Each film-coated tablet contains 2.5 mg apixaban. Excipients with known effect: Each 2.5 mg film-coated tablet contains 51.43 mg lactose (see section 4.4). For the full list of excipients, see section 6.1.

PHARMACEUTICAL FORM

Film-coated tablet Yellow, round tablets debossed with 893 on one side and 21/2 on the other side.

CLINICAL PARTICULARS

Posology and method of administration

The recommended dose of Eliquis is 2.5 mg taken orally twice daily. The initial dose should be taken 12 to 24 hours after surgery. Physicians may consider the potential benefits of earlier anticoagulation for VTE prophylaxis as well as the risks of post-surgical bleeding in deciding on the time of administration within this time window.

Preventionofstrokeandsystemicembolisminpatientswithnon-valvularatrialfibrillation(NVAF)

The recommended dose of Eliquis is 2.5 mg taken orally twice daily in patients with NVAF and at least two of the following characteristics: age >= 80 years, body weight <= 60 kg, or serum creatinine >= 1.5 mg/dl (133 micromole/l). Therapy should be continued long term.

If a dose is missed, the patient should take Eliquis immediately and then continue with twice daily intake as before.

Switching treatment from parenteral anticoagulants to Eliquis (and vice versa) can be done at the next scheduled dose (see section 4.5).

When converting patients from Vitamin K antagonist (VKA) therapy to Eliquis, discontinue warfarin or other VKA therapy and start Eliquis when the international normalized ratio (INR) is < 2.0.

When converting patients from Eliquis to VKA therapy, continue administration of Eliquis for at least 2 days after beginning VKA therapy. After 2 days of coadministration of Eliquis with VKA therapy, obtain an INR prior to the next scheduled dose of Eliquis. Continue coadministration of Eliquis and VKA therapy until the INR is >= 2.0.

As there is no clinical experience in patients with creatinine clearance < 15 ml/min, or in patients undergoing dialysis, apixaban is not recommended in these patients (see sections 4.4 and 5.2).

No dose adjustment is necessary in patients with mild or moderate renal impairment (see section 5.2). Limited clinical data in patients with severe renal impairment (creatinine clearance 15-29 ml/min) indicate that apixaban plasma concentrations are increased in this patient population, therefore, apixaban is to be used with caution in these patients (see sections 4.4 and 5.2).

Preventionofstrokeandsystemicembolisminpatientswithnon-valvularatrialfibrillation(NVAF)

No dose adjustment is necessary in patients with mild or moderate renal impairment (see section 5.2). Patients with serum creatinine >= 1.5 mg/dL (133 micromole/l) associated with age >= 80 years or body weight <= 60 kg should receive the lower dose of apixaban 2.5 mg twice daily.

Patients with exclusive criteria of severe renal impairment (creatinine clearance 15-29 ml/min) should also receive the lower dose of apixaban 2.5 mg twice daily.

Eliquis 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 sections 4.4. and 5.2). It should 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). Patients with elevated liver enzymes (ALT/AST >2 x ULN) or total bilirubin >=1.5 x ULN were excluded in clinical trials. Therefore Eliquis should be used with caution in this population (see sections 4.4 and 5.2). Prior to initiating Eliquis, liver function testing should be performed.

VTEp - No dose adjustment required (see section 5.2). NVAF - No dose adjustment required, unless criteria for dose reduction are met (see Dose reduction at the beginning of section 4.2).

VTEp - No dose adjustment required (see sections 4.4 and 5.2). NVAF - No dose adjustment required, unless criteria for dose reduction are met (see Dose reduction at the beginning of section 4.2).

The safety and efficacy of Eliquis in children and adolescents below age 18 have not been established. No data are available.

Contraindications

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 anticoagulant agent e.g. unfractionated heparin (UFH), low molecular weight heparins (enoxaparin, dalteparin, etc. ), heparin derivatives (fondaparinux, etc. ), oral anticoagulants (warfarin, rivaroxaban, dabigatran, etc.) except under the circumstances of switching therapy to or from apixaban (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).

Special warnings and precautions for use

As with other anticoagulants, patients taking Eliquis are to be carefully observed for signs of bleeding. It is recommended to be used with caution in conditions with increased risk of haemorrhage. Eliquis administration should be discontinued if severe haemorrhage occurs (see sections 4.8 and 4.9). Although treatment with apixaban does not require routine monitoring of exposure, the Rotachrom(r) anti-FXa assay may be useful in exceptional situations where knowledge of apixaban exposure may help to inform clinical decisions, e.g., overdose and emergency surgery (see section 5.1).

Due to an increased bleeding risk, concomitant treatment with any other anticoagulants is contraindicated (see section 4.3). The concomitant use of Eliquis with antiplatelet agents increases the risk of bleeding (see section 4.5). Care is to be taken if patients are treated concomitantly with non-steroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid. Following surgery, other platelet aggregation inhibitors are not recommended concomitantly with Eliquis (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 Eliquis. In a clinical trial of patients with atrial fibrillation, concomitant use of ASA 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. In this clinical trial, there was limited (2.1%) use of concomitant dual antiplatelet therapy. In a clinical trial of high-risk post acute coronary syndrome patients, characterized by multiple cardiac and non-cardiac comorbidities, who received ASA or the combination of ASA and clopidogrel, a significant increase in risk of ISTH (International Society on Thrombosis and Haemostasis) major bleeding was reported for apixaban (5.13% per year) compared to placebo (2.04% per year) .

