APIBAN Film-Coated Tablets

                                                         Apixaban 2.5/5 mg

PRESENTATION

Each Tablet Contains Apixaban 2.5/ 5 mg.

Pack size: 3*10 Blisters

CLINICAL PARTICULARS

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 ischemic 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.

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, and immobilization).

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.

Table 1: Dose Recommendation (VTEt)

The duration of overall therapy should be individualized after careful assessment of the treatment benefit against the risk for bleeding.

Missed Dose

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

Switching

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

Switching from vitamin K antagonist (VKA) therapy to APIBAN

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

Switching from APIBAN to VKA therapy

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

Elderly

VTEt - No dose adjustment required.

NVAF - No dose adjustment required, unless criteria for dose reduction are met.

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.
• 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.
• In patients with severe renal impairment (creatinine clearance 15-29 mL/min) the following recommendations apply:
• 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.

Hepatic Impairment

APIBAN is contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk.

It is not recommended in patients with severe hepatic impairment.

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.

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 APIBAN should be used with caution in this population (see sections 4.4 and 5.2). Prior to initiating APIBAN, liver function testing should be performed.

Body Weight

VTEt - No dose adjustment required.

NVAF - No dose adjustment required, unless criteria for dose reduction are met.

Gender

No dose adjustment required.

Patients Undergoing Catheter Ablation (NVAF)

Patients can continue Apixaban use while undergoing catheter ablation.

Patients Undergoing Cardio Version

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

For patients not previously treated with anticoagulants, exclusion of left atrial thrombus using an image guided approach (e.g. Tran’s esophageal echocardiography (TEE) or computed tomographic scan (CT)) prior to cardio version 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 cardio version to ensure adequate anticoagulation. 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.

If cardio version 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 cardio version.

For all patients undergoing cardio version, confirmation should be sought prior to cardio version 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 cardio version 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 hemostasis is achieved.

Pediatric population

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

Method of Administration

Oral Use

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

For patients who are unable to swallow whole tablets, APIBAN 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. Alternatively, APIBAN tablets may be crushed and suspended in 60 mL of water or G5W and immediately delivered through a nasogastric tube.

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

CONTRAINDICATIONS

• Hypersensitivity to the active substance or to any of the excipients.
• Active clinically significant bleeding.
• Hepatic disease associated with coagulopathy and clinically relevant bleeding risk.
• 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 hemorrhage, known or suspected esophageal 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, 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.

SPECIAL WARNINGS AND PRECAUTIONS FOR USE

Hemorrhage 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 hemorrhage. Apixaban administration should be discontinued if severe hemorrhage occurs.

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.

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

INTERACTION WITH OTHER MEDICINAL

Due to an increased bleeding risk, concomitant treatment with any other anticoagulants is contraindicated.

The concomitant use of Apixaban with antiplatelet agents increases the risk of bleeding.

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.

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 APIBAN.

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.

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.

In a clinical study of high-risk post-acute coronary syndrome patients without atrial fibrillation, characterized by multiple cardiac and non-cardiac comorbidities, who received ASA or the combination of ASA and clopidogrel, a significant increase in risk of ISTH 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.

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 anti- phospholipid 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 hemostasis has been established.

For patients undergoing catheter ablation for atrial fibrillation, Apixaban treatment does not need to be interrupted.

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.

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).

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;

In patients with creatinine clearance < 15 mL/min, or in patients undergoing dialysis, there is no clinical experience therefore Apixaban is not recommended.

Elderly Patients

Increasing age may increase hemorrhagic risk. 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 Hemorrhagic Risk.

Patients with Hepatic Impairment

Apixaban is contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk.

It is not recommended in patients with severe hepatic impairment.

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

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. 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 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 co- administration 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:

• 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.

INTERACTION WITH OTHER MEDICINAL PRODUCTS AND OTHER FORMS OF INTERACTION

Inhibitors of CYP3A4 and P-gp

Co- administration of Apixaban with ketoconazole (400 mg once a day), a strong inhibitor of both CYP3A4 and P-gp, led to a 2-fold increase in mean Apixaban AUC and a 1.6-fold increase in mean Apixaban C_max.

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).

Active substances which are not considered strong inhibitors of both CYP3A4 and P-gp, (e.g., amiodarone, clarithromycin, diltiazem, fluconazole, naproxen, quinidine, and verapamil) are expected to increase Apixaban plasma concentration to a lesser extent. No dose adjustment for Apixaban is required when co- administered 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 C_max. Naproxen (500 mg, single dose) an inhibitor of P-gp but not an inhibitor of CYP3A4, led to a 1.5-fold and 1.6-fold increase in mean Apixaban AUC and C_max, respectively. Clarithromycin (500 mg, twice a day), an inhibitor of P-gp and a strong inhibitor of CYP3A4, led to a 1.6-fold and 1.3-fold increase in mean Apixaban AUC and C_max 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 C_max, 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.

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.

