Varixa 15/20 15mg. 20mg Tablet

VARIXA 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).

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

SPAF u2013 Recommended usual dose and frequency administration: The recommended dose is one VARIXA 20 mg tablet once daily. For patients with moderate renal impairment (creatinine clearance u02c2 50 to 30 ml/min) the recommended dose is one VARIXA 15 mg tablet daily. VARIXA should be taken with food. Therapy should be continued as long as risk factors for stroke and systemic embolism persist. If a dose is missed the patient should take VARIXA 15 or VARIXA 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 daily dose is one VARIXA 20 SPAF u2013 Additional information on special populations: SPAF u2013 Patients with hepatic impairment. VARIXA is contraindicated in patients with hepatic disease with or without coagulopathy (see u201csection 4.3u201d). SPAF u2013 Patients with renal impairment: No dose adjustment is required if VARIXA is administered in patients with mild (creatinine clearance u2264 80 to 50 ml/min) renal impairment. For patients with moderate (creatinine clearance u02c2 50 to 30 ml/min) renal impairment the recommended dose is 15 mg once daily. VARIXA plasma levels are significantly increased in patients with severe renal impairment. Therefore VARIXA 15 must be used with caution in these patients. Use of VARIXA is not recommended in patients with creatinine clearance u02c2 15 ml/min (see section 4.4u201d and u201csection 5.2u201d). SPAF u2013 Converting from warfarin to VARIXA: Warfarin treatment should be stopped and VARIXA therapy should be initiated when the INR is u2264 3,0. When converting patients from warfarin to VARIXA, INR values will be falsely elevated after the intake of VARIXA. The INR is not valid to measure the anticoagulant activity of VARIXA, and therefore should not be used (see u201csection 4.5u201d). SPAF u2013 Converting from VARIXA to warfarin: There is a potential for inadequate anticoagulation during the translation from VARIXA to warfarin. Continuous adequate anticoagulation should be ensured during any transition to an alternate anticoagulant. It should be noted that VARIXA can contribute to an elevated INR. In patients converting from VARIXA to warfarin, warfarin should be given concurrently until the INR is u2265 2,0. For the first two days of the conversation period, standard warfarin dosing should be used followed by warfarin dosing guided by INR testing. While patients are on both VARIXA and warfarin, the INR should not be tested earlier than 24 hours (after the previous dose but prior to the next dose of VARIXA). Once VARIXA is discontinued INR testing may be done reliably 24 hours after the last dose (see u201csection 4.5u201d). SPAF u2013 Converting from parenteral anticoagulants to VARIXA: For patients currently receiving a parenteral anticoagulant, start VARIXA, 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 VARIXA to parenteral anticoagulants: Discontinue VARIXA and give the first dose of parenteral anticoagulants at the time that the next VARIXA dose would have been taken. SPAF u2013 Children and adolescent (from birth to 18 years): Safety and efficacy have not been established in children and adolescent below 18 years. SPAF u2013 Body weight: No dose adjustment is required based on body weight (see u201cPharmacokinetic propertiesu201d). 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 15 mg twice daily for the first three weeks followed by one 20 mg tablet once daily for the continued treatment and the prevention of recurrent DVT and PE. VARIXA 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 VARIXA 15 twice daily treatment phase the patient should take VARIXA 15 immediately to ensure intake of 30 mg per day. In this case two VARIXA 15 tablets may be taken at once. The patient should continue with the regular one VARIXA 15 twice daily intake as recommended on the following day. If a dose is missed during the VARIXA 20 once daily treatment phase the patient should take VARIXA 20 immediately to insure intake of 20 mg per day. The patient should continue with the regular one VARIXA 20 once daily intake as recommended on the following day. DVT and PE treatment u2013 Maximum daily dose: The maximum daily dose is 30 mg during the first three weeks of treatment. In the following treatment phase the recommended maximum daily dose is 20 mg. DVT and PE treatment u2013 Patients with hepatic impairment: VARIXA 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 5.2). DVT and PE treatment u2013 Patients with renal impairment: No dose adjustment is required if VARIXA is administered in patients with mild (creatinine clearance u2264 80 to 50 mL /min) or moderate (creatinine clearance u02c2 50 to 30 mL/min) renal impairment (see u201cPharmacokinetic propertiesu201d). VARIXA plasma levels are significantly increased in patients with severe renal impairment (creatinine clearance u02c2 30 to 15 m L/min). VARIXA must therefore be used with caution in these patients. Use of VARIXA is not recommended in patients with creatinine clearance u02c2 15 mL/min (see u201csection 4.4 and section 5.2u201d). DVT and PE treatment u2013 Converting from warfarin to VARIXA 15: Warfarin treatment should be stopped and VARIXA 15 therapy should be initiated once the INR is u2264 2,5. When converting patients from warfarin to VARIXA 15, INR values will be falsely elevated after the intake of VARIXA 15. The INR is not valid to measure the anticoagulant activity of VARIXA 15, and therefore should not be used (see u201csection 4.5u201d). DVT and PE treatment u2013 Converting from VARIXA to warfarin: There is a potential for inadequate anticoagulation during the transition from VARIXA to warfarin. Continuous adequate anticoagulation should be ensured during any transition to an alternate anticoagulant. It should be noted that VARIXA can contribute to an elevated INR. In patients converting from VARIXA 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 VARIXA and warfarin, the INR should not be tested earlier than 24 hours (after the previous dose but prior to the next dose of VARIXA). Once VARIXA is discontinued INR testing may be done reliably 24 hours after the last dose (see u201csection 4.5u201d). DVT and PE treatment u2013 Converting from parental anticoagulants to VARIXA 15: For patients currently receiving a parental anticoagulant, start VARIXA 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 parental medicine (e.g. intravenous unfractionated heparin). DVT and PE treatment u2013 Converting from VARIXA to parenteral anticoagulants: Discontinue VARIXA and give the first dose of parenteral anticoagulant at the time that the next VARIXA 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 u201cPharmacokinetic propertiesu201d).

