ELIQUIS 2.5mg tablets medication leaflet

Eliquis 2.5 mg film-coated tablets

Each film-coated tablet contains 2.5 mg apixaban.

Each 2.5 mg film-coated tablet contains 51 mg lactose (see section 4.4).

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet)

Yellow, round tablets (diameter of 6 mm) debossed with 893 on one side and 2½ on the other side.

Prevention of venous thromboembolic events (VTE) in adult patients who have undergone elective hipor knee replacement surgery.

Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation(NVAF), with one or more risk factors, such as prior stroke or transient ischaemic attack (TIA); age≥ 75 years; hypertension; diabetes mellitus; symptomatic heart failure (NYHA Class ≥ II).

Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent

DVT and PE in adults (see section 4.4 for haemodynamically unstable PE patients).

Treatment of venous thromboembolism (VTE) and prevention of recurrent VTE in paediatric patientsfrom 28 days to less than 18 years of age.

Prevention of VTE (VTEp): elective hip or knee replacement surgery in adults

The recommended dose of apixaban is 2.5 mg taken orally twice daily. The initial dose should betaken 12 to 24 hours after surgery.

Physicians may consider the potential benefits of earlier anticoagulation for VTE prophylaxis as wellas the risks of post-surgical bleeding in deciding on the time of administration within this timewindow.

The recommended duration of treatment is 32 to 38 days.

The recommended duration of treatment is 10 to 14 days.

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

The recommended dose of apixaban is 5 mg taken orally twice daily.

The recommended dose of apixaban is 2.5 mg taken orally twice daily in patients with NVAF and atleast 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.

Treatment of DVT, treatment of PE and prevention of recurrent DVT and PE (VTEt) in adults

The recommended dose of apixaban for the treatment of acute DVT and treatment of PE is 10 mgtaken orally twice daily for the first 7 days followed by 5 mg taken orally twice daily. As per availablemedical guidelines, short duration of treatment (at least 3 months) should be based on transient riskfactors (e.g., recent surgery, trauma, immobilisation).

The recommended dose of apixaban for the prevention of recurrent DVT and PE is 2.5 mg taken orallytwice daily. When prevention of recurrent DVT and PE is indicated, the 2.5 mg twice daily doseshould be initiated following completion of 6 months of treatment with apixaban 5 mg twice daily orwith another anticoagulant, as indicated in Table 1 below (see also section 5.1).

Table 1: Dose recommendation (VTEt)

Dosing schedule Maximum daily dose

Treatment of DVT or PE 10 mg twice daily for the first 20 mg7 daysfollowed by 5 mg twice daily 10 mg

Prevention of recurrent DVT and/or 2.5 mg twice daily 5 mg

PE following completion of 6 monthsof treatment for DVT or PE

The duration of overall therapy should be individualised after careful assessment of the treatmentbenefit against the risk for bleeding (see section 4.4).

Apixaban treatment for paediatric patients from 28 days to less than 18 years of age should be initiatedfollowing at least 5 days of initial parenteral anticoagulation therapy (see section 5.1).

Treatment with apixaban in paediatric patients is based on weight-tiered dosing. The recommendeddose of apixaban in paediatric patients weighing ≥ 35 kg is shown in Table 2.

Table 2: Dose recommendation for treatment of VTE and prevention of recurrent VTE inpaediatric patients weighing ≥ 35 kg (after initial parenteral anticoagulation)

Days 1-7 Day 8 and beyond

Body weight Dosing schedule Maximum daily Dosing schedule Maximum daily(kg) dose dose≥ 35 10 mg twice daily 20 mg 5 mg twice daily 10 mg

For paediatric patients weighing < 35 kg, refer to the summary of product characteristics for Eliquisgranules in capsules for opening and Eliquis coated granules in sachets.

Based on VTE treatment guidelines in the paediatric population, duration of overall therapy should beindividualised after careful assessment of the treatment benefit and the risk for bleeding (seesection 4.4).

Missed dose in adults and paediatric patients

A missed morning dose should be taken immediately when it is noticed, and it may be taken togetherwith the evening dose. A missed evening dose can only be taken during the same evening, the patientshould not take two doses the next morning. The patient should continue with the intake of the regulardose twice daily as recommended on the following day.

Switching treatment from parenteral anticoagulants to Eliquis (and vice versa) can be done at the nextscheduled dose (see section 4.5). These medicinal products should not be administeredsimultaneously.

When converting patients from vitamin K antagonist (VKA) therapy to Eliquis, warfarin or other

VKA therapy should be discontinued and Eliquis started when the international normalised ratio (INR)is < 2.

When converting patients from Eliquis to VKA therapy, administration of Eliquis should be continuedfor at least 2 days after beginning VKA therapy. After 2 days of coadministration of Eliquis with VKAtherapy, an INR should be obtained prior to the next scheduled dose of Eliquis. Coadministration of

Eliquis and VKA therapy should be continued until the INR is ≥ 2.

No data are available for paediatric patients.

VTEp and VTEt - 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 reductionat the beginning of section 4.2).

Adult patients

In adult patients with mild or moderate renal impairment, the following recommendations apply:

- for the prevention of VTE in elective hip or knee replacement surgery (VTEp), for the treatmentof DVT, treatment of PE and prevention of recurrent DVT and PE (VTEt), no dose adjustmentis necessary (see section 5.2).

- for the prevention of stroke and systemic embolism in patients with NVAF and serum creatinine≥ 1.5 mg/dL (133 micromole/L) associated with age ≥ 80 years or body weight ≤ 60 kg, a dosereduction is necessary (see above subheading regarding Dose reduction). In the absence of othercriteria for dose reduction (age, body weight), no dose adjustment is necessary (see section 5.2).

In adult patients with severe renal impairment (creatinine clearance 15-29 mL/min) the followingrecommendations apply (see sections 4.4 and 5.2):

- for the prevention of VTE in elective hip or knee replacement surgery (VTEp), for the treatmentof DVT, treatment of PE and prevention of recurrent DVT and PE (VTEt) apixaban is to beused with caution;

- for the prevention of stroke and systemic embolism in patients with NVAF, patients shouldreceive the lower dose of apixaban 2.5 mg twice daily.

In patients with creatinine clearance < 15 mL/min, or in patients undergoing dialysis, there is noclinical experience therefore apixaban is not recommended (see sections 4.4 and 5.2).

Based on adult data and limited data in paediatric patients (see section 5.2), no dose adjustment isnecessary in paediatric patients with mild to moderate renal impairment. Apixaban is notrecommended in paediatric patients with severe renal impairment (see section 4.4).

Eliquis is contraindicated in adult patients with hepatic disease associated with coagulopathy andclinically 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 (seesections 4.4 and 5.2).

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

Apixaban has not been studied in paediatric patients with hepatic impairment.

VTEp and VTEt - No dose adjustment required in adults (see sections 4.4 and 5.2).

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

Apixaban paediatric administration is based on a fixed-dose by weight-tier regimen (see section 4.2).

No dose adjustment required (see section 5.2).

Patients can continue apixaban use while undergoing catheter ablation (see sections pct. 4.3, pct. 4.4 and 4.5).

Apixaban can be initiated or continued in NVAF adult patients who may require cardioversion.

For patients not previously treated with anticoagulants, exclusion of left atrial thrombus using animage guided approach (e.g. transesophageal echocardiography (TEE) or computed tomographic scan(CT)) prior to cardioversion should be considered, in accordance with established medical guidelines.

For patients initiating treatment with apixaban, 5 mg should be given twice daily for at least 2.5 days(5 single doses) before cardioversion to ensure adequate anticoagulation (see section 5.1). The dosingregimen should be reduced to 2.5 mg apixaban given twice daily for at least 2.5 days (5 single doses)if the patient meets the criteria for dose reduction (see above sections Dose reduction and Renalimpairment).

If cardioversion is required before 5 doses of apixaban can be administered, a 10 mg loading doseshould be given, followed by 5 mg twice daily. The dosing regimen should be reduced to a 5 mgloading dose followed by 2.5 mg twice daily if the patient meets the criteria for dose reduction (seeabove sections Dose reduction and Renal impairment). The administration of the loading dose shouldbe given at least 2 hours before cardioversion (see section 5.1).

For all patients undergoing cardioversion, confirmation should be sought prior to cardioversion thatthe patient has taken apixaban as prescribed. Decisions on initiation and duration of treatment shouldtake established guideline recommendations for anticoagulant treatment in patients undergoingcardioversion into account.

Patients with NVAF and acute coronary syndrome (ACS) and/or percutaneous coronary intervention(PCI)

There is limited experience of treatment with apixaban at the recommended dose for NVAF patientswhen used in combination with antiplatelet agents in patients with ACS and/or undergoing PCI afterhaemostasis is achieved (see sections 4.4 and 5.1).

The safety and efficacy of Eliquis in paediatric patients aged 28 days to less than 18 years have notbeen established in indications other than treatment of venous thromboembolism (VTE) andprevention of recurrent VTE. No data are available in neonates and for other indications (see alsosection 5.1). Therefore, Eliquis is not recommended for use in neonates and in paediatric patients aged28 days to less than 18 years in indications other than treatment of VTE and prevention of recurrent

VTE.

The safety and efficacy of Eliquis in children and adolescents below age 18 have not been establishedfor the indication of thromboembolism prevention. Currently available data on thromboembolismprevention are described in section 5.1 but no recommendation on a posology can be made.

Method of administration in adults and paediatric patients

Oral use

Eliquis should be swallowed with water, with or without food.

For patients who are unable to swallow whole tablets, Eliquis tablets may be crushed and suspended inwater, or 5% glucose in water (G5W), or apple juice or mixed with apple puree and immediatelyadministered orally (see section 5.2). Alternatively, Eliquis tablets may be crushed and suspended in60 mL of water or G5W and immediately delivered through a nasogastric tube (see section 5.2).

