Vibanex 2,5 mg and 5 mg Film-coated tablets

Prevention of VTE: elective hip or knee replacement surgery
VIBANEX is indicated for the prevention of venous thromboembolic events (VTE) in adult patients who have undergone elective hip or knee replacement surgery.

Prevention of stroke and systemic embolism: nonvalvular atrial fibrillation (NVAF)
VIBANEX is also indicated to reduce the risk of stroke, systemic embolism and death in patients with nonvalvular atrial fibrillation with one or more risk factors.

VIBANEX can be taken with or without food. If a dose is missed, the patient should take VIBANEX immediately and then continue with twice daily administration as before.

Posology
Prevention of VTE: elective hip or knee replacement surgery
The recommended dose of VIBANEX 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 VIBANEX 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 micromole/L), the recommended dose of VIBANEX is 2,5 mg twice daily.

Body weight
No dose adjustment required (see section 5.2).

Converting from or to parenteral anticoagulants
In general, switching treatment from parenteral anticoagulants to VIBANEX (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 VIBANEX, discontinue warfarin or other VKA therapy and start VIBANEX when the INR is below 2,0. When converting from VIBANEX to warfarin or other VKA therapy, continue VIBANEX for 48 hours after the first dose of warfarin or other VKA therapy.

Patients undergoing cardioversion
VIBANEX can be initiated or continued in NVAF patients who may require cardioversion. For patients not previously treated with anticoagulants, at least 5 doses of VIBANEX 5 mg twice daily (2,5 mg twice daily in patients who qualify for a dose reduction) should be given before cardioversion to ensure adequate anticoagulation. If cardioversion is required before 5 doses of VIBANEX can be administered, a 10 mg loading dose should be given, followed by 5 mg twice daily. The dosing regimen should be reduced to a 5 mg loading dose followed by 2,5 mg twice daily if the patient meets the criteria for dose reduction. The administration of the loading dose should be given at least 2 hours before cardioversion. Confirmation should be sought prior to cardioversion that the patient has taken VIBANEX as prescribed. Decisions on initiation and duration of treatment should take established guideline recommendations for anticoagulant treatment in patients undergoing cardioversion into account.

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, moderate or severe (creatine clearance 15 u2013 29 mL/min) renal impairment (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, VIBANEX is not recommended in these patients (see section 4.4 and section 5.2).

Prevention of stroke and systemic embolism: NVAF
In patients with AF, no dose adjustment is recommended in patients with creatinine clearance 15 to 29 mL/min, except as described under section 4.2, 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, VIBANEX is not recommended in these patients.

Hepatic impairment
VIBANEX 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 section 4.4 and section 5.2). VIBANEX is not recommended in patients with severe hepatic impairment (see section 4.4 and section 5.2).

Elderly population
No dose adjustment required (see section 5.2).

Surgery and invasive procedures
VIBANEX 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.

Paediatric and adolescent
The efficacy and safety of VIBANEX is children below age 18 have not been established. No data are available.

Method of administration
For oral use.

• Hypersensitivity to apixaban or to any of the excipients (listed in section 6.1).
• Clinically significant active bleeding.
• VIBANEX is not recommended in patients with severe renal disease (CrCl < 15 mL/min).
• VIBANEX is not recommended in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk.
• VIBANEX should not be administered with antiplatelet medicines other than aspirin (see section 4.4).
• Patients with antiphospholipid syndrome (APS) with persistent positivity for all three antiphospholipid antibodies (patients with triple positive APS).

Haemorrhage risk
Patients taking VIBANEX are to be carefully observed for signs of bleeding. VIBANEX 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. VIBANEX administration should be discontinued if severe haemorrhage occurs (see section 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 no clinical experience with the use of 4-factor PCC medicines to reverse bleeding in individuals who have received apixaban. Reversal of apixaban pharmacodynamic effects, as demonstrated by changes in the thrombin generation assay, has been demonstrated after administration of 4-factor PCCs in healthy subjects. However, there is currently no experience with the use of recombinant factor VIIa in individuals receiving apixaban. Standard anticoagulation tests cannot be used to monitor VIBANEX (see section 4.5).