VARIXA is contraindicated 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.
• Hepatic disease with or without coagulopathy.
• VARIXA is contraindicated throughout pregnancy (see u201csection 4.6u201d).
• VARIXA is contraindicated during breastfeeding and may only be administered after breastfeeding is discontinued (see u201csection 4.6u201d).
• 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).

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

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

Patients with prosthetic valves: VARIXA should not be used for thromboprophylaxis in patients having recently undergone transcatheter aortic valve replacement (TAVR). Treatment with VARIXA is not recommended for these patients.

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

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

Other bleeding risk factors: VARIXA 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 ophthalmological surgery
• Bronchiectasis or history of pulmonary bleeding

The use of VARIXA 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 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).

Renal impairment: VARIXA is to be used with caution in patients with moderate renal impairment (creatinine clearance 30 < 50 mL/min) receiving co-medication leading to increased rivaroxaban plasma concentrations (see section 4.5). In patients with severe renal impairment (creatinine clearance < 30 ml/min) VARIXA plasma levels may be significantly increased which may lead to an increased bleeding risk and thrombosis. VARIXA 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).

Invasive procedures and surgical interventions: If an invasive procedure or surgical intervention is required, VARIXA should be stopped at least 24 hours before the intervention, if possible and based on clinical judgment of the medical practitioner. If the procedure cannot be delayed the increased risk of bleeding should be assessed against the urgency of the intervention. VARIXA 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 u201csection 5.2u201d).

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. There is no clinical experience with the use of 15 mg or 20 mg VARIXA in these situations. To reduce the potential risk of bleeding associated with the concurrent use of VARIXA and neuraxial (epidural/spinal) anaesthesia or spinal puncture, consider the pharmacokinetic profile of VARIXA. Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of VARIXA 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 (see section 5.2). Following removal of the catheter, at least 6 hours should elapse before the next VARIXA dose is administered. If traumatic puncture occurs the administration of rivaroxaban is to be delayed for 24 hours.

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

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 during post-marketing surveillance in association with the use of rivaroxaban (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. VARIXA 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.

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 nonvalvular atrial fibrillation who undergo PCI with stent placement. Data on efficacy in this population are limited (see sections 4.2 and 5.1).

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

Information about excipients: Since VARIXA contain lactose, patients with rare hereditary problems of lactose or galactose intolerance (e.g total lactose deficiency or glucose-galactose malabsorption) should not take VARIXA.

Women of childbearing potential: VARIXA should be used in woman of childbearing potential only with effective contraception.

Pregnancy: Safety and efficacy of VARIXA have not been established in pregnant woman. In rats and rabbits VARIXA 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 passes the placenta, VARIXA is contraindicated in pregnancy (see u201csection 4.3u201d).

Breast-feeding: Safety and efficacy of VARIXA have not been established in nursing mothers. In rats VARIXA is secreted into breast milk. Therefore VARIXA 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 Drug Reactions Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8

Cases of overdose up to 600 mg have been reported without bleeding complications or other adverse reactions. Due to limited absorption a celling effect with no further increase in average plasma exposure is expected at supratherapeutic doses of 50 mg or above. A specific antidote antagonising pharmacodynamics effect of VARIXA is not available. The use of activated charcoal to reduce absorption in case of VARIXA overdose may be considered. Due to the high plasma protein binding VARIXA is not expected to be dialysable. Managing of bleeding: Should a bleeding complication arise in a patient receiving VARIXA, the next administration should be delayed or treatment should be discontinued as appropriate. VARIXA 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 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 VIIa (r-FVIIa). However, there is currently very limited clinical experience with the use of these products in individuals receiving VARIXA. Protamine sulphate and Vitamin K are not expected to affect the anticoagulant activity of VARIXA. There is no experience with antifibrinolytic agents (tranexamic acid, aminocaproic acid) in individuals receiving VARIXA. There is neither scientific rationale for benefit nor experience with the systemic haemostatics desmopressin and aprotinin in individuals receiving VARIXA.