Crushed Eliquis tablets are stable in water, G5W, apple juice, and apple puree for up to 4 hours.

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

- Active clinically significant bleeding.

- Hepatic disease associated with coagulopathy and clinically relevant bleeding risk (seesection 5.2).

- Lesion or condition if considered a significant risk factor for major bleeding. This may includecurrent or recent gastrointestinal ulceration, presence of malignant neoplasms at high risk ofbleeding, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, recentintracranial haemorrhage, known or suspected oesophageal varices, arteriovenousmalformations, 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 etexilate, etc.) except under specificcircumstances of switching anticoagulant therapy (see section 4.2), when UFH is given at dosesnecessary to maintain an open central venous or arterial catheter or when UFH is given duringcatheter ablation for atrial fibrillation (see sections 4.4 and 4.5).

As with other anticoagulants, patients taking apixaban are to be carefully observed for signs ofbleeding. It is recommended to be used with caution in conditions with increased risk of haemorrhage.

Apixaban administration should be discontinued if severe haemorrhage occurs (see sections 4.8 and4.9).

Although treatment with apixaban does not require routine monitoring of exposure, a calibratedquantitative anti-Factor Xa assay may be useful in exceptional situations where knowledge ofapixaban exposure may help to inform clinical decisions, e.g., overdose and emergency surgery (seesection 5.1).

A specific reversal agent (andexanet alfa) antagonising the pharmacodynamic effect of apixaban isavailable for adults. However, its safety and efficacy have not been established in paediatric patients(refer to the summary of product characteristics of andexanet alfa). Transfusion of fresh frozenplasma, administration of prothrombin complex concentrates (PCCs), or recombinant factor VIIa maybe considered. However, there is no clinical experience with the use of 4-factor PCC products toreverse bleeding in paediatric and adult patients who have received apixaban.

Due to an increased bleeding risk, concomitant treatment with any other anticoagulants iscontraindicated (see section 4.3).

The concomitant use of apixaban with antiplatelet agents increases the risk of bleeding (seesection 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 non-steroidal anti-inflammatorydrugs (NSAIDs), including acetylsalicylic acid.

Following surgery, other platelet aggregation inhibitors are not recommended concomitantly withapixaban (see section 4.5).

In patients with atrial fibrillation and conditions that warrant mono or dual antiplatelet therapy, acareful assessment of the potential benefits against the potential risks should be made beforecombining this therapy with apixaban.

In a clinical study of adult patients with atrial fibrillation, concomitant use of ASA increased the majorbleeding risk on apixaban from 1.8% per year to 3.4% per year and increased the bleeding risk onwarfarin from 2.7% per year to 4.6% per year. In this clinical study, there was limited (2.1%) use ofconcomitant dual antiplatelet therapy (see section 5.1).

A clinical study enrolled patients with atrial fibrillation with ACS and/or undergoing PCI and aplanned treatment period with a P2Y12 inhibitor, with or without ASA, and oral anticoagulant (eitherapixaban or VKA) for 6 months. Concomitant use of ASA increased the risk of ISTH (International

Society on Thrombosis and Hemostasis) major or CRNM (Clinically Relevant Non-Major) bleeding inapixaban-treated subjects from 16.4% per year to 33.1% per year (see section 5.1).

In a clinical study of high-risk post acute coronary syndrome patients without atrial fibrillation,characterised by multiple cardiac and non-cardiac comorbidities, who received ASA or thecombination of ASA and clopidogrel, a significant increase in risk of ISTH major bleeding wasreported for apixaban (5.13% per year) compared to placebo (2.04% per year).

In study CV185325, no clinically important bleeding events were reported in the 12 paediatric patientstreated with apixaban and ASA ≤ 165 mg daily concomitantly.

Use of thrombolytic agents for the treatment of acute ischaemic stroke

There is very limited experience with the use of thrombolytic agents for the treatment of acuteischaemic stroke in patients administered apixaban (see section 4.5).

Safety and efficacy of apixaban have not been studied in patients with prosthetic heart valves, with orwithout atrial fibrillation. Therefore, the use of apixaban is not recommended in this setting.

Apixaban has not been studied in paediatric patients with prosthetic heart valves; therefore, the use ofapixaban is not recommended.

Direct acting Oral Anticoagulants (DOACs) including apixaban are not recommended for patientswith a history of thrombosis who are diagnosed with antiphospholipid syndrome. In particular forpatients that are triple positive (for lupus anticoagulant, anticardiolipin antibodies, and anti-beta2-glycoprotein I antibodies), treatment with DOACs could be associated with increased rates ofrecurrent thrombotic events compared with vitamin K antagonist therapy.

Apixaban should be discontinued at least 48 hours prior to elective surgery or invasive procedureswith a moderate or high risk of bleeding. This includes interventions for which the probability ofclinically significant bleeding cannot be excluded or for which the risk of bleeding would beunacceptable.

Apixaban should be discontinued at least 24 hours prior to elective surgery or invasive procedureswith a low risk of bleeding. This includes interventions for which any bleeding that occurs is expectedto be minimal, non-critical in its location or easily controlled.

If surgery or invasive procedures cannot be delayed, appropriate caution should be exercised, takinginto consideration an increased risk of bleeding. This risk of bleeding should be weighed against theurgency of intervention.

Apixaban should be restarted after the invasive procedure or surgical intervention as soon as possibleprovided the clinical situation allows and adequate haemostasis has been established (for cardioversionsee section 4.2).

For patients undergoing catheter ablation for atrial fibrillation, apixaban treatment does not need to beinterrupted (see sections 4.2, pct. 4.3 and 4.5).

Discontinuing anticoagulants, including apixaban, for active bleeding, elective surgery, or invasiveprocedures places patients at an increased risk of thrombosis. Lapses in therapy should be avoided andif anticoagulation with apixaban must be temporarily discontinued for any reason, therapy should berestarted 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 riskof 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 orthe concomitant use of medicinal products affecting haemostasis. Indwelling epidural or intrathecalcatheters must be removed at least 5 hours prior to the first dose of apixaban. The risk may also beincreased by traumatic or repeated epidural or spinal puncture. Patients are to be frequently monitoredfor signs and symptoms of neurological impairment (e.g., numbness or weakness of the legs, bowel orbladder dysfunction). If neurological compromise is noted, urgent diagnosis and treatment isnecessary. Prior to neuraxial intervention the physician should consider the potential benefit versus therisk 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 epiduralcatheters. In case there is such need and based on the general PK characteristics of apixaban, a timeinterval of 20-30 hours (i.e., 2 x half-life) between the last dose of apixaban and catheter withdrawalshould elapse, and at least one dose should be omitted before catheter withdrawal. The next dose ofapixaban may be given at least 5 hours after catheter removal. As with all new anticoagulant medicinalproducts, experience with neuraxial blockade is limited and extreme caution is therefore recommendedwhen using apixaban in the presence of neuraxial blockade.

No data are available on the timing of the placement or removal of neuraxial catheter in paediatricpatients while on apixaban. In such cases, discontinue apixaban and consider a short acting parenteralanticoagulant.

Haemodynamically unstable PE patients or patients who require thrombolysis or pulmonaryembolectomy

Apixaban is not recommended as an alternative to unfractionated heparin in patients with pulmonaryembolism who are haemodynamically unstable or may receive thrombolysis or pulmonaryembolectomy since the safety and efficacy of apixaban have not been established in these clinicalsituations.

Patients with active cancer can be at high risk of both venous thromboembolism and bleeding events.

When apixaban is considered for DVT or PE treatment in cancer patients, a careful assessment of thebenefits against the risks should be made (see also section 4.3).

Adult patients

Limited clinical data indicate that apixaban plasma concentrations are increased in patients with severerenal impairment (creatinine clearance 15-29 mL/min) which may lead to an increased bleeding risk.

For the prevention of VTE in elective hip or knee replacement surgery (VTEp), the treatment of DVT,treatment of PE and prevention of recurrent DVT and PE (VTEt), apixaban is to be used with cautionin patients with severe renal impairment (creatinine clearance 15-29 mL/min) (see sections 4.2 and5.2).

For the prevention of stroke and systemic embolism in patients with NVAF, patients with severe renalimpairment (creatinine clearance 15-29 mL/min), and patients with serum creatinine ≥ 1.5 mg/dL(133 micromole/L) associated with age ≥ 80 years or body weight ≤ 60 kg should receive the lowerdose 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 noclinical experience therefore apixaban is not recommended (see sections 4.2 and 5.2).

Paediatric patients with severe renal impairment have not been studied and therefore should notreceive apixaban (see sections 4.2 and 5.2).

Increasing age may increase haemorrhagic risk (see section 5.2).

Also, the coadministration of apixaban with ASA in elderly patients should be used cautiously becauseof a potentially higher bleeding risk.

In adults, low body weight (< 60 kg) may increase haemorrhagic risk (see section 5.2).

Apixaban is contraindicated in patients with hepatic disease associated with coagulopathy andclinically 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 wereexcluded in clinical studies. Therefore apixaban should be used cautiously in this population (seesection 5.2). Prior to initiating apixaban, liver function testing should be performed.

Apixaban has not been studied in paediatric patients with hepatic impairment.

The use of apixaban is not recommended in patients receiving concomitant systemic treatment withstrong 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). Thesemedicinal products may increase apixaban exposure by 2-fold (see section 4.5), or greater in thepresence of additional factors that increase apixaban exposure (e.g., severe renal impairment).

No clinical data are available in paediatric patients receiving concomitant systemic treatment withstrong inhibitors of both CYP 3A4 and P-gp (see section 4.5).

