Voziberin

CHARACTERISTICS OF THE MEDICINAL PRODUCT

1. NAME OF THE MEDICINAL PRODUCT

Voziberin, 5 mg, film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 5 mg of apixaban.
Excipients with known effects
Each film-coated tablet contains approximately 103 mg of lactose monohydrate (see section 4.4).
Full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet (tablet)
Pink, oval (approximately 10 x 5 mm), biconvex film-coated tablets, with engraved "M" on one side and "5" on the other side.

4. CLINICAL PARTICULARS

4.1 Therapeutic Indications

Adults
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; 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 "Patients with haemodynamically unstable PE").
Children and adolescents
Treatment of venous thromboembolic disease (VTE) and prevention of recurrent VTE in children and adolescents from 28 days to less than 18 years of age.

4.2 Posology and Method of Administration

Posology
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.
Dose Reduction
In patients with non-valvular atrial fibrillation (NVAF) and at least two of the following criteria: age ≥ 80 years, body weight ≤ 60 kg or serum creatinine ≥ 1.5 mg/dL (133 micromole/L), the recommended dose of apixaban is 2.5 mg taken orally twice daily.
Treatment should be continued long-term.
Treatment of DVT, treatment of PE and prevention of recurrent DVT and PE in adults
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.
In accordance with available medical guidelines, a short treatment duration (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. If prevention of recurrent DVT and PE is indicated, after completing 6 months of treatment with apixaban 5 mg twice daily or other anticoagulant therapy, treatment should be switched to 2.5 mg twice daily, as indicated in Table 1 below (see also section 5.1).

Table 1: Recommended posology (treatment of DVT and PE and prevention of recurrent DVT and PE)

The duration of the entire treatment should be individualised after careful assessment of the benefit of treatment compared to the risk of bleeding (see section 4.4).
Treatment of VTE and prevention of recurrent VTE in children and adolescents
Treatment with apixaban in children and adolescents from 28 days to less than 18 years of age should be initiated after at least 5 days of initial parenteral anticoagulant treatment (see section 5.1).
Treatment with apixaban in children and adolescents is based on a body weight-adjusted dose.
The recommended dose of apixaban for children and adolescents with a body weight ≥ 35 kg is presented in Table 2.

Table 2. Dosing recommendations for treatment and prevention of VTE in children and adolescents with a body weight ≥ 35 kg

Table 2. Dosing recommendations for treatment and prevention of VTE in children and adolescents with a body weight ≥ 35 kg

To obtain information on the use in children and adolescents with a body weight <35 kg, please refer to the summary of product characteristics for apixaban granules in capsules opening and coated sachets available on market from another pharmaceutical company.
Based on the guidelines for the treatment of VTE in children and adolescents, the duration of the entire treatment should be individualised after careful assessment of the benefit of treatment compared to the risk of bleeding (see section 4.4).
Missed dose in adults and children and adolescents
A missed morning dose should be taken as soon as possible and can be taken with the evening dose. A missed evening dose can only be taken on the same evening. The patient should not take two doses on the next day.
Switching from other anticoagulants
Switching from parenteral anticoagulants to apixaban can be done at the next scheduled dose (see section 4.5). These medications should not be administered simultaneously.
Switching from vitamin K antagonist (VKA) to apixaban
In patients being treated with VKA, apixaban therapy should be started after discontinuation of VKA therapy, when the INR is <2.
Switching from apixaban to VKA
When switching from apixaban to VKA, apixaban should be continued for at least 2 days after starting VKA therapy. After 2 days of concurrent apixaban and VKA therapy, INR should be measured prior to the next scheduled apixaban dose. Concurrent administration of apixaban and VKA should be continued until the INR is ≥ 2.
Elderly patients
Treatment of DVT, PE and prevention of recurrent DVT and PE - no dose adjustment is required (see sections 4.4 and 5.2).
Non-valvular atrial fibrillation - no dose adjustment is required unless criteria for dose reduction are met (see Dose Reductionabove in section 4.2).
Renal impairment
Adult patients
For adult 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, no dose adjustment is required (see section 5.2).
for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation and serum creatinine ≥ 1.5 mg/dL (133 micromole/L) in conjunction with age ≥ 80 years or body weight ≤ 60 kg, a dose reduction is recommended (see Dose Reductionabove). In the absence of other criteria for dose reduction (age, body weight), no dose adjustment is required (see section 5.2).
For adult 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, apixaban should be used with caution.
for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF), patients should receive a reduced dose of apixaban 2.5 mg twice daily.
There is no clinical experience in patients with creatinine clearance <15 ml min or patients on dialysis, therefore apixaban is not recommended in these (see sections 4.4 and 5.2).
Children and adolescents
Based on the data in adult patients and limited data in children and adolescents (see section 5.2), no dose adjustment is required in children and adolescents with mild to moderate renal impairment. Apixaban is not recommended in children and adolescents with severe renal impairment (see section 4.4).

• 4.4).