There is very limited experience with the use of thrombolytic agents for the treatment of acute ischemic stroke in patients administered apixaban.

Eliquis 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. Eliquis 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. Apixaban 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.

Discontinuing anticoagulants, including Eliquis, 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 Eliquis must be temporarily discontinued for any reason, therapy should be restarted as soon as possible.

When neuraxial anaesthesia (spinal/epidural anaesthesia) or spinal/epidural puncture is employed, patients treated with antithrombotic agents 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 medicinal products affecting haemostasis. Indwelling epidural or intrathecal catheters must be removed at least 5 hours prior to the first dose of Eliquis. 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 physician 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 apixaban with indwelling intrathecal or epidural catheters. In case there is such need and based on the general PK characteristics of apixaban, a time interval of 20-30 hours (i.e., 2 x half-life) between the last dose of apixaban and catheter withdrawal should elapse, and at least one dose should be omitted before catheter withdrawal. The next dose of apixaban may be given at least 5 hours after catheter removal. As with all new anticoagulant drugs, experience with neuraxial blockade is limited and extreme caution is therefore recommended when using apixaban in the presence of neuraxial blockade.

As there is no clinical experience in patients with creatinine clearance < 15 ml/min, or in patients undergoing dialysis, apixaban is not recommended in these patients (see sections 4.2 and 5.2).

No dose adjustment is necessary in patients with mild or moderate renal impairment (see section 5.2). Limited clinical data in patients with severe renal impairment (creatinine clearance 15-29 ml/min) indicate that apixaban plasma concentrations are increased in this patient population, therefore, apixaban alone or in combination with acetylsalicylic acid (ASA) is to be used with caution in these patients because of a potentially higher bleeding risk (see sections 4.2 and 5.2).

Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF)

No dose adjustment is necessary in patients with mild or moderate renal impairment (see section 4.2 and 5.2).

Patients with serum creatinine >= 1.5 mg/dL (133 micromole/l) associated with age >= 80 years or body weight <= 60 kg should receive the lower dose of apixaban 2.5 mg twice daily. Patients with exclusive criteria of severe renal impairment (creatinine clearance 15-29 ml/min) should also receive the lower dose of apixaban 2.5 mg twice daily (see section 4.2).

The co-administration of Eliquis with ASA in elderly patients should be used cautiously because of a potentially higher bleeding risk.

Eliquis 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 ALT/AST > 2 x ULN or total bilirubin >= 1.5 x ULN were excluded in clinical trials. Therefore Eliquis should be used cautiously in this population (see section 5.2). Prior to initiating Eliquis, liver function testing should be performed.

The use of Eliquis 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 HIV protease inhibitors (e.g., ritonavir). These medicinal products may increase apixaban exposure by 2-fold (see section 4.5) or greater in the presence of additional factors that increase apixaban exposure (e.g., severe renal impairment).

The concomitant use of Eliquis with strong CYP3A4 and P-gp inducers (e.g., rifampicin, phenytoin, carbamazepine, phenobarbital or St. John's Wort) may lead to a ~50% reduction in apixaban exposure. In a clinical study in atrial fibrillation patients, diminished efficacy and a higher risk of bleeding were observed with coadministration of apixaban with strong inducers of both CYP3A4 and P-gp compared with using apixaban alone. Strong inducers of both CYP3A4 and P-gp should be co-administered with caution (see section 4.5).

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

Clotting tests (e.g., PT, INR, and aPTT) are affected as expected by the mechanism of action of apixaban. 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).

Eliquis contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Interaction with other medicinal products and other forms of interaction

Co-administration of apixaban 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 AUC and a 1.6-fold increase in mean apixaban Cmax. The use of Eliquis is not recommended in patients receiving concomitant systemic treatment with strong inhibitors of both CYP3A4 and P-gp, such as as azole-antimycotics (e.g., ketoconazole, itraconazole, voriconazole and posaconazole) and HIV protease inhibitors (e.g., ritonavir) (see section 4.4). Active substances which are not considered strong inhibitors of both CYP3A4 and P-gp, (eg. diltiazem, naproxen, amiodarone, verapamil, quinidine) are expected to increase apixaban plasma concentration to a lesser extent. 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 apixaban AUC and a 1.3-fold increase in Cmax. 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 Cmax, respectively. No dose adjustment for apixaban is required when co-administered with less potent inhibitors of CYP3A4 and/or 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 Cmax, respectively. The concomitant use of apixaban with other strong CYP3A4 and P-gp inducers (e.g., phenytoin, carbamazepine, phenobarbital or St. John's Wort) may also lead to reduced apixaban plasma concentrations. No dose adjustment for apixaban 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).