The concomitant use of apixaban 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 wereobserved with coadministration of apixaban with strong inducers of both CYP3A4 and P-gp comparedwith using apixaban alone.

In patients receiving concomitant systemic treatment with strong inducers of both CYP3A4 and P-gpthe following recommendations apply (see section 4.5):

- for the prevention of VTE in elective hip or knee replacement surgery, for the prevention ofstroke and systemic embolism in patients with NVAF and for the prevention of recurrent DVTand PE, apixaban should be used with caution;

- for the treatment of DVT and treatment of PE, apixaban should not be used since efficacy maybe compromised.

No clinical data are available in paediatric patients receiving concomitant systemic treatment withstrong inducers of both CYP 3A4 and P-gp (see section 4.5).

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

Clotting tests [e.g., prothrombin time (PT), INR, and activated partial thromboplastin time (aPTT)] areaffected as expected by the mechanism of action of apixaban. Changes observed in these clotting testsat 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, total lactasedeficiency or glucose-galactose malabsorption should not take this medicinal product.

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially“sodium-free”.

Coadministration 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 meanapixaban Cmax.

The use of apixaban is not recommended in patients receiving concomitant systemic treatment withstrong 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) (seesection 4.4).

Active substances which are not considered strong inhibitors of both CYP3A4 and P-gp, (e.g.,amiodarone, clarithromycin, diltiazem, fluconazole, naproxen, quinidine, verapamil) are expected toincrease apixaban plasma concentration to a lesser extent. No dose adjustment for apixaban is requiredwhen coadministered with agents that are not strong inhibitors of both CYP3A4 and P-gp. Forexample, 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 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-foldincrease in mean apixaban AUC and Cmax, respectively. Clarithromycin (500 mg, twice a day), aninhibitor of P-gp and a strong inhibitor of CYP3A4, led to a 1.6-fold and 1.3-fold increase in meanapixaban AUC and Cmax respectively.

Coadministration of apixaban with rifampicin, a strong inducer of both CYP3A4 and P-gp, led to anapproximate 54% and 42% decrease in mean apixaban AUC and Cmax, respectively. The concomitantuse 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 doseadjustment for apixaban is required during concomitant therapy with such medicinal products,however in patients receiving concomitant systemic treatment with strong inducers of both CYP3A4and P-gp apixaban should be used with caution for the prevention of VTE in elective hip or kneereplacement surgery, for the prevention of stroke and systemic embolism in patients with NVAF andfor the prevention of recurrent DVT and PE.

Apixaban is not recommended for the treatment of DVT and PE in patients receiving concomitantsystemic treatment with strong inducers of both CYP3A4 and P-gp since efficacy may becompromised (see section 4.4).

Due to an increased bleeding risk, concomitant treatment with any other anticoagulants iscontraindicated except under specific circumstances of switching anticoagulant therapy, when UFH isgiven at doses necessary to maintain an open central venous or arterial catheter or when UFH is givenduring catheter ablation for atrial fibrillation (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 wascoadministered with ASA 325 mg once a day.

Apixaban coadministered with clopidogrel (75 mg once a day) or with the combination of clopidogrel75 mg and ASA 162 mg once daily, or with prasugrel (60 mg followed by 10 mg once daily) in

Phase I studies did not show a relevant increase in template bleeding time, or further inhibition ofplatelet aggregation, compared to administration of the antiplatelet agents without apixaban. Increasesin 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. Nochanges were observed in the effect of naproxen on arachidonic acid-induced platelet aggregation andno clinically relevant prolongation of bleeding time was observed after concomitant administration ofapixaban and naproxen.

Despite these findings, there may be individuals with a more pronounced pharmacodynamic responsewhen antiplatelet agents are coadministered with apixaban. Apixaban should be used with cautionwhen coadministered with SSRIs/SNRIs, NSAIDs, ASA and/or P2Y12 inhibitors because thesemedicinal products typically increase the bleeding risk (see section 4.4).

There is limited experience of co-administration with other platelet aggregation inhibitors (such as

GPIIb/IIIa receptor antagonists, dipyridamole, dextran or sulfinpyrazone) or thrombolytic agents. Assuch agents increase the bleeding risk, co-administration of these medicinal products with apixaban isnot recommended (see section 4.4).

In study CV185325, no clinically important bleeding events were reported in the 12 paediatric patientstreated with apixaban and ASA ≤ 165 mg daily concomitantly.

No clinically significant pharmacokinetic or pharmacodynamic interactions were observed whenapixaban was coadministered with atenolol or famotidine. Coadministration of apixaban 10 mg withatenolol 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 were15% and 18% lower than when administered alone. The administration of apixaban 10 mg withfamotidine 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 μM) and weak inhibitory effect on the activityof CYP2C19 (IC50 > 20 μM) at concentrations that are significantly greater than peak plasmaconcentrations observed in patients. Apixaban did not induce CYP1A2, CYP2B6, CYP3A4/5 at aconcentration up to 20 μM. Therefore, apixaban is not expected to alter the metabolic clearance ofcoadministered medicinal products that are metabolised by these enzymes. Apixaban is not asignificant inhibitor of P-gp.

In studies conducted in healthy subjects, as described below, apixaban did not meaningfully alter thepharmacokinetics of digoxin, naproxen, or atenolol.

Coadministration 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 substratetransport.

Coadministration 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.

Coadministration 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).

Interaction studies have not been performed in paediatrics.

The above mentioned interaction data was obtained in adults and the warnings in section 4.4 should betaken into account for the paediatric population.

There are no data from the use of apixaban in pregnant women. Animal studies do not indicate director indirect harmful effects with respect to reproductive toxicity (see section 5.3). As a precautionarymeasure, it is preferable to avoid the use of apixaban during pregnancy.

It is unknown whether apixaban or its metabolites are excreted in human milk. Available data inanimals have shown excretion of apixaban in milk (see section 5.3). A risk to the suckling child cannotbe excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain fromapixaban therapy taking into account the benefit of breast-feeding for the child and the benefit oftherapy for the woman.

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

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

In adults, the safety of apixaban has been investigated in 7 Phase III clinical studies including morethan 21 000 patients: more than 5 000 patients in VTEp studies, more than 11 000 patients in NVAFstudies and more than 4 000 patients in the VTE treatment (VTEt) studies, for an average totalexposure of 20 days, 1.7 years and 221 days respectively (see section 5.1).

Common adverse reactions were haemorrhage, contusion, epistaxis, and haematoma (see Table 3 foradverse reaction profile and frequencies by indication).

In the VTEp studies, in total, 11% of the patients treated with apixaban 2.5 mg twice daily experiencedadverse reactions. The overall incidence of adverse reactions related to bleeding with apixaban was10% in the apixaban vs enoxaparin studies.

In the NVAF studies, the overall incidence of adverse reactions related to bleeding with apixaban was24.3% in the apixaban vs warfarin study and 9.6% in the apixaban vs acetylsalicylic acid study. In theapixaban 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 majorintraocular bleeding with apixaban was 0.18%/year.

In the VTEt studies, the overall incidence of adverse reactions related to bleeding with apixaban was15.6% in the apixaban vs enoxaparin/warfarin study and 13.3% in the apixaban vs placebo study (seesection 5.1).

Table 3 shows the adverse reactions ranked under headings of system organ class and frequency usingthe following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1 000to < 1/100); rare (≥ 1/10 000 to < 1/1 000); very rare (< 1/10 000); not known (cannot be estimatedfrom the available data) in adults for VTEp, NVAF, and VTEt and in paediatric patients from 28 daysto < 18 years of age for VTEt and prevention of recurrent VTE.

The frequencies of adverse reactions reported in Table 3 for paediatric patients are derived from study

CV185325, in which they received apixaban for treatment of VTE and prevention of recurrent VTE.

Table 3: Tabulated adverse reactions

System organ class Prevention of Prevention of Treatment of Treatment

VTE in adult stroke and DVT and PE, of VTE andpatients who systemic and preventionhave embolism in prevention of of recurrentundergone adult patients recurrent VTE inelective hip or with NVAF, DVT and PE paediatricknee with one or (VTEt) in patientsreplacement more risk adult patients fromsurgery factors 28 days to(VTEp) (NVAF) less than18 years ofage

Anaemia Common Common Common Common

Thrombocytopenia Uncommon Uncommon Common Common

Hypersensitivity, allergic Rare Uncommon Uncommon Common‡oedema and Anaphylaxis

Pruritus Uncommon Uncommon Uncommon* Common

Angioedema Not known Not known Not known Not known

Brain haemorrhage† Not known Uncommon Rare Not known

Eye haemorrhage (including Rare Common Uncommon Not knownconjunctival haemorrhage)

Haemorrhage, haematoma Common Common Common Common

Hypotension (including Uncommon Common Uncommon Commonprocedural hypotension)

Intra-abdominal Not known Uncommon Not known Not knownhaemorrhage

Epistaxis Uncommon Common Common Verycommon

Haemoptysis Rare Uncommon Uncommon Not known

Respiratory tract Not known Rare Rare Not knownhaemorrhage

Nausea Common Common Common Common

Gastrointestinal Uncommon Common Common Not knownhaemorrhage

Haemorrhoidal haemorrhage Not known Uncommon Uncommon Not known

Mouth haemorrhage Not known Uncommon Common Not known

Haematochezia Uncommon Uncommon Uncommon Common

Rectal haemorrhage, Rare Common Common Commongingival bleeding

Retroperitoneal haemorrhage Not known Rare Not known Not known

System organ class Prevention of Prevention of Treatment of Treatment

VTE in adult stroke and DVT and PE, of VTE andpatients who systemic and preventionhave embolism in prevention of of recurrentundergone adult patients recurrent VTE inelective hip or with NVAF, DVT and PE paediatricknee with one or (VTEt) in patientsreplacement more risk adult patients fromsurgery factors 28 days to(VTEp) (NVAF) less than18 years ofage

