4.1. Therapeutic indications

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).

4.2. Posology and method of administration

Posology

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

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

Dose reduction

The recommended dose of apixaban is 2.5 mg taken orally twice daily in patients with NVAF and at least two of the following characteristics: age ≥ 80 years, body weight ≤ 60 kg, or serum creatinine ≥ 1.5 mg/dL (133 micromole/L).

Therapy should be continued long-term.

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

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

The recommended dose of apixaban for the prevention of recurrent DVT and PE is 2.5 mg taken orally twice daily. When prevention of recurrent DVT and PE is indicated, the 2.5 mg twice daily dose should be initiated following completion of 6 months of treatment with apixaban 5 mg twice daily or with 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 7 days

20 mg

followed by 5 mg twice daily

10 mg

Prevention of recurrent DVT and/or PE following completion of 6 months of treatment for DVT or PE

2.5 mg twice daily

5 mg

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

Missed dose

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

Switching

Switching treatment from parenteral anticoagulants to Apixaban (and vice versa) can be done at the next scheduled dose (see section 4.5). These medicinal products should not be administered simultaneously.

Switching from vitamin K antagonist (VKA) therapy to Apixaban

When converting patients from vitamin K antagonist (VKA) therapy to Apixaban, warfarin or other VKA therapy should be discontinued and Apixaban started when the international normalised ratio (INR) is < 2.

Switching from Apixaban to VKA therapy

When converting patients from Apixaban to VKA therapy, administration of Apixaban should be continued for at least 2 days after beginning VKA therapy. After 2 days of coadministration of Apixaban with VKA therapy, an INR should be obtained prior to the next scheduled dose of Apixaban. Coadministration of Apixaban and VKA therapy should be continued until the INR is ≥ 2.

Elderly

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 reduction at the beginning of section 4.2).

Renal impairment

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

- for the treatment of DVT, treatment of PE and prevention of recurrent DVT and PE (VTEt), no dose adjustment is 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 dose reduction is necessary and described above. In the absence of other criteria for dose reduction (age, body weight), no dose adjustment is necessary (see section 5.2).

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

- for the treatment of DVT, treatment of PE and prevention of recurrent DVT and PE (VTEt) apixaban is to be used with caution;

- for the prevention of stroke and systemic embolism in patients with NVAF, patients should receive 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 no clinical experience therefore apixaban is not recommended (see sections 4.4 and 5.2).

Hepatic impairment

Apixaban is contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk (see section 4.3).

It is not recommended in patients with severe hepatic impairment (see sections 4.4. and 5.2).

It should be used with caution in patients with mild or moderate hepatic impairment (Child Pugh A or B). No dose adjustment is required in patients with mild or moderate hepatic impairment (see sections 4.4 and 5.2).

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

Body weight

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 reduction at the beginning of section 4.2).

Gender

No dose adjustment required (see section 5.2).

Patients undergoing catheter ablation (NVAF)

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

Patients undergoing cardioversion

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

For patients not previously treated with anticoagulants, exclusion of left atrial thrombus using an image 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 dosing regimen 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 Renal impairment).

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

For all patients undergoing cardioversion, confirmation should be sought prior to cardioversion that the patient has taken apixaban as prescribed. Decisions on initiation and duration of treatment should take established guideline recommendations for anticoagulant treatment in patients undergoing cardioversion 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 patients when used in combination with antiplatelet agents in patients with ACS and/or undergoing PCI after haemostasis is achieved (see sections 4.4, 5.1).

Paediatric population

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

Method of administration

Oral use

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

For patients who are unable to swallow whole tablets, Apixaban tablets may be crushed and suspended in water, or 5% glucose in water (G5W), or apple juice or mixed with apple puree and immediately administered orally (see section 5.2). Alternatively, Apixaban tablets may be crushed and suspended in 60 mL of water or G5W and immediately delivered through a nasogastric tube (see section 5.2).

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

4.3. Contraindications

• 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 (see section 5.2).

• Lesion or condition if considered a significant risk factor for major bleeding. This may include current or recent gastrointestinal ulceration, presence of malignant neoplasms at high risk of bleeding, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial haemorrhage, known or suspected oesophageal varices, arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities.

