Clotixar 2,5 / 5 mg Film-coated tablets.

Prevention of venous thromboembolic events (VTE): elective hip or knee replacement surgery
CLOTIXAR is indicated for the prevention of VTE in adult patients who have undergone elective hip or knee replacement surgery.
Prevention of stroke and systemic embolism: nonvalvular atrial fibrillation (NVAF)
CLOTIXAR is indicated to reduce the risk of stroke, systemic embolism, and death in patients with NVAF with one or more risk factors.
Treatment of VTE
CLOTIXAR is indicated for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE.

Posology
Prevention of VTE: elective hip or knee replacement surgery
The recommended dose of CLOTIXAR is 2,5 mg taken orally twice daily. The initial dose should be taken 12 to 24 hours after surgery.
In patients undergoing hip replacement surgery, the recommended duration of treatment is 32 to 38 days.
In patients undergoing knee replacement surgery, the recommended duration of treatment is 10 to 14 days.
Prevention of stroke and systemic embolism: NVAF
The recommended dose of CLOTIXAR is 5 mg taken orally twice daily.
Age, body weight, serum creatinine: In patients with at least 2 of the following characteristics, age u2265 80 years, body weight u2264 60 kg, or serum creatinine u2265 1,5 mg/dL (133 mmol/L), the recommended dose of CLOTIXAR is 2,5 mg twice daily.
Treatment of DVT and PE
The recommended dose of CLOTIXAR is 10 mg taken orally twice daily for 7 days, followed by 5 mg taken orally twice daily.
Prevention of recurrent DVT and PE
The recommended dose of CLOTIXAR is 2,5 mg taken orally twice daily after at least 6 months of treatment for DVT or PE.
Special populations
Renal impairment
Prevention of VTE: elective hip or knee replacement surgery
In surgical patients, no dose adjustment is necessary in patients with mild to moderate or severe renal impairment (creatinine clearance 15 u2013 29 mL/min) (see section 5.2). Because there is limited clinical experience in patients with creatinine clearance < 15 mL/min and there are no data in patients undergoing dialysis, CLOTIXAR is not recommended in these patients (see sections 4.4 and 5.2).
Prevention of stroke and systemic embolism: NVAF
In patients with AF no dose adjustment is recommended in patients with creatinine clearance 15 u2013 29 mL/min, except as described under Posology and method of administration, Prevention of stroke and systemic embolism: NVAF. Because there is no clinical experience in patients with creatinine clearance < 15 mL/min, a dosing recommendation cannot be provided. There are no data in patients undergoing dialysis, therefore, CLOTIXAR is not recommended in these patients.
Treatment of VTE
No dose adjustment is necessary in patients with mild, moderate or severe (creatinine clearance 15 u2013 29 mL/min) renal impairment. Because there is limited clinical experience in patients with creatinine clearance < 15 mL/min and no data in patients undergoing dialysis, CLOTIXAR is not recommended in these patients (see section 5.2).
Hepatic impairment
CLOTIXAR may be used with caution in patients with mild or moderate hepatic impairment (Child Pugh A or B). No dose adjustment is required in patients with mild or moderate hepatic impairment (see sections 4.4 and 5.2). CLOTIXAR is not recommended in patients with severe hepatic impairment (see sections 4.4 and 5.2).
Body weight
Prevention of VTE: elective hip or knee replacement surgery
No dose adjustment required (see section 5.2).
Prevention of stroke and systemic embolism: NVAF
See Posology and method of administration, Prevention of stroke and systemic embolism: NVAF.
Treatment of VTE
No dose adjustment required (see section 5.2).
Paediatric and adolescent patients
The efficacy and safety of CLOTIXAR in children below the age of 18 years have not been established. No data are available.
Elderly patients
Prevention of VTE: elective hip or knee replacement surgery
No dose adjustment required (see section 5.2).
Prevention of stroke and systemic embolism: NVAF
See Posology and method of administration, Prevention of stroke and systemic embolism: NVAF.
Treatment of VTE
No dose adjustment required (see section 5.2).
Converting from or to parenteral anticoagulants
In general, switching treatment from parenteral anticoagulants to CLOTIXAR (and vice versa) can be done at the next scheduled dose.
Converting from or to warfarin or other vitamin K antagonists (VKA)
When converting patients from warfarin or other VKA therapy to CLOTIXAR, discontinue warfarin or other VKA therapy and start CLOTIXAR when the international normalised ration (INR) is below 2,0. When converting from CLOTIXAR to warfarin or other VKA therapy, continue CLOTIXAR for 48 hours after the first dose of warfarin or other VKA therapy.