Hepatic impairment
Apixaban is contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk (see section 4.3).
Apixaban is not recommended in patients with severe hepatic impairment (see sections 4.4 and 5.2).
Apixaban should be used with caution in patients with mild or moderate hepatic impairment (Child-Pugh class A or B). No dose adjustment is required in patients with mild or moderate hepatic impairment (see sections 4.4 and 5.2).
Patient with elevated hepatic enzymes alanine transaminase (ALT)/aspartate transaminase (AST) > 2 x upper limit of normal (ULN) or total bilirubin ≥ 1.5 x ULN were excluded from clinical trials. Therefore, caution should be exercised when using apixaban in this patient population (see sections 4.4 and 5.2). Liver function tests should be performed before starting apixaban.
There is no experience with the use of apixaban in children and adolescents with hepatic impairment.
Body weight
Treatment of DVT, PE and prevention of recurrent DVT and PE - no dose adjustment is required in adults (see sections 4.4 and 5.2).
Non-valvular atrial fibrillation - no dose adjustment is required unless criteria for dose reduction are met (see Dose Reductionabove in section 4.2).
Apixaban dosing in children and adolescents is based on a fixed dose according to the body weight category (see section 4.2).
Gender
No dose adjustment is required (see section 5.2).
Patients undergoing cardioversion (NVAF)
Patients undergoing cardioversion may continue apixaban treatment (see sections 4.3, 4.4 and 4.5).
Patients undergoing catheter ablation
Adult patients with non-valvular atrial fibrillation (NVAF) who require cardioversion, apixaban treatment may be started or continued.
In patients not previously treated with anticoagulants, before cardioversion is performed, it is recommended to consider excluding the presence of thrombus in the left atrium by imaging (e.g. transoesophageal echocardiography (TEE) or computed tomography (CT)) in accordance with clinical guidelines.
Patients starting apixaban treatment before cardioversion should receive 5 mg apixaban twice daily for at least 2.5 days (5 single doses) to ensure adequate anticoagulation (see section 5.1). If the patient meets the criteria for dose reduction, apixaban dosing should be reduced to 2.5 mg twice daily for at least 2.5 days (5 single doses) (see Dose Reductionand Renal impairmentabove).
If cardioversion is required before 5 doses of apixaban can be administered, then a loading dose of 10 mg should be given, followed by 5 mg twice daily. In patients meeting the criteria for dose reduction (see Dose Reductionand Renal impairmentabove), a loading dose of 5 mg should be given, followed by 2.5 mg twice daily. The loading dose should be given at least 2 hours before cardioversion (see section 5.1).
In all patients undergoing cardioversion, confirmation that the patient has taken apixaban as prescribed should be obtained before cardioversion is performed. Decisions on starting and duration of anticoagulation should be based on guidelines for anticoagulation in patients undergoing cardioversion.
Patients with non-valvular atrial fibrillation (NVAF) and acute coronary syndrome (ACS) and/or undergoing percutaneous coronary intervention (PCI)
Experience with the use of apixaban in patients with NVAF in combination with antiplatelet therapy in patients with ACS and/or undergoing PCI is limited (see sections 4.4, 5.1).
Children and adolescents
The safety and efficacy of apixaban have not been established in children and adolescents from 28 days to less than 18 years of age in indications other than the treatment of VTE and prevention of recurrent VTE. There are no data on the use of this medicinal product in neonates and in other indications (see also section 5.1). Therefore, the use of apixaban is not recommended in neonates, children and adolescents from 28 days to less than 18 years of age in indications other than the treatment of VTE and prevention of recurrent VTE.
There is no established safety or efficacy of apixaban in children and adolescents under 18 years of age for the prevention of thromboembolic disease. Current data on thromboembolic disease prevention are presented in section 5.1, but there are no dosing recommendations.
Method of administration in adults and children and adolescents
Oral use.
Apixaban should be taken with water, without regard to food.
In patients who are unable to swallow the tablets whole, apixaban tablets may be crushed and mixed with water, 5% water for injection (WFI), or 5% glucose solution (G5W), or apple juice or 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 administered 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).
• Lesions or conditions that may increase the risk of significant bleeding, such as recent gastrointestinal ulcer, presence of malignant neoplasms with high risk of bleeding, recent intracranial or intraspinal haemorrhage, recent brain, spinal or ophthalmologic surgery.
• Concomitant treatment with any other anticoagulant, such as unfractionated heparin (UFH), low molecular weight heparins (e.g. enoxaparin, dalteparin, etc.), heparin derivatives (e.g. fondaparinux, etc.), oral anticoagulants (e.g. warfarin, rivaroxaban, dabigatran etexilate, etc.), except in specific situations of switching of anticoagulant therapy (see section 4.2), situations where UFH is administered at doses necessary to maintain the patency of a central venous or arterial catheter in a patient or when UFH is administered during a catheter ablation procedure for atrial fibrillation (see sections 4.4 and 4.5).