• Concomitant treatment with any other anticoagulant agent e.g., unfractionated heparin (UFH), low molecular weight heparins (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux, etc.), oral anticoagulants (warfarin, rivaroxaban, dabigatran, etc.) except under specific circumstances of switching anticoagulant therapy (see section 4.2), when UFH is given at doses necessary to maintain an open central venous or arterial catheter or when UFH is given during catheter ablation for atrial fibrillation (see sections 4.4 and 4.5).

4.4. Special warnings and precautions for use

Haemorrhage risk

As with other anticoagulants, patients taking apixaban are to be carefully observed for signs of bleeding. 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 and 4.9).

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

An agent to reverse the anti-factor Xa activity of apixaban is available.

Interaction with other medicinal products affecting haemostasis

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

The concomitant use of apixaban with antiplatelet agents increases the risk of bleeding (see section 4.5).

Care is to be taken if patients are treated concomitantly with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs), or non-steroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid.

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

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

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

A clinical study enrolled patients with atrial fibrillation with ACS and/or undergoing PCI and a planned treatment period with a P2Y12 inhibitor, with or without ASA, and oral anticoagulant (either apixaban 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 in apixaban-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 the combination of ASA and clopidogrel, a significant increase in risk of ISTH major bleeding was reported for apixaban (5.13% per year) compared to placebo (2.04% per year).

Use of thrombolytic agents for the treatment of acute ischemic stroke

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

Patients with prosthetic heart valves

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

Patients with antiphospholipid syndrome

Direct acting Oral Anticoagulants (DOACs) including apixaban are not recommended for patients with a history of thrombosis who are diagnosed with antiphospholipid syndrome. In particular for patients that are triple positive (for lupus anticoagulant, anticardiolipin antibodies, and anti-beta 2- glycoprotein I antibodies), treatment with DOACs could be associated with increased rates of recurrent thrombotic events compared with vitamin K antagonist therapy.

Surgery and invasive procedures

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

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

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

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

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

Temporary discontinuation

Discontinuing anticoagulants, including apixaban, for active bleeding, elective surgery, or invasive procedures places patients at an increased risk of thrombosis. Lapses in therapy should be avoided and if anticoagulation with apixaban must be temporarily discontinued for any reason, therapy should be restarted as soon as possible.

Haemodynamically unstable PE patients or patients who require thrombolysis or pulmonary embolectomy

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

Patients with active cancer

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 the benefits against the risks should be made (see also section 4.3).

Patients with renal impairment

Limited clinical data indicate that apixaban plasma concentrations are increased in patients with severe renal impairment (creatinine clearance 15-29 mL/min) which may lead to an increased bleeding risk. For the treatment of DVT, treatment of PE and prevention of recurrent DVT and PE (VTEt), apixaban is to be used with caution in patients with severe renal impairment (creatinine clearance 15-29 mL/min) (see sections 4.2 and 5.2).

For the prevention of stroke and systemic embolism in patients with NVAF, patients with severe renal impairment (creatinine clearance 15-29 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 lower dose of apixaban 2.5 mg twice daily (see section 4.2).

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

Elderly patients

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

Also, the co-administration of apixaban with ASA in elderly patients should be used cautiously because of a potentially higher bleeding risk.

Body weight

Low body weight (< 60 kg) may increase haemorrhagic risk (see section 5.2).

Patients with hepatic impairment

Apixaban is contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk (see section 4.3).

It is not recommended in patients with severe hepatic impairment (see section 5.2).

It should be used with caution in patients with mild or moderate hepatic impairment (Child Pugh A or B) (see sections 4.2 and 5.2).

Patients with elevated liver enzymes ALT/AST > 2 x ULN or total bilirubin ≥ 1.5 x ULN were excluded in clinical studies. Therefore apixaban should be used cautiously in this population (see section 5.2). Prior to initiating apixaban liver function testing should be performed.

Interaction with inhibitors of both cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp)

The use of apixaban is not recommended in patients receiving concomitant systemic treatment with strong inhibitors of both CYP3A4 and P-gp, such as azole-antimycotics (e.g., ketoconazole, itraconazole, voriconazole and posaconazole) and HIV protease inhibitors (e.g., ritonavir). These medicinal products may increase apixaban exposure by 2-fold (see section 4.5) or greater in the presence of additional factors that increase apixaban exposure (e.g., severe renal impairment).