Liver function test abnormal, Uncommon Uncommon Uncommon Commonaspartate aminotransferaseincreased, blood alkalinephosphatase increased, bloodbilirubin increased

Gamma-glutamyltransferase Uncommon Common Common Not knownincreased

Alanine aminotransferase Uncommon Uncommon Common Commonincreased

Skin rash Not known Uncommon Common Common

Alopecia Rare Uncommon Uncommon Common

Erythema multiforme Not known Very rare Not known Not known

Cutaneous vasculitis Not known Not known Not known Not known

Muscle haemorrhage Rare Rare Uncommon Not known

Haematuria Uncommon Common Common Common

Anticoagulant-related Not known Not known Not known Not knownnephropathy

Abnormal vaginal Uncommon Uncommon Common Veryhaemorrhage, urogenital common§haemorrhage

Application site bleeding Not known Uncommon Uncommon Not known

Occult blood positive Not known Uncommon Uncommon Not known

System organ class Prevention of Prevention of Treatment of Treatment

VTE in adult stroke and DVT and PE, of VTE andpatients who systemic and preventionhave embolism in prevention of of recurrentundergone adult patients recurrent VTE inelective hip or with NVAF, DVT and PE paediatricknee with one or (VTEt) in patientsreplacement more risk adult patients fromsurgery factors 28 days to(VTEp) (NVAF) less than18 years ofage

Contusion Common Common Common Common

Post procedural Uncommon Uncommon Uncommon Commonhaemorrhage (including postprocedural haematoma,wound haemorrhage, vesselpuncture site haematoma andcatheter site haemorrhage),wound secretion, incisionsite haemorrhage (includingincision site haematoma),operative haemorrhage

Traumatic haemorrhage Not known Uncommon Uncommon Not known

* There were no occurrences of generalised pruritus in CV185057 (long term prevention of VTE).† The term “Brain haemorrhage” encompasses all intracranial or intraspinal haemorrhages (i.e., haemorrhagic stroke orputamen, cerebellar, intraventricular, or subdural haemorrhages).‡ Includes anaphylactic reaction, drug hypersensitivity, and hypersensitivity.§ Includes heavy menstrual bleeding, intermenstrual bleeding, and vaginal haemorrhage.

The use of apixaban may be associated with an increased risk of occult or overt bleeding from anytissue or organ, which may result in posthaemorrhagic anaemia. The signs, symptoms, and severitywill vary according to the location and degree or extent of the bleeding (see sections 4.4 and 5.1).

The safety of apixaban has been investigated in 1 Phase I and 3 Phase II/III clinical studies including970 patients. Of these patients, 568 patients received one or more doses of apixaban for average totalexposure of 1, 24, 331 and 80 days, respectively (see section 5.1). The patients received weightadjusted doses of an age-appropriate formulation of apixaban.

Overall, the safety profile of apixaban in paediatric patients 28 days to < 18 years of age was similar tothat in adults and was generally consistent across different paediatric age groups.

The most commonly reported adverse reactions in paediatric patients were epistaxis, and abnormalvaginal haemorrhage (see Table 3 for adverse reaction profile and frequencies by indication).

In paediatric patients, epistaxis (very common), abnormal vaginal haemorrhage (very common),hypersensitivity and anaphylaxis (common), pruritus (common), hypotension (common),haematochezia (common), aspartate aminotransferase increased (common), alopecia (common), andpost procedural haemorrhage (common) were reported more frequently as compared to adults treatedwith apixaban, but in the same frequency category as the paediatric patients in the standard of care(SOC) arm; the only exception was abnormal vaginal haemorrhage, which was reported as common inthe SOC arm. In all but one case, hepatic transaminase elevations were reported in paediatric patientsreceiving concomitant chemotherapy for an underlying malignancy.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Overdose of apixaban may result in a higher risk of bleeding. In the event of haemorrhagiccomplications, treatment must be discontinued and the source of bleeding investigated. The initiationof appropriate treatment, e.g., surgical haemostasis, the transfusion of fresh frozen plasma or theadministration of a reversal agent for factor Xa inhibitors should be considered (see section 4.4).

In controlled clinical studies, orally-administered apixaban in healthy adult subjects at doses up to50 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 reactions.

In healthy adult subjects, administration of activated charcoal 2 and 6 hours after ingestion of a 20 mgdose 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 to5.3 hours and 4.9 hours, respectively, when activated charcoal was administered 2 and 6 hours afterapixaban. Thus, administration of activated charcoal may be useful in the management of apixabanoverdose or accidental ingestion.

Haemodialysis decreased apixaban AUC by 14% in subjects with end-stage renal disease (ESRD),when a single dose of apixaban 5 mg was administered orally. Therefore, haemodialysis is unlikely tobe an effective means of managing apixaban overdose.

For situations in which reversal of anticoagulation is needed due to life-threatening or uncontrolledbleeding, a reversal agent for factor Xa inhibitors (andexanet alfa) is available for adults (seesection 4.4). Administration of prothrombin complex concentrates (PCCs) or recombinant factor VIIamay also be considered. Reversal of apixaban pharmacodynamic effects, as demonstrated by changesin the thrombin generation assay, was evident at the end of infusion and reached baseline valueswithin 4 hours after the start of a 30 minute 4-factor PCC infusion in healthy subjects. However, thereis no clinical experience with the use of 4-factor PCC products to reverse bleeding in individuals whohave received apixaban. Currently there is no experience with the use of recombinant factor VIIa inindividuals receiving apixaban. Re-dosing of recombinant factor VIIa could be considered and titrateddepending on improvement of bleeding.

A specific reversal agent (andexanet alfa) antagonising the pharmacodynamic effect of apixaban is notestablished in the paediatric population (refer to the summary of product characteristics of andexanetalfa). Transfusion of fresh frozen plasma, or administration of PCCs, or recombinant factor VIIa mayalso be considered.

Depending on local availability, coagulation expert consultation should be considered in case of majorbleeding.

Pharmacotherapeutic group: Antithrombotic agents, direct factor Xa inhibitors, ATC code: B01AF02

Apixaban is a potent, oral, reversible, direct and highly selective active site inhibitor of factor Xa. Itdoes not require antithrombin III for antithrombotic activity. Apixaban inhibits free and clot-boundfactor Xa, and prothrombinase activity. Apixaban has no direct effects on platelet aggregation, butindirectly inhibits platelet aggregation induced by thrombin. By inhibiting factor Xa, apixabanprevents thrombin generation and thrombus development. Preclinical studies of apixaban in animalmodels have demonstrated antithrombotic efficacy in the prevention of arterial and venous thrombosisat 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 andactivated partial thromboplastin time (aPTT). In adults, changes observed in these clotting tests at theexpected therapeutic dose are small and subject to a high degree of variability. They are notrecommended to assess the pharmacodynamic effects of apixaban. In the thrombin generation assay,apixaban reduced endogenous thrombin potential, a measure of thrombin generation in human plasma.

Apixaban also demonstrates anti-Factor Xa activity (AXA) as evident by reduction in Factor Xaenzyme activity in multiple commercial anti-Factor Xa kits, however results differ across kits. Datafrom adult clinical studies are only available for the Rotachrom® Heparin chromogenic assay.

Anti-Factor Xa activity exhibits a close direct linear relationship with apixaban plasma concentration,reaching maximum values at the time of apixaban peak plasma concentrations. The relationshipbetween apixaban plasma concentration and anti-Factor Xa activity is approximately linear over awide dose range of apixaban. Results from apixaban paediatric studies indicate that the linearrelationship between apixaban concentration and AXA is consistent with the previously documentedrelationship in adults. This lends support to the documented mechanism of action of apixaban as aselective inhibitor of FXa.

Table 4 below shows the predicted steady state exposure and anti-Factor Xa activity for each adultindication. In patients taking apixaban for the prevention of VTE following hip or knee replacementsurgery, the results demonstrate a less than 1.6-fold fluctuation in peak-to-trough levels. Innon-valvular atrial fibrillation patients taking apixaban for the prevention of stroke and systemicembolism, the results demonstrate a less than 1.7-fold fluctuation in peak-to-trough levels. In patientstaking apixaban for the treatment of DVT and PE or prevention of recurrent DVT and PE, the resultsdemonstrate a less than 2.2-fold fluctuation in peak-to-trough levels.

Table 4: Predicted apixaban steady-state exposure and anti-Factor Xa activity

Apix. Apix. Apix. anti-Factor Apix. anti-Factor

Cmax (ng/mL) Cmin (ng/mL) Xa activity max Xa activity min(IU/mL) (IU/mL)

Median [5th, 95th percentile]

Prevention of VTE: elective hip or knee replacement surgery2.5 mg twice 77 [41, 146] 51 [23, 109] 1.3 [0.67, 2.4] 0.84 [0.37, 1.8]daily

Prevention of stroke and systemic embolism: NVAF2.5 mg twice 123 [69, 221] 79 [34, 162] 1.8 [1.0, 3.3] 1.2 [0.51, 2.4]daily*5 mg twice daily 171 [91, 321] 103 [41, 230] 2.6 [1.4, pct. 4.8] 1.5 [0.61, 3.4]

Apix. Apix. Apix. anti-Factor Apix. anti-Factor

Cmax (ng/mL) Cmin (ng/mL) Xa activity max Xa activity min(IU/mL) (IU/mL)

Treatment of DVT, treatment of PE and prevention of recurrent DVT and PE (VTEt)2.5 mg twice 67 [30, 153] 32 [11, 90] 1.0 [0.46, 2.5] 0.49 [0.17, 1.4]daily5 mg twice daily 132 [59, 302] 63 [22, 177] 2.1 [0.91, pct. 5.2] 1.0 [0.33, 2.9]10 mg twice daily 251 [111, 572] 120 [41, 335] 4.2 [1.8, 10.8] 1.9 [0.64, 5.8]

* Dose adjusted population based on 2 of 3 dose reduction criteria in the ARISTOTLE study.