4.4 Special Warnings and Precautions for Use

Bleeding risk
As with other anticoagulants, patients taking apixaban are to be closely monitored for signs of bleeding. Caution should be exercised when using apixaban in conditions with increased risk of bleeding. In case of significant bleeding, apixaban should be discontinued (see sections 4.8 and 4.9).
Although apixaban treatment does not require routine coagulation monitoring, a calibrated quantitative anti-Xa assay may be useful in exceptional situations where knowledge of apixaban exposure may help to inform clinical decisions, such as overdose or urgent surgery (see section 5.1).
A specific reversal agent (andexanet alfa) that reverses the pharmacodynamic effects of apixaban is available for adults. However, its safety and efficacy have not been established in children and adolescents (see the Summary of Product Characteristics for andexanet alfa). Fresh frozen plasma, prothrombin complex concentrate (PCC) or recombinant factor VIIa may also be considered. However, there is no clinical experience with the use of 4-factor PCC to reverse bleeding in children and adolescents or adults treated with apixaban.
Interactions with other medicinal products affecting haemostasis
Due to increased bleeding risk, concomitant use of other anticoagulants is contraindicated (see section 4.3).
Concomitant use of apixaban with antiplatelet agents increases the bleeding risk (see section 4.5).
Caution should be exercised when apixaban is co-administered with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs), or non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin.
After surgical procedures, it is not recommended to use other platelet aggregation inhibitors concomitantly with apixaban (see section 4.5).
In patients with atrial fibrillation who are candidates for single or dual antiplatelet therapy, a careful assessment of the potential benefits versus the potential risks should be made before concomitant administration of such therapy and apixaban.
In a clinical study in adult patients with atrial fibrillation, concomitant use of aspirin increased the bleeding risk when used with apixaban from 1.8% per year to 3.4% per year, as well as increased the bleeding risk when used with warfarin from 2.7% to 4.6% per year. In this clinical study, only a limited number of patients (2.1%) received concomitant dual antiplatelet therapy (see section 5.1).
A clinical study in patients with atrial fibrillation and acute coronary syndrome (ACS) and/or undergoing percutaneous coronary intervention (PCI) planned for a treatment duration of 6 months with a P2Y12 inhibitor, in combination with aspirin with or without a third antiplatelet agent, and an oral anticoagulant (apixaban or vitamin K antagonists (VKAs)) found that concomitant use of aspirin in patients treated with apixaban increased the bleeding risk from 16.4% to 33.1% per year (see section 5.1).
In the CV185325 study, no clinically significant bleeding was reported in 12 paediatric patients treated with apixaban and aspirin ≤ 165 mg/day.
Use of thrombolytic medicinal products for the treatment of acute ischaemic stroke
Experience with the use of thrombolytic medicinal products for the treatment of acute ischaemic stroke in patients taking apixaban is very limited (see section 4.5).
Patients with prosthetic heart valves
The safety and efficacy of apixaban have not been studied in patients with prosthetic heart valves, with or without atrial fibrillation. Therefore, apixaban is not recommended in these patients.
There is no experience with the use of apixaban in children and adolescents with prosthetic heart valves, therefore apixaban is not recommended in this patient population.
Patients with antiphospholipid syndrome
Oral anticoagulants with a direct mechanism of action, such as apixaban, are not recommended for patients with thrombosis and diagnosed antiphospholipid syndrome. In particular, for patients with triple positive antiphospholipid syndrome (positive for lupus anticoagulant, anticardiolipin and anti-β2-glycoprotein I antibodies), treatment with direct oral anticoagulants may be associated with a higher risk of recurrent thrombotic events compared to treatment with vitamin K antagonists.
Surgical and other invasive procedures
Apixaban should be discontinued at least 48 hours before elective surgery or invasive procedures with a moderate or high risk of bleeding. This includes procedures where the risk of bleeding is high or where the consequences of bleeding would be severe, such as spinal or epidural anaesthesia, spinal puncture or major surgical procedures.
Apixaban should be discontinued at least 24 hours before elective surgery or invasive procedures with a low risk of bleeding. This includes procedures where bleeding is minimal, occurs in a confined space and can be easily controlled.
If it is not possible to delay the procedure, apixaban should be discontinued and caution should be exercised. The risk of bleeding should be weighed against the urgency of the procedure.
Apixaban treatment should be resumed as soon as possible after the procedure, provided adequate haemostasis has been established (for cardioversion, see section 4.2).
In patients undergoing catheter ablation for atrial fibrillation, there is no need to interrupt apixaban treatment (see sections 4.2, 4.3 and 4.5).
Temporary interruption of treatment
Discontinuation of anticoagulants, including apixaban, increases the risk of thrombosis. Delays in resuming anticoagulant therapy should be minimised. If temporary interruption of apixaban is necessary for any reason, therapy should be restarted as soon as possible.
Neuraxial anaesthesia or spinal puncture
When neuraxial anaesthesia (spinal or epidural) or spinal puncture is performed, patients treated with anticoagulants for thromboprophylaxis are at risk of developing an epidural or spinal haematoma, which can result in long-term or permanent paralysis.
The risk of these complications may be increased by the post-operative use of indwelling epidural catheters or the concomitant use of medicinal products affecting haemostasis. The catheters must be removed at least 5 hours before the first dose of apixaban is administered. Traumatic or repeated neuraxial puncture increases the risk, as well as an indwelling catheter for continuous administration of local anaesthetics.
Patients should be frequently monitored for signs and symptoms of neurological impairment (e.g. numbness or weakness of the legs, bowel or bladder dysfunction). If neurological compromise is noted, urgent diagnosis and treatment are necessary.
Before neuraxial intervention is performed, the physician should consider the potential benefit versus risk in patients taking anticoagulants or being treated with anticoagulants for thromboprophylaxis.
There is no clinical experience with the use of apixaban in patients with an indwelling epidural or intrathecal catheter. If such a procedure is planned, the physician should consider the potential benefit versus risk. Based on the pharmacokinetics of apixaban, between the last administration of apixaban and the removal of the catheter, at least 20-30 hours (2 x apixaban half-life) should elapse. The next dose of apixaban should not be administered earlier than 5 hours after the removal of the catheter. As with all new anticoagulant medicinal products, the experience with neuraxial blockade is limited, therefore, caution is advised when using apixaban in these settings.
There are no data available on the timing of the placement or removal of a central catheter in children and adolescents treated with apixaban. In such cases, apixaban treatment should be interrupted and consideration should be given to the use of a short-acting parenteral anticoagulant.
Patients with haemodynamically unstable PE or who require thrombolytic therapy or pulmonary embolectomy
Apixaban is not recommended as an alternative to unfractionated heparin in patients with pulmonary embolism who are haemodynamically unstable or may require thrombolysis or pulmonary embolectomy, as the safety and efficacy of apixaban have not been established in these clinical situations.
Patients with active cancer
Patients with active cancer may be at increased risk of both venous thromboembolism and bleeding. The benefit of treatment with apixaban should be carefully weighed against the potential risk in patients with cancer (see also section 4.3).
Renal impairment
Adult patients
Limited clinical data indicate that apixaban plasma levels are increased in patients with severe renal impairment (creatinine clearance 15-29 mL/min). This may increase the risk of bleeding. Caution should be exercised when using apixaban in the treatment of DVT, treatment of PE and prevention of recurrent DVT and PE in patients with severe renal impairment (creatinine clearance 15-29 mL/min) (see sections 4.2 and 5.2).
In the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF), patients with severe renal impairment (creatinine clearance 15-29 mL/min) and serum creatinine ≥ 1.5 mg/dL (133 micromole/L) in conjunction with age ≥ 80 years or body weight ≤ 60 kg should receive a reduced dose of apixaban 2.5 mg twice daily (see section 4.2).
There is no clinical experience in patients with creatinine clearance <15 ml min or patients on dialysis, therefore apixaban is not recommended in these (see sections 4.2 and 5.2).
Children and adolescents
Apixaban has not been studied in children and adolescents with severe renal impairment and therefore is not recommended in these patients (see sections 4.2 and 5.2).
Elderly patients
With increasing age, there is an increased risk of bleeding (see section 5.2).
In addition, caution should be exercised when apixaban is co-administered with aspirin in elderly patients due to an increased risk of bleeding.
Body weight
In adults, low body weight (<60 kg) may increase the risk of bleeding (see section 5.2).
Hepatic impairment
Apixaban is contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk (see section 4.3).
Apixaban is not recommended in patients with severe hepatic impairment (see section 5.2).
Apixaban should be used with caution in patients with mild or moderate hepatic impairment (Child-Pugh class A or B) (see sections 4.2 and 5.2).
Patient with elevated hepatic enzymes ALT/AST > 2 x ULN and total bilirubin ≥ 1.5 x ULN were excluded from clinical trials. Therefore, apixaban should be used with caution in this patient population (see section 5.2). Liver function tests should be performed before starting apixaban.
There is no experience with the use of apixaban in children and adolescents with hepatic impairment.
Interactions with cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp) inhibitors
Apixaban should not be used in patients receiving concomitant systemic treatment with strong CYP3A4 and P-gp inhibitors, 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 or more, especially in the presence of additional factors that may increase apixaban exposure (e.g. severe renal impairment). There are no clinical data on the use of apixaban in children and adolescents receiving concomitant systemic treatment with strong CYP3A4 and P-gp inhibitors (see section 4.5).
Interactions with CYP3A4 and P-gp inducers
Concomitant use of apixaban with strong CYP3A4 and P-gp inducers (e.g. rifampicin, phenytoin, carbamazepine, phenobarbital or St. John's Wort) may decrease apixaban exposure by approximately 50%. In a clinical study in patients with atrial fibrillation, reduced efficacy and increased bleeding risk were observed when apixaban was co-administered with strong CYP3A4 and P-gp inducers compared to apixaban alone.
For patients receiving concomitant systemic treatment with strong CYP3A4 and P-gp inducers (see section 4.5):