Interaction with inducers of both CYP3A4 and P-gp

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 were observed with coadministration of apixaban with strong inducers of both CYP3A4 and P-gp compared with using apixaban alone.

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

- for the prevention of stroke and systemic embolism in patients with NVAF and for the prevention of recurrent DVT and PE, apixaban should be used with caution;

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

Laboratory parameters

Clotting tests [e.g., prothrombin time (PT), INR, and activated partial thromboplastin time (aPTT)] are affected as expected by the mechanism of action of apixaban. Changes observed in these clotting tests at the expected therapeutic dose are small and subject to a high degree of variability (see section 5.1).

Information about excipients

Apixaban contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency 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".

4.5. Interaction with other medicinal products and other forms of interaction

Inhibitors of CYP3A4 and P-gp

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 mean apixaban Cmax.

The use of apixaban is not recommended in patients receiving concomitant systemic treatment with strong inhibitors of both CYP3A4 and P-gp, such as azole-antimycotics (e.g., ketoconazole, itraconazole, voriconazole and posaconazole) and HIV protease inhibitors (e.g., ritonavir) (see section 4.4).

Active substances which are not considered strong inhibitors of both CYP3A4 and P-gp, (eg., amiodarone, clarithromycin, diltiazem, fluconazole, naproxen, quinidine, verapamil) are expected to increase apixaban plasma concentration to a lesser extent. No dose adjustment for apixaban is required when coadministered with agents that are not strong inhibitors of both CYP3A4 and P-gp. For example, diltiazem (360 mg once a day), considered a moderate CYP3A4 and a weak P-gp inhibitor, led to a 1.4-fold increase in mean apixaban AUC and a 1.3-fold increase in Cmax. Naproxen (500 mg, single dose) an inhibitor of P-gp but not an inhibitor of CYP3A4, led to a 1.5-fold and 1.6-fold increase in mean apixaban AUC and Cmax, respectively. Clarithromycin (500 mg, twice a day), an inhibitor of P-gp and a strong inhibitor of CYP3A4, led to a 1.6-fold and 1.3-fold increase in mean apixaban AUC and Cmax respectively.

Inducers of CYP3A4 and P-gp

Coadministration of apixaban with rifampicin, a strong inducer of both CYP3A4 and P-gp, led to an approximate 54% and 42% decrease in mean apixaban AUC and Cmax, respectively. The concomitant use of apixaban with other strong CYP3A4 and P-gp inducers (e.g., phenytoin, carbamazepine, phenobarbital or St. John's Wort) may also lead to reduced apixaban plasma concentrations. No dose adjustment for apixaban is required during concomitant therapy with such medicinal products, however in patients receiving concomitant systemic treatment with strong inducers of both CYP3A4 and P-gp apixaban should be used with caution for the prevention of stroke and systemic embolism in patients with NVAF and for the prevention of recurrent DVT and PE. Apixaban is not recommended for the treatment of DVT and PE in patients receiving concomitant systemic treatment with strong inducers of both CYP3A4 and P-gp since efficacy may be compromised (see section 4.4).

Anticoagulants, platelet aggregation inhibitors, SSRIs/SNRIs and NSAIDs

Due to an increased bleeding risk, concomitant treatment with any other anticoagulants is contraindicated except under specific circumstances of switching anticoagulant therapy, when UFH is given at doses necessary to maintain an open central venous or arterial catheter or when UFH is given during catheter ablation for atrial fibrillation (see section 4.3).

After combined administration of enoxaparin (40 mg single dose) with apixaban (5 mg single dose), an additive effect on anti-Factor Xa activity was observed.

Pharmacokinetic or pharmacodynamic interactions were not evident when apixaban was coadministered with ASA 325 mg once a day.

Apixaban coadministered with clopidogrel (75 mg once a day) or with the combination of clopidogrel 75 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 of platelet aggregation, compared to administration of the antiplatelet agents without apixaban. Increases in clotting tests (PT, INR, and aPTT) were consistent with the effects of apixaban alone.