Although treatment with apixaban does not require routine monitoring of exposure, a calibratedquantitative anti-Factor Xa assay may be useful in exceptional situations where knowledge ofapixaban exposure may help to inform clinical decisions, e.g., overdose and emergency surgery.

Apixaban paediatric studies used the STA® Liquid Anti-Xa apixaban assay. Results from these studiesindicate that the linear relationship between apixaban concentration and anti-Factor Xa activity (AXA)is consistent with the previously documented relationship in adults. This lends support to thedocumented mechanism of action of apixaban as a selective inhibitor of FXa.

Across weight tiers 9 to ≥ 35 kg in Study CV185155, the geometric mean (%CV) AXA min and AXAmax ranged between 27.1 (22.2) ng/mL and 71.9 (17.3) ng/mL, corresponding to geometric mean(%CV) Cminss and Cmaxss of 30.3 (22) ng/mL and 80.8 (16.8) ng/mL. The exposures achieved at these

AXA ranges using the paediatric dosing regimen were comparable to those seen in adults whoreceived an apixaban dose of 2.5 mg twice daily.

Across weight tiers 6 to ≥ 35 kg in Study CV185362, the geometric mean (%CV) AXA min and AXAmax ranged between 67.1 (30.2) ng/mL and 213 (41.7) ng/mL, corresponding to geometric mean(%CV) Cminss and Cmaxss of 71.3 (61.3) ng/mL and 230 (39.5) ng/mL. The exposures achieved at these

AXA ranges using the paediatric dosing regimen were comparable to those seen in adults whoreceived an apixaban dose of 5 mg twice daily.

Across weight tiers 6 to ≥ 35 kg in Study CV185325, the geometric mean (%CV) AXA min and AXAmax ranged between 47.1 (57.2) ng/mL and 146 (40.2) ng/mL, corresponding to geometric mean(%CV) Cminss and Cmaxss of 50 (54.5) ng/mL and 144 (36.9) ng/mL. The exposures achieved at these

AXA ranges using the paediatric dosing regimen were comparable to those seen in adults whoreceived an apixaban dose of 5 mg twice daily.

The predicted steady state exposure and anti-Factor Xa activity for the paediatric studies suggests thatthe steady state peak-to-trough fluctuation in apixaban concentrations and AXA levels wereapproximately 3-fold (min, max: 2.65-3.22) in the overall population.

The apixaban clinical program was designed to demonstrate the efficacy and safety of apixaban for theprevention of VTE in a broad range of adult patients undergoing elective hip or knee replacement. Atotal of 8,464 patients were randomised in two pivotal, double-blind, multi-national studies, comparingapixaban 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 orolder, 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) withmoderate 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 receivedeither apixaban 2.5 mg given orally twice daily (po bid) or enoxaparin 40 mg administeredsubcutaneously 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 weregiven 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 hyperlipidaemia, 9% had diabetes, and 8% hadcoronary 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 5).

Table 5: Efficacy results from pivotal phase III studies

Study ADVANCE-3 (hip) ADVANCE-2 (knee)

Study treatment Apixaban Enoxaparin p-value Apixaban Enoxaparin p-value

Dose 2.5 mg po 40 mg sc 2.5 mg po 40 mg sc

Duration of twice daily once daily twice daily once dailytreatment 35 ± 3 d 35 ± 3 d 12 ± 2 d 12 ± 2 d

Total VTE/all-cause death

Number of 27/1,949 74/1,917 147/976 243/997events/subjects 1.39% 3.86% 15.06% 24.37%

Event rate < 0.0001 < 0.0001

Relative risk 0.36 0.6295% CI (0.22, 0.54) (0.51, 0.74)

Major VTE

Number of 10/2,199 25/2,195 13/1,195 26/1,199events/subjects 0.45% 1.14% 1.09% 2.17%

Event rate 0.0107 0.0373

Relative risk 0.40 0.5095% CI (0.15, 0.80) (0.26, 0.97)

The safety endpoints of major bleeding, the composite of major and CRNM bleeding, and all bleedingshowed similar rates for patients treated with apixaban 2.5 mg compared with enoxaparin 40 mg (see

Table 6). All the bleeding criteria included surgical site bleeding.

Table 6: Bleeding results from pivotal phase III studies*

ADVANCE-3 ADVANCE-2

Apixaban Enoxaparin Apixaban Enoxaparin2.5 mg po twice 40 mg sc once 2.5 mg po twice 40 mg sc once dailydaily daily daily 12 ± 2 d35 ± 3 d 35 ± 3 d 12 ± 2 d

All treated n = 2,673 n = 2,659 n = 1,501 n = 1,508

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%)

ADVANCE-3 ADVANCE-2

Apixaban Enoxaparin Apixaban Enoxaparin2.5 mg po twice 40 mg sc once 2.5 mg po twice 40 mg sc once dailydaily daily daily 12 ± 2 d35 ± 3 d 35 ± 3 d 12 ± 2 d

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%)

* All the bleeding criteria included surgical site bleeding1 Includes events occurring after first dose of enoxaparin (pre-surgery)2 Includes events occurring after first dose of apixaban (post-surgery)

The overall incidences of adverse reactions of bleeding, anaemia and abnormalities of transaminases(e.g., ALT levels) were numerically lower in patients on apixaban compared to enoxaparin in thephase 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 arm4 cases of PE were diagnosed against no cases in the enoxaparin arm. No explanation can be given tothis higher number of PE.

A total of 23,799 adult patients were randomised in the clinical program (ARISTOTLE: apixabanversus warfarin, AVERROES: apixaban versus ASA) including 11,927 randomised to apixaban. Theprogram was designed to demonstrate the efficacy and safety of apixaban for the prevention of strokeand systemic embolism in patients with non-valvular atrial fibrillation (NVAF) and one or moreadditional risk factors, such as:

- prior stroke or transient ischaemic attack (TIA)

- age ≥ 75 years

- hypertension

- diabetes mellitus

- symptomatic heart failure (NYHA Class ≥ II)

In the ARISTOTLE study a total of 18,201 adult patients were randomised to double-blind treatmentwith apixaban 5 mg twice daily (or 2.5 mg twice daily in selected patients [4.7%], see section 4.2) orwarfarin (target INR range 2.0-3.0), patients were exposed to study active substance for a mean of20 months. The mean age was 69.1 years, the mean CHADS2 score was 2.1 and 18.9% of patients hadprior stroke or TIA.

In the study, apixaban achieved statistically significant superiority in the primary endpoint ofprevention of stroke (haemorrhagic or ischaemic) and systemic embolism (see Table 7) compared withwarfarin.

Table 7: Efficacy outcomes in patients with atrial fibrillation in the ARISTOTLE study

Apixaban Warfarin Hazard ratio p-value

N = 9,120 N = 9,081 (95% CI)n (%/yr) n (%/yr)

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)

For patients randomised 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 thedifferent levels of center TTR; within the highest quartile of TTR according to center, the hazard ratiofor 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-specifiedhierarchical testing strategy to control the overall type 1 error in the trial. Statistically significantsuperiority was also achieved in the key secondary endpoints of both major bleeding and all-causedeath (see Table 8). With improving monitoring of INR the observed benefits of apixaban compared towarfarin regarding all cause death diminish.

Table 8: Secondary endpoints in patients with atrial fibrillation in the ARISTOTLE study

Apixaban Warfarin Hazard ratio p-value

N = 9,088 N = 9,052 (95% CI)n (%/year) n (%/year)

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 + 613 (4.07) 877 (6.01) 0.68 (0.61, 0.75) < 0.0001

CRNM†

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 90 (0.53) 102 (0.61) 0.88 (0.66, 1.17)infarction

* Major bleeding defined per International Society on Thrombosis and Haemostasis (ISTH) criteria.† Clinically Relevant Non-Major

The overall discontinuation rate due to adverse reactions was 1.8% for apixaban and 2.6% for warfarinin 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 efficacyresults for the overall population studied in the trial.

The incidence of ISTH major gastrointestinal bleeds (including upper GI, lower GI, and rectalbleeding) 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 forthe overall population studied in the trial.

In the AVERROES study a total of 5,598 adult patients considered to be unsuitable for VKA by theinvestigators were randomised to treatment with apixaban 5 mg twice daily (or 2.5 mg twice daily inselected 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 wereexposed to study active substance 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 includedunable/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 berelied on to adhere to VKA medicinal product instruction (15.0%), and difficulty/expected difficulty incontacting 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 acceptablesafety profile.

The overall discontinuation rate due to adverse reactions was 1.5% for apixaban and 1.3% for ASA inthe AVERROES study.

In the study, apixaban achieved statistically significant superiority in the primary endpoint ofprevention of stroke (haemorrhagic, ischaemic or unspecified) or systemic embolism (see Table 9)compared to ASA.

Table 9: Key efficacy outcomes in patients with atrial fibrillation in the AVERROES study

Apixaban ASA Hazard ratio p-value

N = 2,807 N = 2,791 (95% CI)n (%/year) n (%/year)

Stroke or systemic embolism* 51 (1.62) 113 (3.63) 0.45 (0.32, 0.62) < 0.000

Stroke

Ischaemic or 43 (1.37) 97 (3.11) 0.44 (0.31, 0.63)unspecified

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, 132 (4.21) 197 (6.35) 0.66 (0.53, 0.83) 0.003

MI, or vascular death*†

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

* 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 apixabanand ASA (see Table 10).