• apixaban should be used with caution in the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF) and in the prevention of recurrent DVT and PE;
• apixaban should not be used in the treatment of DVT and PE, as its efficacy may be decreased.

There are no clinical data on the use of apixaban in children and adolescents receiving concomitant systemic treatment with strong CYP3A4 and P-gp inducers (see section 4.5).
Laboratory parameters
As expected from its mechanism of action, apixaban affects the coagulation parameters (e.g. prothrombin time (PT), INR and activated partial thromboplastin time (aPTT)). Changes in coagulation parameters are expected after the anticipated therapeutic dose and are small and show high variability (see section 5.1).
Information on excipients
Voziberin contains lactose. The medicinal product should not be administered to patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption.
This medicinal product contains less than 1 mmol (23 mg) sodium per tablet, i.e. essentially sodium-free.

4.5 Interactions with Other Medicinal Products and Other Forms of Interaction

CYP3A4 and P-gp Inhibitors
Concomitant administration of apixaban with ketoconazole (400 mg once daily), a strong inhibitor of both CYP3A4 and P-gp, resulted in a 2-fold increase in apixaban's mean area under the curve (AUC) and a 1.6-fold increase in apixaban's mean maximum concentration (Cmax).
The use of apixaban is not recommended in patients concomitantly treated with systemic strong CYP3A4 and P-gp inhibitors, such as azole antimycotics (e.g., ketoconazole, itraconazole, voriconazole, and posaconazole) and HIV protease inhibitors (e.g., ritonavir) (see section 4.4).
Active substances that are not considered strong inhibitors of both CYP3A4 and P-gp (e.g., amiodarone, clarithromycin, diltiazem, fluconazole, naproxen, quinidine, and verapamil) have a lesser impact on increasing apixaban plasma concentrations. When concomitantly administering apixaban with substances that are not strong CYP3A4 or P-gp inhibitors, there is no need to adjust the apixaban dose. For example, diltiazem (360 mg once daily), considered a moderate CYP3A4 inhibitor and a weak P-gp inhibitor, resulted in a 1.4-fold increase in mean AUC and a 1.3-fold increase in apixaban's Cmax. Naproxen (single dose of 500 mg), a P-gp inhibitor not inhibiting CYP3A4, resulted in a 1.5-fold and 1.6-fold increase in mean AUC and Cmax of apixaban, respectively. Clarithromycin (500 mg twice daily), a P-gp inhibitor and a strong CYP3A4 inhibitor, resulted in a 1.6-fold and 1.3-fold increase in mean AUC and Cmax of apixaban, respectively.
CYP3A4 and P-gp Inducers
Concomitant administration of apixaban with rifampicin, a strong inducer of both CYP3A4 and P-gp, resulted in a decrease of apixaban's mean AUC and Cmax by approximately 54% and 42%, respectively.
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 a decrease in apixaban plasma concentrations. There is no need to adjust the apixaban dose when concomitantly using such medicinal products; however, in the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF) and in the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) and prevention of recurrent DVT and PE, apixaban should be used with caution in patients treated concomitantly with systemic strong CYP3A4 and P-gp inducers. In patients treated concomitantly with systemic strong CYP3A4 and P-gp inducers, apixaban is not recommended for the treatment of DVT and PE, as its efficacy may be decreased (see section 4.4).
Anticoagulants, Antiplatelet Agents, SSRIs/SNRIs, and NSAIDs
Due to an increased risk of bleeding, concomitant use of any other anticoagulant is contraindicated, except in specific situations of switching anticoagulant therapy, when unfractionated heparin (UFH) is administered at doses necessary to maintain an open central venous or arterial catheter or when UFH is administered during a catheter ablation procedure for atrial fibrillation (see section 4.3).
After concomitant administration of enoxaparin (single dose of 40 mg) and apixaban (single dose of 5 mg), an additive effect on the inhibition of factor Xa activity was observed.
No significant pharmacokinetic or pharmacodynamic interactions were found when apixaban was concomitantly administered with aspirin (acetylsalicylic acid, ASA) at a dose of 325 mg once daily.
Apixaban administered concomitantly with clopidogrel (75 mg once daily) or the combination of clopidogrel 75 mg and ASA 162 mg once daily, or with prasugrel (60 mg loading dose, then 10 mg once daily) in Phase I studies did not result in significant prolongation of bleeding time or further inhibition of platelet aggregation compared to the administration of antiplatelet agents without apixaban. The increase in coagulation parameters (PT, INR, and APTT) was consistent with the effect of apixaban when administered alone.
Naproxen (500 mg dose), a P-gp inhibitor, resulted in a 1.5-fold and 1.6-fold increase in mean AUC and Cmax of apixaban, respectively. A corresponding increase in coagulation parameters for apixaban was observed. No changes in the effect of naproxen on arachidonic acid-induced platelet aggregation or clinically significant prolongation of bleeding time were observed after concomitant administration of apixaban and naproxen.
Despite these observations, in some individuals, concomitant use of apixaban with antiplatelet agents may result in a more pronounced pharmacodynamic effect. Caution should be exercised when concomitantly using apixaban with SSRIs or SNRIs, NSAIDs, ASA, and/or P2Y12 inhibitors, as these medicinal products typically increase the risk of bleeding (see section 4.4).
Experience with concomitant use of other antiplatelet agents (e.g., GPIIb/IIIa receptor antagonists, dipyridamole, dextrans, or sulfinpyrazone) or thrombolytic agents is limited. Since these medicinal products increase the risk of bleeding, their concomitant use with apixaban is not recommended (see section 4.4).
In the CV185325 study, no clinically significant bleeding was reported in 12 pediatric patients treated with apixaban and ASA ≤ 165 mg once daily.
Other Concomitant Therapies
No significant pharmacokinetic or pharmacodynamic interactions were found when apixaban was concomitantly administered with atenolol or famotidine.
Concomitant administration of apixaban (10 mg dose) with atenolol (100 mg dose) did not have a clinically significant effect on apixaban pharmacokinetics. After concomitant administration of these two medicinal products, mean AUC and Cmax of apixaban were 15% and 18% lower, respectively, than after administration of apixaban alone. Concomitant administration of 10 mg apixaban with 40 mg famotidine did not affect AUC and Cmax of apixaban.
Effect of Apixaban on Other Medicinal Products
In vitro studies have shown that apixaban, at concentrations significantly higher than the maximum concentration observed in patients, did not inhibit the activity of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2D6, or CYP3A4 (IC50 > 45 μM) and had a weak inhibitory effect on the activity of CYP2C19 (IC50 > 20 μM). Apixaban, at concentrations up to 20 μM, did not induce CYP1A2, CYP2B6, or CYP3A4/5. Therefore, it is not expected that apixaban will have a significant impact on the metabolic clearance of concomitantly administered medicinal products that are metabolized by these enzymes. Apixaban is not a significant inhibitor of P-gp.
In studies conducted in healthy subjects, as described below, apixaban did not have a significant effect on the pharmacokinetics of digoxin, naproxen, or atenolol.
Digoxin
Concomitant administration of apixaban (20 mg once daily) and digoxin (0.25 mg once daily), a P-gp substrate, did not affect digoxin AUC or Cmax. Therefore, apixaban does not inhibit P-gp-mediated transport.
Naproxen
Concomitant administration of a single dose of apixaban (10 mg) and naproxen (500 mg), a commonly used NSAID, did not affect naproxen AUC or Cmax.
Atenolol
Concomitant administration of a single dose of apixaban (10 mg) and atenolol (100 mg), a commonly used beta-adrenergic blocker, did not affect the pharmacokinetics of atenolol.
Activated Charcoal
Administration of activated charcoal reduces apixaban exposure (see section 4.9).
Pediatric Population
No interaction studies have been performed in children and adolescents. The above interaction data are from studies in adults, and the warnings in section 4.4 should be taken into consideration for the pediatric population.