There is no reversal medication for VIBANEX. Temporary discontinuation of VIBANEX
Discontinue VIBANEX in the presence of active bleeding, elective surgery, or invasive procedures that place patients at an increased risk of haemorrhage. Restart VIBANEX therapy 12 u2013 24 hours after the danger of haemorrhage has ceased.

Interaction with strong inhibitors of both cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp)
VIBANEX can be administered with caution in patients receiving concomitant systemic treatment with strong inhibitors of both cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp), such as azole-antimycotics (e.g. ketoconazole, itraconazole, voriconazole and posaconazole), HIV protease inhibitors (e.g. ritonavir). These medicines may increase VIBANEX exposure by 2-fold (see section 4.5).

Interaction with strong inducers of both CYP3A4 and P-gp
The concomitant use of VIBANEX with strong CYP3A4 and P-gp inducers (e.g. rifampicin, phenytoin, carbamazepine, phenobarbitone or St. Johnu2019s Wort) may lead to a uf07e 50 % reduction in apixaban exposure. Use caution when co-administering VIBANEX with strong inducers of both CYP3A4 and P-gp (see section 4.5). For the treatment of DVT of PE, VIBANEX is not recommended in patients receiving concomitant systemic treatment with strong inducers of both CYP3A4 and P-gp (see section 4.5). For prevention of recurrent DVT and PE, use caution when co-administering VIBANEX with strong inducers of both CYP3A4 and P-gp (see section 4.5).

Interaction with other medicines affecting haemostasis
The concomitant use of VIBANEX with antiplatelet medicines increases the risk of bleeding. Care is to be taken if patients are treated concomitantly with non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin. Other platelet aggregation inhibitors or other antithrombotic medicines are not recommended concomitantly with VIBANEX following surgery (see section 4.5). In patients with atrial fibrillation and a condition that warrants chronic use of aspirin, VIBANEX may be used with due regard to increased risk of major bleeding. In a clinical trial of patients with atrial fibrillation, concomitant use of aspirin increased the major bleeding risk on apixaban from 1,8 % per year to 3,4 % per year and increased the bleeding risk on warfarin from 2,7 % per year to 4,6 per year.

Patients with prosthetic heart valves
Safety and efficacy of VIBANEX have not been studied in patients with prosthetic heart valves, with or without atrial fibrillation. Therefore, the use of VIBANEX is not recommended in this setting.

Patients with antiphospholipid syndrome
Treatment of patients with established APS is not recommended as evidence regarding safety and efficacy, including the benefit/harm balance of VIBANEX in patients with APS, is inconclusive/incomplete. There is some evidence that treatment with VIBANEX may be associated with an increased risk of recurrent arterial thrombotic events in patients with APS compared to treatment of these patients with warfarin, a vitamin K antagonist.

Surgery and invasive procedures
VIBANEX 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.

Temporary discontinuation of VIBANEX
Discontinue VIBANEX in the presence of active bleeding, elective surgery, or invasive procedures that place patients at an increased risk of haemorrhage. Restart VIBANEX therapy 12 u2013 24 hours after the danger of haemorrhage has ceased.

Spinal/epidural anaesthesia or puncture
Prevention of VTE: elective hip or knee replacement surgery
When neuraxial anaesthesia (spinal/epidural anaesthesia) or spinal/epidural puncture is employed, patients treated with antithrombotic medicines, such as VIBANEX, 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. When an indwelling epidural or intrathecal catheter is planned, VIBANEX should be stopped 48 hours beforehand. Indwelling epidural or intrathecal catheters must be removed at least 6 hours prior to the first dose of VIBANEX. 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 of anticoagulated patients or in patients to be anticoagulated for thromboprophylaxis.

