Varixa 10 10mg Tablet

VARIXA 10 film-coated tablets are indicated for the prevention of venous thromboembolism (VTE) in patients undergoing major orthopaedic surgery of the lower limbs.

Posology
Recommended dose and frequency of administration
The recommended dose is one VARIXA 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 VARIXA 10 immediately and continue on the following day with the once daily intake as before.
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.
Special populations
Elderly Population
No dose adjustment is required for these patient populations.
Hepatic Impairment
VARIXA 10 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 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.
Renal Impairment
No dose adjustment is required if VARIXA 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 VARIXA 10 must be used with caution in these patients (see section 4.4)
Paediatric Population
The safety and efficacy of VARIXA 10 has not been established in children. No clinical data is available for children.
Method of administration
For oral use VARIXA 10 may be taken with or without food.

VARIXA 10 is contraindicated in patients with:
u2022 Hypersensitivity to the rivaroxaban or to any of the excipients listed in section 6.1
u2022 Clinically significant active bleeding (e.g. intracranial bleeding, gastrointestinal bleeding).
u2022 Significant hepatic disease which is associated with coagulopathy leading to a clinically relevant bleeding risk.
u2022 Pregnancy and lactation (see section 4.6).
u2022 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.
u2022 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).
u2022 Hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic patients with Child Pugh B and C (see section 5.2)

Clinical surveillance in line with anticoagulation practice is recommended throughout the treatment period. Haemorrhagic risk
Patients taking VARIXA 10 are to be carefully observed for signs of bleeding. It is recommended to be used with caution in conditions with increased risk of haemorrhage. VARIXA 10 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 VARIXA 10 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 below, are at increased risk of bleeding. These patients are to be carefully monitored for signs and symptoms of bleeding complications and anaemia after initiation of treatment (see section 4.8). Any unexplained fall in haemoglobin or blood pressure should lead to a search for a bleeding site. Although treatment with VARIXA 10 does not require routine monitoring of exposure, VARIXA 10 levels measured with a calibrated quantitative anti-factor Xa assay may be useful in exceptional situations where knowledge of VARIXA 10 exposure may help to inform clinical decisions, e.g. overdose and emergency surgery (see sections 5.1 and 5.2).
Renal impairment
VARIXA 10 should be used with caution in patients with renal impairment concomitantly receiving other medicines which increase VARIXA 10 plasma concentrations (see section 4.5). In patients with severe renal impairment (creatinine clearance < 30 mL/min) VARIXA 10 plasma levels may be significantly increased which may lead to an increased bleeding risk and thrombosis. VARIXA 10 is to be used with caution in patients with creatinine clearance u02c2 30 to 15 mL/min. Use is not recommended in patients with creatinine clearance < 15 mL/min (see sections 4.2 and 5.2).

The use of VARIXA 10 is not recommended in patients receiving concomitant systemic treatment with azole-antimycotics (such as ketoconazole, itraconazole, voriconazole and posaconazole) or HIV protease inhibitors (e.g. ritonavir). These active substances are strong inhibitors of both CYP3A4 and P-gp and therefore may increase VARIXA 10 plasma concentrations to a clinically relevant degree (2.6-fold on average) which may lead to an increased bleeding risk (see section 4.5). Care is to be taken if patients are treated concomitantly with medicines affecting haemostasis such as non-steroidal anti-inflammatory medicines (NSAIDs), acetylsalicylic acid and platelet aggregation inhibitors or selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs). For patients at risk of ulcerative gastrointestinal disease an appropriate prophylactic treatment may be considered (see section 4.5).
Bleeding risk factors:
VARIXA 10 should be used with caution in patients with an increased bleeding risk such as:
u2022 Congenital or acquired bleeding disorders
u2022 Uncontrolled severe arterial hypertension
u2022 other gastrointestinal disease without active ulceration that can potentially lead to bleeding complications (e.g. inflammatory bowel disease, oesophagitis, gastritis and gastroesophageal reflux disease)
u2022 Vascular retinopathy
u2022 Recent intracranial or intracerebral vascular abnormalities
u2022 Shortly after brain, spinal ophthalmological surgery
u2022 Bronchiectasis or history of pulmonary bleeding
Patients with prosthetic valves VARIXA 10 should not be used for thromboprophylaxis in patients having recently undergone transcatheter aortic valve replacement (TAVR). Treatment with VARIXA 10 is not recommended for these patients.
Patients with antiphospholipid syndrome Direct acting Oral Anticoagulants (DOACs) including VARIXA 10 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 Rivaroxaban has not been studied in interventional clinical studies in patients undergoing hip fracture surgery to evaluate efficacy and safety.
Haemodynamically unstable PE patients or patients who require thrombolysis or pulmonary embolectomy VARIXA 10 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 VARIXA 10 have not been established in these clinical situations.
Spinal/epidural anaesthesia or puncture When neuraxial anaesthesia (spinal/epidural anaesthesia) or spinal/epidural puncture is employed, patients treated with antithrombotic medicines for prevention of thromboembolic complications are at risk of developing an epidural or spinal haematoma which can result in long-term or permanent paralysis. The risk of these events may be increased by the post-operative use of indwelling epidural catheters or the concomitant use of medicines affecting haemostasis. The risk may also be increased by traumatic or repeated epidural or spinal puncture. Patients are to be frequently monitored for signs and symptoms of neurological impairment (e.g. numbness or weakness of the legs, bowel or bladder dysfunction). If neurological compromise is noted, urgent diagnosis and treatment is necessary. Prior to neuraxial intervention the medical practitioner should consider the potential benefit versus the risk in anticoagulated patients or in patients to be anticoagulated for thromboprophylaxis. To reduce the potential risk of bleeding associated with the concurrent use of VARIXA 10 and neuraxial (epidural/spinal) anaesthesia or spinal puncture, consider the pharmacokinetic profile of VARIXA 10. Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of VARIXA 10 is estimated to be low. However, the exact timing to reach a sufficiently low anticoagulant effect in each patient is unknown. For the removal of an epidural catheter and based on the general PK characteristics at least 2 x half-life, i.e. at least 18 hours in young patients and 26 hours in elderly patients should elapse after the last administration of VARIXA 10 (see section 5.2). Following removal of the catheter, at least 6 hours should elapse before the next VARIXA 10 dose is administered. If traumatic puncture occurs the administration of rivaroxaban is to be delayed for 24 hours.