Naproxen (500 mg), an inhibitor of P-gp, led to a 1.5-fold and 1.6-fold increase in mean apixaban AUC and Cmax, respectively. Corresponding increases in clotting tests were observed for apixaban. No changes were observed in the effect of naproxen on arachidonic acid-induced platelet aggregation and no clinically relevant prolongation of bleeding time was observed after concomitant administration of apixaban and naproxen.

Despite these findings, there may be individuals with a more pronounced pharmacodynamic response when antiplatelet agents are coadministered with apixaban. Apixaban should be used with caution when coadministered with SSRIs/SNRIs, NSAIDs, ASA and/or P2Y12 inhibitors because these medicinal 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. As such agents increase the bleeding risk, co-administration of these medicinal products with apixaban is not recommended (see section 4.4).

Other concomitant therapies

No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when apixaban was coadministered with atenolol or famotidine. Coadministration of apixaban 10 mg with atenolol 100 mg did not have a clinically relevant effect on the pharmacokinetics of apixaban. Following administration of the two medicinal products together, mean apixaban AUC and Cmax were 15% and 18% lower than when administered alone. The administration of apixaban 10 mg with famotidine 40 mg had no effect on apixaban AUC or Cmax.

Effect of apixaban on other medicinal products

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 activity of CYP2C19 (IC50 > 20 μM) at concentrations that are significantly greater than peak plasma concentrations observed in patients. Apixaban did not induce CYP1A2, CYP2B6, CYP3A4/5 at a concentration up to 20 μM. Therefore, apixaban is not expected to alter the metabolic clearance of coadministered medicinal products that are metabolised by these enzymes. Apixaban is not a significant inhibitor of P-gp.

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

Digoxin

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 substrate transport.

Naproxen

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.

Atenolol

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

Activated charcoal

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

4.6. Fertility, pregnancy and lactation

Pregnancy

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

Breast-feeding

It is unknown whether apixaban or its metabolites are excreted in human milk. Available data in animals have shown excretion of apixaban in milk (see section 5.3). A risk to the suckling child cannot be excluded.

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

Fertility

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

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Summary of the safety profile

The safety of apixaban has been investigated in 4 Phase III clinical studies including more than 15,000 patients: more than 11,000 patients in NVAF studies and more than 4,000 patients in the VTE treatment (VTEt) studies, for an average total exposure of 1.7 years and 221 days respectively (see section 5.1).

Common adverse reactions were haemorrhage, contusion, epistaxis, and haematoma (see Table 2 for adverse reaction profile and frequencies by indication).

In the NVAF studies, the overall incidence of adverse reactions related to bleeding with apixaban was 24.3% in the apixaban vs warfarin study and 9.6% in the apixaban vs acetylsalicylic acid study. In the apixaban vs warfarin study the incidence of ISTH major gastrointestinal bleeds (including upper GI, lower GI, and rectal bleeding) with apixaban was 0.76%/year. The incidence of ISTH major intraocular bleeding with apixaban was 0.18%/year.

In the VTEt studies, the overall incidence of adverse reactions related to bleeding with apixaban was 15.6% in the apixaban vs enoxaparin/warfarin study and 13.3% in the apixaban vs placebo study (see section 5.1).

Tabulated list of adverse reactions

Table 2 shows the adverse reactions ranked under headings of system organ class and frequency using the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data) for NVAF, and VTEt respectively.

Table 2: Tabulated adverse reactions

System Organ Class

Prevention of stroke and systemic embolism in adult patients with NVAF, with one or more risk factors (NVAF)

Treatment of DVT and PE, and prevention of recurrent DVT and PE (VTEt)

Blood and lymphatic system disorders

Anaemia

Common

Common

Thrombocytopenia

Uncommon

Common

Immune system disorders

Hypersensitivity, allergic oedema and Anaphylaxis

Uncommon

Uncommon

Pruritus

Uncommon

Uncommon*

Angioedema

Not known

Not known

Nervous system disorders

Brain haemorrhage†

Uncommon

Rare

Eye disorders

Eye haemorrhage (including conjunctival haemorrhage)

Common

Uncommon

Vascular disorders

Haemorrhage, haematoma

Common

Common

Hypotension (including procedural hypotension)