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 pharmacodynamics interactions were not evident when Apixaban was co- administered with ASA 325 mg once a day.

Apixaban co- administered with clopidogrel (75 mg once a day) or with the combination of clopidogrel 75 mg and ASA 162 mg once daily, 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 C_max, 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 pharmacodynamics response when antiplatelet agents are co- administered with Apixaban. Apixaban should be used with caution when co- administered with SSRIs/SNRIs, NSAIDs, ASA and/or P2Y12 inhibitors because these medicinal products typically increase the bleeding risk.

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.

Other Concomitant Therapies

No clinically significant pharmacokinetic or pharmacodynamics interactions were observed when Apixaban was co- administered 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 C_max 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 C_max.

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, and CYP3A4/5 at a concentration up to 20 µM. Therefore, Apixaban is not expected to alter the metabolic clearance of co- 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 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 C_max. 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 C_max.

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.

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. 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. 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.

Effects on Ability to Drive and Use Machines

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

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.

Common adverse reactions were hemorrhage, contusion, epistaxis, and hematoma (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.

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

* There were no occurrences of generalized pruritus in CV185057 (long term prevention of VTE)

^† The term “Brain hemorrhage” encompasses all intracranial or intraspinal hemorrhages (i.e., hemorrhagic stroke or putamen, cerebellar, intra ventricular, or subdural hemorrhages).

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 anemia. The signs, symptoms, and severity will vary according to the location and degree or extent of the bleeding.

OVERDOSE

Overdose of apixaban may result in a higher risk of bleeding. In the event of hemorrhagic complications, treatment must be discontinued and the source of bleeding investigated. The initiation of appropriate treatment, e.g., surgical hemostasis, 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 C_max. Mean half-life of apixaban decreased from 13.4 hours when apixaban was administered alone to 5.3 hours and 4.9 hours, respectively, when activated charcoal was administered 2 and 6 hours after apixaban. Thus, administration of activated charcoal may be useful in the management of 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. Administration of prothrombin complex concentrates (PCCs) or recombinant factor VIIa may also be considered. Reversal of apixaban pharmacodynamics 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.

Hemodialysis 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, hemodialysis is unlikely to be an effective means of managing apixaban overdose.

PHARMACOLOGICAL PROPERTIES

Pharmacodynamics Properties

Pharmacotherapeutic Group: Antithrombotic Agents, Direct Factor Xa Inhibitors.

Mechanism of Action

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

Pharmacodynamics Effects

The pharmacodynamics effects of Apixaban are reflective of the mechanism of action (FXa inhibition). As a result of FXa inhibition, Apixaban prolongs clotting tests such as prothrombin time (PT), INR and activated partial thromboplastin time (aPTT). Changes observed in these clotting tests at the expected therapeutic dose are small and subject to a high degree of variability. They are not recommended to assess the pharmacodynamics effects of Apixaban. In the thrombin generation assay, Apixaban reduced endogenous thrombin potential, a measure of thrombin generation in human plasma.

Pharmacokinetic Properties

Absorption

The absolute bioavailability of Apixaban is approximately 50% for doses up to 10 mg. Apixaban is rapidly absorbed with maximum concentrations (C_max) appearing 3 to 4 hours after tablet intake. Intake with food does not affect Apixaban AUC or C_max at the 10 mg dose. Apixaban can be taken with or without food.

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

Following oral administration of 10 mg of Apixaban as 2 crushed 5 mg tablets suspended in 30 mL of water, exposure was comparable to exposure after oral administration of 2 whole 5 mg tablets. Following oral administration of 10 mg of apixaban as 2 crushed 5 mg tablets with 30 g of apple puree, the C_max and AUC were 21% and 16% lower, respectively, when compared to administration of 2 whole 5 mg tablets. The reduction in exposure is not considered clinically relevant.

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

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

Distribution

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

Biotransformation and Elimination

Apixaban has multiple routes of elimination. Of the administered apixaban dose in humans, approximately 25% was recovered as metabolites, with the majority recovered in faces. Renal excretion of apixaban accounts for approximately 27% of total clearance. Additional contributions from biliary and direct intestinal excretion were observed in clinical and nonclinical studies, respectively.

Apixaban has a total clearance of about 3.3 L/h and a half-life of approximately 12 hours.

O-demethylation and hydroxylation at the 3-oxopiperidinyl moiety are the major sites of biotransformation. Apixaban is metabolized mainly via CYP3A4/5 with minor contributions from CYP1A2, 2C8, 2C9, 2C19, and 2J2. Unchanged Apixaban is the major active substance-related component in human plasma with no active circulating metabolites present. apixaban is a substrate of transport proteins, P-gp and breast cancer resistance protein (BCRP).

Elderly

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

Renal Impairment

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

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

Hepatic Impairment

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

Gender

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

Ethnic Origin and Race

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

Body Weight

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

Pharmacokinetic/Pharmacodynamics Relationship

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

SPECIAL PRECAUTIONS FOR STORAGE

This medicinal product does not require any special storage condition.