4.6 Fertility, Pregnancy, and Lactation

Pregnancy
There are no data on 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 recommended to avoid the use of apixaban during pregnancy.
Breast-feeding
It is not known whether apixaban or its metabolites are excreted in human milk. Available data from animal studies indicate that apixaban is excreted in milk (see section 5.3). A risk to the breast-fed 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 apixaban therapy for the mother.
Fertility
Animal studies with apixaban have shown no effects 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 evaluated in 4 Phase III clinical studies in over 15,000 patients: in over 11,000 patients in studies for non-valvular atrial fibrillation (NVAF) and in over 4,000 patients in studies for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) and prevention of recurrent DVT and PE, with a mean total exposure of 1.7 years and 221 days, respectively (see section 5.1).
Common adverse reactions included bleeding, bruising, nosebleeds, and hematoma (adverse reaction profile with frequency according to indication is presented in Table 3).
In the NVAF studies, the overall rate of adverse reactions related to bleeding after apixaban treatment was 24.3% in the study comparing apixaban with warfarin and 9.6% in the study comparing apixaban with aspirin. In the study comparing apixaban with warfarin, the rate of major gastrointestinal bleeding meeting ISTH criteria (including upper gastrointestinal bleeding, lower gastrointestinal bleeding, and rectal bleeding) after apixaban treatment was 0.76% per year. The rate of major intracranial bleeding meeting ISTH criteria after apixaban treatment was 0.18% per year.
In the DVT and PE treatment and prevention of recurrent DVT and PE studies, the overall rate of adverse reactions related to bleeding after apixaban treatment was 15.6% in the study comparing apixaban with enoxaparin/warfarin and 13.3% in the study comparing apixaban with placebo (see section 5.1).
Tabular List of Adverse Reactions
Table 3 presents adverse reactions by system organ class and frequency, according to the following convention: very common (≥ 1/10), common (≥ 1/100 to <1>

Table 3: Tabular List of Adverse Reactions

In the CV185057 study (long-term VTE prevention), there were no cases of generalized pruritus.
The term "intracranial hemorrhage" refers to any hemorrhage within the skull or spinal canal (e.g., hemorrhagic stroke, subarachnoid hemorrhage, subdural hemorrhage, epidural hemorrhage, or intracranial hemorrhage).
This includes anaphylactic reaction, drug hypersensitivity, and hypersensitivity.
This includes menorrhagia, metrorrhagia, and vaginal hemorrhage.
Apixaban treatment may be associated with an increased risk of occult or overt bleeding from any tissue or organ, which may lead to anemia. The signs, symptoms, and severity (mild or severe) may vary according to the bleeding location and extent (see sections 4.4 and 5.1).
Pediatric Population
The safety of apixaban has been evaluated in 1 Phase I clinical study and 3 Phase II/III clinical studies, involving 970 patients. Of these, 568 received at least one dose of apixaban, with a mean total exposure of 1, 24, 331, and 80 days, respectively (see section 5.1). Patients received apixaban doses adjusted for their body weight, in a formulation suitable for their age.
Overall, the safety profile of apixaban in children and adolescents aged from 28 days to less than 18 years was similar to that in adults and was generally consistent across different age groups of children and adolescents.
The most common adverse reactions reported in children and adolescents were nosebleeds and abnormal uterine bleeding (information on the adverse reaction profile and frequency according to indication is presented in Table 3).
In children and adolescents, nosebleeds (very common), abnormal uterine bleeding (very common), hypersensitivity and anaphylaxis (common), pruritus (common), hypotension (common), hematochezia (common), increased aspartate aminotransferase (common), alopecia (common), and postoperative bleeding (common) were reported more frequently than in adults treated with apixaban, but in the same frequency category as in children and adolescents in the standard treatment group; the only exception was abnormal uterine bleeding, which was reported with a frequency of "common" in the standard treatment group. In all cases, except one, increased liver enzymes were reported in children and adolescents undergoing chemotherapy for malignancy.