Hip fracture surgery
Apixaban has not been studied in clinical trials in patients undergoing hip fracture surgery to evaluate efficacy and safety in these patients. Therefore, VIBANEX is not recommended in these patients.

Laboratory parameters
Clotting tests e.g. prothrombin time (PT), INR and activated partial thromboplastin time (aPTT) are affected as expected by the mechanism of action of VIBANEX (see section 5.1). Changes observed in these clotting tests at the expected therapeutic dose are small and subject to a high degree of variability (see section 5.1). These parameters should not be used to monitor VIBANEX therapy.

Special populations
Renal impairment
Prevention of VTE: elective hip or knee replacement surgery
Because there is limited clinical experience in patients with creatinine clearance < 15 mL/min and there are no data in patients undergoing dialysis, VIBANEX is not recommended in these patients (see section 4.2, section 5.2 and section 4.3).

Prevention of stroke and systemic embolism: NVAF
VIBANEX has not been studied in patients undergoing dialysis and is not recommended in these patients.

Hepatic impairment
VIBANEX is not recommended in patients with severe hepatic impairment (see section 5.1 and section 4.3). VIBANEX may be used with caution in patients with mild or moderate hepatic impairment (Child Pugh A or B) (see section 4.2 and section 5.1).

Paediatric use
The efficacy and safety of VIBANEX in children below age 18 have not been established. No data are available.

Effect of other medicines on VIBANEX
Inhibitors of CYP3A4 and P-gp
Co-administration of VIBANEX with ketoconazole (400 mg once a day), a strong inhibitor of both CYP3A4 and P-gp, led to a 2-fold increase in mean VIBANEX AUC and a 1,6-fold increase in mean apixaban C max (see section 4.4). The dose of VIBANEX must not exceed 2,5 mg twice daily when used with these medicines. Active substances that are not considered strong inhibitors of both CYP3A4 and P-gp (e.g. diltiazem, naproxen, amiodarone, clarithromycin, verapamil, quinidine) are expected to increase apixaban plasma concentration to a lesser extent. No dose adjustment for VIBANEX is required when co-administered with less potent inhibitors of CYP3A4 and/or P-gp. Diltiazem (360 mg once a day), for instance, considered a moderate CYP3A4 and a weak P-gp inhibitor, led to a 1,4-fold increase in mean VIBANEX AUD and 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 VIBANEX 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 VIBANEX AUC and C max respectively.

Inducers of CYP3A4 and P-gp
Co-administration of apixaban 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 VIBANEX with other strong CYP3A4 and P-gp inducers (e.g. phenytoin, carbamazepine, phenobarbitone or St. Johnu2019s Wort) may also lead to reduced VIBANEX plasma concentrations. No dose adjustment for VIBANEX is required during concomitant therapy with such agents, however strong inducers of both CYP3A4 and P-gp should be co-administered with caution (see section 4.4). For the treatment of DVT and PE, concomitant therapy with strong inducers of both CYP3A4 and P-gp is not recommended (see section 4.4). For prevention of recurrent DVT and PE, strong inducers of both CYP3A4 and P-gp should be co-administered with caution (see section 4.4).