Surgery and invasive procedures
CLOTIXAR should be discontinued 2 to 3 days prior to elective surgery or invasive procedures, such as neuraxial regional anaesthesia. If surgery or invasive procedures cannot be delayed, exercise appropriate caution taking into consideration an increased risk of bleeding. This risk of bleeding should be weighed against the urgency of intervention.
Method of administration
Oral use. CLOTIXAR should be swallowed with water and can be taken with or without food. If a dose is missed, the patient should take CLOTIXAR immediately and then continue with twice daily administration as before.

• Hypersensitivity to apixaban or to any of the excipients of CLOTIXAR listed in section 6.1.
• Active clinically significant bleeding.
• CLOTIXAR is not recommended in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk.
• CLOTIXAR is not recommended in patients with severe renal disease (CrCl < 15 mL/min).
• Lesion or condition if considered a significant risk factor 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.
• CLOTIXAR should not be administered with antiplatelet medicines other than aspirin (see section 4.4). Concomitant treatment with any other anticoagulant medicine, e.g. unfractionated heparin (UFH), low molecular weight heparins (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux, etc.), oral anticoagulants (warfarin, rivaroxaban, dabigatran, etc.) except under specific circumstances of switching anticoagulant therapy (see section 4.2), when UFH is given at doses necessary to maintain an open central venous or arterial catheter or when UFH is given during catheter ablation for atrial fibrillation (see sections 4.4 and 4.5).
• Patients with antiphospholipid syndrome (APS) with persistent positivity for all three antiphospholipid antibodies (patients with triple positive APS).

Haemorrhage risk
Patients taking CLOTIXAR are to be carefully observed for signs of bleeding. It is recommended to be used with caution in conditions with increased risk of haemorrhage, such as congenital or acquired bleeding disorders; active ulcerative gastrointestinal disease; bacterial endocarditis; thrombocytopenia; platelet disorders; history of haemorrhagic stroke; severe uncontrolled hypertension and recent brain, spinal or ophthalmological surgery. CLOTIXAR administration should be discontinued if severe haemorrhage occurs (see sections 4.8 and 4.9). In the event of haemorrhagic complications, treatment must be discontinued, and the source of bleeding investigated. The initiation of appropriate treatment, e.g. surgical haemostasis or the transfusion of fresh frozen plasma should be considered. If life-threatening bleeding cannot be controlled by the above measures, administration of recombinant factor VIIa may be considered. However, there is currently no experience with the use of recombinant factor VIIa in individuals receiving CLOTIXAR. Standard anticoagulation test cannot be used to monitor CLOTIXAR (see section 4.5). There is no reversal medicine for CLOTIXAR.
Interaction with other medicines affecting haemostasis
Due to an increased bleeding risk, concomitant treatment with any other anticoagulants is contraindicated (see section 4.3). The concomitant use of CLOTIXAR with antiplatelet medicines increases the risk of bleeding (see section 4.5). Care is to be taken if patients are treated concomitantly with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs), or nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin. Following surgery, other platelet aggregation inhibitors or other antithrombotic medicines are not recommended concomitantly with CLOTIXAR (see section 4.5). In patients with atrial fibrillation and conditions that warrant mono or dual antiplatelet therapy, a careful assessment of the potential benefits against the potential risks should be made before combining this therapy with CLOTIXAR.
Use of thrombolytic medicines for the treatment of acute ischaemic stroke
There is very limited experience with the use of thrombolytic medicines for the treatment of acute ischaemic stroke in patients administered CLOTIXAR.
Patients with prosthetic heart valves
Safety and efficacy of CLOTIXAR have not been studied in patients with prosthetic heart valves, with or without atrial fibrillation. Therefore, the use of CLOTIXAR is not recommended in this setting.
Patients with antiphospholipid syndrome
Direct acting oral anticoagulants (DOACs), including CLOTIXAR, 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 (see section 4.3).
Surgery and invasive procedures
CLOTIXAR should be discontinued at least 48 hours prior to elective surgery or invasive procedures with a moderate or high risk of bleeding. This includes interventions for which the probability of clinically significant bleeding cannot be excluded or for which the risk of bleeding would be unacceptable. CLOTIXAR should be discontinued at least 24 hours prior to elective surgery or invasive procedures with a low risk of bleeding. This includes interventions for which any bleeding that occurs is expected to be minimal, non-critical in its location or easily controlled. If surgery or invasive procedures cannot be delayed, appropriate caution should be exercised, taking into consideration an increased risk of bleeding. This risk of bleeding should be weighed against the urgency of intervention. CLOTIXAR 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 (for cardioversion see section 4.2).