Due to an increased bleeding risk, concomitant treatment with any other anticoagulants is contraindicated (see section 4.3). After combined administration of enoxaparin (40 mg single dose) with apixaban (5 mg single dose), an additive effect on anti-Factor Xa activity was observed. Pharmacokinetic or pharmacodynamic interactions were not evident when apixaban was co- administered with ASA 325 mg once a day. Apixaban co-administered with clopidogrel (75 mg once a day) or with the combination of clopidogrel 75 mg and ASA 162 mg once daily in Phase 1 studies did not show a relevant increase in template bleeding time, or further inhibition of platelet aggregation, compared to administration of the antiplatelet agents without apixaban. Increases in clotting tests (PT, INR, and aPTT) were consistent with the effects of apixaban 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 Cmax, 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 apixaban and naproxen. Despite these findings, there may be individuals with a more pronounced pharmacodynamic response when antiplatelet agents are co-administered with apixaban. Eliquis should be used with caution when co-administered with NSAIDs (including acetylsalicylic acid) because these medicinal products typically increase the bleeding risk. A significant increase in bleeding risk was reported with the triple combination of apixaban, ASA and clopidogrel in a clinical study in patients with acute coronary syndrome (see section 4.4). Agents associated with serious bleeding are not recommended concomitantly with Eliquis, such as: thrombolytic agents, GPIIb/IIIa receptor antagonists, thienopyridines (e.g., clopidogrel), dipyridamole, dextran and sulfinpyrazone.

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 medicinal products together, mean apixaban AUC and Cmax were 15% and 18% lower than when administered alone. The administration of apixaban 10 mg with famotidine 40 mg had no effect on apixaban AUC or Cmax.

In vitro apixaban studies showed no inhibitory effect on the activity of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2D6 or CYP3A4 (IC50 > 45 M) and weak inhibitory effect on the activity of CYP2C19 (IC50 > 20 M) at concentrations that are significantly greater than peak plasma concentrations observed in patients. Apixaban did not induce CYP1A2, CYP2B6, CYP3A4/5 at a concentration up to 20 M. Therefore, apixaban is not expected to alter the metabolic clearance of coadministered drugs that are metabolized by these enzymes. Apixaban is not a significant inhibitor of P-gp. In studies conducted in healthy subjects, as described below, apixaban did not meaningfully alter the pharmacokinetics of digoxin, naproxen, or atenolol. Digoxin: Co-administration of apixaban (20 mg once a day) and digoxin (0.25 mg once a day), a P-gp substrate, did not affect digoxin AUC or Cmax. Therefore, apixaban does not inhibit P-gp mediated substrate transport. Naproxen: Co-administration of single doses of apixaban (10 mg) and naproxen (500 mg), a commonly used NSAID, did not have any effect on the naproxen AUC or Cmax.

: Co-administration of a single dose of apixaban (10 mg) and atenolol (100 mg), a common beta-blocker, did not alter the pharmacokinetics of atenolol.

Administration of activated charcoal reduces apixaban exposure (see section 4.9).

Fertility, pregnancy and lactation

There are no data from the use of apixaban in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. Apixaban is not recommended during pregnancy.

It is unknown whether apixaban or its metabolites are excreted in human milk. Available data in animals have shown excretion of apixaban in milk. In rat milk, a high milk to maternal plasma ratio (Cmax about 8, AUC about 30) was found, possibly due to active transport into the milk. A risk to newborns and infants cannot be excluded. A decision must be made to either discontinue breast-feeding or to discontinue/abstain from apixaban therapy.

Studies in animals dosed with apixaban have shown no effect on fertility (see section 5.3).

Effects on ability to drive and use machines

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

Undesirable effects

Summaryofthesafetyprofile

The safety of apixaban has been investigated in 5,924 patients in VTEp studies and in 11,886 patients in NVAF studies, for an average total exposure of 20 days and 1.7 years respectively. In the VTEp studies, in total, 11% of the patients treated with apixaban 2.5 mg twice daily experienced adverse reactions. Common adverse reactions were anaemia, haemorrhage, contusion, and nausea. Over the two phase III studies in NVAF, 24.4% (apixaban vs warfarin study) and 9.6% (apixaban vs aspirin study) of the patients treated with apixaban (5 mg or 2.5 mg) twice daily experienced adverse reactions. Common adverse reactions for apixaban were epistaxis, contusion, haematuria, haematoma, eye haemorrhage, and gastrointestinal haemorrhage. The overall incidence of adverse reactions related to bleeding with apixaban was 24.3% in the apixaban vs warfarin study and was 9.6% in the apixaban vs aspirin study (see section 5.1). In the apixaban vs warfarin study the incidence of ISTH major gastrointestinal bleeds (including upper GI, lower GI, and rectal bleeding) with apixaban was 0.76%/year. The incidence of ISTH major intraocular bleeding with apixaban was 0.18%/year.