Table 10: Bleeding events in patients with atrial fibrillation in the AVERROES study

Apixaban ASA Hazard ratio p-value

N = 2,798 N = 2,780 (95% CI)n (%/year) n (%/year)

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

*Major bleeding defined per International Society on Thrombosis and Haemostasis (ISTH) criteria.† Clinically relevant non-major

AUGUSTUS, an open-label, randomised, controlled, 2 by 2 factorial design trial, enrolled 4614 adultpatients with NVAF who had ACS (43%) and/or underwent PCI (56%). All patients receivedbackground therapy with a P2Y12 inhibitor (clopidogrel: 90.3%) prescribed per local standard of care.

Patients were randomised up to 14 days after the ACS and/or PCI to either apixaban 5 mg twice daily(2.5 mg twice daily if two or more of the dose-reduction criteria were met; 4.2% received lower dose)or VKA and to either ASA (81 mg once daily) or placebo. The mean age was 69.9 years, 94% ofpatients randomised had a CHA2DS2-VASc score > 2, and 47% had a HAS-BLED score > 3. Forpatients randomised to VKA, the proportion of time in therapeutic range (TTR) (INR 2-3) was 56%,with 32% of time below TTR and 12% above TTR.

The primary objective of AUGUSTUS was to assess safety, with a primary endpoint of ISTH major or

CRNM bleeding. In the apixaban versus VKA comparison, the primary safety endpoint of ISTH majoror CRNM bleeding at month 6 occurred in 241 (10.5%), and 332 (14.7%) patients in the apixaban armand in the VKA arm respectively (HR = 0.69, 95% CI: 0.58, 0.82; 2-sided p < 0.0001 for noninferiority and p < 0.0001 for superiority). For VKA, additional analyses using subgroups by TTRshowed that the highest rate of bleeding was associated with the lowest quartile of TTR. The rate ofbleeding was similar between apixaban and the highest quartile of TTR.

In the ASA versus placebo comparison, the primary safety endpoint of ISTH major or CRNMbleeding at month 6 occurred in 367 (16.1%), and 204 (9.0%) patients in the ASA arm and in theplacebo arm respectively (HR = 1.88, 95% CI: 1.58, 2.23; two-sided p < 0.0001).

Specifically, in apixaban-treated patients, major or CRNM bleeding occurred in 157 (13.7%), and 84(7.4%) patients in the ASA arm and in the placebo arm respectively. In VKA-treated patients, major or

CRNM bleeding occurred in 208 (18.5%), and 122 (10.8%) patients in the ASA arm and in theplacebo arm respectively.

Other treatment effects were evaluated as a secondary objective of the study, with compositeendpoints.

In the apixaban versus VKA comparison, the composite endpoint of death or re-hospitalisationoccurred in 541 (23.5%) and 632 (27.4%) patients in the apixaban and in the VKA arm, respectively.

The composite endpoint of death or ischaemic event (stroke, myocardial infarction, stent thrombosisor urgent revascularisation) occurred in 170 (7.4%), and 182 (7.9%) patients in the apixaban and in the

VKA arm, respectively.

In the ASA versus placebo comparison, the composite endpoint of death or re-hospitalisation occurredin 604 (26.2%) and 569 (24.7%) patients in the ASA and in the placebo arm, respectively. Thecomposite endpoint of death or ischaemic event (stroke, myocardial infarction, stent thrombosis orurgent revascularisation) occurred in 163 (7.1%), and 189 (8.2%) patients in the ASA and in theplacebo arm, respectively.

EMANATE, an open-label, multi-center study, enrolled 1500 adult patients who were either oralanticoagulant naïve or pre-treated less than 48 hours, and scheduled for cardioversion for NVAF.

Patients were randomised 1:1 to apixaban or to heparin and/or VKA for the prevention ofcardiovascular events. Electrical and/or pharmacologic cardioversion was conducted after at least5 doses of 5 mg twice daily apixaban (or 2.5 mg twice daily in selected patients (see section 4.2)) or atleast 2 hours after a 10 mg loading dose (or a 5 mg loading dose in selected patients (see section 4.2))if earlier cardioversion was required. In the apixaban group, 342 patients received a loading dose(331 patients received the 10 mg dose and 11 patients received the 5 mg dose).

There were no strokes (0%) in the apixaban group (n = 753) and 6 (0.80%) strokes in the heparinand/or VKA group (n = 747; RR 0.00, 95% CI 0.00, 0.64). All-cause death occurred in 2 patients(0.27%) in the apixaban group and 1 patient (0.13%) in the heparin and/or VKA group. No systemicembolism events were reported.

Major bleeding and CRNM bleeding events occurred in 3 (0.41%) and 11 (1.50%) patients,respectively, in the apixaban group, compared to 6 (0.83%) and 13 (1.80%) patients in the heparinand/or VKA group.

This exploratory study showed comparable efficacy and safety between apixaban and heparin and/or

VKA treatment groups in the setting of cardioversion.

The adult clinical program (AMPLIFY: apixaban versus enoxaparin/warfarin, AMPLIFY-EXT:apixaban versus placebo) was designed to demonstrate the efficacy and safety of apixaban for thetreatment of DVT and/or PE (AMPLIFY), and extended therapy for the prevention of recurrent DVTand/or PE following 6 to 12 months of anticoagulant treatment for DVT and/or PE (AMPLIFY-EXT).

Both studies were randomised, parallel-group, double-blind, multinational trials in patients withsymptomatic proximal DVT or symptomatic PE. All the key safety and efficacy endpoints wereadjudicated by an independent blinded committee.

In the AMPLIFY study a total of 5,395 adult patients were randomised to treatment with apixaban10 mg twice daily orally for 7 days followed by apixaban 5 mg twice daily orally for 6 months, orenoxaparin 1 mg/kg twice daily subcutaneously for at least 5 days (until INR≥ 2) and warfarin (target

INR range 2.0-3.0) orally for 6 months.

The mean age was 56.9 years and 89.8% of randomised patients had unprovoked VTE events.

For patients randomised to warfarin, the mean percentage of time in therapeutic range (INR 2.0-3.0)was 60.9. Apixaban showed a reduction in recurrent symptomatic VTE or VTE-related death acrossthe different levels of center TTR; within the highest quartile of TTR according to center, the relativerisk for apixaban vs enoxaparin/warfarin was 0.79 (95% CI, 0.39, 1.61).

In the study, apixaban was shown to be non-inferior to enoxaparin/warfarin in the combined primaryendpoint of adjudicated recurrent symptomatic VTE (nonfatal DVT or nonfatal PE) or VTE-relateddeath (see Table 11).

Table 11: Efficacy results in the AMPLIFY study

Apixaban Enoxaparin/Warfarin Relative risk

N = 2,609 N = 2,635 (95% CI)n (%) n (%)

VTE or VTE-related death 59 (2.3) 71 (2.7) 0.84 (0.60, 1.18)*

DVT 20 (0.7) 33 (1.2)

PE 27 (1.0) 23 (0.9)

VTE-related death 12 (0.4) 15 (0.6)

VTE or all-cause death 84 (3.2) 104 (4.0) 0.82 (0.61, 1.08)

VTE or CV-related death 61 (2.3) 77 (2.9) 0.80 (0.57, 1.11)

VTE, VTE-related death, or 73 (2.8) 118 (4.5) 0.62 (0.47, 0.83)major bleeding

* Noninferior compared to enoxaparin/warfarin (p-value < 0.0001)

Apixaban efficacy in initial treatment of VTE was consistent between patients who were treated for a

PE [Relative Risk 0.9; 95% CI (0.5, 1.6)] or DVT [Relative Risk 0.8; 95% CI (0.5, 1.3)]. Efficacyacross subgroups, including age, gender, body mass index (BMI), renal function, extent of index PE,location of DVT thrombus, and prior parenteral heparin use was generally consistent.

The primary safety endpoint was major bleeding. In the study, apixaban was statistically superior toenoxaparin/warfarin in the primary safety endpoint [Relative Risk 0.31, 95% confidence interval(0.17, 0.55), P-value < 0.0001] (see Table 12).

Table 12: Bleeding results in the AMPLIFY study

Apixaban Enoxaparin/Warfarin Relative risk

N = 2,676 N = 2,689 (95% CI)n (%) n (%)

Major 15 (0.6) 49 (1.8) 0.31 (0.17, 0.55)

Major + CRNM 115 (4.3) 261 (9.7) 0.44 (0.36, 0.55)

Minor 313 (11.7) 505 (18.8) 0.62 (0.54, 0.70)

All 402 (15.0) 676 (25.1) 0.59 (0.53, 0.66)

The adjudicated major bleeding and CRNM bleeding at any anatomical site were generally lower inthe apixaban group as compared to the enoxaparin/warfarin group. Adjudicated ISTH majorgastrointestinal bleeding occurred in 6 (0.2%) apixaban-treated patients and 17 (0.6%)enoxaparin/warfarin-treated patients.

In the AMPLIFY-EXT study a total of 2,482 adult patients were randomised to treatment withapixaban 2.5 mg twice daily orally, apixaban 5 mg twice daily orally, or placebo for 12 months aftercompleting 6 to 12 months of initial anticoagulant treatment. Of these, 836 patients (33.7%)participated in the AMPLIFY study prior to enrollment in the AMPLIFY-EXT study.

The mean age was 56.7 years and 91.7% of randomised patients had unprovoked VTE events.

In the study, both doses of apixaban were statistically superior to placebo in the primary endpoint ofsymptomatic, recurrent VTE (nonfatal DVT or nonfatal PE) or all-cause death (see Table 13).