4.9 Overdose

Overdose of apixaban may increase the risk of bleeding. In the event of bleeding complications, treatment should be discontinued and the source of bleeding should be identified. Appropriate management, such as surgical hemostasis, transfusion of fresh frozen plasma, or administration of a reversal agent for factor Xa inhibitors (see section 4.4), should be considered.
In controlled clinical studies, apixaban administered orally to healthy adult subjects at doses up to 50 mg daily for 3-7 days (25 mg twice daily for 7 days or 50 mg once daily for 3 days) did not result in significant adverse reactions.
In healthy adult subjects, administration of activated charcoal 2 and 6 hours after a 20 mg dose of apixaban reduced mean apixaban AUC by 50% and 27%, respectively, and had no impact on Cmax. The mean apixaban half-life was reduced from 13.4 hours after administration of apixaban alone to 5.3 hours and 4.9 hours, respectively, when charcoal was administered 2 and 6 hours after apixaban. Therefore, administration of activated charcoal may be useful in the treatment of apixaban overdose or accidental ingestion.
After administration of a single 5 mg dose of apixaban to patients with end-stage renal disease (ESRD), hemodialysis decreased apixaban AUC by 14%. Therefore, it is unlikely that hemodialysis would be effective in treating apixaban overdose.
In situations where reversal of anticoagulant effect is needed due to life-threatening or uncontrolled bleeding, a specific reversal agent for factor Xa inhibitors (andexanet alfa) is available for adults (see section 4.4). Prothrombin complex concentrates (PCC) or recombinant factor VIIa may also be considered.
In healthy subjects, reversal of apixaban's pharmacodynamic effects, as measured by changes in thrombin generation, was evident at the end of a 4-hour infusion of 4-factor PCC. However, there is no clinical experience with the use of 4-factor PCCs in patients treated with apixaban. There is currently no experience with the use of recombinant factor VIIa in patients treated with apixaban. A repeat dose of recombinant factor VIIa may be considered, and the dose may be adjusted based on the degree of bleeding reduction.
A specific antidote (andexanet alfa) to reverse the pharmacodynamic effects of apixaban has not been established in children and adolescents (see the summary of product characteristics for andexanet alfa). Fresh frozen plasma, PCC, or recombinant factor VIIa may also be considered.
Depending on local availability, in the event of major bleeding, it may be useful to consult a coagulation expert.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic Group: Anticoagulants, Direct Factor Xa Inhibitors, ATC Code: B01AF02
Mechanism of Action
Apixaban is a potent, oral, reversible, direct, and highly selective inhibitor of factor Xa. It does not require antithrombin III for anticoagulant activity. Apixaban inhibits free and prothrombinase-bound factor Xa, as well as platelet aggregation induced by thrombin. By inhibiting factor Xa, apixaban prevents thrombin formation and clotting. Preclinical studies of apixaban in animal models have demonstrated antithrombotic activity in the prevention of arterial and venous thrombosis at doses that preserved hemostasis.
Pharmacodynamic Effects
The pharmacodynamic effects of apixaban reflect its mechanism of action (inhibition of factor Xa). As a result of factor Xa inhibition, apixaban prolongs coagulation tests such as prothrombin time (PT), INR, and activated partial thromboplastin time (APTT). In adults, the changes in these coagulation tests at expected therapeutic doses are small and show considerable variability. These coagulation tests are not recommended 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 exhibits an inhibitory effect on factor Xa activity, as demonstrated by a decrease in the activity of factor Xa in several commercial factor Xa activity assays; however, the results vary depending on the assay. Data from clinical studies in adults are only available for the chromogenic anti-factor Xa assay using the Rotachrom kit.

Table 4: Predicted Exposure and Factor Xa Inhibition in the Steady State

Apixaban

C (ng/mL)

Apixaban

C (ng/mL)

Apixaban Maximum Factor Xa Inhibition

(ng/mL)

Apixaban Minimum Factor Xa Inhibition

(ng/mL)

Median [5th/95th Percentile]

Stroke Prevention in Non-Valvular Atrial Fibrillation: NVAF

2.5 mg twice daily
123 [69; 221]
79 [34; 162]
1.8 [1.0; 3.3]
1.2 [0.51; 2.4]
5 mg twice daily
171 [91; 321]
103 [41; 230]
2.6 [1.4; 4.8]
1.5 [0.61; 3.4]
Treatment of DVT, Treatment of PE, and Prevention of Recurrent DVT and PE

2.5 mg twice daily
67 [30; 153]
32 [11; 90]
1.0 [0.46; 2.5]
0.49 [0.17; 1.4]
5 mg twice daily
132 [59; 302]
63 [22; 177]
2.1 [0.91; 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]

In patients with non-valvular atrial fibrillation receiving apixaban for stroke prevention, results indicate a less than 1.7-fold difference between maximum and minimum concentrations. In patients receiving apixaban for the treatment of DVT and PE or prevention of recurrent DVT and PE, results indicate a less than 2.2-fold difference between maximum and minimum concentrations.
Although apixaban treatment does not require routine monitoring of exposure, a calibrated quantitative anti-Xa assay may be useful in exceptional situations where knowledge of apixaban exposure may help inform clinical decisions, such as overdose or urgent surgery.
Pediatric Population
In clinical studies of apixaban in children and adolescents, the STA Liquid Anti-Xa assay was used to measure apixaban activity. Results from these studies indicate that the linear relationship between apixaban concentration and anti-Xa activity (AXA) is consistent with the previously documented relationship in adults. This confirms the established mechanism of action of apixaban as a selective factor Xa inhibitor.
In weight ranges from 9 to ≥ 35 kg, in study CV185155, the geometric mean (%CV) values for AXA min and AXA max ranged from 27.1 (22.2) ng/mL to 71.9 (17.3) ng/mL, corresponding to geometric mean (%CV) Cmin and Cmax values of 30.3 (22) ng/mL and 80.8 (16.8) ng/mL, respectively. The exposures achieved with these AXA ranges, with the dosing regimen in children and adolescents, were comparable to those observed in adults receiving apixaban 2.5 mg twice daily.
In weight ranges from 6 to ≥ 35 kg, in study CV185362, the geometric mean (%CV) values for AXA min and AXA max ranged from 67.1 (30.2) ng/mL to 213 (41.7) ng/mL, corresponding to geometric mean (%CV) Cmin and Cmax values of 71.3 (61.3) ng/mL and 230 (39.5) ng/mL, respectively. The exposures achieved with these AXA ranges, with the dosing regimen in children and adolescents, were comparable to those observed in adults receiving apixaban 5 mg twice daily.
In weight ranges from 6 to ≥ 35 kg, in study CV185325, the geometric mean (%CV) values for AXA min and AXA max ranged from 47.1 (57.2) ng/mL to 146 (40.2) ng/mL, corresponding to geometric mean (%CV) Cmin and Cmax values of 50 (54.5) ng/mL and 144 (36.9) ng/mL, respectively. The exposures achieved with these AXA ranges, with the dosing regimen in children and adolescents, were comparable to those observed in adults receiving apixaban 5 mg twice daily.
Predicted exposure and factor Xa inhibition in the steady state in studies in children and adolescents suggest that changes in apixaban concentration and anti-Xa activity from peak to trough in the steady state were approximately 3-fold (minimum, maximum: 2.65 to 3.22) across the population.