Tabulatedlistofadversereactions

Table 1 shows the adverse reactions ranked under headings of System Organ Class and frequency using the following convention: very common (>=1/10); common (>=1/100 to < 1/10); uncommon (>=1/1,000 to < 1/100); rare (>=1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data) for both VTEp and NVAF. Table 1

System Organ Class	VTEp	NVAF
Blood and lymphatic system disorders
Anaemia (including postoperative and haemorrhagic	Common	-
System Organ Class	VTEp	NVAF
anaemia, and respective laboratory parameters)
Thrombocytopenia (including platelet count decreases)	Uncommon	-
Immune system disorders
Hypersensitivity (including skin rash, anaphylactic reaction and allergic edema)	-	Uncommon
Hypersensitivity	Rare	-
Nervous system disorders
Brain haemorrhage, other intracranial or intraspinal haemorrhage (including subdural haematoma, subarachnoid haemorrhage, and spinal haematoma)	-	Uncommon
Eye disorders
Eye haemorrhage (including conjunctival haemorrhage)	-	Common
Ocular haemorrhage (including conjunctival haemorrhage)	Rare	-
Vascular disorders
Haemorrhage (including haematoma, and vaginal and urethral haemorrhage)	Common	-
Other haemorrhage, haematoma	-	Common
Hypotension (including procedural hypotension)	Uncommon	-
Intra-abdominal haemorrhage	-	Uncommon
Respiratory, thoracic and mediastinal disorders
Epistaxis	Uncommon	Common
Haemoptysis	Rare	-
Respiratory tract haemorrhage (including pulmonary alveolar haemorrhage, laryngeal haemorrhage and pharyngeal haemorrhage)	-	Rare
Gastrointestinal disorders
Nausea	Common	-
Gastrointestinal haemorrhage (including haematemesis and melaena). rectal haemorrhage, gingival bleeding	-	Common
Gastrointestinal haemorrhage (including haematemesis and melaena), haematochezia	Uncommon	-
Haemorrhoidal haemorrhage, haematochezia, mouth haemorrhage	-	Uncommon
Rectal haemorrhage, gingival bleeding	Rare	-
Retroperitoneal haemorrhage	-	Rare
Hepatobiliary disorders
Transaminases increased (including alanine aminotransferase increased and alanine aminotransferase abnormal), aspartate aminotransferase increased, gamma-glutamyltransferase increased, liver function test abnormal, blood alkaline phosphatase increased, blood bilirubin increased	Uncommon	-
Musculoskeletal and connective tissue disorders
Muscle haemorrhage	Rare	-
Renal and urinary disorders
Haematuria	-	Common
Haematuria (including respective laboratory parameters)	Uncommon	-
Reproductive system and breast disorders
Abnormal vaginal haemorrhage, urogenital haemorrhage	-	Uncommon
General disorders and administration site conditions
System Organ Class	VTEp	NVAF
Application site bleeding	-	Uncommon
Investigations
Occult blood positive	-	Uncommon
Injury, poisoning and procedural complications
Contusion	Common	Common
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	Uncommon	-
Traumatic haemorrhage, post procedural haemorrhage, incision site haemorrhage	-	Uncommon

The use of Eliquis may be associated with an increased risk of occult or overt bleeding from any tissue or organ, which may result in posthaemorrhagic anaemia. The signs, symptoms, and severity will vary according to the location and degree or extent of the bleeding (see section 4.4 and section 5.1).

Overdose

There is no antidote to Eliquis. Overdose of apixaban may result in a higher risk of bleeding. 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. In controlled clinical trials, orally-administered apixaban in healthy subjects at doses up to 50 mg daily for 3 to 7 days (25 mg twice daily (bid) for 7 days or 50 mg once daily (OD) for 3 days) had no clinically relevant adverse effects. In healthy subjects, 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 Cmax. 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 apixaban overdose or accidental ingestion. 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 apixaban. Re-dosing of recombinant factor VIIa could be considered and titrated depending on improvement of bleeding. Depending on local availability, a consultation of a coagulation expert should be considered in case of major bleedings.

PHARMACOLOGICAL PROPERTIES

Pharmacodynamic properties

Apixaban is a potent, oral, reversible, direct and highly selective active site inhibitor of factor Xa. It does not require antithrombin III for antithrombotic activity. Apixaban inhibits free and clot-bound factor Xa, and prothrombinase activity. Apixaban has no direct effects on platelet aggregation, but indirectly inhibits platelet aggregation induced by thrombin. By inhibiting factor Xa, apixaban prevents thrombin generation and thrombus development. Preclinical studies of apixaban in animal models have demonstrated antithrombotic efficacy in the prevention of arterial and venous thrombosis at doses that preserved haemostasis.