Common

Uncommon

Intra-abdominal haemorrhage

Uncommon

Not known

Respiratory, thoracic and mediastinal disorders

Epistaxis

Common

Common

Haemoptysis

Uncommon

Uncommon

Respiratory tract haemorrhage

Rare

Rare

Gastrointestinal disorders

Nausea

Common

Common

Gastrointestinal haemorrhage

Common

Common

Haemorrhoidal haemorrhage

Uncommon

Uncommon

Mouth haemorrhage

Uncommon

Common

Haematochezia

Uncommon

Uncommon

Rectal haemorrhage, gingival bleeding

Common

Common

Retroperitoneal haemorrhage

Rare

Not known

Hepatobiliary disorders

Liver function test abnormal, asparate aminotransferase increased, blood alkaline phosphatase increased, blood bilirubin increased

Uncommon

Uncommon

Gamma-glutamyltransferase increased

Common

Common

Alanine aminotransferase increased

Uncommon

Common

Skin and subcutaneous tissue disorders

Skin rash

Uncommon

Common

Alopecia

Uncommon

Uncommon

Erythema multiforme

Very rare

Not known

Cutaneous vasculitis

Not known

Not known

Musculoskeletal and connective tissue disorders

Muscle haemorrhage

Rare

Uncommon

Hemarthrosis

Not known

Not known

Renal and urinary disorders

Haematuria

Common

Common

Anticoagulant-related nephropathy

Not known

Not known

Reproductive system and breast disorders

Abnormal vaginal haemorrhage, urogenital haemorrhage

Uncommon

Common

General disorders and administration site conditions

Application site bleeding

Uncommon

Uncommon

Investigations

Occult blood positive

Uncommon

Uncommon

Injury, poisoning and procedural complications

Contusion

Common

Common

Post procedural haemorrhage (including post procedural haematoma, wound haemorrhage, vessel puncture site haematoma and catheter site haemorrhage), wound secretion, incision site haemorrhage (including incision site haematoma), operative haemorrhage

Uncommon

Uncommon

Traumatic haemorrhage

Uncommon

Uncommon

* 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 or putamen, cerebellar, intraventricular, or subdural haemorrhages).

Description of selected adverse reactions

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

Known complications secondary to severe bleeding such as anticoagulant-related nephropathy has occasionally been reported in patients receiving anticoagulants in the post-marketing setting. In patients with pre-existing kidney disease, ARN may occur, possibly in relation to episodes of excessive anticoagulation and haematuria. The possibility of haemorrhage is to be considered in evaluating the condition in any anticoagulated patient (see section 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme at Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Overdose of apixaban may result in a higher risk of bleeding. In the event of haemorrhagic complications, treatment must be discontinued and the source of bleeding investigated. The initiation of appropriate treatment, e.g., surgical haemostasis, the transfusion of fresh frozen plasma or the administration of a reversal agent for factor Xa inhibitors should be considered.

In controlled clinical studies, orally-administered apixaban in healthy subjects at doses up to 50 mg daily for 3 to 7 days (25 mg twice daily (bid) for 7 days or 50 mg once daily (od) for 3 days) had no clinically relevant adverse reactions.

In healthy subjects, administration of activated charcoal 2 and 6 hours after ingestion of a 20 mg dose of apixaban reduced mean apixaban AUC by 50% and 27%, respectively, and had no impact on Cmax. Mean half-life of apixaban decreased from 13.4 hours when apixaban was administered alone to 5.3 hours and 4.9 hours, respectively, when activated charcoal was administered 2 and 6 hours after apixaban. Thus, administration of activated charcoal may be useful in the management of apixaban overdose or accidental ingestion.

For situations when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding, a reversal agent for factor Xa inhibitors is available (see section 4.4). Administration of prothrombin complex concentrates (PCCs) or recombinant factor VIIa may also be considered. Reversal of apixaban pharmacodynamic effects, as demonstrated by changes in the thrombin generation assay, was evident at the end of infusion and reached baseline values within 4 hours after the start of a 4-factor PCC 30 minute infusion in healthy subjects. However, there is no clinical experience with the use of 4-factor PCC products to reverse bleeding in individuals who have received apixaban. Currently there is no experience with the use of recombinant factor VIIa in individuals receiving apixaban. Re-dosing of recombinant factor VIIa could be considered and titrated depending on improvement of bleeding.

Depending on local availability, a consultation of a coagulation expert should be considered in case of major bleedings.

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 to be an effective means of managing apixaban overdose.