Women of childbearing potential
VARIXA 10 should be used in woman of childbearing potential only with effective contraception.
Pregnancy
Safety and efficacy of VARIXA 10 have not been established in pregnant woman. In rats and rabbits VARIXA 10 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 VARIXA 10 passes the placenta, VARIXA 10 is contraindicated in pregnancy (see u201csection 4.3u201d)
Breast-feeding
Safety and efficacy of VARIXA 10 have not been established in nursing mothers. In rats VARIXA 10 is secreted into breast milk. Therefore VARIXA 10 may only be administered after breastfeeding is discontinued (see u201csection 4.3u201d).
Fertility
No specific studies with rivaroxaban 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 u201csection 4.8u201d). Patients experiencing these adverse reactions should not drive or use machines.

Blood and the lymphatic system disorders:
Frequent: Anaemia (including respective laboratory parameters)
Less frequent: Thrombocythemia (incl. platelet counts increased), thrombocytopaenia
Immune system disorders:
Less frequent: Allergic reaction, allergic dermatitis, angioedema and allergic oedema, anaphylactic reactions including anaphylactic shock.
Nervous system disorder:
Frequent: Dizziness, headache
Less frequent: Cerebral and intracranial haemorrhage, syncope
Eye disorders:
Frequent: Eye haemorrhage (Incl. conjunctival haemorrhage)
Cardiac disorders:
Less frequent: Tachycardia
Vascular disorder:
Frequent: Hypotension, haematoma
Respiratory tract disorder:
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: Abnormal hepatic function, jaundice, bilirubin conjugated increased (with or without concomitant increase of ALT), cholestasis, hepatitis, (including hepatocellular injury).
Skin and subcutaneous tissue disorder:
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, connective tissue and bone disorders:
Frequent: Pain in extremity
Less frequent: Haemarthrosis, muscle haemorrhage
Frequency unknown: compartment syndrome secondary to a bleeding
Renal and urinary disorder:
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:
Less frequent: Increased LDH, increased lipase, increased amylase
Injury, poisoning and postprocedural complications:
Frequent: Postprocedural haemorrhage (incl. postoperative anaemia and wound haemorrhage), contusion, wound secretion
Less frequent: Vascular pseudoaneurysm
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Medicine Reactions Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8

Overdose following administration of VARIXA 10 may lead to haemorrhagic complications due to its pharmacodynamic properties. The use of activated charcoal to reduce absorption in case of VARIXA 10 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 VARIXA 10 is not expected to be dialysable. Should bleeding occur, management of the haemorrhage may include the following steps:
u2022 Delay of next VARIXA 10 administration or discontinuation of treatment as appropriate. Rivaroxaban has a half-life of approximately 5 to 13 hours.
u2022 Appropriate symptomatic treatment, e.g. mechanical compression (e.g., for severe epistaxis), surgical interventions, fluid replacement and haemodynamic support, blood product or component transfusion should be considered. If bleeding cannot be controlled by the above measures, consider administration of one of the following procoagulants:
u2022 Activated prothrombin complex concentrate (APCC)
u2022 Prothrombin complex concentrate (PCC)
u2022 Recombinant Factor VIIa (rF VIIa).
Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of VARIXA 10. There is no scientific rationale for benefit or experience with systemic haemostatics (e.g. desmopressin, aprotinin, tranexamic acid, aminocaproic acid) in individuals receiving VARIXA 10.