The pharmacodynamic effects of apixaban are reflective of the mechanism of action (FXa inhibition). As a result of FXa inhibition, apixaban prolongs clotting tests such as prothrombin time (PT), INR and activated partial thromboplastin time (aPTT). Changes observed in these clotting tests at the expected therapeutic dose are small and subject to a high degree of variability. They are not recommended to assess the pharmacodynamic effects of apixaban. Apixaban also demonstrates anti-FXa activity as evident by reduction in Factor Xa enzyme activity in multiple commercial anti-FXa kits, however results differ across kits. Data from clinical trials are only available for the Rotachrom Heparin chromogenic assay and results are presented below. Anti-FXa activity exhibits a close direct linear relationship with apixaban plasma concentration, reaching maximum values at the time of apixaban peak plasma concentrations. The relationship between apixaban plasma concentration and anti-FXa activity is linear over a wide dose range of apixaban, and precision of the Rotachrom assay is well within acceptable limits for use in a clinical laboratory. The dose- and concentration-related changes observed following apixaban administration are more pronounced, and less variable, with anti-FXa activity compared with clotting tests. In patients treated with apixaban 2.5 mg twice a day following elective knee or hip replacement surgery the predicted steady-state peak and trough anti-FXa activity with apixaban 2.5 mg BID dosing are 1.3 IU/ml (5th/95th percentile 0.67-2.4 IU/ml) and 0.84 IU/ml (5th/95th percentile 0.37-1.8 IU/ml), respectively, demonstrating less than a 1.6-fold fluctuation in peak-to-trough anti- FXa activity over the dosing interval. In patients with atrial fibrillation, the predicted steady-state peak and trough anti-FXa activity with apixaban 5 mg BID are 2.55 IU/ml (5th/95th percentile 1.36-4.79 IU/ml) and 1.54 IU/ml (5th/95th percentile 0.61-3.43 IU/ml), respectively. In AF patients who meet the criteria for a dose reduction to 2.5 mg BID, the predicted peak and trough anti-FXa values are 1.84 IU/ml (5th/95th percentile 1.02-3.29 IU/ml) and 1.18 IU/ml (5th/95th percentile 0.51-2.42 IU/ml), respectively. Although treatment with apixaban does not require routine monitoring of exposure, the Rotachrom(r) anti-FXa assay may be useful in exceptional situations where knowledge of apixaban exposure may help to inform clinical decisions, e.g., overdose and emergency surgery.

The apixaban clinical program was designed to demonstrate the efficacy and safety of apixaban for the prevention of VTE in a broad range of adult patients undergoing elective hip or knee replacement. A total of 8,464 patients were randomized in two pivotal, double-blind, multi-national studies, comparing apixaban 2.5 mg given orally twice daily (4,236 patients) or enoxaparin 40 mg once daily (4,228 patients). Included in this total were 1,262 patients (618 in the apixaban group) of age 75 or older, 1,004 patients (499 in the apixaban group) with low body weight (<= 60 kg), 1,495 patients (743 in the apixaban group) with BMI >= 33 kg/m2, and 415 patients (203 in the apixaban group) with moderate renal impairment. The ADVANCE-3 study included 5,407 patients undergoing elective hip replacement, and the ADVANCE-2 study included 3,057 patients undergoing elective knee replacement. Subjects received either apixaban 2.5 mg given orally twice daily (po bid) or enoxaparin 40 mg administered subcutaneously once daily (sc od). The first dose of apixaban was given 12 to 24 hours post-surgery, whereas enoxaparin was started 9 to 15 hours prior to surgery. Both apixaban and enoxaparin were given for 32-38 days in the ADVANCE-3 study and for 10-14 days in the ADVANCE-2 study. Based on patient medical history in the studied population of ADVANCE-3 and ADVANCE-2 (8,464 patients), 46% had hypertension, 10% had hyperlipidemia, 9% had diabetes, and 8% had coronary artery disease. Apixaban demonstrated a statistically superior reduction in the primary endpoint, a composite of all VTE/all cause death, and in the Major VTE endpoint, a composite of proximal DVT, non-fatal PE, and VTE-related death, compared to enoxaparin in both elective hip or knee replacement surgery (see Table 2). Table 2: Efficacy results from pivotal phase III studies

The safety endpoints of major bleeding, the composite of major and clinically relevant non-major (CRNM) bleeding, and all bleeding showed similar rates for patients treated with apixaban 2.5 mg compared with enoxaparin 40 mg (see Table 3). All the bleeding criteria included surgical site bleeding. Table 3: Bleeding results from pivotal phase III studies *

The overall incidences of adverse reactions of bleeding, anaemia and abnormalities of transaminases (e.g., alanine aminotransferase levels) were numerically lower in patients on apixaban compared to enoxaparin in the phase II and phase III studies in elective hip and knee replacement surgery. In the knee replacement surgery study during the intended treatment period, in the apixaban arm 4 cases of PE were diagnosed against no cases in the enoxaparin arm. No explanation can be given to this higher number of PE.

Preventionofstrokeandsystemicembolisminpatientswithnon-valvularatrialfibrillation(NVAF)

A total of 23,799 patients were randomised in the clinical program (ARISTOTLE: apixaban versus warfarin, AVERROES: apixaban versus ASA) including 11,927 randomised to apixaban. The program was designed to demonstrate the efficacy and safety of apixaban for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (NVAF) and one or more additional risk factors, such as:

In the ARISTOTLE study a total of 18,201 patients were randomized to double-blind treatment with apixaban 5 mg twice daily (or 2.5 mg twice daily in selected patients [4.7%], see section 4.2) or warfarin (target INR range 2.0-3.0), patients were exposed to study drug for a mean of 20 months. The mean age was 69.1 years, the mean CHADS2 score was 2.1 and 18.9 % of patients had prior stroke or TIA. In the study, apixaban achieved statistically significant superiority in the primary endpoint of prevention of stroke (haemorrhagic or ischaemic) and systemic embolism (see Table 4) compared with warfarin. Table 4: Efficacy Outcomes in Patients with Atrial Fibrillation in the ARISTOTLE Study