Efficacy and Safety

Stroke Prevention in Non-Valvular Atrial Fibrillation (NVAF)

A total of 23,799 adult patients were randomized to apixaban or control in clinical studies (ARISTOTLE: apixaban versus warfarin, AVERROES: apixaban versus aspirin), including 11,927 patients randomized to apixaban. The objective of this program was to demonstrate the efficacy and safety of apixaban for stroke prevention in non-valvular atrial fibrillation patients with at least one additional risk factor, such as:

• previous stroke or transient ischemic attack (TIA)
• age ≥ 75 years
• hypertension
• diabetes
• symptomatic heart failure (NYHA Class ≥ II).

ARISTOTLE Study

In the ARISTOTLE study, 18,201 adult patients were randomized to apixaban 5 mg twice daily (or 2.5 mg twice daily in selected patients [4.7%], see section 4.2) or warfarin (target INR range: 2.0-3.0); patients received the study drug for a mean of 20 months. The mean age was 69.1 years, the mean CHADS2 score was 2.1, and 18.9% of patients had a history of stroke or TIA.
In this study, apixaban demonstrated a statistically significant reduction in the primary endpoint of stroke (ischemic or hemorrhagic) or systemic embolism (see Table 5) compared to warfarin.

Table 5: Efficacy Results in Patients with Non-Valvular Atrial Fibrillation in the ARISTOTLE Study

Apixaban Warfarin Hazard Ratio

(95% CI)

p-Value

Stroke or Systemic Embolism
212 (1.27)
265 (1.60)
0.79 (0.66; 0.95)
0.0114
Ischemic or Unknown Stroke
162 (0.97)
175 (1.05)
0.92 (0.74; 1.13)
Hemorrhagic Stroke
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)

Among patients randomized to warfarin, the median percentage of time in the therapeutic INR range (2-3) was 66%.
In the apixaban group, there was a reduction in the rate of stroke or systemic embolism compared to warfarin across different levels of center-based TTR; in the highest quartile of center-based TTR, the hazard ratio for apixaban compared to warfarin was 0.73 (95% CI: 0.38; 1.40).
Key secondary endpoints, including major bleeding and all-cause death, were tested using a pre-specified hierarchical testing strategy to control the overall Type I error rate in the study. Apixaban also demonstrated a statistically significant reduction in these key secondary endpoints (see Table 6).

Table 6: Secondary Endpoints in Patients with Non-Valvular Atrial Fibrillation in the ARISTOTLE Study

Apixaban Warfarin Hazard Ratio

(95% CI)

p-Value

Bleeding Events

Major*
327 (2.13)
462 (3.09)
0.69 (0.60; 0.80)
<0.0001

Fatal Bleeding
10 (0.06)
37 (0.24)

Intracranial Hemorrhage
52 (0.33)
122 (0.80)

Major + Clinically Relevant Non-Major (CRNM)†
613 (4.07)
877 (6.01)
0.68 (0.61; 0.75)
<0.0001

All Bleeding Events
2356 (18.1)
3060 (25.8)
0.71 (0.68; 0.75)
<0.0001

Other Endpoints

All-Cause Death
603 (3.52)
669 (3.94)
0.89 (0.80; 1.00)
0.0465

Myocardial Infarction
90 (0.53)
102 (0.61)
0.88 (0.66; 1.17)

Major bleeding was defined according to the ISTH criteria.
Clinically relevant non-major bleeding (CRNM).

The overall rate of patients discontinuing study treatment due to adverse reactions in the ARISTOTLE study was 1.8% in the apixaban group and 2.6% in the warfarin group.
The efficacy results in pre-specified subgroups, categorized by CHADS2 score, age, body weight, sex, renal function, prior stroke or TIA, and diabetes, were consistent with the overall efficacy results in the study population.
The rate of major gastrointestinal bleeding meeting ISTH criteria (including upper gastrointestinal bleeding, lower gastrointestinal bleeding, and rectal bleeding) was 0.76% per year after apixaban treatment and 0.86% per year after warfarin treatment.
The results for major bleeding in pre-specified subgroups, categorized by CHADS2 score, age, body weight, sex, renal function, prior stroke or TIA, and diabetes, were consistent with the results in the overall study population.
AVERROES Study

In the AVERROES study, 5,598 adult patients were randomized to apixaban 5 mg twice daily (or 2.5 mg twice daily in selected patients [6.4%], see section 4.2) or aspirin; aspirin was given as a single daily dose of 81 mg (64%), 162 mg (26.9%), 243 mg (2.1%), or 324 mg (6.6%), at the discretion of the investigator. Patients received the study drug for a mean of 14 months. The mean age was 69.9 years, the mean CHADS2 score was 2.0, and 13.6% of patients had a history of stroke or TIA.
Common reasons for not being a candidate for VKA therapy in the AVERROES study included inability or low likelihood of INR measurements at required intervals (42.6%), patient refusal to take VKA (37.4%), CHADS2 score = 1 and not recommended for VKA by the physician (21.3%), risk of non-compliance with VKA instructions (15.0%), and anticipated difficulty in contacting the patient in the event of a need for urgent dose adjustment (11.7%).
The AVERROES study was stopped early due to a recommendation by the independent Data Monitoring Committee, based on clear evidence of a reduction in stroke or systemic embolism with an acceptable safety profile.
The overall rate of patients discontinuing study treatment due to adverse reactions in the AVERROES study was 1.5% in the apixaban group and 1.3% in the aspirin group.
In this study, apixaban demonstrated a statistically significant reduction in the primary endpoint of stroke (ischemic, hemorrhagic, or unknown) or systemic embolism (see Table 7) compared to aspirin.