Temporary discontinuation
Discontinuing anticoagulants, including CLOTIXAR, for active bleeding, elective surgery, or invasive procedures places patients at an increased risk of thrombosis. Lapses in therapy should be avoided and if anticoagulation with CLOTIXAR must be temporarily discontinued for any reason, therapy should be restarted as soon as possible (12 u2013 24 hours after the danger of haemorrhage has ceased).
Haemodynamically unstable pulmonary embolism (PE) patients or patients who require thrombolysis or pulmonary embolectomy
CLOTIXAR 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 apixaban have not been established in these clinical situations.
Patients with active cancer
Efficacy and safety of CLOTIXAR in the treatment of deep vein thrombosis (DVT), treatment of PE and prevention of recurrent DVT and PE (VTEt) in patients with active cancer have not been established.
Patients with renal impairment
Limited clinical data indicate that apixaban plasma concentrations are increased in patients with severe renal impairment (creatinine clearance 15 u2013 29 mL/min), which may lead to an increased bleeding risk. For the treatment of DVT, treatment of PE and prevention of recurrent DVT and PE (VTEt), CLOTIXAR is to be used with caution in patients with severe renal impairment (creatinine clearance 15 u2013 29 mL/min) (see sections 4.2 and 5.2).
For the prevention of stroke and systemic embolism in patients with NVAF, patients with severe renal impairment (creatinine clearance 15 u2013 29 mL/min), and patients with serum creatinine > 1,5 mg/dL (133 mmol/L) associated with age > 80 years or body weight < 60 kg should receive the lower dose of apixaban 2,5 mg twice daily (see section 4.2). In patients with creatinine clearance < 15 mL/min, or in patients undergoing dialysis, there is no clinical experience, therefore, CLOTIXAR is not recommended (see sections 4.2 and 5.2).
Elderly patients
Increasing age may increase haemorrhagic risk (see section 5.2). Also, the co-administration of CLOTIXAR with aspirin in elderly patients should be used cautiously because of a potentially higher bleeding risk.
Paediatric patients
The efficacy and safety of CLOTIXAR in children below age 18 have not been established. No data are available.
Body weight
Low body weight (< 60 kg) may increase haemorrhagic risk (see section 5.2).
Patients with hepatic impairment
CLOTIXAR is contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk (see section 4.3). It is not recommended in patients with severe hepatic impairment (see section 5.2). It should be used with caution in patients with mild or moderate hepatic impairment (Child Pugh A or B) (see sections 4.2 and 5.2). Patients with elevated liver enzymes alanine aminotransferase (ALT) / aspartate transaminase (AST) > 2 x ULN or total bilirubin > 1,5 x the upper limit of normal (ULN) were excluded in clinical trials. Therefore, CLOTIXAR should be used cautiously in this population (see section 5.2). Prior to initiating CLOTIXAR, liver function testing should be performed.

Inhibitors of CYP3A4 and P-gp
Co-administration of CLOTIXAR with ketoconazole (400 mg once a day), a strong inhibitor of both CYP3A4 and P-gp, led to a 2-fold increase in mean apixaban area under the curve (AUC) and a 1,6-fold increase in mean apixaban C max. The dose of CLOTIXAR must not exceed 2,5 mg twice daily when used with these medicines. The use of CLOTIXAR is not recommended in patients receiving concomitant systemic treatment with strong inhibitors of both CYP3A4 and P-gp, such as azole-antimycotics (e.g. ketoconazole, itraconazole, voriconazole and posaconazole) and human immunodeficiency virus (HIV) protease inhibitors (e.g. ritonavir) (see section 4.4). Active substances which are not considered strong inhibitors of both CYP3A4 and P-gp (e.g. diltiazem, naproxen, clarithromycin, amiodarone, verapamil, quinidine), are expected to increase apixaban plasma concentration to a lesser extent. No dose adjustment for CLOTIXAR is required when co-administered with medicines that are not strong inhibitors of both CYP3A4 and P-gp. For example, diltiazem (360 mg once a day), considered a moderate CYP3A4 and a weak P-gp inhibitor, led to a 1,4-fold increase in mean apixaban AUC and a 1,3-fold increase in C max. Naproxen (500 mg, single dose), an inhibitor of P-gp but not an inhibitor of CYP3A4, led to a 1,5-fold and 1,6-fold increase in mean apixaban AUC and C max, respectively. Clarithromycin (500 mg, twice a day), an inhibitor of P-gp and a strong inhibitor of CYP3A4, led to a 1,6-fold and 1,3-fold increase in mean apixaban AUC and C max, respectively.