For patients randomized to warfarin, the median percentage of time in therapeutic range (TTR) (INR 2-3) was 66%. Apixaban showed a reduction of stroke and systemic embolism compared to warfarin across the different levels of center TTR; within the highest quartile of TTR according to center, the hazard ratio for apixaban vs warfarin was 0.73 (95% CI, 0.38, 1.40). Key secondary endpoints of major bleeding and all cause death were tested in a pre-specified hierarchical testing strategy to control the overall type 1 error in the trial. Statistically significant superiority was also achieved in the key secondary endpoints of both major bleeding and all-cause death (see Table 5). With improving monitoring of INR the observed benefits of apixaban compared to warfarin regarding all cause death diminish. Table 5: Secondary endpoints in Patients with Atrial Fibrillation in the ARISTOTLE Study

*Major bleeding defined per International Society on Thrombosis and Haemostasis (ISTH) criteria. The overall discontinuation rate due to adverse reactions was 1.8% for apixaban and 2.6% for warfarin in the ARISTOTLE study. The efficacy results for prespecified subgroups, including CHADS2 score, age, body weight, gender, status of renal function, prior stroke or TIA and diabetes were consistent with the primary efficacy results for the overall population studied in the trial. The incidence of ISTH major gastrointestinal bleeds (including upper GI, lower GI, and rectal bleeding) was 0.76%/year with apixaban and 0.86%/year with warfarin. The major bleeding results for prespecified subgroups including CHADS2 score, age, body weight, gender, status of renal function, prior stroke or TIA and diabetes were consistent with the results for the overall population studied in the trial.

In the AVERROES study a total of 5,598 patients considered to be unsuitable for VKA by the investigators were randomized to treatment with apixaban 5 mg twice daily (or 2.5 mg twice daily in selected patients [6.4%], see section 4.2) or ASA. ASA was given at a once daily dose of 81 mg (64%), 162 (26.9%), 243 (2.1%), or 324 mg (6.6%) at the discretion of the investigator. Patients were exposed to study drug for a mean of 14 months. The mean age was 69.9 years, the mean CHADS2 score was 2.0 and 13.6% of patients had prior stroke or TIA. Common reasons for unsuitability for VKA therapy in the AVERROES study included unable/unlikely to obtain INRs at requested intervals (42.6%), patient refused treatment with VKA (37.4%), CHADS2 score = 1 and physician did not recommend VKA (21.3%), patient could not be relied on to adhere to VKA medication instruction (15.0%), and difficulty/expected difficulty in contacting patient in case of urgent dose change (11.7%). AVERROES was stopped early based on a recommendation by the independent Data Monitoring Committee due to clear evidence of reduction of stroke and systemic embolism with an acceptable safety profile. The overall discontinuation rate due to adverse reactions was 1.5% for apixaban and 1.3% for ASA in the AVERROES study. In the study, apixaban achieved statistically significant superiority in the primary endpoint of prevention of stroke (haemorrhagic, ischaemic or unspecified) or systemic embolism (see Table 6) compared to ASA. Table 6: Key Efficacy Outcomes in Patients with Atrial Fibrillation in the AVERROES Study

* Assessed by sequential testing strategy designed to control the overall type I error in the trial. + Secondary endpoint. There was no statistically significant difference in the incidence of major bleeding between apixaban and ASA (see Table 7). Table 7: Bleeding Events in Patients with Atrial Fibrillation in the AVERROES Study

*Major bleeding defined per International Society on Thrombosis ad Haemostasis (ISTH) criteria.

The European Medicines Agency has deferred the obligation to submit the results of studies with Eliquis in one or more subsets of the paediatric population in venous and arterial embolism and thrombosis (see section 4.2 for information on paediatric use).

Pharmacokinetic properties

The absolute bioavailability of apixaban is approximately 50% for doses up to 10 mg. Apixaban is rapidly absorbed with maximum concentrations (Cmax) appearing 3 to 4 hours after tablet intake. Intake with food does not affect apixaban AUC or Cmax at the 10 mg dose. Apixaban can be taken with or without food. Apixaban demonstrates linear pharmacokinetics with dose proportional increases in exposure for oral doses up to 10 mg. At doses 25 mg apixaban displays dissolution limited absorption with decreased bioavailability. Apixaban exposure parameters exhibit low to moderate variability reflected by a within-subject and inter-subject variability of ~20% CV and ~30% CV, respectively.

Plasma protein binding in humans is approximately 87%. The volume of distribution (Vss) is approximately 21 litres.