Table 7: Key Efficacy Results in Patients with Non-Valvular Atrial Fibrillation in the AVERROES Study

Apixaban ASA Hazard Ratio

(95% CI)

p-Value

Stroke or Systemic Embolism

5.2 Pharmacokinetic properties

Absorption
In adults, the absolute bioavailability of apixaban is approximately 50% for doses up to 10 mg. Apixaban is rapidly absorbed, with maximum concentrations (Cmax) attained 3 to 4 hours after administration of the tablet. Administration of apixaban with food does not affect AUC or Cmax for a 10 mg dose. Apixaban can be taken with or without food.

Apixaban exhibits linear pharmacokinetics, with exposure increasing proportionally to dose in the dose range up to 10 mg. At doses ≥ 25 mg, apixaban exhibits dissolution-limited absorption, resulting in decreased bioavailability.

Parameters of exposure to apixaban display little or moderate variability, resulting in inter-individual and intra-individual variability of approximately 20% CV and 30% CV, respectively.

After administration of 10 mg apixaban as 2 crushed 5 mg tablets in 30 mL of water, exposure was comparable to that after administration of 2 whole 5 mg tablets. After administration of 10 mg apixaban as 2 crushed 5 mg tablets with 30 g of applesauce, Cmax and AUC values were 21% and 16% lower, respectively, than after administration of 2 whole 5 mg tablets. The reduction in exposure is not considered clinically significant.

After administration of crushed 5 mg apixaban tablet in 60 mL of 5% dextrose in water through a nasogastric tube, exposure was similar to that observed in other clinical studies in healthy subjects receiving a 5 mg apixaban tablet.

Given the predictable, dose-proportional pharmacokinetic profile of apixaban, the results of the bioavailability studies can be extrapolated to lower doses of apixaban.

Children and adolescents
Apixaban is rapidly absorbed, with a median time to Cmax of approximately 2 hours after a single dose.

Distribution
In adults, apixaban is approximately 87% bound to plasma proteins. The volume of distribution (Vd) is approximately 21 liters.

Metabolism and elimination
Apixaban has multiple routes of elimination. Of the dose recovered, approximately 25% was recovered as metabolites, with the majority found in the feces. In adults, renal excretion of apixaban accounted for approximately 27% of total clearance. In clinical studies and nonclinical studies, additional routes of elimination included hepatic excretion via bile and direct intestinal excretion.

In adults, the total clearance of apixaban is approximately 3.3 L/h, and the half-life is approximately 12 hours.

In children and adolescents, the total apparent clearance of apixaban is approximately 3.0 L/h.

The main pathways of metabolism are O-demethylation and hydroxylation of the 3-oxopiperidinyl ring. Apixaban is metabolized mainly via CYP3A4/5, and to a lesser extent by CYP1A2, 2C8, 2C9, 2C19, and 2J2. Apixaban (active substance) is present in human plasma predominantly in the unchanged form; no active metabolites have been found in plasma.

For the pediatric population, there are no data available on the binding of apixaban to plasma proteins.

Elderly
In elderly patients (≥ 65 years), higher systemic exposure to apixaban was observed compared to younger patients. Mean AUC values were increased by approximately 32%, with no difference in Cmax.

Renal impairment
No significant impact of renal impairment on apixaban Cmax was observed. An increase in apixaban exposure was correlated with a decrease in renal function, as assessed by measured creatinine clearance. In patients with mild (creatinine clearance 51-80 mL/min), moderate (creatinine clearance 30-50 mL/min), and severe (creatinine clearance 15-29 mL/min) renal impairment, apixaban plasma concentrations (AUC) were increased by approximately 16%, 29%, and 44%, respectively, compared to patients with normal renal function.

After administration of a single dose of apixaban 5 mg to patients with end-stage renal disease (ESRD) immediately after hemodialysis, the AUC of apixaban was increased by 36% compared to that in patients with normal renal function. Hemodialysis initiated 2 hours after administration of a single dose of apixaban 5 mg reduced apixaban AUC by 14% in those ESRD patients, corresponding to a dialysis clearance of apixaban of 18 mL/min. Therefore, it is unlikely that hemodialysis will be effective in treating apixaban overdose.

5.3 Preclinical safety data

Non-clinical data, derived from conventional pharmacological safety studies, studies of toxicity after repeated administration, genotoxicity, potential carcinogenic effect, toxic effect on fertility and embryonic/fetal development, and toxicity to offspring, do not indicate any special hazard for humans. Significant findings observed in repeated dose toxicity studies were related to the pharmacodynamic effect of apixaban on blood coagulation parameters. In toxicity studies, a trend towards slight bleeding or no increase in bleeding was observed. However, this result should be interpreted with caution when extrapolated to humans, as it may be due to the lower sensitivity of the species in non-clinical studies compared to humans. In female rats, a high ratio of apixaban concentration in milk to plasma concentration was found (C approximately 8, AUC approximately 30), possibly due to active transport into milk.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Core

Lactose monohydrate

Microcrystalline cellulose (E 460)

Croscarmellose sodium (E 468)

Sodium lauryl sulfate (E 487)

Magnesium stearate (E 470b)

Coating

Hypromellose (E 464)

Lactose monohydrate

Titanium dioxide (E 171)

Triacetin

Red iron oxide (E 172)

6.2 Incompatibilities

None

6.3 Shelf life

3 years.

6.4 Special precautions for storage

No special precautions for storage of the medicinal product.

6.5 Nature and contents of container

PVC/PVDC/Aluminum blister.

Pack sizes:

Cartons containing 14, 20, 28, 56, 60, 168, and 200 film-coated tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

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

7. MARKETING AUTHORISATION HOLDER

RESPONSIBLE FOR BATCH RELEASE

MSN Labs Europe Limited

KW20A Corradino Park

Paola, PLA 3000

Malta

8. MARKETING AUTHORISATION NUMBER

Authorisation number: 29056

9. DATE OF FIRST AUTHORISATION

AND DATE OF REVISION OF THE TEXT

Date of first authorisation: 2025-05-20

10. DATE OF REVISION OF THE TEXT

OF THE SUMMARY OF PRODUCT CHARACTERISTICS

2025-05-27