Inducers of CYP3A4 and P-gp
Co-administration of CLOTIXAR with rifampicin, a strong inducer of both CYP3A4 and P-gp, led to an approximate 54 % and 42 % decrease in mean apixaban AUC and C max, respectively. The concomitant use of CLOTIXAR with other strong CYP3A4 and P-gp inducers (e.g. phenytoin, carbamazepine, phenobarbital or St Johnu2019s wort) may also lead to reduced apixaban plasma concentrations. No dose adjustment for CLOTIXAR is required during concomitant therapy with such medicines, however in patients receiving concomitant systemic treatment with strong inducers of both CYP3A4 and P-gp, CLOTIXAR should be used with caution for the prevention of stroke and systemic embolism in patients with NVAF and for the prevention of recurrent DVT and PE. CLOTIXAR is not recommended for the treatment of DVT and PE in patients receiving concomitant systemic treatment with strong inducers of both CYP3A4 and P-gp since efficacy may be compromised (see section 4.4).
Anticoagulants, platelet aggregation inhibitors, SSRIs/SNRIs and NSAIDs
Due to an increased bleeding risk, concomitant treatment of CLOTIXAR with any other anticoagulants is contraindicated, except under specific circumstances of switching anticoagulant therapy, when UFH is given at doses necessary to maintain an open central venous or arterial catheter or when UFH is given during catheter ablation for atrial fibrillation (see section 4.3). After combined administration of enoxaparin (40 mg single dose) with CLOTIXAR (5 mg single dose), an additive effect on anti-Factor Xa activity was observed. Pharmacokinetic or pharmacodynamic interactions were not evident when CLOTIXAR was co-administered with aspirin 325 mg once a day. CLOTIXAR co-administered with clopidogrel (75 mg once a day) or with the combination of clopidogrel 75 mg and aspirin 162 mg once daily, or with prasugrel (60 mg followed by 10 mg once daily) did not show a relevant increase in template bleeding time, or further inhibition of platelet aggregation, compared to administration of the antiplatelet medicines without CLOTIXAR. Increases in clotting tests (PT, INR and aPTT) were consistent with the effects of CLOTIXAR alone. Naproxen (500 mg), an inhibitor of P-gp, led to a 1,5-fold and 1,6-fold increase in mean apixaban AUC and C max, respectively. Corresponding increases in clotting tests were observed for apixaban. No changes were observed in the effect of naproxen on arachidonic acid-induced platelet aggregation and no clinically relevant prolongation of bleeding time was observed after concomitant administration of CLOTIXAR and naproxen. Despite these findings, there may be individuals with a more pronounced pharmacodynamic response when antiplatelet medicines are co-administered with CLOTIXAR. CLOTIXAR should be used with caution when co-administered with SSRIs/SNRIs or NSAIDs (including aspirin) because these medicines typically increase the bleeding risk. A significant increase in bleeding risk was reported with the triple combination of apixaban, aspirin and clopidogrel in a clinical study in patients with acute coronary syndrome (see section 4.4).

Pregnancy
There are no data from the use of CLOTIXAR in pregnant women. Treatment may increase the risk of haemorrhage during pregnancy and delivery. CLOTIXAR is not recommended during pregnancy.
Lactation
It is unknown whether apixaban or its metabolites are excreted in human milk. A risk to newborns and infants cannot be excluded. CLOTIXAR is not recommended in mothers who are breastfeeding.
Fertility
Studies in animals dosed with CLOTIXAR have shown no effect on fertility (see section 5.3).

CLOTIXAR has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile
Common adverse reactions were haemorrhage, contusion, epistaxis and haematoma (see Table 1: Adverse reaction profile and frequencies by indication).