Apixaban has multiple routes of elimination. Of the administered apixaban dose in humans, approximately 25% was recovered as metabolites, with the majority recovered in faeces. Renal excretion of apixaban accounts for approximately 27% of total clearance. Additional contributions from biliary and direct intestinal excretion were observed in clinical and nonclinical studies, respectively. Apixaban has a total clearance of about 3.3 l/h and a half-life of approximately 12 hours. O-demethylation and hydroxylation at the 3-oxopiperidinyl moiety are the major sites of biotransformation. Apixaban is metabolized mainly via CYP3A4/5 with minor contributions from CYP1A2, 2C8, 2C9, 2C19, and 2J2. Unchanged apixaban is the major drug-related component in human plasma with no active circulating metabolites present. Apixaban is a substrate of transport proteins, P-gp and breast cancer resistance protein (BCRP).

There was no impact of impaired renal function on peak concentration of apixaban. There was an increase in apixaban exposure correlated to decrease in renal function, as assessed via measured creatinine clearance. In individuals with mild (creatinine clearance 51-80 ml/min), moderate (creatinine clearance 30-50 ml/min) and severe (creatinine clearance 15-29 ml/min) renal impairment, apixaban plasma concentrations (AUC) were increased 16, 29, and 44% respectively, compared to individuals with normal creatinine clearance. Renal impairment had no evident effect on the relationship between apixaban plasma concentration and anti-FXa activity.

In a study comparing 8 subjects with mild hepatic impairment, Child-Pugh A score 5 (n = 6) and score 6 (n = 2), and 8 subjects with moderate hepatic impairment (Child-Pugh B score 7 (n = 6) and score 8 (n = 2), to 16 healthy control subjects, the single-dose pharmacokinetics and pharmacodynamics of apixaban 5 mg were not altered in subjects with hepatic impairment. Changes in anti-Factor Xa activity and INR were comparable between subjects with mild to moderate hepatic impairment and healthy subjects.

Elderly patients (above 65 years) exhibited higher plasma concentrations than younger patients, with mean AUC values being approximately 32% higher and no difference in Cmax.

The results across phase 1 studies showed no discernible difference in apixaban pharmacokinetics between White/Caucasian, Asian and Black/African American subjects. Findings from a population pharmacokinetic analysis in patients who received apixaban were generally consistent with the phase 1 results.

Compared to apixaban exposure in subjects with body weight of 65 to 85 kg, body weight > 120 kg was associated with approximately 30% lower exposure and body weight < 50 kg was associated with approximately 30% higher exposure.

The pharmacokinetic /pharmacodynamic (PK/PD) relationship between apixaban plasma concentration and several PD endpoints (anti-FXa activity, INR, PT, aPTT) has been evaluated after administration of a wide range of doses (0.5 - 50 mg). The relationship between apixaban plasma concentration and anti-factor Xa activity was best described by a linear model. The PK/PD relationship observed in patients was consistent with that established in healthy subjects.

Preclinical safety data

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, fertility and embryo-foetal development and juvenile toxicity. The major observed effects in the repeated dose toxicity studies were those related to the pharmacodynamic action of apixaban on blood coagulation parameters. In the toxicity studies little to no increase of bleeding tendency was found. However, since this may be due to a lower sensitivity of the non-clinical species compared to humans, this result should be interpreted with caution when extrapolating to humans.

PHARMACEUTICAL PARTICULARS

List of excipients

Microcrystalline cellulose (E460) Croscarmellose sodium Sodium laurilsulfate Magnesium stearate (E470b)

Lactose monohydrate Hypromellose (E464) Titanium dioxide (E171) Triacetin (E1518) Yellow iron oxide (E172)

Incompatibilities

Shelf life

Special precautions for storage

Nature and contents of container

Alu-PVC/PVdC blisters. Cartons of 10, 20, 60 and 168 film-coated tablets. Alu PVC/PVdC perforated unit dose blisters of 60x1 and 100x1 film-coated tablets. Not all pack sizes may be marketed.

Special precautions for disposal

MARKETING AUTHORISATION HOLDER

Bristol-Myers Squibb/Pfizer EEIG, Bristol-Myers Squibb House, Uxbridge Business Park, Sanderson Road, Uxbridge, Middlesex UB8 1DH United Kingdom

MARKETING AUTHORISATION NUMBER(S)

EU/1/11/691/001 EU/1/11/691/002 EU/1/11/691/003 EU/1/11/691/004 EU/1/11/691/005 EU/1/11/691/013

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu

Study	ADVANCE-3 (hip)			ADVANCE-2 (knee)
Study treatment Dose Duration of treatment	Apixaban 2.5 mg po bid 35 +- 3 d	Enoxaparin 40 mg sc od 35 +- 3 d	p- value	Apixaban 2.5 mg po bid 12 +- 2 d	Enoxaparin 40 mg sc od 12 +- 2 d	p- value
Total VTE/all-cause death
Number of	27/1949	74/1917	<0.000 1	147/976	243/997	<0.000 1
events/subjects Event Rate	1.39%	3.86%		15.06%	24.37%
Relative Risk	0.36			0.62
95% CI	(0.22, 0.54)			(0.51, 0.74)
Major VTE
Number of	10/2199	25/2195	0.0107	13/1195	26/1199	0.0373
events/subjects	0.45%	1.14%		1.09%	2.17%
Event Rate
Relative Risk	0.40			0.50
95% CI	(0.15, 0.80)			(0.26, 0.97)

