oedema and anaphylactic reactions including anaphylactic shock
• Nervous system disorders Frequent Dizziness and headache. Less frequent Cerebral and intracranial haemorrhage, syncope.
• Eye disorders Frequent Eye haemorrhage (incl. conjunctival haemorrhage).
• Cardiac disorders Less frequent Tachycardia
• Vascular disorders Frequent Hypotension and haematoma
• Respiratory, thoracic and mediastinal disorders Frequent Epistaxis, haemoptysis
• Gastrointestinal disorders Frequent Gingival bleeding, gastrointestinal tract haemorrhage (incl. rectal haemorrhage), gastrointestinal and abdominal pains, dyspepsia, nausea, constipation, diarrhoea, vomiting Less frequent Dry mouth
• Hepato-biliary disorders Frequent Increase in transaminases Less frequent Hepatic impairment, increased bilirubin, increased blood alkaline phosphatase, increased GGT, jaundice, bilirubin conjugated increased (with or without concomitant increase of ALT), cholestasis, hepatitis (incl. hepatocellular injury)
• Skin and subcutaneous tissue disorders Frequent Pruritus (incl. uncommon cases of generalised pruritus), rash, ecchymosis, cutaneous and subcutaneous haemorrhage Less frequent Urticaria, Stevens-Johnson Syndrome/ Toxic Epidermal Necrolysis, DRESS syndrome
• Musculoskeletal and connective tissue disorders Frequent Pain in extremity Less frequent Haemarthrosis, muscle haemorrhage
• Unknown frequency Compartment syndrome secondary to a bleeding
• Renal and urinary disorders Frequent Urogenital tract haemorrhage (incl. haematuria and menorrhagia), renal impairment (incl. blood creatinine increased, blood urea increased) Frequency unknown Renal failure/acute renal failure secondary to a bleeding sufficient to cause hypoperfusion
• General disorders and administration site conditions Frequent Fever, peripheral oedema, decreased general strength and energy (incl. fatigue and asthenia) Less frequent Feeling unwell (incl. malaise), localised oedema
• Investigations Frequent Increase in transaminase (incl. ALT increase, AST increase). Less frequent Increased LDH, increased lipase, increased amylase Increase in GGT

c. Description of selected adverse reactions

Due to the pharmacological mode of action, the use of VAROXO 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, genitourinary including abnormal vaginal or increased menstrual bleeding) and anaemia have been reported more frequently during long term VAROXO 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 VAROXO. 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 antidote antagonising the pharmacodynamic effect of rivaroxaban is not available. Overdose following administration of VAROXO may lead to haemorrhagic complications due to its pharmacodynamic properties. The use of activated charcoal to reduce absorption in case of VAROXO overdose may be considered. Administration of activated charcoal up to 8 hours after overdose may reduce the absorption of rivaroxaban. Due to the high plasma protein binding, VAROXO is not expected to be dialysable. Should bleeding occur, management of the haemorrhage may include the following steps:

• Delay of the next VAROXO administration or discontinuation of treatment as appropriate. Rivaroxaban, as in VAROXO, has a half-life of approximately 5 to 13 hours (see section 5.2).
• Appropriate symptomatic treatment, e.g. mechanical compression (e.g., for severe epistaxis), surgical interventions, fluid replacement and haemodynamic support, blood product (packed red cells or fresh frozen plasma, depending on associated anaemia or coagulopathy) or platelets.
• If bleeding cannot be controlled by the above measures, consider administration of one of the following procoagulants:
• Specific factor Xa inhibitor reversal agent (and exanet alfa), which antagonises the pharmacodynamic effect of rivaroxaban, as in VAROXO
• Activated prothrombin complex concentrate (APCC)
• Prothrombin complex concentrate (PCC)
• Recombinant Factor VIIa (rF VIIa)
• However, there is currently very limited clinical experience with the use of these medicines in individuals receiving rivaroxaban, as in VAROXO.
• Protamine Sulphate and Vitamin K are not expected to affect the anticoagulant activity of rivaroxaban as in VAROXO. There is no experience with antifibrinolytic medicines (tranexamic acid, aminocaproic acid) in individuals receiving VAROXO. There is neither scientific rationale for benefit nor experience with the system haemostatics desmopressin and aprotinin in individuals receiving VAROXO.