Table 1: Adverse reaction profile and frequencies by indication
System organ class
Prevention of VTE in adult patients who have undergone elective hip or knee replacement surgery (VTEp)
Prevention of stroke and systemic embolism in adult patients with NVAF, with one or more risk factors (NVAF)
Treatment of DVT and PE, and prevention of recurrent DVT and PE (VTEt)
Blood and lymphatic system disorders
Anaemia
Frequent
Frequent
Frequent
Thrombocytopenia
Less frequent
Less frequent
Frequent
Immune system disorders
Hypersensitivity, allergic oedema, anaphylaxis
Less frequent
Less frequent
Less frequent
Pruritus
Less frequent
Less frequent
Less frequent
Angioedema
Frequency unknown
Frequency unknown
Frequency unknown
Nervous system disorders
*Brain haemorrhage
Frequency unknown
Less frequent
Less frequent
Eye disorders
Ocular haemorrhage (including conjunctival haemorrhage)
Less frequent
Frequent
Less frequent
Vascular disorders
Haemorrhage, haematoma
Frequent
Frequent
Frequent
Hypotension (including procedural hypotension)
Less frequent
Frequent
Less frequent
Intra-abdominal haemorrhage
Frequency unknown
Less frequent
Frequency unknown
Respiratory, thoracic and mediastinal disorders
Epistaxis
Less frequent
Frequent
Frequent
Haemoptysis
Less frequent
Less frequent
Less frequent
Respiratory tract haemorrhage
Frequency unknown
Less frequent
Less frequent
Gastrointestinal disorders
Nausea
Frequent
Frequent
Frequent
Gastrointestinal haemorrhage (including haematemesis and melaena)
Less frequent
Frequent
Frequent
Haemorrhoidal haemorrhage
Frequency unknown
Less frequent
Less frequent
Mouth haemorrhage
Frequency unknown
Less frequent
Frequent
Haematochezia
Less frequent
Less frequent
Less frequent
Rectal haemorrhage, gingival bleeding
Less frequent
Frequent
Frequent
Retroperitoneal haemorrhage
Frequency unknown
Less frequent
Frequency unknown
Hepatobiliary disorders
Liver function test abnormal, aspartate aminotransferase increased, blood alkaline phosphatase increased, blood bilirubin increased
Less frequent
Less frequent
Less frequent
Gamma-glutamyltransferase increased
Less frequent
Frequent
Frequent
Alanine aminotransferase increased
Less frequent
Less frequent
Frequent
Skin and subcutaneous tissue disorders
Skin rash
Frequency unknown
Less frequent
Frequent
Alopecia
Less frequent
Less frequent
Less frequent
Musculoskeletal and connective tissue disorders
Muscle haemorrhage
Less frequent
Less frequent
Less frequent
Renal and urinary disorders
Haematuria
Less frequent
Frequent
Frequent
Reproductive system and breast disorders
Abnormal vaginal haemorrhage, urogenital haemorrhage
Less frequent
Less frequent
Frequent
General disorders and administration site conditions
Application site bleeding
Frequency unknown
Less frequent
Less frequent
Investigations
Occult blood positive
Frequency unknown
Less frequent
Less frequent
Injury, poisoning and procedural complications
Contusion
Frequent
Frequent
Frequent
Post procedural haemorrhage (including post procedural haematoma, wound haemorrhage, vessel puncture site haematoma and catheter site haemorrhage), wound secretion, incision site haemorrhage (including incision site haematoma), operative haemorrhage
Less frequent
Less frequent
Less frequent
Traumatic haemorrhage
Frequency unknown
Less frequent
Less frequent
* The term u201cbrain haemorrhageu201d encompasses all intracranial or intraspinal haemorrhages (i.e. haemorrhagic stroke or putamen, cerebellar, intraventricular, or subdural haemorrhages). The use of CLOTIXAR 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 will vary according to the location and degree or extent of the bleeding (see sections 4.4 and 5.1).

Overdose of CLOTIXAR may result in a higher risk of bleeding. In the event of haemorrhagic complications, treatment must be discontinued and the source of bleeding investigated. Administration of activated charcoal 2 and 6 hours after ingestion of a 20 mg dose of apixaban, as in CLOTIXAR, reduced mean apixaban AUC by 50 % and 27 %, respectively, and had no impact on C max. Mean half-life of apixaban decreased from 13,4 hours when apixaban was administered alone, to 5,3 hours and 4,9 hours, respectively, when activated charcoal was administered 2 and 6 hours after apixaban. Thus, administration of activated charcoal may be useful in the management of CLOTIXAR overdose or accidental ingestion. Haemodialysis is unlikely to be an effective means of managing CLOTIXAR overdose. Treatment should be symptomatic and supportive.