	ADVANCE-3		ADVANCE-2
	Apixaban 2.5 mg po bid 35 +- 3 d	Enoxaparin 40 mg sc od 35 +- 3 d	Apixaban 2.5 mg po bid 12 +- 2 d	Enoxaparin 40 mg sc od 12 +- 2 d
All treated	n = 2673	n = 2659	n = 1501	n = 1508
Treatment Period 1
Major	22 (0.8%)	18 (0.7%)	9 (0.6%)	14 (0.9%)
Fatal	0	0	0	0
Major + CRNM	129 (4.8%)	134 (5.0%)	53 (3.5%)	72 (4.8%)
All	313 (11.7%)	334 (12.6%)	104 (6.9%)	126 (8.4%)
Post-surgery treatment period 2
Major	9 (0.3%)	11 (0.4%)	4 (0.3%)	9 (0.6%)
Fatal	0	0	0	0
Major + CRNM	96 (3.6%)	115 (4.3%)	41 (2.7%)	56 (3.7%)
All	261 (9.8%)	293 (11.0%)	89 (5.9%)	103 (6.8%)

	Apixaban N=9120 n (%/yr)	Warfarin N=9081 n (%/yr)	Hazard Ratio (95% CI)	P-Value
Stroke or systemic embolism	212 (1.27)	265 (1.60)	0.79 (0.66, 0.95)	0.0114
Stroke
Ischaemic or unspecified	162 (0.97)	175 (1.05)	0.92 (0.74, 1.13)
Haemorrhagic	40 (0.24)	78 (0.47)	0.51 (0.35, 0.75)
Systemic embolism	15 (0.09)	17 (0.10)	0.87 (0.44, 1.75)

	Apixaban N = 9088 n (%/year)	Warfarin N = 9052 n (%/year)	Hazard Ratio (95% CI)	p-value
Bleeding Outcomes
Major *	327 (2.13)	462 (3.09)	0.69 (0.60, 0.80)	< 0.0001
Fatal	10 (0.06)	37 (0.24)
Intracranial	52 (0.33)	122 (0.80)
Major + CRNM	613 (4.07)	877 (6.01)	0.68 (0.61, 0.75)	< 0.0001
All	2356 (18.1)	3060 (25.8)	0.71 (0.68, 0.75)	< 0.0001
Other Endpoints
All-cause death	603 (3.52)	669 (3.94)	0.89 (0.80, 1.00)	0.0465
Myocardial infarction	90 (0.53)	102 (0.61)	0.88 (0.66, 1.17)

	Apixaban N = 2807 n (%/year)	ASA N = 2791 n (%/year)	Hazard Ratio (95% CI)	P-Value
Stroke or systemic embolism *	51 (1.62)	113 (3.63)	0.45 (0.32, 0.62)	< 0.0001
Stroke
Ischaemic or unspecified	43 (1.37)	97 (3.11)	0.44 (0.31, 0.63)
Haemorrhagic	6 (0.19)	9 (0.28)	0.67 (0.24, 1.88)
Systemic embolism	2 (0.06)	13 (0.41)	0.15 (0.03, 0.68)
Stroke, systemic embolism, MI, or vascular death * +	132 (4.21)	197 (6.35)	0.66 (0.53, 0.83)	0.003
Myocardial infarction	24 (0.76)	28 (0.89)	0.86 (0.50, 1.48)
Vascular Death	84 (2.65)	96 (3.03)	0.87 (0.65, 1.17)
All-cause death +	111 (3.51)	140 (4.42)	0.79 (0.62, 1.02)	0.068

ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

NAME OF THE MEDICINAL PRODUCT

QUALITATIVE AND QUANTITATIVE COMPOSITION

PHARMACEUTICAL FORM

CLINICAL PARTICULARS

Therapeutic indications

Posology and method of administration

Contraindications

Special warnings and precautions for use

Interaction with other medicinal products and other forms of interaction

Fertility, pregnancy and lactation

Effects on ability to drive and use machines

Undesirable effects

Overdose

PHARMACOLOGICAL PROPERTIES

Pharmacodynamic properties

Pharmacokinetic properties

Preclinical safety data

PHARMACEUTICAL PARTICULARS

List of excipients

Incompatibilities

Shelf life

Special precautions for storage

Nature and contents of container

Special precautions for disposal

MARKETING AUTHORISATION HOLDER

MARKETING AUTHORISATION NUMBER(S)

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

DATE OF REVISION OF THE TEXT

	Apixaban N = 2798 n(%/year)	ASA N = 2780 n (%/year)	Hazard Ratio (95%CI)	p-value
Major *	45 (1.41)	29 (0.92)	1.54 (0.96, 2.45)	0.0716
Fatal, n	5 (0.16)	5 (0.16)
Intracranial, n	11 (0.34)	11 (0.35)
Major + CRNM	140 (4.46)	101 (3.24)	1.38 (1.07, 1.78)	0.0144
All	325 (10.85)	250 (8.32)	1.30 (1.10, 1.53)	0.0017