Anticoagulants, platelet aggregation inhibitors and NSAIDs
After combined administration of enoxaparin (40 mg single dose) with apixaban (5 mg single dose), an additive effect on anti-FXa activity was observed. Pharmacokinetic or pharmacodynamic interactions were not evident in healthy subjects when apixaban was co-administered with aspirin 325 mg once a day. Apixaban co-administered with clopidogrel (75 mg once daily) or with the combination of clopidogrel 75 mg and aspirin 162 mg once daily in Phase 1 studies did not show a relevant increase in bleeding time or further inhibition of platelet aggregation compared to administration of the antiplatelet agents without VIBANEX. Increases in clotting tests (PT, INR, and aPTT) were consistent with the effects of apixaban with clopidogrel, ticagrelor or other antiplatelet medicines, except aspirin, are not recommended due to the resulting associated increased risk of major bleeds (see section 4.3). Naproxen (500 mg), and inhibitor of P-gp, led to a 1,5-fold and 1,6-fold increase in mean apixaban AUC and C max, in healthy subjects, respectively. Corresponding increases in clotting tests were observed for apixaban. No clinically relevant prolongation of bleeding time was observed after concomitant administration of apixaban and naproxen. VIBANEX should be used with caution when co-administered with NSAIDs (including aspirin) because these medicinal products typically increase the bleeding risk. Medicines associated with serious bleeding are not recommended concomitantly with VIBANEX, such as unfractionated heparins and heparin derivatives (including low molecular weight heparins (LMWH)), FXa inhibiting oligosaccharides (e.g. fondaparinux), direct thrombin II inhibitors (e.g. desirudin), thrombolytic agents, GPIIb/IIIa receptor antagonists, dipyridamole, dextran, sulfinpyrazone, vitamin K antagonists, and other oral anticoagulants. It should be noted that unfractionated heparin can be administered at doses necessary to maintain a patent central venous or arterial catheter (see section 4.4).

Other concomitant therapies
No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when apixaban was co-administered with atenolol or famotidine. Co-administration of apixaban 10 mg with atenolol 100 mg did not have a clinically relevant effect on the pharmacokinetics of apixaban. Following administration of the two medicines together, mean apixaban AUC and C max were 15 % and 18 % lower than administered alone. The administration of apixaban 10 mg with famotidine 40 mg had no effect on apixaban AUC or C max.

Safety has not been established.

Pregnancy
VIBANEX is not recommended during pregnancy. Treatment may increase the risk of haemorrhage during pregnancy and delivery.

Breastfeeding
It is unknown whether VIBANEX or its metabolites are excreted in human milk. A risk to newborns and infants cannot be excluded. Women taking VIBANEX should not breastfeed their infants.

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

Summary of the safety profile
Prevention of VTE: elective hip or knee replacement surgery
The safety of apixaban has been evaluated in 5 924 patients exposed to apixaban 2,5 mg twice daily undergoing major orthopaedic surgery of the lower limbs (elective hip replacement or elective knee replacement) treated for up to 38 days. In total, 11 % of the patients treated with apixaban 2,5 mg twice daily experienced adverse reactions. Bleeding may occur during apixaban therapy in the presence of associated risk factors such as organic lesions liable to bleed. Common adverse reactions were anaemia, haemorrhage, contusion and nausea. The use of apixaban may be associated with an increased risk of occult or overt bleeding from any tissue or organ (see section 4.4).

Tabulated list of adverse reactions
Table 1 shows the adverse reactions ranked under headings of system organ class and frequency using the following convention: Frequent; Less frequent; Frequency unknown.

Table 1: Tabulated adverse reactions
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 and 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 ua749 Frequency unknown Less frequent Less frequent
Eye disorders Eye 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 Less frequent Frequent Frequent
Haemorrhoidal haemorrhage Frequency unknown Less frequent 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, increased aspartate aminotransferase, increased blood alkaline phosphatase, increased blood bilirubin Less frequent Less frequent Less frequent
Increased gamma-glutamyltransferase Less frequent Frequent Frequent
Increased alanine aminotransferase 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 Positive occult blood 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
* There were no occurrences of generalized pruritus in CV185057 (long term prevention of VTE).
ua749 The term u201cbrain haemorrhageu201d encompasses all intracranial or intraspinal haemorrhages (i.e. haemorrhagic stroke or putamen, cerebellar, intraventricular, or subdural haemorrhages).

There is no antidote to apixaban. Overdose of apixaban may result in a higher risk of bleeding. Administration of activated charcoal 2 and 6 hours after ingestion of a 20 mg dose of apixaban 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 VIBANEX overdose or accidental ingestion. Haemodialysis is unlikely to be an effective means of managing VIBANEX overdose. Treatment should be symptomatic and supportive.