Table 13: Efficacy results in the AMPLIFY-EXT study

Apixaban Apixaban Placebo Relative risk (95% CI)2.5 mg 5.0 mg Apix 2.5 mg Apix 5.0 mg(N = 840) (N = 813) (N = 829) vs. placebo vs. placebon (%)

Recurrent VTE or 19 (2.3) 14 (1.7) 77 (9.3) 0.24 0.19all-cause death (0.15, 0.40)¥ (0.11, 0.33)¥

DVT* 6 (0.7) 7 (0.9) 53 (6.4)

PE* 7 (0.8) 4 (0.5) 13 (1.6)

All-cause death 6 (0.7) 3 (0.4) 11 (1.3)

Recurrent VTE or 14 (1.7) 14 (1.7) 73 (8.8) 0.19 0.20

VTE-related death (0.11, 0.33) (0.11, 0.34)

Recurrent VTE or 14 (1.7) 14 (1.7) 76 (9.2) 0.18 0.19

CV-related death (0.10, 0.32) (0.11, 0.33)

Nonfatal DVT† 6 (0.7) 8 (1.0) 53 (6.4) 0.11 0.15(0.05, 0.26) (0.07, 0.32)

Nonfatal PE† 8 (1.0) 4 (0.5) 15 (1.8) 0.51 0.27(0.22, 1.21) (0.09, 0.80)

VTE-related death 2 (0.2) 3 (0.4) 7 (0.8) 0.28 0.45(0.06, 1.37) (0.12, 1.71)¥ p-value < 0.0001

* For patients with more than one event contributing to the composite endpoint, only the first event was reported (e.g., if asubject experienced both a DVT and then a PE, only the DVT was reported)† Individual subjects could experience more than one event and be represented in both classifications

Apixaban efficacy for prevention of a recurrence of a VTE was maintained across subgroups,including age, gender, BMI, and renal function.

The primary safety endpoint was major bleeding during the treatment period. In the study, theincidence in major bleeding for both apixaban doses was not statistically different from placebo. Therewas no statistically significant difference in the incidence of major + CRNM, minor, and all bleedingbetween the apixaban 2.5 mg twice daily and placebo treatment groups (see Table 14).

Table 14: Bleeding results in the AMPLIFY-EXT study

Apixaban Apixaban Placebo Relative risk (95% CI)2.5 mg 5.0 mg Apix 2.5 mg Apix 5.0 mg(N = 840) (N = 811) (N = 826) vs. placebo vs. placebon (%)

Major 2 (0.2) 1 (0.1) 4 (0.5) 0.49 0.25(0.09, 2.64) (0.03, 2.24)

Major + CRNM 27 (3.2) 35 (4.3) 22 (2.7) 1.20 1.62(0.69, 2.10) (0.96, 2.73)

Minor 75 (8.9) 98 (12.1) 58 (7.0) 1.26 1.70(0.91, 1.75) (1.25, 2.31)

All 94 (11.2) 121 (14.9) 74 (9.0) 1.24 1.65(0.93, 1.65) (1.26, 2.16)

Adjudicated ISTH major gastrointestinal bleeding occurred in 1 (0.1%) apixaban-treated patient at the5 mg twice daily dose, no patients at the 2.5 mg twice daily dose, and 1 (0.1%) placebo-treated patient.

Treatment of venous thromboembolism (VTE) and prevention of recurrent VTE in paediatric patientsfrom 28 days to < 18 years of age

Study CV185325 was a randomised, active controlled, open label, multi-centre study of apixaban forthe treatment of VTE in paediatric patients. This descriptive efficacy and safety study included217 paediatric patients; requiring anticoagulation treatment for VTE and prevention of recurrent VTE;137 patients in age group 1 (12 to < 18 years), 44 patients in age group 2 (2 to < 12 years), 32 patientsin age group 3 (28 days to < 2 years) and 4 patients in age group 4 (birth to < 28 days). The index VTEwas confirmed by imaging, and was independently adjudicated. Prior to randomization, patients weretreated with SOC anticoagulation for up to 14 days (mean (SD) duration of treatment with SOCanticoagulation prior to start of study medication was 4.8 (2.5) days, and 92.3% of patients was started≤ 7 days). Patients were randomised according to a 2:1 ratio to an age-appropriate formulation ofapixaban (doses adjusted for weight equivalent to a loading dose of 10 mg twice daily for 7 daysfollowed by 5 mg twice daily in adults) or SOC. For patients 2 to < 18 years, SOC was comprised oflow molecular weight heparins (LMWH), unfractionated heparins (UFH) or vitamin K antagonists(VKA). For patients 28 days to < 2 years of age, SOC will be limited to heparins (UFH or LMWH).

The main treatment phase lasted 42 to 84 days for patients aged < 2 years, and 84 days in patients aged> 2 years. Patients aged 28 days to < 18 years who were randomised to receive apixaban had theoption to continue apixaban treatment for 6 to 12 additional weeks in the extension phase.

The primary efficacy endpoint was the composite of all image-confirmed and adjudicatedsymptomatic and asymptomatic recurrent VTE and VTE-related death. No patient in either treatmentgroup had a VTE-related death. A total of 4 (2.8%) patients in the apixaban group and 2 (2.8%)patients in the SOC group had at least 1 adjudicated symptomatic or asymptomatic recurrent VTEevent.

The median extent of exposure in 143 treated patients in the apixaban arm was 84.0 days. Exposureexceeded 84 days in 67 (46.9%) patients. The primary safety endpoint of composite of major and

CRNM bleeding was seen in 2 (1.4%) patients on apixaban vs 1 (1.4%) patient on SOC, with a RR of0.99 (95% CI 0.1;10.8). In all cases, this concerned a CRNM bleeding. Minor bleeding was reported in51 (35.7%) patients in the apixaban group and 21 (29.6%) patients in the SOC group, with a RR of1.19 (95% CI 0.8; 1.8).

Major bleeding was defined as bleeding that satisfies one or more of the following criteria: a (i) fatalbleeding; (ii) clinically overt bleeding associated with a decrease in Hgb of at least 20 g/L (2 g/dL) ina 24-hour period; (iii) bleeding that is retroperitoneal, pulmonary, intracranial, or otherwise involvesthe central nervous system; and (iv) bleeding that requires surgical intervention in an operating suite(including interventional radiology).

CRNM bleeding was defined as bleeding that satisfies one or both of the following: (i) overt bleedingfor which a blood product is administered, and which is not directly attributable to the subject’sunderlying medical condition and (ii) bleeding that requires medical or surgical intervention to restorehemostasis, other than in an operating suite.

Minor bleeding was defined as any overt or macroscopic evidence of bleeding that does not fulfill theabove criteria for either major bleeding or clinically relevant, non-major bleeding. Menstrual bleeding,was classified as a minor bleeding event rather than clinically relevant non-major.

In 53 patients who entered the extension phase and were treated with apixaban, no event ofsymptomatic and asymptomatic recurrent VTE or VTE related mortality was reported. No patients inthe extension phase experienced an adjudicated major or a CRNM bleeding event. Eight (8/53; 15.1%)patients in the extension phase experienced minor bleeding events.

There were 3 deaths in the apixaban group and 1 death in the SOC group, all of which were assessedas not treatment-related by the investigator. None of these deaths were due to a VTE or bleeding eventper the adjudication performed by the independent event adjudication committee.

The safety database for apixaban in paediatric patients is based on Study CV185325 for treatment of

VTE and prevention of recurrent VTE, supplemented with the PREVAPIX-ALL study and the

SAXOPHONE study in VTE primary prophylaxis, and single-dose study CV185118. It includes970 paediatric patients, 568 of whom received apixaban.

There is no authorised paediatric indication for the primary prophylaxis of VTE.

Prevention of VTE in paediatric patients with acute lymphoblastic leukaemia or lymphoblasticlymphoma (ALL, LL)

In the PREVAPIX-ALL study, a total of 512 patients age ≥ 1 to < 18 with newly diagnosed ALL or

LL, undergoing induction chemotherapy including asparaginase via an indwelling central venousaccess device, were randomised 1:1 to open-label thromboprophylaxis with apixaban or standard ofcare (with no systemic anticoagulation). Apixaban was administered according to a fixed-dose, bodyweight-tiered regimen designed to produce exposures comparable to those seen in adults who received2.5 mg twice daily (see Table 15). Apixaban was provided as a 2.5 mg tablet, 0.5 mg tablet, or0.4 mg/mL oral solution. The median duration of exposure in the apixaban arm was 25 days.

Table 15: Apixaban dosing in the PREVAPIX-ALL study

Weight Range Dose schedule6 to < 10.5 kg 0.5 mg twice daily10.5 to < 18 kg 1 mg twice daily18 to < 25 kg 1.5 mg twice daily25 to < 35 kg 2 mg twice daily≥ 35 kg 2.5 mg twice daily

The primary efficacy endpoint was a composite of adjudicated symptomatic and asymptomatic non-fatal deep vein thrombosis, pulmonary embolism, cerebral venous sinus thrombosis, and venousthromboembolism-related death. The incidence of the primary efficacy endpoint was 31 (12.1%) in theapixaban arm versus 45 (17.6%) in the standard of care arm. The relative risk reduction did notachieve significance.

Safety endpoints were adjudicated according to ISTH criteria. The primary safety endpoint, majorbleeding, occurred in 0.8% of patients in each treatment arm. CRNM bleeding occurred in 11 patients(4.3%) in the apixaban arm and 3 patients (1.2%) in the standard of care arm. The most common

CRNM bleeding event contributing to the treatment difference was mild to moderate intensityepistaxis. Minor bleeding events occurred in 37 patients in the apixaban arm (14.5%) and 20 patients(7.8%) in the standard of care arm.

Prevention of thromboembolism (TE) in paediatric patients with congenital or acquired heart disease

SAXOPHONE was a randomised 2:1 open-label, multi-center comparative study of patients 28 daysto < 18 years of age with congenital or acquired heart disease who require anticoagulation. Patientsreceived either apixaban or standard of care thromboprophylaxis with a vitamin K antagonist or lowmolecular weight heparin. Apixaban was administered according to a fixed-dose, body weight-tieredregimen designed to produce exposures comparable to those seen in adults who received a dose of5 mg twice daily (see Table 16). Apixaban was provided as a 5 mg tablet, 0.5 mg tablet, or 0.4 mg/mLoral solution. The mean duration of exposure in the apixaban arm was 331 days.

Table 16: Apixaban dosing in the SAXOPHONE study

Weight Range Dose schedule6 to < 9 kg 1 mg twice daily9 to < 12 kg 1.5 mg twice daily12 to < 18 kg 2 mg twice daily18 to < 25 kg 3 mg twice daily25 to < 35 kg 4 mg twice daily≥ 35 kg 5 mg twice daily

The primary safety endpoint, a composite of adjudicated ISTH defined major and CRNM bleeding,occurred in 1 (0.8%) of 126 patients in the apixaban arm and 3 (4.8%) of 62 patients in the standard ofcare arm. The secondary safety endpoints of adjudicated major, CRNM, and all bleeding events weresimilar in incidence across the two treatment arms. The secondary safety endpoint of drugdiscontinuation due to adverse event, intolerability, or bleeding was reported in 7 (5.6%) subjects inthe apixaban arm and 1 (1.6%) subject in the standard of care arm. No patients in either treatment armexperienced a thromboembolic event. There were no deaths in either treatment arm.

This study was prospectively designed for descriptive efficacy and safety because of the expected lowincidence of TE and bleeding events in this population. Due to the observed low incidence of TE inthis study a definitive risk benefit assessment could not be established.

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

In adults, 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 tabletintake. Intake with food does not affect apixaban AUC or Cmax at the 10 mg dose. Apixaban can betaken with or without food.

Apixaban demonstrates linear pharmacokinetics with dose proportional increases in exposure for oraldoses up to 10 mg. At doses ≥ 25 mg apixaban displays dissolution limited absorption with decreasedbioavailability. Apixaban exposure parameters exhibit low to moderate variability reflected by awithin-subject and inter-subject variability of ~20% CV and ~30% CV, respectively.

Following oral administration of 10 mg of apixaban as 2 crushed 5 mg tablets suspended in 30 mL ofwater, exposure was comparable to exposure after oral administration of 2 whole 5 mg tablets.

Following oral administration of 10 mg of apixaban as 2 crushed 5 mg tablets with 30 g of applepuree, the Cmax and AUC were 21% and 16% lower, respectively, when compared to administration of2 whole 5 mg tablets. The reduction in exposure is not considered clinically relevant.

Following administration of a crushed 5 mg apixaban tablet suspended in 60 mL of G5W anddelivered via a nasogastric tube, exposure was similar to exposure seen in other clinical studiesinvolving healthy subjects receiving a single oral 5 mg apixaban tablet dose.

Given the predictable, dose-proportional pharmacokinetic profile of apixaban, the bioavailabilityresults from the conducted studies are applicable to lower apixaban doses.

Apixaban is rapidly absorbed, reaching maximum concentration (Cmax) approximately 2 hours aftersingle-dose administration.

In adults, plasma protein binding is approximately 87%. The volume of distribution (Vss) isapproximately 21 litres.

No data on apixaban plasma protein binding specific to paediatric population is available.

Apixaban has multiple routes of elimination. Of the administered apixaban dose in adults,approximately 25% was recovered as metabolites, with the majority recovered in faeces. In adults,renal excretion of apixaban accounted for approximately 27% of total clearance. Additionalcontributions from biliary and direct intestinal excretion were observed in clinical and nonclinicalstudies, respectively.

In adults, apixaban has a total clearance of about 3.3 L/h and a half-life of approximately 12 hours.

In paediatrics, apixaban has a total apparent clearance of about 3.0 L/h.

O-demethylation and hydroxylation at the 3-oxopiperidinyl moiety are the major sites ofbiotransformation. Apixaban is metabolised mainly via CYP3A4/5 with minor contributions from

CYP1A2, 2C8, 2C9, 2C19, and 2J2. Unchanged apixaban is the major active substance-relatedcomponent in human plasma with no active circulating metabolites present. Apixaban is a substrate oftransport proteins, P-gp and breast cancer resistance protein (BCRP).

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

There was no impact of impaired renal function on peak concentration of apixaban. There was anincrease in apixaban exposure correlated to decrease in renal function, as assessed via measuredcreatinine 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) renalimpairment, apixaban plasma concentrations (AUC) were increased 16, 29, and 44% respectively,compared to individuals with normal creatinine clearance. Renal impairment had no evident effect onthe relationship between apixaban plasma concentration and anti-Factor Xa activity.

In subjects with end-stage renal disease (ESRD), the AUC of apixaban was increased by 36% when asingle dose of apixaban 5 mg was administered immediately after haemodialysis, compared to thatseen in subjects with normal renal function. Haemodialysis, started two hours after administration of asingle dose of apixaban 5 mg, decreased apixaban AUC by 14% in these ESRD subjects,corresponding to an apixaban dialysis clearance of 18 mL/min. Therefore, haemodialysis is unlikely tobe an effective means of managing apixaban overdose.

In paediatric patients ≥ 2 years of age, severe renal impairment is defined as an estimated glomerularfiltration rate (eGFR) less than 30 mL/min/1.73 m2 body surface area (BSA). In Study CV185325, inpatients less than 2 years of age, the thresholds defining severe renal impairment by sex and post-natalage are summarized in Table 17 below; each corresponds to an eGFR < 30 mL/min/1.73 m2 BSA forpatients ≥ 2 years of age.

Table 17: eGFR eligibility thresholds for study CV185325

GFR reference range Eligibility threshold for

Postnatal age (gender)(mL/min/1.73 m2) eGFR*1 week (males and females) 41 ± 15 ≥ 82-8 weeks (males and females) 66 ± 25 ≥ 12> 8 weeks to < 2 years (males and96 ± 22 ≥ 22females)2-12 years (males and females) 133 ± 27 ≥ 3013-17 years (males) 140 ± 30 ≥ 3013-17 years (females) 126 ± 22 ≥ 30

*Eligibility threshold for CV185325 study participation, where estimated glomerular filtration rate (eGFR) was calculatedper the updated bedside Schwartz equation (Schwartz, GJ et al., CJASN 2009). This per protocol threshold corresponded tothe eGFR below which a prospective patient was considered to have “inadequate renal function” that precluded participationin Study CV185325. Each threshold was defined as an eGFR < 30% of 1 standard deviation (SD) below the GFR referencerange for age and gender. Threshold values for patients < 2 years of age correspond to an eGFR < 30 mL/min/1.73 m2, theconventional definition of severe renal failure in patients > 2 years of age.

Paediatric patients with glomerular filtration rates ≤ 55 mL/min/1.73 m2 did not participate in Study

CV185325, although those with mild to moderate levels of renal impairment (eGFR ≥ 30 to< 60 mL/min/1.73 m2 BSA) were eligible. Based on adult data and limited data in all apixaban-treatedpaediatric patients, no dose adjustment is necessary in paediatric patients with mild to moderate renalimpairment. Apixaban is not recommended in paediatric patients with severe renal impairment (seesections 4.2 and 4.4).

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

Apixaban has not been studied in paediatric patients with hepatic impairment.

Exposure to apixaban was approximately 18% higher in females than in males.

Gender differences in pharmacokinetic properties were not studied in paediatric patients.

The results across phase I studies showed no discernible difference in apixaban pharmacokineticsbetween White/Caucasian, Asian and Black/African American subjects. Findings from a populationpharmacokinetic analysis in patients who received apixaban were generally consistent with the phase Iresults.

Differences in pharmacokinetic properties relating to ethnic origin and race were not studied inpaediatric patients.

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

Administration of apixaban to paediatric patients is based on a fixed-dose by weight-tier regimen.

In adults, the pharmacokinetic/pharmacodynamic (PK/PD) relationship between apixaban plasmaconcentration and several PD endpoints (anti-Factor Xa activity [AXA], INR, PT, aPTT) has beenevaluated after administration of a wide range of doses (0.5 - 50 mg). The relationship betweenapixaban 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.

Similarly, results from apixaban paediatric PK/PD assessment indicate a linear relationship betweenapixaban concentration and AXA. This is consistent with the previously documented relationship inadults.

Preclinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, fertility and embryo-foetaldevelopment and juvenile toxicity.

The major observed effects in the repeated dose toxicity studies were those related to thepharmacodynamic action of apixaban on blood coagulation parameters. In the toxicity studies little tono increase of bleeding tendency was found. However, since this may be due to a lower sensitivity ofthe non-clinical species compared to humans, this result should be interpreted with caution whenextrapolating to humans.

In rat milk, a high milk to maternal plasma ratio (Cmax about 8, AUC about 30) was found, possiblydue to active transport into the milk.

Microcrystalline cellulose (E460)

Croscarmellose sodium

Sodium laurilsulfate

Magnesium stearate (E470b)

Lactose monohydrate

Hypromellose (E464)

Titanium dioxide (E171)

Triacetin

Yellow iron oxide (E172)

Not applicable

3 years

This medicinal product does not require any special storage conditions.

Alu-PVC/PVdC blisters. Cartons of 10, 20, 60, 168 and 200 film-coated tablets.

Alu PVC/PVdC perforated unit dose blisters of 60x1 and 100x1 film-coated tablets.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Bristol-Myers Squibb/Pfizer EEIG

Plaza 254

Blanchardstown Corporate Park 2

Dublin 15, D15 T867

Ireland

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

EU/1/11/691/015

Date of first authorisation: 18 May 2011

Date of latest renewal: 11 January 2021

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu